WO2011111027A2

WO2011111027A2 - Oral dispersible delayed release tablet formulation

Info

Publication number: WO2011111027A2
Application number: PCT/IB2011/051031
Authority: WO
Inventors: Adel Penhasi; Maxim Gomberg; Tal Meisler; Janina Gauchman
Original assignee: Dexcel Pharma Technologies Ltd.
Priority date: 2010-03-11
Filing date: 2011-03-11
Publication date: 2011-09-15
Also published as: WO2011111027A3

Abstract

A formulation for delivery of a therapeutic agent to the small intestine which features a combination of a single delayed release mini-tablet for delivery to the gastrointestinal tract, surrounded by a fast disintegrating tablet layer which dissolves in the oral cavity. The oral disintegrating tablet which undergoes rapid disintegration in the oral cavity supports ease of swallowing and hence ease of administration of the mini-tablet, which is responsible for delayed release of a therapeutic agent in the small intestine. The mini-tablet preferably has a relatively small diameter, smaller than that of a regular tablet.

Description

ORAL DISPERSIBLE DELAYED RELEASE TABLET FORMULATION

FIELD OF THE INVENTION

The present invention relates to a novel formulation which rapidly dissolves in the oral cavity yet which also provides delayed release of a therapeutic agent, as well as to methods of use and of manufacture thereof.

BACKGROUND OF THE INVENTION

Formulations for oral delivery of a therapeutic agent are well known in the art. Typically, such formulations fall into one of a number of different categories. Figure 1 shows a number of examples of such known formulations.

Figure 1A shows a typical enteric coated tablet 10, in which the active ingredient is present in a single core 12, which is coated with an enteric coating 14, optionally with an intermediate coating 16 between single core 12 and enteric coating 14. Enteric coating 14 prevents premature dissolution of tablet 10, typically until tablet 10 reaches the small intestine.

Figure IB shows another example of a formulation for oral delivery, comprising a capsule 20, in which the active ingredient is in the form of a powder or granules 22, which is then placed in a capsule shell 24. Powder or granules 22 and/or capsule shell 24 may be enterically coated. The capsule shell 24 in this example protects the formulation from premature dissolution.

Figure 1C shows an example of a MUPS (multiple unit formulation) comprising a compressed tablet 30 in which granules 32 containing the active ingredient are compressed into a rapidly disintegrating matrix 34 with other excipients. The granules may optionally be provided with a subcoating. Compressed tablet 30 comprises an enteric coating 36 to prevent premature dissolution.

Figure ID shows an example of a formulation for oral delivery 40 in which the active ingredient is formulated into a powder 42, which is then placed into a sachet 44.

Figure IE shows another example of a MUPS formulation 50, in which the individual units 52 are placed in a capsule shell 54, rather than being compressed to a tablet. Again the capsule shell protects against premature dissolution of the formulation. The above formulations are useful in different situations. For example, a single large tablet with an enteric coating is very convenient for individuals who do not have trouble swallowing. For the elderly and children, who may have difficulty swallowing such a large tablet, the powder and MUPS type formulations (when present in a capsule or sachet) are convenient because they may be administered in a soft food or drink. However, for individuals who do not have difficulty swallowing, such multiple unit formulations are much less convenient, which may lead to reduced compliance.

Some examples powder and MUPs type formulations are described in the following patents/applications.

US 20080292701 and US 7,431,942 describe formulations featuring fine granules that are compressed into a tablet.

WO2007138606 describes a typical MUPS formulation, featuring compression of a tablet.

To ease administration of an oral formulation for individuals who have difficulty swallowing, or to ease administration with little or no water, salivating agents may be used. These agents induce production of saliva, thereby lubricating the formulation. Examples of such agents are given in US Patent Application No. 20090191267, as well as in US Patent Application No. 20070134331 which describes application of rapidly dissolving salivating agents to a solid formulation in a compressed coating.

Various formulations which dissolve rapidly in the mouth have been described in the art, featuring such salivating agents, which may be very convenient for individuals who have difficulty swallowing. For example, in European Application Nos. EP0181650 and EP1430888, the entire formulation rapidly dissolves in the mouth. A similar formulation is also taught in PCT Application No. WO2008065107.

WO2009060064 teaches a formulation featuring multiple small granules packed into a core, which is then protected with an outer tablet that also features multiple small granules. The outermost tablet is not intended to be rapidly dissolving. SUMMARY OF THE INVENTION

The present invention, in at least some embodiments, is of a formulation for delivery of a therapeutic agent or active pharmaceutical ingredient (API) to the small intestine which features a combination of a single delayed release mini-tablet for delivery to the gastrointestinal tract, surrounded by a fast disintegrating tablet layer which dissolves in the oral cavity. The orally disintegrating outer tablet layer, which undergoes rapid disintegration in the oral cavity, supports ease of swallowing and hence ease of administration of the single enteric coated mini-tablet, which is responsible for delayed release of a therapeutic agent in the small intestine. The single coated mini-tablet preferably has a relatively small diameter, smaller than that of a regular tablet.

According to some embodiments, there is provided a delayed release formulation for a therapeutic agent comprising a single inner mini-tablet and an outer tablet layer surrounding the single inner mini-tablet. The outer tablet layer comprises one or more fast disintegrating excipients, such that the outer tablet layer dissolves in no more than about 5 minutes in saliva. The diameter of the inner mini-tablet is up to about 7 mm. The therapeutic agent comprises from about 30% to about 90% weight per weight of the mini-tablet.

According to some embodiments, there is provided a method for the manufacture of a delayed release formulation for a therapeutic agent, the method comprising preparing an inner mini-tablet having a diameter of up to about 7 mm in diameter, wherein the therapeutic agent comprises at least 30% weight by weight percentage of the total weight of the mini-tablet; and applying a solid layer comprising one or more fast disintegrating excipients on to the mini-tablet to form an outer tablet layer, wherein the outer tablet layer surrounds the inner mini-tablet, such that the outer tablet layer dissolves in 5 minutes or less in saliva.

According to some embodiments, the formulation of the present invention is prepared by application of a double-press (dry coating) tabletting technology to form a double pressed tablet.

According to some embodiments, the mini-tablet is prepared by compression of the therapeutic agent with at least one compression excipient.

Preferably, the method further comprises coating the mini-tablet with an enteric coating before compressing the outer tablet layer onto the mini-tablet. Preferably, the method comprises dry compressing at least one enteric polymer over the mini-tablet.

According to some embodiments, the therapeutic agent or active pharmaceutical ingredient (API) is provided within the mini-tablet, and the outer tablet layer does not comprise a therapeutic agent, but rather a plurality of excipients enabling formation of a solid mass, such as by compression and thus forming an outer tablet layer for covering the inner tablet.

Such excipients are also responsible for fast disintegration in the oral cavity. By "fast disintegration" it is meant disintegration that occurs in fewer than five minutes, preferably fewer than 3 minutes, more preferably fewer than two minutes and most preferably one minute or less.

The outer layer tablet may also optionally comprise a cationic polymer, which is preferably swellable at acidic pH values, such as those in the stomach, but not at more neutral pH values, such as those in the mouth. The cationic polymer therefore preferably disintegrates rapidly in the mouth, but forms a hydrogel blocking or barrier layer in the stomach, which may optionally provide symptomatic relief from heartburn symptoms as described herein.

The single mini-tablet optionally comprises an enteric coating, preferably featuring at least an enteric polymer providing delayed release of the therapeutic agent in the small intestine.

Optionally the single mini-tablet further comprises an intermediate coating, between the core containing the therapeutic agent and the enteric coating. Preferably the intermediate coating provides improved stability, through the application of one or more special coating polymers, such as a specific aqueous moisture barrier polymer as a sub-coating material. The sub-coating material preferably comprises such materials as PVA (polyvinyl alcohol) or wax.

According to at least some embodiments of the present invention, the formulation of the core is controlled to provide an appropriate weight ratio of the therapeutic agent to inactive ingredients (excipients). Such an appropriate weight ratio preferably controls the properties of the tablet, including but not limited to disintegration, dissolution, hardness, friability, etc. The amount of the therapeutic agent in the single mini-tablet is preferably up to about 90% by weight of the total amount of the single mini-tablet, more preferably 30-90% by weight of the total amount of the single mini-tablet.

The core preferably comprises one or more of a disintegrant, lubricant, filler, basifying agent, or combination thereof. According to at least some embodiments, the single mini-tablet is preferably prepared by wet granulation followed by compression, preferably with good flowability of the tabletting mix in order to prevent a wide weight distribution of tablet, and deficiency in assay, and uniformity of content.

The present invention, in at least some embodiments, combines the advantages provided by multi-particulate (MP) modified release (MR) drug delivery systems with those of regular (large) tablet formulations.

Multi-particulate modified release formulations may provide consistent and reliable in-vivo drug release, with a reduced risk of local irritation along the gastrointestinal tract. However, they are more difficult to manufacture; furthermore, for individuals who do not have difficulty swallowing, such multi-particulate compositions are less convenient for administration. On the other hand, regular large tablet compositions are easier to manufacture and are convenient for administration to individuals who do not have difficulty swallowing, but are not convenient for individuals who do have difficulty swallowing.

The mini-tablet technology according to at least some embodiments of the present invention surprisingly combines the advantages of MP dosage forms with established manufacturing techniques used in tableting and surprisingly enables such mini-tablets to be bioequivalent to multi-particulate (MP) drug delivery systems in both fed and fasting conditions. Without wishing to be limited by a single hypothesis, the mini-tablet may provide such beneficial effects by shortening the gastric retention time especially in the fed condition. Furthermore, such systems may benefit from a reduced food effect, especially when an enteric coating for modified release purposes is applied.

However, mini-tablet technology is not simple and can cause many problems, for example due to the limitation in both tablet weight and size. The low weight of mini-tablets results in a high weight ratio of API to inactive ingredients especially where a high dose of API is needed. This may cause difficulties in controlling the tablet properties such as disintegration, dissolution, hardness, friability, etc.

Additionally, the small dimensions of mini-tablets may require good flowability of the tabletting mix in order to prevent a wide weight distribution of tablet, and deficiency in assay, and uniformity of content. When fast release of drug is desired, disintegration is a critical factor. In the case of mini-tablets, due to the low ratio of weight to surface area, fast disintegration may be more difficult to achieve than in a tablet with higher ratio of weight to surface area. On the other hand it is well known that a fast disintegration is a function of the rate of water absorption. This fact can be critical especially when the tablet is coated with an enteric coat. Such a coated tablet may have unsuitable disintegration properties after exposure to an appropriate pH environment and removal of the enteric coat. This can be explained by the fact that during exposure to the gastric fluids, there is slow but continuous penetration of aqueous moisture into the core through the enteric coat. This can cause serious interruption in the disintegration process of the core by reducing the rate of water absorption into the core upon exposure to a medium having higher pH.

