Matrix compositions for controlled delivery of drug substances

• US 8,298,581 B2
• Filed: 03/26/2004
• Issued: 10/30/2012
• Est. Priority Date: 03/26/2003
• Status: Expired due to Fees

• Current Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Original Assignee: Egalet, Ltd. (Assertio Holdings, Inc.)
• Inventors: Bar-Shalom, Daniel, Slot, Lillian, Lademann, Anne-Marie, Fischer, Gina
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): Palenik, Jeffrey T
• Application Number:
  US10/550,685
• Publication Number:
  US 20070042044A1
• Time in Patent Office: 3,140 Days
• Field of Search: None
• US Class Current: 424/480
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2893 Tablet coating processes mechanical aspects A61J3/06
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

A controlled release pharmaceutical composition for oral use is provided in the form of a coated matrix composition, the matrix composition comprising i) a mixture of a first and a second polymer that have plasticizing properties and which have melting points or melting intervals of a temperature of at the most 200° C., the first polymer being selected from the group consisting of polyethylene glycols and polyethylene oxides, and the second polymer being selected form block copolymer of ethylene oxide and propylene oxide including poly(ethylene-glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol (PEG-PLGA PEG), poly((DL-lactic acid-co-glycolic acid)-g-ethylene glycol) (PLGA-g-PEG), poloxamers and polyethylene oxide-polypropylene oxide (PEO-PPO), ii) a therapeutically, prophylactically and/or diagnostically active substance, the matrix composition being provided with a coating having at least one opening exposing at one surface of said matrix, wherein the active substance is released with a substantially zero order release.

Claims

1. A controlled release pharmaceutical composition for oral use in the form of a coated matrix composition, the matrix composition comprising

i) a mixture of a first polymer and a second polymer that have plasticizing properties and which have melting points or melting intervals of a temperature of at the most 200°

C.,

the first polymer being selected from the group consisting of polyethylene glycols and polyethylene oxides having a molecular weight of at least about 20,000 in crystalline and/or amorphous form, or a mixture such polymers, and

the second polymer being selected from poloxamers having an HLB value of at least 18,

ii) a therapeutically, prophylactically and/or diagnostically active substance, wherein the concentration of the second polymer in the matrix composition is from about 5 to about 90% w/w,

the matrix composition being provided with a coating having at least one opening exposing at least one surface of said matrix, the coating comprising

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;

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

a plasticizer, and

a filler,

wherein the active substance is released with a substantially zero order release.

2. A composition according to claim 1, wherein the polyethylene oxide has a molecular weight selected from the group consisting of about 35,000 daltons, about 50,000 daltons, about 100,000 daltons, and about 200,000 daltons.

3. A composition according to claim 1, wherein the first polymer has a melting point of about 20-120°

C.

4. A composition according to claim 1, wherein the concentration of the first polymer in the matrix composition is from about 10 to about 95%.

5. A composition according to claim 1, wherein the second polymer has a molecular weight of at least about 2,000 daltons.

6. A composition according to claim 1, wherein the second polymer is a poloxamer that has the formula HO(C₂H₄O)_a(C₃H₆O)_b(C₂H₄O)_aH, and a is an integer from about 10 to about 150.

7. A composition according to claim 6, wherein the poloxamer has a molecular weight of from about 2,000 daltons to about 20,000 daltons.

8. A composition according to claim 1, wherein the second polymer has a melting point of about 20-120°

C.

9. A composition according to claim 1, wherein the second polymer has an HLB value of at least about 20.

10. A composition according to claim 1, wherein the concentration of the second polymer in the matrix composition is from about 10% to about 80% w/w.

11. A pharmaceutical composition according to claim 1 that provides controlled release of the active substance into an aqueous medium by erosion of at least one surface of the composition.

12. A composition according to claim 1, wherein the active substance is present in any of its crystalline, polymorphous or amorphous forms or mixtures thereof.

13. A pharmaceutical composition according to claim 1, wherein the active substance at least partially is present in solid form in the dispersion.

14. A pharmaceutical composition according to claim 1, wherein the active substance at least partially is present in a molecular dispersion.

15. A pharmaceutical composition according to claim 14, wherein the active substance is present in a molecular dispersion including a solid solution.

16. A pharmaceutical composition according to claim 15, wherein the active substance at least partially is present in a colloidal dispersion.

17. A pharmaceutical composition according to claim 12, wherein the active substance at least partially is present in a crystalline form.

18. A pharmaceutical composition according to claim 1, wherein the active substance at least partially is present in amorphous form with a mean particle size of from about 0.01 μ

m to about 500 μ

m.

19. A composition according to claim 1, wherein the first and the second polymer together form a dispersion medium in which the active substance is contained.

