CA2488499A1 - Nanoparticulate formulations comprising hmg coa reductase inhibitor derivatives ("statins"),combinations thereof as well as manufacturing of these pharmaceutical compositions - Google Patents

Nanoparticulate formulations comprising hmg coa reductase inhibitor derivatives ("statins"),combinations thereof as well as manufacturing of these pharmaceutical compositions Download PDF

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CA2488499A1
CA2488499A1 CA002488499A CA2488499A CA2488499A1 CA 2488499 A1 CA2488499 A1 CA 2488499A1 CA 002488499 A CA002488499 A CA 002488499A CA 2488499 A CA2488499 A CA 2488499A CA 2488499 A1 CA2488499 A1 CA 2488499A1
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composition
statin
ammonium chloride
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CA2488499C (en
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Eugene R. Cooper
Douglas Hovey
Greta Cary
Marie Lindner
Elaine Liversidge
Gary G. Liversidge
Tuula Ryde
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Alkermes Pharma Ireland Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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Abstract

The present invention is directed to nanoparticulate compositions comprising statin such as lovastatin or simvastatin including surface stabilizer. 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 (108)

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; phosphinic acid compounds.
3. The composition of claim 1 or claim 2, wherein the statin is lovastatin or simvastatin.
4. The composition of any one of claims 1-3, wherein the statin is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.
5. The composition of any one of claims 1-4, 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 any one of claims 1-5, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration.
7. The composition of any one of claims 1-6 formulated into a dosage form selected from the group consisting of liquid dispersions, oral suspensions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations.
8. The composition of any one of claims 1-7, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.
9. The composition of any one of claims 1-8, wherein 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.
10. The composition of any one of claims 1-9, wherein 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.
11. The composition of any one of claims 1-10, comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.
12. The composition of any one of claims 1-11, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer.
13. The composition of claim 12, 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 .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside; n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside; n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;

nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl .beta.-D-thioglucopyranoside;
lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, and random copolymers of vinyl acetate and vinyl pyrrolidone.
14. The composition of claim 12, wherein the at least one cationic surface stabilizer is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, and a phospholipid.
15. The composition of claim 12, wherein the surface stabilizer is selected from the group consisting of 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, C12-15dimethyl hydroxyethyl ammonium chloride, C12-15dimethyl 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 (C12-18)dimethylbenzyl ammonium chloride, N-alkyl (C14-18)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-14) 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(C12-14) 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, POLYQUAT
10.TM., tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL.TM., ALKAQUAT.TM., alkyl pyridinium salts; amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.
16. The composition of any of claims 12, 14, or 15, wherein the composition is bioadhesive.
17. The composition of any one of claims 1-16, comprising hydroxypropylmethylcellulose (HPMC) and dioctyl sodium sulfosuccinate (DOSS) as surface stabilizers.
18. The composition of any one of claims 1-17, wherein 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.
19. The composition of claim 18, wherein 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.
20. The composition of any one of claims 1-19, wherein 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.
21. The composition of claim 20, wherein 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.
22. The composition of any one of claims 1-21, wherein 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.
23. The composition of claim 22, wherein 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.
24. The composition of any one of claims 1-23 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 any one of claims 1-25, 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 90% Confidence Interval of between 0.80 and 1.25 for both C max and AUC, when administered to a human.
28. The composition of claim 26, wherein "bioequivalency" is established by 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 any one of claims 1-28, wherein within about 5 minutes at least about 20% 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.
30. The composition of claim 29, in which at least about 30% or at least about 40% of the composition is dissolved within about 5 minutes.
31. The composition of claim 29, wherein upon redispersion the statin particles have an effective average particle size of less than about 2 microns.
32. The composition of any one of claims 1-31, wherein within about 10 minutes at least about 40% 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.
33. The composition of claim 32, wherein at least about 50%, about 60%, about 70%, or about 80% of the composition is dissolved within about 10 minutes.
34. The composition of claim 32, wherein upon redispersion the statin particles have an effective average particle size of less than about 2 microns.
35. The composition of any one of claims 1-34, wherein within about 20 minutes at least about 70% 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.
36. The composition of claim 35, wherein at least about 80%, about 90%, or about 100% of the composition is dissolved within about 20 minutes.
37. The composition of claim 35, wherein upon redispersion the statin particles have an effective average particle size of less than about 2 microns.
38. The composition of any one of claims 1-37, 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; and (l) an active agent useful in treating Alzheimer's disease.
39. The composition of any one of claims 1-38, additionally comprising one or more non-statin active agents selected from the group consisting of cholesterol lowering agents, polycosanols, alkanoyl L-carnitines, antihypertensives, and sterols and/or stanols.
40. The composition of claim 39, wherein 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.
41. The composition of claim 39, wherein 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.
42. The composition of claim 39, wherein 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.
43. The composition of claim 39, wherein 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 any one of claims 39-43, wherein at least one of the non-statin compounds has an effective average particle size of greater than about 2 microns.
45. The composition according to any one of claims 39-43, wherein at least one of the non-statin compounds has an effective average particle size of less than about 2 microns.
46. The composition of any one of claims 1-45, wherein 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.
47. The composition of any one of claims 1-45, wherein 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.
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.
50. The method of claim 49, wherein said grinding comprises wet grinding.
51. The method of claim 48, wherein said contacting comprises homogenizing.
52. The method of claim 48, wherein said contacting comprises:
(a) dissolving the particles of a statin or a salt thereof in a solvent;
(b) adding the resulting statin solution to a solution comprising at least one surface stabilizer; and (c) precipitating the solubilized statin having at least one surface stabilizer adsorbed on the surface thereof by the addition thereto of a non-solvent.
53. The method of any one of claims 48-52, 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 any one of claims 48-53, wherein the statin is lovastatin or simvastatin.
55. The method of any one of claims 48-54, wherein the statin or a salt thereof is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.
56. The method of any one of claims 48-55, 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.
57. The method of any one of claims 48-56, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration.
58. The method of any one of claims 48-57, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.
59. The method of any one of claims 48-58, wherein the 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.
60. The method of any one of claims 48-59, wherein 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%, from about 5.0% to about 99.9%, 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.
61. The method of any one of claims 48-60, comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.
62. The method of any one of claims 48-61, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer.
63. The method of claim 62, 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 .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside; n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside; n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl .beta.-D-thioglucopyranoside;
lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, and random copolymers of vinyl acetate and vinyl pyrrolidone.
64. The method of claim 62, wherein the at least one cationic surface stabilizer is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, and a phospholipid.
65. The method of claim 62, wherein the surface stabilizer is selected from the group consisting of 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, C12-15dimethyl hydroxyethyl ammonium chloride, C12-15dimethyl 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 (C12-18)dimethylbenzyl ammonium chloride, N-alkyl (C14-18)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-14) dimethyl 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(C12-14) 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, POLYQUAT
10.TM., tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL.TM., ALKAQUAT.TM., alkyl pyridinium salts; amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.
66. The method of any of claims 62, 64, or 65, wherein the composition is bioadhesive.
67. The method of any one of claims 48-66, comprising hydroxypropylmethylcellulose (HPMC) and dioctyl sodium sulfosuccinate (DOSS) as surface stabilizers.
68. A method of treating a subject in need 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 or claim 69, wherein the statin is lovastatin or simvastatin.
71. The method of any one of claims 68-70, wherein the statin or a salt thereof is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.
72. The method of any one of claims 68-71, 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.
73. The method of any one of claims 68-72, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration.
74. The method of any one of claims 68-73, wherein the composition is a dosage form selected from the group consisting of liquid dispersions, oral suspensions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations.
75. The method of any one of claims 68-74, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.
76. The method of any one of claims 68-75, wherein the 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.
77. The method of any one of claims 68-76, wherein 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.
78. The method of any one of claims 68-77, comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.
79. The method of any one of claims 68-78, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer.
80. The method of claim 79, 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 .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside; n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside; n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl .beta.-D-thioglucopyranoside;
lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, and random copolymers of vinyl acetate and vinyl pyrrolidone.
81. The method of claim 79, wherein the at least one cationic surface stabilizer is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, and a phospholipid.
82. The method of claim 79, wherein the surface stabilizer is selected from the group consisting of benzalkonium chloride, polymethylmethacrylate trimethylammonium bromide, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, cationic lipids, sulfonium compounds, 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, C12-15dimethyl hydroxyethyl ammonium chloride, C12-15dimethyl 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 (C12-18)dimethylbenzyl ammonium chloride, N-alkyl (C14-18)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C12-14) 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(C12-14) 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, POLYQUAT
10.TM., tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL.TM., ALKAQUAT.TM., alkyl pyridinium salts; amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.
83. The method of any of claims 79, 81, or 82, wherein the composition is bioadhesive.
84. The method of any one of claims 68-83, comprising hydroxypropylmethylcellulose (HPMC) and dioctyl sodium sulfosuccinate (DOSS) as surface stabilizers.
85. The method of any one of claims 68-84, wherein administration of the statin composition does not produce significantly different absorption levels when administered under fed as compared to fasting conditions, when administered to a human.
86. The method of claim 85, 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%.
87. The method of any one of claims 68-86, 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.
88. The method of claim 87, wherein "bioequivalency" is established by a 90%
Confidence Interval of between 0.80 and 1.25 for both C max and AUC, when administered to a human.
89. The method of claim 87, wherein "bioequivalency" is established by 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.
90. The method of any one of claims 68-89, wherein 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.
91. The method of claim 90, wherein 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.
92. The method of any one of claims 68-91, wherein 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.
93. The method of claim 92, wherein 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.
94. The method of any one of claims 68-93, wherein 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.
95. The method of claim 94, wherein 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.
96. The method of any one of claims 68-95, 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; and (l) an active agent useful in treating Alzheimer's disease.
97. The method of any one of claims 68-96, additionally comprising administering one or more non-sterol active agents selected from the group consisting of cholesterol lowering agents, polycosanols, alkanoyl L-carnitines, antihypertensives, and statins.
98. The method of claim 97, wherein 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.
99. The method of claim 97, wherein 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.
100. The method of claim 97, wherein 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.
101. The method of claim 97, wherein 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 any one of claims 68-101, wherein the subject is a human.
103. The method of any one of claims 68-102, wherein the method is used to treat a condition selected from the group consisting of hypercholesterolemia, hypertriglyceridemia, coronary heart disease, cardiovascular disorders, and peripheral vascular disease.
104. The method of any one of claims 68-102, wherein the method is used 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.
105. The method of any one of claims 68-102, wherein the method is used as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia.
106. The method of any one of claims 68-102, wherein the method is used to decrease the risk of pancreatitis.
107. The method of any one of claims 68-102, wherein the method is used to decrease the risk of or to treat Alzheimer's disease.
108. The method of any one of claims 68-102, wherein the method is used to treat indications where lipid regulating agents are typically used.
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AU2003245313A1 (en) 2003-12-22
JP2005532352A (en) 2005-10-27

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