US20040247675 features tablets having less than 50% therapeutic agent weight per weight of the total weight of the tablet which is associated with the disadvantages discussed above. Furthermore, this application teaches the use of a hydro-gel forming polymer in the outermost tablet layer, such that a hydro-gel is formed in the oral cavity upon rapid disintegration of the outermost tablet layer.

US20060193915 teaches a pharmaceutical composition for oral administration comprising a compression coated solid dosage form of a bitter or unpleasant tasting pharmaceutically active agent; however, this compression coating is applied directly to the core, without the formation of a multi-layer tablet that includes a mini-tablet core with an enteric coating.

The outer tablet layer of the formulation of the present invention, in at least some embodiments, is responsible for providing at least some of the following advantages: 1. increased tablet dimensions to overcome compliance problems resulting from the small size of the inner tablet; 2. feeling of "fast disintegration" in the oral cavity; 3. salivation (enhanced saliva excretion) in the oral cavity, to ease the swallowing of the inner tablet without using water; and 4. smoothing the outer surface of the inner tablet, to ease swallowing of the inner tablet

As used herein the term "about" refers to ± 10 %.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a number of prior art formulation structures; FIG. 2 shows the structure of a tablet according to at least some embodiments of the present invention;

FIGS. 3-5 show the dissolution profiles of various granulates and cores containing omeprazole according to some embodiments of the present invention;

FIG. 6 shows the dissolution profile of enteric (two different thicknesses) coated omeprazole mini-tablets in intestinal fluid after exposure of 1 hour in gastric fluid with HPMC as the subcoat;

FIG. 7 shows the dissolution profile of enteric (two different thicknesses) coated omeprazole mini-tablets directly in intestinal fluid without exposure of 1 hour in gastric fluid with HPMC as the subcoat;

FIG. 8 shows the dissolution profile of enteric (two different thicknesses) coated omeprazole mini-tablets in intestinal fluid after exposure of 1 hour in gastric fluid with Opadry AMB as the subcoat;

FIG. 9 shows the dissolution profile of enteric (two different thicknesses) coated omeprazole mini-tablets directly in intestinal fluid without exposure of 1 hour in gastric fluid- Opadry® AMB as the subcoat;

FIG. 10 shows the dissolution profile of enteric coated omeprazole mini-tablets with Protect® as the subcoat;

FIG. 11 shows the dissolution profile of enteric (two different thicknesses) coated omeprazole mini-tablets both directly in intestinal fluid without exposure of 1 hour in gastric fluid and after exposure of 1 hour in gastric fluid with Opadry® AMB versus Protect® as the subcoat;

FIG. 12 shows the dissolution profile of enteric coated omeprazole mini-tablets (28 mg core) in intestinal fluid (buffer phosphate pH 6.8) after 2 hour exposure in gastric fluid;

FIGS. 13-18 relate to lansoprazole release from various tablet formulations according to various embodiments of the present invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is of a formulation for delivery of a therapeutic agent to the small intestine which features a combination of a single delayed release tablet for delivery to the gastrointestinal tract, surrounded by a fast disintegrating tablet formulation which dissolves in the oral cavity. The oral disintegrating tablet which undergoes rapid disintegration in the oral cavity supports ease of swallowing and hence ease of administration of the single enteric coated mini tablet, which is responsible for delayed release of a therapeutic agent in the small intestine. The single coated mini tablet preferably has a relatively small diameter, smaller than that of a regular tablet.

According to some embodiments, there is provided a delayed release formulation for a therapeutic agent comprising a single inner mini-tablet and an outer tablet layer surrounding the inner mini-tablet. The outer tablet layer comprises one or more fast disintegrating excipients, such that the outer tablet layer dissolves in no more than about 5 minutes in saliva. A diameter of the inner mini-tablet is up to about 7 mm. The therapeutic agent comprises from about 30% to about 90% weight per weight of the mini-tablet.

An example of a delayed release formulation 60 according to the principles of the present invention is shown in Figure 2, comprising an inner mini-tablet 62, an enteric coating 64 on mini-tablet 62, and an outer tablet layer 66.

According to some embodiments of the formulation or method of the present invention, the therapeutic agent is a proton pump inhibitor.

According to some embodiments, there is provided an orally dispersible delayed release tablet formulation for a proton pump inhibitor, comprising a single inner mini-tablet and an outer tablet layer surrounding the inner mini-tablet. The outer tablet layer comprises one or more fast disintegrating excipients, such that the outer tablet layer dissolves in no more than about 5 minutes in the oral cavity. A diameter of the inner mini-tablet is up to 7 mm. The proton pump inhibitor comprises at least 30% weight by weight percentage of the total weight of the mini-tablet. According to aspects of some embodiments of the present invention there is provided the formulation of the present invention, for use in treating a disease requiring administration of a proton pump inhibitor.

According to some embodiments, there is provided a method for administering a proton pump inhibitor to a subject in need thereof, the method comprising providing a formulation comprising a single mini-tablet comprising the proton pump inhibitor, wherein the single mini-tablet is surrounded by a rapidly disintegrating outer tablet layer; administering the composition to the oral cavity of the subject, followed by rapid dissolution of the outer tablet layer in 1 minute or less in the oral cavity; swallowing of the single mini-tablet by the subject and release of the proton pump inhibitor from the mini-tablet in the small intestine of the subject from the mini-tablet. Optionally and preferably, the single mini-tablet is intact upon swallowing.

According to some embodiments, there is provided a method for administering a proton pump inhibitor to a subject in need thereof, the method comprising providing a single mini-tablet comprising the proton pump inhibitor; applying a rapidly disintegrating outer tablet layer to the single mini-tablet by dry coating, such that the outer tablet layer surrounds the single mini-tablet, to form a composition; administering the composition to the oral cavity of the subject, followed by rapid dissolution of the outer tablet layer in the oral cavity; swallowing of the single mini- tablet by the subject, wherein the single mini-tablet is intact upon said swallowing; and release of the proton pump inhibitor from the single mini-tablet in the small intestine of the subject.

Non-limiting examples of proton pump inhibitors, according to aspects of some embodiments of the present invention, include omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole and rabeprazole, or combinations thereof.

According to some embodiments of the formulation or method of the present invention, the outer tablet layer is applied to the inner mini-tablet by any dry coating method, such as compression coating.

According to some embodiments, the outer tablet layer is devoid of a gel- forming polymer.

According to some embodiments, the outer tablet layer and the inner mini- tablet in combination have a diameter of up to about 15 mm, such as, for example, preferably up to about 12 mm, more preferably up to about 10 mm. The diameter may therefore be in the range, for example, of from about 0.5 to about 7 mm, preferably from about 1 to about 6 mm, more preferably from about 2 to about 5 mm, and most preferably from about 4 to about 5 mm.

According to aspects of some embodiments of the formulation or method of the present invention, the mini-tablet is adapted to remain intact until the small intestine is reached.

Outer tablet layer

The outer tablet layer preferably comprises one or more excipients which are responsible for rapid disintegration in the oral cavity.

According to some embodiments, the outer tablet layer comprises at least one disintegrating agent (also referred to herein as a disintegrant). Examples of disintegrants in the outer tablet formulation include but are not limited to low- substituted carboxymethyl cellulose sodium, cross-linked polyvinyl pyrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose magnesium aluminum silicate, or a mixture thereof. Preferably, the disintegrating agent comprises crospovidone, starch 1500, sodium starch glycolate, or combinations thereof.

The outer coating layer may optionally further comprise one or more additional excipients. Examples of additional excipients include one or more of a sweetener (such as acesulfame potassium, or sucralose), a flavorant (such as citric acid powder, strawberry flavor, menthol, orange or mint flavor, or a combination thereof), a breath- freshener, a colorant, a glidant (such as silica anhydrous) and a lubricant to ease in swallowing (such as polyethylene glycol or magnesium stearate), and combinations thereof. Flavorants and sweeteners are particularly useful when the active ingredient has a bitter taste, the masking of which would increase patient compliance.

According to some embodiments, the outer tablet layer further comprises a rapidly disintegrating filler.

The filler is optionally and preferably at least one of a sugar (such as lactose, glucose, fructose, or sucrose); dicalcium phosphate; a sugar alcohol (such as sorbitol, manitol, lactitol, xylitol, isomalt, and erythritol); a hydrogenated starch hydrolysate; and a starch, (such as corn starch, or potato starch), or sodium carboxymethycellulose, or mixtures thereof. Suitable commercially available fillers include Pharmaburst® 500 of SPI Pharma, Pharmaburst® C of SPI Pharma, Ludiflash® of BASF, which comprise a mixture of sorbitol and mannitol, Parteck® ODT of Merk Chemicals, PEARLITOL Flash® of Roquette, PROSOLV® ODT of JRS Pharma, and PanExcea® ODT MC200G of Mallinckrodt Baker.

The outer tablet coating may optionally comprise an effervescent. An effervescent material is optionally and preferably included in order to increase dissolution rate of the other excipients. The term "effervescent" includes compounds which evolve gas. The preferred effervescent agents evolve gas by means of a chemical reaction, such as between an acid and a base, which takes place upon exposure of the effervescent to water and other fluids. Such water-activated materials must be kept in a generally anhydrous state and with little or no absorbed moisture or in a stable hydrated form, since exposure to water will prematurely disintegrate the tablet.

According to some embodiments, the effervescent comprises an acid/base pair. The acid may be any acid which is safe for human consumption and may generally include but is not limited to food acids, acid and hydrite antacids, including but not limited to, for example, citric, ascorbic, tartaric, lactic, maleic, malic, fumaric, adipic, and succinic acids.

The base may optionally comprise a carbonate source. Carbonate sources include dry solid carbonate and bicarbonate salt such as, preferably, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate, calcium carbonate, dicalcium phosphate (dibasic calcium phosphate), tricalcium phosphate (tribasic calcium phosphate) and the like, or combinations thereof. Carbonate sources such as sodium bicarbonate are preferable, in that they may also serve as an alkalinizing agent. Optionally and preferably, the concentration of the effervescent in the outer coating is in the range of from about 5 to about 15 % w/w of the total dry outer coating.

