WO2009104205A1 - Delayed release formulation of chloride channel activator - Google Patents

Abstract

The present invention relates to the delayed release formulations of Chloride Channel Activator. The preferred Chloride channel activator is lubiprostone.

Description

DELAYED RELEASE FORMULATION OF CHLORIDE CHANNEL ACTIVATOR

Field of the Invention

The present invention relates to the various delayed release formulations of Chloride Channel activator. The delayed release formulations reduce the incidence of nausea associated with the administration of these agents. The most preferred Chloride channel activator is lubiprostone which is used for the treatment of chronic constipation,

The invention also provides the method of manufacture of delayed release formulation of Chloride channel activator. Background of the Invention Chloride channels are pore-forming proteins that allow the transport of chloride ions, the predominant anion in the extra cellular fluid, across cell membranes. Chloride ions (Cl-) not only manage transportation of water/electrolyte, secretion and regulation of cell volume but also play an important role as a factor affecting the response of cells. Found in virtually all cell types; they play a vital role in the function of epithelial, muscle, and nerve cells. Chloride secretion is the major determinant of mucosal hydration throughout the gastrointestinal tract and chloride transport is also pivotal in the regulation of fluid secretion by organs that drain into the intestine.

It has been reported that various kinds of chloride channels are present in the cell membrane of nerve, muscle and epithelium, and they are involved with various physiological functions and cytophylaxis mechanisms.

Chloride channels are implicated in a variety of diseases including epilepsy, dystrophia myotonica, Bartter syndrome, osteoporosis, and chronic pancreatitis. Other diseases known to be caused by an abnormality in the balance of chloride ions include diseases showing hypercalciuria such as calculus renum, anxiety, insomnia, cystic fibrosis, epilepsia, anesthesia, asthma, bronchitis and neuropathy. One of the most important chloride channels in the Gl tract is the cystic fibrosis trans membrane conductance regulator (CFTR). This cyclic AMP-regulated channel is located on the apical membrane, is normally activated by protein kinase A, and is defective in patients with cystic fibrosis. The variation of genes, which is the cause of this disease, occurs in CFTR genes due to the reduced permeability of chloride ions caused by the deficiency in functions of CFTR in the epithelial cells of air duct, pancreas, bowel, perspiratory gland, alimentary tract, etc. A chloride channel is an ion-transport membrane protein for transporting chloride ions. Further, a chloride channel cloned by cramp fish's electric organ and named CIC-O was later found to form a large family (CIC family). Examples of CIC family are: CIC-1 present in the skeletal muscle of mammals; CIC-2 present in the epithelium of various organs; CIC-3 and CIC-4 distributed in hippocampus, cerebellum, etc.; CIC-5 present in lung, kidney, etc.; CIC-6 and CIC-7 present in brain, testis, skeletal muscle, kidney, etc.; and CICK-1 and CICK-2 specifically shown only in kidney. It is known that the abnormality in CIC-1 causes congenital myotonia and the abnormality in CIC-5 causes hereditary nephrolithiasis.

The transition of chloride ions into or out of cells concurrently accompanies the transport of water and electrolyte, which results in the regulation of cell volume. Therefore, it is suggested that chloride ions play an important role in the growth and division of cells and the programmed cell death that accompany an abrupt change in the cell volume. In the brain, it is known that inhibitory regulation works in the central nervous system by maintaining chloride ions in the nerve cells at a low level. It is also known that chloride ions play an important role in inhibiting anxiety and spasm, and regulating sleep, memory and circadian rhythm.

In the bowel, it is known that chloride ions are deeply involved with such pathology as diarrhea and constipation, and when opioid such as morphine is administered to bring abnormal secretions of electrolyte such as chloride ions and fluid, it will cause intractable constipation. Accordingly, a compound which can open chloride channels and promotes chloride ion transportation are considered to affect on various cell functions and cytophylaxis mechanisms, and also considered to be useful for the treatment of pathology occurring because of abnormal chloride ion balance within or outside the cells due to the reduced permeability of chloride ions by some cause.

