JPH11279054A - Production of sustained release preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a sustained release preparation which can be conveniently recovered in a high yield and possesses reduced risk in the occurrence and contamination of foreign substances by lyophilizing the sustained release preparation in a specifically pretreated tray. SOLUTION: By lyophilizing the sustained release preparation (preferably a microsphere or a microcapsule) in a vessel for lyophilization (e.g. a tray for lyophilization) of which a part or all of the inside are previously coated with an ice layer or a water repellent substrate (preferably an ethylene tetrafluoride resin, a vinylidene fluoride resin, a modified fluororesin or the like), the solid sustained release preparation is conveniently obtained in a high yield without exposure to environment over a long period of time, because the preparation obtained is hot adhered to the vessel. As the drug contained in the sustained-release preparation, a bioactive peptide, e.g. luteinization hormone-releasing hormone, insulin, somatostatin or the like, is preferably illustrated. Further, it is favorable that the ice layer formed is about 0.01-30 mm thick.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a solid sustained-release preparation which enables a sustained-release preparation such as microspheres to be easily recovered without exposing it to the environment for a long time.

[0002]

2. Description of the Related Art A microcapsule (microsphere) powder (hereinafter sometimes abbreviated as MC powder) is obtained by an underwater drying method or the like. , After separating, concentrating, and recovering MC, the MC suspension obtained as a suspension together with a solvent described below is dehydrated and dried by a freeze-drying method. At this time, mannitol or the like may be added and dissolved in the above suspension. Usually, after dispensing the MC suspension to a tray, the MC suspension is frozen and freeze-dried. However, conventionally, after the freeze-drying, the MC powder has to be manually aseptically peeled off and collected from the tray using a scraper, and thus has the following disadvantages. (1) The MC powder adheres to the tray and must be scraped off with a scraper at the time of collection. (2) Since the scraping is performed manually and the collection requires a relatively long time, the time for exposure to the environment is prolonged, and there is always a risk of contamination with microorganisms from the viewpoint of aseptic assurance. In addition, since MC is a preparation requiring moisture control, a long environmental exposure time is dangerous from the viewpoint of physicochemical stability. (3) In the scraping operation, the use of a scraper is indispensable, and there is a risk of foreign matter being generated or mixed due to friction between the tray and the scraper. (4) Since the MC powder adheres to the tray, the MC powder remains on the tray even after being collected by the scraper, and some MC powder cannot be collected.

[0003]

Therefore, a solid sustained-release preparation after freeze-drying can be easily recovered in a high yield, and furthermore, the environmental exposure time is short, and the risk of foreign matter generation and contamination is reduced. It has been desired to develop a method for producing a solid sustained-release preparation with reduced drug.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have formed an ice layer on a tray in advance or coated the inner surface of the tray with a water-repellent substrate. As a result, it has been found that the MC powder after freeze-drying can be recovered in an unexpectedly short time and easily. Further, under reduced pressure, the temperature of the freeze-drying container is 0 ° C. or lower, and by completing the sublimation of the frozen water in the freeze-drying container, the freeze-dried cake is prevented from being broken and scattered, and a higher yield and a constant quality of the cake are obtained. They also found that MC powder could be recovered. The present inventors have further studied based on these findings, and as a result, have completed the present invention. That is, the present invention provides (1) freeze-drying a sustained-release preparation in a freeze-drying container in which part or all of the inner surface is coated with an ice layer or a water-repellent substrate, (2) Freezing a sustained-release preparation in a lyophilization container in which a part or all of the inner surface is coated with a water-repellent substrate and a part or all of the inner surface is coated with an ice layer A method for producing a solid sustained-release preparation characterized by drying; (3) the method according to (1) or (2), wherein the inner surface is only the bottom surface; The manufacturing method according to the above (1) or (2), wherein
(5) The method according to (1) or (2), wherein the thickness of the ice layer is about 0.01 mm to 30 mm, (6) the water-repellent substrate is an ethylene tetrafluoride resin, Ethylene resin, ethylene difluoride resin, vinylidene fluoride resin,
Hexafluoropropylene / tetrafluoroethylene copolymer resin,
(1) The method according to (1) or (2), which is a modified fluororesin, a copolymer resin of tetrafluoroethylene and perfluoroalkoxyethylene, or a copolymer resin of ethylene tetrafluoride and ethylene; 7) The production method according to any one of (1) to (6), wherein the sustained-release preparation is a microsphere, and (8) Freezing at a temperature of a freeze-drying container of 0 ° C. or lower under reduced pressure. Sublimation of frozen water in a drying container is completed, and the production method according to the above (1) or (2) is provided.

Further, the present invention provides (9) the method according to (1) or (2), wherein the thickness of the ice layer is about 1/1000 to about 4/5 of the depth of the container; (10) The method according to (1) or (2), wherein the thickness of the frozen layer of the suspension of the sustained-release preparation is 1/1000 to about 4/5 of the depth of the container, 11) The size of the container is about 5 mm to about 7,000
mm, length about 5mm ~ about 7,000mm, depth about 1mm ~
100 mm and the ice layer is about 0.01 mm to about 30 mm
(1) or (2), wherein (1)
2) The production method according to any one of (1) to (11), wherein the sustained-release preparation is a sustained-release preparation containing a bioactive peptide, and (13) the sustained-release preparation is a bioactive peptide. And a sustained-release preparation containing a biodegradable polymer, the production method according to any one of the above-mentioned items (1) to (11),
(14) The method according to (12) or (13), wherein the bioactive peptide is an LH-RH agonist or an LH-RH antagonist, (15) the bioactive peptide is 5-oxo-Pro-His. -Trp-Ser-Tyr-DLeu-Le
u-Arg-Pro-NH- C 2 H 5 ( leuprorelin) or a (12) a salt claim or the (13) The process according to claim (16) a physiologically active peptide is 5-oxo- Pro-His-
Trp-Ser-Tyr-DLeu- Leu-Arg-Pro-NH-C 2 H
₅ The production method according to item (12) or (13), which is an acetate of (leuprorelin), (17) item (13), wherein the biodegradable polymer is an α-hydroxycarboxylic acid polymer. (18) The method according to (1), wherein the α-hydroxycarboxylic acid polymer is a lactic acid-glycolic acid polymer.
(19) The production method according to (18), wherein the composition ratio of lactic acid and glycolic acid is about 100/0 to about 40/60 (mol%), (20) a polymer. (18) having a weight average molecular weight of about 3,000 to about 100,000
(21) The method according to (13), wherein the biodegradable polymer is polylactic acid, and (22)
The weight average molecular weight of polylactic acid is about 10,000 to about 60,0
(21) The production method according to the above (21), which is 00.

[0006] Examples of sustained-release preparations used in the production method of the present invention include microspheres.
The microspheres referred to in the present invention also include microcapsules, microparticles, and the like. Specifically, JP-A-60-100516 and JP-A-62-2
01816, JP-A-02-124814,
JP-A-04-321622, JP-A-05-112
468, JP-A-05-194200, JP-A-06-293636, JP-A-06-14504
No. 6, JP-A-06-192068, JP-A-06-192068
JP-A-8-169818, JP-A-09-132524, JP-A-09-221417, JP-A-09-214
For example, microspheres or microcapsules described in JP-A-221418 and the like are used.