The outer tablet may further contain one or more components for providing immediate relief of one or more symptoms of heartburn. Heartburn is the colloquial name for a set of symptoms which result from high acidity in the gastrointestinal tract, and which may also include acid reflux from the stomach to the esophageal tract, causing pain and sensitivity in this area. Some non-limiting examples of symptoms include a burning or painful sensation in the chest, throat or stomach; difficulty swallowing; and if present for an extended period of time, may result in chronic cough, sore throat, or chronic hoarseness. Chronic heartburn may be caused by GERD (gastroesophageal reflux disease), which is caused by chronic acid reflux from the stomach to the esophageal tract. Immediate symptomatic relief is valuable for reducing pain and sensitivity throughout the gastrointestinal tract, which may include the esophageal tract.

According to at least some embodiments of the present invention, there is provided a composition (and method of use thereof) for providing immediate relief of one or more symptoms of heartburn, comprising a cationic polymer which swells at acidic pH values (i.e. pH less than about 5.5), and disintegrates in about 5 minutes or less at more basic or neutral pH. This cationic polymer is preferably provided within the outer tablet formulation according to the embodiments described herein. When present in the outer tablet formulation, the cationic polymer does not prevent the fast disintegration of the outer tablet as it contacts either water or natural buffers (such as saliva). Therefore, the outer tablet may undergo a rapid disintegration in the mouth (buccal) cavity upon exposure to the saliva, where the cationic polymer in the outer layer formulation neither prevents nor inhibits the disintegration process. However, when the cationic polymer is exposed to an acidic environment, such as that existing in the stomach, the polymer may first swell to provide blockage physical block for preventing the transition of the gastric fluid into the esophageal tract (esophagus), such that significant relief of one or more heartburn symptoms is expected to be immediately felt. Furthermore, the fact that the polymer is a cation is also expected to increase the pH of the stomach, which would also promote relief of one or more heartburn symptoms.

After swelling of the cationic polymer in the stomach, the polymer is expected to gradually degrade through contact with gastric fluid. Degradation may optionally occur through any of the known degradation mechanisms, including but not limited to dissolution, solution, enzymatic degradation, hydrolysis, physical degradation, ionic degradation and any combination thereof.

The cationic polymer of the outer layer may optionally be either cross-linked or alternatively may optionally be a linear (non cross-linked) polymer. According to some embodiments, the cationic polymer is present in a sufficient amount to provide a hydrogel layer suitable for relieving at least one symptom of heartburn.

The swelling rate of the cationic polymer in an environment of pH of 1 - 5 is expected to be dependent on the degree of cross-linking, viscosity, molecular weight, and the degree of hydrophilicity. The thickness of the hydrogel blockage layer (i.e. of the hydrogel layer formed by the swollen cationic polymer in the stomach) can be determined according to the initial content of the cationic polymer in the outer layer formulation. As the amount of the cationic polymer in the outer tablet formulation increases, the corresponding hydrogel blockage layer formed from the swollen cationic polymer after exposure to the gastric fluid is also expected to increase in thickness. The thickness of the hydrogel layer is also expected to determine the length of time for provision of symptomatic relief of heartburn.

Suitable cationic polymers according to aspects of some embodiments of the present invention may optionally comprise one or more of a cationic polyamine, a polyallylamine or a salt thereof, a polyvinylamine or a salt thereof, a vinyl or polyvinyl containing polymer, a dicyandiamide, a dicyandiamide- polyalkylenepolyamine condensate a polyalkylenepolyamine- dicyandiamideammonium condensate, a dicyandiamide-formalin condensate, an addition polymer comprising epichlorohydrin, a polysaccharide or starch, a polyacrylamide, a methacrylate polymer, and combinations thereof, or any other pharmaceutically effective cationic polyamine known in the art.

For example, the cationic polymer may optionally be polyacrylamide having the following structure;

a cationic polyacrylamide, a cationic polyethyleneimine, a cationic gelatin, or a copolymer comprising polyamidine, and combinations thereof. Optionally and preferably, the cationic polymer is a cationic starch or polysaccharide. More preferably, the cationic polymer is chitosan which is a linear polysaccharide, optionally having the following structure.

Optionally the chitosan has a deacetylation degree ranging from 80% to more than 95%. The chitosan may also optionally have a viscosity ranging from 50 mpa to 800 mpa. The chitosan may optionally be carboxymethylchitosan, trimethylchitosan or quaternised chitosan.

The cationic starch or polysaccharide may optionally comprise polyglucosamine, one of the components of chitosan. For example, the cationic polymer may optionally be the β-1,4 polymer of D-glucosamine or the β-1,4 polymer of D-glucosamine and N-acetyl-D-glucosamine.

Other examples of cationic polymers include but are not limited to cationic starch, cationic polysaccharide, cationic gum such as for example cationic guar, and cationic hydroxypropyl guar, and combinations thereof, as well as any other pharmaceutically acceptable cationic starch, polysaccharide or gum known in the art.

In some embodiments, the cationic polymer optionally comprises an ammonium chloride-containing polymer, non limiting examples of which include a poly(acryloylethyltrimethylammonium chloride), a poly(acrylamidopropyltrimethylammonium chloride) (polyAPTAC), a poly(methacrylamidopropyltrimethylammonium chloride (polyMAPTAC) or a salt thereof, a copolymer of diallyldimethylammoniumchloride-S02, a blend of PVA with N-(3-chloro-2-hydroxypropyl)-N,N,N-trimethylammonium chloride (such as in a dry blend QUAT 188™, available from Dow Chemical, 3-chloro-2- hydroxypropyltrimethylammonium chloride, a polymer of diallyldimethyl ammonium chloride ("DADMAC"), a polymer comprising vinylbenzyltrimethyl ammonium chloride, the cationic polymer comprises (2-methacryloyloxyethyl)trimethyl- ammonium chloride, a copolymer that comprises diallyldimethylammonium chloride, a copolymer that comprises acryloylethyltrimethylammonium chloride or methacrylamidopropyltrimethylammonium chloride in the form of polymerized units, a copolymer that comprises acryloylethyltrimethylammonium chloride or methacrylamidopropyltrimethylammonium chloride in cleaved form, and combinations thereof,and any other pharmaceutically acceptable ammonium chloride- containing cationic polymer known in the art.

In another embodiment, the cationic polymer is a cationic polyvinyl alcohol non limiting examples of which include a methyl chloride quaternary salt of poly(dimethylamino ethyl acrylate)/polyvinyl alcohol graft copolymer or a methyl sulfate quaternary salt of poly(dimethylamino ethyl acrylate)/polyvinyl alcohol graft copolymer, a polyvinyl alcohol that comprises a pendant quaternary ammonium salt, and combinations thereof, or any other pharmaceutically acceptable cationic polyvinyl alcohol known in the art.

In another embodiment, the cationic polymer is a cationic vinyl containing polymer including but not limited to polymers including polyvinylpyrrolidone, a polyvinylimidazole, various other polyvinyl containing polymers, N- vinyl polymers, polyvinylimidazole polymers, and combinations thereof.

Optional non-limiting examples of polyvinylpyrrolidone include PVP (polyvinylpyrrolidone), a copolymer of polyvinylacetate and polyvinylpyrrolidone, a copolymer of polyvinylalcohol and polyvinylpyrrolidone, and combinations thereof, or any other pharmaceutically acceptable cationic polyvinylpyrrolidone known in the art.

Optional non-limiting examples of polyvinylimidazole include a copolymer of vinylimidazole and polyamidine, and any other copolymers comprising vinylimidazole known in the art.

Optional non-limiting examples of other polyvinyl containing polymers include a cationic polyvinylformamide, cationic polyvinylacetamide, a cationic polyvinylmethylformamide a poly(vinylpyridine) or a salt thereof, or a cationic polyvinylmethylacetamide, and combinations thereof.

Optional non-limiting examples of an N-vinyl polymer include a copolymer that comprises N-vinylformamide, a copolymer that comprises N-vinylacetamide, a copolymer of comprises N-vinylpyrrolidone and N-methyl-N-vinylformamide, a cationic polymer that comprises N-vinylpyrrolidone, a cationic polymer that comprises N-methyl-N-vinylformamide, a copolymer that comprises N-methyl-N- vinylacetamide, and combinations thereof, and any other N-vinyl polymer known in the art.

Optionally, the cationic polymer is a polyvinyl-containing compound not falling into one of the above classes.

In another embodiment, the cationic polymer is an epichlorohydrin-containing compound, non-limiting examples of which include a poly(dimethylamine-co- epichlorohydrin), a poly(dimethylamine-co-epichlorohydrin-co-ethylendiamine), a poly(amidoamine-epichlorohydrin), and combinations thereof, and any other pharmaceutically acceptable epichlorohydrin-containing compound known in the art.

In another embodiment, the cationic polymer is a methacrylate polymer, non- limiting examples of which include a cationic polymer comprising monomers of an amine methacr late (e.g. having the following structure):

a cationic polymer that comprises monomers of an amine methacrylate subunit, a cationic polymer that comprises monomers of an aminoalkyl methacrylate subunit, In another embodiment, the amine methacrylate is a quaternary ammonium moiety having the general structure below, wherein Rl, R2, and R3 are independent selected from alk l or heteroalkyl moieties:

Optionally, the amine methacrylate present in the cationic polymer is dimethylaminoethyl methacrylate. Also optionally, the amine methacrylate polymer is selected from the group consisting of a methyl chloride quaternary salt of a poly(dimethylamino ethyl acrylate/polyvinyl alcohol graft copolymer; a methyl sulfate quaternary salt of a poly(dimethylamino ethyl acrylate)/polyvinyl alcohol graft copolymer; a polymer that comprises dimethylaminoethylmethacrylate; poly(dimethylaminoethylacrylate); a copolymer that comprises dimethylaminoethyl acrylate, and diethylaminoethyl acrylate. Also optionally, the amine methacrylate polymer is a poly(dimethylaminopropylmethacrylamide) (DMAPMAM), a poly(dimethylaminoethylacrylate). Also optionally, the amine methacrylate polymer is a neutral methacrylic ester available from Rohm Pharma (Degusa) under the name "Eudragit E™." Also optionally, the amine methacrylate polymer is any other type of pharmaceutically acceptable amine methacrylate known in the art.

Other non-limiting examples of a methacrylate polymer include a polymer comprising monomers of a methacrylic ester, such as for example and without limitation a neutral methacrylic ester, or any other type of pharmaceutically acceptable methacrylic ester known in the art.

Other non-limiting examples of a methacrylate polymer include a copolymer comprising monomers of an aminoalkyl methacrylate subunit and monomers of a methacrylic ester subunit.