20. A composition according to claim 1 comprising a stabilizing agent.

21. A composition according to claim 20, wherein the stabilizing agent is selected from the group consisting of diffusion and dissolution adjusting agents, pH-adjusting agents, buffering agents, agents that does not increase the mobility of the ingredients in the composition, agents that prevent crystal formation and agents that have antioxidative properties.

22. A composition according to claim 20, wherein the stabilizing agent is selected from the group consisting of inorganic acids, inorganic bases, inorganic salts, organic acids or bases and pharmaceutically acceptable salts thereof, saccharides, oligosaccharides, polysaccharides, and cellulose and cellulose derivatives, or mixtures thereof.

23. A composition according to claim 22, wherein the organic acid is selected from the group consisting of acetic acid, ethanoic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, adipic acid, angelic acid, ascorbic acid/vitamin C, carbamic acid, cinnamic acid, citramalic acid, formic acid, fumaric acid, gallic acid, gentisic acid, glutaconic acid, glutaric acid, glyceric acid, glycolic acid, glyoxylic acid, lactic acid, levulinic acid, malonic acid, mandelic acid, oxalic acid, oxamic acid, pimelic acid, pyruvic acid, aspartic and glutamic acid, or mixtures thereof.

24. A composition according to claim 22, wherein the inorganic acid is pyrophosphoric acid, glycerophosphoric acid, phosphoric acid, boric acid, hydrochloric acid, or sulfuric acid, or mixtures thereof.

25. A composition according to claim 22, wherein the suitable inorganic compounds include aluminium.

26. A composition according to claim 22, wherein the suitable organic bases are selected from the group consisting of p-nitrophenol, succinimide, benzenesulfonamide, 2-hydroxy-2cyclohexenone, imidazole, pyrrole, diethanolamine, ethyleneamine, tris (hydroxymethyl) aminomethane, hydroxylamine and derivates of amines, sodium citrate, aniline, and hydrazine, or mixtures thereof.

27. A composition according to claim 22, wherein the suitable inorganic bases are selected from the group consisting of aluminium oxides, sodium hydroxide, potassium hydroxide, calcium carbonate, ammonium carbonate, ammnonium hydroxide, KOH and mixtures thereof.

28. A composition according to claim 22, wherein the pharmaceutically acceptable salt of an organic acid is selected from the group consisting of sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogenphosphate, potassium hydrogenphosphate, calcium phosphate, dicalcium phosphate, sodium sulfate, potassium sulfate, calcium sulfate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, calcium carbonate, magnesium carbonate, sodium acetate, potassium acetate, calcium acetate, sodium succinate, potassium succinate, calcium succinate, sodium citrate, potassium citrate, calcium citrate, sodium tartrate, potassium tartrate, calcium tartrate, zinc gluconate, zinc sulphate and mixtures thereof.

29. A composition according to claim 22, wherein the inorganic salt is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride and mixtures thereof.

30. A composition according to claim 22, wherein the pharmaceutically acceptable excipient is selected from glucose, ribose, arabinose, xylose, lyxose, allose, altrose, inosito, glucose, sorbitol, mannose, gulose, idose, galactose, talose, mannitol, fructose, lactose, sucrose, dextrin, dextran, amylose, xylan, cellulose and cellulose derivatives, amylopectin, pectin, starch, sodium starch, kaolin, bentonit, acacia, alginic acid, sodium alginate, calcium alginate, gelatin, dextrose, molasses, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, veegum, glycollate, magnesium stearate, calcium stearate, stearic acid, talc, titanium dioxide, silicium dioxide, clays, croscarmellose, gums, agar, and mixtures thereof.

31. A composition according to claim 1 further comprising a pharmaceutically acceptable excipient selected from the group consisting of fillers, diluents, disintegrants, glidants, pH-adjusting agents, viscosity adjusting agents, solubility increasing or decreasing agents, osmotically active agents and solvents.

32. A composition according to claim 22, wherein the stabilizing agent is citric acid including solvates and anhydrates thereof.

33. A composition according to claim 32, wherein the citric acid has a water content of at the most about 15% w/w.

34. A composition according to claim 22, wherein the stabilizing agent is a phosphoric acid or a phosphonic acid or a salt thereof.

35. A composition according to claim 34, wherein the phosphoric acid is ortho or meta phoshoric acid or a mixture thereof.

36. A composition according to claim 1, wherein the concentration of the active substance in the composition corresponds to a concentration of at the most the saturated concentration in component i) at a temperature corresponding to the melting point or the lowest end point of the melting interval of component i).

37. A composition according to claim 1, wherein the first polymer is of a quality that ensures that free radicals formed, if any, do not significantly increase the degradation of the active substance in the composition.

