CONTROLLED ABSORPTION OF STATINS IN THE INTESTINE

• US 20090196889A1
• Filed: 11/22/2005
• Published: 08/06/2009
• Est. Priority Date: 11/22/2004
• Status: Abandoned Application

• Current Assignee: Dexcel Pharma Technologies (Dexcel Limited)
• Original Assignee: Dexcel Pharma Technologies (Dexcel Limited)
• Inventors: Penhasi, Adel
• Application Number:
  US11/719,786
• Publication Number:
  US 20090196889A1
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2886 having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer of the type active core-drug layer-inactive layer A61K9/209

Abstract

The present invention provides a controlled absorption formulation in which modified release of active ingredient preferentially occurs in the lower gastrointestinal tract, including the colon. The formulation supports a significantly higher bioavailability of the active ingredient into the body of the subject than can be achieved from the currently used conventional formulation, such that therapeutically significant plasma levels of statin are maintained for an extended period after administration. The formulation preferably features a core over which an outer coating is layered. The core is optionally and preferentially in the form of a tablet.

Claims

1. A delayed burst release formulation for providing an increased blood concentration of a statin and/or active forms of said statin, relative to that resulting from the administration of an equivalent dose of the conventional immediate release formulations, comprising:

a core and an outer coating that surrounds the core;

said core comprising a statin and/or a pharmaceutically acceptable salt and/or ester thereof, said core comprising a burst controlling agent and a disintegrant, and

said coating characterized by at least one of the following;

a. pH dependent coating film, preferably an enteric coating;

b. a combination of at least one water soluble polymer and at least one water insoluble polymer;

c. a combination of at least one swellable polymer and at least one water insoluble polymer;

d. a combination of at least a water soluble pore forming agent and at least one water insoluble polymer;

e. at least one swellable gel forming polymer;

f. at least one biodegradable polymer;

g. at least one erodible polymer;

h. a combination of at least one pH dependent polymer and at least one water insoluble polymer;

i. a two-layer coating comprising a rupturing outer layer and swellable inner layer.

2. The formulation of claim 1, wherein said formulation preferentially releases statin in the intestine of the subject.

3. The formulation of claim 1, wherein said formulation preferentially releases statin in the lower gastrointestinal tract.

4. The formulation of claim 1, wherein said formulation preferentially releases statin in the colon of the subject.

5. The formulation of claim 1 wherein said core is in the form of one of a tablet, pellets, microparticles, agglomerate, and capsule.

6. The formulation of claim 1, wherein said burst controlling agent comprises a water insoluble polymer.

7. The formulation of claim 6, wherein said water insoluble polymer is selected from the group consisting of cross-linked polysaccharide, water insoluble starch, microcrystalline cellulose, water insoluble cross-linked peptide, water insoluble cross-linked protein, water insoluble cross-linked gelatin, water insoluble cross-linked hydrolyzed gelatin, water insoluble cross-linked collagen, modified cellulose, and cross-linked polyacrylic acid.

8. The formulation of claim 7 wherein said cross-linked polysaccharide is selected from the group consisting of insoluble metal salts or cross-linked derivatives of alginate, pectin, xantham gum, guar gum, tragacanth gum, and locust bean gum, carrageenan, metal salts thereof, and covalently cross-linked derivatives thereof.

9. The formulation of claim 7 wherein said modified cellulose is selected from the group consisting of cross-linked derivatives of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, and metal salts of carboxymethylcellulose.

10. The formulation of claim 6, wherein said water insoluble polymer is calcium pectinate.

11. The formulation of claim 6, wherein said water insoluble polymer is microcrystalline cellulose.

12. The formulation of claim 1, wherein said water insoluble polymer is swellable.

13. The formulation of claim 1, wherein said water insoluble polymer is non swellable.

14. The formulation of claim 1, wherein said water insoluble polymer is hydrophobic.

15. The formulation of claim 1, wherein said disintegrant is selected from the group consisting of cross-linked polyvinylpyrrolidinone, sodium starch glycolate, cross-linked sodium carboxymethylcellulose, pregelatinized starch, microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminium silicate, and combinations thereof.

16. The formulation of claim 1, wherein said core further comprises at least one of an absorption enhancer, a binder, a hardness enhancing agent and an excipient.

17. The formulation of claim 16, wherein said binder is selected from the group consisting of starch, polyvinylpyrrolidone, low molecular weight hydroxypropylcellulose, low molecular weight hydroxypropylmethylcellulose, low molecular weight carboxymethylcellulose, ethylcellulose, gelatin, polyethylene oxide, acacia, dextrin, magnesium aluminum silicate, and polymethacrylates.

