GB2527802B

GB2527802B - An orally disintegrating tablet with differentiated absorption

Info

Publication number: GB2527802B
Application number: GB1411839.2A
Authority: GB
Inventors: Canova Fabio
Original assignee: OLIMED Ltd
Current assignee: OLIMED Ltd
Priority date: 2014-07-02
Filing date: 2014-07-02
Publication date: 2019-10-16
Anticipated expiration: 2034-07-02
Also published as: GB2527802A; GB201411839D0

Description

AN ORALLY DISINTEGRATING TABLET WITH DIFFERENTIATED

ABSORPTION

FIELD

The present invention relates to a tablet with differentiated oromucosal and enteric absorption, including in particular glutathione (GSH), or its acetyl or propionyl form, and its precursors, in particular L-cysteine and/or its dimer L-cy stine.

STATE OF THE ART

The technology of orally disintegrating tablets (ODT) has recently received considerable attention as a preferred alternative to conventional tablets and lozenges for swallowing, because of better consumer compliance and the advantages of bioavailability. The oromucosal absorption route offers several advantages: the oral mucosa is well provided with drainage, both vascular and lymphatic, and thereby absorbs directly whatever is dissolved in the mouth, avoiding first-pass metabolism in the liver or presystemic elimination in the gastrointestinal tract. As stated above, however, this applies only for molecules that can pass through the oral mucosa: all other components are swallowed and go into the stomach, where they can be broken down by the stomach acids.

Glutathione (GSH), also known as N-(n-l-gamma-glutamyl-L-cysteinyl) glycine, can either be produced endogenously or come from exogenous (dietary) sources.

The metabolic process leading to biosynthesis has as its protagonists three amino-acids - namely L-cysteine, L-glutamic acid and glycine - and the process involves the enzymes gamma-glutamylcysteine synthetase and glutathione synthetase. On the other hand, glutathione disulfide reductase is the enzyme mainly responsible for keeping GSH in its active reduced form. This enzyme uses NADPH as a cofactor. Pathological conditions or even simply particular states of oxidative stress can lead to its depletion within the organs. Glutathione ingested with food can be estimated at around 100 mg/day. For dietary GSH to be available in the tissue involved, it has to cross many organic barriers, which prevent or impair its absorption. Studies that have been conducted suggest that GSH is completely broken down by gamma-glutamyl transferase in the gut and that only a tiny amount of what is absorbed orally can reach the hepatic portal system. Some studies also reveal that even when glutathione can be absorbed by the enterocytes after ingestion, it may not be released into the bloodstream by these cells because it is used by the cells themselves as an intracellular redox buffer to compensate for “local” oxidative stress conditions.

As can be inferred from the above description, there are many different reasons for organic depletion of GSH. They constitute very real obstacles preventing it from doing its work as a redox buffer (antioxidant), and can lead to cell damage. L-cysteine acts as the main precursor of GSH. After ingestion it is oxidised to L-cystine, which is a dimer composed of two amino-acids of L-cysteine. L-cystine is the oxidised form of L-cysteine. Both L-cysteine and L-cystine are absorbed in the (small) intestine by active transit processes. Once absorbed, it enters the hepatic portal system and arrives at the liver, where it is mostly metabolised to GSH and other useful compounds, while the remaining small amount of L-cysteine that is not metabolised in the liver enters the systemic circulation and is distributed to the various body tissues. As is the case with GSH, if the liver uses L-cysteine for its own purposes the other peripheral regions may suffer depletion. What is more, L-cystine is not very palatable, since it has an unpleasant flavour that may lead to poor consumer compliance.

There is therefore a need to provide an improved tablet with differentiated oromucosal and enteric absorption that can overcome at least one of the drawbacks of the prior art, particularly reducing the problems of absorption and bioavailability of the components swallowed without nonetheless losing the advantages of ODT technology.

The Applicant has studied, researched and produced the present invention to remedy the drawbacks of the prior art and to achieve these and other aims and advantages.