Lubiprostone is a bicyclic fatty acid prostaglandin E 1 derivative that is a locally acting chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Lubiprostone acts by specifically activating CIC-2, which is a normal constituent of the apical membrane of the human intestine, in a protein kinase A-independent fashion. By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby increasing the passage of stool and alleviating symptoms associated with chronic idiopathic constipation. The use of lubiprostone in chronic idiopathic constipation has been disclosed in US 5,317,032. Further lubiprostone at the dose of 8mcg is also approved for use in the treatment of irritable bowel syndrome. It is marketed under the trade name Amitiza^®.

Chronic idiopathic constipation is generally defined by infrequent or difficult passage of stool. The signs and symptoms associated with chronic idiopathic constipation (i.e., abdominal pain or discomfort, bloating, straining, and hard or lumpy stools) may be the result of abnormal colonic motility that can delay the transit

' of intestinal contents and impede the evacuation of rectal contents. It is estimated that 4-5 million Americans (about 2% of the population) are affected, making it one of the most common disorders. It is one of the most common gastrointestinal complaints with prevalence estimates falling in the range of 12-19% and increasing in population over 65 years of age. Despite this high prevalence, treatment for constipation remains unsatisfactory, possibly due to poor understanding of its etiology and the relative lack of conventional therapeutic, approaches for the treatment of constipation include dietary and lifestyle modifications and exercise, and if all else fails, administration of laxatives.

One approach to the treatment of chronic idiopathic constipation is the secretion of fluid into the abdominal lumen through the activation of chloride channel. Lubiprostone has emerged as a novel agent with considerable promise as a treatment for constipation and irritable bowel syndrome.

Lubiprostone activates CIC-2 channels on the apical membrane of intestinal epithelial cells. Although the complete mechanism explaining lubiprostone's efficacy is not completely understood at this time, the primary action is mediated via these channels. When activated, there is an efflux of chloride through the channels into the lumen of the intestinal tract. To maintain electrical neutrality, sodium ions follow through a paracellular pathway. Water then follows, also along the paracellular pathway, to maintain isotonic equilibrium. Opening chloride channels thus causes a net efflux of chloride into the lumen of the intestinal tract, which promotes intestinal fluid secretion. Secretion of fluids into the gastrointestinal tract adds fluid to stool and promotes increased transit, likely through stimulation of local receptors sensitive to stretch and distention. Although the small intestine and colon are able to avidly absorb secreted fluid, the activation of CIC-2 channels throughout both the small intestine and colon likely leads to its net stimulatory effects. Lubiprostone is specific for CIC-2 channels and does not activate other chloride channels such as CFTR. Further the activation of CIC-2 channels by lubiprostone is independent of protein kinase A.

All of the adverse events associated with lubiprostone consist of Gl symptoms including vomiting, nausea, and abdominal cramping. It has been observed that the percentage of patients experiencing nausea is about 17% for 24 meg once daily dose and 29% at a dose of 24 meg twice daily compared to 3% in placebo, when administered for chronic idiopathic constipation. 4% of patients had severe nausea while 9% of patients discontinued treatment due to nausea. The rate of nausea associated with Amitiza^® (any dosage) was substantially lower among male (7%) and elderly patients (18%). In case of patients with irritable bowel syndrome (lubiprostone dose is 8mcg) 8% patients had nausea compared to 4% in placebo. The mechanism of lubiprostone-associated nausea is not known. However, it is possible that fluid secretion could transiently distend the lumen of the upper gastrointestinal tract, thereby, leading to nausea. As expected, subjects receiving lubiprostone experience more nausea than those on placebo. Thus the object of the present invention is to provide a formulation of lubiprostone or any other chloride channel activators, which are devoid of nausea. The object of present invention is to provide a delayed release formulation of lubiprostone, which would release lubiprostone in lower gastrointestinal tract and thereby avoid nausea and vomiting associated with lubiprostone. The formulation of the present invention releases lubiprostone in the lower gastrointestinal tract thereby avoiding distention of upper gastrointestinal tract. Objects of the Invention

The object of the present invention is to provide a delayed release pharmaceutical formulation comprising a therapeutically effective amount of Chloride channel activator or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), prodrug or metabolite or tautomer thereof and one or more delayed release polymer.

Another object of the present invention is to provide a delayed release pharmaceutical formulation comprising a therapeutically effective amount of lubiprostone or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), prodrug, tautomer or metabolite thereof and one or more delayed release polymer.

