Production of sustained-release preparation for injection

Details Production of sustained-release preparation for injection Production of sustained-release preparation for injection

1996-12-13

2001-02-20

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S489000, C424S501000, C514S002600, C514S964000

Reexamination Certificate

active

06190700

ABSTRACT:

The present invention relates to production of a sustained-release preparation for injection.
BACKGROUND OF THE INVENTION
Microsphere type sustained-release drug preparations incorporating a biodegradable polymer are disclosed in, for example, Japanese Patent Unexamined Publication Nos. 118512/1982, 150609/1982, 100516/1985 (EP-A145240), 201816/1987 (EP-A190833), 233926/1988, 42420/1989, 032302/1991, 321622/1922 (EP-A442671), 70363/1993, 112468/1993, 194200/1993 (EP-A535937), 145046/1994 (EP-A582459) and 192068/1994 (EP-A586238). Japanese Patent Unexamined Publication Nos. 100516/1985 and 201816/1987, in particular, disclose a method of preparing sustained-release microspheres of a water-soluble physiologically active substance with high entrapment ratio and high dispersibility by the in-water drying method.
With regard to microsphere type sustained-release drug preparations incorporating a biodegradable polymer, it is necessary to prepare fine particles of uniform microsphere particle form, to ensure satisfactory dispersibility and needle passability during administration, and to prevent aggregation and particle binding from market delivery to use. Also, in the preparation method involving the use of an organic solvent, the residual solvent in the finished preparation is problematic from the viewpoint of preparation stability and safety to the human body, necessitating perfect solvent removal during the production process.
SUMMARY OF THE INVENTION
Through intensive investigation to resolve the above problems, the present inventors found it possible to almost perfectly remove the residual organic solvent and prevent particle binding to produce sustained-release microspheres of good dispersibility, needle passability and storage stability, by heating the sustained-release microspheres in the presence of sugars during freeze drying, and to suppress particle binding during drying, and enable drying at high temperatures exceeding the glass transition temperature of microsphere, to almost perfectly remove the water and solvent during freeze drying by adding sugars.
Accordingly, the present invention relates to a method of producing a sustained-release preparation for injection, which comprises adding to microspheres which are obtained from w/o emulsion with a solution containing a physiologically active peptide as an internal aqueous phase and a solution containing a polylactic acid having a weight-average molecular weight of about 5,000 to about 25,000 as an oil phase, a sugar in an amount of about 2 to about 60% (w/w) relative to the microspheres; freeze drying and subsequent heating at the temperature ranging from the glass transition temperature of the microspheres to the temperature which is higher by about 20° C. than the glass transition temperature for about 24 to about 120 hours.
DETAILED DESCRIPTION OF THE INVENTION
In the present specification, abbreviations for amino acids, protecting groups and others 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
D3Pal: 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 physiologically active peptide is preferably one consisting of 2 or more amino acids and having a molecular weight of about 200 to about 80,000. The physiologically active peptide is preferably LH-RH (luteinizing hormone-releasing hormone) agonist or LH-RH antagonist. Examples of the LH-RH agonist include 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 a D-type amino acid residue; R
4
represents Leu, Ile or Nle; R
5
represents Gly-NH-R
6
(R
6
is H or an alkyl group with or without a hydroxyl group) or NH-R
7
(R
7
is H, an alkyl group with or without an amino or a hydroxyl group, or ureido (—NH—CO—NH
2
)); [hereafter also referred to as peptide (I)] or a salt thereof.
With respect to the formula (I) above, the D-type amino acid residue in R
3
is exemplified by &agr;-D-amino acids having up to 9 carbon atoms (e.g., D-Leu, Ile, Nle, Val, Nval, Abu, Phe, Phg, Ser, Thr, Met, Ala, Trp, &agr;-Aibu). These amino acid residues may optionally have a substituent (e.g., tert-butyl, tert-butoxy, tert-butoxycarbonyl, methyl, dimethyl, trimethyl, 2-naphthyl, indoly-3-yl, 2-methyl-indolyl, benzyl-imidazo-2-yl) as appropriate.
In the formula (I), the alkyl group in R
6
or R
7
is preferably a C
1-4
alkyl group. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
Examples of the salt of the peptide represented by the formula (I) include acid salts (e.g., carbonate, bicarbonate, acetate, trifluoroacetate, propionate, succinate) and metal complex compounds (e.g., copper complex, zinc complex).
Peptide (I) or a salt thereof can be produced, for example, by a method which is described in U.S. Pat. Nos. 3,853,837, 4,008,209 and 3,972,859, British Patent No. 1,423,083, Proceedings of the National Academy of Science of the United States of America, Vol. 78, pp. 6509-6512 (1981), or an analogous method thereto.
Peptide (I) is preferably the following (a) to (j). (a) leuprorelin [a peptide represented by the formula (I) wherein R
1
is His, R
2
is Tyr, R
3
is D-Leu, R
4
is Leu, and R
5
is NHCH
2
—CH
3
];
(b) Gonadrelin
(German Patent No. 2213737); (c) Buserelin
(U.S. Pat. No. 4,024,248, German Patent No. 2438352, Japanese Patent Unexamined Publication No 41359/1976); (d) Triptorelin
(U.S. Pat. No. 4,010,125, Japanese Patent Unexamined Publication No. 31073/1977); (e) Goserelin
(U.S. Pat. No. 4,100,274, Japanese Patent Unexamined Publication No. 136172/1977); (f) Nafarelin
(U.S. Pat. No. 4,234,571, Japanese Patent Unexamined Publication Nos. 164663/1980, 264498/1988 and 25794/1989; (g) Histrelin
(h) Deslorelin
(U.S. Pat. Nos. 4,569,967 and 4,218,439); (i) Meterelin
(WO9118016); (j) Lecirelin
(Belgium Patent No. 897455, Japanese Patent Unexamined Publication No. 59654/1984).
In the above-described formulae (c) to (j), an amino acid which corresponds to R
3
in the formula (I) is of D-configuraiton.
Peptide (I) or a salt thereof is especially preferably leuprorelin or leuprorelin acetate.
Examples of the LH-RH antagonist include those disclosed in U.S. Pat. Nos. 4,086,219, 4,124,577, 4,253,997 and 4,317,815, or a peptide represented by the formula:
wherein X represents hydrogen atom or tetrahydrofurylcarboxamide; Q represents hydrogen atom or methyl; A represents nicotinoyl or N,N′-diethylamidino; B represents isopropyl or N,N′-diethylamidino; (hereafter also referred to as peptide (II)) or a salt thereof.
With respect to the formula (II), X is preferably tetrahydrofurylcarboxamide, more preferably (2S)-tetrahydrofurylcarboxamide. Also, A is preferably nicotinoyl; B is preferably isopropyl.
When peptide (II) has one or more kinds of asymmetric carbon atoms, two or more optical isomers are present. Such optical isomers and mixtures thereof are also included in the scope of the present invention.
Peptide (II) or a salt thereof can be produced by per se known methods. Such methods include the methods described in Japanese Patent Unexamined Publication No. 101695/1991 and the Journal of Medicinal Chemistry, Vol. 35, p. 3942 (1992) and other publications, and similar methods.
The salt of peptide (II) is preferably a pharmacologically acceptable salt. Such salts include salts formed with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid), organic acids (e.g., carbonic acid, bicarbonic acid, succinic acid, acetic acid, propionic acid, trifluor

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