Pharmaceutical compositions of ketotifen

Abstract

The present invention relates to pharmaceutical compositions of Ketotifen and its pharmaceutically acceptable salts, and processes for their preparation, for oral administration that provides a colon specific delivery of Ketotifen. The pharmaceutical composition is in the form of single or multiple dosage units for selectively administering Ketotifen to the colon.

Description

[0001] Title of The Invention: Pharmaceutical Compositions of Ketotifen

[0002] Field of The Invention

[0003] The present invention relates to programmable release-controlled pharmaceutical compositions and methods of providing predetermined concentration of Ketotifen and its pharmaceutically acceptable salts thereof in distal part of small intestine, large intestine / colon for the treatment of irritable bowel syndrome (IBS). More particularly, the present invention relates to dosage forms for delivering Ketotifen in a delayed and extended-release manner upon contacting of the dosage form with a liquid medium such as gastrointestinal (GI) fluid.

[0004] Background of the Invention

[0005] Irritable bowel syndrome (IBS) is a heterogenous disorder of brain-gut interaction characterized by abdominal pain, altered bowel habits, diarrhoea, constipation or a combination of both diarrhoea and constipation, mucus discharge along with stools and changes in the form (appearance) of stools. IBS symptoms occur due to visceral hypersensitivity which refers to an enhanced perception of stimuli originating from the internal organs and is believed to contribute to abdominal pain and bloating in IBS. Sensitization of afferent nerve endings in the gut wall is thought to underlie visceral hypersensitivity. Several lines of evidence indicate that histamine is involved in this process. For instance, supernatant from IBS colonic biopsies contains increased levels of histamine. When applied to human submucous neurons, this supernatant increased neuronal activity and the degree of activation correlated with histamine levels in the supernatant. The pro-nociceptive effect of histamine seems to be mediated - at least partially - by Hi receptors expressed on sensory afferents, which is consistent with the finding that excitation of rat jejunal aff erents by IBS supernatant can be reduced by application of the Hi receptor antagonist pyrilamine. In addition, a role for H4 receptors in mediating visceral sensory signalling and nociception has emerged (A Deiteren et al., Br J Pharmacol. 2015;172(5): 1165-1178).

[0006] Hl and H4 receptor antagonists are hypothesized to cause mast cell stabilization by multiple mechanisms such as inhibitions of the mast cell degranulation by the lipophilic Hl antagonist drugs which cross the cell membrane of the mast cell and stabilizing FcsRI (IgE binding site) or by directly interfering with the Ca+channels, intracellular Ca+release and utilization. (Eliakim R et al., Gut. 1992; 33: 1498- 1503). Ketotifen stabilizes MCs (in addition to Hl receptor antagonist properties), and thus inhibits the release of histamine in the gut; this may indirectly beneficially affect H4 receptor-mediated pathways activated by histamine. Treatment with Ketotifen significantly decreased abdominal pain, bloating, flatulence and diarrhoea in IBS patients (A Deiteren et al., Br J Pharmacol. 2015 Mar; 172(5): 1165-1178).

[0007] The evidence summarized above for the involvement of histamine and mast cells in the pathological processes that initiate or maintain the inflammatory state in IBS provides the rationale to target the Histamine receptors with antihistamine drug such as Ketotifen. Considering mast cell stabilizing properties and the pro- inflammatory effects of the Histamine are mediated through Hl receptor, the use of Hl receptor antagonists like Ketotifen or Norketotifen could be of significant benefit in alleviating the local inflammatory processes of the colonic mucosa associated with IBS. Also, the involvement of histamine through Hl receptor mediated actions and mast cell mechanisms could alleviate the visceral hypersensitivity in the irritable bowel syndrome and weak anti-colinergic / anti- seratonergic properties of Ketotifen could help to subdue the spasm and pain. Ketotifen significantly alleviated gastrointestinal symptoms and improved visceral hypersensitivity in patients with IBS-D. The therapeutic effect of ketotifen is related to a reduced number and decreased activity of mast cells in the intestinal mucosa, especially in the terminal ileum (Wang et al, European Journal of Gastroenterology & Hepatology 32(6):p 706-712. June 2020).

