SOLID PHARMACEUTICAL COMPOSITION WITH A FIRST FRACTION OF A DISPERSION MEDIUM AND A SECOND FRACTION OF A MATRIX, THE LATTER BEING AT LEAST PARTIALLY FIRST EXPOSED TO GASTROINTESTINAL FLUIDS

• US 20090274759A1
• Filed: 06/02/2006
• Published: 11/05/2009
• Est. Priority Date: 06/03/2005
• Status: Abandoned Application

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Bar-Shalom, Daniel, Slot, Lillian
• Application Number:
  US11/915,655
• Publication Number:
  US 20090274759A1
• Time in Patent Office: Days
• US Class Current: 424/484
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28

Abstract

A solid pharmaceutical composition in the form of a single dosage unit for oral use, the composition comprising a first and a second fraction, the first fraction comprises a therapeutically and/or prophylactically active substance dispersed in a dispersion medium that is sufficiently fluid at body temperature and the second fraction comprises a matrix comprising a substantially water soluble and/or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers, the first fraction being included in the composition in such a manner that at least a part of the second fraction is firstly exposed to the gastrointestinal fluids upon administration before the first fraction becomes exposed. The system is designed to release the active substance after a predetermined period of time after administration, and the release of the active substance at that point in time is relatively fast.

Claims

1. A coated solid pharmaceutical composition in the form of a single dosage unit for oral use, the composition comprising a first and a second fraction,

i) the first fraction comprises a therapeutically and/or prophylactically active substance dispersed in a dispersion medium that is sufficiently fluid at body temperature,

wherein the first fraction is placed between two second fractions, between a coating and a second fraction, or alternatively is completely surrounded by a second fraction, the first fraction has a melting point cut off of at the most about 38°

C., and

the active substances contained in the first fraction is released relatively fast once the second fraction has eroded, and

ii) the second fraction comprises an erodable matrix comprising a substantially water soluble or crystalline polymer or a mixture of substantially water soluble and/or crystalline polymers, the polymer being a polyethylene oxide having a MW of from 20,000 daltons to about 700,000 or a block copolymer of ethylene oxide and propylene oxide having a MW of from about 3,000 to about 30,000 daltons, or a mixture thereof,

wherein the composition is coated with a coating having at least one opening exposing one surface of the matrix of the second fraction, and the coating is substantially insoluble in and impermeable to body fluids.

2. A composition according to claim 1, wherein the dispersion medium of the first fraction—

when tested according to the Flow Test described herein—

passes the test.

3. A composition according to claim 1, wherein the first fraction—

when tested according to the Flow Test described herein—

passes the test.

4. A composition according to claim 1, wherein the dispersion medium of the first fraction has a melting point cut off of at the most about 50°

C.

5. A composition according to claim 1, wherein the dispersion medium of the first fraction has a melting point onset of about 0°

C. or more such as, e.g. about 5°

C. or more, about 10°

C. or more, about 15°

C. or more, about 20°

C. or more or about 25°

C. or more.

6. A composition according to claim 1, wherein the first fraction has a melting point onset of about 0°

C. or more such as, e.g. about 5°

C. or more, about 10°

C. or more, about 15°

C. or more, about 20°

C. or more or about 25°

C. or more.

7. A composition according to claim 1 having a delayed release of the active substance contained in the first fraction.

8. A composition according to claim 7, wherein—

when tested in an in vitro dissolution test—

at the most about 5% w/w of the active substance contained in the first fraction is released from the composition within 15 min or more after start of the test.

9. A composition according to claim 8, wherein at the most 5% w/w of the active substance contained in the first fraction is released from the composition within 30 min or more such as, e.g., 1 h or more, 1.5 h or more, 2 h or more, 3 h or more, 4 h or more, 5 h or more, 6 h or more, 7 hours or more or 8 hours or more after start of the test.

10. A composition according to claim 1, wherein the dispersion medium comprises one or more solvents, one or more co-solvents, one or more oils, one or more waxes and/or one or more semi-solid materials.

11. A composition according to claim 1, wherein the dispersion medium is a lipid-based medium.

12. A composition according to claim 1, wherein the dispersion medium is an aqueous-based medium.

13. A composition according to claim 10, wherein the dispersion medium comprises a substance selected from the group consisting of cocoa butter, coca butte substitutes like e.g. vegetable oils modified by esterification, hydrogenation, fractionation etc., shea butter, adeps solidus including those using different triglycerides as starting materials, waxes including beeswax, theobroma oil, hydrogenated vegetable oil bases such as fattybase, wecobee bases, witepsol based water-soluble bases vegetable oil including coconut oil, palm kern oil, cotton seed oil, olive oil, maize oil, peanut oil, sesame oil, sunflower oil, and miglyol 813, and mixtures thereof.

14. A composition according to claim 1, wherein the dispersion medium comprises a polyethylene glycol that has a molecular weight of 20,000 or less, glycerinated gelatine, fatty acid esters of polyethylene glycol.

15. A composition according to claim 12, medium in the first fraction is aqueous based and comprises surface-active agents, emulsifiers and/or nano particles.

16. A composition according to claim 1, wherein the first fraction is contained in an inner layer of the composition, at least one surface of the inner layer being in contact with at least one surface of the matrix of the second fraction.