The drug contained in the sustained-release preparation is preferably a physiologically active peptide, for example, having a molecular weight of about 300 to about 40,000, preferably about 400 to about 40,000.
About 30,000, more preferably from about 500 to
About 20,000 bioactive peptides and the like are used.
Such physiologically active peptides include, for example, pKa
It preferably has a basic group capable of forming a salt with 4.0 or more weak acids (eg, carbonic acid, bicarbonic acid, boric acid, lower alkanemonocarboxylic acid having 1 to 3 carbon atoms, etc.). Further, it may have a free or salt-formed acidic group other than the basic group. A typical example of the activity of the physiologically active peptide is a hormonal action.
In addition, the bioactive peptide may be any of natural products, synthetic products, semi-synthetic products, products of genetic engineering, and analogs and / or derivatives thereof. The mode of action of these bioactive peptides may be either agonistic or antagonistic. Examples of the bioactive peptide include luteinizing hormone-releasing hormone (also referred to as LH-RH or gonadotropin-releasing hormone, Gn-RH).
Insulin, somatostatin, somatostatin derivatives (eg, sandostatin; USP 4,087,390, 4,093,574, 4,1
00,117 and 4,253,998), growth hormone (GH), growth hormone releasing hormone (GH-RH), prolactin, erythropoietin (EPO), adrenocortical hormone (ACTH), ACTH derivatives (eg, eviratide), melanocyte stimulating hormone (MSH) ), thyroid hormone releasing hormone ((pyr) Glu-his- ProNH 2; TRH), salts and derivatives thereof (JP 50-121273, JP-Sho 52-116465 JP), thyroid stimulating hormone (TSH) Luteinizing hormone (LH), follicle-stimulating hormone (FSH), vasopressin, vasopressin derivatives (eg, desmopressin), oxytocin, calcitonin, glucagon, gastrin, secretin, pancreozaimine, cholecystokinin, angiotensin, human placental lactogen, Human chorionic gonadoto Pin (HC
G), enkephalin, enkephalin derivative (eg, US
P4,277,394, EP-31567), endorphin, kyotorphin, interferon (eg, interferon-
α, β, γ), interleukins (eg, various interleukins 1 to 12), tuftsin, thymopoietin, thymosin, thymothymulin, thymic humoral factor (THF),
Blood thymic factor (FTS) and its derivatives (USP 4,229,4
38), tumor necrosis factor (TNF), colony-inducing factor
(Eg, CSF, GCSF, GMCSF, MCSF), motilin, deinfin, bombesin, neurotensin, caerulein, bradykinin, atrial natriuretic factor, nerve growth factor (NGF), cell growth factor (eg, EGF, TGF-β) , PDGF, acidic FGF, basic FGF), neurotrophic factors (eg, NT-3, NT-
4, CNTF, GDNF, BDNF), peptides having endothelin antagonism and their analogs (derivatives)
(EP-436189, EP-457195, EP-496452, JP-A-3-94
692, JP-A-3-130299), insulin receptor, insulin-like growth factor (IGF).
-1 receptor, IGF-2 receptor, transferrin receptor, epidermal growth factor, lowdensity lipoprotein (LDL) receptor, macrophage scavenger receptor, GLUT-4 transporter, growth hormone receptor, and leptin receptor. MHC-I (major
α1 of histocompatibility class I antigen complex)
Domain-derived peptides (Proceedings of
The National Academy of Sciences of USA
emy of Sciences of the United State of America),
91, 9086-9090 (1994); 94, 11692
-11697 (1997)) and its analogs (derivatives), as well as fragments and derivatives of these fragments.

When the physiologically active peptide is a salt, pharmacologically acceptable salts and the like can be mentioned. For example, when the physiologically active peptide has a basic group such as an amino group in the molecule, the basic group and an inorganic acid (eg, hydrochloric acid, sulfuric acid, nitric acid, boric acid, etc.) and an organic acid (eg, carbonic acid, Carbonic acid, succinic acid, acetic acid,
And propionic acid, trifluoroacetic acid and the like). When the physiologically active peptide has an acidic group such as a carboxyl group in the molecule, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium) or an organic base (eg, triethylamine) And organic amines such as arginine, etc.). Further, the physiologically active peptide may form a metal complex compound (eg, a copper complex, a zinc complex, etc.). Preferred specific examples of the bioactive peptide used in the present invention include, for example, LH-RH such as prostate cancer, benign prostatic hyperplasia, endometriosis, uterine fibroids, uterine fibroids, precocious puberty, breast cancer and the like. Induced hormone-dependent diseases and LH-RH analogs and salts thereof effective for contraception, growth hormone, and hormone-dependent diseases and digestive diseases such as peptic ulcer induced thereby, etc. Somatostatin derivatives and salts thereof that are effective against Said L
Specific examples of the H-RH analog or a salt thereof include, for example, Treatment with GnRH Analogs: Contravasis and Perspective (Treatment with
GnRH analogs: Controversies and perspectives)
[Parthenon Publishing Group, Inc. (The Pa
rthenon Publishing Group Ltd.) 1996], JP-T-3-503165, JP-A-3-101695
And the peptides described in JP-A Nos. 7-97334 and 8-259460.

Specific examples of the bioactive peptide having LH-RH antagonism (LH-RH antagonist) include:
For example, the general formula [Ia] X-D2Nal-D4ClPhe-D3Pal-Ser-A-B-Leu-C-Pro-
DAlaNH _{2 wherein} X is N (4H ₂ -furoyl) Gly or NAc,
A is NMeTyr, Tyr, Aph (Atz), NMeAph (At
z is a residue selected from the group consisting of DLys (Nic) and DCi
t, DLys (AzaglyNic), DLys (AzaglyFur), DhAr
g (Et ₂ ), DAph (Atz), DhCi, and C represents Lys (Nisp), Arg, hArg (Et ₂ ), respectively, or a salt thereof. . These peptides can be produced by the method described in the literature or the gazette or a method analogous thereto. Specific examples of the bioactive peptide having an LH-RH agonistic action (LH-RH agonist) include, for example,
General formula [Ib] 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z [where Y is DLeu, DAla, DTrp, DSer (tB
u), D2Nal, a residue selected from DHis (ImBzl), Z can be mentioned physiologically active peptide or a salt thereof with NH-C ₂ H ₅ or Gly-NH ₂ in respectively]. Among them, Y is at DLeu, Z is a peptide or a salt thereof is NH-C ₂ H ₅ are preferred. These peptides can be produced by the method described in the literature or the gazette or a method analogous thereto.

[0010] Specific examples of the somatostatin derivative or a salt thereof include, for example, Procedures of National Academy of Science (Proc.
Natl. Acad. Sci.) USA, 93, 12513-12518 (1996)
Year) or in the literature cited in the literature.

Embedded image Sandostatin (USP 4087390, 4093574, 410011)
7, 4253998) are also suitable. Among the above physiologically active peptides, 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-
Leu-Arg-Pro-NH- C 2 H 5 ( Ryupurerin) or a salt thereof (in particular, acetate) is suitable.

[0011] The abbreviations used herein, the abbreviation name _{N (4H 2 -furoyl) Gly:} N- tetrahydrofuroyl glycine residue NAc: N-acetyl group D2Nal: D-3- (2- naphthyl ) Alanine residue D4ClPhe: D-3- (4-chlorophenyl) alanine residue D3Pal: D-3- (3-pyridyl) alanine residue NMeTyr: N-methyltyrosine residue Aph (Atz): N- [5 '-(3'-amino-1'H-1',2',4'-triazolyl)] phenylalanine residue NMeAph (Atz): N-methyl- [5 '-(3'-amino-1'H-1) ', 2', 4'-Triazolyl)] phenylalanine residue DLys (Nic): D- (ε-N-nicotinoyl) lysine residue DCit: D-citrulline residue DLys (AzaglyNic): D- (azaglycylnicotium) Noil) Lysine residue DLys (AzaglyFur): D- (aza glycyl furanyl) lysine residue _{DhArg (Et 2): D- (} N, N'- diethyl) homoarginine residue DAph (Atz): D-N- [5 '- ( 3'-amino-1'H-1 ', 2', 4'-triazolyl)] phenylalanine residue DhCi: D-homocitrulline residue Lys (Nisp) :( ε-N-isopropyl) lysine residue hArg (Et ₂ ): (N, N′-diethyl) homoarginine residue DSer (tBu): D- (Ot-butyl) serine residue DHis (ImBzl): D- (π-benzyl) histidine residue Other amino acids , Abbreviation, IUPA
C-IUB Commission of Biochemical Nomenture (Commission on Biochemical Nome)
nclature) (European Journal of Biochemistry, Vol. 138, pp. 9-37 (1984)) or conventional abbreviations in the relevant field. Is possible, L-form is indicated unless otherwise specified.

