JP2013514976A - Compositions and methods for oral drug delivery - Google Patents

Abstract

The present invention includes an effective amount of a therapeutic agent, a permeation enhancer, and a pharmaceutically acceptable excipient, and a bioadhesive layer comprising a bioadhesive polymer, optionally therapeutic agent and permeation from a solid dosage form. Pharmaceutical compositions for oral delivery comprising a solid dosage form comprising an impermeable or semi-permeable layer having an opening capable of inducing unidirectional release of an enhancer are provided. Also provided are methods of making and using the pharmaceutical compositions of the invention. In one embodiment, the present invention comprises a bioadhesive layer comprising a bioadhesive polymer comprising an effective amount of a therapeutic agent, a permeation enhancer, and a pharmaceutically acceptable excipient to form a core. A pharmaceutical composition for drug delivery is provided comprising the formulated solid dosage form.

Description

Cross-reference of related applications This application includes Chinese patent application No. 200910201248.3 filed on Dec. 16, 2009, and No. 201010227045.4 filed on Jul. 14, 2010, and No. 61 / 287,146, filed on May 16, and 61 / 365,916, filed July 20, 2010, which are hereby incorporated by reference in their entirety. Insist on priority).

FIELD OF THE INVENTION The present invention generally relates to the field of oral drug delivery, particularly for enhanced absorption and increased bioavailability of therapeutic agents that exhibit low absorption and low bioavailability in conventional oral drug delivery systems. Of the pharmaceutical composition. The invention further relates to methods of making and using the disclosed pharmaceutical compositions.

Background of the Invention Oral drug delivery is one of the most common and accepted routes of drug administration. However, many therapeutic agents are poorly delivered via the oral route. For example, biologically active macromolecules (such as proteins, peptides, polysaccharides, and nucleic acids) often cannot be administered orally due to the combined action of enzymatic degradation, low absorption, or instability. Similarly, oral formulations of a number of small molecule drug classes (such as cyclosporine, fenofibrate, lipid-lowering drug statins, antihypertensive sultans, antibiotics (such as ceftriaxone or azithromycin), and bisphosphonate clodronates) Low absorption and pharmacokinetic profile fluctuations are problematic.

  A number of different approaches are being investigated to improve oral delivery of hypoabsorbent therapeutics. For example, permeation enhancers are commonly used to enhance the absorption of other low-absorbing drugs (for review, see BJ Aungst, J. Pharm. Sci., 2000, 89 (4): 429-442). Numerous examples of permeation enhancers known to improve percutaneous or transmucosal absorption are Patent Literature 1, Patent Literature 2, Patent Literature 3, Patent Literature 4, Patent Literature 5, Patent Literature 6, Patent Literature 7, Patent Document 8, Patent Document 9, Patent Document 10, US Patent Nos. 5,912,014, 5,929,027, 5,952,000, 5,972,911, 6,071,538, 6,156,731, 6,200,602, 6,333,046, 6,423,334, 6,747, No. 014, No. 7,316,819, No. 7,576,067, US Patent Application Publication No. 2007/0148228, No. 2007/0196464, No. 2007/0238707, No. 2008/0275001. No., 2008/02 No. 9079, the No. 2009/0087484, discloses the No. 2009/0111736, and in European Patent No. 1,154,761.

The application of absorption enhancers in oral formulations is often limited by the associated toxicity. One reported example of a successful pharmaceutical that contains an absorption enhancer is a colon suppository ampicillin formulation. It is commercially available in Sweden (DOKTACILLIN ™, Astra Lakemedel AB). Formulations containing 25 mg sodium caprate as a permeation enhancer showed a maximum serum concentration of ampicillin (C _max ), area under the serum concentration time curve (AUC), and urinary recovery of 2 compared to ampicillin alone, respectively. It has been reported to increase by a factor of .6, 2.3, and 1.8 (T. Lindmark et al., Pharm. Res., 1997, 14 (7): 930-935).

  However, the colon environment is very different from the oral route in terms of motility, residence time, water flow, mucus, and intestinal contents. Therefore, the required amount of permeation enhancer for oral delivery is much higher. For example, Burcham et al. Studied the effect of sodium caprate and other permeation enhancers on the absorption of the peptidomimetic DMP728 in dogs (Pharm. Res., 1995, 12 (12): 2065-7200). An enteric formulation containing the same amount of sodium caprate, while a formulation containing 115-120 mg sodium caprate in a gelatin capsule slightly improved bioavailability (13.0% -17.7%) The object could not show any effect.

  In order to consistently and significantly enhance absorption and bioavailability, the required amount of sodium caprate in the same experimental system was found to be in the range of 275-550 mg / tablet (US Patent Application Publication). 2008/0275001). However, the high required amount of permeation enhancers for oral drug delivery is often toxic and raises safety concerns.

US Pat. No. 4,525,339 U.S. Pat. No. 4,722,941 US Pat. No. 5,318,781 US Pat. No. 5,393,738 US Pat. No. 5,424,289 US Pat. No. 5,597,562 US Pat. No. 5,714,477 US Pat. No. 5,817,624 US Pat. No. 5,827,534 US Pat. No. 5,854,281

  To date, no safe and effective solution has been found for the problem of oral delivery of therapeutic agents with low absorption and bioavailability, particularly for macromolecular biopharmaceuticals. Accordingly, there is a need to develop drug delivery systems that can significantly improve absorption and bioavailability without using excessive amounts of permeation enhancers.

SUMMARY OF THE INVENTION One object of the present invention is to provide non-toxic pharmaceutical compositions that can enhance the absorption and / or bioavailability of less absorbable therapeutic agents. Another object is to provide a pharmaceutical composition with enhanced drug delivery that can adjust the pharmacokinetic profile of a therapeutic agent, is inexpensive, and is relatively easy to manufacture.

  In one embodiment, the present invention comprises a bioadhesive layer comprising a bioadhesive polymer comprising an effective amount of a therapeutic agent, a permeation enhancer, and a pharmaceutically acceptable excipient to form a core. A pharmaceutical composition for drug delivery is provided comprising the formulated solid dosage form.

  In some embodiments, the pharmaceutical composition can be further coated with an enteric material to prevent release of the contents in the stomach and release at a preferred site in the gastrointestinal tract (such as the small intestine). .

  The inventors have surprisingly found that the presence of a bioadhesive polymer layer reduces the amount of permeation enhancer required to significantly improve the absorption and bioavailability of less absorbable therapeutic agents. I found that I could do it.

  In some embodiments, the present invention provides a bioadhesive layer comprising a bioadhesive polymer comprising an effective amount of a therapeutic agent to form a core, a permeation enhancer, and a pharmaceutically acceptable excipient. Solid dosage form coated and further coated with an impermeable or semi-permeable layer having openings capable of inducing substantial unidirectional release of the therapeutic agent and permeation enhancer from the solid dosage form A pharmaceutical composition for drug delivery is provided.

  In some embodiments, the pharmaceutical composition can be further coated with an enteric material to prevent release of the contents in the stomach and release at a preferred site in the gastrointestinal tract (such as the small intestine).

  In some embodiments, the therapeutic agent and permeation enhancer are substantially equivalent in relative release rates from the solid dosage form. Thus, the pharmaceutical composition of the present invention allows the therapeutic agent and permeation enhancer to be localized, limited and capable of substantially simultaneous release, thereby significantly reducing compared to the prior art. The amount of permeation enhancer used can improve the absorption of the therapeutic agent.

  In another aspect, the present invention provides a pharmaceutical composition that can modulate the pharmacokinetic profile of a therapeutic agent. The release kinetics of the therapeutic agent and permeation enhancer can vary in composition and / or ratio of components in the core matrix, composition, ratio, and / or thickness of the bioadhesive polymer layer, depending on the desired therapeutic effect, Or adjusted by differences in the composition, ratio, and / or thickness of the impermeable or semi-permeable layer to obtain a burst or immediate release or long or sustained release profile.

  In yet another aspect, the present invention provides a process for making a solid dosage form comprising an effective amount of a therapeutic agent, a permeation enhancer, and a pharmaceutically acceptable excipient, the solid dosage form comprising a bioadhesive polymer Coating with an adhesive layer and, optionally, the solid dosage form comprising an opening capable of inducing a substantially unidirectional release of the therapeutic agent and permeation enhancer from the solid dosage form A method of making a pharmaceutical composition for drug delivery comprising the step of coating with a layer of or a semi-permeable layer.

  In some embodiments, the order of application of the bioadhesive polymer layer and the impermeable or semi-permeable layer is reversed. In some embodiments, the method further comprises coating the composition with an enteric layer.

  In yet another aspect, the invention relates to a subject in need of therapeutic treatment by administering to a subject a pharmaceutical composition of the invention by oral, nasal, buccal, sublingual, rectal, or vaginal route of administration. A method of treating the body is provided.

FIG. 1 shows the simultaneous release of exenatide and absorption enhancer sodium caprate from a tablet coated with a layer of hydroxypropylmethylcellulose (HPMC) and enteric polymer Eudragit® L30D-55. Show. Figures 2A and 2B show the effect of a one-way release layer on the release kinetics of exenatide and sodium caprate from tablets coated with layers of HPMC and enteric polymer. Figures 3A and 3B show the effect of the bioadhesive layer on the bioavailability of exenatide in the presence of 100 and 400 mg sodium caprate and an enteric layer. FIG. 4 shows the effect of sodium caprate content on the bioavailability of exenatide in the presence of AA1 and enteric layers. FIG. 5 shows the effect of a unidirectional release layer on the bioavailability of exenatide in the presence of 50 mg caprate, HPMC layer, and enteric layer. FIG. 6 shows the effect of a unidirectional release layer on the bioavailability of exenatide in the presence of 100 mg caprate, HPMC layer, and enteric layer. FIG. 7 shows the effect of the enteric layer on the bioavailability of exenatide in the presence of 200 mg sodium caprate, HPMC layer, and unidirectional release layer. FIG. 8A shows 0.01 N HCl with insulin in the presence of 200 mg sodium caprate, HPMC layer, and unidirectional release layer (simulated intestinal fluid (SIF) (pH 6.8) (pH 6.8) (3-7) Time) release kinetics. Figures 8B and 8C show the effect of oral insulin treatment on blood glucose and serum insulin concentrations, respectively, in somatostatin treated dogs. Figures 8B and 8C show the effect of oral insulin treatment on blood glucose and serum insulin concentrations, respectively, in somatostatin treated dogs. FIG. 9 compares the effect of two oral insulin formulations on blood glucose levels in somatostatin treated dogs. The first formulation was a bilayer tablet containing 200 mg sodium caprate, an HPMC layer, and a unidirectional release layer. The second formulation was a three-layer tablet containing 200 mg sodium caprate, an HPMC layer, a one-way release layer, and an enteric outer layer. FIGS. 10A-C show 60 ° C. (FIG. 10A), 92.5% relative humidity at 25 ° C. (FIG. 10B), and 0, 5, and 10 days storage at 4500 lux light exposure (FIG. 10C). Compare the stability of exenatide in various solid formulations. FIGS. 10A-C show 60 ° C. (FIG. 10A), 92.5% relative humidity at 25 ° C. (FIG. 10B), and 0, 5, and 10 days storage at 4500 lux light exposure (FIG. 10C). Compare the stability of exenatide in various solid formulations. FIGS. 10A-C show 60 ° C. (FIG. 10A), 92.5% relative humidity at 25 ° C. (FIG. 10B), and 0, 5, and 10 days of storage at 4500 lux light exposure (FIG. 10C). Compare the stability of exenatide in various solid formulations. FIG. 11 shows the effect of oral insulin administration on blood glucose in normal dogs. The insulin formulation used for this experiment was a trilayer tablet containing 100 sodium caprate, HPMC layer, unidirectional release layer, and enteric layer. FIG. 12 compares exenatide absorption mediated by a unidirectional emissive layer generated by a manual process and a laser ablation process. The exenatide formulation used for this experiment is a bilayer tablet containing 200 mg sodium caprate prepared either by hand or laser ablation, an HPMC layer containing L30D-55 enteric material, and a unidirectional release layer. there were. FIG. 13 shows the dose-dependent effect of oral insulin administration (25 U, 25 U × 2, and 50 U) on blood glucose levels in somatostatin treated dogs. The insulin formulation used for this experiment was a bilayer tablet containing 200 mg sodium caprate, an HPMC layer containing L30D-55 enteric material, and a unidirectional release layer. 14A and 14B show the effect of bioadhesive polymer content in the bioadhesive layer on the kinetics of exenatide release and absorption in normal dogs. The exenatide formulation used for this experiment was a bilayer tablet containing 100 mg sodium caprate, an HPMC layer containing 65% or 80% HPMC and L30D-55 enteric material, and a unidirectional release layer prepared by laser ablation. Met. 14A and 14B show the effect of bioadhesive polymer content in the bioadhesive layer on the kinetics of exenatide release and absorption in normal dogs. The exenatide formulation used for this experiment was a bilayer tablet containing 100 mg sodium caprate, an HPMC layer containing 65% or 80% HPMC and L30D-55 enteric material, and a unidirectional release layer prepared by laser ablation. Met.

DETAILED DESCRIPTION OF THE INVENTION Terms and Definitions Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, published patent applications, and other publications and databases mentioned herein are incorporated by reference in their entirety. If the definitions in this section contradict or otherwise contradict definitions in patents, published patent applications, and other publications and other databases incorporated herein by reference, The definitions in this section take precedence over definitions that are incorporated by reference in the text.