38. A composition according to claim 1 further comprising one or more antioxidants that inhibits the formation of peroxides and/or inactivates any peroxides present.

39. A composition according to claim 1, wherein the active substance has antioxidant properties.

40. A composition according to claim 1, wherein the composition is stable with respect to physical stability.

41. A composition according to claim 1, wherein the composition is stable with respect to in vitro dissolution of the active substance from the composition.

42. A composition according to claim 41, wherein the composition is stable with respect to in vitro dissolution behaviour in such a manner that t_50%, (the time for 50% w/w of the active substance to dissolve in a dissolution medium), differs at the most ±

20% w/w when two compositions from the same batch are compared with a time difference of 2 weeks under similar storage and test conditions.

43. A composition according to claim 1, wherein the composition is stable with respect to chemical stability of the active substance.

44. A composition according to claim 43, wherein the concentration of the active substance in the composition decreases at the most 20% w/w when stored at room temperature for a time period of at least 3 months and a relative humidity of at the most 75%.

45. A composition according to claim 1, wherein the active substance is present in the composition in a concentration of from about 0.1 to about 98% w/w.

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

47. A composition according to claim 1, wherein in the aqueous medium in which the composition is to be used, the coating does not completely crumble or erode before the matrix has completely eroded.

48. A composition according to claim 1, wherein said first cellulose derivative is a cellulose ether which, when heated, is shapeable by molding or extrusion.

49. A composition according to claim 48 in which the cellulose ether comprises at least one ethylcellulose.

50. A composition according to claim 1 in which said first cellulose derivative is selected from the group consisting of cellulose acetate, cellulose propionate and cellulose nitrate.

51. A composition according to claim 1 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, hydroxyethylcellylose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxymethylpropylcellulose.

52. A composition according to claim 51 in which said salt of carboxymethylcellulose is selected from the group consisting of alkali metal and alkaline earth metal salts.

53. A composition according to claim 1, 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.

54. A composition according to claim 53 in which said fatty alcohol is selected from the group consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol and myristyl alcohol.

55. A composition according to claim 1 in which said plasticizer is a non-ionic surfactant.

56. A composition according to claim 1, wherein the solid dispersion does not contain polyethylene glycol 2000 monostearate or polyethylene glycol 400 monostearate.

57. A composition according to claim 1, wherein the first polymer has a molecular weight of at least 100,000 daltons and at the most 400,000 daltons.

58. A composition according to claim 1, wherein release of the active substance from the composition is zero order and about 50% w/w of the active substance is released from the composition within 5-6 hours from start of release as measured by an in vitro dissolution test (USP) at 50 RPM in 0.1N HCl (pH 1) or in buffer (pH 6.8).

59. A composition according to claim 1, wherein release of the active substance from the composition is zero order and about 50% w/w of the active substance is released from the composition within 4-5 hours from start of release as measured by an in vitro dissolution test (USP) at 50 RPM in 0.1N HCl (pH 1) or in buffer (pH 6.8).

60. A composition according to claim 1, wherein release of the active substance from the composition is zero order and about 50% w/w of the active substance is released from the composition within 3-4 hours from start of release as measured by an in vitro dissolution test (USP) at 50 RPM in 0.1N HCl (pH 1) or in buffer (pH 6.8).

61. A composition according to claim 1, wherein release of the active substance from the composition is zero order and about 50% w/w of the active substance is released from the composition within 2-3 hours from start of release as measured by an in vitro dissolution test (USP) at 50 RPM in 0.1N HCl (pH 1) or in buffer (pH 6.8).

62. A composition according to claim 1, wherein release of the active substance from the composition is substantially delayed for 0.25 to 4 hours before the zero order release starts as measured by an in vitro dissolution test (USP) at 50 RPM in 0.1N HCl (pH 1) or in buffer (pH 6.8).

63. A method for preparing a composition according to claim 1, comprising injection moulding of a melted or semi-solid mixture of the matrix composition components into a suitable form, application of the coating by injection moulding, and cooling the thus prepared coated composition to solidify the composition.

64. A method according to claim 63, wherein the method is a substantially single continuous process.

65. A method according to claim 64, wherein the cooling is performed under controlled conditions to a temperature of from about 0°

C. to about 20°

C.

66. A method according to claim 1 comprising a step of heating while the polymer and the active substance is in physical contact with each other.

67. A composition according to claim 1, wherein the polyethylene glycol and/or polyethylene oxide has a molecular weight of from about 20,000 to about 700,000 daltons.

68. A composition according to claim 4, wherein the concentration of the first polymer in the matrix composition is from about 20 to about 95%.

69. A composition according to claim 7, wherein the poloxamer has a molecular weight of from about 4,000 daltons to about 15,000 daltons.

