Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-03-07
2004-03-02
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S451000, C424S452000, C424S423000, C424S425000, C424S486000, C424S489000, C514S963000, C514S965000
Reexamination Certificate
active
06699500
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a sustained-release preparation which releases a physiologically active substance over a period of at least about 5 months.
2. Description of Related Art
A microsphere-type sustained-release preparation of drugs containing a biodegradable polymer is described in JP-A 118512/1982 (EP-A 52510), 150609/1982 (EP-A 58481), 100516/1985 (EP-A 145240), 201816/1987 (EP-A 190833), 321622/1992 (EP-A 442671) and 97334/1995 (EP-A 601799), for instance. Especially in JP-A 100516/1985 (EP-A 145240) and 201816/1987 (EP-A 190833), production of sustained-release microcapsules of a water-soluble drug with good dispersibility and high entrapment ratio by an in-water drying method is described. In JP-A 321622/1992 (EP-A 442671), long-term sustained-release microcapsules designed for zero order release of a polypeptide over a period of at least 2 months and containing a copolymer or homopolymer having a lactic acid/glycolic acid ratio of 80/20 to 100/0 and having a weight-average molecular weight of 7,000 to 30,000 are described.
SUMMARY OF THE INVENTION
The present invention relates to
(1) sustained-release preparation comprising 1) a polymer of lactic acid having a weight-average molecular weight of about 25,000 to about 60,000 and 2) a physiologically active substance, and which releases the physiologically active substance over a period of at least about 5 months;
(2) the preparation according to the above (1), wherein the polymer of lactic acid is obtained by hydrolyzing a polylactic acid produced by ring-opening polymerization;
(3) the preparation according to the above (1), wherein the polymer of lactic acid is substantially free from a catalyst;
(4) the preparation according to the above (1), wherein the polymer of lactic acid has a weight-average molecular weight of about 30,000 to about 50,000;
(5) the preparation according to the above (1), wherein the polymer of lactic acid has a dispersity of about 1.2 to about 4.0;
(6) the preparation according to the above (1), which is for injection;
(7) the preparation according to the above (1), which further comprises an excipient;
(8) the preparation according to the above (7), wherein the excipient is sugar;
(9) the preparation according to the above (1), wherein the physiologically active substance is a physiologically active peptide;
(10) the preparation according to the above (9), wherein the physiologically active peptide is a LHRH agonist or a LHRH antagonist;
(11) the preparation according to the above (10), wherein the LHRH agonist is a peptide represented by the formula:
(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 an optionally substituted D-type amino acid residue; R
4
represents Leu, Ile or Nle; R
5
represents Gly-NH—R
6
wherein R
6
is hydrogen or an alkyl group with or without hydroxy group or NH—R
7
wherein R
7
is hydrogen, an alkyl group with or without amino or hydroxy group, or ureido, or a salt thereof;
(12) the preparation according to the above (11), wherein the peptide represented by the formula (I) or a salt thereof is leuprorelin or leuprorelin acetate;
(13) the preparation according to the above (1), wherein the physiologically active substance is contained in an amount of about 0.01 to about 50% (w/w);
(14) the preparation according to the above (1), wherein the ratio of the physiologically active substance relative to the polymer of lactic acid is about 0.01 to about 50% (w/w);
(15) the preparation according to the above (1), wherein the physiologically active substance is leuprorelin acetate, the polymer of lactic acid has a weight-average molecular weight of about 28,400 to about 47,800, and the preparation releases leuprorelin acetate over a period of at least about 6 months; and
(16) method of producing a sustained-release preparation releasing a physiologically active substance over a period of at least about 5 months, which comprises subjecting to microencapsulation a w/o emulsion with a solution containing a physiologically active substance as an internal aqueous phase and with a solution containing a polymer of lactic acid having a weight-average molecular weight of about 25,000 to about 60,000 as an oil phase.
DETAILED DESCRIPTION OF THE INVENTION
In the present specification, regarding references to “weight-average molecular weight” and “dispersity”, the present inventors intend that the former be measured in terms of polystyrene as determined by gel permeation chromatography (GPC) using 9 polystyrenes as reference substances with weight-average molecular weights of 120,000, 52,000, 22,000, 9,200, 5,050, 2,950, 1,050, 580 and 162, respectively, and that the latter be calculated therefrom. The above determination was carried out using a GPC column KF804L (produced by Showa Denko, Japan)x2 and an RI monitor L-3300 (produced by Hitachi, Ltd., Japan), with chloroform as a mobile phase.
Regarding abbreviations for amino acids, protecting groups and others, abbreviations used in the present specification are based on abbreviations specified by the IUPAC-IUB Commission on Biochemical Nomenclature or abbreviations in common use in relevant fields. When an optical isomer may be present in amino acid, it is of the L-configuration, unless otherwise stated.
Abbreviations used in the present specification are defined as follows:
NAcD2Nal: N-acetyl-D-3-(2-naphthyl)alanyl
D4ClPhe: D-3-(4-chlorophenyl)alanyl
D3 Pal: D-3-(3-pyridyl)alanyl
NMeTyr: N-methyltyrosyl
DLys(Nic): D-(epsilon-N-nicotinoyl)lysyl
Lys(Nisp): (Epsilon-N-isopropyl)lysyl
DhArg(Et
2
): D-(N,N′-diethyl)homoarginyl
The polymer of lactic acid used in the present invention is a biodegradable polymer which decomposes in a living body over a period of at least about 5 months and has a free terminal carboxyl group. The present polymer is a homopolymer of lactic acid.
The weight-average molecular weight of the present polymer of lactic acid is about 25,000 to about 60,000, preferably about 27,000 to about 55,000, more preferably about 28,000 to about 50,000. Employment of these ranges of the weight-average molecular weight enables production of a sustained-release preparation showing a small initial burst of drugs and a continuous zero order release of drugs.
The dispersity (weight-average molecular weight
umber-average molecular weight) of the polymer of lactic acid used in the present invention is preferably about 1.2 to about 4.0, more preferably about 1.5 to about 3.5.
The present polymer of lactic acid may be of the L-, D- or DL-configuration, with preference given to the DL-configuration. Regarding the DL-configuration, the ratio of the D-configuration/L-configuration (mol %) is preferably about 75/25 to about 20/80, more preferably about 60/40 to about 25/75, still more preferably about 55/45 to about 25/75.
The polymer of lactic acid used in the present invention is preferably produced by hydrolyzing a starting polylactic acid produced by ring-opening reaction of a cyclic dimer of lactic acid and polymerization.
The starting polylactic acid produced by the ring-opening reaction and polymerization is a polymer of a high molecular weight region, which is not obtained by a dehydration condensation of lactic acid wherein heating is conducted under reduced pressure after addition of a catalyst (JP-A 45920/1981, EP-A 26599), or a method for producing a polymer which is obtained by polymerization of lactic acid without using a catalyst and is substantially free from a catalyst (JP-A 28521/1986, EP-A 172636). The ring-opening reaction and polymerization (hereafter referred to as ring-opening polymerization) is conducted by a method wherein a cyclic dimer of a lactic acid is used and a catalyst is added while heating (e.g. J. H. R. Woodland et. al.; J. Med. Chem., 16, 897 (1973)).
Although the weight-average molecular weight of a polylactic acid produced by ring-opening polymerization is not especially limited as long as it is larger than the w
Douken Yayoi
Okada Hiroaki
Bennett Rachel M.
Page Thurman K.
Takeda Chemical Industries Ltd.
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