18. The formulation of claim 16, wherein said hardness enhancing agent is microcrystalline cellulose.

19. The formulation of claim 1, wherein said core further comprises a buffering agent.

20. The formulation of claim 19, wherein said buffering agent is selected from the group consisting of an inorganic salt compound and an organic alkaline salt compound.

21. The formulation of claim 1, wherein said core further comprises a filler.

22. The formulation of claim 21, wherein said filler is selected from the group consisting of, starch, lactitol, lactose, an inorganic calcium salt, sucrose, and combinations thereof.

23. The formulation of claim 1, wherein said core further comprises a flow regulating agent.

24. The formulation of claim 23, wherein said flow regulating agent includes at least one of colloidal silicon dioxide and aluminum silicate.

25. The formulation of claim 1, wherein said core further comprises a lubricant.

26. The formulation of claim 25, wherein said lubricant is selected from the group consisting of stearate salts;

stearic acid, talc, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol, and glycerol behenate, or a combination thereof.

27. The formulation of claim 1, wherein said coating comprises a pH dependent polymer.

28. The formulation of claim 27, wherein said pH dependent polymer is selected from the group consisting of methacrylic acid copolymers, ammonio methacrylate co-polymers, or a mixture thereof.

29. The formulation of claim 27, wherein said pH dependent polymer is selected from the group consisting of a hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, poly(methacrylic acid, methyl methacrylate)1:

1 and poly(methacrylic acid, ethyl acrylate)1;

1, alginic acid, and sodium alginate.

30. The formulation of claim 27, wherein said pH dependent coating comprises an enteric coating.

31. The formulation of claim 30, wherein said enteric coating comprises Hydroxypropylmethyl cellulose acetate succinate (HPMC AS).

32. The formulation of claim 31, wherein said HPMC AS is present in an amount ranging from about 25% to about 90% of said enteric coating.

33. The formulation of any of claims 30-32, wherein said enteric coating further comprises a plasticizer.

34. The formulation of claim 33, wherein said plasticizer comprises triethyl citrate.

35. The formulation of any of claims 30-34, wherein said enteric coating further comprises a surfactant.

36. The formulation of claim 35, wherein said surfactant comprises sodium lauryl sulfate.

37. The formulation of claim 1, wherein said coating comprises a combination of at least one water soluble polymer and at least one water insoluble polymer.

38. The formulation of claim 37, wherein said water-soluble polymer is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone (PVP), methylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, polyethylene glycol, carboxymethyl cellulose (sodium salt), hydroxyethyl cellulose, a water soluble gum, polysaccharide and/or mixtures thereof.

39. The formulation of claim 37, wherein said water insoluble polymer is selected from the group consisting of a podimethylaminoethylacrylate/ethylmethacrylate copolymer, an ethylmethacrylate/chlorotrimethylammoniumethyl methacrylate copolymer, a dimethylaminoethylmethacrylate/methylmethacrylate and butylmethacrylate copolymer, a copolymer based on neutral methacrylic acid esters and dimethylaminoethyl methacrylate esters, an ethylacrylate and methylacrylate/ethylmethacrylate and methyl methylacrylate copolymer, ethylcellulose, shellac, zein, and waxes, paraffin, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethylmethacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), and poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly (methylacrylate), poly(isopropyl acrylate), poly(isobutyl acrylate) poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly (ethylene oxide), poly(ethyleneterephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) and polyurethane, and/or mixtures thereof.

40. The formulation of claim 39, wherein said water insoluble polymer comprises ethylcellulose.

41. The formulation of claim 38, wherein said water soluble polymer comprises a copolymer of polyvinyl pyrrolidone and vinyl acetate.

42. The formulation of claim 37, wherein said water insoluble polymer is present in an amount ranging from about 20% to about 95% of said coating, and said water soluble polymer is present in an amount ranging from about 5% to about 45% of said coating.

43. The formulation of any of claims 30-32, wherein said coating further comprises a glidant.

44. The formulation of claim 43, wherein said glidant comprises sieved talc.

45. The formulation of claim 1, wherein said coating comprises a combination of at least a water soluble pore forming agent and at least one water insoluble polymer.