The sustained-release base used in the above-mentioned sustained-release preparation is preferably a biodegradable polymer. Specific examples thereof include α-hydroxycarboxylic acids (eg, glycolic acid, lactic acid, Hydroxybutyric acid, etc.), hydroxydicarboxylic acids (eg, malic acid), hydroxytricarboxylic acids (eg, citric acid) and the like, and are synthesized from one or more kinds of polymers and copolymers having a free carboxyl group.
Alternatively, a mixture thereof, poly-α-cyanoacrylate, polyamino acid (eg, poly-γ-benzyl-L
-Glutamic acid, etc.), maleic anhydride copolymers (eg,
Styrene-maleic acid copolymer). The type of polymerization in the polymer may be random, block, or graft. Further, when the α-hydroxycarboxylic acids, hydroxydicarboxylic acids, and hydroxytricarboxylic acids have an optically active center in the molecule,
Any of the D-form, L-form and DL-form can be used. Among them, lactic acid-glycolic acid polymer and poly-α-cyanoacrylate are preferred. More preferably, it is a lactic acid-glycolic acid polymer.

The biodegradable polymer is preferably (A) glycolic acid and a compound of the general formula

Embedded image (Wherein, R represents an alkyl group having 2 to 8 carbon atoms) with a hydroxycarboxylic acid represented by the formula (B):
It is a biodegradable polymer mixed with polylactic acid or a copolymer of lactic acid and glycolic acid.

In the general formula [II], examples of the linear or branched alkyl group having 2 to 8 carbon atoms represented by R include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. Butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. Preferably,
A linear or branched alkyl group having 2 to 5 carbon atoms is used. Specific examples include, for example, ethyl, propyl, isopropyl, butyl, isobutyl and the like. Particularly preferably, R is ethyl. General formula (II)
Examples of the hydroxycarboxylic acid represented by
-Hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methylbutyric acid, 2-hydroxycaproic acid, 2
-Hydroxyisocaproic acid, 2-hydroxycapric acid and the like. Of these, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methylbutyric acid, and 2-hydroxycaproic acid are particularly preferred. The hydroxycarboxylic acid represented by the general formula [II] is particularly preferably 2-hydroxybutyric acid. These hydroxycarboxylic acids may be any of D-form, L-form and D, L-form, but those having D-form / L-form (mol%) in the range of about 75/25 to about 25/75. Is preferred. More preferably, the D-form / L-form (mol%) is about 60/40 to about 40.
/ 60 range hydroxycarboxylic acid. Particularly preferred is a hydroxycarboxylic acid having a D-form / L-form (mol%) in the range of about 55/45 to about 45/55.

In a copolymer of glycolic acid and a hydroxycarboxylic acid represented by the general formula [II] (hereinafter abbreviated as glycolic acid copolymer), the copolymer may be in any of random, block and graft forms. Good. Preferably, it is a random copolymer. One or more hydroxycarboxylic acids represented by the general formula [II] may be used in an appropriate ratio. In the glycolic acid copolymer (A), the composition ratio of glycolic acid to the hydroxycarboxylic acid represented by the general formula [II] is such that glycolic acid is about 10 to 10%.
Preferred is when about 75 mol%, the balance being hydroxycarboxylic acid. More preferably, the glycolic acid has about 20
約 75 mol%, the balance being hydroxycarboxylic acid. Particularly preferred is when glycolic acid is from about 40 to about 70 mol%, the balance being hydroxycarboxylic acid. These glycolic acid copolymers have a weight average molecular weight of about 2,000 to about 100,000. Preferably, the copolymer has a weight average molecular weight of about 3,000 to about 80,000. More preferably, it is a copolymer having a weight average molecular weight of about 5,000 to about 50,000. The dispersity (weight average molecular weight / number average molecular weight) of these glycolic acid copolymers is preferably from about 1.2 to about 4.0. Particularly preferred is a copolymer having a degree of dispersion of from about 1.5 to about 3.5. The glycolic acid copolymer (A) can be produced by a known production method, for example, as described in JP-A-61-2.
It can be synthesized according to the method described in JP-A-8521.

The polylactic acid may be any of L-form, D-form and a mixture thereof, but those having a D-form / L-form (mol%) in the range of about 75/25 to about 20/80. Is preferred. More preferably, D-form / L-form (mol%)
Is in the range of about 60/40 to about 25/75. Particularly preferably, the D-form / L-form (mol%) is about 5%.
Polylactic acid in the range of 5/45 to about 25/75. The polylactic acid has a weight average molecular weight of about 1,500 to about 100,
000 is preferred. More preferably, it is a polylactic acid having a weight average molecular weight in the range of about 2,000 to about 80,000. Particularly preferably, the weight average molecular weight ranges from about 3,000 to about 50,000 or about 10,000.
00 to 60,000 (more preferably, about 15,000
0 to about 50,000). Also,
The polylactic acid preferably has a degree of dispersion of about 1.2 to about 4.0. Particularly preferred is when the degree of dispersion is from about 1.5 to about 3.5. As a method for synthesizing polylactic acid, a method of ring-opening polymerization of lactide, which is a dimer of lactic acid, and a method of dehydrating and polycondensing lactic acid are known.

The glycolic acid copolymer (A) and polylactic acid (B) in the preparation base of the present invention are, for example, (A) /
The mixing ratio (% by weight) represented by (B) is about 10 / 90-
Used in the range of about 90/10. Preferably, the mixing ratio (% by weight) ranges from about 20/80 to about 80/20. More preferably, the range is from about 30/70 to about 70/30. If any one of the components (A) and (B) is too large, only a preparation having almost the same drug release pattern as that obtained when the component (A) or (B) is used alone is obtained. A linear release pattern in the late release cannot be expected. Decomposition / elimination rates of glycolic acid copolymer and polylactic acid vary greatly depending on molecular weight or composition, but in general, the decomposition / elimination rate of glycolic acid copolymer is faster, so the molecular weight of polylactic acid to be mixed is reduced. The release period can be lengthened by increasing it or decreasing the mixing ratio represented by (A) / (B). Conversely, the release period can be shortened by reducing the molecular weight of the polylactic acid to be mixed or by increasing the mixing ratio represented by (A) / (B).
Further, the release period can be adjusted by changing the type and ratio of the hydroxycarboxylic acid represented by the general formula [II].