[0008] From various studies, the present inventors recognize the potential and new therapeutic use of Ketotifen for the treatment of IBS. Further the present inventors comprehend the requirement of an ideal dosage form which can deliver the Ketotifen specifically in distal part of small intestine, large intestine / colon for the treatment of IBS. The site-specific delivery of Ketotifen to lower parts of the GI tract is beneficial for localized management of irritable bowel disease. Hence the present invention focus on the development of colon drug delivery system which refers to targeted delivery of Ketotifen into the lower GI tract, which occurs primarily in the large intestine (i.e. colon). These delivery systems when used orally, allow to release Ketotifen from the delivery system once the delivery system arrives into the colon. These delayed mechanisms are designed to improve the efficacy of the Ketotifen by concentrating the Ketotifen where they are needed mostly and also minimize the potential side effects.

[0009] The delivery of Ketotifen specifically to the colon without being absorbed first in the upper gastrointestinal (GI) tract allows for a higher concentration of the Ketotifen to reach the colon with minimal systemic absorption. The colonic contents have a longer retention time (up to 5 days), and the colonic mucosa is known to facilitate the absorption of Ketotifen, making this organ an ideal site for Ketotifen delivery.

[0010] Object of the Invention

[0011] The object of the invention is to provide a delayed and extended release pharmaceutical composition of Ketotifen for treating irritable bowel syndrome.

[0012] Another object of the invention is to provide a pharmaceutical composition comprising release modifying components enable release of Ketotifen in the large intestine in localized manner to enrich efficacy at site of action and reduce side effects in bowel diseases such as IBS.

[0013] Another object of the invention is to provide a pharmaceutical composition of Ketotifen wherein the said the composition being monolithic unit dosage form, wherein said each unit of the composition comprising a core which includes a Ketotifen and pharmaceutically acceptable excipients and further comprising release control film coating on the core formed from a one or more release modifying agent(s).

[0014] Further the object of the invention is to provide a pharmaceutical composition of Ketotifen wherein the said composition being a multi-unit dosage form of multiparticulates, comprising a core which includes a Ketotifen and pharmaceutically acceptable excipients and further comprising release control film coating on the core formed from a one or more release modifying agent(s). Further the object of the invention is to provide a pharmaceutical composition of Ketotifen wherein the said composition being a multi-unit dosage form of multiparticulates, comprising a) a central core comprising an inert substrate; b) an intermediate layer comprising Ketotifen and one or more pharmaceutically acceptable excipients; c) release control film coating on the core formed from a one or more release modifying agent(s).

[0015] An object of the invention is to provide a pharmaceutical composition of Ketotifen wherein the said composition being a multi-unit dosage form of multiparticulates, comprising: an inert water-soluble or water-swellable core; a seal layer positioned on said core layer, said seal layer comprising a polymeric or non-polymeric material; a layer containing Ketotifen positioned on said seal layer; and a layer of at least one release-controlling film coating of release modifying agent(s) positioned on said layer containing Ketotifen.

[0016] The object of the invention is to provide a pharmaceutical composition of Ketotifen for treating intestinal bowel syndrome comprising a) an inert core, b) an optional isolation layer c) an active ingredient layer and one or more pharmaceutically acceptable excipients, d) an optional inner coating layer comprising a release modifying polymers, and e) an outer coating layer comprising an pH-sensitive polymer.

[0017] Further the object of the invention is to provide a pharmaceutical composition in solid dosage form for oral administration comprising a core containing a therapeutically effective amount of Ketotifen and a pH-sensitive coating comprising a pH sensitive polymers that dissolves at a pH of about 6 or greater and the percent weight gain resulting from the addition of said pH sensitive coating ranges from about 5% up to and including 25%, and optionally pH-independent coating with weight gain from about 5% up to and including 25%, wherein the average percentage amount of Ketotifen released from the composition in an USP apparatus I or II, , at the conclusion of a three stage dissolution test consisting of a first stage wherein said pharmaceutical composition is stirred for 2 hours in buffered to a pH 1.2 solution, a second stage wherein said composition is stirred for 2 hour in solution buffered to a pH of 4.5 and a third stage wherein said composition is stirred for 2 hours in solution buffered to a pH of 6.8, is less than about 10% in first stage and second stage; is more than about 80% at the third stage is a solution buffered to a pH of 6.8.

[0018] Further the object of the invention is to provide an orally administrable pharmaceutical mini-tablet formulation having a delayed and controlled release profile for the treatment of IBS, which comprises a matrix core and an pH- sensitive coating and suitable further pharmaceutically acceptable excipients, wherein Ketotifen and release modifying agents are present in the core and an pH- sensitive coating of core making up at least 5% to 25% by weight of the total weight of the core.

