JP3490171B2 - Esters at terminal carboxyl groups of biodegradable polymers - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an ester useful as a base for sustained-release preparations and the like.

[0002]

2. Description of the Related Art JP-A-5-112468 discloses polylactic acid and glycolic acid / hydroxycarboxylic acid [H
An OCH (C _2-8 alkyl) COOH] copolymer is described as a base for sustained-release preparations. JP-A-2-
JP-A-212436 describes a sustained-release base obtained by directly dehydrating and polycondensing lactic acid and / or glycolic acid and oxycarboxylic acid. JP-A-4-173746 discloses a copolymer of lactic acid and glycolic acid and poly-γ-.
There is described a drug-polymer complex having a sustained release function, which is obtained by incorporating a drug into a polymer mixture in which butyrolactone, poly-δ-valerolactone and / or poly-ε-caprolactone is mixed. JP-A-62-2124
Japanese Patent No. 23 discloses a polymer or copolymer of hydroxypolycarboxylic acid ester such as polymalic acid methyl ester. JP-A-63-92641 discloses a β-benzylmalate / lactic acid copolymer. However, these are composed of α-hydroxymonocarboxylic acid and have a different structure from the ester at the terminal carboxyl group of the linear polyester having a terminal carboxyl group.

[0003]

In a sustained release preparation of the type in which a drug is dispersed in polyester, it is desirable that the drug release can be controlled arbitrarily. In general,
In the sustained-release preparation, the drug release period is controlled by the composition and molecular weight of the base polyester. On the other hand, the initial release of the drug after administration of the sustained-release preparation may be too large. Local concentration of drug due to such initial release,
As a result, the blood concentration may rise rapidly, and an undesirable effect may appear. Therefore, it is desired to develop a base that enables the production of a sustained release preparation with a small initial release.

[0004]

As a result of intensive research to solve the above problems, the present inventors have found that a linear polyester having a terminal carboxyl group esterified with an alkyl group and a straight chain polyester having a terminal carboxyl group. It has been found that, by using a mixture with a chain polyester, it is possible to produce a sustained release preparation having surprisingly little initial release and exhibiting good sustained release. As a result of further intensive studies based on this finding, the present invention has been completed. That is, the present invention comprises (1) an ester at the terminal carboxyl group of a linear polyester having a weight average molecular weight of about 1,500 to about 50,000, which comprises α-hydroxymonocarboxylic acid, and (2) lactic acid- The ester described in (1) above, which is an ester at the terminal carboxyl group of the glycolic acid copolymer, the ester described in (1) above, which is (3) an alkyl ester, and the (4) alkyl ester have 1 to 3 carbon atoms. The ester according to (3) above, which is an alkyl ester of

In the present specification, the weight average molecular weight and the number average molecular weight refer to the polystyrene equivalent weight average molecular weight and number average molecular weight measured by gel permeation chromatography (GPC) using polystyrene as a reference substance. The measurement is GPC column KF804L × 2
(Manufactured by Showa Denko) was used, and chloroform was used as a mobile phase. The dispersity is calculated by (weight average molecular weight / number average molecular weight). In the present invention, the linear polyester having a terminal carboxyl group is composed of α-hydroxymonocarboxylic acid, has a weight average molecular weight of about 1,500 to about 50,000, is hardly soluble or insoluble in water, and is biocompatible. , Which is decomposed in vivo. The linear polyester having a terminal carboxyl group is a linear polyester in which the number average molecular weight measured by GPC and the number average molecular weight measured by terminal group determination are substantially the same. The number average molecular weight by terminal group quantification is calculated as follows. First, polyester (about 1-3 g) is mixed with acetone (25 m
1) dissolved in a mixed solvent of methanol (5 ml) and stirred at room temperature (20 ° C.) with phenolphthalein as an indicator to quickly titrate the carboxyl group in the solution with 0.05N alcoholic potassium hydroxide solution. By doing so, the number average molecular weight by quantifying the end group is calculated from the following formula. Number average molecular weight by end group quantification = 20000 x A / B A: mass of polyester (g) B: amount of 0.05N alcoholic potassium hydroxide solution added by the end of titration (ml) It is expressed as the number average molecular weight according to. For example, in a polyester synthesized from one or more kinds of α-hydroxymonocarboxylic acids by a non-catalytic dehydration polycondensation method and having a free carboxyl group at the terminal, the number average molecular weight by GPC measurement and the number average molecular weight by terminal group quantification are Almost match. On the other hand, in a polyester synthesized from a cyclic dimer by a ring-opening polymerization method using a catalyst and having substantially no free carboxyl group at the terminal, the number average molecular weight measured by the end group is the number average molecular weight measured by GPC. Greatly exceeds. Therefore, due to this difference, the polyester can be clearly distinguished into a polyester having a free carboxyl group at the terminal and a polyester having substantially no free carboxyl group at the terminal.

While the number average molecular weight in the end group quantification is an absolute value, the number average molecular weight measured by GPC is different in various analysis / analysis conditions (eg, mobile phase type, column type,
Since it is a relative value that fluctuates depending on the reference material, selection of slice width, selection of baseline, etc., it is difficult to unambiguously associate the two values, but for example, the number average molecular weight by GPC measurement and the number by end group quantification The number average molecular weight determined by end group quantification is about 0.4 to about 2 times the number average molecular weight determined by GPC quantification.
Times, preferably about 0.5 times to about 2 times, and more preferably about 0.8 times to about 1.5 times.
The term "number average molecular weight determined by end group quantitatively significantly higher than the number average molecular weight determined by GPC" means that the number average molecular weight determined by terminal group determination exceeds about twice the number average molecular weight determined by GPC measurement.

[0007] The weight average molecular weight of the linear polyester having the terminal carboxyl group and comprising the α-hydroxymonocarboxylic acid of the present invention (hereinafter sometimes simply referred to as the linear polyester having the terminal carboxyl group) is about
1,500 to about 50,000. The weight average molecular weight is preferably about 2,000 to about 40,000, particularly preferably about 5,000.
Or about 25,000. The α-hydroxymonocarboxylic acid of the present invention may be one kind or a mixture of two or more kinds. Linear polyesters having a terminal carboxyl group include, for example, α-hydroxymonocarboxylic acids (eg,
Glycolic acid, lactic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methylbutyric acid, 2-hydroxycaproic acid, 2-hydroxyisocaproic acid,
2-hydroxycaprylic acid, etc.) homopolymer (eg, lactic acid polymer), or two or more copolymers (eg, lactic acid / glycolic acid copolymer, 2-hydroxybutyric acid / glycolic acid copolymer), Alternatively, it is a mixture of these homopolymers and / or copolymers (eg, a mixture of a lactic acid polymer and a 2-hydroxybutyric acid / glycolic acid copolymer).

Consisting of α-hydroxymonocarboxylic acid,
A particularly preferable specific example of the linear polyester having a weight average molecular weight of about 1,500 to about 50,000 and having a terminal carboxyl group is, for example, a copolymer of lactic acid / glycolic acid described in JP-A-61-28521. Combined, described in JP-A-5-112468 (A)
Examples include a mixture of polylactic acid and (B) glycolic acid / α-hydroxycarboxylic acid [HOCH (C _2-8 alkyl) COOH] copolymer.

Particularly when a lactic acid / glycolic acid copolymer is used, its composition ratio (lactic acid / glycolic acid) (mol%)
Is preferably 100/0 to about 40/60. More preferably, it is about 90/10 to about 50/50. Here, when the composition ratio is 100/0, it means a homopolymer of lactic acid. The weight average molecular weight of the lactic acid / glycolic acid copolymer is preferably about 5,000 to about 25,000. More preferably, it is about 7,000 to about 20,000. Also,
The dispersity (weight average molecular weight / number average molecular weight) of the lactic acid / glycolic acid copolymer is preferably about 1.2 to about 4.0. More preferably, it is about 1.5 to about 3.5. Lactic acid /
The decomposition / dissociation rate of a glycolic acid copolymer varies greatly depending on the composition or molecular weight, but generally, the lower the glycolic acid content, the slower the decomposition / dissipation. By making it large, the release period can be extended. Conversely, the release period can be shortened by increasing the glycolic acid fraction or decreasing the molecular weight.

When a mixture of (A) polylactic acid and (B) glycolic acid / α-hydroxycarboxylic acid [HOCH (C _2-8 alkyl) COOH] copolymer is used, the hydroxycarboxylic acid is preferably 2- Hydroxybutyric acid,
2-hydroxyvaleric acid, 2-hydroxy-3 methylbutyric acid, 2-hydroxycaproic acid and the like. Particularly preferred is 2-hydroxybutyric acid. These hydroxycarboxylic acids may be any of D-form, L-form and D-, L-form, but it is preferable to use a mixture of D-form and L-form. At this time, the D-form / L-form (mol%) is preferably about 75/25 to about 25/75. More preferably, it is about 60/40 to about 40/60. Particularly preferably,
About 55/45 to about 45/55. Glycolic acid / α-hydroxycarboxylic acid [HOCH (C _2-8 alkyl) CO
The composition ratio of glycolic acid and hydroxycarboxylic acid in the OH] copolymer (hereinafter abbreviated as glycolic acid copolymer) may be about 10 to about 75 mol% of glycolic acid and the rest being hydroxycarboxylic acid. preferable. More preferably, glycolic acid is about 20 to about 75 mol% and the balance is hydroxycarboxylic acid. The weight average molecular weight of these glycolic acid copolymers is usually about 2,000.
From about 50,000. Preferably from about 3,000 to about 40,00
It is 0. More preferably, it is about 8,000 to about 40,000. The dispersity (weight average molecular weight / number average molecular weight) is preferably about 1.2 to about 4.0. More preferably, about 1.
5 to about 3.5.

