Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/47—Euphorbiaceae (Spurge family), e.g. Ricinus (castorbean)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
  • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5015—Organic compounds, e.g. fats, sugars
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof

Definitions

• the present patent application relates to a non-enteric pharmaceutical composition comprising crofelemer.
• the present patent application relates to an acid-stable, immediate release, non-enteric pharmaceutical composition for oral administration comprising crofelemer and a pharmaceutically acceptable excipient; a process for preparing such composition; and its use in treating secretory diarrhea in a subject.
• Crofelemer (CAS No. 148465-45-6) is a purified proanthocyanidin polymer of varying chain lengths derived from the Dragon's Blood of Croton lecheri of the family Euphorbiaceae. Crofelemer has an average molecular weight ranging from about 1900 to about 2700 Dalton. Crofelemer comprises the monomers such as catechin, epicatechin, gallocatechin and epigallocatechin. The chain length of crofelemer ranges from about 3 to about 30 units with an average chain length of about 8 units linked together through common C (4) - 8) bonds as depicted in Formula 1.
• crofelemer composition is labile in the acidic environment (having pH about 1 to about 3) of stomach and is stable at pH 5 to 8. Accordingly, the crofelemer composition was designed to protect it from acidity and enzymatic action of gastric secretions in stomach by way of providing an enteric coating around the crofelemer composition. Such enteric coated crofelemer composition is believed to exhibit delayed onset of action in treating secretory diarrhea.
• the present invention relates to an acid-stable, immediate release, non-enteric pharmaceutical composition for oral administration comprising crofelemer and a pharmaceutically acceptable excipient.
• an acid-stable, non-enteric pharmaceutical composition comprising crofelemer, that releases the crofelemer in acidic conditions of stomach would be useful for treating secretory diarrhea in a subject in need thereof.
• Such acid-stable, immediate release, non-enteric pharmaceutical composition is intended to release a substantial portion of the contained crofelemer in stomach, and hence such compositions of the present invention may exhibit rapid onset of action, which is highly desirable in treating secretory diarrhea.
• the present invention relates to an acid-stable, non- enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient.
• the present invention relates to a non-enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer, wherein the crofelemer contained in said composition undergoes not more than 10% w/w degradation when incubated in 0.1 N hydrochloric acid (pH 1.2) at about 37 °C for about 2 hours.
• the crofelemer contained in said composition undergoes not more than 5% w/w degradation when incubated at the above said conditions.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of the contained crofelemer when tested in United States Pharmacopoeia (USP) type II dissolution apparatus containing about 1000 ml of 0.1 N hydrochloric acid (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• USP United States Pharmacopoeia
• such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.
• the immediate release, non-enteric pharmaceutical composition comprises from about 5 % w/w to about 70 % w/w, preferably from about 10% w/w to about 60% w/w of crofelemer.
• the composition of the present invention comprises from about 10 mg to about 750 mg of crofelemer.
• the said composition comprises from about 10 mg to about 500 mg of or from about 10 mg to about 300 mg of crofelemer.
• the dose may be administered orally per day, in single dose or in divided doses to a subject in need thereof.
• the amount of crofelemer to be administered as a unit dose in the said composition is about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg or about 125 mg or about 250 mg.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising a unit dose of about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg or about 125 mg or about 250 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N hydrochloric acid (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.
• the immediate release, non-enteric pharmaceutical composition for oral administration can be in the form of tablet, capsule, or granules/pellets. Said composition can be administered orally as such or upon reconstitution with a solvent.
• an immediate release, non-enteric pharmaceutical composition as described in the present invention may be in the form of a dispersible tablet having a dispersion time of less than about 5 minutes in 0.1 N hydrochloric acid (pH 1.2) More preferably, it may be in the form of a dispersible tablet having a dispersion time of less than about 2 minutes in 0.1 N hydrochloric acid (pH 1.2).
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration in the form of a tablet, capsule, dispersion or powder comprising from about 10 mg to about 250 mg of crofelemer and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of the contained crofelemer when tested in United States Pharmacopoeia type II dissolution apparatus containing about 1000 ml of 0.1 N hydrochloric acid (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising a unit dose of about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg or about 125 mg or about 250 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 70% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of water stirred at about 75 to 100 rpm at a temperature about 37+0.5 °C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non-enteric, low-dose pharmaceutical composition for oral administration comprising a unit dose of about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N hydrochloric acid (pH 1.2) or stirred at about 75 to 100 rpm at a temperature about 37+0.5 °C within about 60 minutes from the start of the test.
• such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.
• the present invention relates to an immediate release, non-enteric, low-dose pharmaceutical composition for oral administration comprising a unit dose of about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N hydrochloric acid (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test, and wherein the composition exhibits crofelemer content uniformity in the range of about 85 % to about 115% of the label claim.