According to at least some embodiments of the present invention, the cationic polymer is a salt of one of the above cationic polymers, and/or a combination of a plurality of the above cationic polymers, optionally including one or more linear and non-linear polymers in combination, and/or a cationic copolymer.

According to some embodiments, the size of the mini tablet is in the range of from about 5 to about 7 mm.

Enteric coating

The formulation according to the present invention optionally and preferably features an enteric coating, which comprises at least one enteric coating material, layered over the core of the inner mini-tablet. The enteric coating material is preferably a pH dependent polymer, more preferably a polymer selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (also known as hypromellose acetate succinate), cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, poly(methacrylic acid, methyl methacrylate)l:l and poly(methacrylic acid, ethyl acrylate)l:l, alginic acid, and sodium alginate, and combinations thereof.

A suitable enteric coating can be made from Eudragit™ polymers series (available from Rohm Pharma) which are polymeric lacquer substances based on acrylates and/or methacrylates. Suitable polymers which are slightly permeable to water, and exhibit a pH-dependent permeability include, but are not limited to, Eudragit S (poly(methacrylic acid, methyl methacrylate)l:2); Eudragit LI 00 (poly(methacrylic acid, methyl methacrylate)l:l); Eudragit L30D™, (poly(methacrylic acid, ethyl acrylate)l:l); and (Eudragit L100-55) (poly(methacrylic acid, ethyl acrylate)l:l). Eudragit™ L is an anionic polymer synthesized from methacrylic acid and methacrylic acid methyl ester. It is insoluble in acids and pure water. It becomes soluble in neutral to weakly alkaline conditions. The permeability of Eudragit™ L is pH dependent. Above pH 5.0, the polymer becomes increasingly permeable. Mixtures of such polymers may also optionally be used.

Optionally and preferably, the enteric coating further comprises an aqueous solvent.

The enteric coating may optionally further comprise at least one excipient, such as, for example, a plasticizer, a glidant (including but not limited to silicon dioxide), a lubricant and an anti-adherent (including but not limited to talc or titanium dioxide), and combinations thereof.

Sub-coating

According to further features in any of the embodiments of the invention, the mini-tablet optionally and preferably further comprises a sub-coating layered between the inner core and the enteric coating.

According to some embodiments, the sub-coating may optionally include one or more polymers which may at least partially control the permeability of the sub- coating. For example, said one or more polymers may optionally feature a water vapor transition of up to 250 g/m (ΙΟΟμπι) per 24h.

In some demonstrative embodiments, the one or more polymers may be hydrophilic, water soluble and/or have a neutral acidity, e.g., having a pH value of 7. Non-limiting examples of sub-coating polymers include, for example, Povidone (PVP: polyvinyl pyrrolidone), Copovidone (copolymer of vinyl pyrrolidone and vinyl acetate), polyvinyl alcohol, Kollicoat Protect (BASF) which is a mixture of Kollicoat IR (a polyvinyl alcohol (PV A) -polyethylene glycol (PEG) graft copolymer) and polyvinyl alcohol (PVA), Opadry AMB (Colorcon) which is a mixture based on PVA, Aquarius MG which is a cellulosic -based polymer containing natural wax, lecithin, xanthan gum and talc, low molecular weight HPC (hydroxypropyl cellulose), low molecular weight HPMC (hydroxypropyl methylcellulose) such as hydroxypropylcellulose (HPMC E5) (Colorcon), low molecular weight carboxy methyl cellulose, low molecular weight hydroxyethylcellulose, low molecular weight hydroxymethylcellulose, gelatin, hydrolyzed gelatin, polyethylene oxide, acacia, dextrin, starch, and water soluble polyacrylates and polymethacrylates, and combinations thereof. In some cases mixture of water soluble polymers with insoluble agents may be of benefit.

More preferably the sub-coating polymers are polyvinyl alcohol, Kollicoat

Protect (BASF) which is a mixture of Kollicoat IR (a polyvinyl alcohol (PVA)- polyethylene glycol (PEG) graft copolymer) and polyvinyl alcohol (PVA) and silicon dioxide, Opadry AMB (Colorcon) which is a mixture based on PVA, and Aquarius MG which is a cellulosic-based polymer containing natural wax. Theses polymers provide superior barrier properties against water/humidity penetration into the core.

The sub-coating optionally and preferably further comprises an aqueous solvent.

Optionally and preferably the sub-coating may further comprise an excipient which may be at least one of a glidant, a surfactant, filler, a solubilizer, and an alkalinizing agent. In some embodiments, the sub-coating comprises a water- insoluble excipient.

Examples of surfactants include polysorbate 80 (Tween 80) and sodium lauryl sulfate, and combinations thereof.

Examples of fillers include, for example, microcrystalline cellulose, a sugar, such as lactose, glucose, fructose, or sucrose; dicalcium phosphate; sugar alcohols such as sorbitol, manitol, mantitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates; corn starch; potato starch; sodium carboxymethycellulose, ethylcellulose and cellulose acetate, and combinations thereof.

Preferably, the filler is lactose.

Example of glidant includes silicon dioxide.

Examples of alkalinizing agents include, without limitation, sodium stearate, meglumine, disodium phosphate, and ammonia, and combinations thereof.

Inner core

According to at least some embodiments of the present invention, the inner core of the mini-tablet is an active core, comprising the therapeutic agent. The core may optionally further include at least one excipient, such as, for example, a disintegrant, a filler, a binder, a glidant, a lubricant, and a basifying agent and/or alkalizing agent.

Examples of suitable disintegrants in the core of the mini-tablet include, but are not limited, to low- substituted carboxymethyl cellulose sodium, cross-linked polyvinyl pyrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose magnesium aluminum silicate, sodium starch glycolate, croscarmelose sodium, Crospovidone, e.g., Crospovidone having a particle size of about 30-50 microns, and/or combinations thereof.

According to some demonstrative embodiments, the inner-core may include any suitable amount of disintegrant(s) to enable the effective disintegration of the inner-core, for example, the inner core may optionally include Crospovidone up to an amount corresponding to 11% weight by weight percent of the inner-core.

Examples of suitable binders include for example, Povidone (PVP: polyvinyl pyrrolidone), Copovidone (copolymer of vinyl pyrrolidone and vinyl acetate), polyvinyl alcohol, low molecular weight HPC (hydroxypropyl cellulose), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight carboxy methyl cellulose, low molecular weight hydroxyethylcellulose, low molecular weight hydroxymethylcellulose, gelatin, hydrolyzed gelatin, polyethylene oxide, acacia, dextrin, starch, and water soluble polyacrylates and polymethacrylates, low molecular weight ethylcellulose, and combinations thereof. Examples of fillers include, for example, microcrystalline cellulose, a sugar, such as lactose, glucose, fructose, or sucrose; dicalcium phosphate; sugar alcohols such as sorbitol, manitol, mantitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates ; corn starch, potato starch, sodium carboxymethycellulose, ethylcellulose, Eudragit RL, Eudragit RS and cellulose acetate, and combinations thereof.

For those embodiments of the present invention involving a therapeutic agent such as a PPI, an alkalizing agent and/or basifying agent may optionally be used. Non-limiting examples of alkalinizing agents include but are not limited to sodium stearate, meglumine, disodium phosphate, and ammonia. More preferably, the alkalinizing agent comprises meglumine.

The oral dissolution time for the rapidly dispersible solid outer tablet layer of the present invention (i.e. the time for complete disintegration in the oral cavity of healthy adults) is optionally up to about 5 minutes (for example, from about 5 seconds to about 5 minutes), preferably from about 5 to about 120 seconds, more preferably from about 5 to about 50 seconds, more preferably from about 5 to about 35 seconds.

The dissolution time for the rapidly dispersible solid outer tablet layer of the present invention in water is optionally up to about 5 minutes (for example, from about 5 seconds to about 5 minutes), preferably from about 5 to about 40 seconds, more preferably from about 5 to about 30 seconds.

According to some embodiments, the inner-core of the mini-tablet described herein may optionally and preferably rapidly disintegrate, for example, within 30-60 seconds, e.g., more preferably within 30-45 seconds, and/or cause a burst release of a suitable amount of an active ingredient included therein (also referred to herein as "burst release effect").

According to some embodiments, the burst release effect may be achieved by using a suitable disintegrant and/or a suitable enteric coating surrounding the inner- core.

According to some embodiments, the disintegrant may cause the formation of pores and provide capillary force to cause the burst release effect, for example, said disintegrant may include crospovidone having a particle size of about 30-50 microns.

According to some embodiments, the enteric coating may prevent from damp and/or moisture to penetrate into the inner core. In some embodiments, if damp penetrates the inner core, it may cause disruption of the burst effect. Without wishing to be limited by a single hypothesis, in addition, if the composition is administered in a non-fed state, disruption of the burst effect together with activity of the gastrointestinal tract, known as the housekeeping wave, may cause an improper release and/or absorption of the active ingredient contained within the inner-core [often reflected in poor pharmacokinetic results, e.g., lower values Area Under the Curve ("AUC")].

In some demonstrative embodiments, the enteric coating may include one or more polymers that dissolve at a pH between 3 to 7, e.g., pH of 5. The one or more polymers may include, for example, polyvinyl acetate phthalate (PVAP dissolves at pH 5), Eudragit L 30D (dissolves in pH 5.5), Eudragit L 100 (dissolves at pH 6.0), Eudragit S (dissolves at pH 6.5).

According to some embodiments, if one or more of the polymers dissolves in a pH above 5, a dissolution reducing agent may be used to enable dissolution of the enteric coating at a pH of 5, for example, monoethanolamine may be used as a dissolution reducing agent.

In some demonstrative embodiments, the formulation of the present invention may include a subcoating layer. For example, a suitable amount of Carboxymethyl cellulose may be used for sub-coating, e.g., at least 8 mg.

Compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.

The principles and operation of the compositions and methods according to the present invention may be better understood with reference to the accompanying descriptions. Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

Additional objects, advantages, and novel features of the present invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above description, illustrate the invention in a non limiting fashion.

Materials and methods

I. Granulation

A wet granulation process was used to prepare granules of a proton pump inhibitor (PPI) (omeprazole or lansoprazole in these non-limiting examples, although of course the process could optionally be extended to other such PPIs). The granulation process was carried out using a Mini-V processor.

First polyvinyl pyrrolidone (PVP) was dissolved in purified water using a mechanical stirrer. Meglumine was then added to the solution while stirring. The stirring continued till complete dissolution was achieved.