[0019] Another embodiment of the present invention is to provide a dosage form comprising: (a) a capsule shell; and (b) a plurality of delayed- extended release minitablets comprising a compressed matrix comprising Ketotifen provided with an inner pH-independent extended-release coating and an outer pH- dependent coating.

[0020] The object of the invention is to provide a multiparticulate pharmaceutical composition wherein the said composition being a multi-unit dosage form of multiparticulates, comprising: an inert water-soluble or water- swellable core; a seal layer positioned on said core layer, said seal layer comprising a polymeric or non- polymeric material; a layer containing Ketotifen positioned on said seal layer; a layer of at least one release-controlling film coating of release modifying agent(s) positioned on said layer containing Ketotifen and a layer of at least one pH-sensitive coating positioned on said release-controlling film coating.

[0021] It is a further object of the present invention is to provide pharmaceutical compositions that begin to release Ketotifen from the pharmaceutical compositions at a predetermined time delay with controlled onset after administration of the pharmaceutical compositions and which continue releasing Ketotifen from the pharmaceutical compositions at a predetermined release rate locally in large intestine to provide a significant therapeutic benefit to patients suffering from IBS.

[0022] It is yet another object of the present invention to provide a method for administering Ketotifen to a patient in need of therapy by administering a pharmaceutical composition which provides a time delay of between about 2 hours to 6 hours in the delivery of Ketotifen. Description of the Invention

[0023] The present invention provides a modified release formulation of Ketotifen that would allow the dosage form to pass through the stomach and most part of small intestine intact and release Ketotifen in large intestine preferably in a controlled manner. The drug release profiles were optimized by evaluating the influence of formulation and coating parameters.

[0024] As used herein, the term "modified-release" formulation or dosage form includes pharmaceutical preparations that achieve a desired release of the drug from the formulation. A modified-release formulation can be designed to modify the manner in which the active ingredient is exposed to the desired target. For example, a modified-release formulation can be designed to focus the delivery of the active agent entirely in the distal large intestine, beginning at the cecum, and continuing through the ascending, transverse, and descending colon, and ending in the sigmoid colon.

[0025] The term "modified-release" encompasses "extended-release" and "delayed- release" formulations, as well as formulations having both extended- release and delayed-release characteristics. An "extended-release" formulation can extend the period over which drug is released or targeted to the desired site. A "delayed-release" formulation can be designed to delay the release of the pharmaceutically active compound for a specified period. Such formulations are referred to herein as "delayed-release" or "delayed-onset" formulations or dosage forms. Modified-release formulations of the present invention include those that exhibit both a delayed- and extended-release, e.g., formulations that only begin releasing after a fixed period of time or after a physicochemical change has occurred, for example, then continue releasing over an extended period.

[0026] As used herein, the term "immediate -release formulation," is meant to describe those formulations in which more than about 60% of active ingredient is released from the dosage form in less than about 2 hours. Such formulations are also referred to herein as "conventional formulations."

[0027] The object of current invention is related to pharmaceutical compositions of Ketotifen for treatment of irritable bowel syndrome (IBS).

[0028] In one embodiment, the pharmaceutical compositions of the present invention comprise the dose of Ketotifen is ranging from 0.1 mg to 9.99 mg for each consumption.

[0029] In another embodiment, the pharmaceutical compositions of the present invention can be administered with treatment regimen ranging once daily to four times a day.

[0030] The term "pharmaceutical composition" refers to a solid body either a single unit (monolithic) or multiple units selected from neutral spheres, sugar spheres, drug- loaded matrix, non-matrix, pellets, granules, micro-particles, spheres, spheroids and hydro-gel matrix, eventually coated with release modifying agents. The core may be of any suitable dosage form comprising Ketotifen for example, a tablet, a pellet, mini-tablets, beads, spheroids, a hard or soft capsule, multiparticulates, or a powder for suspension. As used herein, "at least Hl receptor antagonists" or "Hl receptor antagonist" refers to any active Hl antagonist such as but not limited to ketotifen, Fexofenadine and Norketotifen which have Hl and H4 antagonist activity with mast cell stabilizing properties which remains intact until the dosage form reaches the colon.