Except where otherwise defined, all the technical and scientific terms used here and below have the same meaning as normally understood by a person with ordinary experience in the field of the art to which the present invention belongs. Even though methods and materials which are similar or equivalent to those described here may be used in practice or in tests to verify the present invention, the methods and materials are described below by way of example. In the event of conflict, the present application, including the definitions, shall prevail. The materials, methods and examples are purely illustrative in nature and must not be understood as being limiting.

SUMMARY OF THE INVENTION

The present invention is presented and characterised in the independent claims, while the dependent claims set out other features of the present invention or variants of the main solution concept.

In accordance with embodiments, an orally disintegrating tablet with differentiated oromucosal and enteric absorption is provided.

The said tablet includes: glutathione and/or its acetyl or propionyl form; microgranules each formed of an inner core of L-cysteine and/or its dimer L-cystine, and an outer gastro-resistant coating consisting of a lipophilic matrix.

In accordance with a further aspect of the invention, a method for producing an orally disintegrating tablet with differentiated oromucosal and enteric absorption is provided. The said method includes: producing microgranules each formed of an inner core of L-cysteine and/or its dimer L-cystine, and an outer gastro-resistant coating consisting of a lipophilic matrix; compressing said microgranules together with at least glutathione and/or its acetyl or propionyl form, to obtain said tablet.

These and other aspects, features and advantages of the present disclosure will be more easily understood by reference to the following description, drawing and the attached claims. The drawing, which is integral to and forms part of the present description, illustrates some embodiments of the present subject matter and, together with the description, propose to describe the principles of the present disclosure.

The skilled person will appreciate that various aspects and features described in the present description may be applied individually, where possible, or in any suitable combination.

DESCRIPTION OF EMBODIMENTS

Reference will now be made in detail to the various embodiments of the invention, each example of which is provided by way of illustration of the invention and is not intended to restrict it. For instance, the features illustrated or described as forming part of one embodiment may be adopted in addition to, or in association with, other embodiments to produce a further embodiment. It should be noted that the present invention will include these modifications and variants.

Embodiments described here relate to an orally disintegrating tablet with differentiated oromucosal and enteric absorption.

According to embodiments described here the tablet with differentiated absorption includes: glutathione (GSH) and/or its acetyl and/or propionyl form; microgranules each formed of an inner core of L-cysteine and/or its dimer L-cystine, and an outer gastro-resistant coating consisting of a lipophilic matrix.

In accordance with the present description, the term “tablet” refers to a pharmaceutical form or dietary supplement containing a single dose of one or more active substances, generally obtained by compressing a volume of particles, generally powders. In accordance with the present invention, the tablet is intended for oral administration. In accordance with the present invention, other dosage forms may also be used, such as but not limited to lozenges, pills, cachet or capsules; and as used herein the term “tablet” is intended to encompass such other dosage forms suitable for oral administration and oral disintegration.

Generally, tablets are obtained by compressing uniform volumes of powders or granules, it being possible in particular to use for example rotary or alternating pressing machines. The formulations for such tablets and other dosage forms can typically include excipients for various purposes: in general, the excipients can be constitutive (for example fillers), production-related (e.g. lubricants and binders), designed to aid release (e.g. disintegrants), preservative (for instance, antioxidants) and for presentation (e.g. colourings and flavourings).

In accordance with various embodiments of the invention, the glutathione and/or its acetyl or propionyl form may be in the range between about 15% and about 30% w/w by weight of the tablet, in particular between about 18% and about 28% w/w, more particularly between about 20% and about 25% w/w. Specific examples of the w/w% of glutathione and/or its acetyl or propionyl form are around 21%, 22%, 23% or 24%.

In accordance with various embodiments of the invention, the L-cysteine and/or its dimer L-cystine are in the range between about 1% and about 10% w/w by weight of the tablet, in particular between about 2% and about 8% w/w, more particularly between about 3% and about 6%, even more particularly between about 4% and about 5%. Examples of the w/w% of L-cysteine and/or its dimer L-cystine are around 4.3%, 4.4%, 4.5% or 4.6%.