The PPI, meglumine, sodium stearyl fumarate, crospovidone and lactose monohydrate 100M were added to a Mini-V processor and mixed for 5 minutes. Then the solution of PVP and meglumine was added to the mixture in the Mini-V- processor and granulation was carried out for 10 minutes. The resulting granules were dried at 55°C under vacuum till a loss on drying (LOD) of less than 1.0% was achieved.

In granulation process Meglumine may be added in a single step or in two or more steps. For example, a certain amount of Meglumine may be added as a powder by simple physical mixing with the rest of the powders. The rest of the Meglumine may be introduced in the granulation solution to prevent direct contact in the aqueous phase between the copovidone and Omeprazole, for example, due to the acidic nature of copovidone.

2. Blending

Microcrystalline cellulose and silicone dioxide were mixed and sieved through a 800 micron mesh sieve. The resulting mixture was added to the PPI granules in a suitable mixing vessel and mixed for 10 minutes. Crospovidone was then added and mixed for an additional 30 minutes. Finally magnesium stearate was added and mixed for an additional 3 minutes.

Magnesium stearate may optionally be introduced in the final mixing phase just before tabletting.

Sodium stearyl fumarate can be added either in the granulation preparation, when used, for example, as a dissolution enhancer for the PPI, e.g., omeprazole, or can be introduced in the final mixing stage, for example, as a replacement lubricant for magnesium stearate.

3. Tabletting

The tabletting process was carried out using a Korsch XL100 tabletting machine. The resulting blend was compressed to form the mini-tablet core using biconcave punches having diameter of 5 mm and concavity radius of 3 mm. The target weight and hardness of tablets were respectively 65 mg and 35 N. 4. Subcoating

The use of a subcoat protects the mini-tablet core against direct contact between the enteric coating, which has naturally acidic properties, and the PPI which is an acid-sensitive molecule, as well as against water vapor penetration into the core which can take place through the enteric coat during time in the stomach.

Different water soluble polymers were used for this purpose. The main polymers tested were hydroxypropylcellulose (HPMC E5) (Colorcon); Kollicoat Protect (BASF) which is a mixture of Kollicoat IR (a polyvinyl alcohol (PVA)- polyethylene glycol (PEG) graft copolymer) and polyvinyl alcohol (PVA); and Opadry AMB (Colorcon) which is a mixture based on PVA.

The subcoating process was carried out using an aqueous solution of the polymer as detailed in the tables below.

5. Enteric coating

The enteric coating of PPI mini-tablets was carried out using methacrylic acid copolymers (Kollicoat MAE, an aqueous dispersion of 30% acrylic enteric system) in a perforated pan under following conditions;

Dissolution test

Dissolution testing of PPI granules and of the enteric coated mini-tablets in hard gelatin capsules was conducted in a dissolution bath (Vanckle Switzerland) according to the USP monograph for both omeprazole as well as lansoprazole using Apparatus II (paddles) at 75 rpm or 100 rpm.

Drug release was measured for 15 mg and 20 mg lanzoprazole and omeprazole respectively, i.e. 1 mini-tablet of each PPI was placed into a size 3 hard gelatin capsule. Dissolution protocol was 1 hour or 2 hours in 0.1N HCl (acid stage) followed by pH 6.8 phosphate buffer, with or without sodium lauryl sulphate (buffer stage) at 37 + 0.5°C. A dual beam UV/VIS spectrophotometer (Lambda 25\Perkin Elmer Instruments, UK) was used for both lansoprazole and omeprazole detection. Measurements at each time point were performed in triplicate, and mean and standard deviation (SD) values were calculated.

Acid resistance of the enteric coated mini-tablets was further investigated by the "acid uptake" test, in 0.1N HCl and at intermediate pH conditions (acetate buffer pH 4.5).

A. Examples I to VII: Omeprazole core formulations

Different core formulations containing 20 mg omeprazole were prepared. Tables 1A and IB summarize these formulations, wherein the percentage is given weight per weight of the total core. The release profile of these cores was tested by a dissolution method in buffer phosphate of pH 6.8. The results of dissolution tests of different cores and related granulates are shown in Tables 2-4 and Figures 3-5.

Table 1A

fumarate

PVP 0.5 0.82 0.7 1.67 0.5 0.77 crospovidone 5 6.56 4 6.15

Magnesium 0.3 0.49 0.5 0.77 stearate

crospovidone 1.8 2.95 3 4.62

MCC 102 8.85 13.62 silica 0.65 1.00 total 61 100 41.9 100 65 100 water (g) 230

Table IB

Example I provided a fine granulate, having poor flowability. Example II provided overly wet granules, thus drying difficulties were encountered. Examples III and IV provided compressible granules, but with slow dissolution.

Example V provides fast dissolution but poor compressibility. Example VI did not provide a granulate. Example VII provided good flowability with desirable dissolution.

Example 1 Example 2 Example 3 Example 4

mg/tab % mg/tab % mg/tab % mg/tab %

Omeprazole 20 32.52% 20 36.20% 20 31.20% 20 33.96%

Meglumine 13 21.14% 13 23.53% 12 18.72% 13.1 22.24% lactose mono 13.5 21.95% 13.5 24.43% 24 37.44% 25.1 42.61% sodium

stearyl

fumarate 14 22.76% 6.25 11.31%

Mg stearate

PVP 1.5 2.71% 0.4 0.62% 0.7 1.19% crospovidone

sodium

stearyl

fumarate 3 4.68%

Mg stearate 1 1.63% 1 1.81% 0.7 1.09%

Sodium

Starch

glycolate 4 6.24%

crospovidone

PVP

MCC 102

Silica

total 61.5 100.00' < 5 2 100.00' < 64.1 lOO.OO r 5S.<⁾ 100.00' <

Il20<gi 300 250 180 200

Properties

discribsion Fine granulate thus a Over wet granules thus Compressible granules C ompressible granules poor flowability was dying difficulties were 3ut slow dissolution bi at slow dissolution resulted seen was received w as received

Table 1C - materials and results

Table 2 and Figure 3 show the dissolution profile of the granulate and the core of Example V.

Table 2

Table 3 and Figure 4 show the dissolution profile of the core of Example VII

Table 3 Table 4: dissolution profile of the core containing omeprazole- Example V

Figure 5 shows a dissolution profile of the core containing omeprazole.

B. Example VII Coated formulations

Formulations were prepared using mini-tablets with HPMC E5, Opadry®, or Protect® as subcoat, and water vapor uptake and dissolution profiles were studied.

The results of humidity (water vapor) uptake of mini-tablets coated with an enteric coat, e.g., methacrylic acid copolymer (weight gain of 4 mg and 11 mg per mini-tablet) and HPMC E5 as the subcoat are summarized in Table 5.

The humidity uptake of the mini-tablets may be measured by any method known in the art. For example, the coated cores may be placed in a vessel containing 0.1N HCl at 37 degrees C. For every measurement the tablets were removed from the vessel, carefully dried from remains of acid and weighed by analytical scale.

min 0.4373 0.4539 0.0166 3.80% 0.4723 0.4901 0.0178 3.77% min 0.4368 0.4600 0.0232 5.31% 0.4755 0.4991 0.0236 4.96%

Table 5

The dissolution profile of enteric coated mini-tablets (weight gain of 4 mg and 11 mg per mini-tablet) with HPMC as the subcoat is shown in Figure 6 and summarized in Table 6. Table 6 shows results for intestinal dissolution only, and for dissolution after 1 hour exposure to gastric fluid. Figure 6 shows the dissolution profile of omeprazole-containing mini-tablets coated with two different thicknesses of enteric coating in intestinal fluid after exposure of 1 hour in gastric fluid- HPMC as the subcoat.

50 77.3 77.2 77.8 77.43 71.6 76.9 81.7 76.73

60 79.9 79.9 80.6 80.13 76.3 80.6 85.8 80.90

75 84.6 84.9 85.6 85.03 83.4 85.3 92.4 87.03

Table 6

Figure 7 shows the dissolution profile of enteric (two different thicknesses) coated omeprazole mini-tablets directly in intestinal fluid without exposure to 1 hour in gastric fluid, with HPMC as the subcoat.

Table 7 shows the dissolution profile of omeprazole-containing mini-tablets with two different thicknesses of enteric coating, with Opadry® AMB as the subcoat.

75 90.9 91.3 91.10 91.7 88.4 91.3 90.47

Table 7

Figure 8 shows the dissolution profile of omeprazole-containing mini-tablets with two different thicknesses of enteric coating with Opadry® AMB as the subcoat, in intestinal fluid after exposure of 1 hour to gastric fluid.

Figure 9 shows the dissolution profile of omeprazole-containing mini-tablets with two different thicknesses of enteric coating with Opadry® AMB as the subcoat, directly in intestinal fluid without exposure of 1 hour in gastric fluid.

Table 8 and Figure 10 show the dissolution profile of enteric-coated omeprazole-containing mini-tablets with Kollicoat Protect® as the subcoat.

Table 8

Figure 11 shows the dissolution profile of omeprazole-containing mini-tablets with two different thicknesses of enteric coating, both directly in intestinal fluid without exposure of 1 hour in gastric fluid and after exposure of 1 hour in gastric fluid, withOpadry® AMB versus Protect® as the subcoat. C. Example VIII: Omeprazole mini-tablet, 28 mg core

A mini-tablet containing 20 mg omeprazole based on a core weighing 28 mg was prepared according to the formulation of Table 9. The dissolution profile in intestinal fluid (buffer phosphate pH 6.8) after 2h exposure in gastric fluid (HCl, pH 1.2) is shown in Table 10 and Figure 12.

METACR ACID COP 72.00%

C30%(KOLICOAT)

PROPYLENE GLYCOL 10.10%

TALC 17.90%

Table 9

Table 10

D. Examples IX-XVI: lansoprazole mini-tablets

Lansoprazole mini-tablets were prepared according to the formulations of Table 11.