[0031] In one embodiment of the present invention is to provide a process for preparation of Ketotifen composition comprising: preparing a seal coating suspension; performing a seal coating in the fluid bed coater by applying the seal coating suspension on the inert sphere to form seal coated pellets; preparing a drug layering suspension comprising Ketotifen; performing a drug layering in the fluid bed coater by applying the drug layering suspension on seal coated pellets to form drug layered pellets; preparing an extended release coating suspension; performing an extended release coating in the fluid bed coater by applying extended release coating suspension on the drug layered pellets to form extended release pellets; preparing a pH-sensitive coated extended release pellets; performing a pH-sensitive coating in the fluid bed coater by applying the pH- sensitive polymer coating suspension on the extended release pellets to form pH- sensitive coated pellets.

[0032] In one embodiment of the present invention is to provide a process for preparation of Ketotifen composition, where in the pH dependent polymer coating applied on to the ketotifen core with weight gain of 5% to 25% w / w.

[0033] In another embodiment of the present invention is to provide a process for preparation of Ketotifen composition, where in, first a pH independent polymer coating applied on to the ketotifen core with weight gain of 5% to 25% w / w and resulted coated core further coated with pH independent polymer with weight gain of 5% to 25% w / w.

[0034] Another embodiment of the present invention is to provide a pharmaceutical composition wherein the composition exhibits a drug-release profile that is dependent of surrounding pH, and wherein the composition exhibits the following dissolution profile, when tested in a U.S.P. Type I or II apparatus at 37 °C and different speed (25-150 rpm), in pH 1.2 buffer for the test: 2 hours: less than or equal to 10% drug released; in pH 4.5 buffer for the test: 2 hours: less than or equal to 10% drug released; in pH 6.0 or above buffer for the test: 2 hours: more than or equal to 80% drug released.

[0035] The pharmaceutically acceptable excipients are selected from not limited to diluents, glidants, disturbing agents, binders, lubricants, surfactants, opacifiers, disintegrants, pore forming agents, plasticizers, colouring agents and the like.

[0036] The release modifying agents are selected from matrix-forming polymers, pH- dependent soluble polymers, pH-independent soluble polymers, disruption agents, pore-forming agents, plasticizers, disintegrants and swelling agents.

[0037] The matrix-forming polymers are selected from water-insoluble polymers, water- soluble polymers, gel-forming polymers, swelling polymers and hydrophobic polymers.

[0038] The water-insoluble polymer may be at least one polymer selected from the group consisting of ethylcellulose, purified shellac, white shellac, cellulose acetate, polymethylmethacrylate copolymer, polyethylene oxide, polyvinyl acetate, and acetate-poly vinyl pyrrolidone copolymer, aminoalkyl methacrylate copolymer RS, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl-cellulose, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, etc. The polymethylmethacrylate copolymer may be selected from the group consisting of commercially available Eudragit RS 100, RS PO, RS 30D, RL100, RL PO, RL 30D, NE30D, and NE40D. For the vinyl acetate-polyvinyl pyrrolidone copolymer, commercially available Kollidon SR and Kollicoat SR may be used.

[0039] The gel-forming polymer may be at least one polymer selected from the group consisting of gelatin, agar, a polyethylene glycol, starch, casein, chitosan, soya bean protein, safflower protein, alginates, gellan gum, carrageenan, xanthan gum, gelatin, cellulose phthalate-acetate, oleoresin, polyvinyl acetate, acrylic or methacrylic esters, polyvinyl acetate -phthalate and any derivative of any of the foregoing; or a mixture of one or more such a hydrogel-forming polymers.

[0040] The swellable polymer may be at least one polymer selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethylcellulose, polyvinyl alcohol and carbomer.

[0041] The pH-dependent soluble polymers include polycarboxylic acid polymers. The polycarboxylic acid polymers include Eudragit® L, Eudragit® S, Eudragit® FS 30 D, Eudragit® L30D-55, Eudragit® L100-55, Eudratec@COL, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), cellulose acetate trimellitate (CAT), xanthan gum, alginates, and shellac.

[0042] Acrylic and methacrylic acid polymers and copolymers are for example those commonly available on the market as Eudragit®, Kollicoat MAE or a mixture thereof. Preferably, said gastro-resistant coating is the methacrylic acid copolymer type B (Eudragit SI 00), the methacrylic acid copolymer type C (Eudragit L100- 55) or a mixture thereof.