The use of glutathione is envisaged in possible implementations. In other implementations, it is possible to use its acetyl (acetyl glutathione) or propionyl (propionyl glutathione) form. In some embodiment a mixture of glutathione, acetyl glutathione and/or propionyl glutathione may be used.

The use of L-cystine is envisaged in possible implementations.

In accordance with various embodiments, the tablet according to the present description can include one or more surfactants. The surfactants can act as wettability additives and for that purpose can be chosen with a desired hydrophilicity profile, to favour the hydrophilic, oromucosal absorption route of GSH. The oromucosal absorption mechanics of GSH can thereby be controlled and influenced, so that it follows the hydrophilic route. In particular, surfactants that can be used can have an HLB (hydrophilic-lipophilic balance) value in the range between 10 and 20, in particular between 12 and 18, more particularly between 14 and 16. Examples of one or more surfactants that can be used are polysorbates in general, poloxamers, di- and triethanolamine, glyceryl monostearate, polyethylene glycol (PEG), soya lecithin, sucrose esters or mixtures of sucrose esters, or mixtures of these surfactants.

Preferred as used herein, the term sucrose ester refers to a sucrose ester with higher organic acids, which normally takes the form of odourless and flavourless white powders.

In accordance with various embodiments, the one or more surfactants may be in the range between about 0.5% and about 10% w/w by weight of the tablet, in particular between about 0.75% and about 9% w/w, more particularly between about 1% and about 8%, even still more particularly between about 1.25% and about 7%.

In accordance with various embodiments, the gastro-resistant lipophilic matrix is formed of hydrogenated vegetable fats.

In accordance with possible embodiments, the outer gastro-resistant coating amounts to between about 20% and about 40% of the weight of each microgranule.

In accordance with various embodiments, the hydrogenated vegetable fats may be chosen from the group consisting of: mono-, di-, triglyceride behenates, glyceryl palmitostearate, polyethylene glycol esters of fatty acids and/or waxes, such as camauba wax, beeswax, and coconut butter, etc.

In accordance with various embodiments, the hydrogenated vegetable fats suitably have a melting point between 30°C and 100°C, in particular between 50°C and 80°C.

In accordance with various embodiments, the hydrogenated vegetable fats may be hydrogenated fatty acids or mixtures thereof having a chain of 14 to 22 carbon atoms.

In accordance with various embodiments, the L-cysteine and/or its dimer L-cystine amount to between about 50% and about 90% of the weight of each microgranule, in particular between about 60% and about 80%.

In accordance with various embodiments, the microgranules may have a particle size of between 250 and 3000 microns, in particular between 250 and 1000 microns.

In accordance with various embodiments, the tablet can contain pharmaceutically acceptable adjuvants or excipients. Examples of such pharmaceutically acceptable adjuvants or excipients include one or more of fillers, binders, lubricants, antiagglomerants and sweeteners, such as amides, mannitol, cellulose, crospovidone or polyvinylpyrrolidone (PVP) etc., or precipitated silica, silicon dioxide, magnesium stearate, stearic acid or glycerides of stearic acid (vegetable stearine). In suitable implementations, each of the aforesaid microgranules may contain pharmaceutically acceptable adjuvants or excipients amounting to between about 2% and about 10% of the weight of the microgranule, particularly between about 3% and about 5%.

The tablet according to the present invention can be used in the case of molecules such as GSH and/or its acetyl or propionyl form, L-cysteine and/or its dimer L-cystine or vitamin C, where a particular treatment is required for: improving absorption and bioavailability; minimising or even neutralising critical aspects such as hygroscopicity, poor palatability or reactivity owing to the nature of the molecules; improving the release site specificity; preserving both the pharmacokinetics and pharmacodynamics of the molecules; and/or improving consumer compliance in the case of the poor flavour of the components.

The orally disintegrating tablet according to the present invention is innovatively distinctive from simple orally disintegrating tablets (ODTs) in the differentiated release of selected ingredients: some components such as, in particular, GSH, are supplied by fast oromucosal release and others, such as L-cystine, by slow intestinal release, owing to the lipophilic coating. Moreover, selected components of the tablet, including at least L-cysteine and/or its dimer L-cystine, are suitably coated with an edible lipid matrix: when swallowed, the gastro-resistant microgranules of the coated ingredients are beneficially not destroyed by the fatty acids and may thus reach the gut undamaged, where they are assimilated through the natural course of fat absorption.