• the pharmaceutical composition of the present invention can be administered orally once or two/three/four times a day to the subject.
• the present invention relates to an immediate release, non- enteric, taste masked pharmaceutical composition for oral administration comprising a unit dose of about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg or about 125 mg or about 250 mg of crofelemer, and a taste masking agent, wherein said composition releases at least about 70% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of water stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non- enteric pharmaceutical composition for oral administration comprising crofelemer and a pharmaceutically acceptable excipient, wherein the crofelemer is at least partially coated by a taste masking agent.
• said coating is not an enteric coating.
• the taste masking agent comprises non- enteric excipients such as hydroxypropylmethylcellulose (HPMC), ethyl cellulose, an aminoalkyl methacrylate copolymer, poly (butylmethacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate), stearic acid, or mixtures thereof.
• HPMC hydroxypropylmethylcellulose
• ethyl cellulose an aminoalkyl methacrylate copolymer
• stearic acid or mixtures thereof.
• the present invention relates to an immediate release, non- enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer which is at least partially coated by a taste masking agent, and a pharmaceutically acceptable excipient wherein the weight ratio of the crofelemer to the taste masking agent ranges from about 1:0.01 to about 1:10.
• the present invention relates to a non-enteric, taste masked pellets for oral administration comprising about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg or about 125 mg or about 250 mg of crofelemer, a taste masking agent, wherein the taste masking agent comprises non- enteric excipients such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, an aminoalkyl methacrylate copolymer, poly(butylmethacrylate-co-(2- dimethylaminoethyl)methacrylate-co-methyl methacrylate), stearic acid, palmitic acid, lauric acid, and myristic acid or mixtures thereof.
• non-enteric excipients such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, an aminoalkyl methacrylate copolymer, poly(butylmethacrylate-co-(2- dimethyl
• the present invention relates to taste masked pellets, wherein the weight ratio of the crofelemer to the taste masking agent ranges from about 1:0.01 to about 1:10.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration in the form of a tablet, capsule, dispersion or powder comprising the taste masked pellets.
• the present invention relates to an acid-stable, non- enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient.
• the present invention relates to an acid stable, non- enteric pharmaceutical composition wherein said composition releases at least about 40% of the contained crofelemer when tested in United States Pharmacopoeia type II dissolution apparatus containing about 1000 ml of an aqueous medium stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration in the form of a tablet, capsule, dispersion or powder comprising about 10 mg to about 250 mg of crofelemer and a pharmaceutically acceptable excipient, wherein said composition releases at least about 50% of the contained crofelemer when tested in United States Pharmacopoeia type II dissolution apparatus containing about 1000 ml of an aqueous medium stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non-enteric dry powder for oral administration, comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient and optionally a taste masking agent.
• the present invention relates to an immediate release, non- enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient for the treatment of secretory diarrhea in a subject in need thereof.
• the present invention relates to a method of treating secretory diarrhea in a subject in need thereof, said method comprising administering to the subject the pharmaceutical composition of the present invention.
• the present invention relates to use of a crofelemer in the preparation of an immediate release, non-enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient for the treatment of secretory diarrhea in a subject in need thereof.
• the present invention relates to a process for preparation of an immediate release, non-enteric pharmaceutical composition for oral administration comprising crofelemer and a pharmaceutically acceptable excipient, said process comprising admixing crofelemer with one or more pharmaceutically acceptable excipient.
• the process may optionally comprise the step of taste masking by coating or addition of a taste masking agent.
• the present invention relates to an acid-stable, immediate release, non-enteric pharmaceutical composition for oral administration comprising crofelemer and a pharmaceutically acceptable excipient.
• active ingredient (used interchangeably with “active” or “active substance” or “active pharmaceutical ingredient” or “drug”) used herein includes crofelemer.
• compositions that show sufficient stability in the acid medium or has minimal degradation in acidic environment.
• aqueous medium used herein includes purified water, an acidic medium having pH of about 1-3, or 0.1 N hydrochloric acid (pH 1.2).
• the aqueous medium is 0.1 N HC1.
• Crofelemer used herein comprises two or more monomer units that may be of the same or different monomeric structure.
• the monomer units (generally termed "leucoanthocyanidin") are generally monomeric flavonoids which include catechins, epicatechins, gallocatechins, galloepicatechins, flavanols, flavonols, and flavan-3,4- diols, leucocyanidins and anthocyanidins.