When polylactic acid or a lactic acid-glycolic acid copolymer (hereinafter simply referred to as a lactic acid-glycolic acid polymer) is used as the biodegradable polymer, the lactic acid / glycolic acid composition ratio (mol%) is 100. / 0-40 / 60
Is preferable, 100/0 to 45/55 are more preferable, and 100/0 to 50/50 are particularly preferable. The weight average molecular weight of the lactic acid-glycolic acid polymer is 3.0
It is preferably from 100 to 100,000, and more preferably from 5,000 to 8
000 is particularly preferred. The dispersity (weight average molecular weight / number average molecular weight) of the lactic acid-glycolic acid polymer is preferably about 1.2 to about 4.0, and more preferably about 1.5 to about 3.5. The rate of decomposition and disappearance of the lactic acid-glycolic acid polymer greatly changes depending on the composition or molecular weight.
In general, the lower the glycolic acid content, the slower the decomposition and disappearance. Therefore, the release period can be lengthened by lowering the glycolic acid content or increasing the molecular weight. Conversely, the release period can be shortened by increasing the glycolic acid fraction or decreasing the molecular weight. Long term (e.g., 1-6 months, preferably 1
(4 months) In order to form a sustained-release preparation (solid), a lactic acid-glycolic acid polymer having the above composition ratio and weight average molecular weight is preferable. If a lactic acid-glycolic acid polymer that decomposes faster than the lactic acid-glycolic acid polymer in the range of the above composition ratio and weight average molecular weight is selected, it is difficult to suppress the initial burst, and conversely, the above composition ratio and weight average molecular weight When a lactic acid-glycolic acid polymer having a lower decomposition rate than that of the lactic acid-glycolic acid polymer is selected, a period in which an effective amount of the drug is not released is likely to occur.

The weight average molecular weight, the number average molecular weight and the degree of dispersion in the present specification mean that the weight average molecular weight is 120,0.
00, 52,000, 22,000, 9,200, 5,05
The molecular weight in terms of polystyrene measured by gel permeation chromatography (GPC) using nine types of polystyrene of 0, 2,950, 1,050, 580, and 162 as a reference substance and the calculated degree of dispersion. Measurement is GP
C column KF804L × 2 (manufactured by Showa Denko) and RI monitor L-3300 (manufactured by Hitachi, Ltd.) are used, and chloroform is used as a mobile phase. In addition, the biodegradable polymer is dissolved in an acetone-methanol mixed solvent, and the carboxylic acid group is titrated with phenolphthalein as an indicator using an alcoholic potassium hydroxide solution to calculate the number average molecular weight by terminal group determination. Hereinafter, this is referred to as a number average molecular weight determined by terminal group quantification. Whereas the number average molecular weight determined by terminal group quantification is an absolute value, the number average molecular weight determined by GPC is determined by analysis or analysis conditions (eg, the type of mobile phase, column type, reference material, selection of slice width, baseline Selection, etc.), it is difficult to make a unique numerical value because it is a relative value that fluctuates depending on the selection. , The number average molecular weight determined by GPC and the number average molecular weight determined by terminal group quantification are almost the same. The lactic acid-glycolic acid polymer almost coincides with the case where the number average molecular weight determined by the terminal group determination is G
It means that the number average molecular weight is within a range of about 0.5 to about 2 times, preferably about 0.7 to about 1.5 times the number average molecular weight by PC measurement.

A lactic acid-glycolic acid polymer is prepared by subjecting a lactic acid and glycolic acid to noncatalytic dehydration polycondensation (Japanese Patent Laid-Open No.
No. 21) or ring-opening polymerization using a catalyst from a cyclic body such as lactide and glycolide (Encyclopedic Handbook)
of Biomaterials and Bioengineering PartA: Material
s, Volume 2, Marcel Dekker, Inc. 1995). The polymer synthesized by ring-opening polymerization is a polymer having no carboxyl group, but a polymer obtained by chemically treating the polymer to form a free carboxyl group at the terminal (Journal of Controlled Release (J. Controlled Re
lease), vol. 41, pages 249-257 (1996)). The lactic acid-glycolic acid polymer having a free carboxyl group at the terminal can be prepared by a known production method (for example, a non-catalytic dehydration polycondensation method, Japanese Patent Application Laid-Open No. 61-28521).
The polymer having a free carboxyl group which is not specified at the terminal can be produced by a known production method (for example, see WO94 / 15587). A lactic acid-glycolic acid polymer whose terminal is converted into a free carboxyl group by a chemical treatment after ring-opening polymerization is, for example, Boehringer Engelheim (Boehri
ngerIngelheim KG) may be used.

The suspension of the sustained-release preparation used in the production method of the present invention is prepared by adding the above-mentioned sustained-release preparation to a solvent used for the following suspension. In the case of MC, the suspension of the sustained-release preparation is usually about 1 mg to about 3 mg as MC.
000 mg / ml, preferably about 5 mg to about 1000 m
Adjust to g / ml. The suspension may further contain an anticoagulant, for example, a water-soluble saccharide [eg, mannitol, lactose, glucose, starch (eg, corn starch)], an amino sugar (eg, glycine, alanine, etc.), a protein (eg, Gelatin, fibrin, collagen, etc.),
An inorganic salt (eg, sodium chloride, sodium bromide, potassium carbonate, etc.) may be added. Mannitol such as D-mannitol is particularly preferable as the aggregation preventing agent. Examples of the solvent used for the suspension include water for injection (eg, water produced by a distillation method or an ultrafiltration method), UF water, RO water, ion-exchanged water, volatile solvents (eg, ethanol, Acetone, etc.), polyethylene glycol, vegetable oils, mineral oils, and mixed solvents thereof, and the like. In particular, water for injection and the like are suitable. Further, a surfactant, a thickener, a pH adjuster, and the like can be added as a suspension stabilizer. Examples of the surfactant include polysorbates (eg, polysorbate 80, polysorbate 20, polysorbate 2).
0, etc.), Pluronics (eg, Pluronic F68 (generic name: polyoxyethylene [160] polyoxypropylene [30] glycol)), polyoxyethylene hydrogenated castor oils (eg, polyoxyethylene hydrogenated castor oil 5)
0, polyoxyethylene hydrogenated castor oil 60, etc.). Examples of the thickener include carboxymethyl celluloses (eg, CMC-K, CMC-Na, etc.),
Polyvinylpyrrolidone (PVP) or the like is used. p
Examples of the H adjuster include hydrochloric acid, sodium hydroxide,
Acetic acid, lactic acid, ammonium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like are used.

The container for freeze-drying used in the production method of the present invention may be any container that is generally used for freeze-drying sustained-release preparations such as MC. A tray or the like is used. Further, as the container, a metal (preferably, stainless steel (SUS316,
304, etc.), glass and ceramics. Further, the container for freeze-drying used in the production method of the present invention also includes a plate-like container. The size of the freeze-drying container can be appropriately selected according to the scale of freeze-drying. Specifically, for example, the width is about 5 mm to about 1 mm.
0,000 mm, length is about 5 mm to about 10,000 mm,
Depth of about 0.1 mm to about 500 mm, preferably about 5 mm to about 7,000 mm in width and about 5 mm in length
To about 7,000 mm, and a depth of about 1 mm to about 100 mm, more preferably, about 5 mm to about 500 m in width.
m, a length of about 5 mm to about 300 mm and a depth of about 5 mm to about 100 mm are used. The ratio of the width, length, and depth is not particularly limited, but is usually about 1 width to 1 width.
From about 1 to about 10, preferably from about 1 to about 10, and from about 1 to about 6 for a depth of 1. The capacity of the container is, for example, about 10 ml to about 100,000 ml, preferably about 100 ml to about 5,000 ml, particularly preferably about 3,000 ml. The container for freeze-drying has a cavity in a part of the container for suction during freeze-drying, but usually a container for freeze-drying without a top plate is used. Examples of the water-repellent substrate used for coating the freeze-drying container include, for example, an ethylene fluoride resin (eg, an ethylene tetrafluoride resin, an ethylene trifluoride resin, an ethylene difluoride resin), a vinylidene fluoride resin, Hexafluoropropylene / tetrafluoroethylene copolymer resin, modified fluororesin, copolymer resin of tetrafluoroethylene and perfluoroalkoxyethylene, copolymer resin of ethylene tetrafluoride and ethylene, etc. However, fluorinated ethylene resin (eg,
Preferred are ethylene tetrafluoride resin, ethylene trifluoride resin, and ethylene difluoride resin, and Teflon (trade name) is preferred. As a method for coating (coating) the freeze-drying container with the water-repellent substrate, a method known per se or a method similar thereto is used, and specifically, a plating method, a vapor deposition method, or the like is used. The solid sustained-release preparation obtained by the production method of the present invention includes any sustained-release preparation obtained by subjecting the sustained-release preparation used in the present invention to the production method (freeze-drying method) of the present invention. It may be a powdery sustained-release preparation (e.g., MC powder or the like), or may be formed into various shapes according to a method known per se (e.g., pellets,
It also contains sustained-release preparations (such as needles).