70. A controlled release pharmaceutical composition for oral use in the form of a coated matrix composition, the matrix composition comprising

(i) a mixture of a first polymer and a second polymer that have plasticizing properties and which have melting points or melting intervals of a temperature of at the most 200°

C.,

the first polymer being selected from the group consisting of polyethylene glycols and polyethylene oxides having a molecular weight of at least about 20,000 daltons in crystalline and/or amorphous form, or a mixture of such polymers, and

the second polymer being selected from block copolymers of ethylene oxide and propylene oxide having an HLB value of at least 18, and

(ii) a therapeutically, prophylactically and/or diagnostically active substance,

wherein the concentration of the second polymer in the matrix composition is from about 5 to about 90% w/w,

the matrix composition being provided with a coating which is substantially insoluble in and impermeable to body fluids during the intended release periods, the coating having at least one opening exposing one surface of said matrix,

the coating comprising one or more coating polymers which can be processed by extrusion, solution, or in the form of a dispersion, the one or more coating polymers being selected from the group consisting of cellulose acetate, polyamide, polyethylene, polyethylene terephthalate, polypropylene, polyurethane, polyvinyl acetate, polyvinyl chloride, silicone rubber, latex, polyhydroxybutyrate, polyhydroxyvalerate, teflon, polylactic acid or polyglycolic acid and copolymers thereof, ethylene vinyl acetate (EVA) copolymers, styrene-butadienestyrene (SBS) copolymers and styrene-isoprene-styrene (SIS) copolymers.

71. The composition according to claim 70, wherein the polyethylene glycol and/or polyethylene oxide has a molecular weight selected from the group consisting of from about 20,000 to about 700,000 daltons, 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, 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 and about 400,000 daltons.

72. The composition according to claim 70, wherein the concentration of the first polymer in the matrix composition is selected from the group consisting of from about 10 to about 99.5% w/w, from about 20 to about 99% w/w, from about 30 to about 99% w/w, from about 35 to about 95% w/w, from about 35 to about 90% w/w, from about 35 to about 85% w/w, from about 35 to about 80% w/w, from about 40 to about 75% w/w, from about 45 to about 70% w/w, from about 45 to about 65% w/w, from about 55 to about 85% w/w and from about 60 to about 85% w/w.

73. The composition according to claim 70, wherein the second polymer has a molecular weight of at least about 2,000 daltons.

74. The composition according to claim 70, wherein the second polymer is a poloxamer having a molecular weight selected from the group consisting of from about 2,000 daltons to about 20,000 daltons, from about 4,000 daltons to about 15,000 daltons and from about 6,000 daltons to about 10,000 daltons.

75. The composition according to claim 70, wherein the second polymer has a melting point selected from the group consisting of from about 20-120°

C., from about 30-100°

C. and from about 40-80°

C.

76. The composition according to claim 70, wherein the second polymer has an HLB value of at least about 20.

77. The composition according to claim 70, wherein the concentration of the second polymer in the matrix composition is selected from the group consisting of from about 10% to about 90% w/w, from about 10% to about 80% w/w, from about 10% to about 70% w/w, from about 10% to about 60%, from about 10% to about 50%, from about 15% to about 50% w/w, from about 10% to about 45% w/w, from about 10% to about 40% w/w, from about 15% to about 40% w/w, from about 15% to about 35% w/w and from about 15% to about 30% w/w.

78. The pharmaceutical composition according to claim 70, wherein said composition provides controlled release of the active substance into an aqueous medium by erosion of at least one surface of the composition.

79. The composition according to claim 70, wherein the active substance is present in any of its crystalline, polymorphous or amorphous forms or mixtures thereof.

80. A pharmaceutical composition according to claim 70, wherein the active substance at least partially is present in a molecular dispersion.

81. The composition according to claim 70, further comprising a stabilizing agent.

82. The composition according to claim 81, wherein the stabilizing agent is selected from the group consisting of inorganic acids, inorganic bases, inorganic salts, organic acids or bases and pharmaceutically acceptable salts thereof, saccharides, oligosaccharides, polysaccharides, cellulose derivatives, and mixtures thereof.

83. The composition according to claim 70, wherein the block copolymer of ethylene oxide and propylene oxide is selected from the group consisting of poly(ethylene-glycol-b-(DL-lactic acid-co-glycolic acid)-b-ethylene glycol (PEG-PLGA PEG), poly((DL-lactic acid-co-glycolic acid)-g-ethylene glycol) (PLGA-g-PEG), poloxamers and polyethylene oxide-polypropylene oxide (PEO-PPO).

84. A method for preparing a composition according to claim 70, wherein the method comprises

injection molding of a melted or semi-solid mixture of the matrix composition components into a suitable form,

application of the coating by injection molding and

cooling the thus prepared coated composition to solidify the composition.