GB2546128A

GB2546128A - Pharamaceutical compositions comprising hexaminolevulinic acid and methods of using the same

Info

Publication number: GB2546128A
Application number: GB1616491.5A
Authority: GB
Inventors: A Kabir Mohammed; A Martin Christopher
Original assignee: Photocure ASA
Current assignee: Photocure ASA
Priority date: 2016-09-28
Filing date: 2016-09-28
Publication date: 2017-07-12
Also published as: GB201616491D0

Abstract

A pharmaceutical composition comprising: (a) an active ingredient selected from the group consisting of hexaminolevulinate, a precursor thereof, a derivative thereof, and a pharmaceutically acceptable salt thereof; (b) optionally at least one triglyceride; and (c) at least one emulsifier, is outlined. Preferably the composition may further comprise one or more of (i) at least one mucoadhesive agent; (ii) at least one surface penetration agent; (iii) at least one chelating agent; and (iv) citric acid. Preferably the composition further comprises at least one coating selected from the group consisting of triethyl citrate, talc, a copolymer of methacrylic acid and methyl methacrylate, and a copolymer of methacrylic acid and ethyl acrylate. A pharmaceutical composition comprising hexaminolevulinate, or a pharmaceutically acceptable salt thereof; (b) a diluent; and (c) a lubricant, wherein the composition is enterically coated with at least one coating is also provided. The compositions are useful in conducting photodynamic diagnosis (PDD) or photodynamic therapy (PDT), in particular to diagnose or treat a condition in the lower gastrointestimal tract of a subject, such as, for example, colorectal cancer.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING HEX AMINOLEVULINIC ACID AND METHODS OF USING THE SAME

BACKGROUND

Photodynamic diagnosis (PDD) is a technique for the diagnosis of pre-cancerous lesions, cancer and non-cancerous diseases. PDD involves the administration of a photosensitizer or a precursor thereof to an area of interest. The photosensitizer or precursor thereof (which subsequently converts to a photosensitizer) is taken up into the cells. Upon exposure of the area of interest to light, the photosensitizer is excited and displays a detectable fluorescence. The photosensitizer accumulates preferentially in metabolically active tissue, such as inflamed or neoplastic tissue; hence such tissue can be distinguished from healthy tissue. 5-aminolevulinic acid (5-ALA) and certain derivatives thereof, e.g. 5-ALA esters, are precursors of photosensitizers and once taken up into cells, are converted to protoporphyrins, such as protoporphyrin IX (PpIX). However, limited stability of 5-ALA and 5-ALA esters in aqueous media limits the shelf life of the water-containing pharmaceutical products in which they are present. Furthermore, the use of 5-ALA and 5-ALA ester as precursors in PDD can require their conversion into a photosensitizer, which is not an immediate process. Hence there can be a delay in the form of an incubation period between the administration of a PDD precursor and the light excitation and detection. To obtain diagnostic results, the enema or locally administered probe is placed in contact with the colon walls during such an incubation period, although some patients are unable to keep an enema inside their colon for the required period of time

In addition, such compounds can be useful in the application of photochemotherapy (photodynamic therapy, or PDT). When activated by light, photosensitizing drugs can exert their effects by becoming toxic or by generating a toxic species (e.g. oxidizing agents such as singlet oxygen or other oxygen-derived free radicals) which destroy cellular material and biomolecules such as lipids, proteins and nucleic acids. Thus, it would be useful to provide a photosensitive agent which can penetrate tumor or other metabolically active abnormal cells which have an enhanced photochemotherapeutic effect over those described in the prior art.

Thus, there is a need to provide a convenient ready-to-use form of a PPD compound that allows for the preparation of compositions at a reliable and accurate concentration. In particular, there is a need for alternative formulations of 5-ALA and 5- ALA esters and thus pharmaceutical products comprising 5-ALA and 5-ALA ester for use in PDD of the lower part of the gastrointestinal tract, in particular the colon and rectum.

SUMMARY OF TUI INVENTION

In one aspect, the present invention is directed to a composition or a pharmaceutical product including a) an active ingredient selected from 5-ALA, a precursor thereof, a derivative thereof, and a pharmaceutically acceptable salt thereof, b) at least one triglyceride and c) at least one emulsifier. In some embodiments, the composition or product further includes at least one mucoadhesive, at least one additional pharmaceutically acceptable excipient, other than the triglyceride at least one surface penetration agent, and/or at least one chelating agent.

In yet another aspect, the present invention is directed to a composition or a pharmaceutical product including an active ingredient selected from 5-ALA, a precursor thereof, a derivative thereof, and a pharmaceutically acceptable salt thereof, and at least one emulsifier. In certain embodiments, the composition or product additionally includes at least one triglyceride, at least one mucoadhesive, at least one additional pharmaceutically acceptable excipient, other than the triglyceride, at least one surface penetration agent, and/or at least one chelating agent.

In some embodiments, the pharmaceutical product or composition includes citric acid. The presence of citric acid can serve to affect the stability of the API, dissolution and/or release properties of the pharmaceutical product or composition.

In some embodiments, the pharmaceutical product or composition is a solid. In some embodiments, the pharmaceutical product or composition is in the form of a suppository. In some embodiments, the pharmaceutical product or composition is formulated as a mini-tablet. In some embodiments, the pharmaceutical product or composition is formulated as an enteric-coated mini-tablet. In some embodiments, the pharmaceutical product or composition is formulated as mini-tablets encapsulated in a tablet or a capsule. In some embodiments, the tablet or capsule has an enteric coating.

In some embodiments, the pharmaceutical product or composition contains hexaminolevulinate (HAL), microcrystalline cellulose (MCC), Cab-O-Sil and magnesium stearate, and is a mini-tablet. In some embodiments, the mini-tablet has an enteric coating.

In some embodiments, the pharmaceutical product or composition contains hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (NA-CMC), Cab-O-Sil and magnesium stearate, and is a mini-tablet. In some embodiments, the mini-tablet has an enteric coating.

In some embodiments, the pharmaceutical product or composition contains hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (NA-CMC), hydroxypropyl methylcellulose (HPMC, K4M), Plasdone® S630, Cab-O-Sil and magnesium stearate, and is a mini-tablet. In some embodiments, the mini-tablet has an enteric coating.

In some embodiments, the pharmaceutical product or composition contains hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (NA-CMC), hydroxypropyl methylcellulose (HPMC, K4M or K100M), Cab-O-Sil and magnesium stearate, and is a minitablet. In some embodiments, the mini-tablet has an enteric coating.

In some embodiments, the pharmaceutical product or composition contains hexaminolevulinate (HAL), silicified microcrystalline cellulose, citric acid and stearic acid, and is a mini-tablet. In some embodiments, the mini-tablet has an enteric coating.

In some embodiments, the pharmaceutical product or composition contains hexaminolevulinate (HAL), silicified microcrystalline cellulose, citric acid, crospovidone and stearic acid, and is a mini-tablet. In some embodiments, the mini-tablet has an enteric coating.

In some embodiments, the pharmaceutical product or composition contains hexaminolevulinate (HAL), silicified microcrystalline cellulose, citric acid, mannitol, hydroxypropylcellulose and stearic acid, and is a mini-tablet. In some embodiments, the minitablet has an enteric coating.

In some embodiments, the pharmaceutical product or composition contains hexaminolevulinate (HAL), silicified microcrystalline cellulose, citric acid, mannitol, hydroxypropylcellulose, Carbopol 974P and stearic acid, and is a mini-tablet. In some embodiments, the mini-tablet has an enteric coating.

In some embodiments, the pharmaceutical product or composition contains hexaminolevulinate (HAL), silicified microcrystalline cellulose, mannitol, polyplasdone (e.g. Plasdone XL) , and stearic acid, and is a mini-tablet. In some embodiments, the mini-tablet has an enteric coating.

In some embodiments, the pharmaceutical product or composition contains hexaminolevulinate (HAL), silicified microcrystalline cellulose, mannitol, hydroxy propyl cellulose (e.g. Klucel), and stearic acid, and is a mini-tablet. In some embodiments, the minitablet has an enteric coating.

In some embodiments, the pharmaceutical product or composition contains hexaminolevulinate (HAL), silicified microcrystalline cellulose, mannitol, hydroxy propyl cellulose (e.g. Klucel), Carbopol (974P) and stearic acid, and is a mini-tablet. In some embodiments, the mini-tablet has an enteric coating.

In some embodiments, the pharmaceutical product or composition contains hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (SMC), hydroxypropyl methylcellulose (HPMC, e.g. K4M or K100M), hydroxy propyl cellulose (e.g. Klucel EXF, JFX, GXF, HXF and MXF), filler (e.g. Cab-O-Sil) and magnesium stearate, and is a mini-tablet. In some embodiments, the mini-tablet has an enteric coating.

In any of the foregoing embodiments, the mini-tablet can have a sub-coat. For example, the mini-tablet can have a clear sub-coat comprised of Opadry. In some embodiments, the minitablet is coated with a sub-coat of up to about 0.5%, 1%, 2%, 3%, 4% or 5% (w/w) dry basis.

In any of the foregoing embodiments, wherein the mini-tablet is enteric-coated, the minitablet can have a methacrylic acid-based coating of up to about 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% (w/w) dry basis. In some embodiments, the methacrylic acid-based coating comprises Eudragit L30D. In some embodiments, the methacrylic acid-based coating comprises Eudragit LI 00.

In some embodiments, the pharmaceutical product or composition includes a tablet or capsule containing a plurality of mini-tablet formulations as disclosed herein. For example, the tablet or capsule can contain about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75 or 100 mini-tablets of the formulations as disclosed herein.

In some embodiments, the pharmaceutical product or composition contains a mixture of at least two different mini-tablet formulations as disclosed herein, wherein the mixture is provided in a single tablet or capsule.

In some embodiments, the active ingredient is a 5-ALA ester or a pharmaceutically acceptable salt thereof. In some embodiments, the product contains between about 10% and about 40% (w/w) of active ingredient. In some embodiments, the product contains about 20% (w/w) of active ingredient.

The triglyceride may be either a solid or a liquid triglyceride. In some embodiments, the at least one triglyceride is a solid triglyceride selected from the group of cocoa butter, tallow, hard fat, hydrogenated coco-glycerides, hydrogenated palm oil, tristearin, tripalmitin and trimyristin. In some embodiments, the at least one triglyceride is a liquid triglyceride selected from the group of a triglyceride comprising glycerol and three identical or different C2-C22 fatty acids, a triglyceride comprising three identical or different C4-C18 fatty acids, a triglyceride comprising three identical or different Ce-Cis fatty acids, a triglyceride comprising three identical or different Ce-Cn fatty acids, tricaprylin, tricaproin, triheptanoin, caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride and caprylic/capric/succinic triglyceride.

In some embodiments, the at least one emulsifier is a non-ionic emulsifier obtained from a reaction between polyethylene glycol and a natural or a hydrogenated oil.

In some embodiments, the composition or pharmaceutical product is substantially water- free.

In some embodiments, the composition or pharmaceutical product comprises a liquid, semi-solid or solid mixture in a solid capsule. In some embodiments, the solid capsule is coated with at least one enteric coating.

In some embodiments, the composition or pharmaceutical product comprises a liquid, semi-solid or solid mixture in a solid mini-capsule. In some embodiments, the solid mini-capsule is coated with at least one enteric coating.

In some embodiments, the at least one enteric coating allows for the pH controlled release of the active ingredient at a pH of about 5.5 to a pH of about 7.5. In some embodiments, the at least one enteric coating allows for the pH controlled release of the active ingredient at a pH of about 6.0 to a pH of about 6.5. In some embodiments, the at least one enteric coating allows for the pH controlled release of the active ingredient at a pH above 6.5. In some embodiments, the at least one enteric coating allows for the pH controlled release of the active ingredient at a pH of about 6.0. In some embodiments, the at least one enteric coating allows for the pH controlled release of the active ingredient at a pH above 6.0. In some embodiments, the at least one enteric coating allows for the pH controlled release of the active ingredient at a pH of about 5.5. In some embodiments, the at least one enteric coating allows for the pH controlled release of the active ingredient at a pH above 5.5. In some embodiments, the at least one enteric coating comprises at least one of: Eudragit®L30D-55, Eudragit® S100, Eudragit® L100, or mixtures thereof In some embodiments, the at least one enteric coating further includes triethyl citrate and talc. In some embodiments, the at least one enteric coating is between about 5% to about 25% (w/w) of the composition or pharmaceutical product. In some embodiments, the at least one enteric coating is about 12% (w/w) of the composition or pharmaceutical product. In some embodiments, the at least one enteric coating is about 9% (w/w) of the composition or pharmaceutical product.

In yet another aspect, the present invention is directed to a pharmaceutical composition including hexaminolevulinate, or a pharmaceutically acceptable salt thereof; a diluent; and a lubricant, wherein the composition is enterically coated with at least one coating

In one embodiment, the pharmaceutical composition further comprises a polymer. In another embodiment, the diluent IS microcrystalline cellulose, silicified microcrystalline cellulose, starch, or mannitol, or combinations thereof. In another embodiment, the polymer is hydroxypropylmethyl cellulose, hydroxypropyl cellulose, a homopolymer or co-polymer of acrylic acid crosslinked with a polyalkenyl polyether (Carbopol®) and a polymer of methacrylic acid and methacrylate (Eudragit®), or combinations thereof.

In some embodiments, the pharmaceutical composition further comprises citric acid.

In one embodiment, the at least one coating is selected from the group consisting of triethyl citrate (TEC), talc, a copolymer of methacrylic acid and methyl methacrylate, and a copolymer of methacrylic acid and ethyl acrylate.

In another embodiment, the pharmaceutical composition is a solid. In one embodiment, the composition is formulated as a mini-tablet. In another embodiment, the composition is formulated as a microgranule.

In yet another embodiment, the pharmaceutical composition is encapsulated in a capsule. In one embodiment, the the capsule is coated with at least one enteric coating. In one embodiment, the at least one coating allows for the pH controlled release of the active ingredient at a pH of about 5.5 to about 7.5. In another embodiment, the at least one coating allows for the pH controlled release of the active ingredient at a pH of 6.5 or more.

In one embodiment, the pharmaceutical composition comprises hexaminolevulinate (HAL), microcrystalline cellulose (MCC), Cab-O-Sil and magnesium stearate. In another embodiment, the composition comprises hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (SMC), Cab-O-Sil and magnesium stearate. In yet another embodiment, the composition comprises hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (SMC), hydroxypropyl methylcellulose (HPMC, K4M), Plasdone® S630, Cab-O-Sil and magnesium stearate. In a further embodiment, the composition comprises hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (SMC), hydroxypropyl methylcellulose (HPMC, K4M or K100M), Cab-O-Sil and magnesium stearate. In another embodiment, the composition comprises hexaminolevulinate (HAL), silicified microcrystalline cellulose, citric acid and stearic acid. In yet another embodiment, the composition comprises hexaminolevulinate (HAL), silicified microcrystalline cellulose, citric acid, crospovidone and stearic acid. In one embodiment, the composition comprises hexaminolevulinate (HAL), silicified microcrystalline cellulose, citric acid, mannitol, hydroxypropylcellulose and stearic acid.

In one embodiment, the pharmaceutical composition comprises hexaminolevulinate (HAL), silicified microcrystalline cellulose (Prosolv), Mannitol (Pearlitol), polyplasdone (Plasdone XL) , and stearic acid. In another example, the composition comprises hexaminolevulinate (HAL), silicified microcrystalline sellulose (Prosolv), Mannitol (Pearlitol), hydroxy propyl cellulose (Klucel), and stearic acid. In a further example, the composition comprises hexaminolevulinate (HAL), silicified microcrystalline sellulose (Prosolv), Mannitol (Pearlitol), hydroxy propyl cellulose (Klucel), Carbopol (974P) and stearic acid. In yet another embodiment, the composition comprises hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (SMC), hydroxypropyl methylcellulose (HPMC, K4M or K100M), hydroxy propyl cellulose (Klucel EXF, JFX, GXF, HXF and MXF), Cab-O-Sil and magnesium stearate.

In one embodiment, the composition is a mini-tablet. In another example, the composition is a microgranule.

In some embodiments, the pharmaceutical composition comprises a single tablet or capsule comprising at least two different compositions.

Embodiments relate to methods of conducting a photodynamic diagnosis (PDD) of a condition in a subject in need thereof, comprising administering a composition or pharmaceutical product as disclosed herein to the subject. In some embodiments, the condition is one selected from the group of: a cancer, a pre-cancerous condition, a non- cancerous condition, and an infection associated with a cancer. In some embodiments, the composition or pharmaceutical product is administered to the colon of the subject. In some embodiments, the composition or pharmaceutical product is administered to the rectum of the subject. In some embodiments, the condition is one selected from: irritable bowel syndrome (IBS), colorectal cancer, stomach cancer, Barrett’s esophagus, esophageal cancer, esophagitis, diverticular disease, infectious colitis, ulcerative colitis, Crohn’s disease; ischemic colitis, radiation colitis, esophagitis, inflammatory bowel disease, small intestinal bacterial overgrowth, chronic pancreatitis, pancreatic insufficiency, hepatic encephalopathy, diarrhea, constipation, gastrointestinal motility disorders, gastroesophageal reflux disease (GERD), gastroparesis, chronic intestinal pseudoobstruction (Ogilvie’s syndrome), colonic pseudo-obstruction, functional heartburn, postoperative ileus, hypertrophic pyloric stenosis, dyspepsia (including functional dyspepsia or nonulcer dyspepsia), gastrointestinal damage, anal fissure, achlorhydria, achalasia, hemorrhoids, intestinal polyps, gastrointestinal tract cancer, pancreatic cancer, prostatic cancer, gastrointestinal tract inflammation, and a bacterial infection. In some embodiments, the bacterial infection is caused by at least one selected from the group of: H. pylon, C. jejuni, Salmonella, and Shigella.

Embodiments relate to methods of conducting a photodynamic diagnosis (PDD) of a condition in a subject, comprising administering a composition or pharmaceutical product as disclosed herein to the gastrointestinal area of the subject. For example, the composition or pharmaceutical product can be administered to the esophagus, the stomach, the small intestine, the large intestine, or the rectum of the subject. In some embodiments, the condition is one selected from the group of: a cancer, a pre-cancerous condition, a non-cancerous condition, and an infection associated with a cancer. In some embodiments, the composition or pharmaceutical product is administered to the lower gastrointestinal area of the subject. In some embodiments, the composition or pharmaceutical product is administered to the colon of the subject. In some embodiments, the composition or pharmaceutical product is administered to the rectum of the subject.

In some embodiments, methods of detecting a condition in a subject are provided, comprising: (i) administering a composition or pharmaceutical product as disclosed herein to the gastrointestinal area of the subject, (ii) waiting for a period of time sufficient to allow the active ingredient to be converted to a photosensitizer and achieve an effective tissue concentration at a target site in the lower gastrointestinal area, (iii) photoactivating the photosensitizer and (iv) detecting a fluorescent signal from the photosensitizer, wherein the presence of a fluorescent signal is indicative of the condition. In some embodiments, the condition is one selected from the group of: a cancer, a pre-cancerous condition, a non-cancerous condition, and an infection associated with a cancer. In some embodiments, the condition is one selected from the group of: irritable bowel syndrome (IBS), colorectal cancer, diverticular disease, infectious colitis, ulcerative colitis, Crohn’s disease; ischemic colitis, radiation colitis, inflammatory bowel disease, small intestinal bacterial overgrowth, chronic pancreatitis, pancreatic insufficiency, hepatic encephalopathy, diarrhea, constipation, gastrointestinal motility disorders, gastroesophageal reflux disease (GERD), gastroparesis, chronic intestinal pseudo-obstruction (Ogilvie’s syndrome), colonic pseudo-obstruction, post-operative ileus, gastrointestinal damage, anal fissure, hemorrhoids, intestinal polyps, gastrointestinal tract cancer, pancreatic cancer, prostatic cancer, gastrointestinal tract inflammation, and a bacterial infection. In some embodiments, the bacterial infection is caused by at least one selected from the group of: H. pylori, C. jejuni, Salmonella, and Shigella. The composition or pharmaceutical product can be administered to the esophagus, the stomach, the small intestine, the large intestine, or the rectum of the subject. In some embodiments, the composition or pharmaceutical product is administered to the colon of the subject. In some embodiments, the composition or pharmaceutical product is administered to the rectum of the subject.

In some embodiments, a purgative or a bowel preparation is administered to the subject prior to administration of the pharmaceutical product or composition. In some embodiments, the purgative or bowel preparation is administered from between about 30 minutes to about 24 hours prior to administration of the pharmaceutical product. Exemplary purgatives may comprise polyethylene glycol (PEG), sodium phosphate, L- sugars, and other bowel preparations that are available on the market.

In some embodiments, ingestible fluid is administered to the subject after administration of the pharmaceutical product. The ingestible fluid can be administered from about 15 minutes to about 2 hours after administration of the pharmaceutical product. The ingestible fluid can be from about 50 mL to about 500 mL of fluid. In some embodiments, the ingestible fluid is a purgative or bowel preparation. Exemplary purgatives include, but are not limited to, polyethylene glycol (PEG), sodium phosphate, L-sugars, and other bowel preparations that are available on the market. Also useful are colonic purgatives embodied in WO/2012/079118, entitled “Gastric and Colonic Formulations and Methods For Making and Using Them.”

In some embodiments, a method of detecting a condition in a subject is provided, wherein the method includes: (i) administering a first purgative dose in the evening, (ii) administering a second purgative dose in the following morning, (iii) administering a composition or pharmaceutical product as disclosed herein between about 30 minutes to about 2 hours after the second purgative dose to the subject, (iv) waiting for a period of time sufficient to allow the active ingredient to be converted to a photosensitizer and achieve an effective tissue concentration at a target site in the lower gastrointestinal area, (v) photoactivating the photosensitizer and (vi) detecting a fluorescent signal from the photosensitizer, wherein the presence of a fluorescent signal is indicative of the condition. In some embodiments, the volume of the ingestible fluid is from about 50 mL to about 500 mL, or from about 75 mL to about 400 mL, or from about 100 mL to about 300 mL. In some embodiments, the volume of ingestible fluid is about 250 mL.

In some embodiments, a method of detecting a condition in a subject is provided, wherein the method includes: (i) administering a first purgative dose in the evening, (ii) administering a second purgative dose in the following morning, (iii) administering a composition or pharmaceutical product as disclosed herein between about 30 minutes to about 2 hours after the second purgative dose to the subject, (iv) administering a volume of ingestible fluid to the subject between about 15 minutes to about 60 minutes after the administration of the pharmaceutical product, (v) waiting for a period of time sufficient to allow the active ingredient to be converted to a photosensitizer and achieve an effective tissue concentration at a target site in the lower gastrointestinal area, (vi) photoactivating the photosensitizer and (vii) detecting a fluorescent signal from the photosensitizer, wherein the presence of a fluorescent signal is indicative of the condition. In some embodiments, the volume of the ingestible fluid is from about 50 mL to about 500 mL, or from about 75 mL to about 400 mL, or from about 100 mL to about 300 mL. In some embodiments, the volume of ingestible fluid is about 250 mL.

In some embodiments, a method of detecting a condition in a subject is provided, wherein the method includes: (i) administering a first purgative dose in the evening, (ii) administering a composition or pharmaceutical product as disclosed herein the following morning, (iii) administering a second purgative dose between about 30 minutes to about 2 hours after administration of the composition or pharmaceutical product, (iv) waiting for a period of time sufficient to allow the active ingredient to be converted to a photosensitizer and achieve an effective tissue concentration at a target site in the lower gastrointestinal area, (v) photoactivating the photosensitizer and (vi) detecting a fluorescent signal from the photosensitizer, wherein the presence of a fluorescent signal is indicative of the condition.

Embodiments are directed to the use of a photosensitizer which is 5-ALA or a precursor or derivative thereof (e.g. an ALA ester), in the manufacture of a pharmaceutical product for use in the photodynamic treatment or diagnosis e.g, of a cancer, an infection associated with a cancer, or in the treatment or diagnosis of a non-cancerous condition, wherein said pharmaceutical product is in the form of a solid. In some embodiments, the product is for use in the photodynamic treatment or diagnosis of a cancerous or non-cancerous condition in the lower part of the gastrointestinal system or in the female reproductive system.

Embodiments are directed to the use of a photosensitizer which is 5-ALA or a precursor or derivative thereof (e.g. an ALA ester), in the manufacture of a pharmaceutical product for use in the photodynamic treatment of a cancer in the lower part of the gastrointestinal system, wherein said pharmaceutical product is in the form of a solid.

Embodiments can relate to the use of a photosensitizer which is 5-ALA or a precursor or derivative thereof (e.g. an ALA ester), in the manufacture of a pharmaceutical product for use in the photodynamic diagnosis of a cancer in the lower part of the gastrointestinal system, wherein said pharmaceutical product is in the form of a solid.