17. A composition according to claim 1, wherein the release of the active substance from the first fraction follows a kinetic that is different from a zero order release.

18. A composition according to claim 1, wherein the release of the active substance from the first fraction—

when tested using an in vitro dissolution test method—

is at the most about 20% w/w such as at the most about 15% w/w, at the most about 10% w/w, at the most 5% w/w, at the most about 2.5% w/w, at the most about 1% w/w or at the most about 0.1% w/w when measured 2 hours or more such as, e.g., 3 hours or more, 4 hours or more, 5 hours or more, 6 hours or more, 7 hours or more, 8 hours or more, 9 hours or more, 10 hours or more, 11 hours or more, 12 hours or more, 13 hours or more, 14 hours or more, 15 hours or more or 16 hours or more after start of the test.

19. A composition according to claim 1, wherein at least about 75% w/w such as, e.g., at least about 80% w/w, at least about 85% w/w, at least about 90% w/w or at least about 95% w/w of the total amount of the active substance contained in the first fraction is released within 90 minutes—

when tested using an in vitro dissolution test method and the starting point of the test being defined as the point in time when 20% w/w of the total amount of the active substance contained in the first fraction is released.

20. A composition according to claim 1, wherein the amount of the active substance in the first fraction corresponds to a daily or part of a daily therapeutic dose.

21. A composition according to claim 1 further comprising an active substance in the second fraction.

22. A composition according to claim 20, wherein the active substance in the second fraction is the same or different from the active substance contained in the first fraction.

23. A composition according to claim 1, wherein the active substance has a water-solubility at room temperature of at the most about 3 mg/ml.

24. A composition according to claim 1, wherein the active substance is a peptide, a polypeptide or a protein.

25. A composition according to claim 1, wherein the polyethylene glycol, a polyethylene oxide and/or a block copolymer of ethylene oxide and propylene oxide has a molecular weight of from about 20,000 to about 600,000 daltons, from about 35,000 to about 500,000 daltons, from about 35,000 to about 400,000 daltons, from about 35,000 to about 300,000 daltons, from about 50,000 to about 300,000 daltons, such as, e.g. about 35,000 daltons, about 50,000 daltons, about 75,000 daltons, about 100,000 daltons, about 150,000 daltons, about 200,000 daltons, about 250,000 daltons, about 300,000 daltons or about 400,000 daltons.

26. A composition according to claim 25, wherein the block copolymer of ethylene oxide and propylene oxide comprises up to about 30% w/w of the propylene oxide based block, and has a molecular weight of about 5,000 to about 30,000 daltons such as, e.g. from about 8,000 to about 15,000 daltons.

27. A composition according to claim 1, wherein the matrix of the second fraction comprises a polymer which has a melting point of about 20-120°

C. such as, e.g. from about 30 to about 100°

C. or from about 40 to about 80°

C.

28. A composition according to claim 1, wherein the coating is a coating having at least one opening exposing at the one surface of said matrix of the second fraction, the coating comprising

a) a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in the aqueous medium in which the composition is to be used,

and at least one of

b) a second cellulose derivative which is soluble or dispersible in water,

c) a plasticizer, and

d) a filler.

29. A composition according to claim 28, wherein in the aqueous medium in which the composition is to be used, the coating does not completely crumble or erode before the matrix of the second fraction has completely eroded.

30. A composition according to claim 28, wherein said first cellulose derivative is a cellulose ether which, when heated, is shapeable by molding or extrusion, including injection molding, blow molding and compression molding.

31. A composition according to claim 30 in which the cellulose ether comprises at least one ethylcellulose.

32. A composition according to claim 31 in which said ethylcellulose has an ethoxyl content in the range of 44.5-52.5%.

33. A composition according to claim 32 in which said ethylcellulose has an ethoxyl content in the range of 45-49.5%.

34. A composition according to claim 28 in which said first cellulose derivative is selected from the group consisting of cellulose acetate, cellulose propionate and cellulose nitrate.

35. A composition according to claim 28 in which said second cellulose derivative is selected from the group consisting of methylcellulose, carboxymethylcellulose and salts thereof, cellulose acetate phthalate, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydrocyethylcellylose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose.

36. A composition according to claim 35 in which said salt of carboxymethylcellulose is selected from the group consisting of alkali metal and alkaline earth metal salts.

37. A composition according to claim 28, in which said plasticizer is selected from the group consisting of phosphate esters;

phthalate esters;

amides;

mineral oils;

fatty acids and esters thereof with polyethylene glycol, glycerin or sugars;

fatty alcohols and ethers thereof with polyethylene glycol, glycerin or sugars;

vegetable oils and hydrogenated vegetable oils;

nitrobenzene, carbon disulfide, β

-naphtyl salicylate, phthalyl glycolate, and diocyl phthalate.

38. A composition according to claim 37 in which said fatty alcohol is selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol and myristyl alcohol.

39. A composition according to claim 28 in which said plasticizer is a non-ionic surfactant.

40. A composition according to claim 28, wherein said filler is a filler, a diluent, a binder, a lubricant a disintegrant or a water-soluble anti-oxidant, a lipid soluble antioxidant and/or a preservative.