Extended release pharmaceutical formulations

• US 5,133,974 A
• Filed: 01/24/1990
• Issued: 07/28/1992
• Est. Priority Date: 05/05/1989
• Status: Expired due to Term

• Current Assignee: DrugTech Corporation (PD International Holdings LLC)
• Original Assignee: KV Pharmaceutical Company (Apollo Global Management, Inc.)
• Inventors: Paradissis, George N., Garegnani, James A., Whaley, Roy S.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Harrison, Robert H.
• Application Number:
  US07/469,210
• Time in Patent Office: 916 Days
• Field of Search: 424/451, 424/456, 424/465, 424/474, 424/480, 424/475, 424/494, 514/960, 514/961, 514/962, 514/963, 514/964
• US Class Current: 424/480
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077

Abstract

An extended release pharmaceutical formulation adapted to approach zero order release of drug over a 12 to at least 24 hour period, comprised of a mixture of 0 to aobut 50% of an immediate release particle containing a drug, inert substrate and binder, coated with talc and up to 100% of an extended release particle comprising the immediate release particle coated with a dissolution modifying system containing plasticizers and a film forming agent.

Claims

1. An extended release pharmaceutical formulation for oral administration, which comprises:

a pharmaceutical formulation which is adapted to approach zero order release of drug over a 12 to at least a 24 hour period, which formulation is comprised of a mixture of a) about 0% to about 50% of an immediate release particle containing a core comprising a therapeutically effective amount of at least one water-soluble or water-insoluble drug, about 15% to about 40% by weight inert spherical substrate particles, and about 0.5% to about 4% by weight binder, coated with about 4% to about 20% by weight talc and having a particle size of -10+60 mesh size, U.S. Standard sieve size, and b) up to 100% of an extended release particle comprising about 65% to about 95% by weight of the immediate release particle of a) additionally coated with about 5.0% to about 35% by weight of a dissolution modifying system comprising a film forming agent and plasticizer, wherein the extended release particle has a particle size of -10+60 mesh size, U.S. Standard sieve mesh size, and wherein all percentages are based on the total weight of the pharmaceutical formulation.

2. The extended release pharmaceutical formulation of claim 1, wherein the drug is selected from the group consisting of analgesics, anti-inflammatories, antihistamines, antitussives, expectorants, decongestants, narcotics, antibiotics, bronchodilators, cardiovasculars, central nervous system drugs, and mixtures thereof.

3. The extended release pharmaceutical formulation of claim 1, wherein the inert spherical substrate particles are selected from the group consisting of sugar spheres and non- toxic plastic resin beads.

4. The extended release pharmaceutical formulation of claim 1, which additionally contains preblended with the drug a non-toxic carrier selected from the group consisting of sugar, lactose, gelatin, starch, silicon dioxide and mixtures thereof.

5. The extended release pharmaceutical formulation of claim 1 wherein the binder is soluble in a solvent selected from water and an organic solvent.

6. The formulation of claim 5, wherein the binder is selected from the group consisting of povidone, pharmaceutical glaze, sugar, hydroxpropylmethylcellulose, hydroxpropylcellulose, ethylcellulose, acrylic and methacrylic acid co-polymers and mixtures thereof.

7. The extended release pharmaceutical formulation of claim 1 wherein the plasticizers which are used to form the extended release particle are selected from the group consisting of diethyl phthalate, diethyl sebacate, triethyl citrate, crotonic acid, propylene glycol, castor oil, citric acid esters, dibutyl phthalate, dibutyl sebacate and mixtures thereof.

8. The extended release pharmaceutical formulation of claim 1 wherein the film forming agent is selected from the group consisting of ethylcellulose, methylcellulose, hydroxypropylcellulose, cellulose acetate, hydroxypropylmethylcellulose, hydroxyethylcellulose and mixtures thereof.

9. The extended release pharmaceutical formulation of claim 1 wherein the immediate release particle contains a core comprising about 15 to about 40% inert spherical substrate particles, about 0.5 to about 4% binder and about 4 to about 85% drug, all percents herein are by weight of the final product.

10. The extended release pharmaceutical formulation of claim 2 wherein the expectorant is guaifenesin.

12. The formulation of claim 1, wherein the coating over the immediate release particle contains about 0.5 to about 25% film forming agent by weight, about 0.01 to about 5% plasticizer by weight, and up to 25% of porosity modifying agents.