  Citation of a publication or document is not intended to be an endorsement of any such publication or document by any prior art and is without any approval as to the content or date of these publications or documents.

  As used herein, “a” or “an” means “at least one” or “one or more”.

  As used herein, the term “pharmaceutical composition” or “pharmaceutically acceptable formulation” effectively distributes a portion or compound in the physical location most appropriate for its desired activity. Refers to a possible composition or formulation.

  As used herein, the term “effective amount” or “therapeutically effective amount” of an active agent is non-toxic but sufficient to obtain the desired therapeutic or prophylactic effect for most patients or individuals. The amount of drug. It is generally recognized that an effective amount of a pharmacologically active agent can vary depending on the route of administration and the age, weight, and sex of the individual to whom the drug or pharmacologically active agent is administered. Those skilled in the art will consider factors such as metabolism, bioavailability, and other factors that affect the plasma levels of the active agent after administration within the unit dosage ranges further disclosed herein for different routes of administration. It is generally recognized that an appropriate effective amount can be determined accordingly.

  As used herein, the term “pharmaceutically acceptable” refers to a non-toxic, inert composition that is physiologically compatible with humans or other mammals.

  As used herein, the term “pharmaceutical excipient” refers to materials such as adjuvants, carriers, pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, and preservatives.

  As used herein, the terms “subject”, “individual”, “host”, and “patient” are used interchangeably to refer to an animal that is the subject of treatment, observation, and / or experimentation. To do. The term “animal” includes vertebrates and invertebrates (such as fish, crustaceans, reptiles, birds, especially mammals). The term “mammal” includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates (such as monkeys, chimpanzees, and apes, particularly humans). Not.

  As used herein, the term “treatment” repairs or prevents a disease or infection state or symptom, or otherwise prevents, prevents, delays, progression of disease / infection or other undesirable symptoms, Or any and all uses that reverse. As used herein, the terms “treatment” and “treatment” refer to any improvement or amelioration of any outcome of the disease and need not be completely eradicated. Improvement of the symptoms of a particular disorder refers to any alleviation of symptoms that may contribute to or be associated with administration of the therapeutic composition of the present invention, whether persistent or transient.

  As used herein, the term “administration” or “administration” refers to any method suitable for providing a subject with a composition of the invention. The pharmaceutical compositions of the invention can be administered by the oral, nasal, buccal, sublingual, rectal, or vaginal route of administration. The pharmaceutical composition can be formulated in dosage unit formulations suitable for each route of administration.

  As used herein, the term “solid dosage form” includes solids (tablets, caplets, capsules (such as those made from hard or soft materials such as gelatin or natural or synthetic gelatin substitutes). ), Lozenges, and combinations thereof, and the like.

  As used herein, the term “permeation enhancer” refers to an agent that improves the transport rate of a pharmacologically active agent across a mucosal surface. Typically, permeation enhancers increase the permeability of mucosal tissue to therapeutic agents. For example, permeation enhancers increase the rate at which the therapeutic agent penetrates the membrane and enters the bloodstream. Enhancement of permeation using permeation enhancers can be observed, for example, by measuring the flow of pharmacologically active agents across animal or human membranes. As used herein, an “effective” amount of permeation enhancer desirably increases mucosal permeability, thereby obtaining, for example, the desired absorption and / or bioavailability of a selected compound. Refers to the amount to be produced.

  As used herein, the term “bioadhesive” generally refers to any adhesive that binds living tissue and / or body fluids. The term “bioadhesive layer” refers to a solid layer intended to adhere to the mucosal tissue of a subject. The bioadhesive layer includes at least one “bioadhesive polymer”. The bioadhesive layer is composed of carbomer, polycarbophil, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyvinyl alcohol, sodium hyaluronate, chitosan, alginate, xantum gum, acrylic acid polymer, and derivatives thereof. And can be selected from, but not limited to, mixtures.

  As used herein, the term “impermeable or semipermeable” refers to the flow of physiological fluids and components contained within a drug delivery system through an impermeable or semipermeable material. A material that is sufficiently impermeable so that the movement of animals and components into and out of the system is so slow that it does not substantially adversely affect the function of the system.

  As used herein, the term “substantially unidirectional release” refers to greater than about 50%, greater than 60%, greater than 70%, preferably approximately about the therapeutic agent and permeation enhancer included in the solid dosage form. More than 80%, more preferably more than about 90%, most preferably more than about 95% from a solid dosage form in the same unidirectional direction defined by an opening in an impermeable or semi-permeable layer Means released.

  As used herein, the term “substantially equivalent relative release rate” refers to substantially simultaneous release of a therapeutic agent and a permeation enhancer from a solid dosage form (ie, at a given time). The difference between the release portion (%) of the therapeutic agent released and the release portion of the permeation enhancer is less than about 50%, less than 40%, less than 30%, preferably less than about 20%, more preferably about Less than 10%, most preferably less than about 5%).

  As used herein, the terms “enteric coating”, “enteric layer”, “enteric material”, and “enteric polymer” apply to solid dosage forms and are used in the oral cavity, esophagus, or A mixture of pharmaceutically acceptable excipients that prevents the release of the active ingredient in the stomach but allows rapid and complete release of the drug when the dosage form passes through the proximal part of the lower gastrointestinal tract. The enteric layer preferably comprises about 1-15%, more preferably about 3-12%, and most preferably about 6-10% by weight, based on the combination of solid dosage form weight and coating weight. Enteric coating polymers may be cellulose acetate phthalate (Eudragit® S or L), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate, It can be selected from, but not limited to, shellac and methacrylic acid copolymers. The thickness of the coating is selected to obtain the desired release rate depending on the nature and thickness of the coating.

As used herein, the term “plasticizer” refers to a material that can be incorporated into a pharmaceutical composition to reduce the glass transition temperature and melt viscosity of a polymer by increasing the free volume between polymer chains. . Plasticizers include citrate esters (eg, triethyl citrate, triacetin), low molecular weight polyalkylene oxides (eg, polyethylene glycol, polypropylene glycol, polyethylene / propylene glycol), glycerol, pentaerythritol, glycerol monoacetate, diacetate, Or including, but not limited to, triacetate, propylene glycol, and diethyl sodium sulfosuccinate. The plasticizer can be present at a concentration of about 0.1 to about 25%, preferably about 0.5 to 15% or about 1 to 20% by weight of the pharmaceutical composition. Further examples of plasticizers are described in M.M. & I. ^{Ash, THE HANDBOOK OF PHARMACEUTICAL ADDITIVES (} 3 rd ed., Synapse Information Resources, Inc., 2007) can be found in.

  Throughout this disclosure, various aspects of this invention can be presented in a range format. It should be understood that the description in range format is for convenience and brevity only and should not be construed as limiting the scope of the invention invariably. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges and numerical values within that range. For example, descriptions of ranges such as 1-6 are specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 2-6, and the like. Each numerical value within the range (eg, 1, 2, 3, 4, 5, and 6) should be considered. This applies regardless of the breadth of the range.

Drug Delivery System As described above, the present invention comprises a bioadhesive layer comprising a bioadhesive polymer comprising an effective amount of a therapeutic agent to form a core, a permeation enhancer, and a pharmaceutically acceptable excipient. A pharmaceutical composition for drug delivery comprising a solid dosage form of tablets, patches, discs, or powders further coated with.

  In some embodiments, the pharmaceutical composition is further coated with an enteric material for release at a preferred site in the gastrointestinal tract.

  Despite the common practice of coating membranes with polymers such as hydroxypropylmethylcellulose, polyvinyl alcohol, and polyethylene glycol to enhance the enteric coating process, the inventors have surprisingly found that bioadhesive polymers It has been found that the presence of a layer can reduce the amount of permeation enhancer required to significantly improve the absorption and bioavailability of low absorption therapeutics.

  Examples of the disclosed pharmaceutical compositions are given in the examples. In the examples, the permeation enhancer is sodium caprate and the drug tested is exenatide (a 39 amino acid peptide) (commercially available from Amylin and Eli Lilly as BYETTA® for the treatment of type 2 diabetes). there were. In the prior art, the required amount of sodium caprate to achieve significant absorption enhancement ranged from 275 to 550 mg in dogs (US Patent Application Publication No. 2008/0275001). Enteric coated formulations containing smaller amounts of sodium caprate (115-120 mg) have been found to be ineffective in the same animal model (Burcham et al., Pharm. Res., 1995, 12 (12): 2065-2070).

  In accordance with the prior art, the inventors have found that formulations containing only 100 mg sodium caprate are also ineffective. Surprisingly, however, formulations containing the same amount of sodium caprate (100 mg) and the bioadhesive layer were equivalent or more effective compared to formulations containing only higher amounts of sodium caprate. Further enhancement of absorption was observed when the bioadhesive layer was incorporated into a formulation containing higher amounts of sodium caprate (400 mg). It was completely unexpected that the presence of the bioadhesive layer affected the required amount of permeation enhancer to such a substantial range.

  In some embodiments, the present invention provides a bioadhesive layer comprising a bioadhesive polymer comprising an effective amount of a therapeutic agent to form a core, a permeation enhancer, and a pharmaceutically acceptable excipient. Further coated and then further coated with an impermeable or semi-permeable layer having openings that can induce a substantial unidirectional release of the therapeutic agent and permeation enhancer from the solid dosage form. Pharmaceutical compositions for drug delivery comprising solid dosage forms of tablets, patches, disks, or powders are provided.

  In some embodiments, the pharmaceutical composition can be further coated with an enteric material for release at a preferred site in the gastrointestinal tract. Surprisingly, it has been found that this composition can further reduce the amount of permeation enhancer without adversely affecting enhanced absorption.

  The prior art includes different examples of unidirectional release dosage forms. For example, US Pat. Nos. 4,772,470 and 5,827,525 disclose patches or oral dressings for oral drug administration. Similarly, oral patch formats that include a site selective layer, a drug, an adhesive layer, and an impermeable layer are described in US Pat. No. 7,097,851 and numerous non-patent publications (eg, S. Eimtrakarn et al., Biomaterials, 2002, 23 (1): 145-152; S. Eimtrakarn et al., Intl. J. Pharm., 2003, 250 (1): 111-117; and SL Tao & TA Desai, Drug Discov.Today, 2005, 10 (13): 909-915). Bioadhesive patches coated with an impermeable ethylcellulose layer have been reported to deliver insulin in a rat in situ model, and permeation enhancers have been found to be unimportant to the action of this delivery system (K. Whitehead). Et al., J. Control. Release, 2004, 98 (1): 37-45). All these publications are incorporated herein by reference in their entirety.

  In particular, although numerous patents and non-patent publications disclose oral patch formats and unidirectional release dosage forms, no subsequent commercial application has been reported in this pharmaceutically important field. This indicates that the oral patch format continues to pose serious technical difficulties.

  The effect of the unidirectional release layer on exenatide absorption and bioavailability in the presence of sodium caprate is shown in Example 6. Exenatide absorption in dogs was minimal in formulations containing 50 mg sodium caprate but no unidirectional release layer. This was consistent with previous reports in the field (US Pat. No. 7,605,123). However, exenatide absorption was significantly enhanced when the unidirectional release layer was applied. The coating material can be either impermeable or semi-permeable.

  It is known in the art that permeation enhancers often require a certain minimum effective concentration. For example, the concentration of sodium caprate required to achieve a permeation enhancing effect is estimated to be at least 10-13 mM (EK Anderberg et al., Pharm. Res., 1993, 10 (6): 857- 864). The release of permeation enhancers needs to be relatively rapid and the release of therapeutic agents must be substantially simultaneous to avoid rapid dilution in the gastrointestinal tract in a constant flow of fluid. Is further recognized. For example, US Patent Application Publication No. 2008/0275001 discloses immediate release (IR) and sustained release (SR) formulations of low molecular weight heparin containing sodium caprate as a permeation enhancer. When considering the same amount of sodium caprate, the sustained release formulation was significantly less effective than the immediate release formulation.

  Thus, it has been found that formulations containing a further impermeable or semi-permeable layer and having a broad release profile compared to simpler formulations show a relatively high level of absorption enhancement. Was a surprise. We use unidirectional release formulations to determine the thickness of the impermeable or semipermeable layer, the plasticizer used to modify the impermeable or semipermeable material. It has further been found that the pharmacokinetic profile of a therapeutic agent can be adjusted by changing the content and nature, as well as the size of the opening. In some embodiments, the therapeutic agent and permeation enhancer are released from the pharmaceutical composition in a substantially simultaneous manner. In some embodiments, the pharmaceutical composition has a prolonged release time and is capable of sustained absorption.

Therapeutic Agents In some embodiments, the therapeutic agent to be delivered has low absorption in the gastrointestinal tract and is biopharmaceutical classification system (BCS) classification (Food and Drug Administration, “Guidance for Industry: Waive of In Vivo Bioavailability) and Bioequivalence Studios for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceuticals Classification System ”).