Internal tablet (Mini-Tab)

PH102

HYDROXYPROPYL CELLULOSE LF 0.00 0.00 0.00 1.50 1.40

LACTOSE MONO DCL11/SUPER-TAB 11.35 24.60 15.00 16.00 10.20

CROSPOVIDONE 3.00 4.00 4.00 0.00 1.40

SOLUTION

POVIDONE K-30 0.85 0.70 0.70 0.60 0.60

MEGLUMINE 2.10 2.10 2.10 1.37 2.10

TOTAL GRANULATE 36.20 50.70 41.45 37.10 37.10

BLEND

CROSPOVIDONE 3.00 3.00 3.00 1.20 2.00

MICROCRYSTAL.CELLULOSE

PH102 24.00 10.00 19.20 0.00 5.00

SILICA 0.65 0.65 0.65 0.36 0.36

MAGNESIUM STEARATE 0.65 0.70 0.70 0.54 0.54

LACTOSE MONO DCL11/SUPER-TAB 0.00 0.00 0.00 3.00 0.00

HPMC K 15 0.00 0.00 0.00 2.80 0.00

TOTAL CORE 65.00 65.00 65.00 45.00 45.00

PRECOATING

OPADRY AMB 80W-32896

YELLOW 4.00 4.00 4.00 2.7 0.00

KOLLICOAT PROTECT 0.00 0.00 0.00 0.00 1.36

TALC 0.00 0.00 0.00 0.00 0.53

TITANIUM DIOXIDE 0.00 0.00 0.00 0.00 0.31

ENTERIC COATING

METHACRYLIC ACID COPOLYMER C 30% 5.70(dry) 5.70(dry) 5.70(dry) 5.7(dry) 1.43(dry)

PROPYLENE GLYCOL 0.86 0.86 0.86 0.60 0.21

TALC 1.44 1.44 1.44 1.00 0.36

TOTAL COATED TABLET 77.00 77.00 77.00 55.00 49.20 Example XIV Example XV Example XVI

Material mg/tab % tab mg/tab % tab mg/tab % tab

LANSOPRAZOLE 15.00 23.08% 15.00 23.08% 15.00 23.08%

LACTOSE 15.00 23.08% 18.00 27.69% 18.00 27.69% MONOHYDRATE

CROSPOVIDONE 3.00 4.62% 0.00 0.00% 0.00 0.00%

SODIUM STEARYL 0.75 1.15% 0.75 1.15% 0.75 1.15% FUMARATE

MEGLUMINE 6.00 9.23% 6.00 9.23% 6.00 9.23%

POVIDONE K 30 0.70 1.08% 0.00 0.00% 0.70 1.08%

HYDROXYPROPYL 1.65 2.54% 0.00 1.54% 1.65 2.54% CELLULOSE

Total granulate 42.10 64.77% 39.75 62.69% 42.10 64.77%

MICROCRYSTALLYN 18.50 28.46% 21.85 27.54% 21.50 33.08% CELLULOSE PH 102

CROSPOVIDONE 3.00 4.62% 2.00 0.00% 0.00 0.00%

COLLOIDAL SILICON 0.65 1.00% 0.65 1.00% 0.65 1.00% DIOXYDE

MAGNESIUM 0.75 1.15% 0.75 1.08% 0.75 1.15% STEARATE

Total core tablet 65.00 100.00% 65.00 92.30% 65.00 100.00%

Table 11

5 Release of lansoprazole from the granulates of Examples IX and X was studied with dissolution conditions of buffer 6.8 ,Paddle, 900ml, 75rpm. Results are shown in Table 12.

0 0.0% 0.0%

5 100.9% 88.1%

10 102.5% 89.7%

15 103.1% 90.5%

20 103.4% 90.9%

30 103.9% 91.2%

45 104.5% 91.4%

60 105.1% 92.6%

Table 12

Release of lansoprazole from the cores of Examples IX- XI was studied, with dissolution conditions of buffer 6.8, paddle, 900ml, 75rpm. Results are shown in Table 13.

Table 13

Release of lansoprazole from the enteric coated tablets of Examples IX-XI was studied, with dissolution conditions of lhour in 0.1N HCL, then buffer 6.8 with SLS, Paddle, 900ml, 75rpm. Results are shown in Table 14.

coated tablet coated tablet Enteric coated

tablet

0 0.0% 0.0% 0.0%

60 0.0% 0.0% 0.0%

70 13.1% 8.3% 2.4%

75 20.4% 16.9% 37.3%

80 27.1% 28.0% 68.4%

90 32.6% 40.9% 91.6%

105 46.9% 63.4% 97.1%

120 59.7% 74.4% 100.9%

Table 14

Figures 13-15 show lansoprazole release from various tablet formulations according to various embodiments of the present invention.

Release of lansoprazole from the core of Examples XIV-XVI was studied, with dissolution conditions: buffer 6.8, Paddle, 900ml, 75rpm.

Results are shown in Tables 15 and Figure 16.

Table 15 Release of lansoprazole from the enteric coated tablets of Example XIV is shown in Table 16 and Figure 17.

Table 16

Table 17 shows additional Examples XVII-XXIII of lansoprazole-containing formulations; dissolution profiles at lhour in 0.1N HCL, then buffer 6.8 with SLS, Paddle, 900ml, 75rpm are shown in Table 18 and in Figure 18.

LLULOSE PH102

MICROCRYSTAL.CE 0.00 0.00 0.00 0.00 0.00 0.00 4.00 LLULOSE PH101

CROSCARMELOSE 1.50 1.50 1.50 0.55 0.00 0.00 0.00 SODIUM

LACTOSE MONO 0.00 0.00 3.70 1.35 1.35 1.35 1.10 DCL11/SUPER-TAB

CROSPOVIDONE 0.00 0.00 0.00 0.00 2.80 2.80 2.90

SOLUTION

COPOVIDONE 0.30 0.30 0.30 0.30 0.30 0.30 0.30

MEGLUMINE 0.60 0.60 0.60 0.60 0.60 0.60 0.60

TOTAL 26.80 26.50 26.80 26.60 26.75 26.60 26.70 GRANULATE

BLEND

CROSCARMELOSE 0.00 0.00 0.00 0.00 0.55 0.00 0.00 SODIUM

CROSPOVIDONE 0.50 0.80 0.50 0.70 0.00 0.70 0.60

SILICA 0.35 0.35 0.35 0.35 0.35 0.35 0.35

MAGNESIUM 0.35 0.35 0.35 0.35 0.35 0.35 0.35 STEARATE

TOTAL CORE 28.00 28.00 28.00 28.00 28.00 28.00 28.00

PRECOATING

KOLLICOAT 1.24 1.24 1.24 1.24 1.24 1.24 1.24 PROTECT

TALC 0.48 0.48 0.48 0.48 0.48 0.48 0.48

TITANIUM DIOXIDE 0.28 0.28 0.28 0.28 0.28 0.28 0.28

ENTERIC COATING

METHACRYLIC 1.43(d 1.43(d 1.43(d 1.43(d 1.43(d 1.43(d 1.43(d ACID COPOLYMER ry) ry) ry) ry) ry) ry) ry) C 30%

PROPYLENE 0.21 0.21 0.21 0.21 0.21 0.21 0.21 GLYCOL TALC 0.36 0.36 0.36 0.36 0.36 0.36 0.36

TOTAL COATED 32.0 32.0 32.0 32.0 32.0 32.0 32.00 TABLET

Table 17

Time, EXP EXP EXP EXP EXP EXP

min XVII XVIX XX XXI XXII XXIII

0 0 0 0 0 0 0

60 0 0 0 0 0 0

75 57 10.4 50.2 72.4 56.1 70.1

90 71.8 34.1 74.1 84.2 74.9 87.1

105 81.6 56.9 83.7 89.9 84.7 93.5

120 84.7 73.8 89.5 93.6 90.6 96.7

Table 18

Tables 19 - 25 demonstrate different formulations for the outer compressed coating of the orally disintegrating tablet (ODT) described herein according to some demonstrative embodiments.

MAGNESIUM 1.2 1.2 1.2 1.2 12.0 STEARATE NF

Total 100.0 100.0 100.0 100.0 100.0

Table 19

Table 20

Table 21 Materials %

Citric Acid 4.0

Strawberry flavor 2.0

Crospovidone 10.0

Pharmaburst C (Mannitol/Sorbitol) 70.0

Avicel PH105 9.5

Silica Anhydrous 0.8

Acessulfam Potassium 3.2

Magnesium Stearate 0.5

Total 100.0

Table 22

Table 23

Ludiflash BASF SE 67.0%

Silica Anhydrous 1.0%

Sucralose micronized(TATE&LYLI) 0.3%

Magnesium Stearate 0.7%

Total 100.0%

Table 24

Table 25

Examples of coated lansoprazole mini-tablets comprising carboxymethyl chiotsan (CMC) are shown below:

Example XXIV

Table 26:

Subcoat

Material g % solids % solids mg / tablet

CMC 91.00 4.27 91.00 68.94 2.07

PEG 400 30.00 1.41 30.00 22.73 0.68

Titanium dioxide 11.00 0.52 11.00 8.33 0.25 Purified water 2000.00 93.81 0.00 0.00

Total 2132.00 100.00 132.00 100.00 3.00

Enteric coating

Material g % solids % solids mg / tablet

Kollicot MAE 397.00 31.99 119.10 69.20 2.77

Triethyl citrate 22.00 1.77 22.00 12.78 0.51

Talc 31.00 2.50 31.00 18.01 0.72

Monoethanolamine 1.00 0.08 1.00 0.58 0.02

Purified water 790.00 63.66 0.00 0.00

Total 1241.00 100.00 172.10 100.00 4.00

Example XXV - Table 27

Subcoat

Example XXVI - Table 28

Subcoat

PEG 400 30.00 1.41 30.00 22.73 0.68

Titanium diox 11.00 0.52 11.00 8.33 0.25

Purified water 2000.00 93.81 0.00 0.00 total 2132.00 100.00 132.00 100.00 3.00

Enteric coating

Material g % solids % solids mg / tablet

PVAP (polyvinyl

acetate phthalate) 100.00 9.09 100.00 100.00 5.70

Purified water 1000.00 90.91 0.00 0.00

Total 1100.00 100.00 100.00 100.00 5.70

Example XXVII - Table 29

Subcoat

Release of lansoprazole from the enteric coated lansoprazole mini-tablets of Examples XXIV-XXVII, as well as from the core alone and from reference Example XXVIII is shown in Table 30 and in Figure 19. Table 30

The dissolution test for coated tablets was performed at 37° C, first in 900 ml 0.1N HC1 for one hour then buffer phosphate pH=6.8 and SLS. Paddle rotation was 50 rpm. The core (W/O coating) was introduced directly into buffer phosphate pH=6.8 and SLS. The mean cumulative release percentage was calculated from 6 tablets. The above tablet demonstrates the average of release profile of coated tablets and the core (w/o coating).