• Forced degradation studies generally involve the exposure of active pharmaceutical ingredient (API) or product comprising API to the relevant stress conditions such as acid/base degradation, oxidative degradation, photostability, and thermal stability. These studies are generally performed by exposing the API or the product comprising API to the stress condition specified above and measuring the reduction in assay and/or increase impurities using suitable analytical techniques known to a person skilled in the art such as for example high performance liquid chromatography (HPLC).
• HPLC high performance liquid chromatography
• an acid-stable, immediate release, non-enteric pharmaceutical composition comprising crofelemer that releases the crofelemer in acidic conditions of stomach, as invented by the inventors of the present invention, would be useful for treating secretory diarrhea in a subject in need thereof.
• the present invention relates to an acid- stable, non-enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient.
• the acid- stable, immediate release, non-enteric pharmaceutical composition of the present invention is intended to release a substantial portion of the contained crofelemer at the acidic condition of stomach (e.g., at pH 1 to 3).
• the present invention relates to a non-enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer, wherein the crofelemer contained in said composition undergoes not more than 10 % w/w degradation when incubated in 0.1 N hydrochloric acid (pH 1.2) at about 37 °C for about 2 hours.
• the crofelemer contained in said composition undergoes not more than 5 % w/w degradation when incubated at the above said conditions.
• the present invention relates to an immediate release, non- enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of the contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of an 0.1N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.
• an immediate release, non-enteric pharmaceutical composition comprises from about 5% w/w to about 70% w/w, preferably from about 10% w/w to about 60% w/w of crofelemer.
• the composition of the present invention comprises from about 10 mg to about 750 mg of crofelemer.
• said composition comprises from about 10 mg to about 500 mg of crofelemer or from about 10 mg to about 300 mg of crofelemer.
• the discrete, doses of crofelemer to be administered per day are 10 mg or 12.5 mg or 25 mg or 50 mg or 100 mg or 125 mg or 250 mg or 500 mg or 750 mg.
• the dose may be administered orally per day, in single dose or in divided doses to a subject in need thereof.
• the amount of crofelemer to be administered as a unit dose in the said composition is about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg or about 125 mg or about 250 mg.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising about 10 mg or 12.5 mg or 25 mg or 50 mg or 100 mg or 125 mg or 250 mg of crofelemer and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of the contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising a unit dose of about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg or about 125 mg or about 250 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature at about 37+0.5°C within about 60 minutes from the start of the test.
• such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising a unit dose of about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg or about 125 mg or about 250 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 70% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of water stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non-enteric, low-dose pharmaceutical composition for oral administration comprising a unit dose of about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.
• the present invention relates to an immediate release, non-enteric, low-dose pharmaceutical composition for oral administration comprising a unit dose of about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N hydrochloric acid (pH 1.2) stirred at about 75 to 100 rpm at a temperature 37+0.5 °C within about 60 minutes from the start of the test, and wherein the composition exhibits crofelemer content uniformity in the range of about 85 % to about 115% of the label claim.
• the pharmaceutical composition of the present invention can be administered orally once or two/three/four times a day to the subject.
• the immediate release, non-enteric pharmaceutical composition as described herein, can be in the form of tablet, capsule, dispersion, powder, or particles/ granules/beads/pellets/agglomerates. Said composition can be administered orally as such or upon reconstitution with a solvent.
• the immediate release, non-enteric pharmaceutical composition which is in the form of dry powder, particles, granules, beads or pellets, as described above, may display a bulk density ranging of from about 0.25 g/ml to about 0.76g/ml.
• the bulk density may range from about 0.38 g/ml to about 0.75 g/ml or from about 0.430 g/mL to about 0.51 g/ml.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration in the form of powder, particles, granules, beads or pellets having a bulk density ranging from about 0.25 g/mL to about 0.76 /mL, or from about 0.38 g/ml to about 0.75 g/ml, or from about 0.43 g/ml to about 0.51 g/ml, wherein said composition releases at least about 40% of the contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5 °C within about 60 minutes from the start of the test.
• USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5 °C within about 60 minutes from the start of the test.
• the immediate release, non-enteric pharmaceutical composition as described above may have a compressibility index ranging from about 5% to about 30%, and preferably from about 10% to about 25%.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration in the form of powder, particles, granules, beads or pellets having a compressibility index ranging from about 5% to about 30%, or from about 10% to about 25%, wherein said composition releases at least about 40% of the contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the bulk density and compressibility index measurements may be followed according to methods well known in the art. In the present context the process for calculation followed is according to US Pharmacopoeia.
• dosage form of the present invention is suitable for administration to pediatric or geriatric subjects, such as dispersible tablet, or dry powder for reconstitution.
• the tablet as mentioned herein includes but is not limited to conventional acid-stable, non-enteric (IR) tablet, coated IR tablet, multiple compressed tablet, layer tablet, inlay tablet, effervescent tablet, dispersible tablet, flash tablet, melt in mouth tablet, mouth dissolving tablet, chewable tablet, soluble tablet, buccal tablet or sublingual tablet.