Embodiments also relate to the use of a photosensitizer which is 5-ALA or a precursor or derivative thereof (e.g. an ALA ester), in the manufacture of a pharmaceutical product for use in the photodynamic diagnosis of a non-cancerous condition in the lower part of the gastrointestinal system, wherein said pharmaceutical product is in the form of a solid.

Embodiments are directed to the use of a photosensitizer which is 5-ALA or a precursor or derivative thereof (e.g. an ALA ester), in the manufacture of a pharmaceutical product for use in the photodynamic treatment of a non-cancerous condition in the lower part of the gastrointestinal system, wherein said pharmaceutical product is in the form of a solid.

Embodiments are also directed to the use of a photosensitizer which is 5-ALA or a precursor or derivative thereof (e.g. an ALA ester), in the manufacture of a pharmaceutical product for use in the photodynamic treatment of a cancer in the female reproductive system (e.g. cervical cancer), wherein said pharmaceutical product is in the form of a solid.

Embodiments also relate to the use of a photosensitizer which is 5-ALA or a precursor or derivative thereof (e.g. an ALA ester), in the manufacture of a pharmaceutical product for use in the photodynamic diagnosis of a cancer in the female reproductive system (e.g. cervical cancer), wherein said pharmaceutical product is in the form of a solid.

Embodiments can also relate to the use of a photosensitizer which is 5-ALA or a precursor or derivative thereof (e.g. an ALA ester), in the manufacture of a pharmaceutical product for use in the photodynamic diagnosis of a non-cancerous condition in the female reproductive system, wherein said pharmaceutical product is in the form of a solid.

Embodiments are also directed to the use of a photosensitizer which is 5-ALA or a precursor or derivative thereof (e.g. an ALA ester), in the manufacture of a pharmaceutical product for use in the photodynamic treatment of a non-cancerous condition in the female reproductive system, wherein said pharmaceutical product is in the form of a solid.

DESCRIPTION OF THE DRAWINGS

Figure 1 depicts photos of exemplary uncoated and coated mini-tablet formulations as disclosed herein.

Figure 2 is a graph illustrating the dissolution profile of an exemplary mini-tablet formulation of hexaminolevulinate (HAL) as a function of time.

Figure 3 is a graph illustrating the dissolution profile of an exemplary mini-tablet formulation of hexaminolevulinate (HAL) as a function of time.

Figure 4 is a graph illustrating a release profile of an exemplary mini-tablet formulation of hexaminolevulinate (HAL) as a function of time.

Figure 5 is a graph illustrating the dissolution profile of exemplary mini-tablet formulations of hexaminolevulinate (HAL) as a function of time.

Figure 6 is a graph illustrating the dissolution profile of an exemplary coated mini-tablet formulation of hexaminolevulinate (HAL) as a function of time.

Figure 7 is a graph illustrating the dissolution profile of exemplary coated mini-tablet formulations of hexaminolevulinate (HAL) as a function of time.

Figure 8 is a graph illustrating the dissolution profile of exemplary coated mini-tablet formulations of hexaminolevulinate (HAL) as a function of time.

Figure 9 is a graph illustrating the dissolution profile of exemplary coated mini-tablet formulations of hexaminolevulinate (HAL) as a function of time.

Figure 10 is a graph illustrating the dissolution profile of exemplary coated mini-tablet formulations of hexaminolevulinate (HAL) as a function of time.

Figure 11 is a closer view of the same graph in Figure 10, which illustrates the dissolution profile of exemplary coated mini-tablet formulations of hexaminolevulinate (HAL) as a function of time.

Figure 12 is a graph illustrating the dissolution profile of an exemplary coated mini-tablet formulation (Formulation E as disclosed herein) of hexaminolevulinate (HAL) as a function of time.

Figure 13 is a graph illustrating the dissolution profiles of exemplary coated mini- tablet formulation (medium and sustained release), in which the tablets are coated with Eudragit® L30D-55.

Figure 14 is a graph illustrating the dissolution profiles of exemplary coated mini- tablet formulation (medium and sustained release), in which the tablets are coated with Eudragit® L100.

DETAILED DESCRIPTION

It has surprisingly been found that certain pharmaceutical products and compositions comprising 5-ALA or a derivative thereof (e.g. an ALA ester) exhibit the desired properties of stability at room temperature, ease of handling and convenient use so as to allow for delivery thereof to a subject for therapeutic and diagnostic use. For example, the pharmaceutical products or compositions described herein may be conveniently and effectively delivered to the gastrointestinal system, and, in particular, to the lowest part of the gastrointestinal system such as the lower small intestine, the colon and the rectum. Also by way of example, such products and compositions can readily be delivered locally to the female reproductive system, especially the cervix These products are capable of providing an effective concentration of 5-ALA or derivatives thereof at the desired treatment and/ or diagnostic site (e.g, in the lower part of the gastrointestinal tract or in the female reproductive system). They can also provide a substantially homogenous or uniform distribution of the active photosensitizing agent at the target site, thereby improving photodynamic therapy (PDT) or photodynamic diagnosis (PDD). Compositions and Products

Embodiments are directed to a pharmaceutical product or composition comprising a photosensitizer which is 5-ALA, a precursor thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical product is a solid pharmaceutical product. As used herein, the term “solid” refers to the physical state of the entity being described. Liquids, solutions, gels, and creams are therefore not encompassed by this term. Representative examples of solid pharmaceutical products include, but are not limited to, powders, granules, capsules, tablets, mini-tablets, pellets, pessaries and suppositories.

In some embodiments, the pharmaceutical product is a solid when administered. For example, a solid pharmaceutical product can be a solid at a temperature of at least about 18°C, at least about 20°C, at least about 30°C, at least about 37°C, or at least about 40°C.

In some embodiments, the pharmaceutical product is a suppository, capsule, pellet, pessary, tablet, or mini-tablet. In some embodiments, the pharmaceutical product is provided in the form of a capsule containing a powder, pellet, bead or granulate composition. In some embodiments, the pharmaceutical product is provided in the form of a capsule containing a semisolid or a liquid (including non-aqueous liquid) composition.

In embodiments where the product is provided in the form of pellets (e.g. tiny pills or mini-tablets), these can be administered as such. In some embodiments, the pellets can be incorporated into a tablet or capsule. Tablets or capsules comprising a plurality of pellets can be used in the methods as disclosed herein. Similarly, in embodiments where the product is provided in the form of a tablet, this can be administered as such. In some embodiments, the product can be incorporated into a capsule to provide a capsule-unit dose comprising a plurality of mini-tablets.

In some embodiments, the product is formulated by a wet granulation process (e.g. with 0.1 N HC1) into beads or microgranules. In some embodiments, the beads are spheronization beads. In some embodiments, the beads are extruded spheronization beads. The beads can range in size from about 0.1 to about 3 mm in diameter. In some embodiments, the beads are about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3 mm in diameter. In some embodiments, the beads are about 0.6 mm or less in diameter. In some embodiments, the beads are between about 1 to 2.5 mm in diameter. The beads or microgranules can be coated with an enteric coating as described herein. In some embodiments, the beads or microgranules are further formulated into a mini-tablet or encapsulated in a capsule.

In some embodiments, wherein the product is provided as a capsule, the capsule can be coated. Capsule coatings suitable for capsule embodiments are described herein.

As used herein the term “treatment” encompasses curative as well as prophylactic treatment.

The term “precursors” as used herein refers to precursors for 5-ALA which are converted metabolically to 5-ALA and are thus essentially equivalent thereto. Thus, the term can cover biological precursors for protoporphyrin in the metabolic pathway for heme biosynthesis.

As used herein, the term “derivative” encompasses a pharmaceutically acceptable salt or a chemically modified agent, for example esters such as 5-ALA esters. In some embodiments, a “derivative” of 5-ALA can refer to chemically modified 5-ALA.

The use of 5-ALA and derivatives thereof (e.g. 5-ALA esters) in PDT is described m, for example, International Patent Publication Nos. WO 2006/051269, WO 2005/092838, WO 03/011265, WO 02/09690 and WO 02110120 as well as U.S. Pat. No. 6,034,267, each of which is incorporated herein by reference in its entirety. All such derivatives of 5-ALA and their pharmaceutically acceptable salts are suitable for use in the methods herein described.

Active Agents

The 5-ALA derivatives useful in accordance with a composition or formulation as disclosed herein can be any derivative of 5-ALA capable of forming protoporphyrin IX (PpIX) or any other photosensitizer (e.g. a PpIX derivative) in vivo. Such derivatives can be a precursor of PpIX or of a PpIX derivative (e.g. a PpIX ester) in the biosynthetic pathway for heme and are therefore capable of inducing an accumulation of PpIX at the site of the disease following administration in vivo. Suitable precursors of PpIX or PpIX derivatives include 5-ALA prodrugs which are able to form 5-ALA in vivo as an intermediate in the biosynthesis of PpIX or which can be converted (e.g. enzymatically) to porphyrins without forming 5-ALA as an intermediate. In some embodiments, the 5- ALA derivative is a 5-ALA ester, or a pharmaceutically acceptable salt thereof. In some embodiments, the 5-ALA derivative is an ester of 5-aminolevulinic acid, or an N-substituted derivative thereof. In some embodiments, the 5-ALA derivative is a 5-ALA compound in which the 5-amino group is unsubstituted. Such compounds are described in the literature, for example, in International Patent Publication Nos. WO 96/28412 and WO 02/10120, each of which is incorporated herein by reference.

In some embodiments, the 5-ALA derivative is an ester of 5-aminolevulinic acid with substituted or unsubstituted, alkanols. For example, the 5-ALA derivative can be an alkyl ester or a substituted alkyl ester of 5-aminolevulinic acid. Exemplary compounds include those of general formula I: R22N-CH2 COCIh-CIhCO-OR1 (I) wherein R * represents a substituted or unsubstituted straight-chained, branched or cyclic 2 alkyl group (e.g. a substituted straight-chained alkyl group); and each R independently represents a hydrogen atom or an optionally substituted alkyl group, or a pharmaceutically acceptable salt thereof.

The term “alkyl” encompasses any long or short chain, cyclic, straight-chained or branched aliphatic saturated or unsaturated hydrocarbon group. The unsaturated alkyl groups can be mono- or polyunsaturated and include both alkenyl and alkynyl groups. Such groups can contain up to 40 carbon atoms. In some embodiments, the alkyl group can contain up to 30, up to 10, up to 8, up to 6, or up to 4 carbon atoms. For example, the alkyl group can contain up to 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 carbon atoms. 1 2

The substituted alkyl R and R groups can be mono- or poly-substituted. Suitable substituents can be selected from hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo, fluoro, — SR3, —NR32 and — PR32 groups, and each alkyl group can be optionally 3 3 3 interrupted by one or more --0-, -NR -, —S- or —PR — groups, in which R is a hydrogen atom or a Ci-6 alkyl group). In some embodiments, if R * is a substituted alkyl group, one or more substituents can be either attached to the alkyl group and/or interrupt the alkyl group. Exemplary substituents that can interrupt the alkyl group include but are not limited to --0--, —NR —, —S— 3 and —PR —groups. 2

In some embodiments, the compound of formula I is provided, wherein at least one R group represents a hydrogen atom. In some embodiments, the compound is provided wherein 2 each R represents a hydrogen atom.

Compounds of formula I in which R ^ represents an unsubstituted alkyl group (such as, for example, Ci-8 alkyl or Ci-6 alkyl) or an alkyl group (such as, for example, C1.2 alkyl or Ci alkyl) substituted by a substituent as hereinbefore defined (e.g. by an aryl group such as, for example, a phenyl, or by an alkoxy group such as, for example, a methoxy) are also contemplated.

Unsubstituted alkyl groups which can be used in the compositions and formulations disclosed herein include both branched and straight-chained hydrocarbon groups. In some embodiments, the compound of formula I comprises an R ^ that is a C4.8, preferably a C5.8, straight chain alkyl group which is branched by one or more Cm (e.g. C1.2 alkyl) groups. Representative examples of suitable unsubstituted branched alkyl groups include 2-methylpentyl, 4-methylpentyl, 1-ethylbutyl and 3,3-dimethyl-l-butyl.

In some embodiments, the compound of formula I comprises an R^ that is a C1-10 straight-chained alkyl group. Representative examples of suitable unsubstituted alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, n-propyl, n-butyl, n- pentyl, n-hexyl and n-octyl.

In some embodiments, the compound of formula I comprises an R^ that is a C1-2 alkyl group optionally substituted by an aryl group. In some embodiments, the compound of formula I comprises an R^ that is a Ci alkyl group optionally substituted by an aryl group.

In some embodiments, the compound of formula I comprises an R^ that is an alkyl group, e.g. substituted by at least one aryl group, that is optionally substituted. In some embodiments, 1 R is an alkyl group substituted with one aryl group that is optionally substituted. In some embodiments, the substituted alkyl R^ groups can be a C,_6 alkyl, a Cm alkyl, a Ci or a C2 alkyl, e.g., substituted by an optionally substituted aryl group. In some embodiments, the substituted alkyl R* group is terminally substituted by an optionally substituted aryl group.

An “aryl group” refers to a group which is aromatic. In some embodiments, the aryl group comprises up to 20 carbon atoms, up to 12 carbon atoms, up to 10 carbon atoms, or up to 6 carbon atoms. For example, the aryl group can comprise up to 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.

In some embodiments, an aryl group which can be present in a compound as disclosed herein is a heteroaromatic group. In some embodiments, the aryl group is a, e.g. 5-7 membered heteroaromatic group.

In some embodiments, an aryl group which can be present in the compound is a nonheteroaromatic group. A “non-heteroaromatic” group is an aryl group having an aromatic system comprising electrons originating solely from carbon atoms. In some embodiments, the aryl group is a phenyl or a napthyl group. In some embodiments, the compound comprises one or two aryl groups. In some embodiments, the compound comprises one aryl group.

In some embodiments, an aryl group which can be present in a compound as disclosed herein can optionally be substituted by one or more groups. In some embodiments, the aryl group is optionally substituted by between, e.g., 1 and 5 groups. In some embodiments, the aryl group is optionally substituted by one or two groups. In some embodiments, the aryl group is optionally substituted by one group. In some embodiments, the aryl group is substituted at the me ία or para position. Suitable substituent groups can include, but are not limited to, haloalkyl (e.g. trifluoromethyl), alkoxy (e.g. —OR groups wherein R is a Ci_6 alkyl group), halo (e.g. iodo, bromo, chloro or fluoro), nitro, Ci.6 alkyl, and Cm alkyl. Suitable Ci_6 alkyl groups include, but are not limited to, methyl, isopropyl and t-butyl.

In some embodiments, the aryl group is unsubstituted.

In some embodiments, the compound, or composition or formulation comprising the same, includes an aryl-substituted R^ group that is one selected from the group of benzyl, 4-isopropylbenzyl, 4-methylbenzyl, 2-methylbenzyl, 3-methylbenzyl. 4-[t-butyl] benzyl, 4-[trifluoromethyl]benzvl, 4-methoxybenzyl, 3,4-[di-chloro]benzyl, 4- chlorobenzyl, 4-fluorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 2,3,4,5,6- pentafluorobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2 -phenyl ethyl, 4-phenylbutyl, 3- pyridinyl-methyl, 4-diphenyl-methyl and benzyl- 5-[(l-acetyloxyethoxy)-carbonyl], In some embodiments, the aryl-substituted R * group that is one selected from the group of: benzyl, 4-isopropylbenzyl, 4-methylbenzyl 4-nitrobenzyl and 4- chlorobenzyl. In some embodiments, the aryl-substituted R * group is benzyl.

In some embodiments in which R * is a substituted alkyl group, one or more oxo substituents are present. In some embodiments, R * is a straight-chained C4.12 alkyl group which is substituted by one or more oxo groups. For example, the alkyl group can be substituted by between one and five oxo groups, e.g, a straight-chained C4.12 alkyl or Cg-io alkyl group substituted by one, two or three oxo groups. In some embodiments, the oxo groups are present in the substituted alkyl group in an alternating order, e.g. forming short polyethylene glycol substituents. In some embodiments, the substituted alkyl group is selected from the group of 3,6-dioxa-l-octyl and 3,6,9-trioxa-l-decyl.

In some embodiments, the compound comprises an Ri that is methyl or hexyl and both R2 represent hydrogen. In some embodiments, the compound comprises an Rl that is hexyl and both R2 represent hydrogen. In some embodiments, the compound comprises an Rl that is n-hexyl and both R2’s being hydrogen.

In some embodiments, the compound for use in the methods or formulated in the pharmaceutical products disclosed herein is one selected from the group of: methyl ALA ester, ethyl ALA ester, propyl ALA ester, butyl ALA ester, pentyl ALA ester, hexyl ALA ester, octyl ALA ester, 2-methoxyethyl ALA ester, 2-methylpentyl ALA ester, 4- methylpentyl ALA ester, 1-ethylbutyl ALA ester, 3,3-dimethyl-l-butyl ALA ester, benzyl ALA ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester, 2- methylbenzyl ALA ester, 3-methylbenzyl ALA ester, 4-[t-butyl]benzyl ALA ester, 4- [trifluoromethyl]benzyl ALA ester, 4-methoxybenzyl ALA ester, 3,4-[di-chloro]benzyl ALA ester, 4-chlorobenzyl ALA ester, 4-fluorobenzyl ALA ester, 2-fluorobenzyl ALA ester, 3-fluorobenzyl ALA ester, 2,3,4,5,6-pentafluorobenzyl ALA ester, 3-nitrobenzyl ALA ester, 4-nitrobenzyl ALA ester, 2-phenylethyl ALA ester, 4-phenylbutyl ALA ester, 3-pyridinyl-methyl ALA ester, 4-diphenyl-methyl ALA ester and benzyl-5-[(1- acetyloxyethoxy)-carbonyl]amino levulinate.

In some embodiments, the compound for use in the methods or formulated in the pharmaceutical products disclosed herein is one selected from the group of: methyl ALA ester, ethyl ALA ester, 2-methoxyethyl ALA ester, benzyl ALA ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester, 2-methylbenzyl ALA ester, 3-methylbenzyl ALA ester, 4-[t-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl ALA ester, 4- methoxybenzyl ALA ester, 3,4-[di-chloro]benzyl ALA ester, 4-chlorobenzyl ALA ester, 4-fluorobenzyl ALA ester, 2-fluorobenzyl ALA ester, 3-fluorobenzyl ALA ester, 2,3,4,5,6-pentafluorobenzyl ALA ester, 3-nitrobenzyl ALA ester, 4-nitrobenzyl ALA ester, 2-phenylethyl ALA ester, 4-phenylbutyl ALA ester, 3-pyridinyl-methyl ALA ester, 4-diphenyl-methyl ALA ester and benzyl-5-[(l- acetyloxyethoxy)-carbonyl]amino levulinate

In some embodiments, the compound for use in the methods or formulated in the pharmaceutical products disclosed herein is one selected from the group of: benzyl ALA ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester, 2-methylbenzyl ALA ester, 3- methylbenzyl ALA ester, 4-[t-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl ALA ester, 4-methoxybenzyl ALA ester, 3,4-[di-chloro]benzyl ALA ester, 4-chlorobenzyl ALA ester, 4-fluorobenzyl ALA ester, 2-fluorobenzyl ALA ester, 3-fluorobenzyl ALA ester, 2,3,4,5,6-pentafluorobenzyl ALA ester, 3-nitrobenzyl ALA ester, 4-nitrobenzyl ALA ester, 2-phenylethyl ALA ester, 4-phenylbutyl ALA ester, 3- pyridinyl-methyl ALA ester, 4-diphenyl-methyl ALA ester and benzyl-5-[(l- acetyloxyethoxy)-carbonyl]amino levulinate.

In some embodiments, the compound for use in the methods or formulated in the pharmaceutical products disclosed herein is one selected from the group of: benzyl ALA ester, 4-isopropylbenzyl ALA ester and 4-methylbenzyl ALA ester, especially benzyl ALA ester. 4-Nitrobenzyl ALA ester, 4-chlorobenzyl ALA ester and benzyl ALA ester are especially preferred.

In some embodiments, the compound for use in the methods or formulated in the pharmaceutical products disclosed herein is one selected from the group of: 5-ALA, 5- ALA methyl ester, 5-ALA hexyl ester, 5-ALA benzyl ester and physiologically acceptable salts thereof. In some embodiments, the compound is 5-ALA hexyl ester or a physiologically tolerable salt thereof. In some embodiments, the compound, e.g., 5-ALA hexyl ester, is in the form of its HC1 salt, its sulfonic acid salt, or its sulfonic acid derivative salt.

In some embodiments, the compound for use in the methods or formulated in the pharmaceutical products disclosed herein is hexaminolevulinate (HAL), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds can be in the form of a free amine (e.g. — NH2, — 2 2 2 NHR or —NR R ) or in the form of a physiologically acceptable salt. Such salts can be acid addition salts with physiologically acceptable organic or inorganic acids. Suitable acids include, for example, hydrochloric, nitric, hydrobromic; phosphoric, sulfuric, sulfonic and sulfonic acid derivatives. In some embodiments, the acid addition salts with sulfonic acid or sulfonic acid derivatives are those as described in International Patent Publication No. WO 2005/092838, which is incorporated herein by reference in its entirety. Procedures for salt formation are known to those skilled in the art.

Methods of making compounds of the invention can be carried out according to techniques known in the art. For example, methods of making compounds of formula I have been described in International Publication No. WO 96/28412, which is incorporated herein by reference in its entirety. 5-ALA esters and pharmaceutically acceptable salts thereof have also been described, for example, in International Patent Publication No. WO 02/10120, which is incorporated herein by reference in its entirety. Briefly, 5-ALA esters can be prepared by reaction of 5-ALA with the appropriate alcohol in the presence of a catalyst, e.g. an acid. Pharmaceutically acceptable salts of 5-ALA esters can be prepared as described by reaction of a pharmaceutically acceptable 5-ALA salt, e.g. 5-ALA hydrochloride with the appropriate alcohol. Compounds for use in the methods as disclosed herein (e.g. 5-ALA methyl ester or 5-ALA hexyl ester) are also available commercially.

The synthesis of 5-ALA is also known in the art, and 5-ALA as well as pharmaceutically acceptable salts thereof are commercially available, for example, from Sigma Aldrich. Pharmaceutical Products

The compounds as disclosed herein can be used for the manufacture of a pharmaceutical product in any manner. The desired concentration of photosensitizer in the pharmaceutical products of the invention will vary depending on several factors including the nature of the compound, the nature and form of the product in which the product is presented, the intended mode of administration, the nature of the condition, for example, cancer, the infection associated with the cancer, or the non-cancerous condition, to be treated or diagnosed and the subject to be treated. Generally, however, the concentration of photosensitizer in the product is in the range of from about 1% to about 50%, from about 1% to about 40%, e.g. from about 2% to about 25%, or from about 5% to about 20% by weight of the total weight of the pharmaceutical product For example, the concentration of photosensitizer in the product can be present at a concentration of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, or about 50% by weight of the total weight of the pharmaceutical product. In some embodiments, the concentration of photosensitizer in the product is present at a concentration of between about 5% to 35% by total weight of the product. In some embodiments, the concentration of photosensitizer in the product is present at a concentration of between about 10% to 30% by total weight of the product. In some embodiments, the concentration of photosensitizer in the product is present at a concentration of between about 12% to 25% by total weight of the product. In some embodiments, the concentration of photosensitizer in the product is present at a concentration of between about 15% to 20% by total weight of the product. In some embodiments, the concentration of photosensitizer in the product is present at a concentration of about 17% by total weight of the product. In some embodiments, the concentration of photosensitizer in the product is present at a concentration of about 20% by total weight of the product. A pharmaceutical product for use in the methods as disclosed herein can comprise at least one pharmaceutically acceptable carrier and/or excipient. The skilled artisan will be able to select suitable carriers and excipients based on, for example, the route of administration chosen and the cancer, the infection associated with cancer, or the non- cancerous condition to be treated or diagnosed. Representative examples of excipients and carriers that can be used in the pharmaceutical products include agar, alginic acid, ascorbic acid, amino acids, calcium salts (e.g. calcium hydrogen phosphate), ammonium salts (e.g. ammonium acetate), and materials that are suitable for sustained, controlled or delayed release as disclosed herein. Miglyol® oils, which are esters of saturated coconut and palm kernel oil-derived caprylic and capric fatty acids and glycerin or propylene glycol, are also contemplated for use in formulation of the product. These can, for example, be used when forming capsules containing the photosensitizing agent.

In some embodiments, the pharmaceutical product or formulation includes citric acid. The amount of citric acid can range from about 0.1% to about 10% (w/w) of the product, or any percentage in between. In further embodiments, the amount of citric acid ranges from about 0.25% to about 5.0% (w/w) of the product. For example, the amount of citric acid in the pharmaceutical product or formulation can be about 0.1%, 0.25%, 0.5%, 1%, 1.25%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8,5%, 9%, 9.5% or 10% (w/w). In some embodiments, the amount of citric acid in the pharmaceutical product or formulation is about 5% (w/w).

