FORM 2

THE PATENTS ACT  1970
(39 of 1970)
&
THE PATENTS RULES  2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

Title of the invention: NON-ENTERIC PHARMACEUTICAL COMPOSITION COMPRISING CROFELEMER

Applicant:
GLENMARK PHARMACEUTICALS LIMITED 
An Indian Company registered under
The Companies Act  1956  India
and having its office at
Glenmark House  HDO – Corporate Bldg 
Wing A  B. D. Sawant Marg 
Chakala  Andheri (East) 
MUMBAI – 400 099

The following specification describes the invention and the manner in which it is to be performed.

NON-ENTERIC PHARMACEUTICAL COMPOSITION COMPRISING CROFELEMER

PRIORITY
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.

FIELD OF THE INVENTION
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 OF THE INVENTION
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)-C(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 OF THE INVENTION
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 OF THE INVENTION
The present invention relates to an acid-stable  immediate release  non-enteric pharmaceutical composition for oral administration comprising crofelemer and a pharmaceutically acceptable excipient.
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 HCl.
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 (HCl) 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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 HCl (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 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 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.
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.
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.
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.
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 HCl (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  5µm
Flow Rate : 1.5mL / minute
Detection : UV 280 nm
Injection Volume : 10 µL
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.

Crofelemer Control Acidic degradation
(at pH 0.4) Alkaline degradation
(at pH 12.8)
HPLC peak area 14984278 13155581 3098818
Assay (% w/w) 100 87.79 20.68

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.

Crofelemer Control Incubation at pH 1.2
HPLC peak area 16328964 15696842
Assay (% w/w) 100 96.13

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
(Avicel PH 101) 45.850
Croscarmellose Sodium 2.132
Colloidal silicon dioxide 1.598
Lactose monohydrate 3.731

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.
Ingredients Composition (%w/w)
Step 1 - Crofelemer granules
Crofelemer 16.170
HPMC 5 cps (Methocel E 5) 2.888
MCC (Avicel PH 101) 19.410
Croscarmellose Sodium 1.282
Colloidal silicon dioxide 0.958
Lactose monohydrate 26.600
Step 2- Taste masked Crofelemer
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 Taste masked granules of Step 2 81.110
Base granules** 14.250
Croscarmellose Sodium 3.529
Colloidal silicon dioxide 0.264
Dry powder flavour Tutti Frutti 0.352
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)
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.
Ingredients Composition (%w/w)
Step 1- Crofelemer granules
Crofelemer 32.350
HPMC 15cps (Methocel E15) 3.023
MCC (Avicel PH 101) 7.058
Colloidal silicon dioxide 0.705
Lactose monohydrate 27.540
Step 2- Taste masked Crofelemer granules
Crofelemer granules of Step 1 70.680
Ethyl cellulose 10 cps 11.940
HPMC 5 cps (Methocel E 5) 1.211
Talc 1.305
Step 3- Lubrication
Crofelemer taste masked granules of Step 2 85.140
Base granules** 10.210
Croscarmellose Sodium 3.529
Colloidal silicon dioxide 0.264
Dry powder flavour Tutti Frutti 0.352
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)

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 (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)
Ingredients Composition (% w/w)
Purified water q.s.
Maltodextrin 10.500
Propylene glycol 6.500
Isopropyl alcohol q.s.
Crofelemer 42.500
Sugar spheres 60/80 # 20.000

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

Base Coating Phase
Ingredients Composition (% w/w)
Isopropyl alcohol q.s.
Opadry YS-1-19025-A 5.000
Methylene chloride q.s.
Crofelemer drug loaded Pellets 79.500

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 6A using fluid bed processor (Glatt GPCG 1.1).

EXAMPLE 7: Taste masking of Crofelemer pellets
Ingredients Composition (% w/w)
Example 7 A Example 7 B
Purified water q.s. q.s.
Sodium hydroxide 0.180 --
Sodium lauryl sulphate -- 3.000
Eudragit L 30 D 55 13.670 --
Eudragit EPO -- 30.000
Opadry YS-1-19025-A -- --
Stearic acid -- 4.500
Isopropyl alcohol -- --
Methyelene chloride -- --
Talc -- 14.900
Triethyl citrate 1.400 --
Glyceryl stearate (Imwitor 900K) 0.250 --
Crofelemer base coated Pellets 84.500 79.500

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
Ingredients Composition (% w/w)
Opadry YS-1-19025-A 5.000
Stearic acid 30.000
Isopropyl alcohol q.s.
Methyelene chloride q.s.
Crofelemer drug loaded pellets 79.500

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
Ingredients Composition (% w/w)
Crofelemer taste masked pellets # 10.440
Sodium Benzoate 0.270
MCC and Sodium Carboxymethyl cellulose (Avicel CL 611) 0.180
Colloidal silicon dioxide 0.050
Tutti frutti 0.140
Pharma grade sugar 40 # 89.100
Purified Water q.s.
# % 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 with15 ml purified water to produce 30 ml of suspension.

EXAMPLE 10: Crofelemer (25 mg/50 mg/100 mg) dispersible tablets.
Ingredients Composition (% w/w)
Crofelemer taste masked pellets# 57.600
Prosolv Easytab (MCC  Colloidal silicon dioxide  Sodium starch glycolate  Sodium stearyl fumarate)
34.470
Sodium lauryl sulphate 0.790
Croscarmellose sodium 3.970
Red oxide of Iron 0.480
Black oxide of Iron 0.160
Sodium saccharin 0.790
Strawberry 1.240
Mint 0.490
#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 11A: 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
Composition % Crofelemer released
45 minutes 60 minutes
Example 3 94.6 94.3
Example 4 94.0 97.8
Example 5 94.9 98.0

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 HCl (pH 1.2)  1000 ml.
Temperature: 37 ± 0.5°C
Composition % Crofelemer released
45 minutes 60 minutes
Example 3 70.6 73.1
Example 7B 49.8 52.2
Example 8 40.5 49.5

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
501103 AP0551 0.352
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

Ingredients Composition (% w/w)
25 mg (13A) 75 mg
(13B) 100 mg
(13C)
Crofelemer Taste masked granules
Crofelemer 60/80 # 32.89
Ethyl cellulose 7cps 6.842
Hypromellose (Methocel E 5) 0.684
Talc 0.752
Base Granules
Microcrystalline cellulose (Avicel PH 101) 45.85
Croscarmellose Sodium (Ac di sol) 2.132
Colloidal silicon dioxide 1.598
Lactose monohydrate 3.731
Lubrication
Croscarmellose Sodium (Ac di sol) 3.947
Colloidal silicon dioxide 0.296
Dry powder flavour Tutti Frutti
501103 AP0551 0.585
Saccharin Sodium 0.394
Magnesium Stearate 0.296

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
Composition % Crofelemer released
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
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.

Dated this 12th day of October 2012

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Taranpreet S. Lamba
(General Manager-Intellectual Property Management)
Glenmark Pharmaceuticals Limited