Process for producing solid oral dosage forms with sustained release of active ingredient

• US 7,413,750 B2
• Filed: 06/05/2001
• Issued: 08/19/2008
• Est. Priority Date: 06/19/2000
• Status: Expired due to Term

• Current Assignee: BASF SE
• Original Assignee: BASF AG (BASF SE)
• Inventors: Kolter, Karl, Ascherl, Hermann, Flick, Dieter
• Primary Examiner(s): Hartley; Michael G.
• Assistant Examiner(s): Fubara; Blessing M
• Application Number:
  US09/873,431
• Publication Number:
  US 20020012701A1
• Time in Patent Office: 2,632 Days
• Field of Search: 424/400, 424/464, 424/468, 424/469, 424/470, 424/484, 424/486, 424/489, 424/494, 424/497, 514/772.4
• US Class Current: 424/469
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The present invention relates to a process for producing solid oral dosage forms with sustained release of active ingredient, comprising at least one active ingredient, a preformulated mixture of polyvinyl acetate and polyvinylpyrrolidone, where appropriate, water-soluble polymers or lipophilic additives and, where appropriate, other conventional excipients, wherein this mixture or parts of this mixture are granulated by heating to from 40° C. to 130° C., and the granules are, after admixture with conventional excipients, subsequently tabletted.

Claims

1. A process for producing an oral dosage form with sustained release of active ingredient, wherein the dosage form comprises

a) a formulated mixture of polyvinyl acetate and polyvinylpyrrolidone which acts as a binder and a matrix former, and wherein the polyvinylpyrrolidone has a molecular weight of from 20,000 to 1,000,000, and the polyvinylpyrrolidone is finely dispersed in the polyvinyl acetate,

b) at least one active ingredient,

c) optionally water-soluble polymers or low or high molecular weight lipophilic additives,

d) and, optionally, excipients, wherein the process comprises granulating a mixture of a) to d) or a) to c) or a) and b) and d) or a) and b) by heating to a temperature of from 40°

C. to 130°

C. in the absence of solvents.

2. A process as claimed in claim 1, wherein the polyvinyl acetate to polyvinylpyrrolidone ratio is 6:

4 to 9;

1.

3. A process as claimed in claim 1, wherein the active ingredient water-soluble polymers or low or high molecular weight lipophilic additives ratio employed is from 5:

95 to 85;

15.

4. A process as claimed in claim 1, wherein polyvinyl acetate and polyvinylpyrrolidone each have a molecular weight of from 20,000 to 1,000,000.

5. A process as claimed in claim 1, wherein the mixture is granulated by heating to from 45 to 100°

C.

6. A process as claimed in claim 1, wherein the particle size of the active ingredients employed is in a range from 20 to 700 μ

m.

7. A process as claimed in claim 1, wherein the excipients employed are fillers, disintegrants and adsorbents, lubricants, flowability agents, dyes, stabilizers, antioxidants, wetting agents, preservatives, release agents, flavorings or sweeteners.

8. A process as claimed in claim 1, wherein fillers selected from the group consisting of lactose, cellulose powder, mannitol, calcium diphosphate and starch are employed as excipients.

9. A process as claimed in claim 1, wherein the granules can be produced by employing the process of mixer granulation, fluidized bed granulation or extrusion granulation.

10. A process as claimed in claim 1, wherein besides the formulated mixture of polyvinyl acetate and polyvinylpyrrolidone, further release-sustaining excipients may optionally be employed before, during or after the granulation.

11. A process as claimed in claim 1, wherein water-soluble, water-soluble highly swelling or lipophilic excipients are employed for further modification of release.

12. A process as claimed in claim 1, wherein the water-soluble polymers are selected from the group consisting of:

polyvinyl alcohols, polyethylene glycols, polyoxyethylene/polyoxypropylene block copolymers, polyvinylpyrrolidones, vinyl acetate/vinyl pyrrolidone copolymers, polyethylene glycols, polyvinylpyrrolidones, vinyl acetate/vinylpyrrolidone copolymers, maltodextrins, and salts thereof.

13. A process as claimed in claim 1, wherein the production is either continuously or batchwise.

14. A process as claimed in claim 1, wherein the granulated mixture is further processed by forced screening of the granules in the hot state or in the cooled state.

15. A process as claimed in claim 1, wherein the water-soluble polymers are selected from the group consisting of alginates, pectins, galactomannans, carrageenans, dextran, curdlan, pullulan, gellan, chitin, gelatin, xanthans, hemicelluloses, cellulose derivatives selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and carboxymethylcellulose, starch derivatives selected from the group consisting of carboxymethylstarch and degraded starch, maltodextrins, polyacrylic acid, polymethacrylic acid, acrylic acid/methacrylic acid copolymers, polyvinyl alcohols, high molecular weight polyethylene glycols, polyoxyethylene/polyoxypropylene block copolymers and high molecular weight polyvinylpyrrolidones.

16. A process as claimed in claim 1, wherein the lipophilic additives are selected from the group consisting of fatty alcohols, fatty acids, glycerides, fatty acid esters, fatty alcohol esters and lipophilic polymers.

17. A process as claimed in claim 16, wherein the fatty alcohol is stearyl alcohol;

the fatty acid is stearic acid; and

the lipophilic polymers are selected from the group consisting of ethylcellulose, cellulose acetate, acrylic ester/methacrylic ester copolymers, methacrylic acid/acrylic ester copolymers, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate and hydroxypropyl-methylcellulose acetate succinate.