Another object of the present invention is a delayed release pharmaceutical formulation of lubiprostone comprising (i) a core comprising therapeutically effective amount of lubiprostone or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), prodrug, tautomer or metabolite thereof and (ii) one or more delayed release coating.

Another object of the present invention is a delayed release pharmaceutical formulation of lubiprostone comprising (1) a capsule comprising therapeutically effective amount of lubiprostone or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), prodrug, tautomer or metabolite thereof and one or more pharmaceutically acceptable excipients and (2) one or more delayed release coating. Detailed Description of Invention

The present invention is directed towards delayed release formulations of chloride channel activators. The most preferred chloride channel activator is lubiprostone.

For the present invention lubiprostone would include lubiprostone or its pharmaceutically acceptable salts or metabolites or tautomers or polymorph(s), solvate(s), hydrate(s), or prodrug there of.

Therapeutically effective amount" means that the amount of lubiprostone, which halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition. A person skilled in the art can easily determine such an amount by routine experimentation and with an undue burden.

Thus the present invention is directed towards delayed release formulations of lubiprostone or its pharmaceutically acceptable salts or metabolites or tautomers or polymorph(s), solvate(s), hydrate(s), or prodrug there of. It has now been found that delivering lubiprostone or its pharmaceutically acceptable salts or metabolites or tautomers or polymorph(s), solvate(s), hydrate(s), or prodrug there of to the lower gastrointestinal tract would avoid or reduce the nausea associated with the administration of lubiprostone. Lubiprostone acts by activating the chloride channels, which causes transportation of chloride ions, sodium ions and water in the gastrointestinal tract. Secretion of fluids in the Gl tract adds fluid to stool and as a result shows anti-constipating effect.

The object of the present invention is to delay the release of lubiprostone, so that the dosage form releases lubiprostone in the lower gastrointestinal tract avoiding opening of chloride channels in the stomach or upper gastrointestinal tract, which would further avoid the transportation of chloride ions, sodium ions and water that would in turn avoid distension of stomach. This is likely to minimize the nausea associated with lubiprostone therapy.

Thus, according to present invention there is provided a pharmaceutical dosage form adapted for administration to the gastrointestinal tract of the patient, comprising therapeutically effective amount of lubiprostone or pharmaceutical acceptable salts or metabolites or tautomers or polymorph(s), solvate(s), hydrate(s), or prodrug there of and a pharmaceutically acceptable adjuvant, characterized in that the dosage form is adapted to release lubiprostone to the lower gastrointestinal tract of the patient.

The dosage form of the invention may be of the delayed release type. Delayed release dosage form means a dosage form, which would provide a time-delay before release of drug. Further the dosage form would release lubiprostone in the lower gastrointestinal tract. Lower gastrointestinal tract" means the portion of the gastrointestinal tract between the regions of duodenum to rectum inclusive.

By "pharmaceutically acceptable" is meant a carrier comprised of a material that is not biologically or otherwise undesirable.

The formulation of the present invention may include (a) Those in which the lubiprostone, is in a capsule coated with coating which delays the release

(b) Those in which the lubiprostone is embedded in a matrix from which it is released by diffusion or erosion;

(c) Those in which the lubiprostone is present in a multiparticulate core; (d) Those in which there is an impermeable coating provided with an aperture through which the lubiprostone is released;

(e) Those in which there is a coating of low aqueous solubility;

(f) Those in which there is a semipermeable coating; (g) Those in which the lubiprostone is present as an ion exchange resin complex; and (h) Pulsatile devices from which the lubiprostone is released at specific points in the gastrointestinal tract. The above formulations are the non-limiting examples of prepared to release the drug in the lower gastrointestinal tract.

Other formulations, which, releases the active agent in the lower gastrointestinal tract are also included within the scope of this invention.

The dosage form according to present invention may be tablet, capsules including soft capsule, hard capsules, pellet, bead, spheroids, microcapsules, microspheres, mini tablet, powder, granules, drug loaded particles, liquids which may include suspension or emulsions and others.

The dosage form may also be a capsule, in which case the active agent- containing composition may be encapsulated in the form of a liquid or solid (including particulates such as granules, beads, powders, or pellets). Suitable capsules may be either hard or soft, and are preferably made up of gelatin, starch, or a cellulosic material, natural or synthetic gelatin, pectin, casein, collagen, protein, modified starch, polyvinyl pyrrolidone, acrylic polymers, and combinations thereof, optionally with one or more plasticizers and/or water. Capsular materials may also include one or more preservatives, coloring and opacifying agents, flavorings and sweeteners, sugars, gastroresistant substances, or combinations thereof Two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like.