In some embodiments, the amount of citric acid in the pharmaceutical product or formulation is less than about 5% (w/w). In some embodiments, the amount of citric acid in the pharmaceutical product or formulation is about 2.5% (w/w). In some embodiments, the amount of citric acid in the pharmaceutical product or formulation is less than about 2.5% (w/w). In some embodiments, the amount of citric acid in the pharmaceutical product or formulation is about 1.25% (w/w). In some embodiments, the amount of citric acid in the pharmaceutical product or formulation is less than about 1.25% (w/w). In some embodiments, the amount of citric acid in the pharmaceutical product or formulation is about 0.5% (w/w). In some embodiments, the amount of citric acid in the pharmaceutical product or formulation is less than about 0.5% (w/w). In some embodiments, the amount of citric acid in the pharmaceutical product or formulation is about 0.25% (w/w). In some embodiments, the amount of citric acid m the pharmaceutical product or formulation is less than about 0.25% (w/w).

Other pharmaceutical excipients and carriers that can be used in the pharmaceutical products described herein are listed in various handbooks (e.g. D. E. Bugay and W. P. Findlay (Eds) Pharmaceutical excipients (Marcel Dekker, New York, 1999), E-M Hoepfner, A. Reng and P. C. Schmidt (Eds) Fiedler Encyclopedia of Excipients for Pharmaceuticals. Cosmetics and Related Areas (Editio Cantor, Munich, 2002) and Η. P. Fielder(Ed) Lexikon der Hilfsstffe fur Pharmazie. Kosmetik und angrenzende Gebiete (Editio Cantor Aulendorf, 1989)).

As described herein, the term “active ingredient” can refer to 5-ALA and pharmaceutically acceptable salts thereof, precursors of 5-ALA and pharmaceutically acceptable salts thereof and derivatives of 5-ALA and pharmaceutically acceptable salts thereof.

In some embodiments, a pharmaceutical product is provided, comprising an active ingredient that is a derivative of 5-ALA or a pharmaceutically acceptable salt thereof, at least one triglyceride and at least one emulsifier. In some embodiments, the 5-ALA derivative is a 5-ALA ester. Methods of diagnosing or treating a condition, such as cancer, a pre-cancerous condition or a non-cancerous condition in the lower gastrointestinal tract are also provided, the method comprising administration of the solid pharmaceutical product to a subject in need thereof.

In some embodiments, the product comprises optionally one or more mucoadhesives, optionally one or more pharmaceutically acceptable excipients, optionally one or more surface penetration agents and optionally one or more chelating agents. Such additional components are described infra.

In some embodiments, the 5-ALA ester is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R* represents an unsubstituted alkyl group. In some embodiments, R * represents an unsubstituted saturated straight-chained or branched alkyl group. In some embodiments, represents an unsubstituted saturated straight-chained Ci-io alkyl group. In some embodiments, the 5-ALA ester is 5-ALA hexyl ester. In some embodiments, the pharmaceutically acceptable salt of 5-ALA hexyl ester is one selected from the group of: an HC1 salt, a sulfonic acid salt and a sulfonic acid derivative salt. In some embodiments, the sulfonic acid derivative salt IS one selected from the group of: a mesylate salt, a tosylate salt, and a napsylate salt.

In some embodiments, a pharmaceutical product is provided, comprising: a) an active ingredient that is a derivative of 5-ALA or a pharmaceutically acceptable salt thereof, with 10% acidic water (0.1 N HC1), b) Prosolv®, c) HPMC E5, d) Kollidon VA 64, e) crospovidone, f) sodium stearyl fumarate, g) mannitol and h) Cab-O-Sil® (a fumed silica agent). In some embodiments, the product is coated with at least one selected from the group of: Eudragit® S100, Eudragit® L100, Eudragit® L30D, TEC and talc. Methods of diagnosing or treating a cancer, a pre-cancerous condition or a non-cancerous condition in the lower gastrointestinal tract are also provided, the method comprising administration of the solid pharmaceutical product to a subject in need thereof.

In some embodiments, a pharmaceutical product is provided, comprising: a) an active ingredient that is a derivative of 5-ALA or a pharmaceutically acceptable salt thereof, b) silicified microcrystalline cellulose, c) hydroxypropylcellulose d) mannitol and e) citric acid. In some embodiments, the product is coated with at least one selected from the group of: Eudragit® S100, Eudragit® L100, Eudragit® L30D, TEC and talc. Methods of diagnosing or treating a cancer, a pre-cancerous condition or a non-cancerous condition in the lower gastrointestinal tract are also provided, the method comprising administration of the solid pharmaceutical product to a subject in need thereof.

In some embodiments, the pharmaceutical product is encapsulated with an alginate material that is “seamless.” Exemplary alginate materials for encapsulation and methods of encapsulation are described, for example, in WO 2003/084516, which is incorporated herein by reference in its entirety. In some embodiments, the alginate- encapsulated pharmaceutical product is further encapsulated with enteric polymers as described herein.

In some embodiments, the pharmaceutical product as disclosed herein is a solid pharmaceutical product.

Triglycerides

In embodiments comprising a triglyceride, the triglyceride is comprised of one molecule glycerol and three fatty acid molecules. The three fatty acids can be identical or different fatty acids.

The triglycerides can be solid or liquid at room temperature, e.g. at temperatures of about 18°C to about 25°C. Solid triglycerides are commonly denoted as fat, while liquid triglycerides are commonly denoted as oil. If solid triglycerides are used, the solid triglycerides can have a melting point of below or at the body temperature of a human or a non-human animal to which the solid pharmaceutical product is administered. In some embodiments, the solid pharmaceutical product is administered to a human, and the melting point of a solid triglyceride comprised in said pharmaceutical product is between about 26°C and about 37°C.

The triglycerides can be synthetic, semi-synthetic or of animal and/or vegetable origin. The triglycerides can be pure/isolated triglycerides or a part of a mixture, such as a mixture of triglycerides, monoglycerides and/or diglycerides and/or free fatty acids and/or unsaponifiable lipids. Such mixtures are typically found in edible oils of animal and/or vegetable origin. If the triglycerides are part of a mixture, they can constitute the major part of said mixture. In the following, such mixtures are also referred to as “triglycerides.”

Any triglyceride used in a pharmaceutical product as disclosed herein will be of pharmaceutical grade and will fulfill the requirements and standards of such products with regard to physiological acceptance, tolerability and safety. Further, the triglycerides can be inert compounds that do not react with the 5-ALA derivative or pharmaceutically salt thereof or that do not promote degradation of the same. “At least one triglyceride” can refer to a solid pharmaceutical product as disclosed herein which contains one triglyceride or a mixture of several different triglycerides. By way of example, the solid pharmaceutical product can contain tricaprylin (caprylic acid triglyceride) or tricaprylin and caprylic/capric triglyceride. Further, by way of example, the solid pharmaceutical product can contain soybean oil, which is a mixture of triglycerides of alpha-linolenic acid, linoleic acid, oleic acid, stearic acid and palmitic acid.

In some embodiments, the at least one triglyceride is selected from the group of edible oils of animal and/or vegetable origin and/or fractions thereof. For example, the at least one triglyceride can include soybean oil, palm oil, palm kernel oil, com oil, olive oil, almond oil, safflower oil, peanut oil, coconut oil, sunflower oil, castor oil, pine oil, jojoba oil, cocoa butter, and palm olein, or mixtures thereof. Further examples of triglycerides include illipe butter, shea butter, cocoa butter, kokum butter, sal butter and other natural oils or fractions thereof. Other examples of triglycerides include hydrogenated or partially hydrogenated triglycerides selected from partially or fully hydrogenated soybean oil, rapeseed oil, cottonseed oil, sunflower oil, coconut oil and fractions thereof. The triglycerides can also be synthetic or semisynthetic triglycerides, such as medium-chain triglycerides (MCT).

In some embodiments, the triglyceride can be a triglyceride comprising glycerol and three identical or different C2-C22 fatty acids. In some embodiments, the triglyceride can comprise three identical or different C4-C18 fatty acids. In some embodiments, the triglyceride can comprise three identical or different Q'Clg fatty acids. In some embodiments, the triglyceride can comprise three identical or different C6-C12 fatty acids. In some embodiments, the triglyceride is a triglyceride comprising glycerol and three identical C2-C22 fatty acids. In some embodiments, the triglyceride can comprise three identical C4-C18 fatty acids. In some embodiments, the triglyceride can comprise three identical fatty acids. In some embodiments, the triglyceride can comprise three identical Q‘^12 fatty acids.

In some embodiments, the solid triglyceride can be cocoa butter, tallow, hard fat, hydrogenated coco-glycerides, hydrogenated palm oil, tristearin, tripalmitin, trimyristin, and mixtures thereof. Such solid triglycerides can be used, particularly if the solid pharmaceutical product is a suppository. Suppository formulations containing such hard or solid fats are described supra.

Liquid triglycerides can include tricaprylin, tricaproin, triheptanoin, caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride and caprylic/capric/succinic triglyceride. Several such liquid triglycerides are marketed under the name Miglyol®. For example, Miglyol 812 comprises caprylic/capric triglyceride, Miglyol 818 comprises caprylic/capric/linoleic triglyceride and Miglyol 808 comprises tricaprylin.

The amount of triglyceride in a pharmaceutical product as disclosed herein can range from about 50% to about 90% by weight, or from about 60% to about 80% by weight. For example, the amount of triglyceride in the pharmaceutical product can be about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90% by weight of the total weight of the pharmaceutical product.

The triglycerides can be prepared using standard processes and procedures well- known in the art, and are generally commercially available from various manufacturers such Sasol, Croda, Cognis, Gattefosse and others.

Emulsifiers

The emulsifier used in a pharmaceutical product as disclosed herein can be solid or liquid at room temperature, e.g. at temperatures of about 18°C to about 25°C.

In some embodiments, the emulsifier is a non-ionic emulsifier. Exemplary non- ionic emulsifiers include, but are not limited to, short chain partial glycerides (i.e. esters of glycerol with short chain fatty acids, whereby only a part of the existing hydroxyl groups are esterified, e.g. mono- or diglycerides or mixtures of mono- and diglycerides), esters of glycerol with fatty acids and alpha-hydroxy acids, fatty alcohols and/or ethoxylated fatty alcohols, ethoxylated fatty acids, non-ethoxylated and ethoxylated esters of sorbitan and fatty acids, lecithins, polyethylene glycol based compounds, ethoxylated glycerides and poloxamers (i.e. triblock copolymers composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene), Each exemplary non-ionic emulsifier is discussed in more detail infra.

Exemplary partial glycerides include, but are not limited to, mono- or diglycerides or mixtures of mono- and diglycerides of C6-C10 fatty acids.

Exemplary esters of glycerol with fatty acids and alpha-hydroxy acids include, for instance, glyceryl stearate citrate, glyceryl citrate/lactate/oleate/linoleate, glyceryl cocoate/citrate/lactate and glyceryl isostearate.

Exemplary fatty alcohols and/or ethoxylated fatty alcohols include, but are not limited to, cetostearyl alcohol or cetomacrogol.

Exemplary ethoxylated fatty acids include, but are not limited to, ethoxylated castor oil.

Exemplary non-ethoxylated and ethoxylated esters of sorbitan and fatty acids include, but are not limited to, products sold under brand names Span® and Tween®. These include, for example, polysorbates, (polyoxyethylene) sorbitan monolaurate, (polyoxyethylene) sorbitan monopalmitate, (polyoxyethylene) sorbitan monostearate, (polyoxyethylene) sorbitan monooleate, (polyoxyethylene) sorbitan tristearate and (polyoxyethylene) sorbitan trioleate.

Exemplary lecithins, include, but are not limited to, egg yolk lecithin, soybean lecithin and phospholipids derived from lecithin (e.g. phosphatidylcholine).

Exemplary polyethylene glycol based compounds include, but are not limited to, polyethylene glycol 400 monostearate.

Exemplary ethoxylated glycerides include, but are not limited to, ethoxylated caprylocaproyl glyceride or products obtained from the reaction of polyethylene glycol and natural or hydrogenated oils, such as, for example, palm kernel oil, hydrogenated palm kernel oil, castor oil, hydrogenated castor oil, almond oil, apricot kernel oil and the like.

Other non-ionic emulsifiers include, but are not limited to, lauroyl macrogol-32 glyceride, Gelucire® 44/14 (Gattefosse); stearoyl macrogol glyceride, Gelucire® 50/13 (Gattefosse); PEG-50 castor oil, Emalex C-50 (Nihon Emulsion); Eumulgin® HRE 40 (Cognis); PEG-45 hydrogenated castor oil, PEG-8 caprylic/capric glycerides, Labrasol® (Gattefosse); either alone or in a mixture with other emulsifiers. In some embodiments, several Gelucires are mixed together, such as, for example, Gelucire® 44/14 with Gelucire® 50/02 (saturated polyglycolized glycerides) or Gelucire® 33/01 (glycerol esters of C8-C18 saturated fatty acids).

Exemplary poloxamers (i.e. triblock copolymers composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene, also known by the trade name Pluronics®) include those which are liquid and have a pH below about 7 or about 6. These include, for example, Pluronic® L43, HLB 7-12 and Pluronic® L44, HLB 12-18, either alone or in a mixture with other emulsifiers, such as, for example, poloxamers such as Pluronic® F68.

In embodiments in which the 5-ALA derivative is a alkyl ester of 5-ALA or a pharmaceutically acceptable salt thereof, a non-ionic emulsifier with high hydrophilic-lipophilic balance values (HLB values) can be used. In some embodiments, the non-ionic emulsifier has an HLB value of at least 7. In some embodiments, the non- ionic emulsifier has an HLB value of at least 12. In some embodiments, the non-ionic emulsifier has an HLB value of at about 12 - 18. In embodiments in which more than one emulsifier is used, an emulsifier with an HLB value below 7 or above 18 can be used, provided that the resulting mixture of emulsifiers has a HLB value of at least 7 and preferably a HLB value of about 12-18.

The emulsifier can be present in the pharmaceutical product in an amount that will promote uniform distribution of the pharmaceutical product at the site of use, e.g. in the colon and rectum. A suitable amount of the emulsifier can be chosen in view of the amount of triglycerides present in the product. For example, the emulsifier can be present in a pharmaceutical product as disclosed herein in an amount ranging from about 0.5% to about 50%, about 1% to about 35%, or about 2% to about 30% by weight of the total weight of the solid pharmaceutical product. For example, the emulsifier can be present at a concentration of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 50% by weight of the total weight of the solid pharmaceutical product.

The emulsifier or mixture of emulsifiers can be prepared using standard processes and procedures well-known in the art, although many are available commercially from various manufacturers such like Sasol, Croda, Cognis, Gattefosse, American Lecithin Company, BASF, Cytec and others.

Mucoadhesives A mucoadhesive encompasses a compound which exhibits an affinity for a mucosa surface, i.e., adheres to that surface through the formation of bonds which can be non-covalent in nature, whether binding occurs through interaction with the mucous and/or the underlying cells. The mucosa surface includes a mucosa surface of the lower gastrointestinal tract, in particular the mucosa of the colon and the rectum. A mucoadhesive which is optionally present in a solid pharmaceutical product as disclosed herein can be one that is not degraded or metabolized by bacterial and non- bacterial enzymes present in the lower gastrointestinal tract, in particular in the colon and the rectum.

The mucoadhesive can be a natural or a synthetic compound, polyanionic, polycationic or neutral, water-soluble or water-insoluble. In some embodiments, the mucoadhesive is large and has a molecular weight ranging from about 500 kDa to about 3000 kDa or from about 1000 kDa to about 2000 kDa. The mucoadhesive can also be water-insoluble cross-linked. For example, the mucoadhesive can contain from about 0.05% to about 2% cross-linker by weight of the total polymer, prior to any hydration, in a water-swellable polymer capable of forming hydrogen bonds. The mucoadhesive compound can have a mucoadhesive force greater than about 100, greater than 120, or greater than about 150, expressed as a percent relative to a standard in vitro, as assessed according to the method of Smart et al., 1984, J. Pharm. Pharmacal., 36, pp 295-299, which is incorporated herein by reference in its entirety.

Exemplary mucoadhesives can be selected from polysaccharides, such as, for example, dextran, pectin, amylopectin or agar; gums (e.g. guar gum or locust bean gum), salts of alginic acid (e.g. sodium alginate or magnesium alginate); poly(acrylic acid), crosslinked or non-crosslinked copolymers of poly(acrylic acid) and derivatives of poly(acrylic acid) such as salts and esters (e.g. carbomer (Carbopol®)).

When present, the mucoadhesive can be provided in a concentration range of from about 0.05% to about 50%, or from about 0.1 to about 25%, or from about 0.2% to about 10% by weight of the total weight of the solid pharmaceutical product. For example, the mucoadhesive can be present at a concentration of about 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 50% by weight of the total weight of the solid pharmaceutical product.

Additional Excipients

In embodiments comprising an additional excipient other than a triglyceride or an emulsifier, the excipient can be at least one selected from the group of: an antiadherent, a filler, a binder, a flavor, a color, an odor enhancer, a glidant, a lubricant, a disintegrant, a solvent and a preservative. The skilled artisan will be able to select suitable excipients based on, for example, the route of administration chosen. Excipients that can be used in a pharmaceutical product as disclosed herein are listed in various handbooks (e.g. D.E. Bugay and W.P. Findlay (Eds) Pharmaceutical Excipients (Marcel Dekker, New York, 1999), E-M Hoepfner, A. Reng and P. C. Schmidt (Eds) Fiedler Encyclopedia of Excipients for Pharmaceuticals. Cosmetics and Related Areas (Edition Cantor, Munich, 2002) and Η. P. Fielder (Ed) Lexikon der Hilfsstoffe fur Pharmazie. Kosmetik und angrenzende Gebiete (Edition Cantor Aulendorf, 1989)).

In embodiments in which a pharmaceutical product as disclosed herein optionally comprises one or more pharmaceutically acceptable solvents, such solvents can be a free fatty acid, a free fatty alcohol, an aqueous solution (e.g. a buffer), or water. In some embodiments, the pharmaceutical product does not contain any water, i.e. is water-free. By water-free, it is meant that no water is added to the solid pharmaceutical product and that any measurable water content of the product is due to water possibly contained in a photosensitizer agent, a triglyceride, an emulsifier, a mucoadhesive, a pharmaceutically acceptable excipient other than a triglyceride or an emulsifier, a surface penetration agent or a chelating agent that may be a component of the product..

Surface Penetration Assisting Agents

Penetration enhancers can have a beneficial effect in enhancing the photosensitizing effect of the photosensitizer present in the pharmaceutical products of the invention. Surface penetration assisting agents such as, for example, dialkylsulphoxides (e.g. dimethylsulphoxide, or DMSO) can therefore be included in the products. The surface penetration assisting agent can be any of the skin penetration assisting agents described in the pharmaceutical literature, e.g. chelators (e.g. EDTA), surfactants (e.g. sodium dodecyl sulfate), non-surfactants, bile salts (sodium deoxycholate) and fatty acids (e.g. oleic acid). Examples of appropriate surface penetration assisting agents include isopropanol, HPE-101 (available from Hisamitsu), DMSO and other dialkylsulphoxides, in particular n-decylmethyl sulphoxide (NDMS), dimethylsulphacetamide, dimethylformamide (DMFA), dimethylacetamide, glycols, various pyrrolidone derivatives (Woodford et al., J. Toxicol. Cut. & Ocular Toxicology, 1986, 5: 167-177) and Azone® (Stoughton et al., Drug Dpv. Ind. Pharm. 1983, 9: 725-744) or mixtures thereof. In some embodiments, the surface penetration assisting agents employed for use in a product, composition or formulation as herein described are those which are solid at ambient temperature.

In some embodiments, the pharmaceutical product does not contain a glycol (e.g. propylene glycol) as a surface penetration assisting agent.

The surface penetration agent can be provided in a concentration range of from about 0.2% to about 50%, from about 1% to about 40%, from about 2.5% to about 30%, from about 5% to about 25%, from about 7.5% to about 20%, or from about 10% to about 15% by weight of the total weight of the pharmaceutical product in which it is present. In some embodiments, the surface penetration agent is present in a concentration range of from about 0.5% to about 5% by weight of the total weight of the pharmaceutical product in which it is present. In some embodiments, the surface penetration agent is provided in a concentration range of about 0.2%, 0.5%, 1%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% by weight of the total weight of the pharmaceutical product in which it is present.

Chelating Agents

Chelating agents can also have a beneficial effect in enhancing the photosensitizing effect of the photosensitizer present in a pharmaceutical product as disclosed herein. Chelating agents can, for example, be included in order to enhance the accumulation of Pp since the chelation of iron by the chelating agent prevents its incorporation into Pp to form heme by the action of the enzyme ferrochelatase, thereby leading to a build up of Pp. By addition of a chelating agent, the photosensitizing effect can thereby be enhanced.

Suitable chelating agents that can be included in a composition, formulation or pharmaceutical product as disclosed herein include aminopolycarboxylic acids, or any of the chelants described in the literature for metal detoxification or for the chelation of paramagnetic metal ions in magnetic resonance imaging contrast agents. Exemplary chelating agents that are suitable for pharmaceutical use include, for example, EDTA, CDTA (cyclohexane triamine tetraacetic acid), DTPA and DOTA as well as well known derivatives and analogues thereof. To achieve the iron-chelating effect, desferrioxamine and other siderophores can also be used, e.g. in conjunction with aminopolycarboxylic acid chelating agents such as EDTA.

In some embodiments, the chelating agent can also serve as a surface penetration assisting agent. For example, EDTA can act as both a chelating agent as well as a surface penetration assisting agent.

Where present, the chelating agent can be used at a concentration of from about 0.01% to about 20%, from about 0.05% to about 15%, from about 0.1% to about 10%, from about 0.2% to about 5%, or from about 0.5% to about 2.5% by weight based on the total weight of the composition, formulation or pharmaceutical product in which it is present. In some embodiments, the chelating agent is used at a concentration of from about 0.01% to about 12% by weight of the total weight of the product. In some embodiments, the chelating agent is used at a concentration of from about 0.1% to about 10% by weight of the total weight of the product. For example, the chelating agent can be used at a concentration of about 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight of the total weight of the product in which it is present.

Stabilizing Agents

In some embodiments, a stabilizing agent can be included in a composition, formulation or pharmaceutical product as disclosed herein to improve the stability of the photosensitizer. Exemplary stabilizing agents can be an acid, an organic acid, or one or more acids that are known in the art and described in the Handbook of Pharmaceutical Excipients by Rowe, Sheskey and Owen (2005. The Handbook of Pharmaceutical Excipients, Fifth Edition, APhA Publications).

Tablet or Capsule Forms

In some embodiments, a pharmaceutical product as disclosed herein is provided in the form of a capsule comprising one or more liquid triglycerides. In some embodiments, the one or more liquid triglycerides is selected from triglycerides of glycerol and three identical or different C2-C22 fatty acids. In some embodiments, the one or more liquid triglycerides is selected from triglycerides of glycerol and three identical or different C4- Ci8 fatty acids. In some embodiments, the one or more liquid triglycerides is selected from triglycerides of glycerol and three identical or different C6-C18 fatty acids. In some embodiments, the one or more liquid triglycerides is selected from triglycerides of glycerol and three identical or different ^6^12 fatty acids. In some embodiments, the one or more liquid triglycerides is selected from the group of: tricaprylin, tricaproin, triheptanoin, caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride and caprylic/capric triglyceride. To prepare or fill the capsule, the one or more liquid triglycerides can be mixed with the active ingredient, together with the one or more emulsifiers and optionally with a mucoadhesive, an excipient other than a triglyceride or an emulsifier, a surface penetration agent and/or a chelating agent. In some embodiments, the one or more emulsifier is selected from the group of: a lecithin, a phosphatidylcholine, an ethoxylated glyceride, polyoxyethylene sorbitan monooleate, dioctyl sodium sulfosuccinate, sodium lauryl sulfate, a poloxamer and a product obtained from the reaction of polyethylene glycol with a natural or a hydrogenated oil.

In some embodiments, a solid pharmaceutical product as disclosed herein IS provided in the form of a capsule comprising one or more solid triglycerides having a melting point of below or at the body temperature of a human or a non-human animal to which the capsule is administered. In some embodiments, the capsule is administered to a human, and the melting point of said one or more solid triglycerides is between about 26°C and about 37°C. In some embodiments, the one or more solid triglyceride is selected from the group of: cocoa butter, tallow, a hard fat, a hydrogenated coco- glyceride, hydrogenated palm oil, tristearin, tripalmitin trimyristin, and a hydrogenated coco-glyceride optionally mixed with glyceryl ricinoleate (e.g. those marketed under the name Witepsol® and Massa Estarinum®). In some embodiments, the hydrogenated coco-glyceride is one with a low hydroxyl value and a melting point between about 31°C and about 38°C. Exemplary hydrogenated coco-glycerides having such characteristics include, but are not limited to, Witepsol® H 32, Witepsol® H 35, Witepsol® H 37 and Massa Estarinum® 299. To prepare or fill the capsule, the one or more solid triglycerides can be melted, and the active ingredient is mixed with the melted triglycerides, together with the one or more emulsifiers and optionally with a mucoadhesive, an excipient other than a triglyceride or an emulsifier, a surface penetration agent and/or a chelating agent. In some embodiments, the one or more emulsifier is selected from the group of: a lecithin, a phosphatidylcholine, an ethoxylated glyceride, polyoxyethylene sorbitan monooleate, dioctyl sodium sulfosuccinate, sodium lauryl sulfate, a poloxamer and a product obtained from the reaction of polyethylene glycol with a natural or a hydrogenated oil.

