Prolonged release microcapsules and their production

• US 4,711,782 A
• Filed: 12/11/1986
• Issued: 12/08/1987
• Est. Priority Date: 11/04/1983
• Status: Expired due to Term

• Current Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Inventors: Okada, Hiroaki, Ogawa, Yasuaki, Yashiki, Takatsuka
• Primary Examiner(s): Lovering, Richard D.
• Application Number:
  US06/940,614
• Time in Patent Office: 362 Days
• Field of Search: 264/4.6, 28/402.2, 514/963, 424/455, 424/457, 424/493, 424/497
• US Class Current: 424/455
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 38/33 derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
• CPC Class Codes: A61K 38/37 Factors VIII
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: B01J 13/02 Making microcapsules or microballoons for medical preparations A61K9/50
• CPC Class Codes: B01J 13/125 by evaporation of the solvent apparatus therefor B01J13/043
• CPC Class Codes: Y10S 424/15 Suppositories
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]
• CPC Class Codes: Y10T 428/2985 Solid-walled microcapsule from synthetic polymer
• CPC Class Codes: Y10T 428/2989 Microcapsule with solid core [includes liposome]

Abstract

A microcapsule produced by preparing a water-in-oil emulsion comprising an inner aqueous layer containing said water-soluble drug and a drug retaining substance therefor and an oil layer containing a polymer substance, then thickening or solidifying said inner aqueous layer to a viscosity of not lower than about 5000 centiposes and finally subjecting the resulting emulsion to in water drying gives prolonged release of water-soluble drug.

Claims

1. A prolonged release microcapsule having an average diameter of about 0.5 to 400 μ

m for injection, which is produced by preparing a water-in-oil emulsion comprising an inner aqueous layer containing a water-soluble and non-polypeptidic drug, a drug retaining substance therefor selected from a member of the group consisting of gelatin, albumin, pectin and agar and an oil layer containing a polymer substance of lactic acid-glycolic acid copolymer or lactic acid polymer, then thickening or solidifying said inner aqueous layer to a viscosity of not lower than about 5000 centipoises and finally admixing the resulting emulsion with third aqueous layer to give a water/oil/water ternary layer emulsion and then desorbing the solvent in the oil layer.

2. A microcapsule as claimed in claim 1, wherein the water-soluble and non-polypeptidic drug is a member selected from the group consisting of antibiotic, antitumor agent, antipyretic, analgesic, antinflammatory agent, antitussive and expectorant, sedative, muscle relaxant, antiepileptic, antiulcer agent, antidepressant, antiallergic drug, cardiotonic, antiarrhythmic agent, vasodilator, anti-hypertensive diuretic, antidiabetic, anticoagulant, haemostatic, antituberculotic, hormone drug and anti-narcotics.

3. A microcapsule as claimed in claim 2, wherein the drug is a member selected from the group consisting of bleomycin hydrochloride, methotrexate, actinomycin D, mitomycin C, vinblastine sulfate, vincristine sulfate, daunorubicin hydrochloride, adriamycin, neocarcinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, krestin, picibanil, lentinan, levamisole, bestatin, azximexon, glycyrrhizin, poly I:

C, poly A;

U and poly ICLC.

4. A microcapsule as claimed in claim 3, wherein the drug is mitomycin C.

5. A microcapsule as claimed in claim 2 wherein the drug is a member selected from the group consisting of sodium salicyclate, sulpyrine, sodium flufenamate, sodium diclofenac, sodium indomethacin, morphine hydrochloride, pethidine hydrochloride, levorphanol tartrate and oxymorphone.

6. A microcapsule as claimed in claim 5, wherein the drug is sulpyrine, morphine hydrochloride or sodium diclofenac.

7. A microcapsule as claimed in claim 1, wherein the drug retaining substance is gelatin.

8. A microcapsule as claimed in claim 1, wherein the polymer substance in the oil layer is a copolymer of lactic acid and glycolic acid.

9. A microcapsule as claimed in claim 8, wherein the ratio of lactic acid:

glycolic acid is 75;

25.

10. A microcapsule as claimed in claim 1, wherein the polymer substance in the oil layer is polylactic acid.

11. A microcapsule as claimed in claim 1, wherein the inner aqueous layer is thickened to a viscosity not less than about 10,000 centipoises.

12. A microcapsule as claimed in claim 1, where the inner aqueous layer is solidified.

13. A method for producing a prolonged release microcapsule having an average diameter of about 0.5 to 400 μ

m for injection, which comprises preparing a water-in-oil emulsion comprising an inner aqueous layer containing a water-soluble and non-polypeptidic drug, a drug retaining substance therefor selecting from a member of the group consisting of gelatin, albumin, pectin and agar and an oil layer containing a polymer substance of lactic acid-glyucolic acid copolymer or lactic acid polymer, then thickening or solidifying said inner aqueous layer to a viscosity of not lower than about 5000 centipoises and finally admixing the resulting emulsion with a third aqueous layer to give a water/oil/water ternary layer emulsion and then desorbing the solvent in the oil layer.