The formulation of the present invention may further comprise of stabilizer. It is known that in the absence of water, the tautomeric compound, lubiprostone, exist predominantly in the form of the bi-cyclic compound. In aqueous media, it is believed that hydrogen bonding occurs between the water molecule and, for example, the keto group at the hydrocarbon chain of the lubiprostone, thereby hindering bi-cyclic ring formation. Stabilizer such as cyclodextrin, for example,, alpha.,, beta.- or .gamma. - cyclodextrin; etherified cyclodextrin such as dimethyl-.alpha.-, dimethyl-.beta.-, trimethykbeta.- or hydroxypropyl-.beta.-cyclodextrin; branched cyclodextrin such as glucosyl-, maltosyl-cyclodextrin; formylated cyclodextrin, cyclodextrin containing sulfur; phospholipid, triglycerides, non-polar solvents and the like. When the above cyclodextrins are used, inclusion compound with cyclodextrins may be sometimes formed to enhance stability.

Alternatively, phospolipid may be sometimes used to form liposome, resulting in enhanced stability. The present invention may also comprise medium chain fatty acid triglyceride as stabilizer. They can be used to increase the bi-cyclic/mono-cyclic ratio. The triglyceride may be a saturated or unsaturated fatty acid that may have a branched chain. A preferred fatty acid is a straight chain saturated fatty acid, for example, caproic acid, caprylic acid, capric acid, lauric acid and myristic acid. Two or more medium chain fatty acid triglycerides may be used as a mixture.

The composition of the present invention may be dissolved or admixed in the medium chain fatty acid triglyceride. The amount of the medium chain fatty acid triglyceride is not limited. Preferred fatty acid is a straight chain saturated fatty acid for example caproic acid (C6), caprylic acid (C8), capric acid (C10), lauric acid (C12) and myristic acid (C14). In addition, 2 or more medium chain fatty acid triglycerides may be used. Even more non-polar solvents, such as commercially available Miglyol can be employed to increase the bi-cyclic/mono-cyclic ratio.

Any other agent may which can stabilize bicyclic tautomer may also be used as stabilizer. The formulation of the present invention may further include other excipients such as binders, diluents, lubricants, disintegrating agents, glidants, stabilzers, solubilizers and surface-active agents. The amount of excipients employed will depend upon how much active agent is to be used. One excipient can perform more than one function. Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose, celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations there of and other materials known to one of ordinary skill in the art and mixtures thereof.

Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used. Disintegrating agents, which may be used, includes crospovidone, hydroxy propylcellulose.croscarmellose, sodium starch glycolate and the likes. Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.

Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art.

The present formulations may optionally contain a surface-active agent. The preferred agent is poloaxmer. However, other agents may also be employed such as dioctyl sodium sulfosuccinate (DSS), triethanolamine, sodium lauryl sulphate (SLS), polyoxyethylene sorbitan and poloxalkol derivatives, quaternary ammonium salts or other pharmaceutically acceptable surface-active agents known to one ordinary skilled in the art. The formulation of the present invention may further comprise of hydrophilic substance or/and hydrophobic substance.

Hydrophilic substance which may be used in the present invention includes hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, vinyl acetate copolymers, polysaccharides as alginates, xanthan gum, Chitosan, carrageenan, dextran and the like, polyalkylene oxides as polyethylene oxide and the likes, methaacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers, carbomer (Carbopol(TM)), guar gum, locust bean gum, poly vinyl acetate, polyvinyl alcohol and the like. Hydrophobic substance includes acrylates, cellulose derivatives as ethylcellulose, cellulose acetate and the likes, methaacrylates, high molecular weight polyvinyl alcohols, waxes, hydrogenated vegetable oil, purified grades of beeswax; fatty acids; long chain fatty alcohols, such as cetyl alcohol, myristyl alcohol, and stearyl alcohol; glycerides such as glyceryl esters of fatty acids like glyceryl monostearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil and the like; oils such as mineral oil and the like, or acetylated glycerides; stearic acid , paraffin, camauba wax, talc; and the stearate salts such as calcium, magnesium, zinc and other materials known to one of ordinary skill in the art,