  In some embodiments, the hypoabsorbent therapeutic agent is acetylcysteine, acamprosate, acyclovir, albendazole, alcuronium, alendronate, alfuzosin, alprazolam, alprostadil, amikacin, aminobisphosphonate, amiodarone, amitriptyline, amlodipine , Amoxiline, Amphetamine, Amphotericin B, Ampicillin B, Ampicillin, Artemether, Artesunate, Aspirin, Atazanavir, Atenolol, Atomoxetine, Atorvastatin, Atropine, Azithromycin, AZT, Bacitracin, Beclomethasone, Benzanthine benzylpenicillin, benzylpenicenline Bupivacaine, buprenorphine, bupropion, candesartan, potassium Doxatoryl, capreomycin, captopril, carbamazepine, carbidopa, carvedilol, caspofungin, cefazolin, cefdinir, cefixime, cefotaxime, ceftazidime, ceftriaxone, celecoxib, chlorambucil, chloramphenicol, chloroquine, chlorfenazidin, chlorprozine, chlorprozine Profloxacin, clarithromycin, clofazimine, clomipramine, clonidine, clopidogrel, clotrimazole, cloxacillin, cyclophosphamide, cyclosporine, cytarabine, d-9-tetrahydrocannabinol, dacarbazine, dactinomycin, danazol, dapsone, daunorubicin , Deferoxamine, desipramine, dexamethasone, didanoshi , Diethylcarbamazine, digoxin, dihydroergotamine, diltiazem, dimercaprol, dolarzine, domperidone, domperidone, dopamine, doxazosin, doxetaxel, doxorubicin, duloxetine, efavirenz, efflornitine, enalapril, emprostilin, epinetroel Esomeprazole, estradiol, eszopiclone, etoposide, ezetimibe, famotidine, felodipine, fenofibrate, fentanyl, fexofenadine, finasteride, flucytosine, fludrocortisone, fluorouracil, fluoxetine, flufenadine, flurbiprofen, fluticazone, fluticasone , Formoterol, furosemide, moth Bapentine, ganciclovir, gemcitabine, gentamicin, glibenclamide, glimepiride, glyceryl trinitrate, griseofulvin, griseofulvin, haloperidol, hydralazine, hydrochlorothiazide, hydrocortisone (hydrocortizone), hydroxocobalamin, ibandronic acid, ibuprofen, imiproneimine , Irinotecan, isocyanide, isosorbide dinitrate, itraconazole, kanamycin, ketoconazole, ketoprofen, labetalol, latanoprost, levamisole, levodopa, lidocaine, lisinopril, loperamide, lopinavir, losartan, lovastatin, benmefazoleme Gesterone, mefloquine, meglumine antimonate, meralsoprole, mercaptopurine, mesna, metformin, methadone, methotrexate, methyldopa, methylphenidate, methylthioninium chloride, metoprolol, mifepristone, misoprostol, modafinil, mometasone, montelukast, Morphine, nadolol, naloxone, naproxen, neostigmine, nevirapine, niclosamide, nifedipine, niflutimox, nitrofurantoin, norethisterone, nortriptyrene, nystatin, ofloxacin, olmesartan, omeprazole, ondansetron, oxaliplatin, paclitaxel, paclitaxel, paclitaxel Salicylic acid, paromomycin, pemetrexed, penicillamine, pe Tamidine, phenoxymethylpenicillin, phenylacetate mustard, phenytoin, phytomenadione, plant sterol, piroxicam, pilocarpine, piperacillin, pravastatin, praziquantel, prazosin, prednisolone, prednisone, procaine benzylpenicillin, procarbazine, progesterone, progesterol, prologranol , Propylthiouracil, prostaglandin, pyrantel, pyridostigmine, quetiapine, quinidine, quinine, rabeprazole, raloxifene, ramipril, ranitidine, rapamycin, ribavirin, risedronic acid, ritonavir, ropinirole, rosuvastatin, salbutamol, salicylicol, salmeterol, sallicymol cell Toraline, sildenafil, simvastatin, sodium nitroprusside, spectinomycin, stavudine, steroids, stibogluconate, stigmasterol, sulfadoxine, sulfamethoxazole, sulfasalazine, sumatriptan, suramin, skisamethonium, tacrolimus, tadalafil , Tamoxifen, tegaserod, telmisartan, temozolomide, tenidap, tenofovir, tenofovir disoproxil fumarate, terfenadine, testosterone, tetracaine, tetracycline, timolol, tiotropium, triamcinalone, triclabendazole, trovafloxacin, tubocaraline, ubiquinone, ubiquinone Valproic acid, valsartan, vancomycin, vardena I le, vecuronium, venlafaxine, verapamil, vinblastine, vincristine, vitamin B12, zidovudine, ziprasidone, zoledronic acid, zolpidem, salts thereof, selected analog, and from the group consisting of derivatives.

  In some embodiments, the therapeutic agent comprises a therapeutic agent that is selectively absorbed at a particular site of absorption, including but not limited to the upper small intestine. Therapeutic agents include, but are not limited to, riboflavin, levodopa, melformin, and furosemide.

  In some embodiments, the therapeutic agent comprises a biologically active macromolecule selected from proteins, peptides, polysaccharides, nucleic acids, lipids, carbohydrates, or combinations thereof.

  In some embodiments, the protein is antithrombin, albumin, alpha-1-proteinase inhibitor, antihemophilic factor, coagulation factor, antibody, anti-CD20 antibody, anti-CD52 antibody, anti-CD33 immunotoxin, DNase, erythropoietin , Factor IX, factor VII, factor VIII, follicle stimulating hormone, granulocyte colony stimulating factor (G-CSF), pegylated G-CSF, galactosidase alpha or beta, glucagon, glucocerebrosidase, granulocyte-macrophage colony Stimulating factor (GM-CSF), chorionic gonadotropin, hepatitis B antigen, hepatitis B surface antigen, hepatitis B core antigen, hepatitis B coat antigen, hepatitis C antigen, hirudin, anti-HER-2 antibody, anti IgE antibody, anti-IL-2 receptor antibody, insulin, insulin glargine, insulin aspal , Insulin detemir, insulin lispro, interferon, pegylated interferon, interferon alpha or alpha 2a or alpha 2b or consensus, interferon beta or beta-1a or beta-1b or betacer, interferon gamma, interleukin-2, interleukin-11, interleukin-11 Leukin-12, luteinizing hormone, nesiritide, bone morphogenetic protein-1, bone morphogenetic protein-2, lime vaccine, platelet-derived growth factor, antiplatelet antibody, anti-RSV antibody, somatotropin, antitumor necrosis factor (TNF) ) Antibody, TNF receptor-Fc fusion protein, tissue plasminogen activator (tPA), TNK-tPA, thyroid stimulating hormone (TSH), fibrinolytic enzyme, blood Lytic enzyme, adenosine deaminase, pegylated adenosine deaminase, anistreplase, asparaginase, collagenase, streptokinase, sucrase, urokinase, aprotinin, botulinum toxin, fibroblast growth factor, vascular endothelial growth factor, venom, antibody, antibody fragment, and It is selected from the group consisting of any combination. Proteins can be produced by recombinant technology, chemical synthesis, or extracted from biological sources. Proteins also include wild type modified analogs or derivatives. The protein source can be human or derived from other species.

  In some embodiments, the peptide is ACTH, an anti-angiogenic peptide, Adamtosostatin, adiponectin, lipid mobilization hormone, diponutrin, fat desneutrin, adrenomedullin, agouti related protein, allarin, allatostatin, amelogenin, calcitonin, amylin , Amyloid, angiopoietin, angiotensin, anorexia-inducing peptide, anti-inflammatory peptide, antidiuretic factor, antibacterial peptide, apelin, apidecin, RGD peptide, atrial natriuretic peptide, atriopeptin, auricrine, autotaxin , Bombesin, Bombinakinin, Brandykinin, Brain natriuretic peptide, Brain-derived neurotrophic factor, Brevinin, C-peptide, Caspase inhibitor, Pancreas Polypeptide, buccalin, brucine, C-type natriuretic peptide, calcitonin related peptide, calcitonin receptor stimulating peptide, calmodulin, CART, calcyrostatin, casomokinin, casomorphin, catestatin, cathepsin, cecropin, cerebelline, chemerin, cholecystokinin, chromogranin Ciliary neurotrophic factor, conantkin, conopressin, conotoxin, copeptin, cortical androgen stimulating hormone, corticotropin releasing factor, cortisatin, conjugate factor, defensin, delta sleep-inducing peptide, delmorphin, vasopressin, desamino-vasopressin, diuretic hormone, Dynorphin, endokinin, endomorphin, endorphin, endostatin, endothelin, enkephalin Enterostatin, exendin, exendin-4, erythropoietic peptide, epidermal growth factor, fat targeting peptide, galanin, gastric inhibitory peptide, gastrin, gastrin releasing peptide, ghrelin, glucagon, glucagon-like peptide, glutathione derivative, gluten exo Ruffin, growth hormone releasing factor, GM-CSF inhibitor peptide, growth hormone peptide, guanylin, HIV peptide, herodemine, hemokinin, HCV peptide, HBV peptide, HSV peptide, herpes virus peptide, hirudin, hydra peptide, insulin-like growth factor, hydrin , Intermedin, cassinine, keratinocyte growth factor, kinetensin, kininogen, kisspeptin, kyotorphin, laminin peptide, leptin peptide , Leucokinin, leucopyrokinin, leupeptin, luteinizing hormone-releasing hormone (LHRH), lymphokine, melanin-concentrating hormone and its inhibitor, melanocyte stimulating hormone-releasing inhibitor, melanotropin promoter, morphine-regulating neuropeptide, MSH, neoendorphin, nesfatin, neuro Kinin, neuromedin, neuropeptide Y, neurotensin, neurotrophic factor, nociceptin, obestatin, opioid receptor antagonist, orexin, osteocalcin, oxytocin, pancreatatin, peptide YY, fisalemin-like peptide, secretin, somatostatin, sperm activation peptide, Substance P, syndiphalin, thrombospondin, thymopoietin, thymosin, thyroid From the group consisting of stimulating hormone-releasing hormone, transforming growth factor, tuftsin, tumor necrosis factor antagonist or related peptide, usrexakikinin, urocortin, urotensin antagonist, barolphine, vasotocin, VIP, xenopsin or related peptide, and any combination thereof Selected. Peptides can be produced by recombinant technology, chemical synthesis, or extracted from biological sources. Peptides include modified analogs or derivatives of wild type proteins. The peptide source can be human or derived from other species.

  In some embodiments, the biologically active macromolecule is an adenovirus, anthrax, BCG, Clostridium botulinum, cholera, diphtheria toxin, diphtheria and tetanus toxin, diphtheria tetanus and pertussis, hemophilus B, type A Hepatitis, hepatitis B, influenza, encephalitis, measles, mumps, rubella, meningococcus, plague, whooping cough, pneumococci, polio, rabies, rotavirus, rubella, smallpox, tetanus toxin, typhoid fungus, chickenpox, yellow A vaccine against a microorganism selected from the group consisting of fever, bacterial antigens, and any combination thereof.

  In some embodiments, the biologically active macromolecule is selected from the group consisting of dust mites, animal dander, mold, pollen, ragweed, latex, bee venom, and insect-derived allergens, and any combination thereof. Is an allergen.

  Biologically active macromolecules include combinations of macromolecules with similar biological functions, including combinations of wild type molecules and their chemically or biologically modified analogs. be able to. Examples of such wild-type macromolecules and analogs include, but are not limited to, glucagon-like peptide 1 (GLP-1) and analogs thereof, liraglutide, taspoglutide, arubyglutide, lixenatide, and exenatide and analogs and any combinations thereof. Not.

  In some embodiments, the therapeutic agent is exenatide, a 39-amino acid peptide (commercially available from Amylin and Eli Lilly as BYETTA® for the treatment of type 2 diabetes) and salts and functional derivatives (pegylated exenatide Etc.), exenatide fusion proteins (such as albumin), transferrin, XTEN, Fc fusions, and fatty acid modified derivatives thereof.

Permeation enhancers As noted above, a number of permeation enhancers are known in the art. In some embodiments, the permeation enhancer is from the group consisting of fatty acids, medium chain glycerides, surfactants, steroidal detergents, acylcarnitines, alkanoylcholines, N-acetylated amino acids, and esters, salts, and derivatives thereof. Selected.

  In some embodiments, the permeation enhancer is a fatty acid (butyric acid, caproic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, linoleic acid, linolenic acid. Acids, including, but not limited to, linolinic acid, salts, derivatives, and any combination thereof. In some embodiments, the permeation enhancer is a fatty acid (butyric acid, caproic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, oleic acid, linoleic acid, linolenic acid. Glycerides of acids (including, but not limited to, linolinic acid, salts, derivatives, and any combination thereof). The glycerides can be monoglycerides, diglycerides, or triglycerides. And a fatty acid can contain the same or different fatty acid. In some embodiments, the permeation enhancer comprises a fatty chain having 8-14 carbon atoms.

  In some embodiments, the permeation enhancer is a bile acid or salt (conjugated or unconjugated bile acid (cholate, deoxycholate, taurocholate, glycocholate, taurodeoxycholate, ursodeoxycholate, tauroursodeoxycholate, chenodeoxyl Collate, its derivatives and combinations thereof).