[0043] Evonik is the global leader for delayed release, with its broad range of pH- sensitive polymers such as EUDRAGIT® L 30 D-55 and EUDRAGIT® FS 30 D, having set the gold standard in gastric resistance and gastrointestinal targeting for more than 60 years. EUDRAGIT® L and EUDRAGIT® S polymers are highly stable and can be easily combined with other polymers or oral drug delivery technologies for precise targeting and rapid drug release either in the small intestine or the colon. In addition to EUDRAGIT® L and EUDRAGIT® S polymers having many well- defined characteristics to protect the gastric mucosa from aggressive drugs, they also have decades of literature highlighting their ability to safely protect the transit of drugs that are sensitive to gastric fluid. EUDRAGIT® pH-sensitive polymers have also been used to achieve high drug concentrations in the intestine, help reduce the daily dose, and avoid potential systematic side effects associated with specific parts of the gastrointestinal tract. Evonik has also developed an advanced new combination polymer marketed as EUDRAGIT® FL 30 D-55 that provides highly flexible coatings without the need for plasticizer addition. Thus, it is the new polymer of choice for pH-sensitive coatings on multiparticulates for further compression to multi-unit tablets.

[0044] According to a preferred embodiment, methacrylic acid - methyl methacrylate copolymer (1:1) (Eudragit® LI 00 soluble at a pH greater than 6) and methacrylic acid copolymer - methyl methacrylate (1:2) (Eudragit® S 100- soluble at a pH greater than 7). This Eudragit® L100 copolymer makes it possible to delay the release in the intestinal tract of the compounds coated by this copolymer up to the level of the jejunum. This Eudragit® S 100 copolymer makes it possible to delay the release in the intestinal tract of the compounds coated by this copolymer up to the level of the ileum and the colon. The mixture of these copolymers of the coating makes it possible to obtain a release of the pharmaceutical composition which differs depending on the pH because these three polymers solubilize at different pHs.

[0045] In one embodiment, the present pharmaceutical composition comprise at least one water-soluble polymer chosen from polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose of different grades (i.e. viscosity) (HPMC), polyethylene glycol, and mixtures thereof or at least one water-insoluble polymer chosen from ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), poly (ethylene), poly (ethylene) low density, poly (ethylene) high density, poly (ethylene oxide), poly (ethylene terephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), poly (vinyl chloride) or polyurethane, and mixtures thereof; hydroxypropyl methylcellulose phthalate (HPMCP), sodium carboxymethylcellulose (SCMC), polypropylene glycol, polyethylene sorbitan ester, polyethylene oxide, polyvinyl pyrrolidone, polysaccharide and poloxamer (Pluronic F68, F127). The water-soluble polymer is selected from the group consisting of cellulose, ethylene oxides, HMPC, MHPC, HEMC, MHEC, HEC, and CMC. Of these polymers, HPMC may be most preferable. Typical hydrophilic polymers used for this purpose as water-soluble polymer include one or more of polyvinyl alcohol, povidone, starch or its derivatives, sodium alginate, calcium alginate, calcium carboxymethylcellulose, polyethylene glycol (PEG) (e.g., PEG 3350, PEG 4600, PEG 6000, PEG 8000, PEG 12000 and PEG 20000) and pH- sensitive polymers.

[0046] With the term "inert" according to the invention, it is intended a substrate, or core, without active principle.

[0047] Non-limiting examples of inert core spheres are starch, dextrose, Maltose, Sucrose (Suglets (Colorcon; Bazainville; France); Pharm-a-spheres (pharm- a- spheres GmbH; Tornesch; Germany); Surinerts (IPS srl, Milan, Italy); Vivapharm Sugar Spheres (JRS Pharma GmbH&Co.KG.; Weissenbom; Germany); Sugar pellets (Umang Pharmatech Pvt Ltd.; Thane; India), Microcrystalline cellulose (MCC) (Vivapur® MCC spheres (JRS Pharma GmbH&Co.KG.; Weissenbom; Germany); Cellets (IPC Process-Center GmbH; Dresden;