Solubilizers include surfactants, hydrophilic or hydrophobic solvents, oils or combinations thereof. Solubilizer may also sometimes stabilize the lubiprostone. One type of solubilizer that may be used is a vitamin E substance. This group of solubilizers includes a substance belonging to the group of .alpha.-, .beta.-, .gamma.-, .delta.-, .zeta.1-, .zeta.2- and .eta. -tocopherols, their dl, d and I forms and their structural analogues, such as tocotrienols; the corresponding derivatives, e.g., esters, produced with organic acids; and mixtures thereof. Preferred vitamin E substance solubilizers include tocopherols, tocotrienols and tocopherol derivatives with organic acids such as acetic acid, propionic acid, bile acid, lactic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, polyethylene glycol succinate and salicylic acid. Particularly preferred vitamin E substance solubilizers include alpha-tocopherol, alpha-tocopheryl acetate, alpha-tocopheryl acid succinate, alpha-tocopheryl polyethylene glycol 1000 succinate and mixtures thereof. Another group of solubilizers are monohydric alcohol esters of organic acids. The monohydric alcohol can be, for example, ethanol, isopropanol, t-butanol, a fatty alcohol, phenol, cresol, benzyl alcohol or a cycloalkyl alcohol. The organic acid can be, for example, acetic acid, propionic acid, butyric acid, a fatty acid of 6-22 carbon atoms, bile acid, lactic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid and salicylic acid. Preferred solubilizers in this group include trialkyl citrates, lower alcohol fatty acid esters and lactones. Preferred trialkyl citrates include triethyl citrate, acetyltriethyl citrate, tributyl citrate, acetyltributyl citrate and mixtures thereof with triethyl citrate being particularly preferred. Particularly preferred lower alcohol fatty acid esters include ethyl oleate, ethyl linoleate, ethyl caprylate, ethyl caprate, isopropyl myristate, isopropyl palmitate and mixtures thereof. Lactones may also serve as a solubilizer. Examples include, epsilon.-caprolactone, . delta. -valerolactone, .beta.-butyrolactone, isomers thereof and mixtures thereof.

The solubilizer may be a nitrogen-containing solvent. Preferred nitrogen- containing solvents include dimethylformamide, dimethylacetamide, N- alkylpyrrolidone, N-hydroxyalkylpyrroIidone, N-alkylpiperidone, N-alkylcaprolactam and mixtures thereof wherein alkyl is a C. sub.1-12 branched or straight chain alkyl. Particularly preferred nitrogen-containing solvents include N-methyl 2-pyrrolidone, N- ethyl 2-pyrrolidone or a mixture thereof. Alternatively, the nitrogen-containing solvent may be in the form of a polymer such as polyvinylpyrrolidone. Another group of solubilizers includes phospholipids. Preferred phospholipids include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lecithins, lysolecithins, lysophosphatidylcholine, polyethylene glycolated phospholipids/liysophospholipids, lecithins/lysolecithins and mixtures thereof.

Another group of solubilizers are glycerol acetates and acetylated glycerol fatty acid esters. Preferred glycerol acetates include acetin, diacetin, triacetin and mixtures thereof, with triacetin being particularly preferred. Preferred acetylated glycerol fatty acid esters include acetylated monoglycerides, acetylated diglycerides and mixtures thereof.

