Nanoparticulate statin formulations and novel statin combinations

• US 20110027371A1
• Filed: 03/06/2006
• Published: 02/03/2011
• Est. Priority Date: 10/01/1998
• Status: Abandoned Application

• Current Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Original Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Inventors: Liversidge, Elaine, Ryde, Tuula, Cooper, Eugene R., Liversidge, Gary G., Lindner, Marie, Cary, Greta, Hovey, Douglas
• Application Number:
  US11/367,716
• Publication Number:
  US 20110027371A1
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

The present invention is directed to nanoparticulate compositions comprising statin such as lovastatin or simvastatin. The statin particles of the composition have an effective average particle size of less than about 2000 nm. In another aspect of this invention, novel combinations of statins and other cholesterol lowering agents are described and methods of using same are taught.

Claims

1. A statin composition comprising:

(a) particles of at least one statin or a salt thereof, wherein the particles have an effective average particle size of less than about 2000 nm; and

(b) at least one surface stabilizer.

2. The composition of claim 1, wherein the statin is selected from the group consisting of atorvastatin;

a 6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones and derivative other than atorvastatin;

lovastatin;

a keto analog of mevinolin other than lovastatin;

pravastatin;

simvastatin;

velostatin;

fluindostatin;

pyrazole analogs of mevalonolactone derivatives;

rivastatin;

a pyridyldihydroxyheptenoic acid other than rivastatin;

SC-45355;

dichloroacetate;

imidazole analogs of mevalonolactone;

3-carboxy-2-hydroxy-propane-phosphonic acid derivatives;

2,3-di-substituted pyrrole derivatives;

2,3-di-substituted furan derivatives;

2,3-di-substituted thiophene derivatives;

naphthyl analogs of mevalonolactone;

octahydronaphthalenes; and

phosphinic acid compounds.

3. The composition of claim 1, wherein the statin is lovastatin or simvastatin.

4. The composition of claim 1, wherein the statin is selected from the group consisting of a crystalline phase, an amorphous phase, and a semi-crystalline phase.

5. The composition of claim 1, wherein the effective average particle size of the statin particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.

6. The composition of claim 1, wherein the composition is formulated:

(a) for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration;

(b) into a dosage form selected from the group consisting of liquid dispersions, oral suspensions, gels, aerosols, ointments, creams, tablets, capsules;

(c) into a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations;

or

(d) a combination thereof.

8. The composition of claim 1, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.

9. The composition of claim 1, wherein:

(a) the at least one statin or a salt thereof is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined weight of the statin or a salt thereof and at least one surface stabilizer, not including other excipients;

(b) the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999% by weight, from about 5.0% to about 99.9% by weight, and from about 10% to about 99.5% by weight, based on the total combined dry weight of the statin or a salt thereof and at least one surface stabilizer, not including other excipients;

or

(c) a combination thereof.

11. The composition of claim 1, comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.

12. The composition of claim 1, wherein the surface stabilizer is selected from the group consisting of a nonionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer.

13. The composition of claim 1, wherein the at least one surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hypromellose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers;

poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide;

n-decyl β

-D-glucopyranoside;

n-decyl β

-D-maltopyranoside;

n-dodecyl β

-D-glucopyranoside;

n-dodecyl β

-D-maltoside;

heptanoyl-N-methylglucamide;

n-heptyl-β

-D-glucopyranoside;

n-heptyl β

-D-thioglucoside;

n-hexyl β

-D-glucopyranoside;

nonanoyl-N-methylglucamide;

n-noyl β

-D-glucopyranoside;

octanoyl-N-methylglucamide;

n-octyl-β

-D-glucopyranoside;

octyl β

-D-thioglucopyranoside;

lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, lysozyme, random copolymers of vinyl acetate and vinyl pyrrolidone, a cationic polymer, a cationic biopolymer, a cationic polysaccharide, a cationic cellulosic, a cationic alginate, a cationic nonpolymeric compound, a cationic phospholipid, cationic lipids, polymethylmethacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, phosphonium compounds, quarternary ammonium compounds, benzyl-di(2-chloroethyl) ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C_12-15dimethyl hydroxyethyl ammonium chloride, C_12-15dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy)₄ ammonium chloride, lauryl dimethyl (ethenoxy)₄ ammonium bromide, N-alkyl (C_12-18)dimethylbenzyl ammonium chloride, N-alkyl (C_14-18)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C_12-14) dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C_12-14) dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C₁₂ trimethyl ammonium bromides, C₁₅ trimethyl ammonium bromides, C₁₇ trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, polyquaternium 10, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, quaternized ammonium salt polymers, alkyl pyridinium salts;

amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.