In some embodiments, a pharmaceutical product as disclosed herein is provided in the form of a capsule comprising several triglycerides, wherein at least one triglyceride is a liquid and at least one triglyceride is a solid. For example, the product can comprise a solid triglyceride and a liquid triglyceride. In some embodiments, the at least one liquid triglyceride comprises glycerol and three identical or different C2C22 fatty acids. In some embodiments, the at least one liquid triglyceride comprises a glycerol and three identical or different C4-C18 fatty acids. In some embodiments, the at least one liquid triglyceride comprises a glycerol and three identical or different C6-C18 fatty acids. In some embodiments, the at least one liquid triglyceride comprises a glycerol and three identical or different Ce-Cn fatty acids. In some embodiments, the at least one liquid triglyceride is selected from the group of: tricaprylin, tricaproin, triheptanoin, caprylic/capric triglyceride and caprylic/capric/linoleic triglyceride. The at least one solid triglyceride can have a melting point of below or at the body temperature of a human or a nonhuman animal to which the capsule is administered. In some embodiments, the capsule is administered to a human and the melting point of said at least one solid triglyceride is between about 26°C and about 37°C. In some embodiments, the one or more solid triglyceride is selected from the group of: cocoa butter, tallow, a hard fat, a hydrogenated coco-glyceride, hydrogenated palm oil, tristearin, tripalmitin trimyristin, and a hydrogenated coco-glyceride optionally mixed with glyceryl ricinoleate (e.g. those marketed under the name Witepsol® and Massa Estarinum®). In some embodiments, the hydrogenated coco-glyceride is one with a low hydroxyl value and a melting point between about 31°C and about 38°C. Exemplary hydrogenated coco-glycerides having such characteristics include, but are not limited to, Witepsol® H 32, Witepsol® H 35, Witepsol® H 37 and Massa Estarinum® 299. To prepare or fill the capsule, the at least one solid triglyceride can be melted and mixed with the at least one liquid triglyceride, the active ingredient, the one or more emulsifiers and optionally with a mucoadhesive, an excipient other than a triglyceride or an emulsifier, a surface penetration agent and/or a chelating agent. In some embodiments, the one or more emulsifier is selected from the group of: a lecithin, a phosphatidylcholine, an ethoxylated glyceride, polyoxyethylene sorbitan monooleate, dioctyl sodium sulfosuccinate, sodium lauryl sulfate, a poloxamer and a product obtained from the reaction of polyethylene glycol with a natural or a hydrogenated oil, and an ethoxylated fatty alcohol.

In some embodiments, a pharmaceutical product as disclosed herein is provided in the form of a capsule comprising several triglycerides, wherein at least one triglyceride is a liquid and at least one triglyceride is a solid, and a non-ionic emulsifier. For example, the product can comprise a solid triglyceride and a liquid triglyceride. In some embodiments, the at least one liquid triglyceride comprises glycerol and three identical or different C2C22 fatty acids. In some embodiments, the at least one liquid triglyceride comprises a glycerol and three identical or different C4-C18 fatty acids. In some embodiments, the at least one liquid triglyceride comprises a glycerol and three identical or different C6-Ci8 fatty acids. In some embodiments, the at least one liquid triglyceride comprises a glycerol and three identical or different ^6^12 fatty acids. In some embodiments, the at least one liquid triglyceride is selected from the group of: tricaprylin, tricaproin, triheptanoin, caprylic/capric triglyceride and caprylic/capric/linoleic triglyceride. In some embodiments, the non-ionic emulsifier is a poloxamer or a product obtained from the reaction of polyethylene glycol with a natural or a hydrogenated oil. In some embodiments, the non-ionic emulsifier is selected from the group of: Pluronic® L43, Pluronic® L44, lauroyl macrogol-32 glyceride, Gelucire® 44/14 (Gattefosse), stearoyl macrogol glyceride, and Gelucire® 50/13 (Gattefosse). To prepare or fill the capsule, the at least one solid triglyceride can be melted and mixed with the at least one liquid triglyceride, the active ingredient, the one or more emulsifiers and optionally with a mucoadhesive, an excipient other than a triglyceride or an emulsifier, a surface penetration agent and/or a chelating agent. In some embodiments, the at least one liquid triglyceride, the emulsifier and optional other compounds can be formed to pellets, mini- tablets or granules. Excipients known in the art to form such pellets, mini-tablets or granules can be added, such as viscosity enhancers or fillers. The so-formed pellets, mini-tablets or granules can then be filled into a capsule.

In embodiments for oral administration, a pharmaceutical product as disclosed herein can be provided in the form of powder, a granule, a tablet, a pellet, a capsule or a mini-tablet, said products comprising as the one or more triglycerides solid and/or liquid triglycerides. Tablets, powder, granules, pellets or mini-tablets can be prepared by any method known to those of skill in the art. For example, tablets and mini-tablets can be prepared by direct compression of the components of the solid pharmaceutical product or by compression after granulation.

In some embodiments, a solid pharmaceutical product as disclosed herein can be provided in the form of a tablet or a capsule comprising a plurality of mini-tablets having a formulation as disclosed herein. The tablet or capsule can contain from about 10 to about 100 mini-tablets, or any number in between. In some embodiments, the tablet or capsule contains about 10 mini-tablets having a formulation as disclosed herein. In some embodiments, the tablet or capsule contains about 25 mini-tablets having a formulation as disclosed herein. In some embodiments, the tablet or capsule contains about 50 mini- tablets having a formulation as disclosed herein In some embodiments, the tablet or capsule contains about 75 mini-tablets having a formulation as disclosed herein. In some embodiments, the tablet or capsule contains about 100 mini-tablets having a formulation as disclosed herein.

In some embodiments, the tablet or capsule comprising mini-tablets releases from about 40 % to 60% of active agent in about 8 to 15 minutes in a pH above about 5.5 to 6.5. For example, the release may begin at a pH above 5.5 or above 6.5 or at any pH between 5.5 and 6.5. In another example, the tablet or capsule can release about 40%, 45%, 50%, 55% or 60% of active agent in about 8, 10 12 or 15 minutes. In some embodiments, the tablet or capsule can release about 50% of active agent in about 10 minutes. In one embodiment, for example, the tablet or capsule releases from between about 35 - 65% of the active agent in about 5-20 minutes.

In some embodiments, the tablet or capsule comprising mini-tablets releases from about 80% to 100% of active agent in about 120 minutes in a pH of above about 5.5 or above about 6.5. For example, the release may begin at a pH above 5.5 or above 6.5 or at any pH between 5.5 and 6.5. In another example, the tablet or capsule can release about 80%, 85%, 90%, 95% or 100% of active agent in about 120 minutes. In some embodiments, the tablet or capsule releases from about 90 to 100% of active agent in about 120 minutes.

In some embodiments, the tablet or capsule comprising mini-tablets releases from about 85% to 100% of active agent in under about 90 to 120 minutes in a pH of above about 5.5 to 6.5. For example, the release may begin at a pH above 5.5 or above 6.5 or at any pH between 5.5 and 6.5. In another example, the tablet or capsule can release about 85%, 90%, 95% or 100% of active agent in under about 90, 100, 110 or 120 minutes. In some embodiments, the tablet or capsule releases from about 90% to about 100% in under about 120 minutes.

In any of the foregoing embodiments, the tablet or capsule can be coated with an enteric or gastroresistant coating as described further herein.

Suppository/Pessary Forms

Suppositories and pessaries for use in the methods as disclosed herein can be prepared by any method known to those of skill in the art, e.g. by direct compression of a composition comprising a photosensitizer as disclosed herein or by compression after granulation or by molding. For example, a suppository can be prepared by melting an at least one solid triglyceride, mixing the melted triglyceride with the other components of the suppository composition, and pouring the mixture into a casting mold where the composition cools and hardens. Such embodiments can be adapted for insertion into the uterus, vagina cervix, or rectum.

Suppositories and pessaries can be formulated using any of the excipients and carriers mentioned above, e.g. lactose, microcrystalline cellulose or crospovidone. In some embodiments, suppositories and pessaries comprising a photosensitizer are formulated to melt or dissolve in the body after being administered to a subject. In such embodiments, the suppository or pessary can be water-soluble and can be made from macrogols, propylene glycols, glycerol, gelatin or mixtures thereof. In some embodiments, the suppository or pessary can further contain a bioadhesive agent, for example a mucoadhesive agent, to promote adhesion and thus prolonged contract of the composition to the mucosa membranes, e.g. the vaginal epithelium.

In some embodiments, suppositories or pessaries can be formulated with a fat or fat-like compound. Fats and fat-like compounds include, for example, hard fat (e.g. glycerides of Cg-is fatty acids), a mixture of hard fat and additives, fat, paraffin, glycerol and synthetic polymers. In some embodiments, the suppository or pessary is formulated with a hard fat, which contain mixtures of the triglyceride esters of higher fatty acids along with varying proportions of mono-and diglycerides. Exemplary hard fats include the range of products sold under the trade name Witepsol (e.g. Witepsol S55, Witepsol S58, Witepsol H32, Witepsol H35 and Witepsol H37). Suppositories and pessaries formulated in this way can melt after administration to the body and thereby release the photosensitizer contained therein. Accordingly, in some embodiments, the suppository or pessary formulated with a hard fat has a melting point between about 30°C to about 42°C. For example, the suppository or pessary formulated with hard fat can have a melting point of about 30°C, about 31°C, about 32°C, about 33°C, about 34°C, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41°C, or about 42°C.

Additional composition or formulation components

The pharmaceutical products can additionally include lubricating agents, wetting agents, preserving agents, flavoring agents and/or odor enhancers. The pharmaceutical products for use in the methods as disclosed herein can be formulated so as to provide quick, sustained or delayed release of the photosensitizer after administration to the patient by employing procedures that are well known in the art. In embodiments intended for oral administration in treating conditions in the lower gastrointestinal tract, the formulation can be a delayed release formulation.

In some embodiments, the pharmaceutical product does not, comprise a non-aqueous liquid which has a dielectric constant of less than about 80 at about 25°C. In some embodiments, the pharmaceutical product does not comprise a non-aqueous liquid selected from the group of: an alcohol, an ether, an ester, a poly(alkylene glycol), a phospholipid, DMSO, N-vinylpyrrolidone, Ν,Ν-dimethylacetamide and mixtures thereof.

Anti-cancer agents

The compositions or pharmaceutical products as disclosed herein can additionally comprise an anti-cancer agent. Accordingly, embodiments are directed to use of a photosensitizer which is 5-ALA or a precursor or derivative thereof (e.g. a 5-ALA ester), together with an anticancer agent in the manufacture of a pharmaceutical product for use in the treatment of cancer or an infection associated with cancer. In some embodiments, the pharmaceutical product is in the form of a solid.

Embodiments are also directed to a kit or pack containing a pharmaceutical product as disclosed herein, and separately an anti-cancer agent for simultaneous, separate or sequential use in a method of treating a cancer or an infection associated with a cancer in a subject.

The anti-cancer agent present m the pharmaceutical product and/or kit as disclosed herein can be an anti-neoplastic agent. Exemplary anti-neoplastic agents include, but are not limited to, alkaloids (e.g. incristine, vinblastine, vinorelbine, topotecan, teniposiode, paclitaxel, etoposide and docetaxel), alkylating agents (e.g. alkyl sulfonates such as busulfan), aziridines (e.g. carboquone, ethylenimines and methylmelamines), nitrogen mustards (e.g. chlorambucil, cyclophosphamide, estramustin, ifosfamide and melphalan), nitrosurea derivatives (e.g. carmustine and lomustine), antibiotics (e.g. mitomycins, doxorubicin, daunorubicin, epirubicin and bleomycins), antimetabolites (e.g. folic acid analogues and antagonists such as methotrexate and raltitrexed), purine analogues (e.g. 6-mercaptopurine), pyrimidine analogues (e.g. tegafur, gemcitabine, fluorouracil and cytarabine), cytokines, enzymes (e.g. L-asparginase, ranpimase), immunomodulators (e.g. interferons, immunotoxins, monoclonal antibodies), taxanes, topoisomerase inhibitors, platinum complexes (e.g. carboplatin, oxaliplatin and cisplatin) and hormonal agents (e.g. androgens, estrogens, antiestrogens) and aromatase inhibitors. Other anti-neoplastic agents for use in a pharmaceutical product or kit as disclosed herein include imiquimod, irenotecan, leucovorin, levamisole, etopisde and hydroxyurea.

In some embodiments, the anti-cancer agent is at least one selected from the group of: 5-fluorouracil, imiquimod, cytokines, mitomycin C, epirubicin, irenotecan, oxalipatin, leucovorin, levamisole, doxorubicin, cisplatin, etoposide, doxirubicin, methotrexate, taxanes, topoisomerase inhibitors, hydroroxyurea and vinorelbine. In some embodiments, the anti-cancer agent is an antibiotic such as mitomycin. In some embodiments, the anti-cancer agent is a pyrimidine analogue such as 5-fluorouracil.

Components and Methods for Delayed or Sustained Release of Compositions and Formulations

In some embodiments, for example, in formulations adapted for oral administration, delayed release of an active agent from the formulation is provided. This can be useful when an oral formulation is to be administered for the treatment or diagnosis of conditions in the lower gastrointestinal tract. Delayed (e.g. sustained) release can be achieved using any of the methods known and described in the art such as, for example, pH-dependent systems designed to release the photosensitizer in response to a change in pH as well as time-dependent (or timed-release) systems designed to release the photosensitizer after a pre-determined time. There are various known methods and systems for oral colonic delivery of pharmaceutically active ingredients. For example, an oral pharmaceutical product can comprise one or more pharmaceutical excipients that provide for controlled release of the active ingredient and/or by coating the oral pharmaceutical product with a coating that provides such a time controlled release.

Pressure-controlled systems utilize the increase in pressure of the luminal contents to effect release of the active ingredient. In some embodiments, the active ingredient is dispersed in a melted solid triglyceride (suppository base) which can melt at body temperature, together with one or more emulsifiers, and the mixture is cooled such that a solid pharmaceutical product is obtained. The solid pharmaceutical product can be coated with ethyl cellulose. After the product is swallowed, the temperature of body allows the suppository base to melt, which increases the volume within the coating such that a balloon is formed of ethyl cellulose filled with liquid. This balloon is capable of remaining intact in the small intestine but can rupture when exposed to the more intense contractions and luminal contents of higher viscosity encountered in the colon.

Time-controlled systems (pulsatile release systems) are based on the principle of delaying the time of drug release until the system transits from mouth to colon. Pulsatile release systems can be formulated to undergo a lag-time of a predetermined span of time of no release, followed by a rapid and complete release or a delayed release of the loaded drugs(s) or active agent. A lagtime of 5 hours can be sufficient since small intestine transit is about 3-4 hours; this transit time is relatively constant and is not typically affected by the nature of formulation administered. In some embodiments, an oral solid pharmaceutical product is coated with lipid barriers such as carnauba wax and/or beeswax along with surfactants such as, for example, polyoxyethylene sorbitan monooleate. When the product comes in contact with an aqueous medium, the coat can emulsify or erode after the lag-time depending on the thickness of coat. The lag time of this system is independent of the gastrointestinal motility, pH, enzyme and gastric residence time. In some embodiments, the pharmaceutical product (liquid or solid) is filled into an insoluble capsule body housing which is sealed with a plug of a swellable hydrogel. Upon contact with gastrointestinal fluid, the plug can swell and push itself out of the capsule after the lag-time, which is controlled by the position and the dimensions of the plug. The plug material can be made up of, for example, (i) swellable materials coated with an insoluble but permeable polymer, e.g. polymethacrylates; (ii) an erodible compressed polymer such as, for example, hydroxypropyl methycellulose (HPMC), polyvinyl alcohol, and polyethylene oxide; or (iii) a congealed melted polymer such as, for example, glyceryl monooleate or an enzymatically controlled erodible polymer such as, for example, pectin. In some embodiments, the capsule is coated with an enteric coating.

Bacteria responsive delivery is based on enzymatic activity of bacteria in the lower gastrointestinal tract, especially in the colon, where the bacterial count is approximately 10 million times higher than that in the proximal gastrointestinal tract. The active agent to be delivered to the colon can be formulated in a compound or matrix that is degraded by enzymes produced and secreted from colonic bacteria. In some embodiments, a solid pharmaceutical product as disclosed herein is coated with a naturally occurring polysaccharide, such as, for example, an amylose. In the glassy state, amylose has suitable film-forming properties and is resistant to degradation by pancreatic enzymes in the small intestines. In combination with water-insoluble polymers, which reduce swelling and release of the active ingredient from the hydrophilic amylose, e.g. ethylcellulose, a film coating can be applied to the solid pharmaceutical product formulated as a tablet, a pellet, a liquid, or as pellets or granules filled in capsules.

Other suitable materials for sustained, controlled or delayed release include, but are not limited to, carbomers, carbopols, cellulose compounds and derivatives (e.g. microcrystalline cellulose (MCC), methylcellulose, carboxyl methyl cellulose sodium (NA-CMC, also referred to as SMC), silicified microcrystalline cellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), hydroxypropylcellulose, starch compounds and derivatives (e.g. com starch, croscaramellose, crospovidone, cyclodextrins such as beta-cyclodextrin, lactose such as anhydrous lactose or hydrous lactose, maltodextrin, mannitol), synthetic polymers (e.g. methacrylic acid copolymers), polyethylene glycol derivatives (e.g. polysorbate), povidone, sorbitan derivatives, talcum, wax, polyethylene glycol, poloxamer, medium- chain triglycerides, glycerides of Cg_18 fatty acids (e.g. hard fat), Miglyol® oils, Kollidon® materials, and mixtures thereof. Such materials can be present in the compositions and pharmaceutical formulations as disclosed herein anywhere from about 1% to about 60% (w/w). For example, such materials can be present in the composition or pharmaceutical formulation at a concentration of about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% (w/w).

For the controlled release of an active ingredient of an oral solid pharmaceutical product as disclosed herein, a pH dependent system can be considered. The pH of the small intestine increases aborally, and pH sensitive pharmaceutically acceptable excipients and coatings with a dissolution threshold in the range of about pH 5 to about pH 8 can be suitable for pH-controlled release of drugs that are to be delivered to the lower intestinal tract, e.g. to the colon. The pH in the terminal ileum is about 1-2 pH units higher than that in the cecum, and pH sensitive pharmaceutically acceptable excipients and coatings can begin to destabilize and degrade in the region of the terminal ileum/cecum. In some embodiments, an oral solid pharmaceutical product is one in which coating degradation is desired to be avoided in the stomach, and the coating can be selected such that it degrades at a more neutral pH. For example, the coating can be selected for degradation at a pH of about 5, 5.5, 6, 6.5, 7, 7.5, 8, or any pH in between. In some embodiments, the coating can be selected for degradation in the range of about pH 5.5 to about pH 7.5, or any pH in between. In some embodiments, the coating degrades at about pH 6.5 or more. In some embodiments, the coating is selected for degradation at about pH 6.5. In some embodiments, the coating degrades at a pH of about 6.0. In some embodiments, the coating degrades at a pH above 6.0. In some embodiments, the coating degrades at a pH of about 5.5. In some embodiments, the coating degrades at a pH above 5.5. In some embodiments, the solid pharmaceutical product is coated with one or more enteric coatings.

In some embodiments, the coating is one which is enterosoluble and gastroresistant. Such coatings can render the composition stable to stomach pH, thus, the composition begins to release the active agent contained therein after entry into the intestinal system, e.g. the colon. Exemplary coating materials that can be used with a composition or formulation as disclosed herein include synthetic, semi-synthetic or synthetic polymers. For example, the coating material can be at least one selected from the group of: cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, a copolymer of methacryclic acid and methacrylic ester, and polyvinvlacetophthalate. Other suitable coatings include cellulose acetate phthalate (CAP), cellulose acetate trimellitate, ethylcellulose, dibutyl phthalate and diethyl phthalate, a pectin, a pectin salt, and a cross-linked polymer and copolymer. Examples of cross-linked polymers and co-polymers include, for example, 2-hydroxy-ethyl methacrylate crosslinked with divinylbenzene and N,N’-bis(beta-styrene sulphonyl-4,4’- diaminobenzene. In some embodiments, the enteric coating is comprised of anionic polymers of methacrylic acid and methacrylate (Eudragit®). The Eudragit® grades of polymer which are capable of sustained release are contemplated for use as coating materials. Eudragit® grades of polymer are based on copolymers of acrylate and methacrylates with quaternary ammonium groups as functional groups as well as ethylacrylate methylmethacrylate copolymers with a neutral ester group. Such polymers are insoluble and permeable and their release profiles can be altered by varying mixing ratios and/or coating thickness. Exemplary Eudragit® polymers include the Eudragit® S-and L-types. In some embodiments, the enteric coating comprises Eudragit® SI00 or Eudragit® LI00, triethyl citrate and talc.

In some embodiments, the coating can comprise one or more Eudragit® polymers (e.g. Eudragit® FS, Eudragit® L30 D55, Eudragit® L30D, Eudragit L100® etc.) at a concentration of from about 1% to about 75% (w/w). For example, the coating can comprise a Eudragit® polymer or a mixture of Eudragit® polymers at a concentration of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or 75% (w/w). In some embodiments, the coating comprises a Eudragit® polymer or a mixture of Eudragit® polymers at a concentration of about 10% (w/w). In some embodiments, the coating comprises a Eudragit® polymer or a mixture of Eudragit® polymers at a concentration of about 12% (w/w). In some embodiments, the coating comprises a Eudragit® polymer or a mixture of Eudragit® polymers at a concentration of about 30% (w/w) dry basis. In some embodiments, the coating comprises a Eudragit® polymer or a mixture of Eudragit® polymers at a concentration of about 60% (w/w) dry basis.

In some embodiments, the coating can comprise triethyl citrate at a concentration of from about 0.1% to about 10% (w/w). For example, the coating can comprise triethyl citrate at a concentration of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1/o, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5% 4.6%, 4.7%, 4.8%, 4.9%, or 5.0%. In some embodiments, the coating can comprise triethyl citrate at a concentration of about 6%, 7%, 8%, 9% or 10% (w/w). In some embodiments, the coating comprises triethyl citrate at a concentration of about 1.0% (w/w). In some embodiments, the coating comprises triethyl citrate at a concentration of about 6% (w/w). In some embodiments, the coating comprises triethyl citrate at a concentration of about 6.25% or 6.5% (w/w) dry basis.

In some embodiments, the coating can comprise talc at a concentration of from about 1% to about 50% (w/w). For example, the coating can comprise talc at a concentration of about 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5% 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9% or 10.0% (w/w). In some embodiments, the coating can comprise talc at a concentration of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% (w/w). In some embodiments, the coating comprises about 2.33% (w/w) talc. In some embodiments, the coating comprises about 5.5% (w/w) talc. In some embodiments, the coating comprises about 6.25% (w/w) talc. In some embodiments, the coating comprises about 35% (w/w) talc dry basis.

In some embodiments, the coating can further comprise a diluent or lubricant. Diluents or lubricants suitable for oral pharmaceutical products are known in the art, and the skilled artisan is able to select a suitable diluent or lubricant based on various handbooks, (e.g. D.E. Bugay and W.P. Findlay (Eds) Pharmaceutical Excipients (Marcel Dekker, New York, 1999), E-M Hoepfner, A. Reng and P. C. Schmidt (Eds) Fiedler Encyclopedia of Excipients for Pharmaceuticals. Cosmetics and Related Areas (Edition Cantor, Munich, 2002) and Η. P. Fielder (Ed) Lexikon der Hilfsstoffe fur Pharmazie. Kosmetik und angrenzende Gebiete (Edition Cantor Aulendorf, 1989)). The coating can comprise a diluent or lubricant at a concentration of from about 0.1% to about 2% (w/w). For example, the coating can comprise a diluents or a lubricant at a concentration of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9% or 2.0% (w/w). In some embodiments, the coating comprises a diluent or lubricant at a concentration of about 0.65% (w/w). In some embodiments, the diluents or lubricant is magnesium stearate or stearic acid.

In some embodiments, the solid pharmaceutical product is coated with a first and second enteric coating, wherein said first enteric coating material is selected from the group of: cellulose acetate, hydroxypropyl methylcellulose, polyvinylacetophthalate, cellulose acetate phthalate (CAP), ethylcellulose, dibutyl phthalate and diethyl phthalate, wherein said second coating is comprised of anionic polymers of methacrylic acid and methacrylate.

