WO2013093655A1

WO2013093655A1 - Non-enteric pharmaceutical composition comprising crofelemer

Info

Publication number: WO2013093655A1
Application number: PCT/IB2012/054191
Authority: WO
Inventors: Ulhas Dhuppad; Vasant KHACHANE; Santosh Patil; Ravindra SATPUTE; Chandrakant DHATRAK
Original assignee: Glenmark Pharmaceuticals Limited
Priority date: 2011-12-22
Filing date: 2012-08-17
Publication date: 2013-06-27
Also published as: RU2014124981A; BR112014015314A8; PH12014501352A1; BR112014015314A2; MX2014007635A; MY197454A; ZA201207398B

Abstract

Non-enteric pharmaceutical composition for oral administration comprising crofelemer and a pharmaceutically acceptable excipient is disclosed. The process for preparing such composition and its use in treating secretory diarrhea in a subject are also disclosed.

Description

NON-ENTERIC PHARMACEUTICAL COMPOSITION COMPRISING

CROFELEMER

PRIORITY DOCUMENT

This patent application claims priority to Indian Provisional Patent

Application number 3614/MUM/2011 (filed on December 22, 2011), the contents of which are incorporated by reference herein.

TECHNICAL FIELD

The present patent application relates to a non-enteric pharmaceutical composition comprising crofelemer. Particularly, 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.

BACKGROUND

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.

Formula 1 United States Patent numbers 5,211,944, 5,494,661, 7,323,195, 7,341,744, and 7,556,831; and United States Patent Application Publication number 20090148397 describe crofelemer, its method of preparation, formulations and uses.

Particularly United States patent numbers 7,323,195 and 7,341,744 disclose that 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.

There is a need for a new acid- stable, immediate release, non-enteric, oral pharmaceutical composition comprising a crofelemer for treating secretory diarrhea in a subject in need thereof.

SUMMARY

The present invention relates to an acid-stable, immediate release, non-enteric pharmaceutical composition for oral administration comprising crofelemer and a pharmaceutically acceptable excipient.

Contrary to the disclosures of US 7,323,195 and US 7,341,744, during the forced degradation studies, the inventors of the present invention surprisingly found that crofelemer degrades in alkaline condition (specifically at pH greater than 7). Even more, it was unexpectedly found that the degradation of the crofelemer in acidic condition was far less than that observed in the alkaline condition. Further, incubation of the crofelemer at about 37°C revealed that it is not acid-labile (i.e., it does not undergo substantial degradation) when incubated at pH about 1 to about 3 for about 2 hours. Thus, without being bound by any theory, inventors of the present invention believe that 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.

Thus, in an embodiment, 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.

In an embodiment, 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. In a preferred aspect of this embodiment, the crofelemer contained in said composition undergoes not more than 5% w/w degradation when incubated at the above said conditions.

In another embodiment, 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. Preferably, such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.

In an embodiment of the present invention, 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.

In an embodiment, the composition of the present invention comprises from about 10 mg to about 750 mg of crofelemer. Preferably, 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. Preferably 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.

In a specific embodiment, 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. Preferably, 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, as described herein, 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.

In a preferred embodiment, 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).

In a specific embodiment, 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. Preferably, such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions. In another specific embodiment, 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.

In a specific embodiment, 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. Preferably, such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.

In yet another specific embodiment, 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. In an embodiment, 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.

In an embodiment, 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. Preferably, said coating is not an enteric coating.

In the context of present invention, 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.

In an embodiment, 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.

In another embodiment, 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.

In another embodiment, 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. In another embodiment, 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.

In another embodiment, 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.

In a specific embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In an embodiment, 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.

In another embodiment, 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. In a further embodiment, 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.

In an embodiment, 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.

DETAILED DESCRIPTION

The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth in an earlier provisional application from which the present application claims priority are in conflict, the definition in this present application shall control the meaning of the terms.