In addition, the solubilizer may be a glycerol fatty acid ester. The fatty acid component is about 6-22 carbon atoms. The glycerol fatty acid ester can be a monoglyceride, diglyceride, triglyceride or mixtures thereof. Preferred glycerol fatty acid esters include monoglycerides, diglycerides, and medium chain triglycerides with fatty acids having about 6-12 carbons and mixtures thereof. Particularly preferred glycerol fatty acid esters include medium chain monoglycerides with fatty acids having about 6-12 carbons, medium chain diglycerides with fatty acids having about 6-12 carbons and mixtures thereof. The solubilizer may be a propylene glycol ester. Preferred propylene glycol esters include propylene carbonate, propylene glycol monoacetate, propylene glycol diacetate, propylene glycol fatty acid esters, acetylated propylene glycol fatty acid esters and mixtures thereof. Alternatively, the propylene glycol fatty acid ester may be a propylene glycol fatty acid monoester, propylene glycol fatty acid diester or mixture thereof. The fatty acid has about 6-22 carbon atoms. It is particularly preferred that the propylene glycol ester is propylene glycol monocaprylate. Other preferred propylene glycol esters include propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol dicaprylate/dicaprate and mixtures thereof. Another group of solubilizers are ethylene glycol esters. Ethylene glycol esters include monoethylene glycol monoacetates, diethylene glycol esters, polyethylene glycol esters and mixtures thereof. Additional examples include ethylene glycol monoacetates, ethylene glycol diacetates, ethylene glycol fatty acid monoesters, ethylene glycol fatty acid diesters, and mixtures thereof. Alternatively, the ethylene glycol ester may be a polyethylene glycol fatty acid monoesters, polyethylene glycol fatty acid diesters or mixtures thereof. Again, the fatty acid component will contain about 6-22 carbon atoms.

Hydrophilic solvents, which may be used, include an alcohol, e.g. a water miscible alcohol, e.g. absolute ethanol, or glycerol. Other alcohols include glycols, e.g. any glycol obtainable from an oxide such as ethylene oxide, e.g. 1 ,2-propylene glycol. Other examples are polyols, e.g. a polyalkylene glycol, e.g. poly(C.sub.2- 3)alkylene glycol. A typical example is a polyethylene glycol. Alternatively the hydrophilic component may preferably comprise an N-alkylpyrolidone, e.g. N- (C.sub.1-14alkyl)pyrolidone, e.g. N-methylpyrolidone, tri(C.sub.1-4alkyl)citrate, e.g. triethylcitrate, dimethylisosorbide, (C.sub.5-C.sub.13)alkanoic acid, e.g. caprylic acid or propylene carbonate.

The hydrophilic solvent may comprise a main or sole component, e.g. an alcohol, e.g. C.sub.1-4-alcohol, e.g. ethanol, or alternatively a co-component, e.g. which may be selected from partial lower ethers or lower alkanols. A liquid composition for oral administration may contain pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir as well as generally used inactive diluent. Such composition may contain, in addition to the inactive diluent, adjuvants such as suspending agents, sweetening agents, flavoring agents, preservatives, solubilizer, anti-oxidants, stabilizer and the like. The details of the additives may be selected from those described in any general textbooks in the pharmaceutical field. Such liquid compositions may be directly enclosed in soft capsules. However, the selection of a diluent other than those mentioned above, which the bi-cyclic/mono-cyclic compound may be dissolved or admixed in, must carefully be selected so as not to affect the bi-cyclic/mono-cyclic ratio. The liquid formulation may also be formulation in such a way that the active agent is released in the lower gastrointestinal tract.

Further in accordance with the present invention the formulation releases the drug in the lower gastro intestinal tract. Those agents, which may delay the release of the active agent, can be used. The most preferred method is by coating. Preferred coating materials are those, which does not dissolves in stomach. The coatings therefore only begin to dissolve when they leave the stomach and enter the lower gastrointestinal tract. A thickness of the coating depends upon the time of delay. For example a thick layer of coating is provided which will dissolve in about 3-4 hours thereby allowing the core underneath to breakup only when it has reached the terminal ileum or the colon.