Coatings can be prepared by mlxmg together components as a solution and spraying or coating the solid formulation with the solution. As an exemplary embodiment for preparing a coating comprising a Eudragit® polymer, a coating solution can be prepared by mixing water and alcohol and slowing adding one or more Eudragit® polymers (e.g. Eudragit® FS, Eudragit® L30 D55, Eudragit® LI 00, etc.) and triethyl citrate to produce a solution (“Solution A”). In a separate receptacle, alcohol, talc and magnesium stearate can be mixed together. Once the solid formulation is ready for coating, the alcohol, talc and magnesium stearate mixture can be added to Solution A, and the resulting mixture can be continuously stirred or mixed until applied to the solid formulation. The mixture can be applied to the solid formulation by, for example, spraying, and the mixture can be applied with suitable parameters up to about a 10% - 20% weight gain. The alcohol and water are subsequently removed by a suitable drying process. A solid formulation as disclosed herein (e.g. tablets, capsules and pellets) can include one or more additional components that prolong the release of the active agent. Such delayed release agents are known in the art and can include, for example, gums such as guar gum. The desired content of such components (e.g. gums) in the solid formulation can readily be determined by those skilled in the art and can, for example, be in the range of from about 10% to about 70%, from about 15% to about 65%, from about 20% to about 60%, from about 25% to about 55%, from about 30% to about 50%, or from about 35% to about 45% by weight. In some embodiments, the content of such components in the solid formulation can be about 50% by weight. In some embodiments, the delayed release agents in the composition as disclosed herein is a Gelucire compositions. A Gelucire composition is an inert semi-solid waxy materials which is amphiphilic in character and is available with varying physical characteristics. Such agents can be identified by their melting point/ Hydrophile-Lipophile Balance (HLB) value. The melting point is expressed in degrees Celsius and the HLB value is a numerical scale extending from 0 to approximately 20. Lower HLB values are indicative of more lipophilic and hydrophobic substances, and higher values are indicative of more hydrophilic and lipophobic substances.

Gelucire compositions are generally considered to be fatty acid esters of glycerol and polyethylene glycol (PEG) esters or polyglycolised glycerides. The family of Gelucire compositions is characterized by a wide range of melting points. For example, a Gelucire composition can have a melting point of from about 33°C to about 64°C or from about 35°C to about 55°C. A Gelucire composition can have a variety of HLB values. For example, a Gelucire composition can have an HLB value ranging from about 1 to about 14 or from about 7 to about 14. For example, Gelucire 44114 designates a melting point of approximately 44°C and an HLB value of about 14. An appropriate choice of melting point/HLB value of a Gelucire or a mixture of Gelucire compositions can provide the desired delivery characteristics for sustained release and is within the skill of the artisan to select. In some embodiments, where a Gelucire composition is present in a composition as disclosed herein, the Gelucire composition is one selected from the group of: Gelucire 44/14, Gelucire 50/02, and a mixture thereof. In embodiments where a mixture of Gelucire compositions is present, the mixture can be present in a mixture ratio ranging from about 25:50 to 75:25 (w/w) of Gelucire 44/14 to Gelucire 50/02. In some embodiments, the mixture is present in a mixture ratio of about 50:50 (w/w) Gelucire 44/14 to Gelucire 50/02. In some embodiments, the mixture is present in a mixture ratio of about 75:25 (w/w) of Gelucire 44/14 and Gelucire 50/02.

In some embodiments, the composition or formulation as disclosed herein includes excipients which degrade at the target site of treatment or where diagnosis is to be performed (e.g. in the lower part of the gastrointestinal system). In this way, the active agent is delivered directly to the desired point of treatment or diagnosis. For example, the photosensitizing agent can be formulated with (e.g. embedded in) a matrix which degrades in the lower part of the gastrointestinal system. In some embodiments, the composition or formulation can be designed comprising enteric polymers that have a relatively high threshold pH for dissolution. Examples of suitable matrix-forming agents include carbohydrates, for example disaccharides, oligosaccharides and polysaccharides, and the like. Other suitable matrix materials include alginates, amylase, celluloses, xanthan gum, tragacanth gum, starch, pectins, dextran, cyclodextrins, lactose, maltose and chitosan, and the like.

It is desired to achieve a high and substantially homogeneous or uniform) concentration of active ingredient in the lower part of the gastrointestinal system. Accordingly, formulations and methods of administration can be used to achieve not only the desired prolonged or delayed release of the photosensitizing agent, but also a high and substantially homogeneous or uniform) concentration of 5-ALA or derivatives thereof in the lower part of the gastrointestinal system. When performing PDT or PDD, an objective is to cover the whole colon with the administered photosensitizing agent. By regulating the time and place of release of the active ingredient in the colon, and by choosing a suitable triglyceride/emulsifier combination, the desired uniform coverage can be achieved. Accordingly, in some embodiments, a dosage form or a dosage regime which comprises a plurality of individual doses (e.g. tablets, capsules or a mixture of pellets) is provided, wherein the dosage form or regime is capable of releasing the active component at different rates and/or at different time intervals following administration. The individual doses can be contained within a single dosage form; for example a plurality of pellets, tiny pills, granules or mini-tablets can be provided within a single tablet or capsule in which the individual pellets, pills, granules or mini-tablets are capable of providing different release profiles for the active photosensitizing agent. These are referred to as “multi-particulate systems.” In some embodiments, the dosage can comprise one or more single dose forms (e.g. one or more tablets or capsules) intended for separate or simultaneous administration in which the individual single dose forms differ in their release profiles. For example, for treatment of a patient, two or more different doses (e.g. capsules or tablets) containing the photosensitizing agent can be administered in which the two or more different doses have different release profiles. For example, in embodiments in which three different capsules are administered to a subject, the beginning, middle and end of the colon can be targeted with the three different capsules. Due to the peristaltic movement of the colon, the different doses can travel further down the colon before releasing their content, thereby allowing a uniform “coating” of the colon wall. In embodiments in which the clinical dose comprises more than one unit dose, different unit doses can be administered at the same time or at different time intervals.

The different release profiles (whether from individual particulates, e.g. pellets, within a single dosage form or from a plurality of single dose forms) can be achieved by any of the means previously described, for example, by altering the nature and/or concentration of any release agent, by providing a suitable coating, etc. In embodiments in which a coating is used, the nature of the coating material, its thickness and/or the concentration of the components within the coating can be varied as required to obtain the desired delayed release. Where the same coating material is used to coat a plurality of pellets, tablets or capsules, delayed release can be achieved by progressively increasing the concentration of the coating agent used to coat the individual doses. When coated pellets or granules are filled into a capsule or compressed together with excipients to form a tablet, the formulation is considered a multi-particulate dosage form. In such dosage forms, the tablets or capsules containing coated pellets or granules can be further coated with a suitable enteric coating, which can be the same or different to that used for coating of the pellets and granules.

In some embodiments, a combination of rapid and slow release agents can be used to provide the desired release profile. A suitable dosage regime can, for example, comprise administration of a plurality of capsules or tablets containing different release agents. For example, capsules containing Miglyol can be administered for relatively rapid release of the photosensitizing agent, while capsules containing Gelucire can be administered for a slower (delayed) release. Administration of a combination of these capsules can therefore be used to provide a more thorough coating of the entire colon mucosa.

Accordingly, embodiments are directed to an oral therapeutic or diagnostic dose of an active agent (e.g. hexaminolevulinate, or a pharmaceutically acceptable salt thereof) which comprises a plurality of tablets or capsules or a mixture of pellets comprising components that are degraded in the lower part of the gastrointestinal system in which the individual tablets, capsules or pellets are degraded with kinetic profiles whereby to secure a high and homogenous distribution of the active agent in the lower part of the gastrointestinal system. In some embodiments, the total dose can comprise several types of pellets in which the pellets degrade with different kinetic profiles. In some embodiments, the total dose comprising several types of pellets can be packaged in a single capsule. The various kinetic degradation profiles of the pellets can prolong release of the active agent. In some embodiments, the total dose can comprise several single dose forms (e.g. more than one tablet or capsule) wherein the single dose forms have different kinetic degradation profiles.

The oral dose formulation as disclosed herein can be provided in a pack which comprises a plurality of individual doses having different release profiles. Accordingly, embodiments are directed to a pack comprising a plurality of individual oral dose formulations, each comprising a photosensitizer agent (e.g. hexaminolevulinate, or a pharmaceutically active salt thereof) and each having a different kinetic release profile, is provided. In some embodiments, the individual doses can be color coded with different colors.

In some embodiments, the formulation comprises a tablet or capsule comprising minitablets which does not release active agent until at least about 5 to 10 minutes after reaching an environment of a pH above about 5.5 to 6.5. For example, the formulation may not release active agent until after at least about 5, 6, 7, 8, 9 or 10 minutes in an environmental pH of above about 5.5.

In some embodiments, the formulation comprises a tablet or capsule comprising minitablets which releases from about 40 % to 60% of active agent in about 50 to 65 minutes at a pH of above about 5.5 to 6.5. For example, the release may begin at a pH above 5.5 or above 6.5 or at any pH between 5.5 and 6.5. For example, the tablet or capsule can release about 40%, 45%, 50%, 55% or 60% of active agent in about 50, 55, 60 or 65 minutes. In some embodiments, the tablet or capsule can release about 50% of active agent in about 60 minutes.

In some embodiments, the formulation comprises a tablet or capsule comprising minitablets which releases from about 40 % to 60% of active agent in about 60 to 90 minutes at a pH of above about 5.5 to 6.5. For example, the release may begin at a pH above 5.5 or above 6.5 or at any pH between 5.5 and 6.5. For example, the tablet or capsule can release about 40%, 45%, 50%, 55% or 60% of active agent in about 60, 65, 70, 75, 80, 85 or 90 minutes. In some embodiments, the tablet or capsule can release about 50% of active agent in about 75 minutes.

In some embodiments, the formulation comprises a tablet or capsule comprising minitablets which releases from about 80% to 100% of active agent in about 270 minutes at a pH of above about 5.5 to 6.5. For example, the release may begin at a pH above 5.5 or above 6.5 or at any pH between 5.5 and 6.5. For example, the tablet or capsule can release about 80%, 85%, 90%, 95% or 100% of active agent in about 270 minutes. In some embodiments, the tablet or capsule releases from about 90 to 100% of active agent in about 270 minutes.

In some embodiments, the formulation comprises a tablet or capsule comprising minitablets which releases from about 95% to 100% of active agent in under about 240 to 270 minutes in an environmental pH of above about 5.5 to 6.5. For example, the tablet or capsule can release about 95%, 96%, 97%, 98%, 99% or 100% of active agent in under about 240, 250, 260 or 270 minutes. In some embodiments, the tablet or capsule releases from about 98% in under about 270 minutes.

Coated mini tablets may be encapsulated using an appropriate capsule encapsulating machine. Capsule sizes will vary depending on the dose and may be, for example, HPMC plus or hard gelatin capsules. In some embodiments, each capsule contains 100 mg HAL. In some embodiments, each capsule contains 50 mg HAL. In some embodiments, each capsule is filled with 50 mini-tablets per capsule. In some embodiments, each capsule is filled with 25 minitablets per capsule.

Other pharmaceutical product embodiments contemplated for use are described m, for example, International Patent Publication No. WO 2010/142456, which is incorporated herein by reference in its entirety.

Methods of manufacture

The pharmaceutical products disclosed herein can be made by methods of manufacture known in the art. In some embodiments, the product is a mini-tablet, and the mini-tablet can be made by a dry-blending process. In some embodiments, the product is a mini-tablet made by a roller compaction process. Subsequent to the dry- blending or roller compaction process, the blend can be pressed into mini-tablet form with the aid of tableting tools.

In some embodiments, the product is coated with an enteric coating as disclosed herein. The enteric coating can be applied by any means known in the art. For example, the enteric coating can be prepared as a solution and spray-dried onto the product. In some embodiments, the product can be submerged in an enteric coating solution and air- or vacuum-dried.

In some embodiments, the methods of manufacture are carried out at a relative humidity of between about 5% and 50%. For example, the methods of manufacture can be carried out at about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% relative humidity. In some embodiments, the conditions of relative humidity vary between about 5% to about 50% during the process, depending on the parameters of the process steps. In some embodiments, the methods of manufacture are carried out at a relative humidity of below about 40%.

Shelf Life/Storage Conditions

Embodiments as disclosed herein are not prone to degradation and/or composition. Accordingly, in some embodiments, the pharmaceutical product can be stored, e.g. at room temperature and humidity, for at least about 6 months, for at least about 12 months, for at least about 24 months or more (e.g. up to about 36 months). In some embodiments, the pharmaceutical product can be stored at between about 2°C to 8°C for about four months. In some embodiments, the pharmaceutical product can be stored at between about 2°C to 8°C for at least about four months, for at least about six months, for at least about 12 months, for at least about 24 months or longer (e.g. up to about 36 months).

Routes of Administration

The pharmaceutical products as disclosed herein can be administered orally or by insertion into the rectum. The selected route of administration will depend on a number of factors including the severity and nature of the cancer, pre-cancerous lesion or non- cancerous condition to be diagnosed, the location of thereof and the nature of the active ingredient.

In some embodiments, a solid pharmaceutical product as disclosed herein is administered orally or topically (e.g. by insertion into the vagina or rectum). The route of administration will depend on a number of factors including the severity and nature of the condition to be treated or diagnosed, the location of the afflicted body part and the nature of the photosensitizer. In embodiments in which oral administration is selected, the pharmaceutical product can be in the form of a tablet or as powder, granules or pellets contained in a capsule (e.g. a tablet). In embodiments in which topical application is selected, the pharmaceutical product can be in the form of a suppository or pessary.

Photodynamic diagnosis (PDD) of cancer, pre-cancerous and non-cancerous conditions in the lower part of the gastrointestinal system can be carried out by endoscopic examination of the lower gastrointestinal tract, e.g. the colon and the distal part of the small bowel with a camera on a flexible tube passed through the anus of a human or non-human animal subject undergoing the endoscopic examination. Apart from diagnosis, endoscopic examination of the region also provides the opportunity for biopsy or removal of suspected lesions or polyps.

For optimal results, it is desirable for the colon to be free of solid matter for the PDD to be performed properly. In some embodiments, for one to three days, the subject to undergo PDD can be advised to follow a low fiber or clear-fluid only diet. The day prior to PDD, the bowels can be cleaned out (“bowel preparation” or “bowel prep”). Various bowel prep agents are available in solution or in tablet from. Bowel prep tablets contain compounds such as, for example, bisacodyl, and bowel prep solutions contain compounds such as, for example, L-sugars, sodium phosphate or polyethylene glycol and electrolytes. In an exemplary regime for a colonoscopy, the amount of bowel prep solution to be ingested is about 4 liters.

On the day of the PDD, an oral solid pharmaceutical product as disclosed herein can be ingested according to a prescribed dosage regime, e.g. in single dose of one unit or a single dose of several units or in multiple doses. In some embodiments, the product is ingested between about 4 to about 12 hours prior to endoscopic examination. In some embodiments, the subject to which the product is administered is allowed to drink fluid. In embodiments in which the product is a suppository, the suppository can be placed at the site of examination. In embodiments in which an examination of the whole lower gastrointestinal tract is carried out, the suppository can be placed at the distal colon, e.g. cecum.

In addition, on the day of the PDD, a purgative or bowel preparation can be administered to the subject between about 30 minutes to 2 hours prior to administration of the oral solid pharmaceutical product on the day of the PDD. Suitable purgatives or bowel preparations are disclosed supra.

In some embodiments and to facilitate distribution of the active ingredient in the pharmaceutical product to the entire lower gastrointestinal tract, the subject can be administered a “booster” of fluid. In some embodiments, the booster of fluid comprises a bowel prep solution. The amount of booster can range from between about 50 mL to about 750 mL. For example, the amount of booster can be about 50 mL, 75 mL, 100 mL, 150 mL, 200 mL, 250 mL, 275 mL, 300 mL, 325 mL, 350 mL. 375 mL. 400 mL. 425 mL, 450 mL, 475 mL, 500 mL, 525 mL, 550 mL, 575 mL, 600 mL, 625 mL, 650 mL, 675 mL, 700 mL, 725 mL or about 750 mL. In some embodiments, the amount of booster is about 500 mL. In some embodiments, the amount of booster is about 250 mL. The booster can be ingested at about 15 min to about 90 min after the ingestion of the pharmaceutical product. In some embodiments, the booster can be ingested at about 30 min to about 60 min after the ingestion of the pharmaceutical product. For example, the booster can be ingested at about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90 minutes or in any intervening amount of time after the ingestion of the pharmaceutical product. In some embodiments, a second booster of fluid can be administered to the patient at about 120 min to about 150 min after the ingestion of the pharmaceutical product. For example, the second booster can be administered at about 120, 125, 130, 135, 140, 145 or 150 minutes or in any intervening amount of time after the ingestion of the pharmaceutical product. In some embodiments, the second booster of fluid is a bowel prep solution. The uniform distribution of the active ingredient can further be promoted by having the subject move or roll from one side to another, e.g. lying 10 min on the right side, rolling to the back and lying 10 min on the back, rolling to the left side and lying 10 min on the left side.

After administration of the pharmaceutical product containing the photosensitizer(s), the site to be treated or diagnosed can be exposed to light to achieve a desired photosensitizing effect. The time period between administration and endoscopic examination including photoactivation (i.e. exposure of the site of examination to light) will depend on the nature of the pharmaceutical product, its form and the nature of the active ingredient. It is desirable that the active ingredient within said pharmaceutical product is converted into a photosensitizer and achieves an effective tissue concentration at the site of the examination prior to photoactivation. The amount of time between administration of the product and subsequent exposure of the target tissue or organ to light can range from about 0.5 hour to about 24 hours, from about 1 hour to about 18 hours, from about 2 hours to about 12 hours, or from about 3 hours to about 6 hours. In some embodiments, the amount of time between administration of the product and exposure to light is from about 1 hour to about 3 hours.

In some embodiments, a photosensitizer is applied to the affected or target site followed by irradiation after a period of time. In some embodiments, this procedure can be repeated from about 1 time to about 3 times, at intervals ranging from about 1 day to about 30 days. For example, the procedure can be repeated from 1 to 3 times at an interval of about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days or about 30 days, In embodiments in which additional treatment is contemplated, an additional treatment can be performed several months later, for example about 2 months later, about 3 months later, about 4 months later, about 5 months later, about 6 months later, about 7 months later, about 8 months later, about 9 months later, about 10 months later, about 11 months later, or about 12 months later.

In some embodiments, the diagnostic methods described herein can also be performed during surgery in which the diagnostic agent is given to the patient and surgery is performed under blue light. The lesion or disease fluoresce under blue light can aid the surgeon in defining the “surgical border” and can facilitate a more selective resection of the diseased area (e.g. tumor) to be performed. The diagnostic methods can comprise use of the photosensitizing agents as disclosed herein.

For therapeutic (e.g. PDT) purposes, methods for irradiation of different areas of the body, e.g. by lamps or lasers are well known in the art (see for example Van den Bergh, Chemistry in Britain, May 1986 p. 430-439). The wavelength of light used for irradiation can be selected to achieve an efficacious photosensitizing effect. An effective light is light in the wavelength range of from about 300nm to about 800 nm, or from about 400nm to about 700 nm, where the penetration of the light is found to be relatively deep. For example, the light wavelength can be about 300 nm, about 325 nm, about 350 nm, about 375 nm, about 400 nm, about 425 nm, about 450 nm, about 475 nm, about 500 nm, about 525 nm, about 550 nm, about 575 nm, about 600 nm, about 625 nm, about 650 nm, about 675 nm, about 700 nm, about 725 nm, about 750 nm, about 775 nm, or about 800 nm. The irradiation can be applied at a dose level of from about 10 Joules/cm2 to about 100 Joules/cm2 with an intensity of from about 20 mW/cm2 to about 200 mW/cm2 when a laser is used or a dose of from about 10 J/cm2 to about 100 J/cm2 with an intensity of about 50 mW/cm to about 150 mW/cm when a lamp is applied. Irradiation can be performed for a duration of from about 5 minutes to about 30 minutes. For example, irradiation can be performed for a duration of about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, or about 30 minutes. In some embodiments, irradiation is performed for about 15 minutes. In some embodiments, a single irradiation is used. In some embodiments, a light split dose in which the light dose is delivered in a number of fractions is used. In embodiments when a light split dose is employed, the light dose can be delivered at intervals ranging from, for example, . a few minutes to a few hours between irradiations. In some embodiments, multiple irradiations can be applied.

For diagnostic (e.g. PDD) use, the area to be examined can first be inspected using blue light, followed optionally by inspection by white light. The area may also be examined first with white light (or other light) followed by blue light. The area may also be inspected alternating blue and white light or other light source. Exposure to blue light can employ light ranging at a wavelength of from about 380 nm to about 450 nm. For example, the affected areas can be exposed to blue light at a wavelength of about 400 nm, about 405 nm, about 410 nm, about 415 nm, about 420 nm, about 425 nm, about 430 nm, about 435 nm, about 440 nm, about 445 nm or about 450 nm. The irradiation can be applied at a dose level of from about 10 Joules/cm2 to about 100 Joules/cm2 with an intensity of from about 20 mW/cm2 to about 200 mW/cm2 when a laser is used or a dose of from about 10 J/cm2 to about 100 J/cm2 with an intensity of about 50 mW/cm to about 150 mW/cm when a lamp is applied. The emitted fluorescence (about 635 nm) can then used to selectively detect affected tissue. Suitable endoscopes, e.g. colonoscopies, include state-of-the-art colonoscopes which are adapted to allow emission of such blue light in addition to white light, e.g. by being equipped with an internal filter assembly which passes primarily blue light. For example, a foot pedal can allow convenient switching between white and blue light. The light source can be a laser or a lamp. To visualize fluorescence, the colonoscope can be equipped with an integrated filter which blocks most of the reflected blue light. A camera-like a modified color charge-coupled device (CCD) camera can be used to capture images of the lower gastrointestinal tract and a standard color monitor can be used to display images of the lower gastrointestinal tract. Irradiation can be performed for a duration of from about 5 minutes to about 30 minutes. For example, irradiation can be performed for a duration of about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, or about 30 minutes. In some embodiments, a single irradiation is used. In some embodiments, a light split dose in which the light dose is delivered in a number of fractions is used. In embodiments when a light split dose is employed, the light dose can be delivered at intervals ranging from, for example, . a few minutes to a few hours between irradiations. In some embodiments, multiple irradiations can be applied. The area of examination can further be inspected by use of white light, e.g. before, during or after irradiation with blue light. Polyps, cancerous tissue or pre-cancerous lesions identified due to its fluorescence may be removed during irradiation or in white light.

Conditions to be Treated or Diagnosed

The abnormalities and disorders which can be treated with the compositions and methods as disclosed herein include any malignant, pre-malignant and non-malignant abnormalities or disorders responsive to photochemotherapy, e.g. tumors or other growths, skin disorders such as psoriasis or actinic keratoses, skin abrasions, and other diseases or infections, e.g. bacterial, viral or fungal infections, and the like. In some embodiments, methods and compositions as disclosed herein can be used in the treatment of diseases, disorders or abnormalities where discrete lesions are formed to which the compositions is directly applied. For example, lesions, including tumors and the like, can be treated with the compositions and methods as disclosed herein.

The internal and external body surfaces which can be treated include the skin and all other epithelial and serosal surfaces, including, for example, mucosa, the linings of organs, e.g. the respiratory, gastro-intestinal and genito-urinary tracts, and glands with ducts which empty onto such surfaces (e.g. liver, hair follicles with sebaceous glands, mammary glands, salivary glands and seminal vesicles). In addition to the skin, such surfaces include, for example, the lining of the vagina, the endometrium and the urothelium. Such surfaces can also include cavities formed in the body following excision of diseased or cancerous tissue, e.g. brain cavities following the excision of tumors such as gliomas. Exemplary surfaces include: (i) the skin and conjunctiva, (ii) the lining of the mouth, pharynx, esophagus, stomach and intestines as well as the lining of intestinal appendages, rectum, and anal canal, (iii) the lining of the nasal passages, nasal sinuses, nasopharynx, trachea, bronchi, and bronchioles, (iv) the lining of the ureters, urinary bladder, and urethra, (v) the lining of the vagina, uterine cervix, and uterus, (vi) the parietal and visceral pleura, (vii) the lining of the peritoneal and pelvic cavities, and the surface of the organs contained within those cavities, (viii) the dura mater and meninges, (ix) any tumors in solid tissues that can be made accessible to photoactivating light.

The methods and compositions as disclosed herein can be used to treat and/or diagnose a pre-cancerous condition, a cancer or an infection associated with a cancer. A “pre-cancerous condition” encompasses a disease, syndrome, or finding that, if left untreated, can lead to cancer. It can be a generalized state associated with a significantly increased risk of cancer. For example, a pre-cancerous condition can manifest itself by extensive/abnormal proliferation of cells, such as, for example, hyperplasia and neoplasia. The term “infection associated with cancer” encompasses any infection that is positively correlated with the development of cancer. An example of such an infection is human papillomavirus (HPV) infections.