Example XXIX

This non-limiting example provides an exemplary, illustrative formulation according to at least some embodiments of the present invention, featuring an outer tablet comprising chitosan (Table 31):

Table 31

CROSPOVIDONE 10.2%

SILICA COLLOIDAL 0.6%

ANHYDROUS

MAGNESIUM STEARATE 0.6%

SUCRALOSE 1.0%

MINT FLAVOR 1.1%

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

Claims

WHAT IS CLAIMED IS:

1. A delayed release formulation for a therapeutic agent comprising: a single inner mini-tablet and at least one outer tablet layer surrounding said single inner mini-tablet, said outer tablet layer comprising one or more fast disintegrating excipients, such that said outer tablet layer dissolves in no more than about 5 minutes in saliva;

wherein a diameter of said inner mini-tablet is between about 5 - 7 millimeters (mm) and wherein said therapeutic agent comprises from about 30% to about 90% weight per weight (w/w) of said mini-tablet.

2. The delayed release formulation of claim 1, wherein said mini-tablet is enteric coated.

3. The delayed release formulation of claim 1, wherein said therapeutic agent comprises a proton pump inhibitor.

4. A delayed release formulation for a therapeutic agent comprising: a single inner mini-tablet and at least one outer tablet layer surrounding said single inner mini-tablet, said outer tablet layer comprising one or more fast disintegrating excipients, such that said outer tablet layer dissolves in no more than about 5 minutes in saliva;

wherein a diameter of said inner mini-tablet is between about 5 - 7 millimeters (mm) and wherein said mini-tablet comprises a core and at least one coating disposed upon said core, wherein upon dissolution of said at least one coating, said core disintegrates within 30-60 seconds in a pH of 4 - 6.

5. The formulation of any of claims 1-4, wherein said mini-tablet

comprises an effective amount of disintegrant corresponding up to 11% of the mini-tablet weight per weight percent.

6. The formulation of claim 4, wherein said at least one coating dissolves at pH 5.

7. An orally dispersible delayed release tablet formulation for a proton pump inhibitor comprising a single inner mini-tablet and an outer tablet layer surrounding said inner mini-tablet, said outer tablet layer comprising one or more fast disintegrating excipients, such that said outer tablet layer dissolves in no more than about 5 minutes in the oral cavity; wherein a diameter of said inner mini-tablet is between 5- 7 mm and wherein said proton pump inhibitor comprises at least 30% weight by weight percentage of the total weight of said mini-tablet.

8. A method for administering a proton pump inhibitor to a subject in need thereof, the method comprising providing a formulation comprising a single mini-tablet comprising the proton pump inhibitor, wherein said single mini-tablet is surrounded by a rapidly disintegrating outer tablet layer; administering said composition to the oral cavity of the subject, followed by rapid dissolution of said outer tablet layer in 1 minute or less in the oral cavity; swallowing of said single mini-tablet by the subject and release of the proton pump inhibitor from said mini-tablet in the small intestine of the subject.

9. The method of claim 8, wherein said single mini-tablet is intact upon said swallowing.

10. A method for administering a proton pump inhibitor to a subject in need thereof, the method comprising providing a single mini-tablet comprising the proton pump inhibitor; applying a rapidly disintegrating outer tablet layer to said single mini-tablet by dry coating, such that said outer tablet layer surrounds said single mini-tablet, to form a composition; administering said composition to the oral cavity of the subject, followed by rapid dissolution of said outer tablet layer in the oral cavity; swallowing of said single mini-tablet by the subject, wherein said single mini-tablet is intact upon said swallowing; and release of the proton pump inhibitor from said single mini-tablet in the small intestine of the subject.

11. The formulation or method of any of claim 1-10, wherein said outer tablet layer is applied to said inner mini-tablet by dry coating.

12. The formulation or method of claim 11, wherein said dry coating

comprises compression coating.

13. The formulation or method of any of claim 1-10, wherein said outer tablet layer is devoid of a gel forming polymer.

14. The formulation or method of any of claim 1-10, wherein said outer tablet layer and said mini-tablet in combination have a diameter of up to about 15 mm.

15. The formulation or method of claim 14, wherein said outer tablet layer and said mini-tablet in combination have a diameter of up to about 12 mm.

16. The formulation or method of claim 15, wherein said diameter is up to about 10 mm.

17. A delayed release formulation for a therapeutic agent comprising: a single inner mini-tablet and at least one outer tablet layer surrounding said single inner mini-tablet, said outer tablet layer comprising one or more fast disintegrating excipients, such that said outer tablet layer dissolves in no more than about 5 minutes in saliva;

wherein a diameter of said inner mini-tablet is between about 0.5 - 7 millimeters (mm) and wherein said therapeutic agent comprises from about 30% to about 90% weight per weight (w/w) of said mini-tablet.

18. The formulation of claim 17, wherein said diameter of is in the range of from about 1 to about 6 mm.

19. The formulation of claim 18, wherein said diameter is in the range of from about 2 to about 5 mm.

20. The formulation of claim 19, wherein said diameter is in the range of from about 4 to about 5 mm.

21. The formulation or method of any of claims 1 to 20, wherein said mini- tablet is adapted to remain intact until the small intestine is reached.

22. The formulation or method of claim 21, wherein said mini-tablet

comprises an active core comprising said therapeutic agent and an enteric coating disposed on said core.

23. The formulation or method of claim 22, wherein said enteric coating comprises a pH dependent polymer.

24. The formulation or method of claim 23, wherein said pH dependent polymer is selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (also known as hypromellose acetate succinate), cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, poly(methacrylic acid, methyl methacrylate)l:l and poly(methacrylic acid, ethyl acrylate)l:l, alginic acid, and sodium alginate, and combinations thereof.

25. The formulation or method of any of claims 22-24, wherein said enteric coating further comprises an aqueous solvent.

26. The formulation or method of any of claims 22-25, wherein said enteric coating further comprises one or more excipients selected from the group consisting of a plasticizer, a glidant, lubricant and anti- adherents, and combinations thereof.

27. The formulation or method of any of claims 22-26, wherein said mini- tablet further comprises an intermediate coating between said core and said enteric coating.

28. The formulation or method of claim 27, wherein said intermediate

coating comprises one or more water-soluble, hydrophilic polymers.

29. The formulation or method of claim 28, wherein said hydrophilic

polymer is selected from the group consisting of Povidone (PVP:

polyvinyl pyrrolidone), Copovidone (copolymer of vinyl pyrrolidone and vinyl acetate), polyvinyl alcohol, Kollicoat Protect®, Opadry® AMB (Colorcon) , low molecular weight HPC (hydroxypropyl cellulose), low molecular weight HPMC (hydroxypropyl

methylcellulose), low molecular weight carboxy methyl cellulose, low molecular weight hydroxyethylcellulose, low molecular weight hydroxymethylcellulose, gelatin, hydrolyzed gelatin, polyethylene oxide, acacia, dextrin, starch, and water soluble polyacrylates and polymethacrylates, and combinations thereof.

30. The formulation or method of any of claims 27-29, wherein said

intermediate coating further comprises a water insoluble excipient.

31. The formulation or method of any of claims 22-30, wherein at least one of said enteric coating and said intermediate coating further comprises an aqueous solvent.

32. The formulation or method of any of claims 27-31, wherein said intermediate coating further comprises one or more excipients selected from the group consisting of a glidant, a surfactant, filler, a solubilizer, and an alkalinizing agent, and combinations thereof.

33. The formulation or method of claim 32, wherein said surfactant is selected from the group consisting of polysorbate 80 (Tween 80) or sodium lauryl sulfate, and combinations thereof.

34. The formulation or method of claim 32, wherein said filler is selected from the group consisting of microcrystalline cellulose; a sugar; dicalcium phosphate; a sugar alcohol; corn starch; potato starch; sodium carboxymethycellulose; ethylcellulose; and cellulose acetate; and combinations thereof.

35. The formulation or method of any of claims 32-34, wherein said alkalinizing agent is selected from the group consisting of sodium stearate, meglumine, disodium phosphate, and ammonia, and combinations thereof. The formulation or method of any of claims 22-35, wherein said core comprises one or more excipients selected from the group consisting of a disintegrant, lubricant, filler, alkalinizing agent, and combinations thereof.

The formulation or method of claim 36, wherein said binder is selected from the group consisting of Povidone (PVP: polyvinyl pyrrolidone), Copovidone (copolymer of vinyl pyrrolidone and vinyl acetate), polyvinyl alcohol, low molecular weight HPC (hydroxypropyl cellulose), low molecular weight HPMC (hydroxypropyl

methylcellulose), low molecular weight carboxy methyl cellulose, low molecular weight hydroxyethylcellulose, low molecular weight hydroxymethylcellulose, gelatin, hydrolyzed gelatin, polyethylene oxide, acacia, dextrin, starch, and water soluble polyacrylates and polymethacrylates, low molecular weight ethylcellulose, and combinations thereof.

The formulation or method of claim 36, wherein said filler is selected from the group consisting of microcrystalline cellulose, a sugar, such as lactose, glucose, fructose, or sucrose; dicalcium phosphate; sugar alcohols such as sorbitol, manitol, mantitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates ; corn starch, potato starch, sodium carboxymethycellulose, ethylcellulose, Eudragit RL, Eudragit RS and cellulose acetate, and combinations thereof.

The formulation or method of any of claims 1-38, wherein said outer tablet layer further comprises a disintegrating agent.

The formulation or method of claim 39, wherein said disintegrating agent in one or more of said core and said outer tablet layer comprises one or more of low- substituted carboxymethyl cellulose sodium, cross- linked polyvinyl pyrolidone, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, pregelatinized starch, microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, low substituted hydroxypropyl cellulose magnesium aluminum silicate, and combinations thereof.

41. The formulation or method of any of claims 1-40, wherein said outer tablet layer further comprises a rapidly disintegrating filler.

42. The formulation or method of claim 41, wherein said rapidly

disintegrating filler is selected from the group consisting of a sugar; a sugar alcohol; a starch; and combinations thereof.

43. The formulation or method of claim 41, wherein said rapidly

disintegrating filler is selected from the group consisting of lactose; glucose; fructose; sucrose; dicalcium phosphate; sorbitol; mantitol; lactitol; xylitol; isomal;, erythritol; a hydrogenated starch hydrolysate; corn starch; potato starch; sodium carboxymethylcellulose;

Pharmaburst® 500, Pharmaburst C®, Ludiflash®, Parteck ODT®, PEARLITOL Flash®, PROSOLV ODT®, PanExcea ODT MC200G®, and combinations thereof.

44. The formulation or method of any of claims 1-43, wherein said outer tablet layer further comprises an excipient selected from the group consisting of a sweetener, a flavorant, a colorant, a glidant; a lubricant; and combinations thereof.