[0048] Germany); CELPHERE™ (Asahi Kasei Corporation; Tokyo; Japan); MCC Pellets MS (Umang Pharmatech Pvt Ltd.; Thane; India), Isomalt (galenlQ (Beneo GmbH; Mannheim; Germany), Anhydrous dibasic calcium phosphate (PharSQ Spheres CM (Chemische Fabrik Budenheim; Budenheim; Germany), Tartaric acid (TAP (IPC Process-Center GmbH; Dresden; Germany); Tartaric acid pellets (Umang Pharmatech Pvt Ltd.; Thane; India); InstaSpheres-TA (Tartaric acid spheres seal coated with hydrophilic polymer; Ideal Cures; Mumbai; India), Silica (Silica Pellets AS (Umang Pharmatech Pvt Ltd.; Thane; India), Xylitol (Xylinerts (Gustave Parmentier GmbH, Germany), Mannitol (Mannitol spheres SANAQ®(Pharmatrans SANAQ; Basel; Switzerland) and Lactose (Lactose pellets LS (Umang Pharmatech Pvt Ltd.; Thane; India).

[0049] A sealant or barrier can also be applied to the polymeric coating. A sealant or barrier layer can also be applied to the core prior to applying the polymeric material. A sealant or barrier layer is not intended to modify the release of at least one mast cell stabilizer. Suitable sealants or barriers are permeable or soluble agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, and xanthan gum.

[0050] Other agents can be added to improve the processability of the sealant or barrier layer. Such agents include talc, colloidal silica, polyvinyl alcohol, titanium dioxide, micronized silica, fumed silica, glycerol monostearate, magnesium trisilicate and magnesium stearate, or a mixture thereof. The sealant or barrier layer can be applied from solution (e.g., aqueous) or suspension using any known means, such as a fluidized bed coater (e.g., Wurster coating) or pan coating system. Suitable sealants or barriers include, for example, OPADRY WHITE Y- 1-7000 and OPADRY OY / B / 28920 WHITE, each of which is available from Colorcon Limited, England. The invention also provides an oral dosage form containing a multiparticulate drug formulation as hereinabove defined, in the form of caplets, capsules, particles for suspension prior to dosing, sachets, or tablets. The dosage form can be of any shape suitable for oral administration of a drug, such as spheroidal, cube-shaped, oval, or ellipsoidal. The dosage forms can be prepared from the multiparticulates in any known manner and can include additional pharmaceutically acceptable excipients. Examples of suitable disruption agents for the compositions of this invention include polymers with the capacity to expand on hydration, such as low substituted hydroxypropyl cellulose, sodium starch glycolate, sodium carboxymethylcellulose, croscarmellose sodium, and carbomers.

[0051] Typical pore-forming agents used for this purpose include mannitol, sorbital and copovidone. In some embodiments, disintegrants can be used as pore-forming agents.

[0052] Non-limiting examples of disintegrants include one or more of starches such as com or potato starch, modified starches (such as sodium starch glycolate) and partially pregelatinized starches (such as Starch 1500); powdered cellulose; crosslinked polyvinylpyrrolidone (crospovidone), crosslinked carboxymethylcellulose sodium (croscarmellose sodium), ion exchange resins (such as Polacrilin potassium, Polacrilex), Neusilins, and low substituted hydroxypropyl cellulose; colloidal silicon dioxide, microcrystalline cellulose, sodium carboxymethylcellulose and dried com starch.

[0053] Useful film-forming agents according to the invention are preferably selected from among hydroxyalkylcellulose, polyvinyl alcohol, povidone or a mixture thereof. More preferably, said film-forming agents are selected from among hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone (for example, povidone K30) or a mixture thereof.

[0054] Useful suspending and / or gliding agents according to the invention are preferably selected from among anhydrous colloidal silica, talc or a mixture thereof.

[0055] Preferably, the pharmaceutical composition according to the invention comprises one or more diluents selected from the group consisting of water- insoluble diluents such as calcium phosphate-dibasic, calcium silicate and water-soluble diluents such as microcrystalline cellulose, lactose, sucrose, starch, polyols such as mannitol, sorbitol, xylitol, maltitol and the like and mixtures thereof.

[0056] The binder can be selected from the group consisting of but not limited to polyvinylpyrrolidone, microcrystalline cellulose, cellulose ether, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose of different grades (i.e. viscosity), starch, povidone, copolyvidone, corn starch, maize starch, pregelatinised starch, polymethacrylate, or mixtures thereof.