Cancers and infections associated with cancer that can be treated and/or diagnosed can be present in any part of the body (e.g. skin, mouth, throat, esophagus, stomach, intestines, rectum, anal canal, nasopharynx, trachea, bronchi, bronchioles, urethra, urinary bladder, ovary, urethra, vagina, cervix, uterus etc).

Accordingly, the methods and compositions as disclosed herein can be used in the treatment and diagnosis of cancer of the uterus, cervix, vagina, rectum and colon. In some embodiments, the methods and uses as disclosed herein are used for the treatment or diagnosis of cervical cancer and colon cancer.

In some embodiments, a method of treating or diagnosing a condition in the colon is provided, the method comprising administering an enterosoluble capsule containing a photosensitizing agent to the colon. In some embodiments, the condition in the colon is colon cancer. In some embodiments, the photosensitizing agent is a 5-ALA derivative as disclosed herein. For example, the photosensitizing agent can be the hexyl ester of 5- ALA).

In some embodiments, a method of treating or diagnosing a condition in a subject is provided, the method comprising administering a composition as disclosed herein to a subject in need thereof, wherein the condition is irritable bowel syndrome (IBS), colorectal cancer, stomach cancer, esophageal cancer, diverticular disease, infectious colitis, ulcerative colitis, Crohn’s disease; ischemic colitis, radiation colitis, esophagitis, inflammatory bowel disease, small intestinal bacterial overgrowth, chronic pancreatitis, pancreatic insufficiency, hepatic encephalopathy, diarrhea, constipation, gastrointestinal motility disorders, gastroesophageal reflux disease (GERD), gastroparesis, chronic intestinal pseudo-obstruction (Ogilvie’s syndrome), colonic pseudo-obstruction, functional heartburn, post-operative ileus, hypertrophic pyloric stenosis, dyspepsia (including functional dyspepsia or nonulcer dyspepsia), gastrointestinal damage, anal fissure, achlorhydria, achalasia, hemorrhoids, intestinal polyps, gastrointestinal tract cancer, pancreatic cancer, prostatic cancer, gastrointestinal tract inflammation, and/or a bacterial infection. In some embodiments, the bacterial infection is caused by one or more of: H. pylori, C. jejuni, Salmonella, and Shigella.

In some embodiments, a method of treating cervical cancer is provided, the method comprising administration of a suppository containing a photosensitizer to the cervix. In some embodiments, the photosensitizer is a 5-ALA derivative as disclosed herein. For example, the photosensitizer can be the hexyl ester of 5-ALA.

The methods and compositions as disclosed herein can also be used to treat a non-cancerous condition. A “non-cancerous condition” includes, but is not limited to, disease conditions such as, for example, colitis, Crohn’s disease, irritable bowel disease and other viral, bacterial or fungal infections or inflammation located in the lower gastrointestinal tract.

Embodiments are also directed to the use of a photosensitizer which is 5-ALA or a precursor or derivative thereof (e.g. an ALA ester), in the manufacture of a pharmaceutical product for use in the photodynamic treatment or diagnosis, e.g., of a cancer, an infection associated with a cancer, or in the treatment or diagnosis of a non- cancerous condition, wherein said pharmaceutical product is in the form of a solid. In some embodiments, the product is for use in the photodynamic treatment or diagnosis of a cancerous or non-cancerous condition in the lower part of the gastrointestinal system or in the female reproductive system.

Doses can range from about 25 mg to about 500 mg of pharmaceutical product per administration. For example, the amount of pharmaceutical product that can be administered to a subject in need thereof can be about 25, 30, 35, 40, 45, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475 or 500 mg, or any number in between.

Combination Therapies

The therapeutic and diagnostic methods as disclosed herein can also be used in the form of a combined therapy. For example, a course of PDT performed in relation to a cancerous or non-cancerous condition using any of the methods as disclosed herein can be followed by a PDD method (e.g. to determine the extent to which PDT has been effective and/or to detect any reoccurrence of the condition).

Accordingly, methods of administering a combined therapy to a subject in need thereof are provided, the methods comprising: (i) conducting a photodynamic treatment of a cancer or a non-cancerous condition in the lower part of the gastrointestinal system or in the female reproductive system of said subject; and (ii) conducting photodynamic diagnosis on said subject, wherein at least one of steps (i) and (ii) is performed following administration to said patient of a photosensitizer which is 5-ALA or a precursor or derivative thereof (e.g. an ALA ester). In some embodiments, the methods comprise steps (i) and (ii) being administered following administration of said photosensitizer.

Embodiments are also directed to a method of photodynamic treatment or diagnosis of a cancer, an infection associated with cancer, or a non-cancerous condition in a subject in need thereof, said method comprising the steps of: (a) administering to said subject a pharmaceutical product comprising a photosensitizer as disclosed herein; (b) optionally waiting for a time period necessary for the photosensitizer to achieve an effective tissue concentration at the desired site; and (c) photoactivating the photosensitizer.

Embodiments also relate to a method of diagnosing cancer, an infection associated with cancer, or a non-cancerous condition in an animal, wherein said animal is pre-administered a pharmaceutical product comprising a photosensitizer as disclosed herein, said method comprising: (i) optionally waiting for a time period necessary for the photosensitizer to achieve an effective tissue concentration at the desired site; and (ii) photoactivating the photosensitizer.

EXAMPLES

It will be appreciated that the invention should not be construed to be limited to the examples, which are now described; rather, the invention is construed to include any and all applications provided herein and all equivalent variations within the skill of the ordinary artisan. EXAMPLE 1 PRE-CLINICAL STUDIES OF ADMINISTRATION OF 11 EXAM INOL EVU LI NAT E (HAL)

In a preclinical single-dose toxicology study, no adverse effects were observed in rats at or below intravenous infusion doses of 400 mg/kg. In a 14-day preclinical repeat-dose toxicology study, no adverse effects were observed following intravenous infusion doses of up to 15 mg/kg/day in the rat; no higher doses were tested in that study. In a 28- day repeat dose study, 25 mg/kg/day and lower doses resulted in no adverse effects in rats. In dogs, HAL HC1 intravenous doses of 25 mg/kg/day for 14 days resulted in increases in ALT (with no structural changes in the liver), along with reduced food consumption and, in females, reduced body weight. No changes in macroscopic or microscopic tissue examinations, organ weights, electrocardiography, hematology, urinalysis, or ophthalmoscopy findings were observed at any dose. The preclinical data as well as the safety profiles in human subjects receiving single enema doses of 200 mg of HAL HC1 (Example 4) or oral doses of up to 400 mg (Example 5) support the use of single enema doses up to 400 mg in a study described below (Example 6). EXAMPLE 2

A PHARMACOKINETIC STUDY OF ADMINISTRATION OF HEXAMINOLEVTTLINATE (HAL) IN HEALTHY SUBJECTS A pharmacokinetics study was performed in healthy female subjects. In the study, the plasma concentration of radioactivity increased rapidly after administration of HAL via intravenous (i.v., 1-hour infusion) and rectal (enema) administration routes, and the maximum mean plasma concentrations of ^C-radioactivity after rectal administration were reached approximately 1 hour post dosing. Systemic exposure to * ^C-radioactivity after rectal (enema) HAL administration was approximately 90% compared to i.v. administration. Single doses of HAL HC1 0.4 mg/kg administered by i.v. infusion and 100 mg administered by rectal enema were found to be safe and well tolerated in the group of healthy female subjects. EXAMPLE 3

A PILOT CLINICAL STUDY OF ADMINISTRATION OF HEXAMINOLEVULINATE (HAL) IN PATIENTS WITH RECTAL CANCER A pilot clinical study in patients with rectal cancer was performed with local administration of HAL to investigate the feasibility of a fluorescence colonoscopy procedure as described m Endlicher et al. (Endlicher, E. et al. 2004. “Hexaminolevulinate-induced fluorescence endoscopy in patients with rectal adenoma and cancer: A pilot study.” Gastrointestinal Endoscopy; 60(3):449-54, which is incorporated herein by reference in its entirety). Ten patients received a 250 mL HAL HC1 3.2 mM enema (200 mg P-1206) and colonoscopy was performed 30-60 minutes following expulsion of the enema using white and blue light inspection of the rectum. Patients were checked for vital signs, blood biochemistry and skin sensitivity, and reported adverse events. Rectal adenomas showed selective tumor fluorescence, and no adverse events related to HAL were reported. EXAMPLE 4

A DOSE-EXPLORING STUDY OF ADMINISTRATION OF HEXAMINOLEVULINATE (HAL) IN PATIENTS SUSPECTED OF HAVING COLORECTAL CANCER

In a dose-exploring study, HAL HC1 (200 mg) was administered as an enema of different concentrations (0.8-3.2 mM) to 35 patients with suspicion of colorectal cancer. The patients were examined with colonoscopy in both blue and white light at different times after different HAL incubation times, and no local or systemic adverse reactions were reported. Three additional patients received HAL as an oral formulation, but no colonic fluorescence was detected. The optimal fluorescence intensity ratio between lesion and normal tissue was obtained after administration of 1.6 mM HAL HC1 as an enema over a period of 30 minutes and expulsion of the enema, followed by 60 minutes of wait time. The efficacy data showed that administration of a 1.6 mM (200 mg in 500 mL) enema solution used in combination with fluorescence colonoscopy increased the detection rate of dysplastic adenomas and carcinomas in patients with known or highly suspected colorectal cancer, compared to standard white-light colonoscopy. Using blue light, 94 lesions were identified and later confirmed by histological examination to be adenomas, as compared to 57 confirmed lesions identified by white light. Thus, 37% of the lesions found in blue light were not seen by white light colonoscopy. A total of 26 adverse events (AEs) were reported in the study. The most common of these were gastrointestinal disorders (n=7) and AEs associated with injury, poisoning and procedural complications (n=6). Three adverse events were characterized as serious (SAEs) by the Investigator, but none of these was considered to be related to the study drug. A total of four patients experienced AEs that were considered to be of uncertain relationship to the study drug; these were three patients with abnormal bilirubin levels at visit 2 and one patient with abnormal WBC count at visit 2. Of the 26 AEs registered, 23 AEs were mild in intensity, while three were of moderate intensity. EXAMPLE 5

A FEASIBILITY STUDY OF FLUORESCENCE IMAGING USING ORALLY ADMINISTERED HEXAMTNOLEVTTLTNATE (HAL) IN PATIENTS SUSPECTED OR AT HIGH RISK OF NEOPLASIA IN THE COLON A clinical study was performed to investigate the feasibility of fluorescence imaging using oral administrated hexaminolevulinate (HAL) to detect adenomas and carcinomas in patients with suspicion or high risk of neoplasia in the colon. This study used different formulations than the 3-patient arm in the local administration dose- exploring study.

This study was an open, dose-finding study of fluorescence colonoscopy with two different capsule formulations, one immediate release and the other sustained release, to optimize the dosing of HAL for fluorescence colonoscopy. The study consisted of two phases: an open-label dose-finding phase followed by a fixed dose phase. After standard bowel cleansing, the patients ingested anywhere from one to four 100 mg HAL HC1 capsules at 6, 7 or 8 hours before colonoscopy using white light then blue light. Three patients at each dose level were tested.

According to the protocol, an additional 32 patients were planned to be tested at the optimal dose, which is selected based on safety and efficacy criteria.

Table 1 summarizes the subject population and the doses that have been administered: Table 1: Summary of Study Subject Population and Dose Administration

The mean fluorescence intensity of the adenomas detected with blue light was 2, on a scale of 1-5, for all treatments. Similar results were observed when the lesions were divided into polypoid and flat. Due to the low number of hyperplastic/inflammatory and other lesions, no comparisons could be made. Blue light colonoscopy did not contribute in a significant extent to an increase in the lesion detection rate, since most of the samples detected in blue light were also detected in white light. Most of the lesions detected with blue light were detected in sigmoid/rectum and cecum/ascending colon. The fluorescence intensity of the lesions was independent of the location of the lesions within the colon. A total of 5 adverse events (AEs) were registered during the study with one AE occurring at doses of 200 mg and 300 mg immediate and sustained release, as well as one AE occurring at a dose of 400 mg immediate release. One AE was characterized as serious, a case of large intestine perforation, however, it was determined by the investigator to not be drug-related. One AE was characterized as severe, and four were characterized as mild in severity. Two patients experienced AEs that were evaluated by the investigators to have an uncertain relationship with the investigational product; one case of increased blood bilirubin (increased blood bilirubin, 200 mg HAL: 2.0 mg/dl before HAL administration, 2.7 mg/dl after HAL administration), and one

case of allergic dermatitis (face and upper chest, occurring 3.5 days after HAL administration). The other AEs were considered to be unrelated to the investigational product. All AEs resolved by the end of the study. None of the patients was withdrawn from the study due to adverse events.

The study was terminated after 13 subjects had been included because satisfactory fluorescence was not observed after administration of either capsule formulation. Hence, the efficacy data are not adequate to draw firm conclusions. EXAMPLE 6

EVALUATION OF GASTROINTESTINALLY ADMINISTERED HEX AMIN OLE VULINATE (HAL) IN PATIENTS WITH A HIGH RISK OF

COLON CANCER

To evaluate the safety and tolerability of hexaminolevulinate (HAL) in subjects with a high risk of colon cancer, an open-label, multi-center trial is conducted. The study can also be used to compare the rates of detection of polypoid lesions of the colon by white versus blue light colonoscopy at various doses of HAL and times after HAL administration. In addition, the study can be used to evaluate the fluorescence duration and intensity in background tissue and polypoid colonic lesions following HAL administration in subjects with a high risk of colon cancer at various doses of HAL and times after HAL administration.

The study is designed for a population of about 60 subjects at approximately three different centers. Subjects are administered hexaminolevulinate hydrochloride (HAL HC1) as an enema in amounts ranging from 200 mg to 400 mg in a 500-mL volume of sterile phosphate-buffered saline (PBS).

Subject Qualification Criteria A subject is considered to be at a high risk of colon cancer if s/he has at least one of the following qualifications: • A close relative (sibling, parent, or child) who has had colorectal cancer or an adenomatous polyp; • A family history of familial adenomatous polyposis; • A family history of hereditary nonpolyposis colorectal cancer; • A personal history of adenomatous polyps; • A personal history of colorectal cancer; • Recent identification (within the previous 12 months) of one or more flat or sessile polypoid lesions of the colon.

Inclusion Criteria

At a screening visit prior to treatment, subjects are screened for the following inclusion criteria: • Male and non-pregnant, non-lactating females > 18 years; • Satisfaction of a qualification criteria as defined above.

Exclusion Criteria A subject can be excluded from the study if s/he has any of the following exclusion criteria: • A medical, surgical, or psychiatric condition that, in the opinion of the Investigator, can interfere with study participation; • An allergy or hypersensitivity to hexaminolevulinate, methyl aminolevulinate, 5-aminolevulinate (ALA) or any aminolevulinate derivative, or any sedative used for colonoscopy if a sedative is used; • A known hypersensitivity to any of the components of the polyethylene glycol-based bowel preparation agent; • Known gastrointestinal obstruction, gastric retention, bowel perforation, toxic colitis, toxic megacolon or ileus; • Known or suspected porphyria; • Cirrhosis or other hepatic impairment, acute or chronic hepatitis, significant renal impairment, or pregnancy; • A positive test for erythema after photosensitivity testing at Screening; • Known concurrent administration of a systemic anticoagulant therapy, including daily aspirin doses >150 mg, or a known bleeding risk from polypectomy in the opinion of the Investigator PDD System and Equipment A PDD system was developed enabling white and blue light modes for diagnosis (D-light C; Karl Storz GmbH, Germany), a PDD videocolonoscope (Karl Storz) as well as a standard pump for gastroenterology (Duomat, Karl Storz). The D-light C light source connects to the videocolonoscope and provides standard white light as well as blue light illumination during the examination. The light source is also connected to the camera system by an accessory cable. The camera controller on the colonoscope is connected to a monitor to observe the colonoscopy. A flexible videoendoscope for photodynamic diagnosis is used in this study. With the exception of the filters that allow blue light illumination and fluorescence visualization, the device has the same specifications as a standard videocolonoscope. PDD-Videocolonoscope 13902 PKS (KARL STORZ)

Channel: 3.8 mm

Working length: 140 cm

Diameter: 13 mm

Deflection: 180° up, 160° down 160° left, 160° right

Image sensor: PAL-format PDD- light source (KARL STORZ) D-light/C 20133620-1 with light adapter 487 VE with a blue light excitation range: 390-430 mm

Formulation and Supply

Each vial of Hexaminolevulinate (HAL) HC1 100 mg powder corresponds to 85 mg of the active moiety HAL. The powder is white to slightly yellow, and contains no excipients.

To prepare the HAL enema (500 mL), the appropriate number of vials of HAL HC1 powder is reconstituted with vials of Sterile Phosphate Buffered Saline to prepare a 500 mL enema solution containing 200 mg, 300 mg, or 400 mg HAL HC1 (1.6 mM, 2.4 mM, or 3.2 mM of the active moiety, respectively). The pH of the enema is 5.7- 6.2. If not used immediately, the reconstituted product is stored at 2°C - 8°C and used within 2 hours of reconstitution. HAL HC1 100 mg powder and Sterile Phosphate Buffered Saline, pH 6, are manufactured according to the principles of Good Manufacturing Practice (GMP).

All study drug is kept in a locked area with limited access. The HAL HC1 100 mg powder and 50 mL Sterile Phosphate Buffered Saline, pH 6 are maintained under room temperature conditions prior to reconstitution and at 2°C - 8°C after reconstitution for up to 2 hours.

Screening (Day -21 to Day 1. Visit 11

Screening at Visit 1 is performed to inform the patient about the study, and check eligibility for participation. No treatment or study related procedures are initiated before signed consent is given.

The following are completed during the Screening Phase (period between signing informed consent and Treatment Day 1), before the subject receives their first dose of study drug: • Obtain written informed consent; • Review and record medical history; • Obtain demographic information (date of birth, sex, ethnicity, and race);

• Perform testing for human immunodeficiency virus (HIV), hepatitis B surface antigen, and hepatitis C virus; • Perform ECG assessment; • Perform vital sign assessments (sitting blood pressure, heart rate, oral temperature, height, and weight - height and weight are used to calculate BMI); • Perform complete physical examination; • Review and record concomitant medications; • Assign subject identification number; • Collect blood and urine for clinical laboratory tests (e.g., serum pregnancy test, hematology, blood chemistry, and urinalysis). Clinical laboratory results are reviewed prior to Treatment Day 1. Clinically significant laboratory test are repeated as necessary prior to initiation of study drug. • Drug screen; • Perform skin photosensitivity testing; • Instruct the subject on proper bowel preparation to begin 6 to 8 hours prior to Treatment Day 1. Schedule the Visit 2 colonoscopy procedure allowing enough time for the subject to complete colon emptying prior to arrival.

Administration/PDD Protocol (Visit 2)

Following successful completion of the Screening Phase, patients continue to Visit 2. Visit 2 takes place within 3 weeks of Visit 1.

The following additional examinations (from Visit 1) and procedures are performed at Visit 2 prior to the colonoscopy (Baseline): • Confirm start and stop date and time of bowel preparation • Assess and record all Non-Treatment Emergent Adverse Event adverse events (NTEAEs) • Review and record concomitant medication (if changed since Visit 1) • Collect blood and urine for clinical laboratory tests (e.g., urine pregnancy test, hematology, blood chemistry, and urinalysis). • Perform vital sign assessments (sitting blood pressure, heart rate, oral temperature) • Perform ECG assessment • Perform skin photosensitivity testing • Perform symptom-directed physical exam (if applicable)

Subjects undergo bowel preparation using a polyethylene glycol-based agent administered in split dosing the day before and the morning of the study. An exemplary bowel preparation procedure is as follows:

Colon Preparation Bowel Prep - Oralav®

The flushing volume required for intestinal cleansing can amount to 3 to 5 liters. Oralav® drink solution is drunk until clear fluid starts to be excreted from the intestine.

The intake rate is about 1 to 1.5 liters per hour, which means that the patient drinks one glass containing Ά liter of the intestinal cleansing solution every 10 to 15 minutes quickly.

Oralav® drink solution is more pleasant to drink when it is cooled (not cold). The patient fasts for 3 to 4 hours prior to the beginning of the intake of Delcoprep © drinking solution. The patient does not eat solid food in the last 2 hours prior to the beginning of the intestinal cleansing. The duration of use depends on the requirements for sufficient cleansing of the intestine, until the rectal discharge is clear.

The intestinal cleansing can be conducted on the evening before (in the case of surgery) or on the day of the diagnostic measure. When the intestinal cleansing with Oralav® drink solution is done on the day of the diagnostic measure, at least one hour passes between the end of the intake of Oralav® drink solution and the beginning of the measure, to ensure a sufficient discharge of the intestine.

After the intestinal cleansing with Oralav® drink solution, the patient fasts until the beginning of the measure. If needed, clear fluid may be drunk.

Colon Preparation Bowel Prep - Prep a col

Prepacol is intended for single-use and is used only after a medical examination. 2 days prior to the examination: • Not permitted: flatulent foods and beverages, like bread, vegetables, legumes, fat-laden food, milk, fruits and fruit juices plus carbonated beverages. • Permitted: Slightly sweetened coffee or tea, biscuit, eggs, lean ham and non-carbonated soda. 1 day prior to the examination: • In addition to the dietary, a high intake of fluids in the form of non-carbonated soda (approx. 3 liters spread out over the day) should be ensured. • The solution is taken at 18:00 at the latest, diluted in approx. 70 ml water. • Immediately after the intake, an additional 250 ml of water is drunk. Subsequently, no food is eaten until the examination. • 3 to 4 hours after the intake of the solution, but by 22:00 at the latest, the 4 tablets are swallowed without chewing with a little water. • Afterwards, an additional 250 ml of water is drunk.

On the dav of the examination: • Any kind of solid food is not permitted. • Coffee or tea without milk are permitted; in addition, plenty of water should be drunk. • In the case of insufficient intestinal voiding, a cleaning enema can be performed by qualified personnel prior to the start of the examination.

Each subject is assigned a set of treatment conditions (including enema dose, instillation time, retention time, and colonoscopy start time) according to a Treatment Assignment Table assigned to each site. The Treatment Assignment Table may be updated and re-issued to the sites based on safety or fluorescence data. In general, a change in the Treatment Assignment Table (dose, instillation time, retention time, or colonoscopy time) may be made with a minimum of one subject’s data for safety considerations, and with a minimum of three subjects’ data for efficacy considerations.

The following treatment descriptions apply unless a change is made for safety reasons.

At least the first three subjects and up to approximately the first 20 subjects receive an enema dose of 200 mg HAL HC1 in 500 mL solution (0.4 mg/mL; 1.6 mM).

Based on safety, tolerability, and fluorescence data, the next dose is selected. A proposed second enema dose is 300 mg HAL HC1 in 500 mL solution (0.6 mg/mL; 2.4 mM).

Based on safety, tolerability, and fluorescence data, in at least three subjects and up to approximately 20 subjects at the second enema dose of 300 mg HAL HC1, the third dose is selected. A proposed third enema dose is 400 mg HAL HC1 in 500 mL solution (0.8 mg/mL; 3.2 mM). The third dose is administered in at least three and up to approximately 20 subjects.

For all subjects, the enema dose is instilled over 30 minutes (approximately 16.7 mL/min) via a rectal catheter, then expelled. The retention time may be adjusted based on data received. A Karl Storz flexible fluorescence video coloscope with a 300-watt short-arc xenon lamp with a switchable bandpass filter (λ = 380 - 430 nm) and an integrated longpass 450 nm observation filter is used for all colonoscopies.

The following additional examinations and procedures are performed after enema expulsion: • Assess and record AEs • Collect blood for clinical laboratory tests (e.g., hematology and chemistry). Hematology and Chemistry are collected at 1 hour after enema expulsion and immediately prior to discharge. • Collect urine for urinalysis. Urinalysis is collected at any one time point on Treatment Day 1 between enema expulsion and subject discharge. • Perform vital sign assessments (sitting blood pressure, heart rate, oral temperature) at 1, 2, 4 and 6 hours after enema expulsion. • Perform ECG assessment approximately 1 hour after enema expulsion. • Perform photosensitivity testing approximately 1 hour after enema expulsion.

Following enema expulsion, the coloscope is inserted and advanced to the cecum beginning 15 minutes prior to the assigned colonoscopy start time. A full colonoscopy is conducted with first white and then blue light beginning at an assigned colonoscopy start time (0.5, 1, 2, 4, or 6 h) after enema expulsion for each subject. Time points may be adjusted based on data received.

The colonoscopy is conducted by advancing the coloscope to the cecum and then visualizing each section of the colon during withdrawal of the scope (cecum/ascending colon; right flexure/transverse colon; left flexure/descending colon; sigmoid colon/rectum) under blue and optionally, under white light.

The location and time of visualization of each lesion is recorded. In addition, video images of each colonoscopy is captured for subsequent evaluation.

Following completion of white and blue light inspection of each section, all lesions in that section are resected or biopsied according to standard of care. Histopathology is assessed by a central reader for the purpose of study data collection and by a local reader according to standard of care.