The embodiments described herein may be used independently or in conjunction with any definition, claim or any other embodiment mentioned herein. Thus, the invention contemplates all possible combinations and permutations of the various independently described embodiments.

The term "active ingredient" (used interchangeably with "active" or "active substance" or "active pharmaceutical ingredient" or "drug") used herein includes crofelemer.

The term "pharmaceutically acceptable" as used in connection with components includes those components approved by a governmental regulatory agency or listed in the U.S. Pharmacopeia or other generally recognized as safe for use in mammals, such as humans. The term "acid-stable" used herein means the composition that shows sufficient stability in the acid medium or has minimal degradation in acidic environment.

The term "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). Preferably, 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).When the inventors of the present invention subjected the crofelemer for forced degradation under extremely alkaline (pH about 12.8) and acidic (pH about 0.4) conditions at about 70°C for about 2 hours, it was surprisingly observed that the crofelemer degrades in alkaline condition, whereas degradation of the crofelemer in the acidic condition was far less than that observed in the alkaline condition. For example, in the forced degradation study as described in Example 1, it was observed that the assay of crofelemer was reduced to 87.79 % under acidic conditions (at pH 0.4) and to 20.68 under alkaline conditions (at pH 12.8) when compared against a control sample. Further, incubation of the crofelemer in 0.1 N hydrochloric acid (HC1) at about 37°C revealed that it is not acid-labile (i.e., it does not undergo degradation) when incubated at pH 1.2 for about 2 hours.

Thus, 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.

In an embodiment, 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).

In an embodiment, 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. In a preferred aspect of this embodiment, the crofelemer contained in said composition undergoes not more than 5 % w/w degradation when incubated at the above said conditions.

In an embodiment, 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. Preferably, such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.

In an embodiment of the present invention, 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.

In another embodiment, the composition of the present invention comprises from about 10 mg to about 750 mg of crofelemer. Preferably, 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.

Preferably 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.

In specific embodiment, 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. Preferably, such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.

In another specific embodiment, 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. Preferably, such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions. In another specific embodiment, 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. Thus, in a specific embodiment, 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. Preferably, such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.

In yet another specific embodiment, 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. Preferably, 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. Thus, in an embodiment, 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.

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%.

Thus, in another specific embodiment, 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.

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.

In an embodiment, 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.

The capsule as described herein includes but is not limited to conventional capsule or hard shell capsule, tablet in capsule, soft shell capsule. In one preferred embodiment, 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).

In a specific embodiment, 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. Preferably, such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.

Preferably 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.

In an specific embodiment, 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.

In another specific embodiment, 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.

In yet another specific embodiment, 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.

In a further specific embodiment, 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.

In another specific embodiment, 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.

In yet another specific embodiment, 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.

In a further specific embodiment, 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).

In an aspect of this embodiment, 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.

In an embodiment, 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.

In an embodiment, 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. Preferably the said coating is not an enteric coating.

In the context of present invention, 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.

In a specific embodiment, 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. Preferably, such pharmaceutical composition releases at least about 50%, or about 55%, or about 60% of the contained crofelemer under the said conditions.

Thus in a specific embodiment, 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.

In an embodiment, 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. Preferably, the weight ratio of crofelemer to the coating agent ranges from about 1:0.03 to about 1:8.

In another embodiment, 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.

In an embodiment, 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.

The term "palatable agent" as used herein 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.

The term "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.

In the context of present invention, 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, carbowax, mineral waxes, glyceryl monostearate, glyceryl distearate, glyceryl tristearate; glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate, polyglyceryl diisostearate, lauroyl macrogolglycerides, oleoyl macrogolglycerides, stearoyl macrogolglycerides, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, decenoic acid, docosanoic acid, stearic acid; palmitic acid; lauric acid; myristic acid, cetyl alcohol, stearyl alcohol, cyclodextrin, hard or soft gelatin capsule shell or combinations thereof. Preferably, the taste masking agent is hypromellose, ethyl cellulose, Eudragit® L 30 D-55, Eudragit® EPO, stearic acid, or combinations thereof.