• IR non-enteric
• an immediate release, non-enteric pharmaceutical composition as described in the present invention may be in the form of a dispersible tablet having a dispersion time of less than about 5 minutes in 0.1 N HC1 (pH 1.2) or water (pH 5.0 to 6.5). More preferably, it may be in the form of a dispersible tablet having a dispersion time of less than about 2 minute in 0.1 N HC1 (pH 1.2) or (pH 5.0 to 6.5).
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration in the form of a tablet, capsule, dispersion or powder comprising from about 10 mg to about 250 mg of crofelemer and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of the contained crofelemer when tested in United States Pharmacopoeia type II dissolution apparatus containing 1000 ml of 0.1N HC1 (pH 1.2) or stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.
• the amount of crofelemer is present in amount of about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg or about 125 mg or about 250 mg.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising about 10 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising about 12.5 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising about 25 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising about 50 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising about 100 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) or water (pH 5.0 to 6.5 stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) or water (pH 5.0 to 6.5 stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising about 125 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising about 250 mg of crofelemer, and a pharmaceutically acceptable excipient, wherein said composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the inventors of the present invention have also found that the crofelemer is orally non-palatable because of its highly unpleasant astringent taste (like tannins).
• the taste masking agent may be admixed (i.e., intimately mixed) with the crofelemer, or it can be, at least in part, coated onto the crofelemer in order to mask the highly unpleasant astringent taste of crofelemer.
• the present invention relates to an comprising a unit dose of about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg or about 125 mg or about 250 mg of crofelemer, and a taste masking agent, wherein said composition releases at least about 70% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of water stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non- enteric pharmaceutical composition for oral administration comprising crofelemer and a pharmaceutically acceptable excipient, wherein the contained crofelemer is at least partially coated by a taste masking agent.
• the said coating is not an enteric coating.
• the taste masking agent comprises non- enteric excipients such as hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, an aminoalkyl methacrylate copolymer, poly (butylmethacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate), stearic acid, or mixtures thereof.
• HPMC hydroxypropylmethyl cellulose
• ethyl cellulose an aminoalkyl methacrylate copolymer
• stearic acid or mixtures thereof.
• the present invention relates to an immediate release, non-enteric, taste masked pharmaceutical composition for oral administration comprising crofelemer which is at least partially coated by a taste masking agent and a pharmaceutically acceptable excipient wherein the composition releases at least about 40% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.
• the present invention relates to an immediate release, non-enteric, taste masked pharmaceutical composition for oral administration comprising crofelemer which is at least partially coated by a taste masking agent, provided the coating is not an enteric coating, and a pharmaceutically acceptable excipient, wherein the composition releases at least about 50% of contained crofelemer when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non- enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer which is at least partially coated by a taste masking agent, and a pharmaceutically acceptable excipient wherein the weight ratio of the crofelemer to the taste masking agent ranges from about 1:0.01 to about 1:10.
• the weight ratio of crofelemer to the coating agent ranges from about 1:0.03 to about 1:8.
• the present invention relates to an acid stable, immediate release, non-enteric, dry powder for oral administration, comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient and optionally a taste masking agent.
• the present invention relates to an immediate release, non- enteric, taste masked pharmaceutical composition for oral administration, wherein said composition is in the form of a dispersible tablet or dry syrup that contains a palatable agent.
• palatable agent refers to agent which modifies sensory perceptions including taste and smell, and to an extent texture.
• Palatable agents of present invention can include flavors, sweeteners or combinations thereof.
• taste masking agent used herein means the agent which is used to reduce an unpleasant taste of active pharmaceutical ingredient for improving patient compliance. Techniques for taste masking are well known to the person skilled in the art.
• the taste masking agent includes non- enteric excipients such as hydroxypropylmethyl cellulose (HPMC, also called Hypromellose); hydroxypropyl cellulose (HPC); ethyl cellulose; an aminoalkyl methacrylate copolymer such as poly (methacrylic acid-co-ethylacrylate) 1:1 (Eudragit® L30D-55) or poly (butylmethacrylate-co-(2- dimethylaminoethyl)methacrylate-co-methyl methacrylate) 1:2:1 (Eudragit® EPO); stearic acid; palmitic acid; lauric acid; myristic acid, spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, castor wax, paraffin wax, microcrystalline wax, petrolatum wax, carbow
• the immediate release, non-enteric pharmaceutical composition of the present invention may further include pharmaceutically acceptable excipients such as one or more sweeteners, flavoring agents, additional taste modifiers, suspending agents, binders, lubricants, glidant, preservatives and other conventional excipients as needed.