The following additional examinations and procedures are performed between the time the colonoscopy is completed and the subject is discharged: • Assess and record AEs immediately after the colonoscopy and prior to discharge. • Review and record concomitant medication including sedation medications, if applicable. • Perform vital sign assessments (sitting blood pressure, heart rate, oral temperature). • Confirm in the source and CRF if a complete endoscopy procedure was performed and if appropriate bowel preparation was achieved.

The patient is instructed to stay at the clinic for at least 6 hours after enema expulsion. Prior to discharge and leaving the clinic, the patient is instructed to avoid exposure to sunlight and to use sunscreen with a Sun Protection Factor > 50 for 48 hours following enema administration if direct sunlight cannot be avoided.

Follow-Up/End of Study Visit (Day 9 ± 2; Visit 3)

The subject returns to the clinic between 7 to 11 days after Visit 2 (Treatment Day 1). The subject is queried as to any adverse events that may have occurred during the post treatment follow-up period, and all AEs are recorded. If the investigator suspects that there are any treatment-related AEs, then the subject is followed until resolution or it is determined that the condition is stable. Completion of the last follow-up visit is considered the end of the study. Current medications are reviewed, including changes from the previous visit (Treatment Day 1). At the discretion of the investigator, the subject may be required to attend the clinic for a followup assessment related to an AE or SAE. This can include additional laboratory tests or investigations, histopathologic examinations, or consultation with other health care professionals.

The follow-up is performed for all subjects. The following assessments are completed at the Follow-up / End of Study Visit (Day 9 ± 2): • Assess and record AEs; • Review and record concomitant medications; • Collect blood and urine for clinical laboratory tests (e.g, hematology and chemistry); • Perform vital sign assessments (sitting blood pressure, heart rate, oral temperature); • Perform symptom-directed physical exam (if applicable).

After the study, all patients are followed-up according to standard routine of the study sites.

The study includes a Screening Visit (Day -21 to -1), a Treatment Visit (Day 1), and a Follow-Up/End of Study Visit (9 ± 2 days following Treatment Visit) to evaluate the ongoing wellbeing of the subjects. If a subject reports any adverse events (AEs) which present a cause for concern, the subject is required to report to the investigational site for a follow-up assessment (as an unscheduled visit).

Efficacy Endpoints

The efficacy endpoints include: (a) number of polypoid lesions detected under white and blue light colonoscopy, (b) intensity of fluorescence, and (c) duration of fluorescence.

Safety Endpoints

Safety endpoints include the following: • Incidence of treatment-emergent adverse events (AEs) and serious AEs (SAEs) grouped by body system; relationship to study medication and severity; • Changes from baseline in clinical laboratory parameters; • Changes from baseline in vital sign measurements; • Changes from baseline in physical examination findings; • Changes from baseline in ECG parameters; • Changes from baseline in skin photosensitivity findings.

Statistical Methodology

The intent-to-treat (ITT) population includes all subjects who receive the study drug. This population is utilized for all safety and efficacy analyses.

Subject disposition is summarized by dose, time point, and overall and includes the number of subjects; number and percentage of subjects who completed or prematurely discontinued the study, classified by reasons for premature discontinuation; the number of subjects at each study site; and the number and percentage of subjects who completed or discontinued the study at each study site.

Demographic and baseline characteristics are summarized descriptively by study variable and overall.

Safety evaluations are based on the incidence, intensity, and type of AEs, and clinically significant changes in vital signs, clinical laboratory results, electrocardiogram (ECG) parameters, and photosensitivity observations. Concomitant medication, exposure to study medication and treatment compliance are summarized descriptively.

Efficacy is evaluated by the number and percentage of lesions detected by white light and blue light, and the true positive detection rate of lesions is calculated for white light and blue light. The analysis is carried out overall, by dose, and by time point.

Clinically Significant Events

All potentially clinically significant values for clinical laboratory tests are assessed by the investigator. Out of range laboratory values that can be potentially clinically significant are flagged for review. If deemed clinically significant, the event is reported as an AE and recorded on the AE CRF page. Table 2 provides a listing of potentially clinically significant values for clinical laboratory tests.

Table 1: Potentially Clinically Significant Events

After evaluation of data from the enema formulation, the protocol is amended to include oral dosing with the improved formulations currently in development. EXAMPLE 7

PREPARATION OF A MINI TABLET FORMULATION FOR IMMEDIATE RELEASE (DIRECT COMPRESSION)

An exemplary direct compression process for preparing a mini tablet formulation for immediate release is described below. All percentages are in (w/w).

Core:

Hexaminolevulinate (HAL): 20% (10% - 40%)

Diluents: 76.9% (10% - 80%) (e.g. microcrystalline cellulose, Prosolv, starch, mannitol, etc) Glidant: 0.1% (0- 1%)

Lubricant: 3.0% (0.1% - 5%) (e.g. stearic acid, magnesium stearate, etc)

Coating**:

Eudragit® L30D-55 or Eudragit® LI 00: 10% (5% - 20%)

Triethyl citrate: 1.0% (0.1% - 2%)

Talc: 2.33% (1% - 5%)

Magnesium Stearate: 0.65% (0.1% - 2%) ** Alcohol and water were removed during coating process by evaporation.

Coating Solution:

Eudragit® L30D-55 or Eudragit® LI00: 16.9% (5% - 30%)

Triethyl citrate: 1.69% (0.5% - 3%)

Water: 11.55% (5% - 20%)

Alcohol: 55.60% (40% - 90%) (e.g. absolute ethanol)

Alcohol: 9.04% (4% - 30%) (e.g. absolute ethanol)

Talc: 4.06% (1% - 10%)

Magnesium Stearate: 1.04% (0.1% - 2%)

Process:

For the core, HAL and all other ingredients were first passed through a 20 or 30 mesh screen. A blender was then provided with HAL, glidant and about 50% of total amount of the diluents, and the mixture was blended for 10 minutes. The remaining amounts of the diluents were added to the blender, and the resulting mixture was blend for an additional 10 minutes. The lubricant was added to the blender, and the resulting mixture was blended for an additional 3 minutes. The contents of the blender were then discharged into a polyethylene bag and compressed into mini tablets using a multi tip punch and rotary tablet press.

The coating solution was prepared according to the coating solution formulation. The water and alcohol were mixed in a receptacle, and Eudragit® and triethyl citrate were slowly added to the mixture to produce a solution. To a separate receptacle was added alcohol, talc and magnesium stearate, which were then mixed together. When ready to be applied, the alcohol, talc and magnesium stearate mixture was added to the first receptacle, and the resulting mixture was continuously mixed until applied as a spray. Using a pan coater with an appropriate coating pan, the mini tablets were coated with appropriate parameters up to a 10% - 20% weight gain. EXAMPLE 8

PREPARATION OF A MINI TABLET FORMULATION FOR IMMEDIATE RELEASE (ROLLER COMPACTION)

An exemplary roller compaction process for preparing a mini tablet formulation for immediate release is described below. All percentages are in (w/w).

Core:

Hexaminolevulinate (HAL): 20% (10% - 40%)

Diluents: 76.9% (10% - 80%) (e.g. microcrystalline cellulose, Prosolv, starch, mannitol, etc)

Dry binders: 5% (1% - 10%) (e.g. Copovidone VA, Plasdone S630, etc.)

Glidant: 0.1% (0-1%)

Lubricant: 3.0% (0.1% - 5%) (e.g. stearic acid, magnesium stearate, etc)

Coating**:

Eudragit® L30D-55 or Eudragit® L100: 10% (5% - 20%)

Triethyl citrate: 1.0% (0.1% - 2%)

Talc: 2.33% (1% - 5%)

Magnesium Stearate: 0.65% (0.1% - 2%) ** Alcohol and water were removed during coating process Coating Solution:

Eudragit® L30D-55 or Eudragit® LI00: 16.9% (5% - 30%)

Triethyl citrate: 1.69% (0.5% - 3%)

Water: 11.55% (5% - 20%)

Alcohol: 55.60% (40% - 90%)

Alcohol: 9.04% ( 4% - 30%)

Talc: 4.06% (1% - 10%)

Magnesium Stearate: 1.04% (0.1% - 2%)

Process:

For the core, HAL and all other ingredients were first passed through a 20 or 30 mesh screen. A blender was then provided with HAL, glidant and about 50% of total amount of the diluents, and the mixture was blended for 10 minutes. The remaining amounts of the diluents were added to the blender, and the resulting mixture was blend for an additional 10 minutes. The contents of the blender were then discharged into a polyethylene bag, and the blend was roller compacted to produce appropriate ribbons. The ribbons were milled using a suitable mill to produce flowable granules. The roller compacted granules and lubricant were then added to a blender and blended for 3 minutes. The lubricated granules were then discharged into a second polyethylene bag and compressed into mini tablets using a multi tip punch and rotary tablet press.

The coating solution was prepared according to the coating solution formulation. The water and alcohol were mixed in a receptacle, and Eudragit® and triethyl citrate were slowly added to the mixture to produce a solution. To a separate receptacle was added alcohol, talc and magnesium stearate, which were then mixed together. When ready to be applied, the alcohol, talc and magnesium stearate mixture was added to the first receptacle, and the resulting mixture was continuously mixed until applied as a spray. Using a pan coater with an appropriate coating pan, the mini tablets were coated with appropriate parameters up to a 10% -20% weight gain. EXAMPLE 9 PREPARATION OF A MINI TABLET FORMULATION FOR EXTENDED RELEASE (DIRECT COMPRESSION)

An exemplary direct compression process for preparing a mini tablet formulation for extended release is described below. All percentages are in (w/w).

Core:

Hexaminolevulinate (HAL): 20% (10% - 40%)

Diluents: 61.9%% (10% - 65%) (e.g. microcrystalline cellulose, Prosolv, starch, mannitol, etc)

Polymers: 15% (5% - 40%) (e.g. HPMCs, HPCs, Eudragit® polymers, etc.)

Glidant: 0.1% (0-1%)

Lubricant: 3.0% (0.1% - 5%) (e.g. stearic acid, magnesium stearate, etc)

Coating**:

Eudragit® L30D-55 or Eudragit® LI00: 10% (5% - 20%)

Triethyl citrate: 1.0% (0.1% - 2%)

Talc: 2.33% (1% - 5%)

Coating Solution:

Eudragit® L30D-55 or Eudragit® LI00: 16.9% (5% - 30%)

Triethyl citrate: 1.69% (0.5% - 3%)

Water: 11.55% (5% - 20%)

Alcohol: 55.60% (40% - 90%) (e.g. absolute ethanol)

Alcohol: 9.04% (4% -30%) (e.g. absolute ethanol)

Talc: 4.06% (1% - 10%)

Magnesium Stearate: 1.04% (0.1% - 2%)

Process:

The coating solution was prepared according to the coating solution formulation. The water and alcohol were mixed in a receptacle, and Eudragit® and triethyl citrate were slowly added to the mixture to produce a solution. To a separate receptacle was added alcohol, talc and magnesium stearate, which were then mixed together. When ready to be applied, the alcohol, talc and magnesium stearate mixture was added to the first receptacle, and the resulting mixture was continuously mixed until applied as a spray. Using a pan coater with an appropriate coating pan, the mini tablets were coated with appropriate parameters up to a 10% -20% weight gain. EXAMPLE 10 PREPARATION OF A MINI TABLET FORMULATION FOR EXTENDED RELEASE (ROLLER COMPACTION)

An exemplary roller compaction process for preparing a mini tablet formulation for extended release is described below. All percentages are in (w/w).

Core:

Hexaminolevulinate (HAL): 20% (10% - 40%)

Diluents: 71.9% (10% - 80%) (e.g. microcrystalline cellulose, Prosolv, starch, mannitol, etc) Polymers: 15% (5% - 40%) (e.g. HPMCs, HPCs, Eudragit® polymers, etc.)

Dry binders: 5% (1% - 10%) (e.g. Copovidone VA, Plasdone S630, etc.)

Glidant: 0.1% (0-1%)

Lubricant: 3.0% (0.1% - 5%) (e.g. stearic acid, magnesium stearate, etc)

Coating**:

Eudragit® L30D-55 or Eudragit® L100: 10% (5% - 20%)

Triethyl citrate: 1.0% (0.1% - 2%)

Talc: 2.33% (1% - 5%)

Eudragit® L30D-55 or Eudragit® L100: 16.9% (5% - 30%)

Triethyl citrate: 1.69% (0.5% - 3%)

Water: 11.55% (5% - 20%)

Alcohol: 55.60% (40% - 90%)

Alcohol: 9.04% (4% - 30%)

Talc: 4.06% (1% - 10%)

Magnesium Stearate: 1.04% (0.1% - 2%)

Process:

The coating solution was prepared according to the coating solution formulation. The water and alcohol were mixed in a receptacle, and Eudragit® and triethyl citrate were slowly added to the mixture to produce a solution. To a separate receptacle was added alcohol, talc and magnesium stearate, which were then mixed together. When ready to be applied, the alcohol, talc and magnesium stearate mixture was added to the first receptacle, and the resulting mixture was continuously mixed until applied as a spray. Using a pan coater with an appropriate coating pan, the mini tablets were coated with appropriate parameters up to a 10% - 20% weight gain. EXAMPLE 11

Core:

Hexaminolevulinate (HAL): 20% (10% - 40%)

Citric acid: 5% (1 - 10%)

Lubricant: 3.0% (0.1% - 5%) (e.g. stearic acid, magnesium stearate, etc)

Coating**:

Eudragit® L30D-55 or Eudragit® L100: 10% (5% - 20%)

Triethyl citrate: 1.0% (0.1% - 2%)

Talc: 2.33% (1% - 5%)

Coating Solution:

Eudragit® L30D-55 or Eudragit® L100: 16.9% (5% - 30%)

Triethyl citrate: 1.69% (0.5% - 3%)

Water: 11.55% (5% - 20%)

Alcohol: 55.60% (40% - 90%) (e.g. absolute ethanol)

Alcohol: 9.04% (4% - 30%) (e.g. absolute ethanol)

Talc: 4.06% (1% - 10%)

Magnesium Stearate: 1.04% (0.1% - 2%)

Process:

For the core, HAL and all other ingredients were first passed through a 20 or 30 mesh screen. A blender was then provided with HAL and citric acid, and the ingredients were blended together. Subsequently, glidant and about 50% of total amount of the diluents were added to the blender, and the mixture was blended for 10 minutes. The remaining amounts of the diluents were added to the blender, and the resulting mixture was blend for an additional 10 minutes. The lubricant was added to the blender, and the resulting mixture was blended for an additional 3 minutes. The contents of the blender were then discharged into a polyethylene bag and compressed into mini tablets using a multi tip punch and rotary tablet press.

The coating solution was prepared according to the coating solution formulation. The water and alcohol were mixed in a receptacle, and Eudragit® and triethyl citrate were slowly added to the mixture to produce a solution. To a separate receptacle was added alcohol, talc and magnesium stearate, which were then mixed together. When ready to be applied, the alcohol, talc and magnesium stearate mixture was added to the first receptacle, and the resulting mixture was continuously mixed until applied as a spray. Using a pan coater with an appropriate coating pan, the mini tablets were coated with appropriate parameters up to a 10% - 20% weight gain. EXAMPLE 12

Core:

Hexaminolevulinate (HAL): 20% (10% - 40%)

Citric acid: 5% (1 - 10%)

Dry binders: 5% (1% - 10%) (e.g. Copovidone VA, Plasdone S630, etc.)

Glidant: 0.1% (0-1%)

Lubricant: 3.0% (0.1% - 5%) (e.g. stearic acid, magnesium stearate, etc)

Coating**:

Eudragit® L30D-55 or Eudragit® L100: 10% (5% - 20%)

Triethyl citrate: 1.0% (0.1% - 2%)

Talc: 2.33% (1% - 5%)

Eudragit® L30D-55 or Eudragit® L100: 16.9% (5% - 30%)

Triethyl citrate: 1.69% (0.5% - 3%)

Water: 11.55% (5% - 20%)

Alcohol: 55.60% (40% - 90%)

Alcohol: 9.04% ( 4% - 30%) Talc: 4.06% (1% - 10%)

Magnesium Stearate: 1.04% (0.1% - 2%)

Process:

For the core, HAL and all other ingredients were first passed through a 20 or 30 mesh screen. A blender was then provided with HAL and citric acid, and the ingredients were blended together. Subsequently, glidant and about 50% of total amount of the diluents were added to the blender, and the mixture was blended for 10 minutes. The remaining amounts of the diluents were added to the blender, and the resulting mixture was blend for an additional 10 minutes. The contents of the blender were then discharged into a polyethylene bag, and the blend was roller compacted to produce appropriate ribbons. The ribbons were milled using a suitable mill to produce flowable granules. The roller compacted granules and lubricant were then added to a blender and blended for 3 minutes. The lubricated granules were then discharged into a second polyethylene bag and compressed into mini tablets using a multi tip punch and rotary tablet press.

The coating solution was prepared according to the coating solution formulation. The water and alcohol were mixed in a receptacle, and Eudragit® and triethyl citrate were slowly added to the mixture to produce a solution. To a separate receptacle was added alcohol, talc and magnesium stearate, which were then mixed together. When ready to be applied, the alcohol, talc and magnesium stearate mixture was added to the first receptacle, and the resulting mixture was continuously mixed until applied as a spray. Using a pan coater with an appropriate coating pan, the mini tablets were coated with appropriate parameters up to a 10% - 20% weight gain. EXAMPLE 13 PREPARATION OF A MINI TABLET FORMULATION FOR EXTENDED RELEASE (DIRECT COMPRESSION)

Core:

Hexaminolevulinate (HAL): 20% (10% - 40%)

Citric acid: 5% (1-10%)

Diluents: 61.9%% (10% - 65%) (e.g. microcrystalline cellulose, Prosolv, starch, mannitol, etc) Polymers: 15% (5% - 40%) (e.g. HPMCs, HPCs, Eudragit® polymers, etc.)

Glidant: 0.1% (0-1%)

Lubricant: 3.0% (0.1% - 5%) (e.g. stearic acid, magnesium stearate, etc)

Coating**:

Eudragit® L30D-55 or Eudragit® L100: 10% (5% - 20%)

Triethyl citrate: 1.0% (0.1% - 2%)

Talc: 2.33% (1% - 5%)

Coating Solution:

Eudragit® L30D-55 or Eudragit® LI 00: 16.9% (5% - 30%)

Triethyl citrate: 1.69% (0.5% - 3%)

Water: 11.55% (5% - 20%)

Alcohol: 55.60% (40% - 90%) (e.g. absolute ethanol)

Alcohol: 9.04% (4% -30%) (e.g. absolute ethanol)

Talc: 4.06% (1% - 10%)

Magnesium Stearate: 1.04% (0.1% - 2%)

Process:

The coating solution was prepared according to the coating solution formulation. The water and alcohol were mixed in a receptacle, and Eudragit® and triethyl citrate were slowly added to the mixture to produce a solution. To a separate receptacle was added alcohol, talc and magnesium stearate, which were then mixed together. When ready to be applied, the alcohol, talc and magnesium stearate mixture was added to the first receptacle, and the resulting mixture was continuously mixed until applied as a spray. Using a pan coater with an appropriate coating pan, the mini tablets were coated with appropriate parameters up to a 10% -20% weight gain. EXAMPLE 14 PREPARATION OF A MINI TABLET FORMULATION FOR EXTENDED RELEASE (ROLLER COMPACTION)

Core:

Hexaminolevulinate (HAL): 20% (10% - 40%)

Citric acid: 5% (1-10%)

Dry binders: 5% (1% - 10%) (e.g. Copovidone VA, Plasdone S630, etc.)

Glidant: 0.1% (0- 1%)

Lubricant: 3.0% (0.1% - 5%) (e.g. stearic acid, magnesium stearate, etc)

Coating**:

Eudragit® L30D-55 or Eudragit® LI 00: 10% (5% - 20%)

Triethyl citrate: 1.0% (0.1% - 2%)

Talc: 2.33% (1% - 5%)

Eudragit® L30D-55 or Eudragit® L100: 16.9% (5% - 30%)

Triethyl citrate: 1.69% (0.5% - 3%)

Water: 11.55% (5% - 20%)

Alcohol: 55.60% (40% - 90%)

Alcohol: 9.04% ( 4% - 30%)

Talc: 4.06% (1% -10%)

Magnesium Stearate: 1.04% (0.1% - 2%)

Process:

The coating solution was prepared according to the coating solution formulation. The water and alcohol were mixed in a receptacle, and Eudragit® and triethyl citrate were slowly added to the mixture to produce a solution. To a separate receptacle was added alcohol, talc and magnesium stearate, which were then mixed together. When ready to be applied, the alcohol, talc and magnesium stearate mixture was added to the first receptacle, and the resulting mixture was continuously mixed until applied as a spray. Using a pan coater with an appropriate coating pan, the mini tablets were coated with appropriate parameters up to a 10% -20% weight gain. EXAMPLE 15

MINI-TABLET FORMULATIONS FOR IMMEDIATE AND EXTENDED

RELEASE

The following tables provide exemplary formulations that were investigated for development of immediate and extended release formulations.

Table 1. Exemplary formulations

All measurements provided in milligrams (mg).

Dissolution profiles for the exemplary formulations of Table 1 are provided in Figure 8. Table 2. Exemplary formulations

All measurements provided in milligrams (mg).

Dissolution profiles for the exemplary formulations of Table 2 are provided in Figure 9.

Table 3. Exemplary formulations

All measurements provided in milligrams (mg).

Dissolution profiles for the exemplary formulations of Table 3 are provided in Figures 10 and 11. The formulations were coated with Eudragit L30D-55 (pH 5.5).

EXAMPLE 16

PREPARATION OF A MINI-TABLET FORMULATION

Blending.. HAL, citric acid and a portion of the full amount of Prosolv SMCC90 were combined in a V-shell blender and blended together for five (5) minutes. The remaining amount of Prosolv SMCC90 was added to the blender and mixed for an additional five (5) minutes. The resulting blend was then lubricated with stearic acid for three (3) minutes and subsequently discharged into a polyethylene bag.

Table 4, Core formulation (Batch size =15 kg)

Compression. The core formulation blend was compressed into mini tablets with a rotary tablet press equipped with a 2.5mm round 7-tips multi-tip tool.

Sub-coat. An Opadry clear suspension was made by dispersing 15% w/w Opadry clear into water. The Opadry clear suspension was then sprayed onto the mini tablets using a conventional coating machine with an appropriate coating pan insert. When the mini tablets achieved a 3% (w/w) gain as dry basis, the sub-coating process was stopped. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert.

Table 5, Sub-coat Solution

Table 6. Sub-coat Application (T)rv Basis!

Enteric Coat (Eudraeit® L30D-55). Eudragit®L30D-55 was weighed in a container, to which triethyl citrate (TEC) was then added. The contents were mixed for 45 minutes. In a separate container, water was weighed and added, and talc was dispersed in the water using a high shear mixer for 45 minutes. The resulting talc suspension was then passed through a #60 mesh screen, added to the Eudragit® mixture and mixed for an additional 20 minutes. The suspension was then sprayed on the mini tablets until a 12% (w/w) based on Eudragit® plus TEC or 19.68 % (w/w) based on total dry weight gain was achieved using a conventional coating machine with appropriate pan insert. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert.

Table 7. Enteric Coat Solution

Table 8. Enteric Coat Application (Dry Basis')

Table 9. Eudragit® Coated Mini Tablet Formulation (Dry Basis)

Enteric Coat (Eudragit® L100). In some embodiments, an enteric coating containing Eudragit®L100 is provided. One thousand (1000) milliliters of purified water was weighed in a container, to which 199 grams of Eudragit® LI00 was slowly added and mixed for five (5) minutes, or until the powder was thoroughly wetted and lump formations were no longer visible. An ammonia solution (112 grams of a 1 A solution) was slowly added to the Eudragit® suspension and stirred for about 60 minutes. Triethyl citrate (TEC, 99.60 grams) was then added to the suspension, and the contents were mixed for another 60 minutes. In a separate container, 489.80 grams of water was weighed and added, and talc (99.60 grams) was added to the water and mixed using a high shear mixer for 45 minutes. The resulting talc suspension was then passed through a #60 mesh screen, added to the Eudragit® mixture and mixed for an additional 30 minutes. The suspension was then sprayed on the mini tablets until a 12% (w/w) based on Eudragit® plus TEC or 19.68 % (w/w) based on total dry weight gain was achieved using a conventional coating machine with appropriate pan insert. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert. EXAMPLE 17

PREPARATION OF A MINI-TABLET FORMULATION

Blending. HAL and a portion of the full amount of silicified microcrystalline cellulose (SMCC, Prosolv) were combined in a blender and blended together for five (5) minutes. The remaining amount of SMCC, citric acid and crospovidone were added to the blender and mixed for an additional five (5) minutes. The resulting blend was then lubricated with stearic acid for three (3) minutes and subsequently discharged into a polyethylene bag. All ingredients were screened through a 30 mess screen prior to being added to the blender.