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. These pharmaceutically acceptable excipients can be used in suitable amounts as known to a person skilled in the art of formulation.

Examples of 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.

Examples of flavoring agent 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.

Examples of 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.

Examples of 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.

In an embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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 term "treating" or "treatment" as used herein 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.

The term "subject" refers any mammal including humans and non human animals. Preferably, 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.

In another specific embodiment, 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.

In a specific embodiment, 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.

In another specific embodiment, 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.

In yet another specific embodiment, 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.

In another embodiment, 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.

In a further embodiment, 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.

Thus in an embodiment, 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.

In another embodiment, 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.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

EXAMPLES

EXAMPLE 1: Forced degradation of crofelemer in acidic and alkaline conditions. Acid degradation:

1) Crofelemer (50 mg) was added to a 5 ml of diluent and sonicated for 20 minutes.

2) 2 ml of 2M HC1 (pH 0.4) was added to Crofelemer dispersion of step 1 under stirring.

3) The mixture of step 2 was heated up to about 70°C for about 2 hours.

4) The mixture of step 3 was cooled and neutralized with addition of 2 ml of 2M

sodium hydroxide (NaOH) (pH 12.8) and further diluted to 10 ml with diluent. 5) The degradation of Crofelemer was calculated as reduction in assay by HPLC method.

Alkaline degradation:

1) Crofelemer (50 mg) was added to a 5 ml of diluent* and sonicated for 20 minutes.

2) 2 ml of 2M NaOH was added to Crofelemer dispersion of step 1 under stirring.

3) The mixture of step 2 was heated up to about 70°C for about 2 hours.

4) 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.

5) The degradation of Crofelemer was calculated as reduction in assay by HPLC method.

[*Diluent was prepared by mixing equal volumes (50:50 v/v) of Solvent A and Solvent B, wherein:

Solvent A = 0.1% Trifluoroacetic acid buffer in water: Methanol (96:04,v/v)

Solvent B = Acetonitrile: Methanol (50:50 v/v)]

Determination of Crofelemer assay using HPLC method:

Chromatographic conditions:

Column XTerra RP-18, 150 X 4.6mm, 5μηι

Flow Rate 1.5mL / minute

Detection UV 280 nm

Injection Volume ΙΟ μΙ,

Column temperature 25°C

Mobile phase:

Mobile Phase A = Buffer: Methanol (96: 04 v/v)

(Buffer: 0.1% Trifluoroacetic acid in water)

Mobile Phase B = Acetonitrile: Methanol (50: 50 v/v)

Gradient program:

Time (min.) % Mobile Phase A % Mobile Phase B

0.01 100 0

20 100 0

65 91 09

67 50 50

77 50 50

79 100 0

95 100 0 The following table provides the reduction in assay of Crofelemer when subjected to force degradation under acidic and alkaline conditions.

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.

The following table provides the HPLC peak area of Crofelemer when incubated at pH 1.2.

From the table above, it is apparent that crofelemer does not undergo substantial degradation when incubated at pH 1.2 for 2 hours. EXAMPLE 3: Crofelemer Dispersible Tablet 50 mg.

Ingredients Composition (%w/w)

Crofelemer taste masked granules

Crofelemer (#60/80) 32.890

Ethyl cellulose 7 cps 6.842

Hypromellose (Methocel E 5) 0.684

Talc 0.752

Base granules

Microcrystalline cellulose 45.850

(Avicel PH 101)

Croscarmellose Sodium 2.132

Colloidal silicon dioxide 1.598

Lactose monohydrate 3.731 Ingredients Composition (%w/w)

Lubrication

Croscarmellose Sodium 3.947

Colloidal silicon dioxide 0.296

Dry powder flavour Tutti Frutti 0.585

Saccharin Sodium 0.394

Magnesium Stearate 0.296

Manufacturing Process:

1) Ethyl cellulose (7 cps) was added under stirring in methylene dichloride to form a clear solution.