18. The composition of claim 1, wherein:

(a) the T_max of the statin, when assayed in the plasma of a mammalian subject following administration, is less than the T_max for a conventional, non-nanoparticulate form of the same statin, administered at the same dosage;

(b) the C_max of the statin, when assayed in the plasma of a mammalian subject following administration, is greater than the C_max for a conventional, non-nanoparticulate form of the same statin, administered at the same dosage;

(c) the AUC of the statin, when assayed in the plasma of a mammalian subject following administration, is greater than the AUC for a conventional, non-nanoparticulate form of the same statin, administered at the same dosage;

or

(d) a combination thereof.

19. The composition of claim 18, wherein:

(a) the T_max is selected from the group consisting of not greater than about 90%, not greater than about 80%, not greater than about 70%, not greater than about 60%, not greater than about 50%, not greater than about 30%, not greater than about 25%, not greater than about 20%, not greater than about 15%, and not greater than about 10% of the T_max, exhibited by a non-nanoparticulate formulation of the same statin, administered at the same dosage;

(b) the C_max is selected from the group consisting of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, and at least about 100% greater than the C_max exhibited by a non-nanoparticulate formulation of the same statin, administered at the same dosage;

(c) the AUC is selected from the group consisting of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, and at least about 100% greater than the AUC exhibited by a non-nanoparticulate formulation of the same statin, administered at the same dosage;

or

(d) a combination thereof.

24. The composition of claim 1 which does not produce significantly different absorption levels when administered under fed as compared to fasting conditions.

25. The composition of claim 24, wherein the difference in absorption of the statin composition of the invention, when administered in the fed versus the fasted state, is selected from the group consisting of less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, and less than about 3%.

26. The composition of claim 1, wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state, when administered to a human.

27. The composition of claim 26, wherein “

bioequivalency”

is established by;

(a) a 90% Confidence Interval of between 0.80 and 1.25 for both C_max and AUC, when administered to a human;

or

(b) a 90% Confidence Interval of between 0.80 and 1.25 for AUC and a 90% Confidence Interval of between 0.70 to 1.43 for C_max, when administered to a human.

29. The composition of claim 1, wherein:

(a) within about 5 minutes at least about 20%, at least about 30%, or at least about 40% of the composition is dissolved;

(b) within about 10 minutes at least about 40%, at least about 50%, about 60%, about 70%, or about 80% of the composition is dissolved;

(c) within about 20 minutes at least about 70%, at least about 80%, about 90%, or about 100% of the composition is dissolved,

wherein dissolution is measured in a media which is discriminating and wherein the rotating blade method (European Pharmacopoeia) is used to measure dissolution, wherein dissolution is measured in a media which is discriminating and wherein the rotating blade method (European Pharmacopoeia) is used to measure dissolution.

37. The composition of claim 29, wherein upon redispersion the statin particles have an effective average particle size of less than about 2 microns.

38. The composition of claim 1, additionally comprising one or more non-statin active agents selected from the group consisting of:

(a) an active agent useful in treating dyslipidemia;

(b) an active agent useful in treating hyperlipidemia;

(c) an active agent useful in treating hypercholesterolemia;

(d) an active agent useful in treating cardiovascular disorders;

(e) an active agent useful in treating hypertriglyceridemia;

(f) an active agent useful in treating coronary heart disease;

(g) an active agent useful in treating peripheral vascular disease;

(h) an active agent useful as adjunctive therapy to diet for the reduction of LDL-C, total-C, triglycerides, and/or Apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb);

(i) an active agent useful as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia);

(j) an active agent useful in treating pancreatitis;

(k) an active agent useful in treating restenosis;

(l) an active agent useful in treating Alzheimer'"'"'s disease;

(m) cholesterol lowering agents;

(n) polycosanols;

(o) alkanoyl L-carnitines,

(p) antihypertensives, and

(q) sterols and/or stanols.