46. The formulation of claim 45, wherein said pore-forming agent is selected from the group consisting of saccharose, sodium chloride, potassium chloride, polyvinylpyrrolidone, and/or polyethyleneglycol, water soluble organic acids, sugars and sugar alcohol.

47. The formulation of claim 45, wherein said pore forming compound is distributed uniformly throughout said water insoluble polymer.

48. The formulation of claim 45, wherein said pore forming compound is distributed randomly throughout said water insoluble polymer.

49. The formulation of claim 45, wherein said pore-forming compound comprises about 1 part to about 35 parts for each about 1 to about 10 parts of said water insoluble polymer.

50. The formulation of claim 1, wherein said coating comprises an erodible polymer.

51. The formulation of claim 50, wherein said erodible composition comprises at least one of a slow dissolving and a slow disintegrating composition.

52. The formulation of claim 50, wherein said erodible composition comprises at least one of a slowly water soluble polymer and a swellable polymer

53. The formulation of claims 51 or 52, wherein said erodible composition further comprises a disintegrant.

54. The formulation of claim 1, wherein said coating comprises at least one swellable gel forming polymer.

55. The formulation of claim 54, wherein said swellable gel-forming polymer is selected from the group consisting of cellulosic polymers;

vinyl polymers;

acrylic polymers and copolymers, methacrylic acid copolymers, ethyl acrylate-methyl methacrylate copolymers, natural and synthetic gums, gelatin, collagen, proteins, polysaccharides, pectin, pectic acid, alginic acid, sodium alginate, carbopol, polyaminoacids, polyalcohols, polyglycols; and

mixtures thereof.

56. The formulation of claim 55, wherein said cellulosic polymer is selected from the group consisting of methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and hydroxyethylcellulose.

57. The formulation of claim 56, wherein said cellulosic polymer comprises hydroxymethylcellulose.

58. The formulation of claim 55, wherein said swellable gel-forming polymer comprises carbopol.

59. The formulation of claim 1, wherein said coating further comprises at least one of a lubricant, a flow promoting agent, a plasticizer, an antisticking agent, natural and synthetic flavorings and natural and synthetic colorants.

60. The formulation of claim 59, wherein said lubricant further comprises at least one of polyethylene glycol, polyvinylpyrrolidone, talc, magnesium stearate, glyceryl behenate, stearic acid, and titanium dioxide.

61. The formulation of claim 1, wherein said coating comprises a combination of at least one swellable polymer and at least one water insoluble polymer.

62. The formulation of claim 61, wherein said swellable polymer comprises hydroxypropyl methyl cellulose (HPMC).

63. The formulation of claim 62, wherein said water insoluble polymer comprises ethyl cellulose.

64. The formulation of claim 63, wherein said water insoluble polymer is present in an amount ranging from about 20% to about 95%, and said swellable polymer is present in an amount ranging from about 5% to about 45% of the coating.

65. The formulation of any of claims 61-64, wherein the coating further comprises a surfactant.

66. The formulation of claim 65, wherein said surfactant comprises sodium lauryl sulphate.

67. The formulation of any of claims 61-66, wherein the coating further comprises a stiffening agent.

68. The formulation of claim 67, wherein said stiffening agent comprises cetyl alcohol.

69. The formulation of any of claims 61-68, wherein the coating further comprises a glidant.

70. The formulation of claim 69, wherein said glidant comprises sieved talc.

71. The formulation of claim 1, wherein said coating comprises a combination of at least one pH dependent polymer and at least one water insoluble polymer.

72. The formulation of claim 1, wherein said coating comprises a two-layer coating comprising a rupturable outer layer and swellable inner layer.

73. The formulation of claim 72, wherein said two-layer coating ruptures independently of said core.

74. The formulation of any one of claims 72 or 73, wherein said inner layer comprises a disintegrant.

75. The formulation of any of claims 72-74, wherein said inner layer comprises at least one polymer being able to swell when contacted by water.

76. The formulation of claim 75, wherein said at least one polymer is selected from the group consisting of hydroxypropylmethyl cellulose, high molecular weight of carboxymethyl cellulose, high molecular weight of hydroxypropyl cellulose, high molecular weight of hydroxyethyl cellulose, high molecular weight of hydroxymethyl cellulose, polyhydroxyethyl methacrylate, polyhydroxymethyl methacrylate, polyacrylic acid, carbopole, polycarbophil, gums, polysaccharides, modified polysaccharides, cross-linked polysaccharide, water insoluble starch, microcrystalline cellulose, water insoluble cross-linked peptide, water insoluble cross-linked protein, water insoluble cross-linked gelatin, water insoluble cross-linked hydrolyzed gelatin, water insoluble cross-linked collagen modified cellulose, and cross-linked polyacrylic acid.