The polylactic acid may be D-form, L-form or a mixture thereof, but it is preferable to use a mixture of D-form and L-form. At this time, D-body / L-
The body (mol%) is preferably about 75/25 to about 20/80. More preferably, it is about 60/40 to about 25/75. Particularly preferred is about 55/45 to about 25/75.
The weight average molecular weight of polylactic acid is preferably about 1,500 to about 30,000. More preferably, it is about 2,000 to about 20,000. Particularly preferably, about 3,000 to about 15,
It is 000. Dispersion degree (weight average molecular weight / number average molecular weight)
Is preferably about 1.2 to about 4.0. More preferably, it is about 1.5 to about 3.5.

The mixing ratio [(A) / (B) (% by weight)] of (A) polylactic acid and (B) glycolic acid copolymer is usually about 10/90 to about 90/10. Preferably about 20/80
Or about 80/20. More preferably, it is about 30/70 to about 70/30. If too much of either component (A) or (B) is used, only a drug product having almost the same drug release pattern as that obtained when the component (A) or (B) is used alone will be obtained, and release by the mixed base will be obtained. A late linear release pattern cannot be expected. The rate of decomposition / disappearance of glycolic acid copolymer and polylactic acid varies greatly depending on the molecular weight or composition, but in general, the rate of decomposition / disappearance of glycolic acid copolymer is faster, so the molecular weight of polylactic acid to be mixed is increased. Alternatively, the release period can be extended by increasing the mixing ratio represented by (A) / (B). On the contrary, the release period can be shortened by decreasing the molecular weight of the polylactic acid to be mixed or by decreasing the mixing ratio represented by (A) / (B). Further, the release period can be adjusted by changing the type and ratio of the hydroxycarboxylic acid used.

As the ester at the terminal carboxyl group, those which can be pharmacologically enjoyed are used.
Specific examples include alkyl esters, aryl esters, aralkyl esters, and the like. Here, the alkyl ester is, for example, a halogen atom such as chlorine, bromine, fluorine, etc., such as methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc., having 1 to 8 carbon atoms.
Which may have 1 to 3 substituents selected from the alkyl-carbonyl and nitro groups of, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert. -Butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, tert-pentyl,
1-ethylpropyl, n-hexyl, isohexyl, 1,
1-dimethylbutyl, 2,2-dimethylbutyl, 3,3
-C1-C6 alkyl-esters such as dimethylbutyl and 2-ethylbutyl.

As the aryl ester, for example, chlorine,
Halogen atom such as bromine, fluorine, etc., eg, carbon number 1 such as methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.
To C6 alkyl-carbonyl and nitro group optionally having 1 to 3 substituents, such as phenyl, naphthyl and the like, C6-10 aryl-
Esters can be mentioned. As aralkyl ester,
For example, it may have a halogen atom such as chlorine, bromine, fluorine, etc., for example, 1 to 3 substituents selected from an alkyl-carbonyl having 1 to 6 carbon atoms such as methylcarbonyl, ethylcarbonyl and butylcarbonyl, and a nitro group. Preferable examples include aralkyl-esters having 7 to 19 carbon atoms such as benzyl, phenylethyl, naphthylmethyl and trityl.

The ester at the terminal carboxyl group is preferably an alkyl ester. More preferably, the ester has 1 to 6 carbon atoms such as methylcarbonyl, ethylcarbonyl and butylcarbonyl.
Which may have 1 to 3 substituents selected from the alkyl-carbonyl and nitro groups of, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert. -Butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, tert-pentyl,
1-ethylpropyl, n-hexyl, isohexyl, 1,
1-dimethylbutyl, 2,2-dimethylbutyl, 3,3
And alkyl-esters having 1 to 6 carbon atoms such as dimethylbutyl and 2-ethylbutyl. The ester is particularly preferably an alkyl-ester having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, iso-propyl and the like.

The ester of the present invention comprises α-hydroxymonocarboxylic acid, has a weight average molecular weight of about 1,500 to about 50,000, and has a terminal carboxyl group, and is a linear polyester (hereinafter sometimes abbreviated as a raw material polymer). )
It is produced by subjecting the terminal carboxyl group of 1 to an esterification reaction. The esterification reaction is carried out by a method known per se, for example, the following method. (1) Solvents that do not inhibit the reaction of the raw material polymer with diazoalkane (eg, diazomethane, phenyldiazomethane, diphenyldiazomethane, etc.) (eg, ethers such as tetrahydrofuran, dioxane, esters such as ethyl acetate, nitriles such as acetonitrile, dichloromethane, React in a mixed solution of halogenated hydrocarbons such as dichloroethane). The reaction temperature is about 0 ° C to the reflux temperature. The reaction time is about 2 minutes to 20 hours. (2) Activated alkyl halides (eg, methyl iodide, benzyl bromide, etc.) of alkali metal salts (eg, sodium salts, potassium salts, lithium salts, etc.) of the starting polymer
p-nitro-benzyl bromide, m-phenoxybenzyl bromide, pt-butylbenzyl bromide, pivaloyloxymethyl chloride, etc.). This reaction is carried out in a solvent that does not inhibit the reaction (for example, amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoramide, and ketones such as acetone). The reaction temperature is about 0 ° C to 60 ° C. The reaction time is about 2 minutes to 4 hours. Coexistence of triethylamine or the like in this reaction solution does not affect the progress of the reaction.

(3) The raw material polymer is reacted with an alcohol such as methanol, ethanol, benzyl alcohol or the like. This reaction is carried out by a carbodiimide condensing agent (for example, dicyclohexylcarbodiimide, 1-ethyl-3-
(3-dimethylaminoisopropyl) -carbodiimide and the like). The reaction temperature is about 0 ° C to the reflux temperature. The reaction time is about 15 minutes to 18 hours. As the solvent, solvents that do not inhibit the reaction, for example, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane are used. (4) Raw material polymer is acid halide (eg ethyl chloroformate, benzyl chloroformate, etc.)
Acid anhydride obtained by reacting with alcohol (for example, methanol, ethanol, benzyl alcohol, etc.),
The reaction is carried out under the reaction conditions described in (3) above. This acid anhydride can be obtained by reacting a raw material polymer with an acid halide, for example, acid chloride, in a solvent that does not interfere with the reaction (for example, ethers such as tetrahydrofuran, halogenated hydrocarbons such as dichloromethane). The reaction temperature is 25 ° C to the reflux temperature. The reaction time is about 15 minutes to 10 hours.

The ester of the present invention is used as a base for sustained-release preparations such as microcapsules. In the ester of the present invention, there is almost no hydrogen bond between carboxyl groups, and there is almost no reaction between the basic drug and the terminal carboxyl group. Therefore, in the sustained-release preparation produced using the ester, the initial release of the drug immediately after administration is suppressed due to the delay of water penetration into the preparation due to the increased hydrophobicity of the base. Further, the sustained-release preparation base containing the ester of the present invention has a slow hydrolysis rate when compared with a sustained-release preparation base containing only a linear polyester having a terminal carboxyl group. It is advantageously used as a base for a sustained-release preparation capable of releasing a drug over a long period of time.

When the ester of the present invention is used as a base for sustained-release preparations, it is preferable to use a mixture of the ester and a linear polyester having a terminal carboxyl group. Here, as the linear polyester having a terminal carboxyl group, the same one as described above is used. The weight ratio of the mixture is usually about 100/0 to about 5/95. It is preferably about 100/0 to about 30/70, more preferably about 100/0 to about 50/50. The linear polyester (D) having a terminal carboxyl group which is used as a mixture with the ester (C) of the present invention may be either a copolymer or a homopolymer, and for example, one type of (C) and 2 You may use combining three or more types of linear polyesters, such as type (D). Combinations such as the type of linear polyester having a terminal carboxyl group, the weight average molecular weight, and the degree of dispersion, and the selection criteria such as the type of the ester of the present invention and the weight average molecular weight are such that a predetermined drug release period can be obtained, and administration The excessive drug release in the initial period is sufficiently suppressed.

A typical example is a combination of a lactic acid / glycolic acid copolymer (E) having a terminal carboxyl group esterified with an alkyl group and a lactic acid / glycolic acid copolymer (F) having a terminal carboxyl group. To be
The weight ratio of (E) to (F) is about 100/0 to about 5/95,
It is preferably about 100/0 to about 20/80, more preferably about 100/0 to about 50/50. In each of (E) and (F), the ratio of lactic acid to glycolic acid may be the same or different. The weight average molecular weights of (E) and (F) may be the same or different. Other representative examples include polylactic acid (G) in which the terminal carboxyl group is esterified with an alkyl group and glycolic acid / 2-hydroxybutyric acid copolymer (H) having a terminal carboxyl group. The weight ratio of (G) to (H) is usually about 100/0 to about 5/95, preferably about 100.
/ 0 to about 20/80, more preferably about 100/0 to about 50/50. The weight average molecular weights of (G) and (H) may be the same or different.

