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Details for Patent: 4,940,556

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Details for Patent: 4,940,556

Title: Method of preparing long acting formulation
Abstract:A long acting sustained release pharmaceutical composition for dihydropyridine calcium channel blockers wherein the calcium channel blocker and a pH-dependent binde are intimately admixed in essentially spherically shaped non-rugose particles of up to 1.2 mm in diameter.
Inventor(s): MacFarlane; Calum B. (Linlitchgow, GB6), Selkirk; Alastair B. (Edinburgh, GB6), Dey; Michael J. (East Calder, GB6)
Assignee: Syntex (U.S.A.) Inc. (Palo Alto, CA)
Filing Date:Jul 26, 1987
Application Number:07/057,469
Claims:1. A method of preparing spheroids which are suitable for administration to humans and which provide long-acting sustained release of a therapeutically effective amount of dihydropyridine calcium channel blocker, which method consists essentially of;

(a) forming an essentially aqueous wet mass comprising an effective amount of the calcium channel blocker in admixture with a pH-dependent binder which is less soluble at lower pH and more soluble at higher pH, wherein the binder constitutes about 5 to 50 weight percent of each spherical partical;

(b) extruding the wet mass to form rod-shaped, substantially cylindrical segments having diameters in the range of up to 1.2 millimeters;

(c) shaping the rod-shaped segments into spheroids; and

(d) drying the spheroids to obtain spheroids having area radius to circumference radius ratios in the range of 0.85 to 1.0.

2. The method of claim 1 in which the spheroids are formed on a rotating disc or pan.

3. The method of claim 1 in which the pH dependent binder is a single material, or a mixture of materials selected from either of the groups a and b consisting of:

(a) phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates and the partial esters thereof; and

(b) polymers and copolymers of lower alkyl acrylic acids and lower alkyl acrylates and the partial esters thereof.

4. The method of claim 3 in which the pH-dependent binder is a copolymer of methacrylic acid and a methacrylic or acrylic acid ester.

5. The method of claim 1 in which the dihydropyridine calcium channel blocker is a compound chosen from the group represented by the formula: ##STR7## where; R.sub.1 is --NO.sub.2, --CF.sub.3, or halo;

R.sub.2 is alkyl or --CH.sub.2 CH.sub.2 OCH.sub.3 ; and

R.sub.6 is hydrogen or alkyl; and

R.sub.3 is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted phenyl alkyl, optionally substituted napthyl alkyl, or ##STR8## in which: A is alkylene;

R.sub.4 is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl; and

R.sub.5 is hydrogen or alkyl;

and the pharmaceutically acceptable salts thereof.

6. The method of claim 5 in which the dihydropyridine calcium channel blocker is nicardipine or a pharmaceutically acceptable salt thereof.

7. The method of claim 6 in which the binder is a copolymer of methacrylic acid and a methacrylic or acrylic acid ester.

8. A method of preparing spheroids which are suitable for administation to humans and which provide sustained release over a period of one day of a therapeutically effective amount, upon twice daily administration thereof when administered at successive 12-hour intervals over the period of one day, of a dihydropyridine calcium channel blocker selected from the group represented by the formula: ##STR9## where R.sub.1 is --NO.sub.2, --CF.sub.3, or halo;

R.sub.2 is alkyl or --CH.sub.2 CH.sub.2 OCH.sub.3 ; and

R.sub.6 is hydrogen or alkyl; and

R.sub.3 is alkyl, alkylenyloxyalkyl, haloalkyl, optionally substituted phenyl alkyl, optionally substituted napthyl alkyl, or ##STR10## in which: A is alkylene;

R.sub.4 is alkyl, alkoxy, or optionally substituted phenyl or phenyl alkyl; and

R.sub.5 is hydrogen or alkyl;

and the pharmaceutically acceptable salts thereof, which method consists essentially of:

(a) forming an essentially aqueous wet mass comprising an effective amount of the calcium channel blocker in admixture with a pH-dependent binder selected from

(i) phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates and the partial esters thereof; and

(ii) polymers and copolymers of lower alkyl acryclic acids and lower alkyl acrylates and the partial esters thereof, which binder is less soluble at a pH of less than about 4.5 and more soluble at a pH of greater than about 5.5 and wherein the binder constitutes about 5 to 50 weight percent of each spherical particle;

(b) extruding the wet mass to form rod-shaped, substantially cylindrical segments having diameters in the range of up to 1.2 millimeters;

(c) shaping the rod-shaped segments into spheroids; and

(d) drying the spheroids to obtain spheroids having area radius to circumference radius ratios in the range of 0.85 to 1.0.

9. A method according to claim 8 wherein the dihydropyridine calcium channel blocker is nicardipine wherein, in the given formula, R.sub.1 is --NO.sub.2, R.sub.2 is --CH.sub.3, R.sub.3 is --CH(CH.sub.3)CH.sub.2 C.sub.6 H.sub.5, and R.sub.6 is H and pharmaceutically acceptable salts thereof.

10. A method according to claim 8 wherein the pH dependent binder is selected from copolymers of methacrylic acid and a lower alkyl methacrylic or acrylic acid ester.

11. A method according to claim 9 wherein the spheroids consist essentially of about 10 to 25 weight percent of nicardipine hydrochloride and about 5 to 25 weight percent of the pH-dependent binder selected from copolymers of methacrylic acid and methyl methacrylate, the balance being non-essential filler, binders and excipients.

12. A method according to claim 11 wherein the spheroids consist essentially of about 20 weight % of nicardipine hydrochloride, about 11 weight % of the methacrylic acid-methyl methacrylate copolymer, about 20 weight % of microcrystalline cellulose, about 20 weight % of maize starch, and about 29 weight % of lactose.
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