40. The composition of claim 38, wherein:

(a) the cholesterol lowering agent is selected from the group consisting of ACE inhibitors, nicotinic acid, niacin, bile acid sequestrants, fibrates, vitamins, fatty acid derivatives, long chain plant extract alcohols, ezetimibe, and celluloses;

(b) the polycosanol is selected from the group consisting of (1) triacontanol, (2) hexacontanol, (3) ecocosanol, (4) hexacosanol, (5) tetracosanol, (6) dotriacontanol, (7) tetracontanol, (8) natural products comprising triacontanol, hexacontanol, ecocosanol, hexacosanol, tetracosanol, dotriacontanol, or tetracontanol; and

(9) extracts of natural products comprising triacontanol, hexacontanol, ecocosanol, hexacosanol, tetracosanol, dotriacontanol, or tetracontanol;

(c) the antihypertensive is selected from the group consisting of diuretics, beta blockers, alpha blockers, alpha-beta blockers, sympathetic nerve inhibitors, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, and angiotensin receptor blockers;

or

(d) the sterol is selected from the group consisting of plant sterols, plant sterol esters, sitosterol, sitostanol, fish oil, phytosterol, campestanol, stigmasterol, coprostanol, cholestanol, and beta-sitosterol.

44. The composition according to claim 40, wherein:

(a) at least one of the non-statin compounds has an effective average particle size of greater than about 2 microns;

or

(b) at least one of the non-statin compounds has an effective average particle size of less than about 2 microns.

46. The composition of claim 1, wherein:

(a) upon administration the composition redisperses such that the statin particles have an effective average particle size selected from the group consisting of less than about 2000 nm, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm;

(b) the composition redisperses in a biorelevant media such that the statin particles have an effective average particle size selected from the group consisting of less than about 2 microns, less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm;

or

(c) a combination thereof.

7. (canceled)

10. (canceled)

14-17. -17. (canceled)

20-23. -23. (canceled)

28. (canceled)

30-36. -36. (canceled)

39. (canceled)

41-43. -43. (canceled)

45. (canceled)

47. (canceled)

48. A method of making a statin composition comprising contacting particles of at least one statin or a salt thereof with at least one surface stabilizer for a time and under conditions sufficient to provide a statin composition having an effective average particle size of less than about 2000 nm.

49. The method of claim 48, wherein said contacting comprises grinding, wet grinding, homogenizing, precipitation, or a combination thereof.

53. The method of claim 48, wherein the statin is selected from the group consisting of atorvastatin;

a 6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones and derivative other than atorvastatin;

lovastatin;

a keto analog of mevinolin other than lovastatin;

pravastatin;

simvastatin;

velostatin;

fluindostatin;

pyrazole analogs of mevalonolactone derivatives;

rivastatin;

a pyridyldihydroxyheptenoic acid other than rivastatin;

SC-45355;

dichloroacetate;

imidazole analogs of mevalonolactone;

3-carboxy-2-hydroxy-propane-phosphonic acid derivatives;

2,3-di-substituted pyrrole derivatives;

2,3-di-substituted furan derivatives;

2,3-di-substituted thiophene derivatives;

naphthyl analogs of mevalonolactone;

octahydronaphthalenes;

phosphinic acid compounds.

54. The method of claim 48, wherein the statin is lovastatin or simvastatin.

56. The method of claim 48, wherein the effective average particle size of the statin particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1000 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.

50-52. -52. (canceled)

55. (canceled)

57-67. -67. (canceled)

68. A method of treating a subject who suffers from hypercholesterolemia, hypertriglyceridemia, coronary heart disease, or peripheral vascular disease, comprising administering to the subject an effective amount of a composition comprising:

(a) particles of a statin or a salt thereof, wherein the statin particles have an effective average particle size of less than about 2000 nm; and

(b) at least one surface stabilizer associated with the surface of the statin particles.