Delayed release formulation may comprise a core, and a coating. The core may include lubiprostone, and excipients, notably a lubricant, and a binder and/or filler, optionally glidants, optionally stabilizer as well as other excipients. The coating may be, for example, a semi-permeable coating to achieve delayed release of lubiprostone. The coating may comprise of a water-insoluble film-forming polymer, together with a plasticizer and a water-soluble polymer. The delayed release polymers such as cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, cellulose derivatives, such as ethylcellulose, a cellulose ester, cellulose acetate, polyvinylalcohol, sodium alginate, acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), ,polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, polymethacrylates, methyl acrylate-methacrylic acid copolymer, methacrylate- methacrylic acid-octyl acrylate copolymer, shellac etc. These may be used either alone or in combination, or together with other polymers than those mentioned above. The enteric coating may also include starch and/or dextrin. A suitable film- forming polymer is ethylcellulose (available from Dow Chemical under the trade name ETHOCEL). In one of the embodiments the coating material is methacrylic acid copolymers. The anionic EUDRAGIT® methacrylic acid copolymers can be used to avoid release of lubiprostone in the stomach and release in upper gastrointestinal tract. The EUDRAGIT® methacrylic acid copolymers of grades L, S and FS contain carboxylic groups and are thus anionic in character. Enteric coatings with these EUDRAGIT® grades release the active ingredient between pH 5.5 and >pH 7, allowing Gl targeting from the small intestine to the colon. The release of active ingredients also depends on the thickness of the film coatings and the solubility characteristics of the active ingredient under physiological conditions. The release of lubiprostone in the lower gastrointestinal tract can be achieved by using different grades of methacrylic acid copolymers. For example preferably, For release in the duodenum: EUDRAGIT® L 100-55 or the aqueous dispersion EUDRAGIT® L 30 D-55 dissolve at pH values above 5.5 is used. For release in the jejunum to ileum: EUDRAGIT® L dissolves at pH values above 6.0. Mixtures of EUDRAGIT® L and EUDRAGIT® S dissolve in a pH range from 6.0 to 7.0 is used. For Colonic delivery: EUDRAGIT® S and EUDRAGIT® FS 30 D dissolve at pH 7.0 is used.

All polymer types can be mixed with each other in different ratios to some extent, thus making it possible to achieve drug release at intermediate values.

The coating composition may include other excipients such as plasticizer, anti tacking agents etc.

Suitable plasticizers include, but are not limited to, triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. The coating can also contain other coating excipients such as detackifiers, antifoaming agents, lubricants (e.g., magnesium stearate), and stabilizers (e.g., hydroxypropylcellulose, acids and bases) to solubilize or disperse the coating material, and to improve coating performance and the coated product.

The pharmaceutical composition of the invention can be manufactured by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like. According to one of the embodiments the formulation of the present invention may be prepared by filling Iubiprostone and other excipients in capsule and then coating the capsule with delayed release coating. One or more coating may be applied. The capsule may be hard or softAdditional coatings to be employed in accordance with the invention may include, but are not limited to, for example, one or more immediate release coatings, protective coatings, enteric or delayed release coatings, sustained release coatings, barrier coatings, and combinations thereof.

A barrier coat may be included between the core and coat or between capsule and an outer coat, between outer coats, or on the outermost coat. The barrier coat may be comprised of an enteric or delayed release coat (as above) or a barrier (non-functional) layer, which serves as a protective coat and/or scavenger to prevent leaching from the shell (e.g., glycerol or water)

Pharmaceutical dosage forms of the invention can be coated by a wide variety of methods. Suitable methods include compression coating, coating in a fluidized bed, or a pan and hot melt (extrusion) coating or spray coating. Such methods are well known to those skilled in the art. The coating(s) may be applied, for example, as a solution, suspension, spray, dust or powder.

The present invention also involves a delayed release dosage form of Iubiprostone comprising (i) a core comprising Iubiprostone and pharmaceutically acceptable excipients (ii) and one or more delayed release coating.

The core includes but not limited to tablets, pellets, beads, granules, spheroids, capsules, microcapsules, tablets in capsules and microspheres, minitablets, powders, particles, matrix formulations, and microencapsules.

The pharmaceutical formulation of the present invention may further comprise of one or more coating.

Another embodiment of the present invention involves delayed release dosage form of Iubiprostone comprising minitablets or pellets or spheroids or particles or granules or tablet of Iubiprostone filled in hard or soft capsules. Another embodiment of the present invention involves delayed release dosage formed lubiprostone comprising lubiprostone and delayed release coating.

Any of the known methods such as but not limiting to dry granulation, wet granulation, spheronization, slugging, direct compression, may be used to prepare the formulation of the present invention. The most preferable method involves adsorbing lubiprostone dissolved in solvent on diluents most preferably on lactose to prepare minitablets or pellets or spheroids or particles or granules or tablet and which are further coated with delayed release coating so as to release lubiprostone in lower gastrointestinal tract.

Lubiprostone may also be dissolved in the solvent and used as granulating fluid.

The following examples are illustrative of the present invention, and the example should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure, and the accompanying claims.

Example 1 : Liquid filled Capsules (Hard gelatin or soft gelatin capsules)

Procedure 1) Dissolve Drug in the solubilizer, Vitamin E TPGS, PEG 400.