The base for sustained-release preparations containing the ester of the present invention can be made into a sustained-release preparation by using any drug. The drug is not particularly limited, and examples thereof include physiologically active peptides, antitumor agents, antibiotics, antipyretics, analgesics, antiphlogistics, antitussives, sedatives, muscle relaxants, antiepileptics, antiulcers, and antiulcers. Depressants, antiallergic agents, cardiotonics, antiarrhythmic agents, vasodilators, antihypertensive diuretics, antidiabetic agents, anticoagulants, hemostatic agents, antituberculous agents, hormone agents, opiate antagonists, osteoporosis therapeutic agents, angiogenesis Examples include inhibitors.

The physiologically active peptide is composed of two or more amino acids and has a molecular weight of about 2
Those from 00 to about 80,000 are preferred. Specific examples of the physiologically active peptide include, for example, luteinizing hormone-releasing hormone (LH-RH) and analogues having the same action as that of, for example, formula [I] (Pyr) Glu-R ₁ -Tr.
p-Ser-R ₂ -R ₃ -R ₄ -Arg-Pro-R ₅ [I] [wherein R ₁ is Hi
s, Tyr, Trp or _{p-N H 2 -Phe, R} 2 is Tyr or Phe, R ₃ is Gly or a D-amino acid residues, R ₄ is L
eu, Ile or Nle, R ₅ is Gly-NH-R ₆ (R ₆ is H or a lower alkyl group having or not having a hydroxyl group) or NH-R ₆ (R ₆ is as defined above)] Examples include the represented peptides or salts thereof [US Pat.
53,837, the same 4,008,209, the same 3,972,
859, UK Patent No. 1,423,083, Proceedings of the National Academy of Sci.
ences of the United States of America), Volume 78,
6509-6512 (1981)]. In the above formula [I], the D-type amino acid residue represented by R ₃ is, for example, an α-D-amino acid having up to 9 carbon atoms (eg, D-Leu, Ile, Nle, Val, Nval, Abu, Ph
e, Phg, Ser, Thr, Met, Ala, Trp, α-Aibu
Etc.) and the like, and they may optionally have a protecting group (eg, t-butyl, t-butoxy, t-butoxycarbonyl, etc.). Of course, acid salts of peptides [I] (eg, carbonates, bicarbonates, acetates, propionates, etc.) and metal complex compounds (eg, copper complexes, zinc complexes, etc.) are also peptides [I].
Can be used as well.

Regarding the amino acids, protecting groups and the like in the peptides represented by the formula [I] and the peptides shown below, when expressed by abbreviations, IUPAC-IUB Commission on Biochemical Nomenclature (Co
abbreviations according to mmission on Biochemical Nomenclature) or abbreviations commonly used in the art, and where amino acids may have optical isomers, L form is shown unless otherwise specified. As a typical compound represented by the above formula [I], R ₁ = His, R ₂ = Ty
_{r, R 3 = D-Leu} , R 4 = Leu, R 5 = NHCH 2 -CH 3
(The acetate salt of this peptide is referred to by the general name leuprorelin acetate and may be abbreviated as TAP-144 hereinafter). In addition, LH-RH analogs include LH-RH antagonists (US Pat. No. 4,086,2).
No. 19, No. 4,124,577, No. 4,253,99
No. 7, No. 4,317,815) and the like.

Examples of the physiologically active peptides include cytokines. Examples of the cytokine include lymphokines and monokines. Examples of lymphokines include interferons (alpha, beta, gamma), interleukins (IL-2 to IL-12), and the like. Examples of monokine include interleukin (IL-1) and tumor necrosis factor (TNF). Cytokines are preferably lymphokines, particularly preferably interferons (alpha, beta, gamma) and the like.

Examples of the physiologically active peptide include insulin, somatostatin and somatostatin derivatives (US Pat. Nos. 4,087,390 and 4,049).
No. 93,574, No. 4,100,117, No. 4,25
3,998), growth hormone, prolactin, adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone (MSH), thyroid hormone releasing hormone [(Py
r) represented by the structural formula of Glu-His-ProNH ₂ , and may be abbreviated as TRH hereinafter) salts and derivatives thereof (see JP-A-50-112273, JP-A-52-116465), Thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), pasopullecin, pasopullesin derivative {desmopressin [Journal of the Endocrine Society of Japan, Vol. 54, No. 5, 676-691]
P. (1978)]}, oxytocin, calcitonin, parathyroid hormone, glucagon, gastrin, secretin, pancreozyme, cholecystokinin, angiotensin, human placental lactogen, human chorionic gonadotropin (HCG), enkephalin, enkephalin derivative [See US Pat. No. 4,277,394, European Patent Application Publication No. 31567], endorphin, kyotorphin, tuftsin, thymopoietin, thymosin, thymostimulin, thymic humoral factor (T
HF), blood thymus factor (FTS) and its derivatives (see U.S. Pat. No. 4,229,438), and other thymus factors [Medical History, Vol. 125, No. 10, 835].
~ 843 (1983)], colony inducing factor (CS
F), motilin, dynorphin, bombesin, neurotensin, cerulein, bradykinin, urokinase, asparaginase, kallikrein, substance P, nerve growth factor, cell growth factor, neurotrophic factor, blood coagulation factor factor VIII, factor IX, chloride Lysozyme, polymyxin B, colistin, gramicidin, bacitracin, erythropoietin (EPO), platelet growth factor (thrombopoietin), and peptides having an endothelin antagonism (European Patent Publication Nos. 436189, 457195, 4965452, JP-A-3). -94
692, No. 3-130299) and the like, and fragments of these physiologically active peptides or derivatives thereof.

Examples of antitumor agents include bleomycin, methotrexate, actinomycin D, mitomycin C, vinplastin sulfate, pinklistin sulfate,
Daunorubicin, adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, krestin,
Picibanil, lentinan, levamisole, bestatin, azimexone, glycyrrhizin, poly I: C, poly A: U, poly ICLC and the like can be mentioned. Examples of antibiotics include gentamicin, dibekacin, canendomycin, ribidomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline hydrochloride, oxytetracycline hydrochloride, loritetracycline, doxycycline hydrochloride, ampicillin, piperacillin, ticarcillin, cephalothin, cephaloridine, Cefotiam, cefthrozine, cefmenoxime, cefmetazole, cefazoline, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, and azthreonam.

Examples of the antipyretic, analgesic and anti-inflammatory agents include salicylic acid, sulpiline, flufenamic acid, diclofenac, indomethacin, morphine, pethidine hydrochloride, leporphanol tartrate and oxymorphone. Examples of antitussive antitussive agents include ephedrine hydrochloride,
Methylephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, alloclamide hydrochloride,
Examples include clofedanol hydrochloride, picoperidamine hydrochloride, cloperastine, protoxylol hydrochloride, isoproterenol hydrochloride, salbutamol sulfate, and terbutaline sulfate. Examples of the sedatives include chlorpromazine, prochlorperazine, trifluoperazine, atropine sulfate, and methylscopolamine bromide. Examples of the muscle relaxant include pridinol methanesulfonate, tubocurarine chloride, pancuronium bromide and the like. Examples of the antiepileptic agent include phenytoin, ethosuximide, sodium acetazolamide, chlordiazepoxide and the like. Examples of anti-ulcer agents include metoclopromide, histidine hydrochloride and the like. Examples of the antidepressant include imipramine, clomipramine, noxiptiline, phenelzine sulfate and the like. Examples of the antiallergic agent include diphenhydramine hydrochloride, chlorpheniramine maleate, tripelenamine hydrochloride, metzirazine hydrochloride, clemizole hydrochloride, diphenylpyraline hydrochloride, methoxyphenamine hydrochloride.

Examples of the cardiotonic agent include transpyoxocamphor, theophyllol, aminophylline, etilefrine hydrochloride and the like. Examples of antiarrhythmic agents include propranol, alprenolol, bufetrol, oxyprenolol and the like. Examples of the vasodilator include oxyfedrine hydrochloride, diltiazem, tolazoline hydrochloride, hexobendine, bamethane sulfate and the like. Examples of the antihypertensive diuretics include hexamethonium bromide, pentolinium, mecamylamine hydrochloride, ecarazine hydrochloride, clonidine and the like. Examples of the antidiabetic agent include glymidine sodium, glipizide, phenformin hydrochloride, buformin hydrochloride, metformin and the like. Examples of the anticoagulant include heparin sodium, sodium citrate and the like. Examples of hemostatic agents include thromboplastin, thrombin, menadione sodium bisulfite, acetomenaphthone, ε-aminocaproic acid, tranexamic acid, sodium carbazochrome sulfonate, adrenochrome monoaminoguanidine methanesulfonate and the like.

Examples of the antituberculous agent include isoniazid,
Examples include ethambutol and para-aminosalicylic acid. Examples of the hormonal agents include prednisolone, sodium prednisolone phosphate, dexamethasone sodium sulfate, betamethasone sodium phosphate, hexestrol phosphate phosphate, hexestrol acetate acetate, and methimazole. Examples of the narcotic antagonist include levallorphan tartrate, nalorphine hydrochloride, naloxone hydrochloride and the like. Examples of the osteoporosis therapeutic agent include (sulfur-containing alkyl) aminomethylenebisphosphonic acid. Examples of angiogenesis inhibitors include angiogenesis inhibitor steroids [Science, Vol.
19 (1983)], fumagillin (see European Patent Publication No. 325119), fumagillol derivative (European Patent Publication Nos. 357061 and 3).
No. 59036, No. 386667, No. 415294.
(See Japanese Patent Publication) and the like.