77. The formulation of claim 76, wherein said cross-linked polysaccharide is selected from the group consisting of insoluble metal salts or cross-linked derivatives of alginate, pectin, xanthan gum, guar gum, tragacanth gum, and locust bean gum, carrageenan, metal salts thereof, and covalently cross-linked derivatives thereof.

78. The formulation of claim 76, wherein said modified cellulose is selected from the group consisting of cross-linked derivatives of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, and metal salts of carboxymethylcellulose.

79. The formulation of any of claims 74-78, wherein said inner layer comprises a disintegrant embedded in a water soluble film forming polymer.

80. The formulation of any of claims 74-78, wherein said inner layer comprises a combination of a water soluble polymer forming a film matrix, and a swellable water insoluble polymer particulate embedded into said film matrix.

81. The formulation of any of claims 72-80, wherein said rupturable outer layer comprises a brittle polymer.

82. The formulation of any of claims 72-81, wherein said rupturable outer layer comprises at least one permeation-enhancing agent.

83. The formulation of claims 81 or 82, wherein said rupturable outer layer comprises a water insoluble polymer selected from the group consisting of a dimethylaminoethylacrylate/ethylmethacrylate copolymer, the copolymer being based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is approximately 1:

20, the polymer corresponding to USP/NF “

Ammonio Methacrylate Copolymer Type A”

, an ethylmethacrylate/chlorotrimethylammoniumethyl methacrylate copolymer, the copolymer based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is 1;

40, the polymer corresponding to USP/NF “

Ammonio Methacrylate Copolymer Type B”

, a dimethylaminoethylmethacrylate/methylmethacrylate and butylmethacrylate copolymer, a copolymer based on neutral methacrylic acid esters and dimethylaminoethyl methacrylate esters wherein the polymer is cationic in the presence of acids, an ethylacrylate and methylacrylate/ethylmethacrylate and methyl methylacrylate copolymer, the copolymer being a neutral copolymer based on neutral methacrylic acid and acrylic acid esters, ethylcellulose, shellac, zein, and waxes.

84. The formulation of claim 83, wherein said water insoluble polymer comprises ethylcellulose.

85. The formulation of claim 1, wherein said coating is a compression coating.

86. The formulation of claim 85, wherein said coating comprises a gum selected from the group consisting of xanthan gum, locust bean gum, galactans, mannans, alginates, gum karaya, pectin, agar, tragacanth, accacia, carrageenan, tragacanth, chitosan, agar, alginic acid, hydrocolloids acacia catechu, salai guggal, indian bodellum, copaiba gum, asafetida, cambi gum, Enterolobium cyclocarpum, mastic gum, benzoin gum, sandarac, gambier gum, butea frondosa (Flame of Forest Gum), myrrh, konjak mannan, guar gum, welan gum, gellan gum, tara gum, locust bean gum, carageenan gum, glucomannan, galactan gum, sodium alginate, tragacanth, chitosan, xanthan gum, deacetylated xanthan gum, pectin, sodium polypectate, gluten, karaya gum, tamarind gum, ghatti gum, Accaroid/Yacca/Red gum, dammar gum, juniper gum, ester gum, ipil-ipil seed gum, gum talha (acacia seyal), and cultured plant cell gums including those of the plants of the genera:

acacia, actinidia, aptenia, carbobrotus, chickorium, cucumis, glycine, hibiscus, hordeum, letuca, lycopersicon, malus, medicago, mesembryanthemum, oryza, panicum, phalaris, phleum, poliathus, polycarbophil, sida, solanum, trifolium, trigonella, Afzelia africana seed gum, Treculia africana gum, detarium gum, cassia gum, carob gum, Prosopis africana gum, Colocassia esulenta gum, Hakea gibbosa gum, khaya gum, scleroglucan, zea, mixtures of any of the foregoing.

87. The formulation of claim 86, wherein said compression coating comprises at least one of a heteropolysaccharide and a homopolysaccharide, or a mixture thereof.