[0057] The lubricant can be selected from the group consisting of but not limited to stearic acid, magnesium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium palmitate, magnesium oleate, calcium stearate, talc, hydrogenated vegetable oil, mineral oil, silicon dioxide, magnesium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium lauryl sulfate, sodium stearyl fumarate, glyceryl behenate, macrogols, talc, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax and white beeswax and / or mixtures thereof.

[0058] The glidant can be selected from the group consisting of but not limited to colloidal silicon dioxide, talc, stearic acid, palmitic acid, polyethylene glycol, corn starch, carnauba wax, and / or mixtures thereof.

[0059] Preferably, the anti-tacking agents can be selected from the group consisting of but not limited to tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate (i.e. calcium phosphate), sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminium silicate, calcium aluminosilicate, bentonite, aluminium silicate, stearic acid and polydimethylsiloxane and / or mixtures thereof.

[0060] Plasticizers can be incorporated depending on the polymer and the process requirement. These, advantageously, when used in the hot-melt extrusion process decrease the glass transition temperature of the polymer. Plasticizers also help in reducing the viscosity of the polymer melt and thereby allow for lower processing temperature and extruder torque during hot-melt extrusion. Examples of plasticizers that can be used in the present invention include but are not limited to, polysorbates such as sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate; acetylated triacetin, citrate phthalate, triethyl citrate, tributyl sebacate, tributyl citrate, glycerol tributyrate, propylene glycol; glycerin; diacetylated monoglyceride, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, diethyl oxalate, diethyl phthalate, diethyl maleate, diethyl fumarate, diethylmalonate, polyethylene glycol (low & high molecular weight), dioctyl phthalate, dibutyl sebacate, dibutyl tartrate, dibutyl sebacate, dibutyl phthalate, dibutyl succinate and mixtures of these. Useful plasticizers according to the invention are preferably selected from among polyalkylene glycols, glycols or a mixture thereof. More preferably, said plasticizers are selected from among polyethylene glycol 400, polyethylene glycol 6000, propylene glycol, triethyl citrate, triacetin or a mixture thereof.

[0061] Examples of diluents include calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, magnesium oxide, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar compressible, sugar confectioners or mixtures thereof.

[0062] Examples of opacifiers include titanium dioxide, talc, calcium carbonate, behenic acid and cetyl alcohol.

[0063] Examples of coloring agents include ferric oxide red, ferric oxide yellow, Lake of Tartrazine, Allura red, Lake of Quinoline yellow and Lake of Erythrosine. The solvents that can be used for the coating are selected from the group consisting of water, ethanol, methanol, isopropyl alcohol, dichloromethane, acetone or mixture thereof.

[0064] The present application now is described in more detail by the following Examples. However, it is noted that the Examples are provided for illustrative purposes only and should not be construed to limit the scope of the invention in any way.

[0065] Example 1

[0066] Manufacturing Process:

[0067] Drug Coated Beads

[0068] 1) Non-pareil seeds were taken in a Wurster fluidized bed dryer.

[0069] 2) Hydroxy Propyl Methyl cellulose E3LV was dispersed in isopropyl alcohol to form a dispersion and mixed with water.

[0070] 3) Ketotifen Fumarate, talc, and colloidal silica were dispersed in the above dispersion.

[0071] 4) The final dispersion was sprayed onto the non-pareil seeds.

[0072] DR Coat

[0073] 5) Eudragit® FS 30 D was dispersed in purified water.

[0074] 6) The dispersion was neutralized with ammonium hydroxide.

[0075] 7) Triacetin and talc were added to the dispersion and mixed well.

[0076] 8) The polymeric dispersion from was sprayed onto drug coated beads

[0077] Example 2

[0078] Manufacturing Process:

[0079] Drug Coated Beads

[0080] 1) Non-pareil seeds were taken in a Wurster fluidized bed dryer.

[0081] 2) Hydroxy Propyl Methyl cellulose E6LV was dispersed in isopropyl alcohol to form a dispersion and mixed with water.

[0082] 3) Ketotifen Fumarate, talc, and colloidal silica were dispersed in the above dispersion.

[0083] 4) The final dispersion was sprayed onto the non-pareil seeds.

[0084] Slow Release Seal Coat

[0085] 5) Hydroxy Propyl Methyl cellulose E15LV was dissolved in water.

[0086] 6) PEG 400 and talc were added in above solution.

[0087] 7)The seal coating solution was sprayed onto the drug coated beads.

[0088] DR Coat

[0089] 8) Eudragit® FS 30 D was dispersed in purified water.