Moreover, the lipid coating may act as an efficient system for masking the taste of components such as L-cystine, which has an unpleasant flavour, and may allow oromucosal formulations to be produced with ingredients considered to be critical from the point of view of palatability, thus improving consumer compliance.

The tablet in accordance with the present invention, and the method by which it is produced, are preferably devoid of water, making this dosage form particularly useful for hygroscopic components, such as GSH and/or its acetyl or propionyl form, L-cysteine and/or its dimer L-cystine, and vitamin C.

In accordance with various embodiments, the tablet with differentiated absorption may also include vitamin C. Vitamin C can be supplied in its various supplement forms, permissible and acceptable for the purposes and functions of the invention, for example, ascorbic acid or salts thereof, such as sodium ascorbate or potassium ascorbate.

In accordance with various embodiments, when used, the vitamin C may be in the range between about 1% and about 10% w/w by weight of the tablet, in particular between 2% and 8% w/w, more particularly between about 3% and about 6%, even more particularly between about 3.5% and about 5%. Specific examples of the w/w% of vitamin C are around 3.5%, 3.6%, 3.7%, 3.8% or 3.9%.

In accordance with various embodiments, the tablet with differentiated absorption may also include selenium. Selenium can be provided in its various supplement forms, permissible and acceptable for the purposes and functions of the invention, for example, L-selenomethionine. Selenium together with glutathione may form glutathione peroxidase, a potent antioxidant.

In accordance with various embodiments, selenium, when used, may be in the range between about 0.001% and about 0.01% w/w by weight of the tablet, in particular between 0.002% and 0.008% w/w, more particularly between about 0.003% and about 0.007%, even more particularly between about 0.004% and about 0.006%. Specific examples of the w/w% of selenium are around 0.0045%, 0.005% or 0.0055%.

In accordance with various embodiments, the tablet with differentiated absorption may also include sweeteners such as mannitol and/or high-intensity sweeteners such as sucralose and neohesperidin DC. For example, when used, mannitol may be in the range between about 50% and about 60% w/w by weight of the tablet, in particular between 52% and 58% w/w, more particularly between about 53% and about 56%, even more particularly between about 54% and about 55%.

In accordance with various embodiments, the tablet with differentiated absorption may also include one or more flavourings, particularly fruit flavour(s), for example fruits of the forest flavour, cherry flavour, orange flavour, lemon flavour or other flavourings. In accordance with some suitable embodiments, the one or more flavourings may be in the range between about 0.5% and about 1.4% w/w by weight of the tablet, in particular between about 0.5% and about 1.4% w/w, more particularly between about 0.6% and about 1.3%, even more particularly between about 0.7% and about 1.2%. Specific examples of the w/w% of flavourings are around 0.8%, 0.9%, 1% or 1.1%.

The tablet according to the present description is suitably produced by making the gastro-resistant microgranules of L-cysteine and/or its dimer L-cystine and using the microgranules to produce the tablet, together with GSH, any excipients, or pharmaceutically acceptable adjuvants, surfactants and flavourings.

In some implementations, the gastro-resistant microgranules of L-cysteine and/or its dimer L-cystine are produced from powdered raw materials with a large grain size. Initially, the powders, including L-cysteine and/or its dimer L-cystine, are subjected to a process of forming granules with, for example, an average grain size of between 250 microns and 3000 microns, in particular between 250 microns and 1000 microns. This can be made for example by forming a granulate through kneading, for example compacting the mixtures of powders by compression, followed by breaking up the “slugs” into granules measuring between 250 microns and 3000 microns, in particular between 250 microns and 1000 microns (for example by means of meshes or plates with calibrated holes). In these phases the use of common excipients and/or adjuvants, fillers, binders and lubricants, can be envisaged.

