Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-07-06
2004-05-25
Wax, Robert A. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S399000, C530S313000, C424S468000, C424S486000
Reexamination Certificate
active
06740634
ABSTRACT:
FIELD OF INDUSTRIAL APPLICATION
The present invention relates to a sustained-release composition of a biologically active substance, and a production method thereof.
PRIOR ART
Japanese Patent Unexamined Publication No. 97334/1995 discloses a sustained-release preparation comprising a biologically active peptide or salt thereof and a biodegradable polymer having a free carboxyl group at one end and a production method thereof.
The patent publications for GB2209937, GB2234169, GB2234896, GB2257909 and EP626170A2 disclose compositions based on a biodegradable polymer containing a separately prepared water-insoluble salt, such as a pamoate of a peptide or protein, or production methods therefor.
The patent publication for WO95/15767 discloses the embonate (pamoate) of cetrorelix (LH-RH antagonist) and a production method therefor, and describes that the peptide-releasing profile of this pamoate remains the same as in its use alone, even when included in a biodegradable polymer.
Problems to be Solved by the Invention
To provide a novel composition that contains a high concentration of biologically active substance, and that is capable of a controlled rate of release.
Means of Solving the Problems
After extensive investigation aiming at resolving the above problem, the present inventors found that when a biologically active substance is incorporated in high concentration in a composition by allowing the biologically active substance and the hydroxynaphthoic acid to be co-present during formation of the composition, and when both are included in a biodegradable polymer, the biologically active substance is released at rates differing from those of the biologically active substance from the counterpart composition of the biologically active substance and hydroxynaphthoic acid prepared in the absence of the biodegradable polymer, which rate of release is controllable by choosing the appropriate kind of biodegradable polymer. The inventors conducted further investigations based on this finding, and developed the present invention.
Accordingly, the present invention provides:
(1) a sustained-release composition containing a biologically active substance or salt thereof, a hydroxynaphthoic acid or salt thereof, and a biodegradable polymer or salt thereof,
(2) a sustained-release composition according to term (1) above wherein the biologically active substance is a biologically active peptide,
(3) a sustained-release composition according to term (2) above wherein the biologically active peptide is an LH-RH derivative,
(4) a sustained-release composition according to term (1) above wherein the hydroxynaphthoic acid is 3-hydroxy-2-naphthoic acid,
(5) a sustained-release composition according to term (1) above wherein the biodegradable polymer is an &agr;-hydroxycarboxylic acid polymer,
(6) a sustained-release composition according to term (5) above wherein the &agr;-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid polymer,
(7) a sustained-release composition according to term (6) above wherein the content ratio of lactic acid and glycolic acid is 100/0 to 40/60 mol %;
(8) a sustained-release composition according to term (7) above wherein the content ratio of lactic acid and glycolic acid is 100/0 mol %,
(9) a sustained-release composition according to term (6) above wherein the weight-average molecular weight of the polymer is about 3,000 to about 100,000,
(10) a sustained-release composition according to term (9) above wherein the weight-average molecular weight of the polymer is about 20,000 to about 50,000,
(11) a sustained-release composition according to term (3) above, wherein the LH-RH derivative is a peptide represented by the formula:
5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z (SEQ ID NO.:1)
wherein Y represents DLeu, DAla, DTrp, DSer(tBu), D2Nal or DHis(ImBzl); Z represents NH-C
2
H
5
or Gly-NH
2
,
(12) a sustained-release composition according to term (6) above, wherein the terminal carboxyl group content of the polymer is 50-90 micromol per unit mass (gram) of the polymer,
(13) a sustained-release composition according to term (3) above, wherein the molar ratio of the hydroxynaphthoic acid or salt thereof and the LH-RH derivative or salt thereof is from 3 to 4 to 4 to 3,
(14) a sustained-release composition according to term (13) above, wherein the LH-RH derivative or salt thereof is contained at 14% (w/w) to 24% (w/w),
(15) a sustained-release composition according to term (1) above, wherein the bioactive substance or salt thereof is very slightly-soluble in water or soluble in water,
(16) a sustained-release composition according to term (1) above, which is intended for injection,
(17) a method of producing the sustained-release composition according to term (1) above, comprising removing the solvent from a mixture of a bioactive substance or salt thereof, a biodegradable polymer or salt thereof, and hydroxynaphthoic acid or a salt thereof,
(18) a method of producing the sustained-release composition according to term (17) above, comprising mixing and dispersing a bioactive substance or salt thereof in an organic solvent solution containing a biodegradable polymer or salt thereof and hydroxynaphthoic acid or a salt thereof, and subsequently removing the organic solvent,
(19) a method of producing the sustained-release composition according to term (18) above, wherein the bioactive substance or salt thereof is in the form of an aqueous solution,
(20) a production method according to term (17) above, wherein the salt of the bioactive substance is a salt with a free base or acid,
(21) a pharmaceutical containing the sustained-release composition according to term (1) above,
(22) an agent for preventing or treating prostatic cancer, prostatic hypertrophy, endometriosis, hysteromyoma, metrofibroma, precocious puberty, dysmenorrhea, or breast cancer, or a contraceptive, containing the sustained-release composition according to term (3) above,
(23) a sustained-release composition containing the hydroxynaphthoate of a bioactive substance and a biodegradable polymer or salt thereof,
(24) a method of suppressing bioactive substance initial burst from a sustained-release composition, comprising using hydroxynaphthoic acid or a salt thereof,
(25) a method of increasing the efficiency of bioactive substance inclusion in a sustained-release composition, comprising using hydroxynaphthoic acid or a salt thereof,
(26) a hydroxynaphthoate of a bioactive peptide,
(27) a hydroxynaphthoate of a bioactive peptide according to term (26) above, which is soluble in water or very slightly soluble in water, and
(28) a sustained-release composition containing the hydroxynaphthoate of a bioactive peptide.
The present invention further provides:
(29) a sustained-release composition according to term (28) above, wherein the content of the hydroxynaphthoic acid or salt thereof is about 1 to about 7 mol, preferably about 1 to about 2 mol, per mol of the bioactive peptide or salt thereof
(30) a production method for the sustained-release composition according to term (17) above, comprising producing a W/O emulsion with a solution containing a bioactive substance or salt thereof as an internal aqueous phase and a solution containing a biodegradable polymer and hydroxynaphthoic acid or a salt thereof as an oil phase, and subsequently removing the solvent,
(31) a production method for the sustained-release composition according to term (17) above, comprising producing a W/O emulsion with a solution containing hydroxynaphthoic acid or a salt thereof as an internal aqueous phase and a solution containing a bioactive substance or salt thereof and a biodegradable polymer or salt thereof as an oil phase, and subsequently removing the solvent,
(32) a production method for the sustained-release composition according to term (28) above, comprising mixing and dissolving a bioactive peptide or salt thereof and hydroxynaphthoic acid or salt thereof, and subsequently removing the solvent, and
(33) the production method for sustained-release composition according to any one of terms (30) through (32), wherein t
Hata Yoshio
Igari Yasutaka
Saikawa Akira
Yamamoto Kazumichi
Chao Mark
Lukton David
Ramesh Elaine M.
Takeda Chemical Industries Ltd.
Wax Robert A.
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