• pharmaceutically acceptable excipients can be used in suitable amounts as known to a person skilled in the art of formulation.
• sweeteners include, but are not limited to, any compatible sweetener groups such as, but are not limited to, natural sweeteners like sucrose, fructose, dextrose, xylitol, sorbitol, or mannitol, as well as artificial sweeteners such as aspartame, saccharine, acesulfame K, sucrolose, sodium saccharine and aspartame are preferred sweeteners.
• natural sweeteners like sucrose, fructose, dextrose, xylitol, sorbitol, or mannitol
• artificial sweeteners such as aspartame, saccharine, acesulfame K, sucrolose, sodium saccharine and aspartame are preferred sweeteners.
• flavoring agent examples include, but are not limited to, orange flavor, vanilla flavor, licorice flavor, orange vanilla flavor, creme de mint, cherry flavor, cherry vanilla flavor, berry mix flavor, passion fruit flavor, mandarin orange flavor, bubble gum flavor, tropical punch flavor, juicy compound for grape, grape flavor, artificial grape flavor, strawberry, grape bubble gum flavor, and tutti-frutti-flavor, and combinations thereof, with artificial grape flavor or tutti-frutti flavor being preferred.
• Glidants can also optionally be used.
• the preferred glidant employed for this formulation is silicon dioxide although other suitable glidants include talc.
• Lubricants include magnesium stearate and colloidal silicon dioxide.
• suspending agents include, but are not limited to, xanthan gum, guar gum, HPMC, HPC, polyvinyl pyrrolidone, alginates, and sodium carboxylmethylcellulose with sodium carboxylmethylcellulose (Na CMC) being preferred.
• Suspending agents may be employed in an amount within the range from about 0.1% to about 20% by weight of the powder formulation, and from about 0% to about 10% by weight of the oral suspension.
• preservatives can be selected from the group consisting of any compound compatible with drug actives such as, but are limited to, methylparaben and propylparaben, benzoic acid, sodium benzoate, potassium sorbate.
• the present invention relates to an immediate release, non- enteric pharmaceutical composition for oral administration comprising therapeutically effective amount of crofelemer, lactose, ethyl cellulose, and hydroxypropylmethyl cellulose, wherein said composition releases at least about 40% of contained crofelemer, or at least about 50% of contained crofelemer, or at least about 60% of contained crofelemer, when tested in USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• USP type II dissolution apparatus containing about 1000 ml of 0.1 N HC1 (pH 1.2) stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention also relates to crofelemer which has an assay value of at least 95 % when incubated at a pH of 1 to 3 for about 2 hours.
• the present invention relates to a non-enteric, taste masked pellets for oral administration comprising about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg or about 125 mg or about 250 mg of crofelemer, a taste masking agent, wherein the taste masking agent comprises non- enteric excipients such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, an aminoalkyl methacrylate copolymer, poly(butylmethacrylate-co-(2- dimethylaminoethyl)methacrylate-co-methyl methacrylate), stearic acid, palmitic acid, lauric acid, and myristic acid or mixtures thereof.
• non-enteric excipients such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, an aminoalkyl methacrylate copolymer, poly(butylmethacrylate-co-(2- dimethyl
• the present invention relates to taste masked pellets, wherein the weight ratio of the crofelemer to the taste masking agent ranges from about 1:0.01 to about 1:10.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration in the form of a tablet, capsule, dispersion or powder comprising the taste masked pellets.
• the present invention relates to an acid-stable, non- enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient.
• the present invention relates to an acid stable, non- enteric pharmaceutical composition wherein said composition releases at least about 40% of the contained crofelemer when tested in United States Pharmacopoeia type II dissolution apparatus containing about 1000 ml of an aqueous medium stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration in the form of a tablet, capsule, dispersion or powder comprising about 10 mg to about 250 mg of crofelemer and a pharmaceutically acceptable excipient, wherein said composition releases at least about 50% of the contained crofelemer when tested in United States Pharmacopoeia type II dissolution apparatus containing about 1000 ml of an aqueous medium stirred at about 75 to 100 rpm at a temperature about 37+0.5°C within about 60 minutes from the start of the test.
• the present invention relates to an acid-stable, non- enteric dry powder for oral administration, comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient and optionally a taste masking agent.
• the present invention relates to an immediate release, non- enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient for the treatment of secretory diarrhea in a subject in need thereof.
• treating also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of secretory diarrhea symptoms of intestine which includes increased electrolyte and water fluxes into the intestine lumen in a subject.
• subject refers any mammal including humans and non human animals.
• the subject is a human.
• Such human may be an infant, a child, an adult or an elderly human.