Subsequently, screening of the granulate produced takes place to remove the fine powder, for example under 250 microns, selecting the desired fraction. The granulate selected can then be loaded into mixers, for example of the rotating screw type, possibly thermostated. After this, the granulate can be coated with the lipid matrix, typically melted, possibly with the addition of surfactants miscible with the oily liquid. The melted fat mass can be added using a peristaltic pump, preferably by using a nebuliser.

If appropriate, pH-dependent powdered substances can be added, to give further functions to the final product, for example Eudragit (RTM) L100-55, cellulose acetate phthalate, suitably modified amides, various salts of shellac or shellac in alcohol, and hydroxypropyl methylcellulose (Methocel (RTM)). The use of antiadherents such as silica, talc, magnesium stearate, etc. can also be envisaged.

Next, any aggregates formed during coating are separated out, for example on a vibrating screen, and the gastro-resistant microgranules of L-cysteine and/or its dimer L-cystine are obtained.

The gastro-resistant microgranules are then combined with the GSH and any excipients, or pharmaceutically acceptable adjuvants, possible fillers, binders and lubricants, surfactants and flavourings, to obtain the tablets according to the present description, typically by means of a phase of compressing the powders and/or granulates.

The tablet according to the present description proves, therefore, to be a tablet produced with ODT technology, in which the rationale for release of either GSH (oromucosal release) or L-cysteine and/or its dimer L-cystine and possibly vitamin C (intestinal release), makes it possible to bypass any possible obstacles preventing the activity of the redox buffer of the GSH, resulting in a high concentration in the blood, and direct absorption from the blood, and avoiding any absorption by hepatic first pass.

In particular, in the case of GSH, the present invention allows it to be administered by an alternative absorption route of the oromucosal type, capable of: preventing intestinal gamma-glutamyl transferase activity, which is responsible for degrading and thereby inactivating it; avoiding increased enterocyte metabolism; clearing the hepatic filter (hence the “first-pass effect”), which would then deprive other peripheral organs of the GSH, reaching the general circulation.

In this connection it should be noted that the oral mucosa can be considered to be halfway between the epidermis and the intestinal mucosa in terms of absorption. Its oral absorption capacity is around 4000 times better than that of the skin. In support of this, in vitro tests conducted by the Applicant have demonstrated that, if applied to a reconstructed membrane of oral mucosa cells, GSH manages to pass through this with a significantly positive result within a brief period of time (10 minutes), and the mucosa does not retain the substance, which passes directly into the general circulation.

On the other hand, as regards L-cysteine and/or its dimer L-cystine and any vitamin C, the present invention allows these to be covered with a lipid matrix so as to produce: protection by the gastric barrier and specific site delivery to the small intestine; prolonged release, at the brush border of the villi of the intestinal mucosa, of both L-cysteine and/or its dimer L-cystine and also any vitamin C, which when released here can be absorbed by the enterocytes by the usual routes of absorption and then sent to the general blood circulation; in the case of L-cysteine and/or its dimer L-cystine, the masking of its unpleasant flavour, to make it more acceptable to the consumer.

Once in circulation, L-cystine and any vitamin C contribute in the first case to the biosynthesis of endogenous GSH and in the second case to its mutual regeneration as shown in Figure 1.

Accordingly, the present invention makes it possible to differentiate methods and timings of absorption of GSH and L-cysteine and/or its dimer L-cystine, to ensure that the body can receive a fresh supply of GSH directly (rapid oromucosal absorption) or as GSH deriving from the precursor L-cystine (slow absorption in the gut).

The present invention facilitates “chronoactive” type administration, taking advantage of the fact that all the molecules involved in making up GSH arrive at their destination simultaneously, whether the liver or various peripheral regions.

The two combined absorption methods, which support the chemical nature of the molecules involved, mainly GSH and L-cysteine and/or its dimer L-cystine, and possibly vitamin C, and the physiological routes of absorption, making a synergistic contribution to bringing about the necessary mutual participation of the molecules which are active and bioavailable even in cells of the peripheral regions that are difficult to reach.

