Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-02-28
2002-07-16
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S426000
Reexamination Certificate
active
06419961
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates mainly to a method of producing sustained-release microcapsules that release a bioactive substance at constant rate over an extended period of time from just after administration with suppressed initial release of the bioactive substance in excess just after administration.
BACKGROUND OF THE INVENTION
PCT International publication No. WO89/04673 [Tokuhyo (Publication of the Translation of International Patent Application) 503315/1990] discloses a method of producing a solid polymer preparation wherein said solid preparation is kept at a temperature not lower than the glass transition point of the constituent polymer.
EPA No. 0586238 discloses a method of producing sustained-release microcapsules containing a biologically active substance from an W/O emulsion comprising an inner aqueous phase containing said biologically active substance and an external oil phase containing a biodegradable polymer, characterized in that microcapsules formed on microencapsulation of said biologically active substance with said biodegradable polymer heated at a temperature not lower than the glass transition temperature of said biodegradable polymer but not so high as to cause aggregation of the microcapsules.
With regard to sustained-release microcapsules incorporating a biodegradable polymer, it is desirable that the initial release of the bioactive substance, especially that in excess within 1 day, be suppressed, and that the release of the bioactive substance be optionally controlled over an extended period of time. However, the description in the above-mentioned patent publications does not enable the production of fully satisfactory sustained-release micro-capsules that release the bioactive substance, especially polypeptide having a high molecular weight, at constant rate over an extended period of time from just after administration with suppressed initial release of the bioactive substance in excess just after administration.
SUMMARY OF THE INVENTION
Through intensive investigation to resolve the above problems, the present inventors found it possible to produce sustained-release microcapsules containing a bioactive substance and a biodegradable polymer possessing pharmaceutical characteristics clinically excellent in that the bioactive substance is released at constant rate over a very long period of time from just after administration with unexpectedly dramatically suppressed initial release of the bioactive substance in excess just after administration and with minimum retention of organic solvent, by incorporating the biodegradable polymer at not less than 60% (w/w), and heating or thermally drying the microcapsules at a temperature not lower than the glass transition point of said polymer for about 24 to 120 hours. After further investigations based on this finding, the inventors developed the present invention.
(1) A method of production of sustained-release microcapsules that comprises obtaining microcapsules comprising a bioactive substance that are encapsulated with a biodegradable polymer, and thermally drying the obtained microcapsules at a temperature not lower than the glass transition temperature of the biodegradable polymer for about 24 to about 120 hours to produce the sustained-release microcapsules comprising, relative to the weight of the sustaind-release microcapsule, not less than 60% (w/w) of the biodegradable polymer.
(2) A method for production of 1, wherein said bioactive substance is a peptide having a molecular weight of about 200 to 20,000.
(3) A method for production of (1), wherein said bioactive substance is luteinizing hormone-releasing hormone or an analog thereof.
(4) A method for production of (1), wherein said bioactive substance is a peptide represented by the formula (I): (Pyr)Glu-R
1
-Trp-Ser-R
2
-R
3
-R
4
-Arg-Pro-R
5
(I) wherein R
1
represents His, Tyr, Trp or p-NH
2
-Phe; R
2
represents Tyr or Phe; R
3
represents Gly or a D type amino acid residue; R
4
represents Leu, Ile or Nle; and R
5
represents Gly-NH—R
6
(R
6
represents a hydrogen atom or a lower alkyl group with or without a hydroxyl group) or NH—R
6
(R6 has the same definition as that shown above); or a salt thereof.
(5) A method for production of (1), wherein said bioactive substance is: (Pyr)Glu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHCH
2
-CH
3
or a salt thereof.
(6) A method for production of (1), wherein said bioactive substance is a peptide represented by the formula. (II):
wherein X represents a hydrogen atom or a tetrahydrofurylcarboxamido; Q represents a hydrogen atom or methyl; A represents nicotinoyl or N,N′-diethylamidino; and B represents isopropyl or N,N′-diethylamidino or a salt thereof.
(7) A method for production of (6), wherein X is a tetrahydrofurylcarboxamido.
(8) A method for production of (6), wherein X is (2S)-tetrahydrofurylcarboxamido.
(9) A method for production of (6), wherein X is (2S)-tetrahydrofurylcarboxamido, Q is methyl, A is nicotinoyl, and B is isopropyl.
(10) A method for production of (1), wherein said bioactive substance is thyroid horomone-releasing hormone.
(11) A method for production of (1), wherein the content ratio of said biodegradable polymer is not less than 70% (w/w).
(12) A method for production of (1), wherein said biodegradable polymer is a homopolymer or copolymer of &agr;-hydroxycarboxylic acids or a mixture thereof.
(13) A method for production of (1), wherein said biodegradable polymer is a homopolymer or copolymer of lactic acid/glycolic acid having a lactic acid/glycolic acid ratio of about 100/0 to 50/50 mol %.
(14) A method for production of (1), wherein said biodegradable polymer is a homopolymer of lactic acid.
(15) A method for production of (1), wherein the weight-average molecular weight of said biodegradable polymer is 3,000 to 30,000.
(16) A method for production of (1), wherein microcapsules are thermally dried in a temperature ranging from the glass transition point of said biodegradable polymer to a temperature about 30° C. higher than the glass transition point.
(17) A method for production of (1), wherein microcapsules are thermally dried at a temperature ranging from the glass transition point of said biodegradable polymer to a temperature by 5° C. higher than the glass transition point.
(18) A method for production of (1), wherein microcapsules are thermally dried for about 48 to 120 hours.
(19) A method for production of (1), wherein the microcapsules are obtained by an in-water drying method.
(20) A method for production of (1), wherein the content ratio of the bioactive substance relative to the sustained-release microcpsules is 0.01 to 40% (w/w).
(21) A method for production of (4), wherein the sustained-release microcapsules contain the bioactive substance at the final content ratio of 5-15% (w/w) and the biodegradable polymer at the final content ratio of 80-95% (w/w).
(22) Sustained-release microcapsules obtained by the method for production of (1).
(23) Microcapsules of (22) which is for injection.
(24) An agent for treatment or prevention of sex hormone-dependent diseases or a contraceptive which comprises the sustained-release microcapsules of (22).
(25) An agent of (24), wherein said sex hormone-dependent disease is prostatic hypertrophy, prostatic cancer, hysteromyoma, endometriosis, dysmenorrhea, precocious puberty or breast cancer.
(26) A method for treatment or prevention of sex hormone-dependent diseases in a subject which comprises administering to said subject in need an effective amount of the microcapsules of (22).
(27) Use of the microcapsules of (22) for manufacture of an agent for treatment or prevention of sex hormone-dependent diseases or a contraceptive.
(28) A composition for the treatment or prevention of sex hormone-dependent disease or a contraceptive, made from a microcapsule as claimed in (22).
(29) A method for treating a microcapsule comprising a bioactive substance that is encapsulated with a biodegradable polymer, which comprises thermally drying the microcapsule at a temperature not lower than the gl
Igari Yasutaka
Kosakai Hiroshi
Takada Shigeyuki
Takeda Chemical Industries Ltd.
Webman Edward J.
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