  In some embodiments, the permeation enhancer is a metal chelator (such as EDTA or EGTA), a surfactant (sodium dodecyl sulfate, polyethylene ether or ester, polyethylene glycol-12 lauryl ether, salicylate, polysorbate 80 (Tween 80 ( Registered trademark)), nonylphenoxypolyoxyethylene, sodium dioctylsulfosuccinate, saponin, palmitoylcarnitine, lauroyl l-carnitine, dodecylmaltoside, acylcarnitine, alkanoylcholine, and any combination thereof. Other permeation enhancers include 3'-nitrobenzoate, closure zone toxins, fatty acid esters of lactate, glycyrrhizinate, hydroxyl β-cyclodextrin, N-acetylated amino acids (N- [8- (2-hydroxy Benzoyl) amino] sodium caprylate, and chitosan), salts and derivatives of these compounds and combinations thereof.

  In some embodiments, permeation enhancers include compounds that selectively target and open tight junctions (eg, chitosan and its derivatives). In some embodiments, the permeation enhancer is capric acid or a salt or derivative thereof.

Formulations and Excipients As noted above, the present invention provides pharmaceutical compositions comprising, among other things, pharmaceutically acceptable excipients. The pharmaceutical composition may be in the form of a capsule, tablet, pellet, patch, or disc. Suitable excipients and their formulations are known in the art and are described in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (21 ^st ed., Lippincott Williams & Wilkins, 2005), the relevant terms of which are It is incorporated in the specification.

  In some embodiments, pharmaceutically acceptable excipients include materials that aid in carrier dispersion. In some embodiments, the pharmaceutical excipient comprises a disintegrant. In some embodiments, the pharmaceutical excipient comprises polyplastidone, croscarmellose, crospovidone, starch glycolate, hydroxypropylcellulose, and any combination thereof.

  The pharmaceutical composition contains other ingredients such as buffers, preservatives, nonionic surfactants, solubilizers, absorption enhancers, stabilizers, softeners, lubricants, and isotonic agents. Can do. The composition can be formulated so that the drug is controlled release.

  The pharmaceutical composition may be in a form suitable for oral use (eg, as a tablet, troche, lozenge, or hard or soft capsule). Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, such as obtaining pharmaceutically stable and delicious preparations, for example. One or more agents for the purpose, such as sweeteners, flavoring substances, coloring agents, and preservatives.

  Excipients used in tablets include, for example, inert diluents or fillers such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, microcrystalline cellulose, sucrose, mannitol, and sorbitol. A granulating or binding agent (such as polyvinylpyrrolidone, polyethylene glycol, or hydroxypropylmethylcellulose, gelatin, starch, or combinations thereof), lubricant (eg, magnesium stearate, silica powder, stearic acid, or talc) may be included. . In the exemplary formulations disclosed herein, excipients comprising the core formulation include the following.

In some embodiments, the amount of permeation enhancer, particularly sodium caprate, in the formulation is about 400 mg, about 300 mg, about 200 mg, about 100 mg, about 50 mg, or about 25 mg, preferably about 200 mg, about 100 mg, Or about 50 mg, more preferably about 100 mg. In some embodiments, the sodium caprate content ranges from about 25-300 mg, about 50-200 mg, or about 100-200 mg.

  The presence of hydroxypropyl methylcellulose (HPMC) in the core modulates the permeation enhancer release profile and therapeutic agent adhesion of the core formulation. Various viscosity HPMCs can be incorporated in ratios or combinations that can tailor the adhesion of the core. The example shows...

  The polymeric drugs incorporated in the present invention are often very powerful and the drug content in the core formulation is as low as about 1%, about 0.1%, or about 0.01%. Low dose formulations such as these often face great difficulty in quality control aspects, including stability, content uniformity, and analytical methods. Often, it is necessary to devise a process to ensure the stability of the therapeutic agent while maintaining content uniformity.

  High dose drug formulations tend to have different difficulties (such as compactability and fluidity difficulties) compared to low dose formulations.

  In some embodiments, the formulation is prepared from U.S. Patent Application Publication No. 2005/0234114, U.S. Patent Application No. 12 / 434,557, and PCT Publication Nos. WO 2005/084637 and WO 2009/135190 (all in its entirety). Can further comprise calcium phosphate nanoparticles, as described in US Pat.

  The pharmaceutical compositions of the invention can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be combined with pharmaceutical compositions and suitable non-irritating excipients (solid at ambient temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug ). Such materials include, but are not limited to, cocoa butter and polyethylene glycol.

  The pharmaceutical compositions of the invention can also be administered via the vaginal route. Formulations suitable for vaginal administration include, but are not limited to, pessaries, tablets, or tampons.

  Pharmaceutical compositions for administration of the compounds of the invention can conveniently be presented in dosage unit form and can be prepared by any method well known in the pharmaceutical art.

Bioadhesive layer As discussed above, the core pharmaceutical composition of the present invention is coated with a bioadhesive layer comprising a bioadhesive polymer. In some embodiments, the bioadhesive layer is coated in direct contact with the solid dosage form. In other embodiments, there can be one or more intermediate layers between the solid dosage form and the bioadhesive layer. In some embodiments, an impermeable or semi-permeable layer is disposed between the solid dosage form and the bioadhesive layer. Alternatively, the bioadhesive layer can be disposed between the solid dosage form and the impermeable or semi-permeable layer.

  In some embodiments, the bioadhesive layer comprises a bioadhesive polymer that can adhere to a desired target site, such as the gastrointestinal tract. Bioadhesive polymers include carbomer, polycarbophil, chitosan, alginate, thiomer, gelatin, hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, fumaric acid Anhydride oligomers, polyesters, polyacrylates, polysaccharides, modified dextrans, sodium hyaluronate, pectin, xanthan gum, and salts, derivatives, and mixtures thereof may be included, but are not limited to these.

  In a preferred embodiment, the bioadhesive layer comprises hydroxypropyl methylcellulose (HPMC) or polycarbophil AA1.

  In some embodiments, the bioadhesive layer comprises a composite of materials, such as bioadhesive polymers, plasticizers, or other materials to adjust the release rate. It is desirable to contain a large amount of bioadhesive material. In some embodiments, the bioadhesive polymer content comprises greater than about 50%, greater than about 65%, about 75%, greater than about 80%, or greater than about 90%.

  In some embodiments, the bioadhesive layer comprises an enteric material (cellulose acetate phthalate (Eudragit® S or L), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate). Trimellitate, polyvinyl acetate phthalate, methacrylic acid copolymer, shellac, and salts, derivatives, and any combinations thereof).

  The presence of enteric material in the bioadhesive layer allows the dosage to be completely retained in the stomach and is released and absorbed in the intestine where the pH increases. Often, a high proportion of enteric material (such as about 50% or more) is required to maintain acid stability. Thus, it is very surprising that dosage acid stability is observed even when a low proportion of enteric material of about 10-20% is used.

  In some embodiments, the content of enteric material in the bioadhesive layer ranges from about 5-50%, preferably about 10-35%, more preferably about 15-25%.

  In some embodiments, the bioadhesive layer can further include a plasticizer (such as glycerol, triacetin, polyvinyl alcohol, polyethylene glycol, derivatives thereof, and any combination thereof). In some embodiments, the plasticizer in the bioadhesive layer ranges from about 1-35%, preferably about 5-25%, more preferably about 10-15%.

  In some embodiments, the bioadhesive layer is in the range of about 0.5% to about 10%, preferably about 1-5%, more preferably about 2-3% by weight of the pharmaceutical composition. It can be present in content.

  In some embodiments, the thickness of the bioadhesive layer can be adjusted to achieve the desired release kinetics and absorption.

  Once the desired pH is reached, the enteric material dissolves rapidly. The dissolution rate between the bioadhesive layer containing the enteric material and the enteric layer is expected to be similar, as the abundance of the bioadhesive in the composition and the enteric layer in the enteric layer is not significantly different. Will.

  Therefore, it is very likely that there will be more rapid absorption and pharmacological effects from formulations using bioadhesive layers containing enteric materials compared to formulations containing enteric layers containing the same enteric material Surprisingly.

  This surprising finding suggests that formulations using enteric materials incorporated into the bioadhesive layer can increase the absorption area in the intestine and achieve a faster clinical response (generally more desirable) doing.

  Formulations using enteric materials incorporated into the bioadhesive layer reduce the need for coating and simplify the manufacturing process. Thereby, the production time and subsequent costs for producing the desired formulation are reduced.

Impermeable or semi-permeable layer As discussed above, an impermeable or semi-permeable layer is used to improve the absorption and bioavailability of low-absorbency therapeutics Adjust release kinetics and further reduce the amount of permeation enhancer. In some embodiments, the impermeable or semi-permeable layer includes an opening that can induce substantial unidirectional release of the therapeutic agent and permeation enhancer from the solid dosage form. The size and shape of the opening will necessarily depend on the nature of the solid dosage form and the desired release kinetics. The determination of the size of the opening is well within the skill of a person skilled in the art. In some embodiments, the opening can completely cover one side of the tablet or caplet.

  In some embodiments, the opening of the one-way release tablet covers about 20-90%, preferably about 40-80%, more preferably about 50-70% of the area of one side of the tablet. .

  The opening of the unidirectional release tablet can have any shape (eg, circular, triangular, square, rectangular, rhombus, parallelogram, trapezoid, or any other shape).

  In some embodiments, the impermeable or semi-permeable layer comprises one or more hydrophilic polymers and / or one or more hydrophobic polymers. Examples of hydrophilic polymers include protein-based polymers (eg gelatin or casein), pectin, agarose (agar), chitosan, carrageenan, starch, dextran, methylcellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose, sodium carboxymethylcellulose Polymers (eg, croscarmellose sodium), microcrystalline cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose ether, cellulose acetate, cellulose acetate phthalate, other cellulose derivatives , Polyvinyl alcohol, polyvinylpyrrolidone (PV ), Cross-linked povidone, other vinyl polymers and copolymers, guar gum, poloxamer, polyethylene glycol, polyethylene oxide, polyacrylic acid, polyether, alkoxy polymer, sodium alginate, xanthan gum, other natural hydrogels or hydrogels derived from natural products, or the like Combinations are included, but are not limited to these. Examples of hydrophobic polymers include ethyl cellulose, polyester (polycaprolactone (PCL), polyesteramide (PEA), polyhydroxyalkanoate (PHA), polylactic acid (PLA), polylactic glycolic acid (PLGA), poly Hydroxybutyrate-co-hydroxyvalerate (PHBV) and polybutylene succinate adipate (PBSA), waxes and low melting waxes, polyethylene and ethylene copolymers, ethylene / vinyl acetate, polypropylene, polyurethane, ethylene / vinyl Examples include, but are not limited to, alcohol, polyvinyl alcohol, polyvinylidene, polyolefin, or combinations thereof.

  In some embodiments, the impermeable or semi-permeable layer further comprises a solvent or plasticizer that makes the layer more flexible. The solvent can be any solvent that is compatible with the impermeable or semipermeable material, including, for example, water and ethanol. Examples of plasticizers include citrate esters (eg, triethyl citrate, triacetin), low molecular weight polyalkylene oxides (eg, polyethylene glycol, polypropylene glycol, polyethylene / propylene glycol), glycerol, pentaerythritol, glycerol monoacetate, These include, but are not limited to, diacetate or triacetate, propylene glycol, sodium diethylsulfosuccinate, sugar alcohol, corn syrup, and any combination thereof.

  In some embodiments, the impermeable layer comprises an ethylcellulose polymer combined with glycerol, polyethylene glycol, or triacetin as a plasticizer. In some embodiments, the semipermeable layer comprises cellulose acetate combined with polyethylene glycol, triacetin, or glycerol as a plasticizer.

  In some embodiments, the plasticizer content in the impermeable or semi-permeable layer ranges from 5-40%, preferably 10-30%, more preferably 15-25%. .

  In some embodiments, the impermeable or semi-permeable layer is about 0.5 to about 10%, preferably about 1 to 5%, more preferably about 2 to 2% by weight of the pharmaceutical composition. It can be present in a content in the range of 4% by weight.

The impermeable layer can further include other ingredients such as preservatives, preservatives, and other ingredients to improve the stability of the pharmaceutical composition. Examples of additional plasticizers and components are & I. Ash, THE HANDBOOK OF PHARMACEUTICAL ADDITIVES can be found in ^{(3 rd ed., Synapse Information} Resources, Inc., 2007) ( related terms are incorporated herein).

  In some embodiments, the unidirectional opening on the formulation is formed by a laser ablation process commonly used in the generation of osmotic pumps. Unlike osmotic pump tablets, the one-way mouth is much larger (3-9 mm diameter compared to less than 0.5 mm diameter for a typical 10 mm diameter tablet) and the coating is thinner. Accordingly, different laser light source and device arrangements must be adapted for the present invention.

Enteric Layer In some embodiments, a pharmaceutical composition of the invention comprises a core formulation coated with a bioadhesive layer and is further selected in the gastrointestinal tract by further coating a unidirectional layer with a site selective agent. Drug can be released at the site. In some embodiments, the site selective agent comprises a pH sensitive polymer that can be dissolved in an environment having a constant pH value. Coating with a site selective agent allows the carrier to selectively expose the adhesive layer to certain areas of the gastrointestinal tract.

  Enteric coating polymers include cellulose acetate phthalate, Eudragit® S or L, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate, methacrylic acid. It can be selected from, but not limited to, acid copolymers, shellac, salts and derivatives thereof, and any combination thereof. In one particularly preferred embodiment, the enteric coating polymer is Eudragit® L30D-55.