• Secretory diarrhea as described herein includes a diarrhea of non-infectious etiology (i.e., non-infectious diarrhea) or a diarrhea that is caused by a bacterial, protozoal or viral infection (i.e., infectious diarrhea).
• the diarrhea of non-infectious etiology includes non-specific diarrhea, ulcerative colitis, and irritable bowel syndrome.
• the infectious diarrhea includes adult acute infectious diarrhea, HIV/AIDS-related diarrhea and pediatric diarrhea.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration in the form of a tablet, capsule, dispersion or powder comprising from about 10 mg to about 250 mg of crofelemer and a pharmaceutically acceptable excipient for the treatment of secretory diarrhea in a subject in need thereof.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising a unit dose of about 10 mg or about 12.5 mg or about 25 mg or about 50 mg or about 100 mg or about 125 mg or about 125 mg or 250 mg crofelemer, and a pharmaceutically acceptable excipient for the treatment of secretory diarrhea in a subject in need thereof.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising crofelemer which is at least partially coated by a taste masking agent and a pharmaceutically acceptable excipient for the treatment of secretory diarrhea in a subject in need thereof.
• the present invention relates to an immediate release, non-enteric pharmaceutical composition for oral administration comprising crofelemer which is at least partially coated by a taste masking agent, provided the coating is not an enteric coating, and a pharmaceutically acceptable excipient for the treatment of secretory diarrhea in a subject in need thereof.
• the present invention relates to a method of treating secretory diarrhea in a subject in need thereof, said method comprising administering to the subject the pharmaceutical composition of the present invention.
• the pharmaceutical composition of the present invention can be administered orally once or two/three/four times a day to the subject.
• the present invention relates to use of a crofelemer in the preparation of an immediate release, non-enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient for the treatment of secretory diarrhea in a subject in need thereof.
• the present invention relates to a process for preparation of an immediate release, non-enteric pharmaceutical composition for oral administration comprising crofelemer and a pharmaceutically acceptable excipient, said process comprising admixing crofelemer with one or more pharmaceutically acceptable excipient.
• the process may optionally comprise the step of taste masking by coating or addition of a taste masking agent.
• the present invention further relates to a method of preparation of an immediate release, non-enteric pharmaceutical composition for oral administration, the method comprising: (a) mixing the crofelemer with one or more pharmaceutically acceptable excipient, and optionally (b) coating the mixture of step (a), and (c) formulating said mixture of step (b) to obtain a powder composition.
• the present invention further relates to a method of preparation of an immediate release, non-enteric pharmaceutical composition for oral administration, the method comprising: (a) mixing the crofelemer with one or more pharmaceutically acceptable excipient, and optionally (b) adding a taste masking agent to step (a), and (c) formulating said mixture of step (b) to obtain a powder composition.
• the powder composition may be further processed to yield a tablet or capsule dosage form using known methods of formulation. Alternately, the powder composition may be processed to obtain a formulation meant for reconstitution with a suitable solvent.
• EXAMPLE 1 Forced degradation of crofelemer in acidic and alkaline conditions. Acid degradation:
• Crofelemer 50 mg was added to a 5 ml of diluent and sonicated for 20 minutes.
• step 2 2) 2 ml of 2M HC1 (pH 0.4) was added to Crofelemer dispersion of step 1 under stirring.
• step 2 The mixture of step 2 was heated up to about 70°C for about 2 hours.
• step 3 The mixture of step 3 was cooled and neutralized with addition of 2 ml of 2M
• Crofelemer was calculated as reduction in assay by HPLC method.
• Crofelemer 50 mg was added to a 5 ml of diluent* and sonicated for 20 minutes.
• step 2 The mixture of step 2 was heated up to about 70°C for about 2 hours.
• step 3 The mixture of step 3 was cooled and neutralized with addition of 2 ml of 2M HCl and further diluted to 10 ml with diluent.
• Solvent A 0.1% Trifluoroacetic acid buffer in water: Methanol (96:04,v/v)
• Solvent B Acetonitrile: Methanol (50:50 v/v)]
• EXAMPLE 2 Incubation studies of crofelemer at pH 1.2.
• Crofelemer (about 50 mg each) was added to a 10 ml of 0.1 N HCl (pH 1.2), and incubated under stirring at about 37 °C for about 2 hours.
• Crofelemer (#60/80) 32.890
• Hypromellose (Methocel E 5) 0.684
• Lactose monohydrate 3.731 Ingredients Composition (%w/w)
• Crofelemer (Sieve size #60/80) were coated with the dispersion of step 3 using fluid bed processor (Glatt GPCG 1.1) by wurster coating.
• the granules had a bulk density of 0.748g/ml and a compressibility index of 5.91%.