[0090] 9) The dispersion was neutralized with ammonium hydroxide.

[0091] 10) Triacetin and talc were added to the dispersion and mixed well. 11) The polymeric dispersion from was sprayed onto seal coated and drug coated beads

[0092] Example 3

[0093] Manufacturing Process: All the ingredients of uncoated cores are mixed well in a blender and compressed in to mini-tablets in a rotary press. These mini-tablets coated with delayed release coating solution in a coating pan. Finally, the minitablets are filled in capsule.

Claims

I / We Claim,1. A modified release pharmaceutical composition of Ketotifen and its pharmaceutically acceptable salts thereof; for treating irritable bowel syndrome comprising a) an inert core b) an optional isolation seal layer c) a Ketotifen layer and one or more pharmaceutically acceptable excipients, d) an optional inner coating layer comprising a release modifying polymers, and e) an outer coating layer comprising an pH-sensitive polymer, wherein: the total amount of Ketotifen in the modified release pharmaceutical composition is from about 0.1 to 9.99g.

2. The modified release pharmaceutical composition as claimed in claim 1 wherein said composition being a multi-unit dosage form of multiparticulates, comprising: an inert water-soluble or water-swellable core; a seal layer positioned on said core layer, said seal layer comprising a polymeric or non-poly meric material; a layer containing Ketotifen positioned on said seal layer; a layer of at least one release-controlling film coating of release modifying agent(s) positioned on said layer containing Ketotifen and a layer of at least one pH- sensitive coating positioned on said release-controlling film coating.

3. The modified release pharmaceutical composition as claimed in claim 1 wherein the release modifying polymers are selected from the group consisting of water soluble and / or water swellable polymers.

4. The modified release pharmaceutical composition as claimed in claim 1 wherein the pH- sensitive polymers are selected from the group consisting of polymers which can soluble at pH at 6.0 or above.

5. The modified release pharmaceutical composition as claimed in claim 1 wherein the process for preparation of Ketotifen composition comprising: preparing a seal coating suspension; performing a seal coating in the fluid bed coater by applying the seal coating suspension on the inert sphere to form seal coated pellets; preparing a drug layering suspension comprising Ketotifen; performing a drug layering in the fluid bed coater by applying the drug layering suspension on seal coated pellets to form drug layered pellets; preparing a release modifying coating suspension; performing an release modifying coating in the fluid bed coater by applying release modifying coating suspension on the drug layered pellets to form modified release pellets; preparing a pH- sensitive coated modified release pellets; performing a pH-sensitive coating in the fluid bed coater by applying the pH-sensitive coating polymers polymer coating suspension on the modified release pellets to form pH-sensitive coated pellets.

6. The modified release pharmaceutical composition as claimed in claim 1, optionally comprises coating of pH-independent coating of polymers on the drug core and the percent weight gain resulting from the addition of said pH independent coating ranges from about 5% up to and including 25% w / w of drug core, further comprising outermost layer of coating of pH-sensitive coating polymers wherein the pH sensitive polymers that dissolves at a pHof about 6 or greater and the percent weight gain resulting from the addition of said pH sensitive coating ranges from about 5% up to and including 25% w / w of final core.

7. The pharmaceutical composition as claimed in claim 1, wherein the composition when subject to in vitro dissolution testing according to USP apparatus Type I or II with dissolution medium of pH 1.2 buffer for 2 hours, followed by pH 4.5 buffer for 2 hours, followed by pH 6.8 buffer for 2 hours, the pharmaceutical composition exhibits less than 10% cumulative release of Ketotifen at pH 1.2 and pH 4.5 buffers, and exhibit extended release of more than 80% Ketotifen within 2 hours at pH 6.8 buffer.

8. A pharmaceutical composition for the oral administration of Ketotifen to a subject, comprising: a delayed-extended release minitablet comprising a compressed matrix provided with an inner pH-independent extended release coating and an outer pH-dependent pH-sensitive coating, wherein the delayed-extended release composition selectively release Ketotifen at a pH of about 6.0 or greater in the colon; wherein the total amount of Ketotifen in the unit dose pharmaceutical product is from about 0.1 to 9.99g.

9. The pharmaceutical composition as claimed in claim 1 and 8, wherein the composition can be in the final dosage forms selected from the group consisting of capsules, caplet, sachets, and particles for suspension prior to dosing.

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