Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-08-31
2003-03-04
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S497000, C424S499000, C530S313000, C530S328000, C514S002600, C514S015800
Reexamination Certificate
active
06528093
ABSTRACT:
The present invention relates to a sustained-release preparation containing a physiologically active peptide and to a method of producing the same.
BACKGROUND OF THE INVENTION
The prior art includes, as disclosed in EP-A-481,732, a sustained-release preparation comprising a drug, a polylactic acid and a glycolic acid-hydroxycarboxylic acid [HOCH(C
2-8
alkyl)COOH] copolymer. The disclosed process comprises preparing a W/O emulsion consisting of an internal water phase comprising an aqueous solution of a physiologically active peptide and an external oil phase comprising a solution of a biodegradable polymer in an organic solvent, adding said W/o emulsion to water or an aqueous medium and processing the resulting W/O/W emulsion into sustained-release microcapsules (drying-in-water method).
EP-A-52510 describes a microcapsule comprising a hormonally active polypeptide, a biodegradable polymer and a polymer hydrolysis control agent. The disclosed, process for its production is a coacervation process which comprises adding a coacervation agent to a W/O emulsion consisting of an aqueous solution of the polypeptide as the internal water phase and a halogenated organic solvent as the oil phase to provide microcapsules.
GB-A-2209937 describes a pharmaceutical composition comprising a polylactide, a polyglycolide, a lactic-acid-glycolic acid copolymer or a mixture of these polymers and a water-insoluble peptide. Also disclosed is a production process which comprises dispersing a salt of the water-insoluble peptide in a solution of said polylactide, polyglycolide, a lactic acid-glycolic acid copolymer or a mixture of these polymers, removing the solvent by evaporation and molding the resulting mixture into solid particles.
EP-A-58481 describes a process for producing a pharmaceutical composition comprising a polylactide and an acid-stable polypeptide which, for instance, comprises dissolving tetragastrin hydrochloride and a polylactide in aqueous dioxane, casting the solution into a film and evaporating the solvent.
EP-A-0467389 teaches a technology for providing a drug delivery system for proteins and polypeptides by the polymer precipitation technique or the microsphere technique. However, this literature contains no specific disclosure about a system containing an LH-RH derivative.
The luteinizing hormone-releasing hormone, known as LH-RH (or GnRH), is secreted from the hypothalamus and binds to receptors on the pituitary gland. The LH (luteinizing hormone) and FSH (follicle stimulating hormone), which are released thereon, act on the gonad to synthesize steroid hormones. As derivatives of LH-RH, the existence of both agonistic and antagonistic peptides is known. When a highly agonistic peptide is repeatedly administered, the available receptors are reduced in number so that the formation of gonad-derived steroidal hormones is suppressed. Therefore, LH-RH derivatives are expected to be of value as therapeutic agents for hormone-dependent diseases such as prostate cancer, benign prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty, mammary cancer, etc. or as contraceptives. Particularly, the problem of histamine-releasing activity was pointed out for LH-RH antagonists of the so-called first and second generations (The Pharmaceuticals Monthly 32, 1599-1605, 1990) but a number of compounds have since been synthesized and recently LH-RH-antagonizing peptides having no appreciable histamine-releasing activity have been developed (cf. U.S. Pat. No. 5,110,904, for instance). In order for any such LH-RH antagonizing peptide to manifest its pharmacological effect, there is a need for a controlled release system so that the competitive inhibition of endogenous LH-RH may be persistent. Moreover, because of histamine-releasing activity which may be low but is not non-existent in such peptides, a demand exists for a sustained-release preparation with an inhibited initial burst immediately following administration.
Particularly, in the case of a sustained-release (e.g. 1-3 months) preparation, it is important to insure a more positive and constant release of the peptide in order that the desired efficacy may be attained with greater certainty and safety.
At the same time, there is a long-felt need for a method of producing a sustained-release preparation having a high peptide trap rate for a physiologically active peptide, particularly LH-RH-antagonizing peptides.
SUMMARY OF THE INVENTION
According to the present invention, there is provided:
1) A sustained-release preparation which comprises a physiologically active peptide of the general formula:
wherein
X represents an acyl group;
R
1
, R
2
and R
4
each represents an aromatic cyclic group;
R
3
represents a D-amino acid residue or a group of the formula:
wherein
R
3
′ is a heterocyclic group;
R
5
represents a group of the formula —(CH
2
)
n
—R
5
′ wherein n is 2 or 3, and R
5
′ is an amino group which may optionally be substituted, an aromatic cyclic group or an O-glycosyl group;
R
6
represents a group of the formula —(CH
2
)
n
—R
6
′ wherein n is 2 or 3, and R
6
′ is an amino group which may optionally be substituted;
R
7
represents a D-amino acid residue or an azaglycyl residue; and
Q represents hydrogen or a lower alkyl group or a salt thereof and a biodegradable polymer having a terminal carboxyl group,
2) The sustained-release preparation according to the above paragraph 1, wherein X is a C
27
alkanoyl group which may optionally be substituted by a 5- or 6-membered heterocyclic carboxamido group,
3) The sustained-release preparation according to the above paragraph 2, wherein X is a C
2-4
, alkanoyl group which may optionally be substituted by a tetrahydrofurylcarboxamide group,
4) The sustained-release preparation according to the above paragraph 1, wherein X is acetyl,
5) The sustained-release preparation according to the above paragraph 1, wherein the biodegradable polymer is a mixture of (A) a copolymer of glycolic acid and a hydroxycarboxylic acid of the general formula:
wherein R represents an alkyl group of 2 to 8 carbon atoms and (B) a polylactic acid,
6) The sustained-release preparation according to the above paragraph 1, wherein X is acetyl, and the biodegradable polymer is a mixture of (A) a copolymer of glycolic acid and a hydroxycarboxylic acid of the general formula (III and (B) a polylactic acid,
7) The sustained-release preparation according to the above paragraph 5, wherein the copolymer has a weight average molecular weight of about 2,000 to 50,000, as determined by GPC,
8) The sustained-release preparation according to the above paragraph 5, wherein the copolymer has a dispersion value of about 1.2 to 4.0,
9) The sustained-release preparation according to the above paragraph 5, wherein the polylactic acid has a weight average molecular weight of about 1,500 to 30,000 as determined by GPC,
10) The sustained-release preparation according to the above paragraph 5, wherein the polylactic acid has a dispersion value of about 1.2 to 4.0,
11) The sustained-release preparation according to the above paragraph 1, wherein the biodegradable polymer Ls a copolymer of lactic acid and glycolic acid,
12) The sustained-release preparation according to the above paragraph 11, wherein the copolymer has a weight average molecular weight of about 5,000 to 25,000, as determined by GPC,
13) The sustained-release preparation according to the above paragraph 11, wherein the copolymer has a dispersion value of about 1.2 to 4.0,
14) The sustained-release preparation according to the above paragraph 1, wherein the proportion of the physiologically active peptide ranges from about 0.01 to 50% (w/w) based on the biodegradable polymer,
15) The sustained-release preparation according to the above paragraph 1, wherein the physiologically active peptide is a LH-RH antagonist,
16) The sustained-release preparation according to the above paragraph 1, wherein the physiologically active peptide is:
or its acetate,
17) The sustained-release preparation according to the a
Igari Yasutaka
Kamei Shigeru
Ogawa Yasuaki
Foley & Lardner
Gupta Amish
Low Christopher S. F.
Takeda Chemical Industries Ltd.
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