The above-mentioned drug may be used alone or as a salt, preferably a pharmacologically acceptable salt is used. Examples of such salts include inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, etc.), organic acids (eg, carbonic acid, succinic acid, acetic acid, etc.) when the drug has a basic group such as an amino group.
Examples thereof include salts with propionic acid, trifluoroacetic acid, etc.). When the drug has an acidic group such as a carboxyl group, 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, an organic amine such as triethylamine, arginine) Basic amino acids, etc.) and the like. Further, the drug is a metal complex compound (eg,
Copper complex, zinc complex, etc.) may be formed.

Of the above-mentioned drugs, in the case of a water-soluble drug, an excessive initial release is often observed. Therefore, it is more preferable to use a water-soluble drug in the present invention.
The water solubility of a drug is defined by the oil-water partition ratio between n-octanol and water, and it is preferable to use a drug having an oil-water partition ratio of 1 or less, preferably 0.1 or less. The oil-water distribution ratio may be measured according to the method described in "Physical Chemistry Experimental Method" by Shinsaburo Samejima, published by Shokabo, 1936. That is, first, a buffer solution of n-octanol and pH 5.5 (1: 1 equivalent mixture) is placed in a test tube. Examples of the buffer solution include Sφerensen buffer solution [Ergeb. Phy
siol. 12 , 393 (1912)], Clark-Lubs buffer [J. Bact. 2 , (1), 109,
191 (1917)], Macllvaine buffer [J. Biol. Chem. 49 , 183 (1921)], Michaelis buffer [Die Wasser-stoffionenko].
nzentration. p. 186 (1914)], Korsov (Ko
lthoff) buffer [Biochem. Z, 179 , 410 (192
6)] and the like. Add an appropriate amount of drug to this,
Further cap it, immerse it in a constant temperature bath (25 ° C), and often shake it vigorously. Then, when it seems that the drug was dissolved between the two liquid layers and reached equilibrium, the liquid was allowed to stand or centrifuged, and a fixed amount of liquid was removed from each of the upper and lower layers with a pipette and analyzed to analyze each layer. The concentration of the drug in the solution is determined, and the ratio of the concentration of the drug in the n-octanol layer / the concentration of the drug in the water layer is taken to give the oil-water distribution ratio.

The drug is preferably a peptide having physiological activity, more preferably LH-RH analog or cytokine. The drug is particularly preferably LH-
RH antagonists or interferons (alpha, beta, gamma) and the like.

Specific examples of the LH-RH antagonist include hormone-dependent diseases such as prostate cancer, benign prostatic hypertrophy, endometriosis, uterine fibroids, precocious puberty, and breast cancer, and peptides effective for contraception. Examples of the salt include, for example, US Pat. No. 5,110,904, Journal of
Journal of MedicinalCh
emistry), 34, 2395-2402 (199)
1 year), Recent Results in Cancer Research, 1st
24, pages 113-136 (1992) and the like, and the salts thereof.

More specifically, examples of the LH-RH antagonist include peptides represented by the general formula [II] and salts thereof.

[Chemical 1] [Wherein X is an acyl group, R ₁ , R ₂ and R ₄ are aromatic ring groups, and R ₃ is a D-amino acid residue or a formula

[Chemical 2] (Wherein, R ₃ 'represents a heterocyclic group) a group represented by, R ₅
Is the formula-(CH ₂ ) _n -R ₅ '(wherein n = 2 or 3,
R ₅ 'is a group represented by indicating) the optionally substituted amino group, an aromatic ring group or O- glycosyl group, R ₆ is the formula -
A group represented by (CH ₂ ) _n -R ₆ ′ (wherein, n = 2 or 3 and R ₆ ′ represents an optionally substituted amino group),
R ₇ represents a D-amino acid residue or an azaglycyl group, and Q represents a hydrogen atom or a lower alkyl group]

In the general formula [II], the acyl group represented by X is preferably an acyl group derived from a carboxylic acid. Examples of the acyl group include optionally substituted C _2-7 alkanoyl, C _7-15 cycloalkenoyl (eg, cyclohexenoyl etc.), C _1-6 alkylcarbamoyl (eg, ethylcarbamoyl etc.), A 5- or 6-membered heterocyclic carbonyl (eg, piperidinocarbonyl etc.), a carbamoyl group and the like can be mentioned. The acyl group is preferably an optionally substituted C _2-7 alkanoyl group (eg,
Acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl or heptanoyl), and more preferably an optionally substituted C _2-4 alkanoyl group (eg, acetyl, propionyl, butyryl, isobutyryl etc.). Examples of the substituent include a C _1-6 alkylamino group (eg, methylamino, ethylamino, diethylamino, propylamino, etc.), a C _1-3 alkanoylamino group (eg, formylamino, acetylamino, propionylamino, etc.), C _7-15 cycloalkenoylamino group (eg, cyclohexenoylamino etc.), C _{7-15 allylcarbonylamino} group (eg, benzoylamino etc.), 5- or 6-membered heterocyclic carboxamide group (eg, tetrahydrofurylcarboxamide, Pyridylcarboxamide, furylcarboxamide, etc.), hydroxyl group, carbamoyl group, formyl group, carboxyl group, 5- or 6-membered heterocyclic group (eg, pyridyl, morpholino, etc.) and the like. The substituent is
Preferably a 5- or 6-membered heterocyclic carboxamide group (eg,
Tetrahydrofurylcarboxamide, pyridylcarboxamide, furylcarboxamide, etc.) and the like.

X is preferably a C _2-7 alkanoyl group which may be substituted with a 5- or 6-membered heterocyclic carboxamide group. X is more preferably a C _2-4 alkanoyl group optionally substituted with a tetrahydrofurylcarboxamide group. Specific examples of X include acetyl,

[Chemical 3] Etc. The tetrahydrofuryl in the above-mentioned tetrahydrofurylcarboxamidoacetyl is particularly preferably (2S) -tetrahydrofuryl.

Examples of the aromatic ring group represented by R ₁ , R ₂ or R ₄ include an aromatic ring group having 6 to 14 carbon atoms. Examples of such an aromatic ring group include phenyl,
Examples include naphthyl and anthryl. Preferably,
Examples thereof include aromatic ring groups having 6 to 10 carbon atoms such as phenyl and naphthyl. These aromatic ring groups may have 1 to 5, preferably 1 to 3 appropriate substituents at appropriate positions on the aromatic ring group. Examples of the substituent include a hydroxyl group, halogen, an amino group substituted with aminotriazolyl, and an alkoxy group.
Preferably, examples thereof include a hydroxyl group, a halogen, and an amino group substituted with aminotriazolyl. Here, as the halogen, for example, fluorine, chlorine, bromine,
Examples thereof include iodine. Examples of the aminotriazolyl group in the amino group substituted with aminotriazolyl include 3-amino-1H-1,2,4-triazol-5-yl,
5-amino-1H-1,3,4-triazol-2-yl, 5-
Amino-1H-1,2,4-triazol-3-yl, 3-amino-2H-1,2,4-triazol-5-yl, 4-amino-
1H-1,2,3-triazol-5-yl, 4-amino-2H
-1,2,3-triazol-5-yl and the like can be mentioned. The alkoxy group is preferably an alkoxy group having 1 to 6 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.). R ₁ is more preferably a naphthyl group or a halogenophenyl group. R ₂ is more preferably halogenophenyl. R ₄ is more preferably a hydroxyphenyl group or a phenyl group substituted with aminotriazolylamino.

The D-amino acid residue represented by R ₃ is
Α-D-amino acid residues having 3 to 12 carbon atoms are preferred.
Examples of the amino acids include leucine, isoleucine,
Norleucine, valine, norvaline, 2-aminobutyric acid,
Phenylalanine, serine, threonine, methionine,
Examples include alanine, tryptophan and aminoisobutyric acid. These amino acids may optionally have a protecting group (eg, protecting groups commonly used in the art, such as t-butyl, t-butoxy, t-butoxycarbonyl).

The heterocyclic group represented by R ₃ 'includes 1 to 2 heteroatoms of nitrogen atom or sulfur atom,
Examples thereof include a 5- or 6-membered heterocyclic group which may be condensed with a benzene ring. Specific examples include, for example, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl,
Pyrazolyl, pyridyl, 3-pyridyl, pyridazinyl,
Examples thereof include pyrimidinyl, pyrazinyl, 3-benzo [b] thienyl, 3-benzo [b] -3-thienyl, indolyl, 2-indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzothiazolyl, quinolyl and isoquinolyl. R ₃ 'is particularly preferably pyridyl or 3-benzo [b] thienyl.

The aromatic ring group represented by R ₅ is the same as the aromatic ring group defined by R ₁ , R ₂ or R ₄ . The aromatic ring group may have 1 to 5, preferably 1 to 3 appropriate substituents at appropriate positions on the aromatic ring group. As such a substituent, the same substituents as defined for R ₁ , R ₂ or R ₄ can be used. Of these, particularly preferred is an amino group substituted with aminotriazolyl. O-represented by R ₅
The glycosyl group in the glycosyl group preferably includes groups of hexasaccharides and derivatives thereof. The 6
Examples of monosaccharides include D-glucose, D-fructose, D-mannose, D-galactose and L-galactose. Derivatives include, for example, deoxy sugars (L- and D-fucose, D-quinose, L-rhamnose, etc.) and amino sugars (D-glucosamine, D-galactosamine, etc.). More preferably, deoxy sugars (L- and D-fucose, D-
(Kinomose, L-rhamnose, etc.). Particularly preferred is L-rhamnose.