88. The formulation of claim 87, wherein said heteropolysaccharide is xanthan gum.

89. The formulation of claim 1, wherein said outer coating further comprises a plasticizer.

90. The formulation of claim 89, wherein said plasticizer is selected from the group consisting of dibutyl sebacate, polyethylene glycol and polypropylene glycol, dibutyl phthalate, diethyl phthalate, triethyl citrate, tributyl citrate, acetylated monoglyceride, acetyl tributyl citrate, triacetin, dimethyl phthalate, benzyl benzoate, butyl and/or glycol esters of fatty acids, refined mineral oils, oleic acid, castor oil, corn oil, camphor, glycerol and sorbitol or a combination thereof.

91. The formulation of claim 1, wherein said coating further comprises a stiffening agent.

92. The formulation of claim 91, wherein said stiffening agent comprises cetyl alcohol.

93. The formulation of claim 1, wherein said coating and/or said core further comprises at least one of a wetting agent, a suspending agent, and a dispersing agent, or a combination thereof.

94. The formulation of claim 93 wherein said wetting agent is selected from the group consisting of poloxamer, polyoxyethylene ethers, polyoxyethylene sorbitan fatty acid esters, polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters, benzalkonium chloride, polyethoxylated castor oil, and docusate sodium.

95. The formulation of claim 93, wherein said suspending agent is selected from the group consisting of alginic acid, bentonite, carbomer, carboxymethylcellulose, carboxymethylcellulose calcium, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, colloidal silicon dioxide, dextrin, gelatin, guar gum, xanthan gum, kaolin, magnesium aluminum silicate, maltitol medium chain triglycerides, methylcellulose, polyoxyethylene sorbitan fatty acid esters, polyvinylpyrrolidinone, propylene glycol alginate, sodium alginate, sorbitan fatty acid esters, and tragacanth.

96. The formulation of claim 95, wherein said dispersing agent is selected from the group consisting of poloxamer, polyoxyethylene sorbitan fatty acid esters and sorbitan fatty acid esters.

97. The formulation of claim 1, further comprising an enteric coating disposed over said coating.

98. The formulation of claim 97, wherein said enteric coating is selected from the group consisting of cellulose acetate phthalate, hydroxy propyl methyl cellulose acetate succinate, poly(methacrylic acid, methyl methacrylate)1:

1 and (Eudragit®

L100), poly(methacrylic acid, ethyl acrylate) 1;

1 (Eudragit®

L30D-55).

99. The formulation of claim 1, wherein said core further comprises a synergistic agent (sequestrate).

100. The formulation of claim 99, wherein said synergistic agent is selected from the group consisting of citric acid and ascorbic acid.

101. The formulation of claim 1, wherein said core further comprises an antioxidant.

102. The formulation of claim 101, wherein said antioxidant is selected from the group consisting of 4,4 (2,3 dimethyl tetramethylene dipyrochatechol), Tocopherol-rich extract (natural vitamin E), α

-tocopherol (synthetic Vitamin E), β

-tocopherol, γ

-tocopherol, δ

-tocopherol, Butylhydroxinon, Butyl hydroxyanisole (BHA), Butyl hydroxytoluene (BHT), Propyl Gallate, Octyl gallate, Dodecyl Gallate, Tertiary butylhydroquinone (TBHQ), Fumaric acid, Malic acid, Ascorbic acid (Vitamin C), Sodium ascorbate, Calcium ascorbate, Potassium ascorbate, Ascorbyl palmitate, Ascorbyl stearate, Citric acid, Sodium lactate, Potassium lactate, Calcium lactate, Magnesium lactate, Anoxomer, Erythorbic acid, Sodium erythorbate, Erythorbin acid, Sodium erythorbin, Ethoxyquin, Glycine, Gum guaiac, Sodium citrates (monosodium citrate, disodium citrate, trisodium citrate), Potassium citrates (monopotassium citrate, tripotassium citrate), Lecithin, Polyphosphate, Tartaric acid, Sodium tartrates (monosodium tartrate, disodium tartrate), Potassium tartrates (monopotassium tartrate, dipotassium tartrate), Sodium potassium tartrate, Phosphoric acid, Sodium phosphates (monosodium phosphate, disodium phosphate, trisodium phosphate), Potassium phosphates (monopotassium phosphate, dipotassium phosphate, tripotassium phosphate), Calcium disodium ethylene diamine tetra-acetate (Calcium disodium EDTA), Lactic acid, Trihydroxy butyrophenone and Thiodipropionic acid.

103. The formulation of claim 1, wherein said core further comprises a chelating agent.

104. The formulation of claim 103, wherein said chelating agent comprises an anti-oxidant.

105. The formulation of claim 104, wherein said antioxidant is selected from the group consisting of antioxidants, dipotassium edentate, disodium edentate, edetate calcium disodium, edetic acid, fumaric acid, malic acid, maltol, sodium edentate, and trisodium edetate.