2) Hydroxypropyl methylcellulose (5 cps) was dispersed under stirring in isopropyl alcohol and was added under stirring to step 1.

3) Talc was dispersed in isopropyl alcohol under sonication for 5-minutes. This dispersion was added to the mixture of step 2 under stirring, and then filtered through 200 # nylon cloth.

4) Crofelemer (Sieve size #60/80) were coated with the dispersion of step 3 using fluid bed processor (Glatt GPCG 1.1) by wurster coating.

5) The granules were then dried to a Loss on Drying of not more than 7.5 % w/w.

The granules had a bulk density of 0.748g/ml and a compressibility index of 5.91%.

6) Microcrystalline cellulose "MCC" (Avicel PH 101), Colloidal silicon dioxide, lactose monohydrate and croscarmellose sodium was sifted twice through 60 # sieve.

7) 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%.

8) 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%. 9) 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.

EXAMPLE 4: Crofelemer Dispersible Tablet 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:

1) 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.

2) 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.

3) The blend of 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. 4) The granules displayed a bulk density of 0.386 g/ml and a compressibility index of 18.07 %.

5) Ethyl cellulose (7 cps) was added under stirring in methylene dichloride to form a clear solution.

6) HPMC (5 cps) was dispersed under stirring in isopropyl alcohol and the

dispersion was added under stirring to the solution of step 5.

7) Talc was dispersed in isopropyl alcohol and sonicated for 5 minutes. This

dispersion was added to the mixture of step 6 under stirring, and then filtered through 200 # nylon cloth.

8) 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 %.

9) 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.

10) 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.

11) All the ingredients were mixed thoroughly in an octagonal blender for 13-min at 8 rpm and sifted through ASTM sieve #40.

12) 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 %.

13) The lubricated blend of step 11 was compressed into tablets using suitable

punches. 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.

2) 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.

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 %.

4) Ethyl cellulose (10 cps) was added under stirring in methylene dichloride to form a clear solution. 5) HPMC (5 cps) was dispersed under stirring in isopropyl alcohol and the dispersion was added under stirring to the solution of step 5.

6) Talc was dispersed in isopropyl alcohol under sonication for 5-minutes. This dispersion was added to the mixture of step 5 under stirring, and then filtered through 200 # nylon cloth.

7) 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%.

8) 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.

9) 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.

10) All the ingredients were mixed thoroughly in an octagonal blender for 13-mins at 8 rpm and sifted through ASTM sieve #40.

11) 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 %.

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)

Manufacturing process:

1) Maltodextrin was added to purified water under stirring.

2) Propylene glycol and Isopropyl alcohol were added under stirring to the

dispersion of step 1.

3) Crofelemer was added under stirring to the dispersion of step 1 to form clear solution. The solution was filtered through 100 # nylon cloth.

4) The solution of step 3 was loaded onto the sugar spheres using Fluid Bed

Processor (Glatt GPCG 1.1).

EXAMPLE 6B: Preparation of Crofelemer base coated pellets

Manufacturing process:

1) Opadry was dispersed in the mixture of methylene chloride and isopropyl alcohol under stirring. The dispersion was filtered through 100 # nylon cloth.

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). EXAMPLE 7: Taste masking of Crofelemer pellets

Manufacturing process for 7A:

1) Triethyl citrate and Glyceryl stearate were added slowly to purified water under stirring at 65°C.

2) Eudragit L30 D55 was taken in a container, and Sodium hydroxide solution in water was added drop wise to Eudragit L30 D55.

3) Solutions from step 1 and step 2 were mixed under stirring for 45 minutes.

4) Purified water was added to solution of step 3 and was further filtered through 100 # nylon cloth.

5) The Crofelemer base coated pellets of Example 6 B were coated with the

solution of step 5 using Fluid Bed Processor (Glatt GPCG 1.1).