The substituent in the optionally substituted amino group represented by R ₅ 'is, for example, an acyl group, a carbamoyl group, a carbazoyl group optionally substituted with an acyl group, or a mono- or di-substituted alkyl group. Amidino group and the like may be mentioned. Examples of the acyl group in the acyl group and the carbazoyl group optionally substituted with an acyl group include, for example, nicotinoyl, furoyl,
Examples include tenoil. The alkyl group in the mono- or dialkylamidino group has 1 to 4 carbon atoms.
A straight chain or branched alkyl group of is used. Examples of the alkyl group include methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, tert
-Butyl and the like. A methyl group or an ethyl group is particularly preferable.

Examples of the substituent in the optionally substituted amino group represented by R ₆ ′ include an alkyl group and an amidino group which may be mono- or di-substituted with alkyl. As the alkyl group and the alkyl group in the mono- or dialkylamidino group, those similar to the alkyl group defined for R ₅ ′ are used. The D-amino acid residue represented by R ₇ has 3 carbon atoms.
9 to 9 D-amino acid residues are preferred, for example D-alanyl, D-leucyl, D-valyl, D-isoleucyl, D-
Examples thereof include phenylalanyl. More preferably, a D-amino acid residue having 3 to 6 carbon atoms, such as D-alanyl,
Examples include D-valyl. Particularly preferably, R ₇ is
It is D-alanyl. As the lower alkyl group represented by Q, those similar to the alkyl group defined for R ₅ ′ above can be used. Q is particularly preferably a methyl group.

As a specific example of R ₁ ,

[Chemical 4] To give a specific example of R ₂ ,

[Chemical 5]

Specific examples of R ₃ include:

[Chemical 6] To give a specific example of R ₄ ,

[Chemical 7]

Specific examples of R ₅ are:

[Chemical 8]

[Chemical 9]

[Chemical 10]

Specific examples of R ₆ include:

[Chemical 11] To give a specific example of R ₇ ,

[Chemical 12]

When the peptide [II] has one or more asymmetric carbon atoms, two or more optical isomers exist. Such optical isomers and mixtures thereof are also included in the present invention. The peptide represented by the general formula [II] can be produced by a method known per se. Specific examples of the method for producing the peptide are described in, for example, US Pat. No. 5,110,904. The peptide [II] may be used as a salt, and a pharmacologically acceptable salt is preferably used. Examples of such salts include inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid) when the peptide has a basic group such as an amino group,
Examples include salts with organic acids (eg, carbonic acid, bicarbonate, succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.),
When the peptide has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium,
Alkaline earth metals such as calcium and magnesium)
And organic bases (eg, organic amines such as triethylamine,
Basic amino acids such as arginine) and the like. In addition, the peptide is a metal complex compound (eg,
Copper complex, zinc complex, etc.) may be formed. The salt of peptide [II] is preferably an organic acid (eg, carbonic acid, bicarbonate,
It is a salt with succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.). Particularly preferred is a salt with acetic acid.

Particularly preferred examples of peptide [II] or a salt thereof are shown below. (1) NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic)-
Leu-Lys (Nisp) -Pro-DAlaNH ₂ or its acetate (2) NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagl
yNic) -Leu-Lys (Nisp) -Pro-DAlaNH ₂ or its acetate (3) NAcD2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagl
yFur) -Leu-Lys (Nisp) -Pro-DAlaNH ₂ or its acetate

[Chemical 13] (5) NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DhArg (Et ₂ ) -Le
u-hArg (Et ₂ ) -Pro-DAlaNH ₂ or its acetate

The abbreviations used in the present specification have the following meanings. 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 DLys (AzaglyNic): D- [1-aza- (N-nicotinoyl) glycyl] lysyl DLys (AzaglyFur): D- [1-Aza- (N-2-furoyl) glycyl] lysyl DhArg (Et ₂ ): D- (N, N'-diethyl) homoarginyl

In the sustained-release preparation of the present invention, the compounding amount of the drug varies depending on the kind of the drug, desired pharmacological effect, duration of effect, etc. Used from 0.01 to about 50% (w / w). More preferably about 0.1 to about 40%
(W / w) used. Particularly preferably, about 1 to about 3
0% (w / w) is used.

The sustained-release preparation of the present invention, such as microcapsules, can be produced by the following method A, method B or a method analogous thereto. (Method A) First, a drug is dissolved or dispersed in water, and if necessary, a drug-retaining substance such as gelatin, agar, alginic acid, polyvinyl alcohol or basic amino acid is added to dissolve or suspend the drug. And In these inner aqueous phases, for example, carbonic acid, acetic acid, oxalic acid, citric acid, tartaric acid, succinic acid, phosphoric acid or their sodium salts or potassium are used as pH adjusters for maintaining the stability or solubility of the drug. Salt, hydrochloric acid, sodium hydroxide, arginine, lysine and salts thereof may be added. Further, as a drug stabilizer, for example, albumin, gelatin, citric acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, a polyol compound such as polyethylene glycol, or the like, or as a preservative, for example, paraoxybenzoic acid esters ( (Eg, methylparaben, propylparaben, etc.), benzyl alcohol, chlorobutanol, thimerosal, etc. may be added.

The inner aqueous phase liquid thus obtained is added to a solution (oil phase) containing an ester, and then an emulsification operation is carried out to prepare a W / O type emulsion. As the solution containing the ester, a solution obtained by dissolving the ester in an organic solvent is used. The organic solvent has a boiling point of about 120 ° C. or less, is not easily miscible with water, and can dissolve the ester, and examples thereof include halogenated hydrocarbons (eg, dichloromethane, chloroform, chloroethane, trichloroethane). , Carbon tetrachloride, etc., fatty acid ester (eg, butyl acetate etc.), ethers (eg, isopropyl ether etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene etc.) and the like. You may use these in mixture of 2 or more types. A known dispersion method is used for the emulsification operation. As the dispersion method, for example, the intermittent shaking method,
Mixer such as propeller type agitator or turbine type agitator, colloid mill method, homogenizer method,
An ultrasonic irradiation method and the like can be mentioned.

Next, the W / O type emulsion thus prepared is subjected to a microencapsulation process. Examples of the microencapsulation step include, for example, an in-water drying method, a phase separation method, a spray drying method, or a method similar thereto, as shown below. (1) In-water drying method W / O type emulsion was further added to the water phase of the third phase to give W / O
After forming the O / W emulsion, the solvent in the oil phase is removed to produce microcapsules. An emulsifier may be added to the above-mentioned third-phase aqueous phase. As the emulsifier, any emulsifier can be generally used as long as it can form a stable O / W emulsion. Specifically, for example, anionic surfactants (sodium oleate, sodium stearate, sodium lauryl sulfate, etc.), nonionic surfactants (polyoxyethylene sorbitan fatty acid ester [Tween 80, Tween] 60, Atlas Powder Co.], polyoxyethylene castor oil derivatives [HCO-60, HCO-50, Nikko Chemicals, etc.], polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, gelatin, hyaluronic acid and the like. One of these may be used, or some of them may be used in combination. The concentration at the time of use is about 0.
It can be appropriately selected from the range of 001 to 20% (w / w). More preferably about 0.01 to 10% (w / w)
Used in the range of. Particularly preferably about 0.05 to 5
Used in the range of% (w / w). The solvent in the oil phase can be removed by a method known per se. For example, a method of evaporating the solvent under normal pressure or gradually reducing the pressure while stirring with a propeller stirrer or a magnetic stirrer, a method of evaporating the solvent while adjusting the degree of vacuum using a rotary evaporator, and the like can be mentioned. The microcapsules thus obtained are separated by centrifugation or filtration, and then the free drug, drug-holding substance, emulsifier, etc. adhering to the surface of the microcapsules are repeated several times with distilled water. After washing, it is dispersed again in distilled water and freeze-dried. In order to prevent the particles from aggregating during washing, an aggregating inhibitor may be added to distilled water as a washing liquid. Examples of the aggregation inhibitor include water-soluble polysaccharides such as mannitol, lactol, glucose, starches (eg, corn starch, etc.), amino acids such as glycine, alanine, proteins such as gelatin, fibrin, collagen, sodium chloride, sodium bromide. , Inorganic salts such as potassium carbonate and sodium hydrogen phosphate. If necessary, heating is performed, and water and organic solvent in the microcapsules are removed more completely under reduced pressure.

(2) Phase Separation Method A coacervation agent is gradually added to a W / O type emulsion with stirring to precipitate and solidify an ester to produce microcapsules. The coacervation agent may be a polymer-based, mineral oil-based, or vegetable oil-based compound that is miscible with the solvent of the ester and does not dissolve the ester. Specific examples include silicone oil, sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane, n-heptane and the like. You may use these in mixture of 2 or more types. The microcapsules thus obtained are filtered and collected, and then repeatedly washed with heptane or the like to remove the coacervation agent.
Further, the free drug and the solvent are removed by the same method as the in-water drying method.

(3) Spray drying method The W / O type emulsion is sprayed into the drying chamber of a spray dryer (spray dryer) using a nozzle, and the organic solvent in the atomized droplets is volatilized in an extremely short time. , To produce fine-grained microcapsules. Examples of the nozzle include a two-fluid nozzle type, a pressure nozzle type, and a rotating disk type. At this time, if desired, it is also effective to spray the above-mentioned aqueous solution of the aggregation preventing agent from another nozzle for the purpose of preventing aggregation of the microcapsules simultaneously with the organic solvent solution of the drug and ester. The microcapsules thus obtained are
If necessary, heating is performed, and water and organic solvent in the microcapsules are further removed under reduced pressure.