• Microcrystalline cellulose "MCC” (Avicel PH 101), Colloidal silicon dioxide, lactose monohydrate and croscarmellose sodium was sifted twice through 60 # sieve.
• step 6 These sifted materials of step 6 were loaded in fluid bed processor (Glatt GPCG 1.1) and granulated with warm water using and dried.
• the granules had a bulk density of 0.376 g/ml and a compressibility index of 20.33%.
• Crofelemer taste masked granules of step 5 and base granules of step 7 were sifted through 40 # sieve, individually.
• Croscarmellose sodium, Colloidal silicon dioxide, tutti frutti flavor and sodium saccharin were also sifted through 40 # sieve. All the ingredients were mixed thoroughly and further lubricated using magnesium stearate by blending in an octagonal blender for 10 minutes at 15 rpm speed for 2 minutes. The blend displayed a bulk density of 0.506 g/ml and a compressibility index of 23.90%.
• the lubricated blend of step 8 was compressed into tablets using suitable punches. The average tablet weight was 152.0 mg.
• the average dispersion time for the above tablet composition was in the range of about 15 seconds to about 20 seconds.
• Base Granules contain MCC (10% w/w), Colloidal silicon dioxide (3% w/w), Lactose monohydrate (83% w/w) and Croscarmellose sodium (4% w/w) Manufacturing Process:
• Crofelemer, MCC (Avicel PH 101), Croscarmellose Sodium , Colloidal silicon dioxide & Lactose monohydrate were sifted through Sieve #80, and mixed in a blender for 10 minutes at 8 rpm.
• HPMC (5 cps) was dissolved in a mixture of isopropyl alcohol and purified water under stirring to obtain a clear solution. The solution was filtered through ASTM #100 nylon cloth.
• step 1 was granulated with the solution of step 2 and the granules thus obtained were dried to Loss on drying (LOD) not more than 7.5% w/w.
• LOD Loss on drying
• HPMC (5 cps) was dispersed under stirring in isopropyl alcohol and the
• step 3 Crofelemer granules of step 3 were coated with the above solution of step 6 using fluid bed processor (Glatt GPCG 1.1) by wurster coating and the granules obtained were dried to a LOD of not more than 7.5 % w/w.
• the granules had a bulk density of 0.503 g/ml and a compressibility index of 29.83 %.
• MCC (Avicel PH 101) (10% w/w), Colloidal silicon dioxide (3% w/w), Lactose monohydrate (83% w/w) and Croscarmellose (4% w/w) were twice sifted through ASTM sieve #60 and granulated in a fluid bed processor (Glatt GPCG 1.1) with warm water.
• Crofelemer taste masked granules of step 7 and base granules of step 8 were sifted through ASTM sieve #40, individually. Croscarmellose sodium, Colloidal silicon dioxide, tutti frutti flavor and sodium saccharin were also sifted through ASTM sieve #40, individually. Croscarmellose sodium, Colloidal silicon dioxide, tutti frutti flavor and sodium saccharin were also sifted through ASTM sieve #40, individually. Croscarmellose sodium, Colloidal silicon dioxide, tutti frutti flavor and sodium saccharin were also sifted through
• Magnesium stearate was passed through ASTM sieve #40 and blended with the blend of step 10 in an octagonal blender for 2 minutes at 8 rpm.
• the lubricated blend exhibited a bulk density of 0.507 g/ml and a compressibility index of 22.12 %.
• the average tablet weight was 85.0 mg.
• the average dispersion time for the above tablet composition was in the range of about 25 seconds to about 30 seconds.
• the tablets displayed an average drug content uniformity of 97.93 % (determined using 10 tablets).
• EXAMPLE 5 Crofelemer Tablet (Dispersible) 12.5 mg.
• Base Granules contain MCC (10% w/w), Colloidal silicon dioxide (3% w/w), Lactose monohydrate (83% w/w) and Croscarmellose sodium (4% w/w) Manufacturing Process:
• Crofelemer, MCC (Avicel PH 101), Croscarmellose Sodium , Colloidal silicon dioxide & Lactose monohydrate were sifted through Sieve #80, and mixed in a blender for 10 minutes at 8 rpm.
• HPMC (15 cps) was dissolved in a mixture of isopropyl alcohol and water under stirring to obtain a clear solution. The solution was filtered through ASTM #100 nylon cloth.
• step 3 The blend of step 1 was granulated with the solution of step 2 using Top spray.
• the granules thus obtained were dried to LOD not more than 7.5% w/w.
• the granules exhibited a bulk density of 0.430 g/ml and a compressibility index of 10.01 %.