106. The formulation of claim 1, wherein the formulation releases substantially no statin in vitro for at least about 1 hour.

107. The formulation of claim 1, wherein the formulation releases substantially no statin in vitro for at least about 90 minutes.

108. The formulation of claim 1, wherein the formulation releases substantially no statin in vitro for at least about 2 hours.

109. The formulation of claim 1, wherein at least about 60% of the statin is released in vitro about one hour after said delayed burst release occurs.

110. The formulation of claim 1, characterized in that the in vivo blood plasma concentration of statin and/or a pharmaceutically acceptable salt and/or ester thereof is substantially zero for at least about two hours after oral administration and is controlled by the lag time, providing an increased blood concentration of a statin and/or active forms of said statin, relative to that resulting from the administration of an equivalent dose of the conventional immediate release formulations.

111. The formulation of claim 110, characterized in that the formulation provides an increased blood concentration of a statin and/or active forms of said statin, relative to that resulting from the administration of an equivalent dose of the conventional immediate release formulations

112. The formulation of claim 111, wherein said in vivo blood plasma concentration is extended at least 24 hours.

113. The formulation of any of the preceding claims wherein said statin is released in the small intestine and/or lower gastrointestinal tract resulting in increased formation of intestinally active forms of said statin.

114. The formulation of any of the preceding claims wherein said statin is released in the small intestine and/or lower gastrointestinal tract resulting in an increased concentration of at least one active forms in the blood.

115. The formulation of claim 114, wherein said formulation comprises a decreased dosage of said statin and/or said pharmaceutically acceptable salt and/or ester thereof.

116. The formulation of claim 114, wherein said core comprises a dose of statin of no more than about one-half of a dose as compared to a corresponding immediate release formulation, but wherein a level of at least one statin active form after administration of said delayed burst release formulation is at least about a level of said active metabolite after administration of said corresponding immediate release formulation.

122. A method for using a modified release formulation according to any of the preceding claims to reduce stress on the liver of the subject treated by at least one other drug metabolized by the liver when administering a statin.

123. A method for using a modified release formulation according to any of the preceding claims to reduce stress on the liver of the subject when administering a statin.

124. A method for using a modified release formulation according to any of the preceding claims to reduce liver side effects including increased level of transaminases when administering a statin.

125. A method for using a modified release formulation according to any of the preceding claims to reduce muscle pain and/or level of CPK when administering a statin.

126. A method for using a modified release formulation according to any of the preceding claims to reduce gastrointestinal effects comprising one or more of nausea, dyspepsia, flatulence or constipation when administering a statin.

127. A method for using a delayed onset modified release formulation according to any of the preceding claims, for providing release of said statin or said pharmaceutically acceptable salt or ester or active form thereof that is not affected by food.

128. A method for using a delayed onset modified release formulation according to any of the preceding claims, for providing treatment for high blood cholesterol to a subject in need thereof.

129. A method for providing a therapeutically effective amount of a statin and/or a pharmaceutically acceptable salt and/or ester and/or active form thereof to a subject, comprising administering orally to the subject a delayed onset modified release formulation according to any of the preceding claims.

136. The formulation of any of the preceding claims wherein said statin is released in the small intestine and/or lower gastrointestinal tract resulting in an increased formation of intestinally active forms of said statin.

151. The formulation of any of the preceding claims wherein said statin is released in the small intestine and/or lower gastrointestinal tract resulting in an increased concentration of at least one active forms in the blood.

152. The formulation of any of the preceding claims wherein said statin is selected from the group comprising simvastatin, beta-hydroxy acid simvastatin, lovastatin, mevastatin, pravastatin, fluvastatin, atorvastatin, pitavastatin, rivastatin and cerivastatin, or pharmaceutically acceptable salts and/or esters thereof.

153. The formulation of any of the preceding claims wherein said statin comprises simvastatin.

117. A formulation for providing enhanced bioavailability of a statin and/or a pharmaceutically acceptable salt and/or ester thereof in a subject, comprising:

a delayed burst release formulation for oral administration comprising a core and an outer coating that surrounds the core;

said core comprising a statin and/or a pharmaceutically acceptable salt and/or ester thereof, a burst controlling agent and a disintegrant; and

said coating comprising a water-insoluble hydrophobic carrier and a hydrophilic particulate matter;

characterized in that at least about 70% of the statin is released in vitro about one hour after said delayed burst release occurs.