(Method B) The sustained-release preparation of the present invention can also be produced by, for example, dissolving or dispersing a drug and an ester in a solvent which is substantially immiscible with water, and then removing the solvent. The solvent that is substantially immiscible with water may be any solvent that is substantially immiscible with water, dissolves the ester, and the resulting solution further dissolves the drug. Preferably, the solvent has a solubility in water of 3% or less at room temperature (20 ° C). The boiling point of the solvent is preferably 120 ° C. or lower. Examples of the solvent include halogenated hydrocarbons (eg, dichloromethane, chloroform, chloroethane, trichloroethane, carbon tetrachloride, etc.), carbon number 3
The above-mentioned alkyl ethers (eg, isopropyl ether, etc.), fatty acid alkyl (C4 or more) esters (eg, butyl acetate etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene etc.) and the like can be mentioned. These may be used as a mixture of two or more kinds at an appropriate ratio. The solvent is more preferably a halogenated hydrocarbon (eg, dichloromethane, chloroform, chloroethane, trichloroethane, carbon tetrachloride, etc.). Particularly preferred is dichloromethane.

The solvent can be removed by a method known per se. For example, a method of evaporating the solvent under normal pressure or gradually reducing the pressure while stirring with a propeller stirrer or a magnetic stirrer, a method of evaporating the solvent while adjusting the degree of vacuum using a rotary evaporator, and the like can be mentioned.

The drug is added to the organic solvent solution of the ester in a weight ratio shown in the above definition of the compounding amount,
Make an organic solvent solution of the drug and ester. At this time, the concentration of the ester in the organic solvent solution varies depending on the molecular weight of the ester and the type of the organic solvent, but is generally about 0.01.
To about 80% (w / w). More preferably, it is about 0.1 to about 70% (w / w). Particularly preferred is about 1 to about 60% (w / w). The organic solvent solution of the drug and ester thus obtained is subjected to the microencapsulation step in the same manner as in the case of the W / O type emulsion described above. The microencapsulation step is carried out, for example, by an in-water drying method, a phase separation method, a spray drying method or a method similar thereto as described above.

The thus obtained microcapsules may be formulated into various dosage forms as they are or using the microcapsules as a raw material, and parenteral preparations (eg, injections or implants for intramuscular, subcutaneous, organ, etc.). , Transnasal agents for nasal cavity, rectum, uterus, etc.), oral agents [eg, capsules (eg, hard capsules, soft capsules, etc.), granules, solid preparations such as powders, syrups, emulsions, suspensions, etc. Liquid preparations such as turbidity, etc.] and the like. These formulations
It can be produced by a method known per se usually used in the formulation process. Injections include, for example, microcapsules such as dispersants (eg, Tween 80, HCO-60, carboxymethylcellulose, sodium alginate, etc.), preservatives (eg, methylparaben, propylparaben, benzyl alcohol, etc.), isotonic agents (eg, Sodium chloride, glycerin, mannitol, sorbitol, glucose, etc.)
Aqueous suspension with olive oil, sesame oil,
It can be produced by dispersing it in a vegetable oil such as peanut oil, cottonseed oil, corn oil, or propylene glycol to prepare an oily suspension. Excipients (eg, mannitol, sorbitol, lactose, glucose, etc.) are added to the injection thus obtained, redispersed, and then freeze-dried or spray-dried to solidify. A more stable sustained-release injection can be produced by adding distilled water or a suitable dispersion medium. When using a microcapsule as a suspension injection, for example,
The particle size of the microcapsules may be in the range satisfying the degree of dispersion and needle penetration as a suspension injection, and is preferably about 1 to 300 μm. More preferably about 5
To 150 μm. Examples of aseptic preparations of microcapsules include, but are not limited to, a method of sterilizing all manufacturing steps, a method of sterilizing with gamma rays, and a method of adding a preservative.

The oral agent is, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrating agent (eg, starch, calcium carbonate, etc.), a binder (eg, starch, gum arabic, carboxymethylcellulose, etc.) in microcapsules. Polyvinylpyrrolidone, hydroxypropyl cellulose, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) are added and compression-molded, and then, if desired, taste masking, enteric coating or sustaining purpose. It can be manufactured by performing coating for. The coating is
It may be carried out by a method known per se, and examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropyl. Methyl cellulose acetate succinate, Eudragit (ROHM,
West Germany, methacrylic acid / acrylic acid copolymer) and pigments such as titanium oxide and red iron oxide are used.

The nasal preparation may be solid, semi-solid or liquid. For example, solid preparations include microcapsules as they are, or excipients (eg glucose, mannitol, starch, microcrystalline cellulose, etc.), thickeners (eg natural gums, cellulose derivatives, acrylic acid polymers, etc.). ) And the like are added and mixed to obtain a powder form. A liquid preparation can be produced by preparing an oily or aqueous suspension in almost the same manner as in the case of injection. The semi-solid preparation is preferably an aqueous or oily gel or an ointment. In addition, all of these preparations are pH regulators (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.) ) Etc. may be included.

The suppository may be oily or aqueous solid, semi-solid or liquid. The oily base used in the production of suppositories may be one that does not dissolve the fine particle formulation, such as glycerides of higher fatty acids [eg, cacao butter, Witepsols (Dynamite Nobel), etc.], intermediate fatty acids [ Examples include Miglyols (Dynamite Nobel) and vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). Also,
Examples of the aqueous base include polyethylene glycols,
Examples of propylene glycol and aqueous gel bases include natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers and the like.

In addition to the above-mentioned microcapsules, a biodegradable polymer composition in which a drug is dispersed by an appropriate method is dissolved and shaped into a spherical shape, rod shape, needle shape, pellet shape, film shape or the like. The sustained-release preparation of the present invention can also be manufactured. The biodegradable polymer composition is, for example, Japanese Patent Publication No.
It is manufactured according to the method described in Japanese Patent Publication No. 17525. More specifically, the biodegradable polymer composition can be produced by dissolving the drug and the polymer in a solvent and removing the solvent by an appropriate method (eg, spray drying, flash evaporation, etc.). The sustained-release preparation of the present invention is an intramuscular, subcutaneous, or injectable or implantable agent for organs, a transmucosal agent for nasal cavity, rectum, uterus, etc., oral agent [eg, capsule (eg, hard capsule, Soft capsules), granules,
Solid preparations such as powders, syrups, emulsions, liquids such as suspensions, etc.] and the like. The sustained-release preparation of the present invention is preferably used for injection.

The sustained-release preparation of the present invention has low toxicity and can be safely used for mammals (eg, human, cow, pig, dog, cat, mouse, rat, rabbit, etc.). The dose of the sustained-release preparation varies depending on the type and content of the drug, the dosage form, the duration of drug release, the target disease, the target animal, etc.
Any effective amount of drug may be used. The dose per administration of the drug is preferably about 0.01 to 100 mg / kg body weight per adult when the sustained-release preparation is a one-month preparation. More preferably, about 0.05 to 50 mg
/ Kg body weight. Particularly preferred is about 0.1 to 10
mg / kg body weight. The dose of the sustained release preparation is preferably about 0.1 mg to 500 mg per adult.
It can be appropriately selected from the range of / kg body weight. More preferably, it can be appropriately selected from the range of about 0.2 mg to 300 mg / kg body weight. Administration frequency is once every few weeks, 1
Once a month or once every several months, it can be appropriately selected depending on the type and content of drug, dosage form, duration of drug release, target disease, target animal and the like.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Experimental Examples, but these do not limit the present invention. Hereinafter,% means% by weight unless otherwise specified. Reference Example 1 300 g of 90% D, L-lactic acid aqueous solution and 90% L were placed in a 1000 ml four-necked flask equipped with a nitrogen introducing tube and a cooling tube.
-Preparation of 100 g of lactic acid aqueous solution, 100 ° C under nitrogen stream,
Distilled water was removed by heating under reduced pressure from 500 mmHg to 150 ° C. and 30 mmHg for 4 hours. Furthermore, 3-5
After heating under reduced pressure at 150 to 180 ° C. for 10 hours in mmHg, it was cooled to obtain amber polylactic acid. The polymer obtained is 1
It was dissolved in 000 ml of dichloromethane and poured into warm water of 60 ° C. at a constant rate with stirring. The rice cake-like high molecular weight polymers that separated were collected and vacuum dried at 30 ° C. The weight average molecular weight and number average molecular weight of the obtained polylactic acid by GPC measurement and the number average molecular weight by end group quantification were 4, and
Since it was 200, 2,192, and 1,572, it was confirmed that the polyester had a terminal carboxyl group. Reference Example 2 182.5 g of glycolic acid and 166.6 g of D, L-2-hydroxybutyric acid were charged into a 1000 ml four-necked flask equipped with a nitrogen introducing tube and a cooling tube, and the mixture was heated to 100 under a nitrogen stream.
Distilled water was removed by heating under reduced pressure from 500 ° C., 500 mmHg to 150 ° C., 30 mmHg over 3.5 hours. Further, it was heated under reduced pressure at 5 to 7 mmHg and 150 to 180 ° C. for 32 hours and then cooled to obtain an amber glycolic acid-2-hydroxybutyric acid copolymer. 1000 m of the obtained polymer
It was dissolved in 1 l of dichloromethane and poured into warm water of 60 ° C. at a constant rate with stirring. The rice cake-like high molecular weight polymers that separated were collected and vacuum dried at 25 ° C. The obtained glycolic acid-2-hydroxybutyric acid copolymer had a terminal carboxyl group because the weight average molecular weight and number average molecular weight by GPC measurement and the number average molecular weight by end group quantification were 14,700, 5,700 and 2,400, respectively. It was confirmed to be polyester.

