JP3491075B2 - Fine particle preparation and production method thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug sustained-release fine particle preparation and a method for producing the same.

[0002]

2. Description of the Related Art As one method for producing a fine particle preparation such as sustained-release microcapsules containing a water-soluble drug, an underwater drying method is conventionally known. In the method of forming a three-phase emulsion according to the conventional technology described in Japanese Patent Application Publication No. H11-27139 and manufacturing microcapsules by an in-water drying method, the water-soluble drug is distributed to the outer aqueous phase, so that the trapping rate in the fine particle preparation is reduced. Therefore, it is difficult to obtain a high-content preparation. In general, microparticle preparations manufactured by the underwater drying method have large variations in the trap rate among lots, and also have a large initial release amount, are greatly affected by scale-up, and it is difficult to maintain a constant quality. The spray drying method is also known. When a fine particle preparation is produced by this method, the problem of the trap rate is small, but generally the initial release is large.
There is much adhesion and aggregation between the fine particle preparations, and the fine particle preparations adhere to the spray dryer. There is a problem that the fine particle preparation has a poor dispersibility in an aqueous dispersion medium as compared with a dried product in water.

[0003]

[Means for Solving the Problems] In view of such circumstances,
The present inventors have conducted intensive studies in order to obtain a water-soluble or liposoluble sustained-release preparation with low adhesion and aggregation between fine particle preparations such as microcapsules and the like. A solution containing a polymer, (2) a solution in which a part or all of a drug or a polymer or both are in a dispersed state, and (3) a solution containing a drug or a polymer or both in O / W, The W / O, W / O / W, O / W / O type emulsion, or (4) a liquid containing a drug or a polymer or both are in the emulsified state of (3), and the drug or The polymer polymer or the liquid in which part or all of both are dispersed are sprayed from the nozzle of the spray dryer (two-fluid nozzle, multi-fluid nozzle or pressure nozzle or two-fluid, rotating disk structured for multi-liquid spray) Atomization and spraying,
By spraying a non-adhesive water-soluble inorganic salt, organic acid or organic acid salt solution for preventing aggregation of microparticle preparations such as microcapsules from another nozzle, adhesion and aggregation between the microparticle preparations is reduced, It has been found that a fine particle preparation having a high trapping rate in a fine particle preparation and excellent properties with a small initial release amount in a release test can be efficiently and continuously obtained in a large amount in a short time. The solution of the water-soluble inorganic salt, organic acid or organic acid salt may be a dispersion of the water-soluble inorganic salt, organic acid or organic acid salt.

When spraying a solution of a water-soluble inorganic salt, organic acid or organic acid salt for preventing aggregation, a nonionic surfactant is added to a non-adhesive substance solution and sprayed. Spraying a non-ionic surfactant solution simultaneously with the dispersion or solution of a water-soluble inorganic salt, organic acid or organic acid salt at the time of forming the fine particle preparation to obtain a fine particle preparation exhibiting better dispersibility And found that the present invention was completed. That is,
The present invention relates to a water-soluble inorganic salt, an organic acid or an organic acid salt,
An object of the present invention is to provide a drug-containing high molecular polymer fine particle preparation which is at least partially or completely coated. Further, the present invention provides that a polymer solution containing a drug and a solution of a water-soluble inorganic salt, an organic acid or an organic acid salt are sprayed and contacted in a spray dryer using separate nozzles. Another object of the present invention is to provide a method for producing a drug-containing polymer fine particle preparation which is at least partially or completely coated with a water-soluble inorganic salt, organic acid or organic acid salt. In the production method of the present invention, a water-soluble inorganic salt,
A fine particle preparation having better dispersibility by adding a nonionic surfactant to a solution of an organic acid or an organic acid salt and spraying the solution or separately spraying and contacting a solution of a nonionic surfactant. Is obtained.