45. The formulation or method of any of claims 1-44, wherein said outer tablet layer further comprises an effervescent.

46. The formulation or method of claim 45, wherein said effervescent comprises an acid/base pair.

47. The formulation or method of claim 46, wherein said acid is selected from the group consisting of food acids and hydrite antacids; and combinations thereof.

48. The formulation or method of claim 47, wherein said acid is selected from the group consisting of citric, ascorbic, tartaric, lactic, maleic, malic, fumaric, adipic, and succinic acids; and combinations thereof.

49. The formulation or method of any of claims 46-48, wherein said base comprises a carbonate source.

50. The formulation or method of claim 49, wherein said carbonate source is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate, calcium carbonate, dicalcium phosphate (dibasic calcium phosphate), tricalcium phosphate (tribasic calcium phosphate); and combinations thereof.

51. The formulation or method of any of claims 3 to 50, wherein said

proton pump inhibitor comprises at least 35% (w/w) of the total weight of said inner mini-tablet.

52. The formulation or method of claim 51, wherein said proton pump inhibitor comprises at least 40% (w/w) of the total weight of said inner mini-tablet.

53. The formulation or method of claim 52, wherein said proton pump inhibitor comprises at least 45% (w/w) of the total weight of said inner mini-tablet.

54. The formulation or method of claim 53, wherein said proton pump inhibitor comprises at least 50% (w/w) of the total weight of said inner mini-tablet.

55. The formulation or method of claim 54, wherein said proton pump inhibitor comprises 50%-90% (w/w) of the total weight of said inner mini-tablet.

56. The formulation or method of any of claims 1-55, wherein said outer tablet layer further comprises a cationic polymer.

57. The formulation or method of claim 56, wherein said cationic polymer swells at a pH value of less than about 5.5 and disintegrates in about 5 minutes or less at a pH of at least 6.

58. The formulation or method of claim 57, wherein said cationic polymer is present in a sufficient amount to provide a hydrogel layer suitable for relieving at least one symptom of heartburn.

59. The formulation or method of any of claims 56-58, wherein said

cationic polymer is selected from the group consisting of a cationic polyamine, a polyallylamine or a salt thereof, a polyvinylamine or a salt thereof, a vinyl or polyvinyl containing polymer, a polyvinyl alcohol, an ammonium chloride-containing polymer, a dicyandiamide, a dicyandiamide-polyalkylenepolyamine condensate, a

polyalkylenepolyamine-dicyandiamideammonium condensate, a dicyandiamide-formalin condensate, an addition polymer comprising epichlorohydrin, a polysaccharide or starch, a gum, a polyacrylamide, a methacrylate polymer; and combinations thereof.

60. The formulation or method of claim 59, wherein said polyacrylamide comprises polyacrylamide having the following structure:

a cationic polyacrylamide, a cationic polyethyleneimine, a cationic gelatin, or a copolymer comprising polyamidine.

61. The formulation or method of claim 59, wherein said cationic starch or polysaccharide comprises chitosan, optionally having the following structure:

62. The formulation or method of claim 61, wherein said chitosan has a deacetylation degree ranging from 80% to more than 95% and/or a viscosity ranging from 50 mpa to 800 mpa.

63. The formulation or method of any of claims 61 or 62, wherein said chitosan is selected from the group consisting of trimethylchitosan or quaternised chitosan.

64. The formulation of claim 59, wherein said cationic starch or

polysaccharide comprises polyglucos amine.

65. The formulation of claim 59, wherein said cationic gum is selected from the group consisting of cationic guar or cationic hydroxypropyl guar, and combinations thereof.

66. The formulation of claim 59, wherein said ammonium chloride- containing polymer is selected from the group consisting of a poly(acryloylethyltrimethylammonium chloride), a

poly(acrylamidopropyltrimethylammonium chloride) (polyAPTAC), a poly(methacrylamidopropyltrimethylammonium chloride

(polyMAPTAC) or a salt thereof, a copolymer of

diallyldimethylammoniumchloride-S02, a blend of PVA with N-(3- chloro-2-hydroxypropyl)-N,N,N-trimethylammonium chloride, a polymer comprising vinylbenzyltrimethyl ammonium chloride, (2- methacryloyloxyethyl)trimethyl-ammonium chloride,

diallyldimethylammonium chloride, acryloylethyltrimethylammonium chloride or methacrylamidopropyltrimethylammonium chloride in the form of polymerized units, and acryloylethyltrimethylammonium chloride or methacrylamidopropyltrimethylammonium chloride in cleaved form, and combinations thereof.

67. The formulation of claim 59, wherein said cationic polyvinyl alcohol is selected from the group consisting of a methyl chloride quaternary salt of poly(dimethylamino ethyl acrylate)/polyvinyl alcohol graft copolymer, a methyl sulfate quaternary salt of poly(dimethylamino ethyl acrylate)/polyvinyl alcohol graft copolymer, and a polyvinyl alcohol comprising a pendant quaternary ammonium salt, and combinations thereof.

The formulation of claim 59, wherein said vinyl containing polymer is selected from the group consisting of polyvinylpyrrolidone, a polyvinylimidazole, polyvinyl containing polymers, N-vinyl polymers, and polyvinylimidazole polymers, and combinations thereof.

The formulation of claim 68, wherein said polyvinylpyrrolidone is selected from the group consisting of PVP (polyvinylpyrrolidone), a copolymer of polyvinylacetate and polyvinylpyrrolidone, a copolymer of polyvinylalcohol and polyvinylpyrrolidone, and combinations thereof.

The formulation of claim 68, wherein said polyvinylimidazole comprises a copolymer of vinylimidazole and polyamidine.

The formulation of claim 59, wherein said polyvinyl containing polymer is selected from the group consisting of a cationic

polyvinylformamide, cationic polyvinylacetamide, a cationic polyvinylmethylformamide a poly(vinylpyridine) or a salt thereof, and a cationic polyvinylmethylacetamide, and combinations thereof.

The formulation of claim 68, wherein said N-vinyl polymer is a copolymer selected from the group consisting of a copolymer comprising N-vinylformamide, a copolymer comprising N- vinylacetamide, a copolymer comprising N-vinylpyrrolidone and N- methyl-N-vinylformamide, a cationic polymer comprising N- vinylpyrrolidone, a cationic polymer comprising N-methyl-N- vinylformamide, and a copolymer comprising N-methyl-N- vinylacetamide, and combinations thereof.

The formulation of claim 59, wherein said addition polymer comprising epichlorohydrin is selected from the group consisting of a

poly(dimethylamine-co-epichlorohydrin), a poly(dimethylamine-co- epichlorohydrin-co-ethylendiamine), and a poly(amidoamine- epichlorohydrin), and combinations thereof.

The formulation of claim 59, wherein said methacrylate polymer is selected from the group consisting of a cationic polymer comprising monomers of an amine methacrylate or subunits thereof, a cationic polymer comprising monomers of an aminoalkyl methacrylate subunit, a quaternary ammonium moiety having the general structure below, wherein Rl, R2, and R3 are independent selected from alkyl or heteroalkyl moieties:

dimethylaminoethyl methacrylate, a methyl chloride quaternary salt of a poly(dimethylamino ethyl acrylate/polyvinyl alcohol graft copolymer, a methyl sulfate quaternary salt of a poly(dimethylamino ethyl acrylate )/polyvinyl alcohol graft copolymer, a polymer comprising dimethylaminoethylmethacrylate; poly(dimethylaminoethylacrylate), a copolymer comprising dimethylaminoethyl acrylate, diethylaminoethyl acrylate, a poly(dimethylaminopropylmethacrylamide) (DMAPMAM), a poly(dimethylaminoethylacrylate), a neutral methacrylic ester, a polymer comprising monomers of a methacrylic ester, and a copolymer comprising monomers of an aminoalkyl methacrylate subunit and monomers of a methacrylic ester subunit, and combinations thereof.

A method for the manufacture of a delayed release formulation for a therapeutic agent, the method comprising:

preparing an inner mini-tablet having a diameter of between about 5 - 7 mm in diameter, wherein said therapeutic agent comprises at least 30% weight by weight percentage of the total weight of said mini- tablet;

applying a solid layer comprising one or more fast disintegrating excipients on to said mini-tablet to form an outer tablet layer, wherein said outer tablet layer surrounds said inner mini-tablet, such that said outer tablet layer dissolves in 5 minutes or less in saliva.

76. The method of claim 75, wherein said preparing said inner mini-tablet comprises compression of the therapeutic agent with at least one compression excipient.

77. The method of claim 75, further comprising coating said mini-tablet with an enteric coating before said compressing said one or more fast disintegrating excipients on to said mini-tablet.

78. The method of claim 77, wherein said coating said mini-tablet

comprises dry compressing at least one enteric polymer onto said mini- tablet.

79. A delayed release formulation for a therapeutic agent comprising: a single inner mini-tablet and at least one outer tablet layer surrounding said single inner mini-tablet, said outer tablet layer comprising one or more fast disintegrating excipients, such that said outer tablet layer dissolves in no more than about 5 minutes in saliva;

wherein a diameter of said inner mini-tablet is between about 5 - 7 mm and wherein said therapeutic agent comprises from about 30% to about 90% weight per weight of said mini-tablet; and

wherein said mini-tablet comprises a sub-coating and an enteric coating disposed on said subcoating.

80. The formulation of claim 79, wherein said enteric coating dissolves at a pH of between 3-8.

81. The formulation of claim 80, wherein said enteric coating dissolves at a pH of between 4-7.

82. The formulation of claim 81, wherein said enteric coating dissolves at a pH of 5.

83. The formulation of any of claims 79-82, wherein said sub-coating comprises a hydrophilic polymer.

84. The formulation of claim 83, wherein said polymer is selected from the group consisting of Povidone (PVP: polyvinyl pyrrolidone),

Copovidone, polyvinyl alcohol, Kollicoat Protect (BASF), polyvinyl alcohol (PVA), Opadry AMB (Colorcon), Aquarius MG, low molecular weight HPC (hydroxypropyl cellulose), low molecular weight HPMC (hydroxypropyl methylcellulose), hydroxypropylcellulose (HPMC E5) (Colorcon), low molecular weight carboxy methyl cellulose, low molecular weight hydroxyethylcellulose, low molecular weight hydroxymethylcellulose, gelatin, hydrolyzed gelatin, polyethylene oxide, acacia, dextrin, starch, water soluble polyacrylates,

polymethacrylates and combinations thereof.