Hereinafter, the production method of the present invention will be described in detail. (1) A method for producing a solid sustained-release preparation characterized by freeze-drying a sustained-release preparation in a freeze-drying container in which part or all of the inner surface is covered with an ice layer. As the water, for example, water for injection (eg, distilled water, etc.), ion-exchanged water and the like are used.
The portion covered with the ice layer is a part or the whole of the inner surface of the freeze-drying container, for example, only the bottom surface of the inner surface of the container,
The entire bottom surface and side surfaces, only a part of the bottom surface, or only a part of the bottom surface and the side surfaces may be used. Further, an ice layer may be formed on the outer surface of the container. The thickness of the ice layer in the lyophilization container can be appropriately selected according to the size of the container used, the volume of the sustained-release preparation (suspension of the sustained-release preparation), the lyophilization temperature, and the like. For example, usually about 1/1000 to about 4/5 of the depth of the container, preferably about 1/100
/ 500 to about 1/5, more preferably about 1/100 to about 1/10, particularly preferably about 1/10, and
It is preferably at least 01 mm. More specifically, about 0.0
1 mm to about 400 mm, preferably about 0.01 mm to about 200 mm, more preferably about 0.01 mm to about 30 m
m, more preferably about 0.1 mm to about 30 mm, particularly preferably about 0.1 mm to about 10 mm, and most preferably about 1 mm. For ice layer, pour water into trays, usually about -8
It is made at 0 ° C to about 0 ° C, preferably at about -50 ° C to about 0 ° C.

After forming an ice layer in the freeze-drying container,
The sustained release preparation (suspension of the sustained release preparation) is dispensed into a container and frozen to form a frozen layer of the sustained release preparation (suspension of the sustained release preparation). Suspension of the sustained release formulation,
Usually, in the case of MC, about 1 mg to about 3000 as MC
mg / ml, preferably about 5 mg to about 1000 mg / m
Adjust to 1. The volume of the sustained-release preparation (suspension of the sustained-release preparation) can be appropriately selected depending on the size of the container to be used, the lyophilization temperature, and the like. The thickness of the frozen layer of the liquid is about 1/1000 of the depth of the container.
To about 1/5, preferably about 1/500 to about 1/5, more preferably about 1/100 to about 1/10, particularly preferably about 1/10. Further, the volume of the suspension of the sustained-release preparation is about 0.1 ml to about 99.9 m per 100 ml of the container.
1, preferably about 1 ml to about 90 ml, more preferably about 1 ml to about 40 ml. further,
When the ice layer is about 1 mm from the bottom of the container, the frozen layer of the suspension of the sustained release preparation can be about 1 to 10 times, preferably about 1 to 5 times. For example, as a container, the width is about 5 mm ~
About 7,000mm, length is about 5mm to about 7,000mm,
When using a layer having a depth of about 1 mm to 100 mm, the thickness of the ice layer is usually about 0.01 mm to about 30 mm, preferably about 0.1 mm to about 30 mm, and more preferably about 0.1 mm.
m to 10 mm, particularly preferably about 1 mm.
On the other hand, the frozen layer of the suspension of the sustained-release preparation is, for example, about 1 mm to about 20 mm, preferably about 2 mm to
It is about 10 mm, preferably about 4 mm. The frozen layer of the sustained-release preparation (suspension of the sustained-release preparation) should be prepared at about −10 ° C.
After dispensing a sustained-release preparation (suspension of a sustained-release preparation) cooled to about 20 ° C., preferably about 0 ° C. to 5 ° C. on an ice layer, usually about −80 ° C. to about 0 ° C, preferably from about -50 ° C to
Prepare at about 0 ° C. In this manner, the ice layer and the frozen layer of the sustained-release preparation (suspension of the sustained-release preparation) were placed in the freeze-dried container.
Make layers. Freeze-drying can be carried out using a method known per se, for example, according to the above-mentioned public publication which discloses MC or microsphere.
As a preferable freeze-drying method, for example, the temperature (shelf temperature) of the freeze-drying container is 0 ° C. or lower under reduced pressure (preferably,
-40 ° C. to 0 ° C., more preferably -20 ° C. to 0 ° C., even more preferably -10 ° C. to 0 ° C.). Specifically, the shelf temperature is reduced to 0 ° C or lower (preferably -40 ° C to 0 ° C, more preferably -20 ° C to 0
(Preferably −10 ° C. to 0 ° C.) to complete the sublimation of the frozen water in the freeze-drying container. Here, the temperature of the freeze-drying container (shelf temperature) means the temperature of the container holding the material to be freeze-dried or the shelf in contact with the container. The frozen water means free water that has been frozen. The shelf temperature is 0 ° C. or lower (preferably −40 ° C. to 0 ° C., more preferably −20 ° C. to 0 ° C., and still more preferably −10 ° C.).
０0 ° C.), about 0.1 hour or more, preferably about 1 hour to 500 hours, more preferably about 5 hours to
The shelf temperature is kept at 0 ° C. or lower for 100 hours to complete the sublimation of the frozen water in the freeze-drying container. By performing freeze-drying by the above-described method, sublimation of frozen water is performed at a temperature of 0 ° C. or less, that is, at a low temperature at which ice does not melt (eutectic point, temperature of the melting point or less). Therefore, collapse of the freeze-dried cake is prevented, scattering of MC powder to the outside of the freeze-drying container and the like are prevented, high yield of MC powder is secured, and MC powder of constant quality can be manufactured.