  In some embodiments, the site-selective agent comprises a polymer that can selectively adhere to or be released into the colon. Such colon-selective agents include, but are not limited to, azopolymers and colonolytic polysaccharides (pectin, amylose, guar gum, xylan, cyclodextrin, dextran, salts and derivatives thereof, and any combinations thereof).

  The thickness of the coating is selected to provide the desired release rate, which depends on both the nature and thickness of the coating. In some embodiments, the enteric layer is about 1-15 wt%, more preferably about 3-12 wt%, most preferably about 6 based on the combination of the weight of the solid dosage form and the weight of the coating. -10% by weight.

Exemplary Formulations In view of the foregoing, the present invention provides a variety of solid dosage forms (therapeutic agents, permeation enhancers, bioadhesive layers, semipermeable or impermeable layers, and / or many different enteric layers). Is intended to be included).

In some embodiments, the solid dosage form comprises exendin or an exendin peptide analog as a therapeutic agent and sodium caprate as a permeation enhancer, and the bioadhesive layer is HPMC or AA1 as a bioadhesive polymer and an enteric polymer. Of Eudragit® L30D-55, the semi-permeable layer comprising cellulose acetate or ethyl cellulose and an opening capable of unidirectional release. In some embodiments, the bioadhesive layer comprises at least about 70% bioadhesive polymer by weight of the layer and at least about 5% enteric polymer by weight of the layer. In some embodiments, the amount of sodium caprate ranges between about 100 mg and 150 mg. In some embodiments, the exendin is exendin-4 and the exendin peptide analog is exenatide or one of its salts or functional derivatives. In some embodiments, the bioadhesive layer comprises HPMC as a bioadhesive polymer, the semipermeable membrane comprises cellulose acetate and an opening capable of unidirectional release, and the solid dosage form is a tablet form. In some embodiments, the bioadhesive layer comprises HPMC as a bioadhesive polymer, the semipermeable layer comprises ethylcellulose and an opening capable of unidirectional release, and the solid dosage form is a tablet form.
In some embodiments, the solid dosage form comprises exendin or an exendin peptide analog as a therapeutic agent and sodium caprate as a permeation enhancer, the bioadhesive layer comprises HPMC or AA1 as a bioadhesive polymer, and is semipermeable The layer includes cellulose acetate or ethyl cellulose and an opening capable of unidirectional release, and the enteric layer includes Eudragit® L30D-55. In some embodiments, the bioadhesive layer comprises at least about 70% bioadhesive polymer by weight of the layer. In some embodiments, the amount of sodium caprate ranges between about 100 mg and 150 mg. In some embodiments, the exendin is exendin-4 and the exendin peptide analog is exenatide or one of its salts or functional derivatives. In some embodiments, the bioadhesive layer comprises HPMC as a bioadhesive polymer, the semipermeable layer comprises cellulose acetate and an opening capable of unidirectional release, and the solid dosage form is a tablet form. In some embodiments, the bioadhesive layer comprises HPMC as a bioadhesive polymer, the semipermeable layer comprises ethylcellulose and an opening capable of unidirectional release, and the solid dosage form is a tablet form.

Method of Production In one aspect, the invention provides the following steps: making a solid dosage form comprising an effective amount of a therapeutic agent, a permeation enhancer, and a pharmaceutically acceptable excipient; Coating with a bioadhesive layer comprising an adhesive polymer, optionally opening impermeability that can induce a substantially one-way release of the therapeutic agent and permeation enhancer from the solid dosage form A method of making a pharmaceutical composition of the present invention comprising the step of coating with a layer of or a semipermeable layer. In some embodiments, the order of application of the bioadhesive polymer layer and the impermeable or semi-permeable layer is reversed. In some embodiments, the method further comprises coating the composition with an enteric layer.

  In some embodiments, an aqueous suspension of bioadhesive and an impermeable or semi-permeable material (such as ethyl cellulose or Eudragit® L30-D55) can be used. In some embodiments, the material can be dispersed directly without the use of a solvent. In some embodiments, polycaprolactone (PCL) or wax can be directly dispersed during heating.

  In a preferred embodiment, the pharmaceutical composition of the present invention is produced in the form of tablets or caplets. Core tablets are formed by tableting, typically performed using a rotary press. The tablet production process (including wet granulation and direct compression) is well described and is well known in the art (DEVELOPING SOLID OLD DOSAGE FORMS: PHARMACEUTICAL THEORY AND PRACTICE, Ed. By Qiu et al., Academic Press). 2009).

  However, the development of tablet forms for polymeric drugs remains difficult. Most macromolecular drugs are peptides and proteins, have a fragile structure and are very unstable. These macromolecular drugs are often very powerful and require low dose formulations, which require special processes (such as wet granulation) to ensure uniform content. (FORMULATION AND ANALYTICAL DEVELOPMENT FOR LOW DOSE ORAL DRUG PRODUCTS, Ed. By Zheng, Wiley 2009).

  The difficulty of process development is illustrated with an example using exenatide and insulin as drugs. When producing tablets using a wet granulation process, the uniformity of content is actually within the specification despite exenatide being unstable, while exenatide powder in the formulation and It has been found that a direct blend of exenatide and excipients remains stable under the same conditions.

  Thus, the direct compression process is a suitable choice for an acceptable dose of drug, such as about 0.5-2 mg. The direct tableting process in normal low dose formulations is often easy. This is because the drug content is so low that the tablet properties (compactability, flowability, hardness, etc.) are unaffected by the presence of the drug, as long as the uniformity of the content can be guaranteed. is there. For example, if the particle size of the drug powder is properly controlled, insulin powder (showing small crystal particles and low water content) can be directly incorporated into the tableting process to produce tablets.

  The formulations of the present invention are further difficult due to the presence of a high proportion of permeation enhancer (such as sodium caprate), which is less compact and can also cause particle separation. In some embodiments, the direct tableting formulations of the present invention are shown in the table below.

For drugs such as exenatide, the unit dose is expected to be lower and / or if the drug powder is hydrous, it is difficult to achieve content uniformity in the manufacturing process due to difficulty in achieving content uniformity. The tablet process is often not recommended (Zheng 2009, ibid.).

  In the present invention, a balance between stability and content uniformity can be maintained by a non-solvent granulation process. In some embodiments, the drug powder can be suspended in a fluid medium in which the drug is insoluble, and the particle size of the drug can be adjusted and monitored by sonication or homogenization. A binding agent can be added to the suspension to promote uniformity. The suspension is added to the excipient mixture, such as in a commonly practiced granulation process. As shown in Examples 12 and 13, the non-solvent granulation process can help maintain stability while ensuring content uniformity.

  In some embodiments, commonly used non-solvents that can be used in the present invention include ethanol, isopropanol, acetone, and ethyl acetate.

Methods of Use The pharmaceutical compositions of the present invention are useful for the delivery of drugs to the desired mucosal surface. The composition can selectively adhere to the mucosal surface, and the therapeutic agent and permeation enhancer contained in the solid dosage form flow unidirectionally from the carrier to the mucosal surface and both have high local concentrations. It will be. Thus, the pharmaceutical compositions of the present invention can enhance the absorption of drugs with small amounts of permeation enhancers or are otherwise ineffective.

  Accordingly, in one aspect, the present invention provides a method of delivering a therapeutic agent using a pharmaceutical composition. In some embodiments, the present invention provides a method of treating a subject in need of therapeutic treatment comprising administering a pharmaceutical composition disclosed herein to a subject, preferably a mucosal surface. To do. The pharmaceutical composition can be administered to the subject by any means known in the art, including but not limited to oral, buccal, sublingual, vaginal, and rectal routes. Administration can be systemic or local.

Example 1: Preparation of tablets 1.1 Preparation of core tablets Core tablets were prepared by compression of the material using a single tablet press according to the formulation listed in Table 1. All ingredients except exenatide and magnesium stearate were first weighed and mixed thoroughly. The granules were then formed using 25% ethanol containing 15% polyvinylpyrrolidone (PVP) as the adhesive material and dried at 60 ° C. for 2 hours. The granules were sieved through a 22-mesh and weighed based on a single tablet with exenatide and magnesium stearate. The composition was mixed and tableted. All tablets were weighed individually and tablets exceeding 5% of the average weight were excluded.

1.2 Bioadhesive layer Core tablets were further coated with a bioadhesive polymer, hydroxypropylmethylcellulose (HPMC), or polycarbophil AA1. For HPMC coating, tablets were coated using a 2% HPMC aqueous solution on a small scale tablet coating machine (BY300A, Yellow Sea Machinery). The weight increase due to the coating was 2% of the tablet weight. Separately, tablets were coated with ethanol containing 4% polycarbophil AA1 using a small tablet coating machine. The weight increase was 3%. The coated tablets were dried at 30 ° C. for 14 hours.

1.3 Unidirectional release layer Core tablets were subsequently coated with a layer containing either impermeable or semi-permeable material. One side of the tablet was first covered with adhesive paper to create a unidirectional release opening. The tablets are then mixed with ethanol and formic acid containing 9% ethanol containing 4% ethylcellulose containing 20% triacetin as plasticizer or 3% cellulose acetate containing 20% polyethylene glycol MW2000 (PEG2000) as plasticizer (9 1 v / v). After coating, the tablets were dried at 30 ° C. for 30 minutes. The weight increase due to coating was adjusted to 2-5%. Finally, the adhesive paper was peeled away to expose the unidirectional release opening.

1.4 Enteric Layer Tablets were coated with Eudragit® L30D-55, an enteric polymer. The coating mixture contained 200 g L30D-55, 12 g ultrafine talc powder, and 6 g polyethylene glycol MW6000 (PEG 6000) and was homogenized in water to a final volume of 400 ml. Coating was performed with a small tablet coating machine. The weight increase due to the enteric coating was 10% of the tablet weight. The tablets were dried at 30 ° C. for 14 hours.

Example 2: Exenatide and sodium caprate release simultaneously The kinetic release profiles of exenatide and sodium caprate in different formulations were evaluated in several in vitro tests.

  First, the acid sensitivity of the formulation was tested by placing enteric coated tablets in 100 ml 0.1 N HCl at 37 ° C. for 2 hours in a drug dissolution apparatus. Samples were taken at various time points and the concentrations of exenatide and sodium caprate were determined using an HPLC system using C18 columns (Waters). The tablets were found to be intact in acidic medium and no exenatide or sodium caprate was detected.

  The kinetic release profile was further studied by removing the acidic medium and placing it in 100 ml simulated intestinal fluid (pH 6.8). Release was monitored at 37 ° C. and samples were taken at various time points to determine the concentration of exenatide or sodium caprate. Table 2 shows the fractions of exenatide or sodium caprate released from enteric coated and HPMC coated tablets containing 50 mg sodium caprate. The results are also summarized in FIG. As can be readily seen, the release of exenatide and sodium caprate at pH 6.8 is substantially simultaneous.

Similarly, Table 3 shows the fraction of exenatide or sodium caprate released from enteric polymer containing 50 mg sodium caprate, cellulose acetate, and HPMC coated tablets. The results are also summarized in FIG. 2A. Once again, the release of exenatide and sodium caprate was substantially simultaneous and was further significantly extended compared to tablets without the cellulose acetate layer (maximum release reached at 3 hours vs. 2 hours).

Table 4 shows the fractions of exenatide or sodium caprate released from tablets coated with enteric polymer containing 50 mg sodium caprate, ethylcellulose, and HPMC. The results are also summarized in FIG. 2B. As in previous experiments, the release of exenatide and sodium caprate is substantially simultaneous. In particular, release from ethylcellulose-coated tablets is further extended compared to tablets containing a cellulose acetate layer (maximum release reached in 5 hours vs. 3 hours).

Example 3: Effect of bioadhesive layer on exenatide absorption in dogs using 100 mg sodium caprate.

  Exenatide absorption in different formulations containing 100 mg sodium caprate as a penetration enhancer was evaluated in healthy beagles.

  Twelve Beagle dogs weighing 8-12 kg were housed in an animal facility (Shanghai TCM University Animal Center). Water was given freely. The dogs were randomly divided into 6 groups and treatment was repeated using a one week rest period. The dogs were fasted overnight and the tablets were administered directly with 10 ml water. The diet was restricted up to 6 hours after administration. The treatment groups evaluated in this experiment are summarized in Table 5.

After treatment, 1.5 ml blood samples were collected at various time points from venous catheters into heparinized tubes, and 0.5-0.6 ml serum samples were collected after centrifugation at 3000 rpm for 10 minutes. Samples were frozen at −20 ° C. and exenatide concentration was measured using an ELISA kit (Phoenix Pharmaceuticals, Inc.).

  All samples including standards were adjusted to contain 20% serum. The serum concentration of exenatide was calculated based on the calibration curve, and the area under the curve was evaluated and compared. The relative bioavailability and kinetics of exenatide absorption for each group are summarized in Table 6 and FIG. 3A.

The results show that exenatide absorption is significantly affected by the bioadhesive layer. When no bioadhesive layer is used, exenatide absorption is minimal in the presence of 100 mg sodium caprate as a permeation enhancer. Coating with AA1, HPMC, or chitosan significantly improved exenatide absorption, although the effect of chitosan was less obvious.

  Example 4: Effect of bioadhesive layer on exenatide absorption in dogs using 400 mg sodium caprate.

  Exenatide absorption in different formulations containing 400 mg sodium caprate was evaluated in healthy beagle.