13. The formulation of claim 1, wherein the dissolution modifying system of the immediate release particles contains additional amounts of drugs.

14. The extended release pharmaceutical formulation of claim 1, wherein the formulation is administered in the form of a tablet, capsule or particle form.

15. The extended release pharmaceutical formulation of claim 2, wherein the analgesics are selected from the group consisting of acetaminophen, ibuprofen, flurbiprofen, ketoprofen, phenacetin, voltaren and salicylamide.

16. The extended release pharmaceutical formulation of claim 2, wherein the anti-inflammatory drugs are selected from the group consisting of naproxen and indomethacin.

17. The extended release pharmaceutical formulation of claim 2, wherein the antihistamines are selected from the group consisting of chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, brompheniramine maleate, dexbrompheniramine maleate, clemastine fumerate, and triprolidine.

18. The extended release pharmaceutical formulation of claim 2, wherein the antitussives are selected from the group consisting of dextromethorphan hydrobromide and guaifenesin.

19. The extended release pharmaceutical formulation of claim 2, wherein the decongestants are selected from the group consisting of phenylephrine hydrochloride, phenypropanolamine hydrochloride, pseudoephedrine hydrochloride and ephedrine.

20. The extended release pharmaceutical formulation of claim 1, wherein the drug is phenylpropanolamine hydrochloride and chlorpheniramine maleate.

22. The extended release pharmaceutical formulation of claim 2, wherein the narcotics are selected from the group consisting of morphine, codeine and derivatives thereof.

23. The extended release pharmaceutical formulation of claim 2, wherein the antibiotics are selected from the group consisting of erythromycin, penicillins, cephalosporins and their derivatives.

24. The extended release pharmaceutical formulation of claim 2, wherein the bronchodilators are selected from the group consisting of theophylline, albuterol and terbutaline.

25. The extended release pharmaceutical formulation of claim 2, wherein the cardiovasculars are selected from the group consisting of diltiazem, propranolol, nifedepine and clonidine.

26. The extended release pharmaceutical formulation of claim 2, wherein the central nervous system drugs are selected from the group consisting of meclizine, ergoloid mesylates, thioridazine, diazepam, chlorpromazine, hydroxyzine, carbidopa and levodopa.

27. The extended release pharmaceutical formulation of claim 1, wherein the drug is pseudoephedrine hydrochloride and triprolidine.

28. The extended release pharmaceutical formulation of claim 1, wherein the drug is pseudoephedrine hydrochloride.

29. The extended release pharmaceutical formulation of claim 1, wherein the drug is pseudoephedrine hydrochloride and chlorpheniramine maleate.

11. The extended release pharmaceutical formulation for oral administration, which comprises:

a pharmaceutical formulation which is adapted to release a drug over a 12 to at least a 24 hour period, which formulation is comprised of a mixture of a) about 0% to about 50% of an immediate release particle containing a core comprising a therapeutically effective amount of at least one water-soluble or water-insoluble drug, about 15% to about 40% by weight inert spherical substrate particles, and about 0.5% to about 5% by weight binder, coated with about 4% to about 20% by weight talc and having a particle size of -10+60 mesh size, U.S. Standard sieve size, and b) up to 100% of an extended release particle comprising about 65% to about 95% by weight of the immediate release particle of a) additionally coated with about 5.0% to about 35% by weight of a dissolution modifying system comprising a film forming agent and plasticizer, wherein the extended release particle has a particle size of -10+60 mesh size, U.S. Standard sieve mesh size, and wherein all percentages are based on the total weight of the pharmaceutical formulation.

21. An extended release pharmaceutical formation for oral administration which comprises:

a pharmaceutical formulation which is adapted to approach zero order release of drug over a 12 to at least 24 hour period, which formulation is comprised of a mixture of;

a) 0 to about 50% of an immediate release particle containing about 15 to about 40% by weight inert spherical substrate particle about 0.5 to about 4% binder and about 4 to about 85% of at least one drug and a coating comprising about 4 to about 20% talc; and

b) up to 100% of an extended release particle comprising an immediate release particle of a) coated with a dissolution modifying system comprising about 0.5 to about 25% film forming agent, about 0.01 to about 5% plasticizer and up to 25% modifying agent, all percents herein are by weight of the final product.