2) Filled in Hard Gelatin/soft gelatin capsule.

3) The hard/soft gelatin capsule may be coated with appropriate polymer to provide a delayed release coating. Example 2: Minitablets filled in Capsule

1 : Using different combination of eudragit would provide release in different regions of GIT for example mixture of Eudragit FS 30 D and Eudragit S combination would release in colon, Eudragit L100 and Eudragit S100 in Jejunum or ileum, and Eudragit L30D 55 would release in duodenum. Procedure:

1) Lubiprostone is dissolved in Ethanol and adsorbed with Lactose previously sifted followed by mixing with HPC/ PGS.

2) The above mix is blended with Aerosil 200 for 5.0 min.

3) The above step 2 is lubricated with Magnesium Stearate for 3-5 minutes.

4) The above blend is compressed using 3mm standard Concave punches/tooling. 5) The core tablets are seal coated using Opadry Clear, YS-1-7006 to 5% weight gain.

6) Seal coated mini tablets were enteric coated with suitable eudragit coating up to 20% weight gain. It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description as well as the examples that follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages, and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains. A person skilled in the art may make variations and modifications without deviating from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the invention.

Claims

Claimi: A delayed release pharmaceutical formulation comprising a therapeutically effective amount of Chloride channel activator or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), prodrug or metabolite or tautomer thereof and one or more delayed release polymer.

Claim 2: A delayed release pharmaceutical formulation according to claim 1 wherein chloride channel activator is lubiprostone or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), prodrug, tautomer or metabolite thereof.

Claim 3: A delayed release pharmaceutical formulation according to claim 1 wherein the delayed release polymer may be selected from cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, cellulose derivatives, such as ethylcellulose, a cellulose ester, polyvinyl alcohol, sodium alginate, acetate trimellitate, hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl butyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer or shellac.

Claim 4: A delayed release pharmaceutical formulation comprising a therapeutically effective amount of lubiprostone or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), prodrug, tautomer or metabolite thereof and one or more delayed release polymer.

Claim 5: A delayed release pharmaceutical formulation according to claim 4 wherein the delayed release polymer may be selected from cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, cellulose derivatives, such as ethylcellulose, a cellulose ester, polyvinylalcohol, sodium alginate, acetate trimellitate, hydroxypropylmethyl cellulose phthalate (HPMCP),, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer or shellac.

Claim 6: A delayed release pharmaceutical formulation of lubiprostone comprising (i) a core comprising therapeutically effective amount of lubiprostone or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), prodrug, tautomer or metabolite thereof and (ii) one or more delayed release coating.

Claim 7: A delayed release pharmaceutical formulation of lubiprostone according to claim 6 wherein the the core may be tablets, pellets, beads, granules, spheroids, microcapsules, and microspheres, minitablets, powders particles, matrix formulations, and microencapsules.

Claim 8: A delayed release pharmaceutical formulation of lubiprostone according to claim 6 wherein delayed release pharmaceutical formulation of lubiprostone comprising (i) a core comprising therapeutically effective amount of lubiprostone or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), prodrug, tautomer or metabolite thereof and (ii) one or more delayed release coating, may optionally filled in capsule.

Claim 9: A delayed release pharmaceutical formulation according to claim 6 wherein the delayed release coating comprise of delayed release polymer selected from cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, cellulose ether, such as ethylcellulose, a cellulose derivatives, polyvinylalcohol, sodium alginate, acetate trimellitate, hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer or shellac.

Claim 10: A delayed release pharmaceutical formulation of lubiprostone comprising (1) a capsule comprising lubiprostone or a pharmaceutically acceptable salt(s), polymorph(s), solvate(s), hydrate(s), prodrug, tautomer or metabolite thereof and one or more pharmaceutically acceptable excipients and (2) one or more delayed release coating.

Claim 11: A delayed release pharmaceutical formulation of lubiprostone according to claim 10 I where in capsule may be soft or hard capsule.

Claim 12: A delayed release pharmaceutical formulation according to claim 10 wherein the delayed release coating comprise of delayed release polymer selected from cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetate phthalate, cellulose derivatives, such as ethylcellulose, a cellulose ester, polyvinylalcohol, sodium alginate, acetate trimellitate, hydroxypropylmethyl cellulose phthalate (HPMCP),, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer or shellac.