  Twelve Beagle dogs weighing 8-12 kg were housed in an animal facility (Shanghai TCM University Animal Center). Water was given freely. The dogs were randomly divided into 4 groups and treatment was repeated using a one week rest period. The dogs were fasted overnight and the tablets were administered directly with 10 ml water. The diet was restricted up to 6 hours after administration. The treatment groups evaluated in this experiment are summarized in Table 7.

After treatment, 1.5 ml blood samples were collected at various time points from venous catheters into heparinized tubes, and 0.5-0.6 ml serum samples were collected after centrifugation at 3000 rpm for 10 minutes. Samples were frozen at −20 ° C. and exenatide concentration was measured using an ELISA kit (Phoenix Pharmaceuticals, Inc.).

  All samples including standards were adjusted to 20% serum. The serum concentration of exenatide was calculated based on the calibration curve, and the area under the curve was evaluated and compared. The relative bioavailability and kinetics of exenatide absorption for each group are summarized in Table 8 and FIG. 3B.

As in Example 3, the results show that exenatide absorption is significantly affected by the bioadhesive layer. When no bioadhesive layer is used, exenatide absorption is moderate in the presence of 500 mg sodium caprate as a permeation enhancer. Coating with AA1 significantly improves exenatide absorption.

  Example 5: Effect of sodium caprate amount on exenatide absorption in dogs.

  Exenatide absorption in formulations containing different amounts of sodium caprate was evaluated in healthy beagles.

  Twelve Beagle dogs weighing 8-12 kg were housed in an animal facility (Shanghai TCM University Animal Center). Water was given freely. The dogs were randomly divided into 6 groups and treatment was repeated using a one week rest period. The dogs were fasted overnight and the tablets were administered directly with 10 ml water. The diet was restricted up to 6 hours after administration. The treatment groups evaluated in this experiment are summarized in Table 9.

After treatment, 1.5 ml blood samples were collected at various time points from venous catheters into heparinized tubes, and 0.5-0.6 ml serum samples were collected after centrifugation at 3000 rpm for 10 minutes. Samples were frozen at −20 ° C. and exenatide concentration was measured using an ELISA kit (Phoenix Pharmaceuticals, Inc.).

  All samples including standards were adjusted to 20% serum. The serum concentration of exenatide was calculated based on the calibration curve, and the area under the curve was evaluated and compared. The relative bioavailability and kinetics of exenatide absorption for each group are summarized in Table 10 and FIG.

The results show that exenatide absorption depends on the amount of sodium caprate. Exenatide absorption is minimal in the presence of 50 mg sodium caprate as a permeation enhancer, while significant exenatide absorption is observed for more than 100 mg sodium caprate. With more than 100 mg sodium caprate, no further improvement was observed.

Example 6: Effect of one-way release dosage on exenatide absorption in dogs Exenatide absorption in formulations containing 50 mg sodium caprate was evaluated in healthy beagle.

  Twelve Beagle dogs weighing 8-12 kg were housed in an animal facility (Shanghai TCM University Animal Center). Water was given freely. The dogs were randomly divided into 5 groups and the treatment was repeated using a one week rest period. The dogs were fasted overnight and the tablets were administered directly with 10 ml water. The diet was restricted up to 6 hours after administration. The treatment groups evaluated in this experiment are summarized in Table 11.

After treatment, 1.5 ml blood samples were collected at various time points from venous catheters into heparinized tubes, and 0.5-0.6 ml serum samples were collected after centrifugation at 3000 rpm for 10 minutes. Samples were frozen at −20 ° C. and exenatide concentration was measured using an ELISA kit (Phoenix Pharmaceuticals, Inc.).

  All samples including standards were adjusted to 20% serum. The serum concentration of exenatide was calculated based on the calibration curve, and the area under the curve was evaluated and compared. The relative bioavailability and kinetics of exenatide absorption for each group are summarized in Table 12 and FIG.

The results show that exenatide absorption can be further enhanced by the use of a unidirectional release layer in conjunction with a bioadhesive layer. Without the use of a unidirectional release layer, exenatide absorption and bioavailability in the presence of 50 mg sodium caprate and HPMC is minimal. Coating tablets with a cellulose acetate semipermeable membrane or an ethylcellulose impermeable membrane containing an opening on one side of the tablet significantly improves exenatide absorption using the same amount of sodium caprate and HPMC.

Example 7: Bioavailability of oral exenatide in dogs Exenatide absorption in formulations containing 100 mg sodium caprate was evaluated in healthy beagle.

  Twelve Beagle dogs weighing 8-12 kg were housed in an animal facility (Shanghai TCM University Animal Center). Water was given freely. The dogs were randomly divided into 3 groups and treatment was repeated using a one week rest period. The dogs were fasted overnight and the tablets were administered directly with 10 ml water. The diet was restricted up to 6 hours after administration. The treatment groups evaluated in this experiment are summarized in Table 13.

After treatment, 1.5 ml blood samples were collected at various time points from venous catheters into heparinized tubes, and 0.5-0.6 ml serum samples were collected after centrifugation at 3000 rpm for 10 minutes. Samples were frozen at −20 ° C. and exenatide concentration was measured using an ELISA kit (Phoenix Pharmaceuticals, Inc.).

  All samples including standards were adjusted to 20% serum. The serum concentration of exenatide was calculated based on the calibration curve, and the area under the curve was evaluated and compared. The relative bioavailability and kinetics of exenatide absorption for each group are summarized in Table 14 and FIG.

The results show that the relative bioavailability of HPMC, ethylcellulose, and enteric-coated tablet oral exenatide in the presence of 100 mg sodium caprate is 4.98% compared to subcutaneous injection. Show. Coating of tablets with an ethylcellulose impermeable membrane with openings on one side of the tablet significantly improves exenatide absorption and relative bioavailability using the same amount of sodium caprate and HPMC (2 37%; see Example 5, Group 4).

  Example 8: Effect of enteric layer on exenatide absorption in dogs.

8.1 Preparation of Core Tablets Core tablets were prepared by compression using a single tablet press according to the formulation listed in Table 15. All ingredients except exenatide and magnesium stearate were first weighed and mixed thoroughly. The granules were then formed using 25% ethanol with 15% polyvinylpyrrolidone (PVP) as the adhesive material and dried overnight under vacuum. The granules were passed through a 22-mesh sieve and weighed based on a single granule with exenatide and magnesium stearate. The composition was mixed and tableted. All tablets were weighed individually and tablets that deviated more than 5% from the average tablet weight were excluded from further experiments.

8.2 Bioadhesive layer Core tablets were coated with hydroxypropyl methylcellulose (HPMC) with or without the enteric material Eudragit® L30D-55. For coatings not using L30D-55, an aqueous solution of 6% HPMC and 1.5% polyethylene glycol MW6000 (PEG 6000) was used in a tablet pan coater (BY300A, Yellow Sea Machinery). Weight increase due to the bioadhesive layer was 3-4 mg. For coatings using L30D-55, an aqueous solution of 3% HPMC and 0.6% L30D-55 was used in a tablet pan coater. The coated tablets were dried at 40 ° C. for about 14 hours. The weight increase due to the bioadhesive layer was 3 mg.

8.3 Unidirectional release layer Tablets coated with a bioadhesive layer were then coated with a semipermeable cellulose acetate layer. One side of the tablet was first covered with adhesive paper to create a unidirectional release opening. The tablets are then coated in a pan coater with a unidirectional coating solution containing a mixture of acetone and formic acid (9: 1 v / v) containing 3% cellulose acetate and 1.2% polyethylene glycol MW2000 (PEG 2000). And dried at 40 ° C. overnight. The weight increase due to the unidirectional release layer was 2 mg. Finally, the adhesive paper was peeled away to expose the unidirectional release opening.

8.4 Enteric Layer Tablets coated with a bioadhesive HPMC layer without using L30D-55 were further coated with an enteric layer. The coating mixture contained 200 g L30D-55, 12 g ultrafine talc powder, and 6 g polyethylene glycol MW6000 (PEG 6000) and was homogenized in a final volume of 400 ml water. Coating was done on a small pan coater and the tablets were dried at 40 ° C. for 14 hours. The weight increase due to the enteric layer was 25 mg.

8.5 Absorption of Oral Exenatide in Dogs Exenatide absorption in a formulation containing 200 mg sodium caprate was evaluated in healthy beagle.

  Twelve Beagle dogs weighing 8-12 kg were housed in an animal facility (Shanghai TCM University Animal Center). Water was given freely. The dogs were randomly divided into 4 groups and repeated treatments using a 1 week drug holiday. The dogs were fasted overnight and the tablets were administered directly with 10 ml water. Diet was restricted during the study. The treatment groups evaluated in this experiment are summarized in Table 16.

After treatment, 1.5 ml blood samples were collected at various time points from venous catheters into heparinized tubes, and 0.5-0.6 ml serum samples were collected after centrifugation at 3000 rpm for 10 minutes. Samples were frozen at −20 ° C. and exenatide concentration was measured using an ELISA kit (Phoenix Pharmaceuticals, Inc.).

  All samples including standards were adjusted to 20% serum. The serum concentration of exenatide was calculated based on a calibration curve. The kinetics of exenatide absorption for each treatment group are summarized in FIG.

  The results show that the absorption of oral exenatide in the form of HPMC and cellulose acetate coated tablets in the presence of 200 mg sodium caprate is equally effective compared to tablets coated with HPMC, cellulose acetate, and enteric materials. Show. In the absence of the enteric outer layer, the maximum concentration of exenatide reached approximately 1 hour faster than in the presence of the enteric layer (3 hours vs. 4 hours). However, neither the maximum concentration nor the area under the curve appeared to be significantly affected by the presence of the enteric layer. Thus, in some embodiments, an enteric layer can optionally be used, but does not appear to be an essential component of the present invention.

  The early absorption and response demonstrated by the bilayer formulation is desirable in the clinical context.

Example 9 Effect of Oral Insulin in Dogs Infused with Somatostatin 9.1 Preparation of Calcium Phosphate Insulin Nanoparticles Calcium phosphate insulin particles were prepared and used as drug carriers in this study. Insulin (5 mg / ml) is added to 40 ml of solution A containing 20 mM disodium phosphate, 20 mM HEPES buffer (pH 6.9), 2% PEG (molecular weight 6000), and 0.5% ursodeoxycholate (UDCA). Dissolved. UDCA was dissolved in 1.5 ml ethanol before addition. Solution B containing an equal volume (40 ml) of 0.01 N HCl and 60 mM CaCl ₂ was mixed with the solution to induce precipitation. The particles were centrifuged at 15000 rpm for 30 minutes and the collected particles were completely dried under vacuum.

  The insulin content in the particles was measured by suspending 0.2 mg / ml particles in 50 mM sodium phosphate buffer (pH 9.1) at 37 ° C. for 15 minutes. Insulin was evaluated by reverse phase high performance liquid chromatography (RP-HPLC) using a known amount of insulin as a standard. The insulin content in this particular calcium phosphate particle batch was 0.56 mg / mg and the insulin recovery rate was 99%.

9.2 Preparation of core tablets Core tablets were prepared by compression using a single tablet press according to the formulation listed in Table 16. All ingredients except insulin, silica powder, and magnesium stearate were first weighed and mixed thoroughly. The granules were then formed using 25% ethanol with 8% polyvinylpyrrolidone (PVP) as the adhesive material and dried overnight under vacuum. The granules were passed through a 22-mesh sieve and weighed based on a single granule with insulin, silica powder, and magnesium stearate. The composition was mixed and tableted. All tablets were weighed and tablets that deviated more than 5% from the average tablet weight were excluded from further experiments. Tablet hardness, thickness, and friability were also monitored.

9.3 Bioadhesive layer Core tablets were coated with hydroxypropyl methylcellulose (HPMC E50) and enteric material Eudragit® L30D-55. An aqueous suspension of 3% HPMC and 0.6% L30D-55 was used in a tablet pan coater (BY300A, Yellow Sea Machinery). The coated tablets were dried at 40 ° C. for about 14 hours. The weight increase due to the bioadhesive layer was 3 mg.

9.4 Unidirectional release layer Tablets coated with a bioadhesive layer were then coated with a semipermeable cellulose acetate layer. One side of a 9 mm diameter tablet was first covered with a 7 mm diameter circular adhesive paper. The tablets are then coated in a pan coater with a unidirectional coating solution containing a mixture of acetone and formic acid (9: 1 v / v) containing 3% cellulose acetate and 1.2% polyethylene glycol MW2000 (PEG 2000). And dried at 40 ° C. overnight. The weight increase due to the unidirectional release layer was 2 mg. Finally, the circular sticker was peeled away to expose the unidirectional release opening.

9.5 Insulin Release Profile Insulin release was first evaluated in 100 ml 0.01 N HCl for 2 hours in an elution apparatus equipped with a basket design set at 100 rpm agitation at 37 ° C. Aliquots were taken after 1 hour and 2 hours and insulin content was measured by RP-HPLC. The tablets were then transferred to 100 ml simulated intestinal fluid (SIF) (pH 6.8) under the same conditions, and aliquots were subjected to RP-HPLC at various time points to measure insulin content.