Manufacturing process for 7B:

1) Sodium lauryl sulphate, Stearic acid and Eudragit EPO were mixed together in purified water under high sheer mixer for 30-60 min.

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.

3) The Crofelemer base coated pellets of Example 6 B were coated with the

dispersion of step 2 using Fluid Bed Processor (Glatt GPCG 1.1). EXAMPLE 8: Taste masking of Crofelemer pellets with stearic acid

Manufacturing process:

1) Stearic acid was dissolved in isopropyl alcohol and methylene chloride under stirring.

2) Opadry was mixed with dispersion from step 1 and filtered through 100# nylon cloth.

3) The Crofelemer coated pellets of Example 6B were coated with the dispersion from step 2 using fluid bed processor (Glatt GPCG 1.1)

EXAMPLE 9: Dry powder for suspension comprising Crofelemer

# % of coating of Crofelemer taste masked pellets' may vary between 30-40 %

Manufacturing process:

1) Crofelemer taste masked pellets, from Example 7 A or 7 B or 8, were sifted through 30 # sieve.

2) Sodium Benzoate, Avicel CL 611, Colloidal Silicon Dioxide, Tutti frutti and pharma grade sugar were individually sifted through 40 # sieve.

3) Part of Crofelemer taste masked pellets from step 1 and blend from step 2 were blended together.

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 %

Manufacturing process:

1) Crofelemer taste masked pellets, from Example 7A or 7B or 8, were sifted through ASTM sieve #30.

2) Part of Prosolv Easytab, sodium lauryl sulphate, croscarmellose sodium, and sodium saccharin were blended and sifted through ASTM sieve #40.

3) Blends from step 1 and 2 were mixed and sifted through ASTM sieve #30 twice.

4) Another part of Prosolv Esaytab, strawberry, and mint, red oxide of iron and black oxide of iron was blended and sifted through 100# sieve twice.

5) Blends from step 3 and step 4 were sifted it through 30 # sieve thrice and

blended in an octagonal blender for 15-min at 8 rpm speed. The blend displayed a bulk density of 0.649 g/ml and a compressibility index of 17.12%.

6) 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).

The average dispersion time for the above compositions was in the range of about 20 seconds to about 50 seconds. EXAMPLE 11: In vitro drug release studies

Example 11 A: The dispersible tablets were evaluated for in vitro drug release under following conditions:

Apparatus: USP Type- II.

Speed: 75 rpm.

Dissolution Medium: Purified water (pH 5.9), 1000 ml.

Temperature: 37 + 0.5°C

Example 11B: Dispersible tablet of Example 3 and Pellets of Examples 7B and 8 were evaluated for in vitro drug release under following conditions:

Apparatus: USP Type- II,

Speed: 100 rpm.

Dissolution Medium: 0.1N HC1 (pH 1.2), 1000 ml.

Temperature: 37 + 0.5°C

EXAMPLE 12: Crofelemer Dispersible Tablets 10 mg

Ingredients Composition (% w/w)

Step-1 Crofelemer Granulation Part

HPMC 5 cps (Methocel E 5) 2.888

Crofelemer 100-120 # mesh 16.170

MCC (Avicel PH 101) 19.410

Croscarmellose Sodium (Ac di sol) 1.282

Colloidal silicon dioxide 0.958

Lactose monohydrate 26.600

Step-2 Crofelemer Masking Part

Crofelemer granules of Step-1 67.310

Ethyl cellulose 7 cps 11.380

HPMC 5 cps (Methocel E 5) 1.152

Talc 1.247 Step-3 Lubrication

Crofelemer masked granules of Step-2 81.110

Base granules * 14.250

Croscarmellose Sodium (Ac di sol) 3.529

Colloidal silicon dioxide 0.264

Dry powder flavour Tutti Frutti 0.352

501103 AP0551

Saccharin Sodium 0.235

Magnesium Stearate 0.264

*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 13: Crofelemer Dispersible Tablets 25, 75 & 100 mg