(2) The sustained-release preparation (suspension of the sustained-release preparation) is freeze-dried in a freeze-drying container in which part or all of the inner surface is coated with a water-repellent substrate. Regarding the method for producing a solid sustained-release preparation, the part covered with the water-repellent substrate is a part or the whole of the inner surface of the freeze-drying container. Or only a part of the bottom and side surfaces. Further, the outer surface of the container may be covered with a water-repellent substrate. The sustained release preparation (suspension of the sustained release preparation) is dispensed into a container and frozen to form a frozen layer of the sustained release preparation (suspension of the sustained release preparation). Suspensions of sustained release formulations are usually
, About 1 mg to about 3000 mg / m as MC
l, preferably about 1 mg to about 300 mg / ml. It can be appropriately selected according to the volume of the sustained-release preparation (suspension of the sustained-release preparation) in the lyophilization container, the size of the container to be used, the lyophilization temperature, and the like. The thickness of the frozen layer of the suspension of the sustained release preparation is about 1/1000 to about 4/5, preferably about 1/100 of the depth of the container.
500 to about 1/5, more preferably about 1/100 to about 1
/ 10, particularly preferably about 1/10. Further, the volume of the suspension of the sustained-release preparation can be about 0.1 ml to about 99.9 ml, preferably about 1 ml to about 90 ml, and more preferably about 1 ml to about 40 ml, per 100 ml of the container. . Furthermore, the ice layer is about 1 mm from the bottom of the container.
In the case of, the frozen layer of the suspension of the sustained release formulation is about 1 to 10 times,
Preferably, it can be about 1 to 5 times. For example, as a container, the width is about 5 mm to about 7,000 mm, and the length is about 5 mm.
mm to about 7,000 mm, depth is about 1 mm to 100 mm
When using those, the thickness of the ice layer is usually about 0.01 mm
About 30 mm, preferably about 0.1 mm to about 30 mm,
More preferably, the thickness is about 0.1 mm to 10 mm, particularly preferably about 1 mm. On the other hand, the frozen layer of the suspension of the sustained-release preparation is, for example, about 1 mm to about 20 m from the bottom ice layer.
m, preferably about 2 mm to about 10 mm, preferably about 4 mm
mm. The frozen layer of the sustained-release preparation (suspension of the sustained-release preparation) is prepared in advance at about -10 ° C to about 20 ° C, preferably at about 0 ° C to
After dispensing the sustained-release preparation (suspension of the sustained-release preparation) cooled to 5 ° C. on an ice layer, the suspension is usually about −80 ° C. to about 0 ° C.
C., preferably at about -50.degree. C. to about 0.degree. In this way, a frozen layer of the sustained-release preparation (suspension of the sustained-release preparation) is prepared in the lyophilization container. Freeze-drying can be performed in the same manner as in the above production method (1).

(3) Sustained-release preparation (suspension of sustained-release preparation) in a lyophilization container in which the inner surface is covered with a water-repellent substrate and a part or all of the inner surface is covered with an ice layer. ) Is freeze-dried, and this method comprises the steps of freeze-drying the inner surface of which is coated with a water-repellent substrate, instead of the freeze-drying container in the above-mentioned production method (1). Except using a drying container, it can be carried out in the same manner as in the production method (1). In the case of this method, it is desirable that at least the entire surface of the inner surface of the freeze-drying container that is in contact with the sustained-release preparation (suspension of the sustained-release preparation) is coated with a water-repellent substrate.

The manufacturing method of the present invention has the following advantages. (1) Since the MC powder does not adhere to the tray, there is no need to use a scraper to scrape the MC powder during collection. (2) Since it is not necessary to use a scraper for scraping, the time of exposure to the environment at the time of collection is reduced, and there is no risk of contamination with microorganisms. In addition, since MC is a preparation requiring moisture control, there is little danger from the viewpoint of physicochemical stability due to short environmental exposure time. (3) Since the scraping operation using a scraper is unnecessary, foreign matter is generated due to friction between the tray and the scraper.
No risk of contamination. (4) Since the adhesion between the MC powder and the tray is small, the recovery rate of the MC powder is high. (5) Further, by applying the above-mentioned more preferable freeze-drying method, it is possible to recover MC powder of higher yield and constant quality.

After freeze-drying a sustained-release preparation (suspension of a sustained-release preparation) using the production method of the present invention, if necessary,
Under reduced pressure, the water and the organic solvent in the sustained-release preparation may be removed by heating under conditions where the sustained-release preparation does not fuse with each other. In this case, the polymer is heated at a temperature slightly higher than the midpoint glass transition temperature of the biodegradable polymer determined by a differential scanning calorimeter under a condition of a heating rate of about 10 to about 20 ° C. per minute. More preferably, heating is performed within a temperature range of about 30 ° C. higher than the midpoint glass transition temperature of the biodegradable polymer. In particular, when a lactic acid-glycolic acid polymer is used as the biodegradable polymer, the temperature range is higher than the midpoint glass transition temperature by 20 ° C. higher than the midpoint glass transition temperature, preferably, from the midpoint glass transition temperature to the midpoint. Heat in a temperature range 10 ° C. higher than the glass transition temperature.
Although the heating time varies depending on the amount of the sustained-release preparation,
Generally, about 12 hours to about 168 hours, preferably about 48 hours to about 120 hours, after the sustained release formulation itself reaches a predetermined temperature. In particular, about 48 hours to about 96
Time is preferred. The heating method is not particularly limited as long as the method can uniformly heat the aggregate of the sustained-release preparation. Preferable specific examples of the heating and drying method include, for example, a method of heating and drying in a constant temperature bath, a fluidized tank, a moving tank or a kiln, and a method of heating and drying with a microwave. Of these, a method of heating and drying in a thermostat is preferred.

The freeze-dried product (solid) of the sustained-release preparation obtained as described above can be administered orally or parenterally as it is or in the form of a preparation as a raw material in various dosage forms. Specifically, injections or implants for intramuscular, subcutaneous, organ, etc., transmucosal agents for nasal cavity, rectum, uterus, etc., oral agents [eg, capsules (eg, hard capsules, soft capsules, etc.)] Solid preparations such as granules and powders, liquid preparations such as syrups, emulsions and suspensions]. For example, in order to make a sustained release preparation (solid) into an injection, it is necessary to use a dispersant (eg, Tween)
80, surfactants such as HCO-60, polysaccharides such as sodium hyaluronate, carboxymethylcellulose, sodium alginate, etc., preservatives (eg, methyl paraben, propyl paraben, etc.), isotonic agents (eg, sodium chloride, mannitol) , Sorbitol, glucose, proline, etc.), or as an aqueous suspension, or dispersed with vegetable oils such as sesame oil and corn oil to give sustained-release injections that can be used as oily suspensions. Sustained-release preparation (solid)
When used as a suspension injection, the particle size of may be within a range that satisfies the degree of dispersion and needle penetration. For example, the average particle size may be in the range of about 0.1 to 300 μm. Preferably, the average particle size is in the range of about 1 to 150 µm. More preferably, the average particle size is in the range of about 2 to 100 µm. In order to make the sustained-release preparation (solid) into a sterile preparation, a method of sterilizing the whole production process, a method of sterilizing with gamma rays, a method of adding a preservative, and the like are mentioned, but are not particularly limited.