The insulin release profile is shown in FIG. 8A. The tablets were stable in acidic solution as evidenced by the observation that less than 10% insulin was released after 2 hours of incubation. Insulin release during SIF occurred gradually and was completed in about 3-4 hours.
Effect of Oral Insulin in Dogs Infused with 9.6 Somatostatin The absorption of oral insulin under somatostatin infusion at 1 μg / kg / min via an indwelling intravenous catheter in beagle was evaluated. Infusion of somatostatin suppresses endogenous glucagon and insulin secretion (Sakurai et al., J. Clin. Invest. 54: 1395, 1974). Blood glucose levels in these animals first decrease and then increase rapidly due to insulin suppression. This model allows simultaneous pharmacokinetic and pharmacodynamic evaluation of oral insulin.

  Twelve beagle dogs weighing 8-12 kg were housed in an animal facility. The dogs were randomly divided into 3 groups and fasted overnight. Water was given freely. Somatostatin infusion (1 μg / kg / min) was performed using a balloon infusion pump via an indwelling venous catheter, and tablets were administered using 10 ml water 4 hours after the start of somatostatin infusion. During the study, diet was restricted and blood samples were collected in heparinized tubes at various times. The treatment groups evaluated in this experiment are summarized in Table 17.

Blood glucose concentration is measured using a blood glucose meter and a compliance test strip (Johnson & Johnson, OneTouch®) and 0.5-0.6 ml of serum sample is collected after collection of the blood sample, Centrifuge for 10 minutes at 3000 rpm. Samples were frozen at −20 ° C. and insulin concentration was measured by ELISA (Linco).

  The effect of oral insulin treatment on blood glucose and serum insulin levels is shown in 8B and 8C, respectively.

  As shown in FIG. 8B, as expected, blood glucose levels first decreased and subsequently increased substantially in animals treated with blank tablets. Insulin injection induced a rapid and marked decrease in glucose levels. Similarly, treatment with oral insulin also induced a significant decrease in blood glucose. Bioactivity based on AUC of glucose levels was estimated to be 5%.

  As shown in FIG. 8C, insulin levels were suppressed during the entire experiment in animals treated with blank tablets, while insulin injection greatly increased insulin concentrations. Interestingly, the increase in insulin concentration in animals treated with oral insulin was only moderate. The bioavailability in this study was about 2% or about 40% of the bioactivity. This finding confirms that oral insulin provides higher bioactivity and lower peripheral insulin, much like portal vein or natural insulin secretion. Thus, the probability of hypoglycemia (a serious problem that limits the clinical use of insulin) is significantly reduced.

Example 10 Effect of Bilayer Oral Insulin Tablets in Dogs Infused with Somatostatin 10.1 Production of Core Tablets Core tablets were made by compression using a single tablet press according to the formulation listed in Table 18. All ingredients except insulin, silica powder, and magnesium stearate were first weighed and mixed thoroughly. The granules were then formed using 25% ethanol with 8% polyvinylpyrrolidone (PVP) as the adhesive material and dried overnight under vacuum. The granules were passed through a 22-mesh sieve and the required amount of each tablet was weighed before adding insulin, silica powder, and magnesium stearate. The composition was mixed and tableted. Tablet hardness, friability, and thickness were also measured.

10.2 Bioadhesive Layer Core tablets were coated with hydroxypropylmethylcellulose (HPMC) with or without the enteric material Eudragit® L30D-55. For coatings not using L30D-55, an aqueous solution of 6% HPMC and 1.5% polyethylene glycol MW6000 (PEG 6000) was used in a tablet pan coater (BY300A, Yellow Sea Machinery). Weight increase due to the bioadhesive layer was 3-4 mg. For coatings using L30D-55, an aqueous solution of 3% HPMC and 0.6% L30D-55 was used in a tablet pan coater. The coated tablets were dried at 40 ° C. for about 14 hours. The weight increase due to the bioadhesive layer was 3 mg.

10.3 Unidirectional Release Layer Tablets coated with a bioadhesive layer were then coated with a semipermeable cellulose acetate layer. One side of a 10 mm diameter tablet was first covered with a 7 mm diameter circular sticker. The tablets were then coated in a pan coater with a unidirectional coating solution containing a mixture of acetone and formic acid (9: 1 v / v) containing 3% cellulose acetate and 1.2% polyethylene glycol MW2000 (PEG 2000). . After coating was complete, the tablets were dried overnight at 40 ° C. The weight increase due to the unidirectional release layer was 2 mg. Finally, the adhesive paper was peeled away to expose the unidirectional release opening.

10.4 Enteric Layer Tablets coated with a bioadhesive HPMC layer without using L30D-55 were further coated with an enteric layer. The coating mixture contained 200 g L30D-55, 12 g ultrafine talc powder, and 6 g polyethylene glycol MW6000 (PEG 6000) and was homogenized in a final volume of 400 ml water. Coating was done on a small pan coater and the tablets were dried at 40 ° C. for 14 hours. The weight increase due to the enteric layer was 25 mg.

Effect of Oral Insulin on 10.5 Glucose Bilayer formulation (core tablet coated with bioadhesive layer containing L30D55 and then unidirectionally coated with cellulose acetate) and trilayer formulation (bioadhesive layer without L30D55) The effects of oral insulin using a core tablet coated with a cellulose acetate followed by a cellulose acetate coating followed by an enteric coating were evaluated in beagle dogs injected with somatostatin as described in Example 9.

  Twelve beagle dogs weighing 8-12 kg were housed in an animal facility. Water was given freely. The dogs were randomly divided into 4 groups and fasted overnight. Approximately 4 hours after the start of somatostatin infusion, the tablets were administered directly into the pharynx using 10 ml water. Diet was restricted during the study. The treatment groups evaluated in this experiment are summarized in Table 19.

A blood sample was collected and the blood glucose concentration was measured using a blood glucose meter. The effect of two oral insulin formulations on blood glucose is shown in FIG.

  As shown in FIG. 9, administration of oral insulin tablets induced a significant decrease in blood glucose similar to insulin injection, whereas blood glucose in blank treated animals initially decreased. After that, a rapid increase was observed. In the absence of the enteric outer layer, a decrease in blood glucose was first observed 1 hour after tablet administration, while the same effect was observed only 4 hours after enteric-coated tablet administration.

  This result is consistent with the findings in a similar formulation using exenatide and demonstrates that an early response with a bilayer formulation is desirable in the clinical context.

Example 11: Directly compressed tablets Direct compression without the use of granulation is a simple and economical tablet manufacturing process and tends to maintain the crystal structure and stability of the drug. The main difficulty with low-dose tablets made using a direct tableting process is to achieve acceptable content uniformity.

  The insulin and exenatide formulations listed in Table 20 were produced by direct compression. Insulin and exenatide powder were passed through a 200-mesh sieve and mixed thoroughly with all excipients. The composition was tableted using a rotary press. Tablet hardness, friability, and thickness were also measured.

Insulin and exenatide blend uniformity was evaluated according to US Pharmacopeia General <905>, “Dosage Unit Uniformity” (“USP <905>”) and equal weight (equal to tablet weight) after thorough blending of the blend Samples were collected from different locations. Insulin or exenatide content was measured by RP-HPLC. The results of blend uniformity are shown in Table 21.

The results show that a blend uniformity of insulin at a unit dose of 1 mg (0.5% of tablet content) can be tolerated. In contrast, 0.6 mg exenatide with a content of 0.27% did not pass the homogeneity test. Exenatide powder exhibits a higher water activity and may contribute to this difficulty. Thus, direct tableting processes to make tablets are feasible and drugs with different properties (such as water content and particle size) can vary in the degree of difficulty in achieving acceptable uniformity.

Example 12: Non-solvent granulation in tablet production As described above, direct tableting presents a problem regarding content uniformity of low dose drugs such as exenatide, whereas wet granulation has a problem with drug stability. There is. Therefore, insulin tablets and exenatide tablets were made by non-solvent granulation. The different lot compositions are listed in Tables 22-26.

  Insulin and exenatide powder were passed through a 200-mesh sieve and suspended in ethanol containing 8% PVP. The drug suspension was lightly sonicated until no visible macroparticles were detected. All other excipients except silica powder and magnesium stearate were weighed and thoroughly premixed in the granulator. The drug suspension was added to the excipient blend to form granules, then sieved through an 18-mesh and dried under vacuum. After drying and adding the silica powder and magnesium stearate, the composition was tableted using a rotary press. Tablet hardness, friability, and thickness were also measured.

The content of insulin or exenatide in these tablets was measured by RP-HPLC and content uniformity was evaluated according to USP <905>. The results are shown in Table 27.

These results demonstrate that the content uniformity of insulin and exenatide tablets made using non-solvent granulation can be tolerated.

Example 13: Exenatide stability in different formulations and processes The stability of exenatide in various formulations was evaluated under stress conditions. The tested formulations are shown in Table 28.

The excipients included in the basic formulation are listed in Table 29.

The entire formulation is placed in a petri dish and placed under stress conditions (temperature 60 ° C., 25 ° C. relative humidity 92.5%, including 10 consecutive days at 4500 lux light exposure). Exenatide content in each formulation was measured by RP-HPLC on days 0, 5, and 10. The content remaining in each formulation is shown in FIGS.

  The results demonstrate that exenatide powder is relatively stable under stress conditions, and exenatide content remains 95% after 10 days of exposure under high temperature, high humidity, and light exposure. Direct blends using all excipients show a similar stability profile, suggesting that the excipients are compatible with exenatide in the tablet formulation.

  However, tablets made by wet granulation show relatively unstable behavior, with a significant loss of exenatide on the 5th and 10th day of exposure. Addition of gelatin or mannitol did not reduce instability. In fact, exenatide instability worsened, especially at high humidity. This finding can be attributed to the ability of gelatin and mannitol to absorb significant amounts of moisture at high humidity.

  In contrast, tablets made by direct compression or non-solvent granulation show good stability at these conditions, similar to exenatide powder. It should be noted that the addition of low molecular weight PEG makes it unstable even in formulations produced by non-solvent granulation processes, which can be attributed to the partial solubility of exenatide in low molecular weight PEG.

Example 14: Effect of oral insulin in dogs 14.1 Preparation of core tablets Core tablets were prepared by non-solvent granulation and subsequent compression in a rotary press according to the formulation listed in Table 30. All ingredients except insulin, PVP, silica powder, and magnesium stearate were first weighed and mixed thoroughly with a granulator. Insulin powder was suspended in ethanol containing 8% polyvinyl pyrrolidone (PVP) and sonicated to break up giant insulin particles. Insulin suspension was added to the other ingredients and the mixture was allowed to dry overnight under vacuum to form granules. Silica powder and magnesium stearate were added to the dried granules, the composition was mixed and tableted. Tablet hardness, friability, and thickness were also measured.

14.2 Bioadhesive layer Core tablets are coated with hydroxypropyl methylcellulose (HPMC) using a solution of 6% HPMC and 1.5% polyethylene glycol (MW 6000) in a tablet pan coater (BY300A, Yellow Sea Machinery) did. The weight increase due to the bioadhesive layer was 4 mg.

14.3 Unidirectional release layer Tablets coated with a bioadhesive layer were then coated with a semipermeable ethylcellulose layer. One side of a 10 mm diameter tablet was first covered with a 7 mm diameter circular sticker. The tablets were then coated in a pan coater with a unidirectional coating solution containing ethanol containing 3% ethylcellulose and 1.2% polyethylene glycol (MW 2000). After coating was complete, the tablets were dried at room temperature. The weight increase due to the unidirectional release layer was 2 mg. Finally, the adhesive paper was peeled away to expose the unidirectional release opening.

14.4 Enteric layer The tablets were further coated with an enteric layer. The coating mixture contained ethanol with 8% L30D-55, 2% polyethylene glycol (MW 6000). The coating was done on a small pan coater and the weight increase due to the enteric layer was 20 mg.
14.5 Effect of Oral Insulin on Blood Glucose Levels in Normal Dogs The effect of oral insulin administration on blood glucose levels was evaluated in normal beagle dogs.

  Nine beagle dogs weighing 8-12 kg were housed in an animal facility. Water was given freely. The dogs were randomly divided into 3 groups and fasted overnight. The tablets were administered directly into the pharynx using 10 ml water. Diet was restricted during the study. The treatment groups evaluated in this experiment are summarized in Table 31.

A blood sample was collected and the blood glucose concentration was measured using a blood glucose meter. The effect of oral insulin administration on blood glucose is shown in FIG.

  As shown in FIG. 11, oral insulin tablets induced a significant decrease in blood glucose within 2-3 hours of administration, similar to insulin injection, whereas blood glucose in blank treated animals It was relatively constant.

  Blood glucose is often regulated within a narrow range in normal subjects. Therefore, even the glucose drop in subcutaneous injection was changed. Oral insulin tablets induced glucose lowering in a similar manner and mode of change as insulin was injected into normal beagle.

Example 15: Laser ablation process in tablet production 15.1 Preparation of core tablets Core tablets were prepared by compression in a rotary press according to the formulation listed in Table 32. All ingredients except exenatide, silica powder, and magnesium stearate were first weighed and mixed thoroughly. The granules are then formed using exenatide dissolved in 25% ethanol containing 8% polyvinylpyrrolidone (PVP) as the adhesive material, the granules are dried under vacuum overnight, passed through a 22-mesh sieve, silica powder and Magnesium stearate was added. The composition was mixed and tableted. Tablet weight, hardness, thickness, and friability were monitored.