118. A method for providing fast release of statin and/or a pharmaceutically acceptable salt and/or ester thereof in the lower gastrointestinal tract in a subject, comprising:

administering orally to the subject a delayed burst release formulation comprising a core and an outer coating that surrounds the core;

said core comprising statin and/or a pharmaceutically acceptable salt and/or ester thereof and

said coating characterized by at least one of the

a. pH dependent coating film, preferably an enteric coating;

b. a combination of at least one water soluble polymer and at least one water insoluble polymer;

c. a combination of at least one swellable polymer and at least one water insoluble polymer;

d. a combination of at least a water soluble pore forming agent and at least one water insoluble polymer;

e. at least one swellable gel forming polymer;

f. at least one biodegradable polymer;

g. at least one erodible polymer;

h. a combination of at least one pH dependent polymer and at least one water insoluble polymer;

i. a two-layer coating comprising a rupturable outer layer and swellable inner layer; and

characterized in that the in vivo blood plasma concentration of statin and/or a pharmaceutically acceptable salt and/or ester thereof is substantially zero for at least about two hours after oral administration and is controlled by the lag time, providing an increased blood concentration of a statin and/or active forms of said statin, relative to that resulting from the administration of an equivalent dose of the conventional immediate release formulations.

119. The method of claim 118, wherein said in vivo blood plasma concentration is extended for at least 24 hours.

120. The method of claims 118 or 119, wherein said statin is released in small intestine and/or lower gastrointestinal tract including colon resulting in an increased intestinal metabolite formation.

121. The method of any of claims 118-120 wherein said statin is released in small intestine and/or lower gastrointestinal tract including colon resulting in an increased concentration of a metabolite in the blood.

130. A method for providing a delayed burst release of a therapeutically effective amount of a statin and/or a pharmaceutically acceptable salt and/or ester thereof to a subject wherein substantially no statin is released in vitro for at least about two hours.

131. A method for providing enhanced bioavailability of statin and/or a pharmaceutically acceptable salts and/or esters thereof and/or its related metabolite in a subject, comprising:

administering orally to the subject a modified release formulation comprising a core and an outer coating that surrounds the core;

said core comprising a statin, or a pharmaceutically acceptable salt thereof and at least one release controlling agent, and

said coating characterized by at least one of

a. pH dependent coating film, preferably an enteric coating;

b. a combination of at least one water soluble polymer and at least one water insoluble polymer;

c. a combination of at least one swellable polymer and at least one water insoluble polymer;

d. a combination of at least a water soluble pore forming agent and at least one water insoluble polymer;

e. at least one swellable gel forming polymer;

f. at least one biodegradable polymer;

g. at least one erodible polymer;

h. a combination of at least one pH dependent polymer and at least one water insoluble polymer;

i. a two-layer coating comprising a rupturable outer layer and swellable inner layer;

characterized in that the in vivo blood plasma concentration of said statin is substantially zero for at least about two hours after oral administration.

132. A modified release formulation that releases a statin and/or a pharmaceutically acceptable salt and/or ester thereof in the lower gastrointestinal tract of a subject, characterized in that the in vivo blood plasma concentration of said statin and/or a pharmaceutically acceptable salt and/or ester thereof is substantially zero for at least about one hour after oral administration and is controlled by the lag time, providing an increased blood concentration of a statin and/or active forms of said statin, relative to that resulting from the administration of an equivalent dose of the conventional immediate release formulations.

133. The method of claim 132, wherein said in vivo blood plasma concentration is extended at least 24 hours.

134. The method of claim 132, wherein said core comprises a dose of statin of no more than about one-half of a dose as compared to a corresponding immediate release formulation, but wherein a level of at least one statin active form after administration of said modified release formulation is at least about a level of said active metabolite after administration of said corresponding immediate release formulation.

135. The method of claim 132, wherein said core comprises a dose of statin of no more than about one-half of a dose in said corresponding immediate release formulation, but wherein a level of at least one statin active metabolite after administration of said modified release formulation is at least about a level of said active metabolite after administration of said corresponding immediate release formulation.