69. The method of claim 68, wherein the statin is selected from the group consisting of atorvastatin;

a 6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones and derivative other than atorvastatin;

lovastatin;

a keto analog of mevinolin other than lovastatin;

pravastatin;

simvastatin;

velostatin;

fluindostatin;

pyrazole analogs of mevalonolactone derivatives;

rivastatin;

a pyridyldihydroxyheptenoic acid other than rivastatin;

SC-45355;

dichloroacetate;

imidazole analogs of mevalonolactone;

3-carboxy-2-hydroxy-propane-phosphonic acid derivatives;

2,3-di-substituted pyrrole derivatives;

2,3-di-substituted furan derivatives;

2,3-di-substituted thiophene derivatives;

naphthyl analogs of mevalonolactone;

octahydronaphthalenes;

phosphinic acid compounds.

70. The method of claim 68, wherein the statin is lovastatin or simvastatin.

72. The method of claim 68, wherein the effective average particle size of the statin particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.

96. The method of claim 68, additionally comprising administering one or more non-statin active agents selected from the group consisting of:

(a) an active agent useful in treating dyslipidemia;

(b) an active agent useful in treating hyperlipidemia;

(c) an active agent useful in treating hypercholesterolemia;

(d) an active agent useful in treating cardiovascular disorders;

(e) an active agent useful in treating hypertriglyceridemia;

(f) an active agent useful in treating coronary heart disease;

(g) an active agent useful in treating peripheral vascular disease;

(h) an active agent useful as adjunctive therapy to diet for the reduction of LDL-C, total-C, triglycerides, and/or Apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb);

(i) an active agent useful as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia);

(j) an active agent useful in treating pancreatitis;

(k) an active agent useful in treating restenosis;

(l) an active agent useful in treating Alzheimer'"'"'s disease;

(m) cholesterol lowering agents;

(n) polycosanols;

(o) alkanoyl L-carnitines;

(p) antihypertensives; and

(q) sterols and/or stanols.

98. The method of claim 96, wherein:

(a) the cholesterol lowering agent is selected from the group consisting of ACE inhibitors, nicotinic acid, niacin, bile acid sequestrants, fibrates, vitamins, fatty acid derivatives, long chain plant extract alcohols, ezetimibe, and celluloses;

(b) the polycosanol is selected from the group consisting of (1) triacontanol, (2) hexacontanol, (3) ecocosanol, (4) hexacosanol, (5) tetracosanol, (6) dotriacontanol, (7) tetracontanol, (8) natural products comprising triacontanol, hexacontanol, ecocosanol, hexacosanol, tetracosanol, dotriacontanol, or tetracontanol; and

(9) extracts of natural products comprising triacontanol, hexacontanol, ecocosanol, hexacosanol, tetracosanol, dotriacontanol, or tetracontanol;

(c) the antihypertensive is selected from the group consisting of diuretics, beta blockers, alpha blockers, alpha-beta blockers, sympathetic nerve inhibitors, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers, and angiotensin receptor blockers;

or

(d) the sterol and/or stanol is selected from the group consisting of plant sterols, plant sterol esters, sitosterol, sitostanol, fish oil, phytosterol, campestanol, stigmasterol, coprostanol, cholestanol, and beta-sitosterol.

102. The method of claim 68, wherein the subject is a human.

103. The method of claim 68, wherein the method is used:

(a) to treat a condition selected from the group consisting of hypercholesterolemia, hypertriglyceridemia, coronary heart disease, cardiovascular disorders, and peripheral vascular disease;

(b) as adjunctive therapy to diet for the reduction of LDL-C, total-C, triglycerides, or Apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia;

(c) as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia;

(d) to decrease the risk of pancreatitis;

(e) to decrease the risk of or to treat Alzheimer'"'"'s disease;

(f) to treat indications where lipid regulating agents are typically used;

or

(g) a combination thereof.

71. (canceled)

73-95. -95. (canceled)

97. (canceled)

99-101. -101. (canceled)

104-108. -108. (canceled)