Method for enhancing the lowering of plasma cholesterol levels

• US 4,997,658 A
• Filed: 11/21/1988
• Issued: 03/05/1991
• Est. Priority Date: 11/21/1988
• Status: Expired due to Term

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Scolnick, Edward M., Repta, Arnold J., Alberts, Alfred W.
• Primary Examiner(s): Cashion, Jr., Merrell C.
• Assistant Examiner(s): Horne, Leon R.
• Application Number:
  US07/274,173
• Time in Patent Office: 834 Days
• Field of Search: 424/473, 514/460
• US Class Current: 424/473
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The instant invention is directed to a method for enhancing the lowering of plasma cholesterol level in a subject in need thereof which comprises the time-controlled administration of a nontoxic therapeutically effective amount of an HMG-CoA reductase inhibitor to said subject which surprisingly affords an equivalent or improved reduction of plasma cholesterol levels while significantly reducing the amount of HMG-CoA reductase inhibitor circulating in the bloodstream of the subject as compared to the same parameters when the oral administration of a conventional rapid release dosage form is utilized.

Claims

1. A method for the lowering of plasma cholesterol level in a subject in need thereof which comprises the time-controlled administration over a period of six (6) to twenty-four (24) hours of a nontoxic therapeutically effective amount of about 2 mg to 2000 mg of an HMG-CoA reductase inhibitor, which affords an lowering equivalent or greater lowering of plasma cholesterol levels while reducing the amount of HMG-CoA reductase inhibitor circulating in the bloodstream of the subject when compared to the oral administration of an equivalent dosage of a rapid-release dosage form, ##STR2## wherein wherein

the HMG-CoA reductase inhibitor is a compound of the following structural formulae (I) and (II):

R¹ is selected from the group consisting of

(1) C_1-10 alkyl;

(2) substituted C_1-10 alkyl in which one or more substituent(s) is

(a) hydroxy,

(b) C_1-5 alkoxycarbonyl,

(c) C_1-5 acyloxy,

(d) C_3-8 cycloalkyl, and

(e) phenyl, and;

(3) C_3-8 cycloalkyl;

R² is selected from the group consisting of

(1) methyl;

(2) substituted C_1-10 alkyl in which the substituent is

(a) hydroxy, or

(b) C_1-5 acyloxy, and

(3) C_1-5 alkoxycarbonyl and;

(4) hydroxy; and

R³ is selected from the group consisting of

(a) hydrogen;

(b) C_1-5 alkyl;

(c) substituted C_1-5 alkyl in which the substituent is

(i) phenyl,

(ii) dimethylamino, and

(iii) acetylamino, and

(d) 2,3-dihydroxypropyl;

a, b, c and d each represent single bonds or one of

a, b, c and d represents a double bond or both a and c or both b and d represent double bonds, provided that when a is a double bond, R² is methyl, substituted C_1-10 alkyl or C_1-5 alkoxycarbonyl;

or a pharmaceutically acceptable salt thereof.

2. A method of claim 1 wherein

R¹ is C_1-10 alkyl;

and

R² is methyl;

or hydroxy.

3. A method of claim 2 wherein the HMG-CoA reductase inhibitor is selected from the group consisting of

(1) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-(2,2-dimethylbutyryloxy-naphthalenyl-1(S)]-3(R),5(R)-dihydroxyheptanoic acid;

(2) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-(2(S)-methylbutyryloxy0-naphthalenyl-1(S)]-3(R)-dihydroxyheptanoic acid; and

(3)7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl 6(R)-hydroxy-8(S)-methylbutyryloxy)-naphthalenyl-1(S)]-3(R),5(R)-dihydroxyheptanoic acid; and

(4) 7-[1,2,6,7,8,8a(R)-hexahydro-2(S)-methyl 6(S)-hydroxy-8(S)-(2(S)-methylbutyryloxu)-naphthalenyl-1(S)]-3(R),5(R)-dihydroxyheptanoic acid.

4. A method of claim 3 wherein the HMG-CoA reductase inhibitor is selected from the group consisting of

(1) 6(R)-[2-[8(S)-(2(S)-methylbutyryloxy-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthtyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one;

and

(2) 6(R)-[2-[8(S)[(2,2)-dimethylbutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthtyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

5. A method of claim 1 wherein the time-controlled administration is the continuous introduction of the HMG-CoA reductase inhibitor into the enviornment of use over a period of six (6) to twenty-four (24) hours.

6. A method of claim 5 wherein the time-controlled administration of a nontoxic therapeutically effective amount of an HMG-CoA reductase inhibitor is accomplished utilizing a drug-delivery device for the controlled release of the therapeutically active ingredient into an environment of use.

7. A method of claim 6 wherein the drug delivery device is selected from the group consisting of diffusion-controlled systems, osmotic devices, dissolution-controlled matrices and erodible/degradable matrices.

8. A method of claim 7 wherein the drug delivery device comprises;

(A) a core composition comprising

(a) a diffusible water soluble HMG-CoA reductase inhibitor, and

(b) an osmotically effective agent; and

(B) a water insoluble wall surrounding said core composition and prepared from

(i) a polymer material that is permeable to water but substantially impermeable to solute and

(ii) 0.1 to 75% by weight, based on the total weight of (i) and (ii), of at least one water leachable pore-forming additive dispersed throughout said wall;

or

(C) a substantially imperforate water insoluble wall surrounding said core composition and prepared from a semipermeable material substantially impermeable to core composition and permeable to the passage of an external fluid in the enviornment of use, with said wall having a means for release of the therapeutic agent through the water insoluble wall.

9. A method of claim 8 wherein the core composition of the drug delivery device comprises:

(a) a water insoluble, nondiffusible charged resin entity, and

(b) a diffusible water soluble ionizable HMG-CoA reductase inhibitor carrying the same charge as said resin entity.

10. A method of claim 9 wherein the core composition of the drug delivery device comprises:

(a) a solubility modulating agent which is either (i) surrounded by a water insoluble coat containing at least one pore-forming additive dispersed throughout said coat, or (ii) dispersed in a matrix substrate, and

(b) a diffusible water soluble HMG-CoA reductase inhibitor.