15.2 Bioadhesive Layer The core tablet was prepared by injecting hydroxypropylmethylcellulose (HPMC E50) and intestine in a pan coater (BY300A, Yellow Sea Machinery) using an aqueous suspension of 3% HPMC and 0.6% L30D-55. It was coated with the melted material Eudragit® L30D-55. The coated tablets were dried at 40 ° C. for about 14 hours. The weight increase due to the bioadhesive layer was 3 mg.

15.3 Unidirectional Release Layer The tablet was further coated with a semipermeable cellulose acetate layer. For the manual process, one side of a 9 mm tablet is first covered with a 7 mm diameter circular adhesive paper, followed by 3% cellulose acetate and 1.2% polyethylene glycol MW2000 (PEG 2000) in a pan coater. It was coated with a solution containing a mixture of acetone and formic acid containing (9: 1 v / v). After coating and drying was complete, the circular sticker was peeled away to expose the one-way release opening.

  For the laser ablation process, the tablets were not covered with a sticker but coated with the same cellulose acetate solution. The coated tablets were dried at 40 ° C. overnight. The finished tablet was ablated with a laser drill machine (CMS) to form an opening with a diameter of 7 mm similar to the opening obtained by the manual process described above. The integrity of the bioadhesive coating was verified by a 2 hour acid sensitivity test in simulated gastric fluid.

  The weight increase due to the unidirectional release layer in both cases was 2-3 mg.

15.4 Absorption of oral exenatide in normal dogs Absorption of oral exenatide mediated by a one-way release coating formed by manual and laser ablation processes was evaluated in normal beagles.

  Twelve beagle dogs weighing 8-12 kg were housed in an animal facility. The dogs were randomly divided into 4 groups and fasted overnight. Water was given freely. Tablets were administered directly into the pharynx using 10 ml water and diet was restricted during the study. Blood samples were collected in heparinized tubes at various time points. The treatment groups evaluated in this experiment are summarized in Table 33.

A 0.5-0.6 ml serum sample was collected after collection of the blood sample and centrifuged at 3000 rpm for 10 minutes. Samples were frozen at −20 ° C. and exenatide concentration was measured using an ELISA kit (Phoenix).

  The effect of oral exenatide treatment on serum exenatide concentration is shown in FIG. Formulations made by manual and laser ablation processes to form unidirectional emission openings achieved similar absorption ranges, but formulations made using laser ablation have some absorption kinetics. It seemed fast.

Example 16: Oral Insulin Dose Response in Dogs Infused with Somatostatin 16.1 Core Tablet Production Core tablets were made by compression using a single tablet press according to the formulation listed in Table 34. All ingredients except insulin, silica powder, and magnesium stearate were first weighed and mixed thoroughly. The granules were then formed using 25% ethanol with 8% polyvinylpyrrolidone (PVP) as the adhesive material and dried overnight under vacuum. The granules were passed through a 22-mesh sieve and the required amount of each tablet was weighed individually before adding insulin, silica powder, and magnesium stearate. The composition was mixed and tableted. Tablet hardness, friability, and thickness were also measured.

16.2 Bioadhesive layer Core tablets were coated with an aqueous suspension of 3% HPMC and 0.6% L30D-55 in a tablet pan coater. The coated tablets were dried at 40 ° C. for 14 hours. The weight increase due to the bioadhesive layer was 3 mg.

16.3 Unidirectional Release Layer Tablets coated with a bioadhesive layer were then coated with a semipermeable cellulose acetate layer. One side of a 10 mm diameter tablet was first covered with a 7 mm diameter circular sticker. The tablets were then coated in a pan coater with a unidirectional coating solution containing a mixture of acetone and formic acid (9: 1 v / v) containing 3% cellulose acetate and 1.2% polyethylene glycol MW2000 (PEG 2000). . After coating was complete, the tablets were dried overnight at 40 ° C. The weight increase due to the unidirectional release layer was 2 mg. Finally, the adhesive paper was peeled away to expose the unidirectional release opening.

Effect of Oral Insulin on Blood Glucose Levels in Dogs Treated with 16.4 Somatostatin As described in Example 9, the effect of oral insulin was evaluated in beagle dogs infused with somatostatin.

  Twelve beagle dogs weighing 8-12 kg were housed in an animal facility. Water was given freely. The dogs were randomly divided into 5 groups and fasted overnight. Tablets were administered directly into the pharynx using 10 ml water 4 hours after the start of somatostatin infusion. Diet was restricted during the study. The treatment groups evaluated in this experiment are summarized in Table 35.

A blood sample was collected and the blood glucose concentration was measured using a blood glucose meter. The effect of the two oral insulin formulations on blood glucose is shown in FIG.

  As shown in FIG. 13, oral insulin tablets induced a significant decrease in blood glucose, similar to insulin injection. The decrease in glucose was dose dependent when the response in 25U oral insulin was compared to either 50U oral insulin or 25U x 2 treatments. The decrease in glucose appeared to be approximately equivalent in the 50 U and 25 U × 2 oral insulin treatment groups.

Example 17: Effect of Bioadhesive Polymer on Exenatide Release and Absorption 17.1 Preparation of Core Tablet Exenatide tablets were prepared using the ethanol granulation process as described above. The tablet batch formulations are listed in Table 36. Exenatide powder (power) was suspended in ethanol containing 8% PVP and lightly sonicated until no visible macroparticles were detected. All other excipients except silica powder and magnesium stearate were weighed and thoroughly premixed in the granulator. The drug suspension was added to the excipient blend to form granules, then sieved through an 18-mesh and dried under vacuum. After the addition of silica powder and magnesium stearate, the composition was tableted with a rotary press. Tablet hardness, friability, and thickness were also measured.

17.2 Bioadhesive layer Core tablets were coated with an aqueous suspension of 50% ethanol containing 3% HPMC and 0.6% L30D-55 in a tablet pan coater. Alternatively, core tablets were coated with 50% ethanol containing 2.6% HPMC, 0.8% L30-D55, and 0.6% PEG. The coated tablets were dried at 40 ° C. for 14 hours. Weight increase due to the bioadhesive layer was 3-4 mg.

17.3 Unidirectional Release Layer The tablets coated with the bioadhesive layer are then unidirectional with 85% ethanol containing 3.2% ethylcellulose, 0.6% polyethylene glycol MW2000, and 0.2% triacetin in a pan coater. The coating solution was used to coat with semipermeable ethylcellulose. After coating was complete, the tablets were dried overnight at 40 ° C. The weight increase due to the unidirectional release layer was 2 mg. One side of the tablet was ablated with a laser to form a 7 mm diameter unidirectional release opening on a 9 mm diameter tablet.

17.4 Exenatide Absorption in Normal Dogs Exenatide absorption was evaluated in normal beagle dogs.

  Twelve beagle dogs weighing 8-12 kg were housed in an animal facility. Water was given freely. The dogs were randomly divided into 4 groups and fasted overnight. The tablets were administered directly into the pharynx using 10 ml water. Diet was restricted during the study. The treatment groups evaluated in this experiment are summarized in Table 37.

Blood samples were taken at various time points and serum samples were collected after centrifugation at 3000 rpm for 5 minutes. Serum exenatide concentration was measured using an ELISA assay (Phoenix). The results are shown in FIGS. 14A and 14B.

  The results indicate that the presence of a bioadhesive layer is required and the bioadhesive polymer content in the bioadhesive layer significantly affects exenatide release and absorption.

  The foregoing examples are included for purposes of illustration and are not intended to limit the scope of the invention. In view of the present disclosure, it is further recognized that one skilled in the art can obtain various embodiments without departing from the spirit and scope of the present invention. Accordingly, the present invention is understood to include all equivalents herein.

Claims (37)

A pharmaceutical composition comprising:
A pharmaceutical composition comprising: a) a solid dosage form comprising an effective amount of a therapeutic agent, a permeation enhancer, and a pharmaceutically acceptable excipient; and b) a bioadhesive layer comprising a bioadhesive polymer.   The pharmaceutical composition according to claim 1, wherein the content of the bioadhesive polymer in the bioadhesive layer is in the range of about 50-100 wt%, about 70-90 wt%, or about 80-90 wt%. object.   The content of the bioadhesive layer in the pharmaceutical composition is in the range of about 0.5-10 wt%, about 1-5 wt%, or about 2-3 wt%. Pharmaceutical composition.   The method of claim 1, further comprising an impermeable or semi-permeable layer having an opening capable of inducing a substantially unidirectional release of the therapeutic agent and the permeation enhancer from the solid dosage form. A pharmaceutical composition as described.   5. The pharmaceutical composition of claim 4, wherein the area of the opening ranges from about 20-90%, about 40-80%, or about 50-70% of the total area of one side of the solid dosage form. .   The content of the impermeable layer or the semipermeable layer in the pharmaceutical composition is in the range of about 0.5 to 10% by weight, about 1 to 5% by weight, or about 2 to 4% by weight. The pharmaceutical composition according to claim 4, wherein   5. The pharmaceutical composition according to claim 1 or 4, wherein the therapeutic agent and the permeation enhancer have a substantially equivalent relative release rate from the solid dosage form.   The pharmaceutical composition according to claim 1 or 4, further comprising an enteric layer.   The pharmaceutical composition according to claim 1 or 4, wherein the bioadhesive polymer is selected from carbomers, polycarbophil, hydroxypropylmethylcellulose, chitosan, and salts and derivatives thereof.   The pharmaceutical composition according to claim 1 or 4, wherein the bioadhesive layer further comprises an enteric polymer.   5. The pharmaceutical composition of claim 4, wherein the impermeable layer or the semipermeable layer comprises a water impermeable or semipermeable material.   12. The pharmaceutical composition according to claim 11, wherein the water-impermeable or semi-permeable material is selected from ethyl cellulose, cellulose acetate, and salts and derivatives thereof.   12. The pharmaceutical composition of claim 11, wherein the impermeable layer or the semipermeable layer further comprises a plasticizer.   The permeation enhancer is selected from the group consisting of fatty acids, medium chain glycerides, surfactants, steroidal detergents, acylcarnitines, alkanoylcholines, N-acetylated amino acids, esters, salts and derivatives thereof, and any combinations thereof The pharmaceutical composition according to claim 1 or 4, wherein   15. A pharmaceutical composition according to claim 14, wherein the permeation enhancer comprises a fatty chain having 8 to 14 carbon atoms.   The pharmaceutical composition according to claim 1 or 4, wherein the permeation enhancer is selected from capric acid and its salts, esters or derivatives.   The pharmaceutical composition according to claim 16, wherein the permeation enhancer is sodium caprate or a derivative thereof.   18. The pharmaceutical composition of claim 17, wherein the content of sodium caprate or a derivative thereof is in the range of about 25-300 mg, about 50-200 mg, or about 100-200 mg.   19. A pharmaceutical composition according to any one of claims 1 to 18, configured to deliver the therapeutic agent and the permeation enhancer to a mucosal surface.   19. A pharmaceutical composition according to any one of claims 1 to 18, configured to deliver the therapeutic agent to a subject in need via the oral route.   21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the therapeutic agent comprises a biologically active polymer.   23. The pharmaceutical composition of claim 21, wherein the biologically active macromolecule is selected from the group consisting of proteins, peptides, polysaccharides, nucleic acids, lipids, and carbohydrates, and combinations thereof.   The biologically active polymer is insulin, erythropoietin, interferon, growth hormone, exenatide, GLP-1 agonist, PTH, calcitonin, leuprolide, octreotide, low molecular weight heparin, and functional analogs and mutants thereof 23. The pharmaceutical composition according to claim 21, wherein the pharmaceutical composition is selected from the group consisting of:   24. The pharmaceutical composition of claim 23, wherein the GLP-1 agonist is exendin or an exendin peptide analog.   25. The pharmaceutical composition of claim 24, wherein the exendin is exendin-4.   25. A pharmaceutical composition according to claim 24, wherein the exendin peptide analogue is selected from exenatide and its salts and functional derivatives.   27. A pharmaceutical composition according to any one of claims 1 to 26, wherein the composition is formulated in the form of capsules, tablets, pellets, powders or granules.   28. The pharmaceutical composition of claim 27, wherein the solid dosage form is produced using a direct tableting process.   28. The pharmaceutical composition of claim 27, wherein the solid dosage form is produced using a non-solvent granulation process.   30. The pharmaceutical composition of claim 29, wherein the non-solvent granulation process uses a non-solvent medium selected from ethanol, isopropanol, butanol, acetone, and ethyl acetate.   28. The pharmaceutical composition of claim 27, wherein the therapeutic agent is substantially stable during storage at room temperature. A method of making a pharmaceutical composition comprising:
a) making a solid dosage form comprising an effective amount of a therapeutic agent, a permeation enhancer, and a pharmaceutically acceptable excipient; and b) coating the solid dosage form with a bioadhesive layer comprising a bioadhesive polymer. A method comprising the steps of: c) an impermeable or semi-permeable layer comprising an opening capable of inducing substantially one-way release of the therapeutic agent and the permeation enhancer from the solid dosage form 35. The method of claim 32, further comprising coating with.   35. The method of claim 32, wherein the opening is formed in one side of the solid dosage form using a laser ablation process.   34. A method according to claim 33, wherein the order of steps b) and c) is reversed.   36. A method according to any one of claims 32 to 35, further comprising coating the composition with an enteric layer.   32. A method of treating a subject in need of therapeutic treatment, comprising administering to the subject the pharmaceutical composition of any one of claims 1-31.