Reference Example 3 4.4 g of an equal mixture of the glycolic acid-2-hydroxybutyric acid copolymer obtained in Reference Example 2 and the methyl ester of polylactic acid obtained in Example 1 was added to 9.1 g of dichloromethane.
(7.0 ml) and was further dissolved in US Pat.
NAcD2Nal-D4ClPhe-D produced by the method described in No. 04
3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Nisp) -Pro-DAlaNH
₂ (manufactured by TAP, hereinafter abbreviated as bioactive peptide A)
600 mg of acetate salt of was dissolved. The resulting solution was poured into 1000 ml of a 0.1% polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry) aqueous solution which had been adjusted to 17 ° C. in advance, and a turbine homomixer was used for 7,000 r.
It was made into an O / W emulsion at pm. The obtained O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane to solidify the oil phase, and then centrifuge (05PR-2).
(2, Hitachi, Ltd.) and collected at 1500 rpm.
This was dispersed in distilled water and further centrifuged to wash free drug and the like. A small amount of distilled water was added to the collected microcapsules to re-disperse them, and then D-mannitol 0.1.
3 g was added and the dispersion was freeze-dried to obtain microcapsules as powder. The content rate of the physiologically active peptide A in the microcapsules was 9.3%. Reference Example 4 Lactic acid / glycolic acid copolymer having a weight average molecular weight of 5,100 (lactic acid / glycolic acid = 50/50 (mol%)) (manufactured by Wako Pure Chemical Industries) and the ethyl ester of lactic acid / glycolic acid obtained in Example 2 1.0 g of an equal mixture with and was dissolved in 2.0 g (1.5 ml) of dichloromethane, and human interferon alfa (7.0 × 10 ⁷ international units / mg) was added.
0 mg was dispersed. The obtained dispersion liquid was adjusted to 17 ° C. with 0.1% polyvinyl alcohol (EG-4
0, manufactured by Nippon Synthetic Chemical Industry) poured into 300 ml of an aqueous solution, and O / W at 6500 rpm using a turbine homomixer
It was an emulsion. The obtained O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane to solidify the oil phase, and then collected at 1500 rpm using a centrifuge (05PR-22, Hitachi Ltd.). This was again dispersed in distilled water and then centrifuged to wash free drug and the like. A small amount of distilled water was added to the collected microcapsules for redispersion, 50 mg of D-mannitol was added, and the dispersion was freeze-dried to obtain microcapsules as powder. The activity of human interferon alfa in the microcapsules was 5.75 × 10 ⁵ (international unit / mg microcapsules).

Reference Example 5 1.0 g of the ethyl ester of lactic acid / glycolic acid obtained in Example 2 was dissolved in 2.0 g (1.5 ml) of dichloromethane, and human interferon alfa (2.0
× 10 ⁸ international units / mg) 40 mg was dispersed. The resulting dispersion is poured into 300 ml of a 0.1% polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry) aqueous solution which has been adjusted to 17 ° C. in advance, and O / W is performed at 6500 rpm using a turbine homomixer. It was an emulsion. The obtained O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane to solidify the oil phase, and then 1500 rpm using a centrifuge (05PR-22, Hitachi Ltd.).
collected by m. This was again dispersed in distilled water and then centrifuged to wash free drug and the like. After a small amount of distilled water was added to the collected microcapsules to redisperse them, D-
Add 50 mg mannitol, freeze-dry the dispersion,
Microcapsules were obtained as a powder. The activity of human interferon alpha in microcapsules is 2.48x
It was 10 ⁶ (international unit / mg microcapsule).

Reference Example 6 Lactic acid / glycolic acid copolymer having a weight average molecular weight of 5,100 (lactic acid / glycolic acid = 50/50 (mol%)) (manufactured by Wako Pure Chemical Industries) and lactic acid / glycolic acid obtained in Example 2 0.9 g of an equal amount mixture with the ethyl ester was dissolved in 2.0 g (1.5 ml) of dichloromethane, and 100 mg of recombinant insulin (manufactured by Wako Pure Chemical Industries) was dispersed.
The resulting dispersion was adjusted to 18 ° C. with 0.1% polyvinyl alcohol (EG containing 5% mannitol).
-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) was poured into an aqueous solution (350 ml), and an O / W emulsion was prepared at 6500 rpm using a turbine homomixer. The resulting O / W emulsion was stirred at room temperature for 3 hours to evaporate dichloromethane,
After solidifying the oil phase, it was collected at 1500 rpm using a centrifuge (05PR-22, Hitachi Ltd.). This was again dispersed in distilled water and then centrifuged to wash free drug and the like. After adding a small amount of distilled water to the collected microcapsules to redisperse them, D-mannitol 50 mg
Was added and the dispersion was freeze-dried to obtain microcapsules as powder (476 mg). The insulin content in the microcapsules was 7.95%. Reference Example 7 Lactic acid / glycolic acid copolymer having a weight average molecular weight of 5,000 (lactic acid / glycolic acid = 50/50 (mol%)) (manufactured by Wako Pure Chemical Industries) and the ethyl ester of lactic acid / glycolic acid obtained in Example 2. 4.5 g (5.0 ml) of dichloromethane was mixed with 4.5 g of an equal mixture with and N- (S) -Te was added to this solution.
trahydrofur-2-oyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeT
Acetate salt of yr-DLys (Nic) -Leu-Lys (Nisp) -Pro-DAlaNH ₂ (manufactured by TAP, hereinafter abbreviated as bioactive peptide B) 50
A solution prepared by dissolving 0 mg in 0.6 ml of distilled water was added, and mixed for 60 seconds with a turbine homomixer to obtain a W / O emulsion. After cooling this W / O emulsion to 16 ° C., an aqueous solution of 0.1% polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry) 10 adjusted to 16 ° C. in advance.
It was poured into 100 ml and made into a W / O / W emulsion at 7,000 rpm using a turbine homomixer. The obtained W / O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane to solidify the W / O emulsion, and then collected at 2000 rpm using a centrifuge (05PR-22, Hitachi Ltd.). did. Hereinafter, in the same manner as in Example 1, microcapsules were obtained as a powder. Content of bioactive peptide B in the microcapsules is 9.2%
Met.

Comparative Example 1 1.5 g of a lactic acid / glycolic acid copolymer having a weight average molecular weight of 5,100 (lactic acid / glycolic acid = 50/50 (mol%)) (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 2.6 g of dichloromethane (2.0 m).
It was dissolved in 1) and further dispersed with 60 mg of human interferon alfa (1.5 × 10 ⁸ international units / mg). The resulting dispersion is poured into 300 ml of a 0.1% polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry) aqueous solution which has been adjusted to 17 ° C. in advance, and O / W is performed at 6500 rpm using a turbine homomixer. It was an emulsion. The obtained O / W emulsion was stirred at room temperature for 3 hours to volatilize dichloromethane to solidify the oil phase, and then collected at 1500 rpm using a centrifuge (05PR-22, Hitachi Ltd.). This was again dispersed in distilled water and then centrifuged to wash free drug and the like. A small amount of distilled water was added to the collected microcapsules for redispersion, 50 mg of D-mannitol was added, and the dispersion was freeze-dried to obtain microcapsules as powder. The activity of human interferon alfa in the microcapsules was 2.24 × 10 ⁶ (international unit / mg microcapsules).

Example 1 Nitrosomethylurea 8 was added to a mixture of 168 ml of 40% potassium hydroxide aqueous solution and 824 ml of ethyl ether with stirring under ice cooling.
Add 1.5 g little by little. The resulting yellow ether layer is separated, granular potassium hydroxide is added and dried. The potassium hydroxide was removed and about 800 ml of diazomethane solution
Got 80 g of polylactic acid having a weight average molecular weight of about 5,000 produced by the same method as in Reference Example 1 was mixed with 50 g of dichloromethane.
It was dissolved in 0 ml and stirred and cooled. The above-mentioned diazomethane solution was added dropwise under ice cooling, and then the mixture was stirred at room temperature for 2 hours. After standing overnight, the solvent was distilled off under reduced pressure, and the residue was vacuum dried at room temperature to give 79 g of polylactic acid methyl ester.
Got The weight average molecular weight and number average molecular weight of the obtained methyl ester of polylactic acid by GPC measurement, and the number average molecular weight calculated from the methyl end were 5,250, respectively.
It was 2,960 and 1,820. In addition, the residual carboxyl group determined by quantitative determination of the terminal group was 0.1% or less as lactic acid, and therefore it was confirmed that the polyester had no terminal carboxyl group. Example 2 To a mixed solution of 168 ml of 40% aqueous potassium hydroxide solution and 1000 ml of ethyl ether, 104 g of nitrosoethylurea was added little by little under ice-cooling stirring. The resulting yellow ether layer was separated, and granular potassium hydroxide was added and dried. Then, the potassium hydroxide was removed and the diazoethane solution was about 900
ml was obtained. A lactic acid / glycolic acid copolymer having a weight average molecular weight of about 5,000 (lactic acid / glycolic acid = 50/50 (mol%)) (manufactured by Wako Pure Chemical Industries), 130 g of dichloromethane 19
It was dissolved in 00 ml and cooled with stirring. The above-mentioned diazoethane solution was added dropwise under ice cooling, and then the mixture was stirred at room temperature for 2 hours. After standing overnight, the solvent was distilled off under reduced pressure, and the residue was vacuum dried at room temperature to obtain 131 g of lactic acid / glycolic acid ethyl ester. The weight average molecular weight and the number average molecular weight of the obtained ethyl ester of lactic acid / glycolic acid by GPC measurement were 5,120 and 2,320, respectively. Also,
The residual carboxyl group determined by quantifying the terminal group was 0.1% or less as lactic acid, and therefore it was confirmed that the polyester had no terminal carboxyl group.