Table 10. Core formulation (Batch size= 1.5 kg')

Compression. The core formulation blend was compressed into mini tablets with a rotary tablet press equipped with a 2.5mm tablet tool.

The blending and tablet compression process was performed at a relative humidity below 40%.

Sub-coat. An Opadry clear suspension was made as described (Example 16). The Opadry clear suspension was then sprayed onto the mini tablets using a conventional coating machine with an appropriate coating pan insert. When the mini tablets achieved a 4% (w/w) gain as dry basis, the sub-coating process was stopped. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert.

Table 11. Sub-coat Application (Dry Basis')

Enteric Coat (Eudrasit® L30D). The methacrylic acid copolymer dispersion was made as described (Example 16). The suspension was then sprayed on the mini tablets until a 21% (w/w) based on total dry weight gain was achieved using a conventional coating machine with appropriate pan insert. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert.

Table 12, Enteric Coat Application (Dry Basis!

Table 13. Enteric Coated Mini Tablet Formulation (mg/unit dose)

The enteric coated mini-tablets were blended with trace quantities of talc prior to encapsulation. EXAMPLE 18

PREPARATION OF A MINI-TABLET FORMULATION

Blendins. HAL, citric acid and Prosolv SMCC90 were combined in a V-shell blender and blended together for five (5) minutes. Mannitol 200SD and HPC HXF (hydroxypropylcellulose) were added to the blender and mixed for an additional five (5) minutes. The resulting blend was then lubricated with stearic acid for three (3) minutes and subsequently discharged into a polyethylene bag.

Table 14. Core formulation

Table 15, Sub-coat Solution

Table 16, Sub-coat Application (Dry Basis)

Table 17, Enteric Coat Solution

Table 18. Enteric Coat Application (Dry Basis)

Table 19. Eudragit® Coated Mini Tablet Formulation (Dry Basis)

Enteric Coat iEudraoit® LI 00). In some embodiments, an enteric coating containing Eudragit®L100 is provided. One thousand (1000) milliliters of purified water was weighed in a container, to which 199 grams of Eudragit® LI00 was slowly added and mixed for five (5) minutes, or until the powder was thoroughly wetted and lump formations were no longer visible. An ammonia solution (112 grams of a 1 N solution) was slowly added to the Eudragit® suspension and stirred for about 60 minutes. Triethyl citrate (TEC, 99.60 grams) was then added

to the suspension, and the contents were mixed for another 60 minutes. In a separate container, 489.80 grams of water was weighed and added, and talc (99.60 grams) was added to the water and mixed using a high shear mixer for 45 minutes. The resulting talc suspension was then passed through a #60 mesh screen, added to the Eudragit® mixture and mixed for an additional 30 minutes. The suspension was then sprayed on the mini tablets until a 12% (w/w) based on Eudragit® plus TEC or 19.68 % (w/w) based on total dry weight gain was achieved using a conventional coating machine with appropriate pan insert. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert.

Figures 11,13 and 14 (Formulation K) illustrates the dissolution profile of an exemplary medium release (MR) formulation at various pH. In Figures 13 and 14, the tablet is placed in an acidic environment for the first half hour before the pH is adjusted to 6 or 6.5, respectively. EXAMPLE 19

PREPARATION OF A MINI-TABLET FORMULATION

Blending. HAL and silicified microcrystalline cellulose (Prosolv) were combined in a blender and blended together for five (5) minutes. Mannitol was added to the blender and mixed for an additional five (5) minutes. Hydroxypropylcellulose and citric acid were then added to the blender and mixed for an additional five (5) minutes. The resulting blend was then lubricated with a portion of stearic acid for three (3) minutes and subsequently discharged into a polyethylene bag. The blend was then subjected to roller compaction (e.g. Example 14). Specifically, the blend in the polyethylene bag was roller compacted to produce appropriate ribbons. The ribbons were milled using a suitable mill to produce flowable granules. The roller compacted granules were then added to a blender and blended with the remaining amount of stearic acid before being discharged into a second polyethylene bag for tablet compression. All ingredients were screened through a 30 mess screen prior to being added to the blender.

Table 20. Core formulation

Sub-coat. An Opadry clear suspension was made as described (Example 18). The Opadry clear suspension was then sprayed onto the mini tablets using a conventional coating machine with an appropriate coating pan insert. When the mini tablets achieved a 4% (w/w) gain as dry basis, the sub-coating process was stopped. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert.

Table 21. Sub-coat Application (Dry Basis)

Enteric Coat (Eudrazit® L30D). The methacrylic acid copolymer dispersion was made as described (Example 18). The suspension was then sprayed on the mini tablets until a 21% (w/w) based on total dry weight gain was achieved using a conventional coating machine with appropriate pan insert. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert.

Table 21, Enteric Coat Application (Dry Basis!

Table 22, Enteric Coated Mini Tablet Formulation (mg/unit dose)

The enteric coated mini-tablets were blended with trace quantities of talc prior to encapsulation. EXAMPLE 20

PREPARATION OF A MINI-TABLET FORMULATION

Blending. HAL, citric acid and Prosolv SMCC90 were combined in a V-shell blender and blended together for five (5) minutes. Mannitol 200SD, HPC HXF (hydroxypropylcellulose) and Carbopol 974P were added to the blender and mixed for an additional five (5) minutes. The resulting blend was then lubricated with stearic acid for three (3) minutes and subsequently discharged into a polyethylene bag.

Table 23, Core formulation

Sub-coat. An Opadry clear suspension was made by dispersing 15% w/w Opadry clear into water. The Opadry clear suspension was then sprayed onto the mini tablets using a conventional coating machine with an appropriate coating pan insert. When the mini tablets

achieved a 3% (w/w) gain as dry basis, the sub-coating process was stopped. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert.

Table 24, Sub-coat Solution

Table 25, Sub-coat Application (Dry Basis!

Enteric Coat (Eudragit® L30D-55). Eudragit®L30D-55 was weighed in a container, to which triethyl citrate (TEC) was then added. The contents were mixed for 45 minutes. In a separate container, water was weighed and added, and talc was dispersed in the water using a high shear mixer for 45 minutes. The resulting talc suspension was then passed through a #60 mesh screen, added to the Eudragit® mixture and mixed for an additional 20 minutes. The suspension was then sprayed on the mini tablets until a 12% (w/w) based on Eudragit® plus TEC or 19.68 % (w/w) based on total dry weight gain was achieved using a conventional coating machine with appropriate pan insert. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert.

Table 26. Enteric Coat Solution

Table 27. Enteric Coat Application (Dry Basis')

Table 28. Eudragit® Coated Mini Tablet Formulation (Dry Basis)

Enteric Coat (Eudragit® LI00). In some embodiments, an enteric coating containing Eudragit®L100 is provided. One thousand (1000) milliliters of purified water was weighed in a container, to which 199 grams of Eudragit® LI00 was slowly added and mixed for five (5) minutes, or until the powder was thoroughly wetted and lump formations were no longer visible. An ammonia solution (112 grams of a 1 N solution) was slowly added to the Eudragit® suspension and stirred for about 60 minutes. Triethyl citrate (TEC, 99.60 grams) was then added to the suspension, and the contents were mixed for another 60 minutes. In a separate container, 489.80 grams of water was weighed and added, and talc (99.60 grams) was added to the water and mixed using a high shear mixer for 45 minutes. The resulting talc suspension was then passed through a #60 mesh screen, added to the Eudragit® mixture and mixed for an additional 30 minutes. The suspension was then sprayed on the mini tablets until a 12% (w/w) based on Eudragit® plus TEC or 19.68 % (w/w) based on total dry weight gain was achieved using a

conventional coating machine with appropriate pan insert. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert. The following tables provide exemplary formulations that were investigated for development of sustained release formulations.

Figures 11, 13 and 14 (Formulation L) illustrates the dissolution profile of an exemplary sustained release (SR) formulation at various pH. In Figures 13 and 14, the tablet is placed in an acidic environment for the first half hour before the pH is adjusted to 6 or 6.5, respectively. EXAMPLE 21

PREPARATION OF A MINI-TABLET FORMULATION HAL and half the amount of silicified microcrystalline cellulose (SMCC, Prosolv) were combined in a blender and blended together for five (5) minutes. Mannitol, carbopol and the remaining amount of SMCC was added to the blender and mixed for an additional five (5) minutes. Hydroxypropylcellulose and citric acid were then added to the blender and mixed for an additional five (5) minutes. The resulting blend was then lubricated with a portion of stearic acid for three (3) minutes and subsequently discharged into a polyethylene bag. The blend was then subjected to roller compaction (e.g. Examples 14, 19). The roller compacted granules were then added to a blender and blended with the remaining amount of stearic acid before being discharged for tablet compression. All ingredients were screened through a 30 mess screen prior to being added to the blender.

Table 29, Core formulation

The core formulation blend was compressed into mini tablets with a rotary tablet press equipped with a 2.5mm tablet tool. The blending and tablet compression process was performed at a relative humidity below 40%. An Opadry clear suspension was made as described (Example 20). The Opadry clear suspension was then sprayed onto the mini tablets using a conventional coating machine with an appropriate coating pan insert. When the mini tablets achieved a 4% (w/w) gain as dry basis, the sub-coating process was stopped. The same coating can be achieved, for example, using a fluid bed dryer with an appropriately sized wurster insert.

Table 30, Sub-coat Application (Dry Basis')

Enteric Coat (Eudrasit® L30D). The methacrylic acid copolymer dispersion was made as described (Example 20). The suspension was then sprayed on the mini tablets until a 21% (w/w) based on total dry weight gain was achieved using a conventional coating machine with appropriate pan insert. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert.

Table 31. Enteric Coat Application (Dry Basis)

Table 32. Enteric Coated Mini Tablet Formulation (mg/unit dose)

The enteric coated mini-tablets were blended with trace quantities of talc prior to encapsulation. EXAMPLE 22

PREPARATION OF A MINI-TABLET FORMULATION

Blendins. For each formulation in Table 3, HAL and Prosolv SMCC90 were combined in a V-shell blender and blended together for two (2) minutes. Mannitol 200SD was added to the

blender and mixed for an additional three (3) minutes, followed by addition of HPC (hydroxypropylcellulose) and citric acid to the blender, which was subsequently mixed for an additional three (3) minutes. The resulting blend was then lubricated with stearic acid for two (2) minutes and subsequently discharged into a polyethylene bag.

Table 33, Core formulations

Compression. The core formulation blend was compressed into mini tablets with a rotary tablet press.

Sub-coat. An Opadry clear suspension was made by dispersing 15% w/w Opadry clear into water. The Opadry clear suspension was then sprayed onto the mini tablets using a conventional coating machine with an appropriate coating pan insert. When the mini tablets achieved about a 3% (w/w) gain as dry basis, the sub-coating process was stopped. Multiple batches were made, with Opadry sub-coat solutions of between about 3% to about 4%. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert.

Table 34. Sub-coat Solution

Table 35. Sub-coat Application (Dry Basis')

Table 36. Enteric Coat Solution

Table 37. Enteric Coat Application (Dry Basis')

Table 38, Eudragit® Coated Mini Tablet Formulation (Dry Basis)

Enteric Coat (Eudrasit® LI00). In some embodiments, an enteric coating containing Eudragit®L100 is provided. One thousand (1000) milliliters of purified water was weighed in a container, to which 199 grams of Eudragit® LI00 was slowly added and mixed for five (5) minutes, or until the powder was thoroughly wetted and lump formations were no longer visible. An ammonia solution (112 grams of a 1 A solution) was slowly added to the Eudragit® suspension and stirred for about 60 minutes. Triethyl citrate (TEC, 99.60 grams) was then added to the suspension, and the contents were mixed for another 60 minutes. In a separate container, 489.80 grams of water was weighed and added, and talc (99.60 grams) was added to the water and mixed using a high shear mixer for 45 minutes. The resulting talc suspension was then passed through a #60 mesh screen, added to the Eudragit® mixture and mixed for an additional 30 minutes. The suspension was then sprayed on the mini tablets until a 12% (w/w) based on Eudragit® plus TEC or 19.68 % (w/w) based on total dry weight gain was achieved using a conventional coating machine with appropriate pan insert. The same coating can be achieved using a fluid bed dryer with an appropriately sized wurster insert.The following tables provide

exemplary formulations that were investigated for development of sustained release formulations. EXAMPLE 23

ENCAPSULATION OF MINI TABLETS

Coated mini tablets were encapsulated using an appropriate capsule encapsulating machine. Capsule size was 00 and was one of three distinct colors. Capsules were HPMC plus or hard gelatin capsules.

Incorporation by Reference

The contents of all references, patents, pending patent applications and published patents, cited throughout this application are hereby expressly incorporated by reference.

Equivalents

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

CLAIMS What is claimed is:

1. A pharmaceutical composition comprising: a) an active ingredient selected from the group consisting of hexaminolevulinate, a precursor thereof, a derivative thereof, and a pharmaceutically acceptable salt thereof; b) optionally at least one triglyceride; and c) at least one emulsifier.

2. The composition of claim 1, wherein the composition further comprises at least one mucoadhesive.

3. The composition of claim 1 or 2, wherein the composition further comprises at least one surface penetration agent.

4. The composition of any one of claims 1-3, wherein the composition further comprises at least one chelating agent.

5. The composition of any one of claims 1-4, wherein the composition further comprises at least one pharmaceutically acceptable excipient other than b).

6. The composition of claim 5, wherein the composition comprises citric acid.

7. The composition of any one of claims 1-6, wherein the composition further comprises at least one coating selected from the group consisting of TEC, talc, a copolymer of methacrylic acid and methyl methacrylate, and a copolymer of methacrylic acid and ethyl acrylate.

8. The composition of any one of claims 1 -7, wherein the composition is a solid.

9. The composition of any one of claims 1-8, wherein the composition is a suppository.

10. The composition of any one of claims 1-9, wherein the active ingredient is a 5-ALA ester, or a pharmaceutically acceptable salt thereof.

11. The composition of any one of claims 1-10, wherein at least one triglyceride is a solid or liquid triglyceride.

12. The composition of claim 11, wherein at least one triglyceride is a solid triglyceride selected from the group consisting of cocoa butter, tallow, hard fat, hydrogenated coco-glycerides, hydrogenated palm oil, tristearin, tripalmitin and trimyristin.

13. he composition of claim 11, wherein at least one triglyceride is a liquid triglyceride selected from the group consisting of a triglyceride comprising glycerol and three identical or different C2-C22 fatty acids, a triglyceride comprising three identical or different C4-C18 fatty acids, a triglyceride comprising three identical or different C6-C18 fatty acids, a triglyceride comprising three identical or different C6~Ci2 fatty acids, tricaprylin, tricaproin, triheptanoin, caprylic/capric triglyceride, caprylic/capric/linoleic triglyceride and caprylic/capric/succinic triglyceride.

14. The composition of any one of claims 1-13, wherein at least one emulsifier is a non-ionic emulsifier obtained from a reaction between polyethylene glycol and a natural or a hydrogenated oil.

15. The composition of any one of claims 1-14, wherein the composition is substantially water-free.

16. The composition of any one of claims 1-15, wherein the composition comprises a liquid, semi-solid or solid mixture in a capsule.

17. The composition of claim 16, wherein the capsule is a solid.

18. The composition of claim 16 or 17, wherein the capsule is coated with at least one enteric coating.

19. The composition of claim 18, wherein at least one enteric coating allows for the pH controlled release of the active ingredient at a pH of about 5.5 to about 7.5.

20. The composition of claim 19, wherein the at least one enteric coating allows for the pH controlled release of the active ingredient at a pH of 6.5 or more.

21. The composition of claim 19-20, wherein at least one enteric coating is selected from the group of TEC, talc, a copolymer of methacrylic acid and methyl methacrylate, and a copolymer of methacrylic acid and ethyl acrylate.

22. The composition of claim 1, comprising hexaminolevulinate (HAL), microcrystalline cellulose (MCC), Cab-O-Sil and magnesium stearate, wherein the composition is a mini-tablet.

23. The composition of claim 1, comprising hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (SMC), Cab-O-Sil and magnesium stearate, wherein the composition is a mini-tablet.

24. The composition of claim 1, comprising hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (SMC), hydroxypropyl methylcellulose (HPMC, K4M), Plasdone® S630, Cab-O-Sil and magnesium stearate, wherein the composition is a mini-tablet.

25. The composition of claim 1, comprising hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (SMC), hydroxypropyl methylcellulose (HPMC, K4M or K100M), Cab-O-Sil and magnesium stearate, wherein the composition is a mini-tablet.

26. The composition of any one of claims 1-15, wherein the composition is a minitablet.

27. A pharmaceutical composition comprising a single tablet or capsule comprising at least two different mini-tablets as set forth in claims 22-25.

28. A pharmaceutical composition comprising: a) hexaminolevulinate, or a pharmaceutically acceptable salt thereof; b) a diluent; and c) a lubricant, wherein the composition is enterically coated with at least one coating.

29. The composition of claim 28, further comprising a polymer.

30. The composition of claim 28, wherein the diluent is at least one selected from the group of microcrystalline cellulose, silicified microcrystalline cellulose, starch, and mannitol.

31. The composition of claim 29, wherein the polymer is at least one selected from the group of: hydroxypropylmethyl cellulose, hydroxypropyl cellulose, a homopolymer or copolymer of acrylic acid crosslinked with a polyalkenyl polyether (Carbopol®) and a polymer of methacrylic acid and methacrylate (Eudragit®).

32. The composition of any one of claims 28-31, wherein the composition comprises citric acid.

33. The composition of claim 28, wherein the at least one coating is selected from the group consisting of triethyl citrate (TEC), talc, a copolymer of methacrylic acid and methyl methacrylate, and a copolymer of methacrylic acid and ethyl acrylate.

34. The composition of claim 28, wherein the composition is a solid.

35. The composition of claim 34, wherein the composition is formulated as a minitablet.

36. The composition of claim 34, wherein the composition is formulated as a microgranule.

37. The composition of claim 34, wherein the composition is encapsulated in a capsule.

38. The composition of claim 37, wherein the capsule is coated with at least one enteric coating.

39. The composition of claim 28, wherein at least one coating allows for the pH controlled release of the active ingredient at a pH of about 5.5 to about 7.5.

40. The composition of claim 28, wherein the at least one coating allows for the pH controlled release of the active ingredient at a pH of 6.5 or more.

41. The composition of claim 28, comprising hexaminolevulinate (HAL), microcrystalline cellulose (MCC), Cab-O-Sil and magnesium stearate.

42. The composition of claim 28 comprising hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (SMC), Cab-O-Sil and magnesium stearate.

43. The composition of claim 28, comprising hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (SMC), hydroxypropyl methylcellulose (HPMC, K4M), Plasdone® S630, Cab-O-Sil and magnesium stearate.

44. The composition of claim 28, comprising hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (SMC), hydroxypropyl methylcellulose (HPMC, K4M or K100M), Cab-O-Sil and magnesium stearate.

45. The composition of claim 28, comprising hexaminolevulinate (HAL), silicified microcrystalline cellulose, citric acid and stearic acid.

46. The composition of claim 28, comprising hexaminolevulinate (HAL), silicified microcrystalline cellulose, citric acid, crospovidone and stearic acid.

47. The composition of claim 28, comprising hexaminolevulinate (HAL), silicified microcrystalline cellulose, citric acid, mannitol, hydroxypropylcellulose and stearic acid.

48. The composition of claim 28, comprising hexaminolevulinate (HAL), silicified microcrystalline cellulose (Prosolv), Manmtol(Pearlitol), polyplasdone (Plasdone XL) , and stearic acid.

49. The composition of claim 28, comprising hexaminolevulinate (HAL), silicified microcrystalline sellulose (Prosolv), Mannitol (Pearlitol), hydroxy propyl cellulose (Klucel), and stearic acid.

50. The composition of claim 28, comprising hexaminolevulinate (HAL), silicified microcrystalline sellulose (Prosolv), Mannitol (Pearlitol), hydroxy propyl cellulose (Klucel), Carbopol (974P) and stearic acid.

51. The composition of claim 28, comprising hexaminolevulinate (HAL), carboxyl methyl cellulose sodium (SMC), hydroxypropyl methylcellulose (HPMC, K4M or K100M), hydroxy propyl cellulose (Klucel EXF, JFX, GXF, HXF and MXF), Cab-O-Sil and magnesium stearate.

52. The composition of any one of claims 41-51, wherein the composition is a minitablet.

53. The composition of any one of claims 41-51, wherein the composition is a microgranule.

54. A pharmaceutical composition comprising a single tablet or capsule comprising at least two different compositions as set forth in claims 41-51.

55. A method of conducting a photodynamic diagnosis (PDD) of a condition in a subject, comprising administering the pharmaceutical composition of any one of claims 1-54 to the subject.

56. The method of claim 55, wherein the composition is administered to the colon of the subject.

57. The method of claim 55, wherein the composition is administered to the rectum of the subject.

58. The method of any one of claims 55-57, wherein the condition is selected from the group consisting of cancer, a pre-cancerous condition, a non-cancerous condition, an infection associated with a cancer, irritable bowel syndrome (IBS), colorectal cancer, stomach cancer, esophageal cancer, diverticular disease, infectious colitis, ulcerative colitis, Crohn’s disease; ischemic colitis, radiation colitis, esophagitis, inflammatory bowel disease, small intestinal bacterial overgrowth, chronic pancreatitis, pancreatic insufficiency, hepatic encephalopathy, diarrhea, constipation, gastrointestinal motility disorders, gastroesophageal reflux disease (GERD), gastroparesis, chronic intestinal pseudo-obstruction (Ogilvie’s syndrome), colonic pseudo-obstruction, functional heartburn, post-operative ileus, hypertrophic pyloric stenosis, dyspepsia (including functional dyspepsia or nonulcer dyspepsia), gastrointestinal damage, anal fissure, achlorhydria, achalasia, hemorrhoids, intestinal polyps, gastrointestinal tract cancer, pancreatic cancer, prostatic cancer, gastrointestinal tract inflammation, and a bacterial infection.

59. The method of claim 58, wherein the bacterial infection is caused by H. pylori, C. jejuni, Salmonella, or Shigella.

60. A method of detecting a condition in a subject, comprising (i) administering the pharmaceutical composition of any one claims 1-54 to the lower gastrointestinal area of the subject, (ii) allowing the active ingredient to convert to a photosensitizer, (iii) photoactivating the photosensitizer and (iv) detecting a fluorescent signal from the photosensitizer, wherein the presence of a fluorescent signal is indicative of the condition.

61. The method of claim 60, wherein the photosensitizer achieves an effective tissue concentration at a target site in the lower gastrointestinal area prior to photoactivation.

62. The method of claim 60 or 61, wherein the condition is selected from the group consisting of cancer, a pre-cancerous condition, a non-cancerous condition, an infection associated with a cancer, irritable bowel syndrome (IBS), colorectal cancer, stomach cancer, esophageal cancer, diverticular disease, infectious colitis, ulcerative colitis, Crohn’s disease; ischemic colitis, radiation colitis, esophagitis, inflammatory bowel disease, small intestinal bacterial overgrowth, chronic pancreatitis, pancreatic insufficiency, hepatic encephalopathy, diarrhea, constipation, gastrointestinal motility disorders, gastroesophageal reflux disease (GERD), gastroparesis, chronic intestinal pseudo-obstruction (Ogilvie’s syndrome), colonic pseudo-obstruction, functional heartburn, post-operative ileus, hypertrophic pyloric stenosis, dyspepsia (including functional dyspepsia or nonulcer dyspepsia), gastrointestinal damage, anal fissure, achlorhydria, achalasia, hemorrhoids, intestinal polyps, gastrointestinal tract cancer, pancreatic cancer, prostatic cancer, gastrointestinal tract inflammation, and a bacterial infection.

63. The method of claim 62, wherein the bacterial infection is caused by H. pylori, C. jejuni, Salmonella, or Shigella.

64. The method of any one of claims 60-63, wherein the composition is administered to the colon of the subject.

65. The method of any one of claims 60-64, wherein the composition is administered to the rectum of the subject.

66. The method of any one of claims 55-65, wherein a purgative or a bowel preparation is administered to the subject prior to administration of the pharmaceutical composition.

67. The method of claim 66, wherein the purgative or bowel preparation is administered between about 30 minutes to about 24 hours prior to administration of the pharmaceutical composition.

68. The method of claim 66 or 67, wherein the purgative or bowel preparation comprises polyethylene glycol (PEG), sodium phosphate, an L-sugar, or a combination thereof.

69. The method of any one of claims 55-68, wherein fluid is administered to the subject after administration of the pharmaceutical composition.

70. The method of claim 69, wherein the fluid is administered from about 15 minutes to about 2 hours after administration of the pharmaceutical composition.

71. The method of claim 69, wherein the fluid is administered about 30 minutes after administration of the pharmaceutical composition.

72. The method of any one of claims 68-71, wherein the subject is administered from about 50 mL to about 500 mL of fluid.

73. The method of claim 72, wherein the subject is administered about 250 mL of fluid.