EXAMPLE 14: In vitro drug release studies

The dispersible tablets of Example 12 and Example 13 (A, B & C) were evaluated for in vitro drug release under following conditions:

Apparatus- USP II (Paddle)

Dissolution Media- 1000 ml Purified Water

Speed- 75rpm

Temperature- 37°C +0.5°C % Crofelemer released

Composition

45 minutes 60 minutes

Example 12 93.2 96.6

Example 13A 84.3 88.7

Example 13B 82.4 85.9

Example 13C 92.2 92.8

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

CLAIMS We claim:

1. An acid-stable, non-enteric pharmaceutical composition for oral administration comprising an effective amount of crofelemer and a pharmaceutically acceptable excipient.

2. The pharmaceutical composition according to claim 1, 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.

3. The pharmaceutical composition according to claim 1, wherein said composition releases at least about 50% or at least about 60% of the contained crofelemer.

4. The pharmaceutical composition according to any one of claims 1-3, wherein said composition contains from about 10 mg to about 750 mg of crofelemer.

5. The pharmaceutical composition according to any one of claims 1-3, wherein said composition contains from about 10 mg to about 500 mg of crofelemer.

6. The pharmaceutical composition according to any one of claims 1-5, wherein said composition comprises from about 5 % w/w to about 70 % w/w of crofelemer.

7. The pharmaceutical composition according to any one of claims 1-5 wherein said composition comprises from about 10 % w/w to about 60 % w/w of crofelemer.

8. The pharmaceutical composition according to any one of claims 1-7, wherein said composition is in the form of a tablet, capsule, dispersion or powder.

9. 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.

10. The pharmaceutical composition according to claim 9, wherein crofelemer is at least partially coated by the taste masking agent.

11. The pharmaceutical composition according to claim 9, wherein the taste masking agent comprises 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.

12. The pharmaceutical composition according to any one of claims 9-11, wherein the weight ratio of the crofelemer to the taste masking agent ranges from about 1:0.01 to about 1:10.

13. The pharmaceutical composition according to any one of claims 9-12, wherein said composition is in the form of a dispersible tablet or dry syrup that contains a palatable agent.

14. 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 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.

15. The taste masked pellets according to claim 14, wherein the weight ratio of the crofelemer to the taste masking agent ranges from about 1:0.01 to about 1:10.

16. 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 according to any one of claims 14-15.

17. 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.

18. The pharmaceutical composition according to claim 17, wherein said composition releases at least about 60% of the contained crofelemer.

19. The pharmaceutical composition according to any one of claims 17-18, wherein said composition comprises about 12.5 mg of crofelemer.

20. The pharmaceutical composition according to any one of claims 17-18, wherein said composition comprises about 25 mg of crofelemer.

21. The pharmaceutical composition according to any one of claims 17-18, wherein said composition comprises about 50 mg of crofelemer.

22. The pharmaceutical composition according to any one of claims 17-18, wherein said composition comprises about 100 mg of crofelemer.

23. The pharmaceutical composition according to any one of claims 17-18, wherein said composition comprises about 125 mg of crofelemer.

24. The pharmaceutical composition according to any one of claims 1-13, wherein said composition is in the form of a dispersible tablet or dry syrup that contains a palatable agent.

25. The pharmaceutical composition according to any one of claims 16-23, wherein said composition is in the form of a dispersible tablet or dry syrup that contains a palatable agent.

26. A method of treating secretory diarrhea in a subject in need thereof, said method comprising administering to the subject the taste masked pellets or the pharmaceutical composition according to claims 1-25.

27. Use of crofelemer in preparation of the taste masked pellets or the pharmaceutical composition according to claims 1-25 for the treatment of secretory diarrhea in a subject in need thereof.

28. The taste masked pellets or the pharmaceutical composition according to claims 1-25 for the treatment of secretory diarrhea in a subject in need thereof.