The sustained-release preparation (solid) has a low toxicity, so that it can be safely used for humans or mammals (eg, monkey, cow, pig, dog, cat, mouse, rat, rabbit, etc.). Can be. The dose of the sustained-release preparation (solid) as an active ingredient is determined by the type and content of the bioactive peptide as the main drug,
Although it varies depending on the dosage form, duration of release of the bioactive peptide, target disease, target animal, administration method, etc., any effective amount of the bioactive peptide may be used. For example, when the sustained release preparation (solid) is a one-month preparation, the dose of the physiologically active peptide as the main drug per administration is preferably about 0.001 mg per adult (50 kg body weight).
It can be appropriately selected from the range of 100 mg / kg body weight. More preferably, it can be appropriately selected from the range of about 0.005 mg to 50 mg / kg body weight, particularly preferably from the range of about 0.01 mg to 10 mg / kg body weight. More specifically, when the LH-RH antagonist represented by the aforementioned general formula [Ia] or the LH-RH agonist represented by the general formula [Ib] is used as a bioactive peptide, for example, prostate cancer, benign prostatic hyperplasia, Endometriosis, uterine fibroids, uterine fibroids, precocious puberty, breast cancer, bladder cancer, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colorectal cancer, gastritis, Hodgkin's disease, malignant melanoma, metastasis , Multiple myeloma, non-Hodgkin's lymphoma, non-small cell lung cancer, ovarian cancer, peptic ulcer, systemic fungal infection, small cell lung cancer, valvular heart disease, mastopathy, polycystic ovary, infertility, chronic anovulation Syndrome, adequacy of ovulation in women, acne, acne, amenorrhea (eg, secondary amenorrhea), cystic disease of the ovaries and breasts (including polycystic ovaries), gynecological cancer, ovarian hypertension Androgenemia and AID by the hair disease, T cell production via the thymus young rejuvenation
S, treatment and prevention agents for hormone-dependent diseases such as male contraception for the treatment of male sex offenders, contraception, premenstrual syndrome (PM
As a drug for alleviating the symptoms of S), a drug for in vitro fertilization (IVF), etc., particularly for the treatment of prostate cancer, prostatic hypertrophy, endometriosis, uterine fibroids, uterine fibroids, precocious puberty, etc.
Can be used as a prophylactic or contraceptive. The dosage of the bioactive peptide varies depending on its dosage form, desired drug release duration, target disease, target animal, etc.,
Any effective amount of the drug may be used. The dose of the drug per dose is, for example, when the sustained-release preparation (solid) is a one-month preparation, preferably from about 0.001 mg per adult.
It can be appropriately selected from the range of about 10 mg / kg body weight. More preferably, it can be appropriately selected from the range of about 0.005 mg to about 5 mg / kg body weight. The dose of the sustained-release preparation (solid) per dose is preferably about 0.5 per adult.
It can be appropriately selected from the range of 005 mg to 50 mg / kg body weight. More preferably, it can be appropriately selected from the range of about 0.01 mg to 30 mg / kg body weight. The frequency of administration is once every several weeks, once a month, or once every several months, such as the type and content of the bioactive peptide as the main drug, dosage form, duration of bioactive peptide release, target disease And the target animal.

[0031]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited by these and does not depart from the scope of the present invention. It may be changed.

[0032]

EXAMPLES Reference Example 1 Preparation of Sustained Release MC (1 Month Formulation) Suspension 2.4 g of gelatin and 15.2 g of leuprorelin acetate were dissolved in 15.0 g of distilled water while heating. In this solution,
Lactic acid / glycolic acid copolymer (hereinafter referred to as PL
GA) (321 g of lactic acid / glycolic acid = 75/25 (mol%), weight average molecular weight: 10500) in dichloromethane (including 121 g of PLGA) was added thereto, and the mixture was stirred and emulsified with a mini mixer for 2 minutes (number of rotations: 10,000 rpm).
m). This was added to 25 L of a 0.1% aqueous solution of polyvinyl alcohol (PVA) dissolved in advance and emulsified again. This W / O / W emulsion was desolvated for about 3 hours with gentle stirring. The obtained MC was passed through a 75 μm sieve to remove coarse particles, and then separated by centrifugation. This was washed with distilled water to remove free drug and PVA, and then 250 µm and 9 µm with a small amount of distilled water.
The mixture was wet-sieved with a 0 μm sieve. To this, 18.4 g of D-mannitol was added and dissolved to obtain a suspension of MC. The amount of each raw material used can be increased or decreased according to the scale.

Reference Example 2 Preparation of Sustained Release MC (3 Month Preparation) Suspension 10.8 g of leuprorelin acetate was dissolved in 12.5 g of distilled water while heating. A lactic acid polymer prepared separately (hereinafter abbreviated as PLA) [weight average molecular weight: 160
00] in dichloromethane solution (including PLA 9
6 g) and stirred and emulsified (rotational speed: 10,000 rpm) for 2 minutes with a mini mixer. This was added to 25 L of a 0.1% aqueous solution of polyvinyl alcohol (PVA) which had been dissolved in advance and emulsified again. This W / O / W emulsion was desolvated for about 3 hours with gentle stirring.
The obtained MC was passed through a 75 μm sieve to remove coarse particles, and then separated by centrifugation. This was washed with distilled water to remove free drug and PVA, and then wet-sieved with 250 µm and 90 µm sieves together with a small amount of distilled water.
To this, 16.3 g of D-mannitol was added and dissolved,
A suspension of MC was obtained. The amount of each raw material used can be increased or decreased according to the scale.

Example 1 An ice layer having a thickness of about 1 mm was previously formed at −30 ° C. on a freeze-drying tray (200 mm wide, 100 mm long, 20 mm deep) using water for injection. At this time, an ice layer was also formed on the inner wall of the tray (ice lining). About 5 in advance
MC suspension 80 obtained in the above Reference Example 1 cooled to
ml was added to a freeze-drying tray on which an ice layer had been formed, and after sufficiently freezing at about −30 ° C., freeze-drying was performed according to a conventional method. Separately, 80 ml of the MC suspension was added to a freeze-drying tray on which an ice layer was not formed, and the MC suspension was sufficiently frozen at about −30 ° C., and then freeze-dried according to a conventional method. After freeze-drying, each tray was inverted, and the state of peeling and recovery of the freeze-dried product from the tray was observed. When a freeze-drying tray formed with an ice layer was used, the freeze-dried product could be easily collected from the tray, and no adhesion of MC powder was observed on the surface of the tray. On the other hand, when a freeze-drying tray that did not form an ice layer was used, the freeze-dried product did not come off the tray. Also,
Even after collecting the MC powder with a scraper, adhesion of the MC powder to the tray was recognized.

Example 2 A freeze-drying tray (200 mm wide and 100 m long) coated on its surface with Teflon (trade name) which is a water-repellent polymer
m, a depth of 20 mm), 80 ml of the MC suspension obtained in Reference Example 1 previously cooled to about 5 ° C. was added thereto, and the mixture was added to about −3.
After sufficient freezing at 0 ° C., lyophilization was performed according to a conventional method. On the other hand, separately, 80 ml of the MC suspension was added to a freeze-drying tray whose surface was not subjected to a water-repellent treatment, and was sufficiently frozen at about −30 ° C., followed by freeze-drying according to a conventional method. Was. After freeze-drying, each tray was inverted, and the state of peeling and recovery of the freeze-dried product from the tray was observed. When a freeze-drying tray having a water-repellent treatment on the surface was used, the freeze-dried product could be easily collected from the tray, and no adhesion of MC powder was observed on the surface of the tray. On the other hand, when a freeze-drying tray whose surface was not subjected to the water-repellent treatment was used, the freeze-dried sample did not come off the tray. Further, even after collecting the MC powder with a scraper, adhesion of the MC powder to the tray was recognized.

Example 3 The same Teflon-coated freeze-drying tray (200 mm wide, 100 mm long, 20 mm deep) as in Example 2 was prepared.
An ice layer having a thickness of about 1 mm was previously prepared using water for injection at -30 ° C.
Formed. At this time, an ice layer was also formed on the inner wall of the tray (ice lining). 80 ml of the MC suspension obtained in Reference Example 1 previously cooled to about 5 ° C. was added, and
After sufficiently freezing at about −30 ° C., freeze-drying was performed according to a conventional method. Separately, 80 ml of the MC suspension was added to a freeze-drying tray on which no ice layer had been formed and the surface of which had not been subjected to water repellency treatment, and was sufficiently frozen at about -30 ° C. After that, freeze-drying was performed according to a conventional method. After freeze-drying, each tray was inverted, and the state of peeling and recovery of the freeze-dried product from the tray was observed. When a freeze-drying tray with a water-repellent surface applied and an ice layer formed is used, the freeze-dried product can be easily collected from the tray, and there is no adhesion of MC powder on the surface of the tray. Was. On the other hand, when using a freeze-drying tray in which an ice layer was not formed and the surface of which was not subjected to the water-repellent treatment, the freeze-dried product did not come off the tray. Also,
Even after collecting the MC powder with a scraper, adhesion of the MC powder to the tray was recognized.