137. A modified release formulation for providing an increased blood concentration of a statin and/or active forms of said statin, relative to that resulting from the administration of an equivalent dose of the conventional immediate release formulations, comprising:

a core and an outer coating that surrounds the core;

said core comprising a statin and/or a pharmaceutically acceptable salt and/or ester thereof, and

said coating characterized by at least one of the following;

a. pH dependent coating film, preferably an enteric coating;

b. a combination of at least one water soluble polymer and at least one water insoluble polymer;

c. a combination of at least one swellable polymer and at least one water insoluble polymer;

d. a combination of at least a water soluble pore forming agent and at least one water insoluble polymer;

e. at least one swellable gel forming polymer;

f. at least one biodegradable polymer;

g. at least one erodible polymer;

h. a combination of at least one pH dependent polymer and at least one water insoluble polymer;

i. a two-layer coating comprising a rupturing outer layer and swellable inner layer.

138. A modified release formulation for providing an increased blood concentration of a statin and/or active forms of said statin, relative to that resulting from the administration of an equivalent dose of the conventional immediate release formulations, comprising:

a core and an outer coating that surrounds the core;

said core comprising a statin and/or a pharmaceutically acceptable salt and/or ester thereof, and

said coating comprising a two-layer coating comprising a rupturing outer layer and swellable inner layer.

139. The formulation of claim 138, wherein said two-layer coating ruptures independently of said core.

140. The formulation of claims 138 or 139, wherein said inner layer comprises a disintegrant.

141. The formulation of any of claims 138-140, wherein said inner layer comprises at least one polymer being able to swell when contacted by water.

142. The formulation of claim 141, wherein said at least one polymer is selected from the group consisting of hydroxypropylmethyl cellulose, high molecular weight of carboxymethyl cellulose, high molecular weight of hydroxypropyl cellulose, high molecular weight of hydroxyethyl cellulose, high molecular weight of hydroxymethyl cellulose, polyhydroxyethyl methacrylate, polyhydroxymethyl methacrylate, polyacrylic acid, carbopol, polycarbophil, gums, polysaccharides, modified polysaccharides, cross-linked polysaccharide, water insoluble starch, microcrystalline cellulose, water insoluble cross-linked peptide, water insoluble cross-linked protein, water insoluble cross-linked gelatin, water insoluble cross-linked hydrolyzed gelatin, water insoluble cross-linked collagen modified cellulose, and cross-linked polyacrylic acid.

143. The formulation of claim 142, wherein said cross-linked polysaccharide is selected from the group consisting of insoluble metal salts or cross-linked derivatives of alginate, pectin, xanthan gum, guar gum, tragacanth gum, and locust bean gum, carrageenan, metal salts thereof, and covalently cross-linked derivatives thereof.

144. The formulation of claim 143, wherein said modified cellulose is selected from the group consisting of cross-linked derivatives of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, and metal salts of carboxymethylcellulose.

145. The formulation of any of claims 140-144, wherein said inner layer comprises a disintegrant embedded in a water soluble film forming polymer.

146. The formulation of any of claims 140-144, wherein said inner layer comprises a combination of a water soluble polymer forming a film matrix, and a swellable water insoluble polymer particulate embedded into said film matrix.

147. The formulation of any of claims 138-146, wherein said rupturable outer layer comprises a brittle polymer.

148. The formulation of any of claims 138-147, wherein said rupturable outer layer comprises at least one permeation-enhancing agent.

149. The formulation of claims 147 or 148, wherein said rupturable outer layer comprises a water insoluble polymer selected from the group consisting of a dimethylaminoethylacrylate/ethylmethacrylate copolymer, the copolymer being based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is approximately 1:

20, the polymer corresponding to USP/NF “

Ammonio Methacrylate Copolymer Type A”

, an ethylmethacrylate/chlorotrimethylammoniumethyl methacrylate copolymer, the copolymer based on acrylic and methacrylic acid esters with a low content of quaternary ammonium groups wherein the molar ratio of the ammonium groups to the remaining neutral (meth)acrylic acid esters is 1;

40, the polymer corresponding to USP/NF “

Ammonio Methacrylate Copolymer Type B”

, a dimethylaminoethylmethacrylate/methylmethacrylate and butylmethacrylate copolymer, a copolymer based on neutral methacrylic acid esters and dimethylaminoethyl methacrylate esters wherein the polymer is cationic in the presence of acids, an ethylacrylate and methylacrylate/ethylmethacrylate and methyl methylacrylate copolymer, the copolymer being a neutral copolymer based on neutral methacrylic acid and acrylic acid esters, ethylcellulose, shellac, zein, and waxes.

150. The formulation of claim 149, wherein said water insoluble polymer comprises ethylcellulose.