Example 3 15 g of lactic acid / glycolic acid copolymer having a weight average molecular weight of about 7,500 (lactic acid / glycolic acid = 75/25 (mol%)) (manufactured by Wako Pure Chemical Industries, Ltd.), ethyl iodide 7.8 g and acetone 15
It was dissolved in 0 ml. Potassium carbonate 1.3 in the resulting solution
8 g was added and refluxed for 6 hours. After cooling the reflux liquid, inorganic substances were filtered, and the filtrate was concentrated under reduced pressure. Dissolve the concentrate in 100 ml of dichloromethane and add 10m ethanol water 100m.
It was washed 3 times with 1 and dried over magnesium sulfate. Magnesium sulfate was filtered off and concentrated to dryness under reduced pressure to obtain 12.5 g of ethyl ester of lactic acid / glycolic acid copolymer. G of the obtained ethyl ester of lactic acid / glycolic acid
The weight average molecular weight and number average molecular weight measured by PC were 5,330 and 3,220, respectively. In addition, the residual carboxyl group determined by quantitative determination of the terminal group was 0.1% or less as lactic acid, and therefore it was confirmed that the polyester had no terminal carboxyl group.

Example 4 9 g of a lactic acid / glycolic acid copolymer having a weight average molecular weight of about 7,500 (lactic acid / glycolic acid = 75/25 (mol%)) (manufactured by Wako Pure Chemical Industries, Ltd.) and 20 ml of dichloromethane and ethanol 2
It was dissolved in a mixed solvent with 0 ml. The resulting solution was stirred and cooled while adding 0.45 ml of triethylamine, 0.29 ml of ethyl chloroformate, and 0.36 g of N, N-dimethylaminopyridine, stirring for 2 hours, and then adding 50 ml of dichloromethane and 50 ml of water, The dichloromethane layer was separated. The dichloromethane layer was washed twice with 50 ml of 10% ethanol water and then dried over magnesium sulfate. Magnesium sulfate was filtered off, concentrated to dryness under reduced pressure,
Ethyl ester of lactic acid / glycolic acid copolymer 7.7 g
Got The weight average molecular weight and the number average molecular weight of the obtained ethyl ester of lactic acid / glycolic acid by GPC measurement were 9,220 and 5,230, respectively. In addition, the residual carboxyl group determined by quantitative determination of the terminal group was 0.1% or less as lactic acid, and therefore it was confirmed that the polyester had no terminal carboxyl group.

Example 5 6 g of a lactic acid / glycolic acid copolymer having a weight average molecular weight of about 7,500 (lactic acid / glycolic acid = 75/25 (mol%)) (Wako Pure Chemical Industries, Ltd.) was added to 60 ml of dichloromethane and 6 parts of ethanol.
It was dissolved in a mixed solvent with 0 ml. 3.83 g of 1-ethyl-3- (3-dimethylaminoisopropyl) -carbodiimide hydrochloride was added to the resulting solution with stirring and cooling, and the mixture was stirred overnight. 50 ml of water was added and the dichloromethane layer was separated. Dichloromethane layer 40% 10% ethanol water
It was washed twice with and dried over magnesium sulfate. Magnesium sulfate was filtered off and concentrated to dryness under reduced pressure to obtain 5.2 g of ethyl ester of lactic acid / glycolic acid copolymer. The weight average molecular weight and number average molecular weight of the obtained ethyl ester of lactic acid / glycolic acid by GPC measurement are respectively
It was 6,620 and 3,350. In addition, the residual carboxyl group determined by quantitative determination of the terminal group was 0.1% or less as lactic acid, and therefore it was confirmed that the polyester had no terminal carboxyl group.

Experimental Example 1 About 14 mg of the microcapsules obtained in Reference Example 3 (1.35 mg as bioactive peptide A) was dispersed in a dispersion medium (2.5
0.5 mg of carboxymethylcellulose, 0.5 mg of polysorbate 80, and 25 mg of mannitol in distilled water) were dispersed in 0.5 ml, and the mixture was subcutaneously administered to the back of 10-week-old male SD rats with a 22G injection needle. Blood is collected from the rat tail at regular time intervals after administration, and the results of quantifying physiologically active peptide A in the blood by the RIA method are shown in [Table 1].

[Table 1] ---------------------------------------------- ----------------------- Physiologically active peptide A concentration (ng / ml) ----------------- -------------------------------------------------- --1 day 1 week 2 weeks 3 weeks 4 weeks 6 weeks ------------------------------------ --------------------------------- Example 1 1.75 4.41 4.31 3.19 2.43 0.76 -------- -------------------------------------------------- ----------- By using polylactic acid in which the terminal carboxyl group is esterified with methyl group, the drug concentration in the blood on the first day after administration is low, and the initial release after administration is extremely high. It turned out to be few. In addition, the blood concentration was almost constant for one month thereafter, and the sustained release was also good.

Experimental Example 2 About 87 mg of the microcapsules obtained in Reference Example 4 (5.0 × 10 ⁷ international units of human interferon alfa) was used as a dispersion medium (2.5 mg of carboxymethyl cellulose, 0.5 mg of polysorbate 80, 25 mg). 0.5 ml of distilled water in which mannitol was dissolved) was subcutaneously administered to the back of 8-week-old male SD rats by a 22G injection needle. Blood was collected from the rat tail at regular intervals after administration, and EIA was performed.
The results of quantifying human interferon alpha in blood by the method are shown in [Table 2]. Experimental Example 3 Using the microcapsules obtained in Comparative Example 1, Experimental Example 2
The results of quantifying human interferon alpha in blood in the same manner as in [Table 2] are shown in [Table 2].

[Table 2] ---------------------------------------------- ---------------------- Human interferon alpha concentration (international unit / ml) ------------------ -------------------------------------------------- -3 hours 6 hours 1 day 2 days 3 days 7 days 9 days ----------------------------------- ---------------------------------- Experimental Example 2 5042.6 3934.3 162.3 122.6 139.9 113.8 43.8 Experimental Example 3 5127.2 6121.6 65.9 42.9 32.3 1.9 0.0 --------------------------------------------------- ----------------------- Use of a lactic acid / glycolic acid copolymer with an ethyl end carboxyl group suppresses the initial release after administration However, the blood concentration in the steady state was kept high and the sustained release was also good.

Experimental Example 4 About 20 mg of the microcapsules obtained in Reference Example 5 (5.0 × 10 ⁷ international units of human interferon alpha) was dispersed in a dispersion medium (2.5 mg of carboxymethyl cellulose, 0.5 mg of polysorbate 80, 25 mg). 0.5 ml of distilled water in which mannitol was dissolved) was administered subcutaneously to the back of 8-week-old male SD rats with a 22G injection needle. Blood was collected from the rat tail at regular intervals after administration, and EIA was performed.
Method was used to quantify human interferon alfa in blood. Although the dose per rat was almost the same as in Experimental Example 2, the concentration of human interferon alpha in the blood was maintained at 133 international units / ml even 14 days after the administration. The use of a lactic acid / glycolic acid copolymer in which the terminal carboxyl group was ethylated resulted in good sustained release.

The ester of the present invention can be used as a base for sustained-release preparations. The sustained-release preparation base is light,
It is stable to heat, moisture, coloring, etc. and has low toxicity. The sustained-release preparation produced using the ester of the present invention shows a constant release of the drug over a long period of time, and a sustained and stable effect is obtained. Moreover, the excessive release of the drug immediately after administration of the sustained-release preparation is small.

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shigeru Kamei 1-7-509 Sumiregaoka, Takarazuka City, Hyogo Prefecture (72) Inventor Masahisa Oka 1-2F1204, Nakagawa, Tsuzuki-ku, Yokohama City, Kanagawa Prefecture (72) Inventor Sano Atsunori Saitama Prefecture Tsurugashima City Matsugaoka 3-chome 25-3 (56) Reference JP-A-7-278018 (JP, A) JP-A-5-112468 (JP, A) (58) Fields investigated (Int.Cl. ⁷⁾ , DB name) A61K 47/34 C08G 63/00-63/91

Claims (4)

(57) [Claims] 1. A consists α- hydroxy monocarboxylic acid, a to 5 0,000 1, 500 weight average molecular weight, poly esters terminal carboxyl group of the linear polyester are esterified with a terminal carboxyl group. Poly ester of claim 1 wherein the glycolic acid copolymer - 2. A linear polyester lactate. 3. A poly ester according to claim 1, wherein the ester of the terminal carboxyl groups are alkyl <br/> glycol ester. 4. A poly S. <br/> ether according to claim 3, wherein the alkyl group of the alkyl ester is an alkyl group having 1 to 3 carbon atoms.