Example 4 The same results as in Examples 1 to 3 can be obtained by combining the size of the freeze-drying tray shown in Table 1 with the thickness of the ice layer.

[Table 1]

Example 5 15.1 g of leuprorelin acetate was dissolved in 15.0 g of distilled water while heating (70 ° C. to 80 ° C.). Into this solution, separately prepared lactic acid / glycolic acid copolymer (PLG
A) Dichloromethane solution of [lactic acid / glycolic acid = 75/25 (mol%), weight average molecular weight: 10500] 32
3.6 g (including 123.9 g of PLGA) (25 to 35 ° C.)
The mixture was controlled to a temperature of 40 ° C. or lower and stirred and emulsified (rotational speed: 10,000 rpm) with a mini mixer for 2 minutes. This is 18-19
The mixture was cooled to 25 ° C., added to 25 L of a 0.1% aqueous solution of polyvinyl alcohol (PVA) (18 to 19 ° C.) dissolved in advance, and emulsified again. This W / O / W emulsion was desolvated for about 3 hours with gentle stirring. The obtained MC is 7
After removing coarse particles through a 5 μm sieve, the mixture was wet-sieved with a 90 μm sieve together with a small amount of distilled water. In addition, 1
8.4 g of D-mannitol was added and dissolved to give a suspension of MC. Preliminary freeze-drying tray (width 170 mm, height 2
60mm, depth 40mm), about 2mm with distilled water for injection
The above-mentioned M was added to a tray on which an ice layer having a thickness of
After adding about 400 ml of the C suspension and sufficiently freezing at about −30 ° C., freeze-drying is performed by a conventional method or according to Example 7 described later. In the freeze-dried product produced by this method, the freeze-dried product can be easily peeled off and collected from each tray, and no adhering of MC powder is observed on the tray surface.

Example 6 15.1 g of leuprorelin acetate was dissolved in 13.0 g of distilled water while heating (70 ° C. to 80 ° C.). Into this solution, separately prepared lactic acid / glycolic acid copolymer (PLG
A) Dichloromethane solution of [lactic acid / glycolic acid = 75/25 (mol%), weight average molecular weight: 10500] 32
3.6 g (including PLGA 123.6 g) (25 to 35 ° C.)
The mixture was controlled to a temperature of 40 ° C. or lower and stirred and emulsified (rotational speed: 10,000 rpm) with a mini mixer for 2 minutes. This is 18-19
The mixture was cooled to 25 ° C., added to 25 L of a 0.1% aqueous solution of polyvinyl alcohol (PVA) (18 to 19 ° C.) dissolved in advance, and emulsified again. This W / O / W emulsion was desolvated for about 3 hours with gentle stirring. The obtained MC is 7
After removing coarse particles through a 5 μm sieve, the mixture was wet-sieved with a 90 μm sieve together with a small amount of distilled water. In addition, 1
8.4 g of D-mannitol was added and dissolved to give a suspension of MC. Preliminary freeze-drying tray (width 170 mm, height 2
60mm, depth 40mm), about 2mm with distilled water for injection
The above-mentioned M was added to a tray on which an ice layer having a thickness of
After adding about 400 ml of the C suspension and sufficiently freezing at about −30 ° C., freeze-drying is performed by a conventional method or according to Example 7 described later. In the freeze-dried product produced by this method, the freeze-dried product can be easily peeled off and collected from each tray, and no adhering of MC powder is observed on the tray surface.

Example 7 Application to Sustained-Release MC (1 Month Formulation) Suspension Using a water for injection in a freeze-drying tray (170 mm wide, 260 mm long, 40 mm deep), use ice for injection to a thickness of about 2 mm in advance. The layer was formed at -30C. At this time, an ice layer was also formed on the inner wall of the tray (ice lining). About 5 ℃ in advance
MC suspension 200 obtained in Reference Example 1
mL was added to a freeze-drying tray on which an ice layer had been formed, and after sufficiently freezing at about −30 ° C., freeze-drying was performed by the method described below. After freezing the suspension at about −30 ° C.,
The shelf temperature was raised to -5 ° C at a rate of ° C / hr, and the temperature was maintained for about 20 hours. After that, the shelf temperature was further increased at 20 ° C./hr for 5
The temperature was raised to 1 ° C. and held for about 48 hours. After lyophilization,
The state of the freeze-dried product and the state of peeling and recovery from the tray were observed. No collapse or scattering was observed in the freeze-dried product. Further, the freeze-dried product could be easily recovered from the tray, and no attachment of MC powder was observed on the surface of the tray.

Example 8 Application to Sustained-Release MC (3 Month Formulation) Suspension Using a water for injection in a freeze-drying tray (170 mm wide, 260 mm long, 40 mm deep), use ice for injection to a thickness of about 2 mm in advance. The layer is formed at -30C. At this time, an ice layer is also formed on the inner side wall of the tray (ice lining). About 5 ℃ in advance
MC suspension 200 obtained in Reference Example 2
Add mL to the freeze-drying tray on which the ice layer is formed, freeze sufficiently at about −30 ° C., and freeze-dry by the method described below. After freezing the suspension at about −30 ° C.,
/ Hr raise shelf temperature to -5 ° C and hold temperature for about 20 hours. Thereafter, the shelf temperature was further increased to 50 ° C. at 20 ° C./hr.
C. and hold for about 48 hours. The freeze-dried product can be easily collected from the tray without collapsing or scattering, and a freeze-drying method can be performed without adhering MC powder to the tray surface.

[0042]

According to the production method of the present invention, the solid sustained-release preparation can be recovered without any scraping operation because the freeze-drying container and the solid sustained-release preparation are not adhered to each other. In addition, the recovery rate of the solid sustained-release preparation is significantly improved. In addition, the time required for the solid sustained-release preparation to be exposed to the environment is shortened, so that the maintenance of sterility is also improved. Furthermore, by applying a freeze-drying method characterized by completing the sublimation of frozen water in the freeze-drying vessel at a temperature of the freeze-drying vessel of 0 ° C. or less under reduced pressure, the freeze-dried cake collapses and scatters. It is possible to recover MC powder of a certain quality with higher yield.

Claims (8)

[Claims] 1. A method for producing a solid sustained-release preparation, which comprises freeze-drying the sustained-release preparation in a freeze-drying container in which part or all of the inner surface is coated with an ice layer or a water-repellent substrate. . 2. Freeze-drying a sustained-release preparation in a freeze-drying container in which part or all of the inner surface is coated with a water-repellent substrate and part or all of the inner surface is coated with an ice layer. A method for producing a solid sustained-release preparation, characterized by comprising: 3. The method according to claim 1, wherein the inner surface is only the bottom surface. 4. The method according to claim 1, wherein the freeze-drying container is a tray. 5. The ice layer has a thickness of about 0.01 mm to about 30 mm.
The production method according to claim 1 or 2, wherein 6. The water-repellent substrate is an ethylene tetrafluoride resin, an ethylene trifluoride resin, an ethylene difluoride resin, a vinylidene fluoride resin, a propylene hexafluoride / ethylene tetrafluoride copolymer resin, or a modified fluororesin. And a copolymer resin of ethylene tetrafluoride and perfluoroalkoxyethylene, or a copolymer resin of ethylene tetrafluoride and ethylene.
Or the production method according to 2. 7. The method according to claim 1, wherein the sustained-release preparation is a microsphere. 8. The method according to claim 1, wherein sublimation of frozen water in the freeze-drying vessel is completed at a temperature of the freeze-drying vessel of 0 ° C. or less under reduced pressure.