The Applicant has found that, after oromucosal administration of the orally disintegrating tablet according to the present invention, the bioavailability of GSH is increased and the beneficial effects of this increase can be observed in both the short and long term. In fact, there is a significant increase in the levels of glutathione in its reduced form of GSH in the blood, of antioxidant enzymatic effect and of non-enzymatic antioxidant capacity of the molecules in the plasma and the corpuscular blood.

The skilled person will appreciate that modifications and/or additions of parts may be made to the tablet with differentiated absorption described herein, without departing from the scope of the present invention as defined by the claims.

Clearly too, although the present invention has been described with reference to some specific examples, a person skilled in the art may of course produce many other equivalent forms of tablet with differentiated absorption, having the features described in the claims and therefore all coming within the scope of protection defined thereby.

Claims

1. An orally disintegrating tablet with differentiated oromucosal and enteric absorption, said tablet comprising: glutathione and/or its acetyl or propionyl form; microgranules each formed of an inner core of L-cysteine and/or its dimer L-cystine, and an outer gastro-resistant coating consisting of a lipophilic matrix.

2. The tablet according to claim 1, wherein the glutathione and/or its acetyl or propionyl form is in the range between 15% and 30% w/w by weight of the tablet.

3. The tablet according to either claim 1 or claim 2, wherein the L-cysteine and/or its dimer L-cystine is in the range between 1% and 10% w/w by weight of the tablet.

4. The tablet according to any of the preceding claims, where said tablet comprises one or more surfactants.

5. The tablet according to claim 4, wherein said surfactants have an hydrophilic-lipophilic balance (HLB) value in the range between 10 and 20.

6. The tablet according to either claim 4 or claim 5, wherein said surfactants are chosen from a group consisting of polysorbates, poloxamers, di- and triethanolamine, glyceryl monostearate, polyethylene glycol (PEG), soya lecithin, sucrose esters or mixtures of sucrose esters, or mixtures of these surfactants.

7. The tablet according to any of claim 4, 5 or 6, wherein said surfactants are in the range between 0.5% and 10% w/w by weight of the tablet.

8. The tablet according to any of the preceding claims, wherein the outer gastro-resistant coating amounts to between 20% and 40% of the weight of each microgranule.

9. The tablet according to any of the preceding claims, wherein said gastro-resistant lipophilic matrix is formed of hydrogenated vegetable fats.

10. The tablet according to claim 9, wherein the hydrogenated vegetable fats are chosen from a group consisting of: mono-, di-, triglyceride behenates, glyceryl palmitostearate, polyethylene glycol esters of fatty acids and/or waxes.

11. The tablet according to claim 9, wherein the hydrogenated vegetable fats are hydrogenated fatty acids or mixtures thereof having a chain of 14 to 22 carbon atoms.

12. The tablet according to any of claims 9, 10, or 11 wherein the hydrogenated vegetable fats have a melting point between 30°C and 100°C.

13. The tablet according to any of the preceding claims, wherein the microgranules have a particle size of between 250 and 3000 microns.

14. The tablet according to any of the preceding claims, wherein said tablet comprises vitamin C, and/or vitamin C in any of its supplement forms.

15. The tablet according to claim 14, wherein the vitamin C is in the range between 1% and 10% w/w by weight of the tablet.

16. The tablet according to any of the preceding claims, wherein said tablet comprises selenium, and/or selenium in any of its supplement forms.

17. The tablet according to claim 16, wherein the selenium is in the range between 0.001% and 0.01% w/w by weight of the tablet.

18. A method for producing an orally disintegrating tablet with differentiated oromucosal and enteric absorption, said method comprising: producing microgranules each formed of an inner core of L-cysteine and/or its dimer L-cystine, and an outer gastro-resistant coating consisting of a lipophilic matrix; compressing said microgranules together with at least glutathione and/or its acetyl or propionyl form, to obtain said tablet.

19. A method according to claim 18, said method providing for one or more surfactants to also be used.

20. A method according to claim 18 or claim 19, wherein the tablet is defined according to any of claims 1 to 17.