• step 3 Crofelemer granules of step 3 were coated with the above solution of step 6 using fluid bed processor (Glatt GPCG 1.1) by wurster coating. The granules were then dried to a Loss on Drying of not more than 7.5 % w/w. The granules so formed had a bulk density of 0.503 g/ml and a compressibility index of 29.83%.
• MCC (Avicel PH 101) (10% w/w), Colloidal silicon dioxide (3% w/w), Lactose monohydrate (83% w/w) and Croscarmellose (4% w/w) were twice sifted through ASTM sieve #60 and granulated in a fluid bed processor (Glatt GPCG 1.1) with warm water.
• Crofelemer taste masked granules of step 7 and base granules of step 8 were sifted through ASTM sieve #40 individually. Croscarmellose sodium, Colloidal silicon dioxide, tutti frutti flavor and sodium saccharin were also sifted through 40 # sieve.
• Magnesium stearate was passed through ASTM sieve #40 and blended with the blend of step 10 in an octagonal blender for 2 minutes at 8 rpm.
• the lubricated blend displayed a bulk density of 0.490 g/ml and a compressibility index of 18.06 %.
• step 12 The lubricated blend of step 11 was compressed into tablets using suitable punches.
• the average tablet weight was 42.50 mg.
• the average dispersion time for the above tablet composition was in the range of about 15 seconds to about 20 seconds.
• the tablets displayed an average drug content uniformity of 97.50 % (determined using 10 tablets).
• EXAMPLE 6A Preparation of Crofelemer loaded pellets (Drug Loading Phase)
• step 3 Crofelemer was added under stirring to the dispersion of step 1 to form clear solution.
• the solution was filtered through 100 # nylon cloth.
• step 3 The solution of step 3 was loaded onto the sugar spheres using Fluid Bed
• Opadry was dispersed in the mixture of methylene chloride and isopropyl alcohol under stirring. The dispersion was filtered through 100 # nylon cloth.
• step 2 The dispersion of step 1 was loaded onto the Crofelemer drug loaded pellets of Example 6 A using fluid bed processor (Glatt GPCG 1.1).
• step 3 The dispersion of step 1 was loaded onto the Crofelemer drug loaded pellets of Example 6 A using fluid bed processor (Glatt GPCG 1.1).
• step 7 Taste masking of Crofelemer pellets
• Eudragit L30 D55 was taken in a container, and Sodium hydroxide solution in water was added drop wise to Eudragit L30 D55.
• step 3 Solutions from step 1 and step 2 were mixed under stirring for 45 minutes.
• step 4 Purified water was added to solution of step 3 and was further filtered through 100 # nylon cloth.
• step 2 Talc was added to dispersion from step 1 under high sheer mixer to form a white colloidal dispersion. This dispersion was passed through 100 # nylon cloth.
• Example 6B The Crofelemer coated pellets of Example 6B were coated with the dispersion from step 2 using fluid bed processor (Glatt GPCG 1.1)
• # % of coating of Crofelemer taste masked pellets' may vary between 30-40 %
• Crofelemer taste masked pellets from Example 7 A or 7 B or 8, were sifted through 30 # sieve.
• step 4 Remaining part of Crofelemer taste masked pellets from step 1 and blend from step 3 were blended to obtain dry powder composition. 22 g of dry powder composition of step 4 can be reconstituted withl5 ml purified water to produce 30 ml of suspension.
• EXAMPLE 10 Crofelemer (25 mg/50 mg/100 mg) dispersible tablets.
• #Crofelemer taste masked pellets' percentage of coating may vary between 30-40 %
• Crofelemer taste masked pellets from Example 7A or 7B or 8, were sifted through ASTM sieve #30.
• step 3 Blends from step 3 and step 4 were sifted it through 30 # sieve thrice and
• the blend displayed a bulk density of 0.649 g/ml and a compressibility index of 17.12%.
• step 5 The blend of step 5 was compressed into tablets so that each tablet contained 25 mg (average tablet weight 126 mg), or 50 mg (average tablet weight 252 mg), or 100 mg (average tablet weight 504 mg).
• Example 11 A The dispersible tablets were evaluated for in vitro drug release under following conditions:
• Dissolution Medium Purified water (pH 5.9), 1000 ml.
• Example 11B Dispersible tablet of Example 3 and Pellets of Examples 7B and 8 were evaluated for in vitro drug release under following conditions:
• Dissolution Medium 0.1N HC1 (pH 1.2), 1000 ml.
• Base Granules contain MCC (10% w/w), Colloidal silicon dioxide (3% w/w), Lactose monohydrate (83% w/w) and Croscarmellose sodium (4% w/w)
• Example 12 The dispersible tablets of Example 12 and Example 13 (A, B & C) were evaluated for in vitro drug release under following conditions:

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