According to the present invention, a solution, emulsion or suspension containing a drug and a high molecular weight polymer is sprayed and dried using a spray drier, so that water is instantaneously volatilized together with an organic solvent. It is possible to manufacture a fine particle preparation such as a microcapsule having an appropriate and strong structure without losing the drug, and it is possible to suppress the initial release amount of the drug in the release test to be lower than that by the underwater drying method . Simultaneously or in advance, by spraying a solution of a water-soluble inorganic salt, an organic acid or an organic acid salt as an anti-agglomeration agent from the other nozzle to prevent aggregation of the fine particle preparation, Fine particles of an organic acid or an organic acid salt cover at least partially or completely around the surface of the fine particle preparation, and significantly prevent aggregation between the fine particle preparations and adhesion of the fine particle preparation to the spray dryer device,
Fine powder particles having excellent fluidity can be obtained in a short time without a freeze-drying step. Further, by spraying a nonionic surfactant solution together with or separately from a water-soluble inorganic salt, organic acid or organic acid salt at the same time as the polymer solution, the surfactant coats the surface of the fine particle preparation, It shows very excellent dispersibility when the formulation is dispersed.

Hereinafter, the present invention will be described in more detail. Specific examples of the fine particle preparation include, for example, microcapsules and the like. Of these, microcapsules are most preferred. The drug used in the fine particle preparation of the present invention is not particularly limited, but includes, for example, peptides having a physiological activity, other antibiotics, antitumor agents, antipyretics, analgesics, anti-inflammatory agents, antitussives, sedatives, muscle relaxation Agents, antiepileptic agents, antiulcer agents, antidepressants, antiallergic agents, cardiotonic agents, antiarrhythmic agents, vasodilators antihypertensive diuretics, antidiabetic agents, anticoagulants,
Examples include hemostatic agents, antituberculous agents, hormonal agents, narcotic antagonists, bone resorption inhibitors, angiogenesis inhibitors, and the like. Among them, a peptide having a physiological activity, a bone resorption inhibitor, and an angiogenesis inhibitor are mentioned as preferred agents. The physiologically active peptide is composed of two or more amino acids, and preferably has a molecular weight of about 200 to 80,000. Specific examples thereof include, for example, luteinizing hormone-releasing hormone (LH-RH), a derivative having a similar action, and represented by the formula (I):

[0007]

(Pyr) Glu-R ¹ -Trp-Ser-R ² -R ³ -R ⁴ -Arg-Pro-R ⁵ (I) wherein R ¹ is His, Tyr, Trp or p-NH ₂ -Phe
R ² is Tyr or Phe, R ³ is a Gly or D type amino acid residue, R ⁴ is Lue, Ile or Nle, R ₅ is G
ly-NH-R ⁶ (R ⁶ is H or, if desired, a lower alkyl group having a hydroxyl group) or NH-R ⁶ (R ⁶ is as defined above), respectively. And salts thereof [US Pat. Nos. 3,853,837, 4,008,209, 3,972,859, British Patent 1,423,083 and Proceedings of the National Academy of Sciences
(Proceedings of the National Academy of
Sciences of the United States of America)
78, pages 6509-6512 (1981)]. In the above formula (I), examples of the D-type amino acid residue represented by R ³ include α-D- having up to 9 carbon atoms.
Amino acids [eg, D- (Lue, Ile, Nle, Val, NVa
l, Abu, Phe, Phg, Ser, Tyr, Met, Ala, Tr
p, α-Aibu)] and the like.
(Eg, t-butyl, t-butoxy, t-butoxycarbonyl, etc.). Of course, the acid salt of the peptide (I) and the metal complex compound can be used in the same manner as the peptide (I). Abbreviations used for amino acids, peptides, protecting groups, and the like in the peptide represented by the formula (I) are IU
PAC-IUB Commission on Biochemical
Nomenclature (Commission on Biochemica)
l Nomenclature) or abbreviations commonly used in the art. For amino acids, if there is an optical isomer, L
Show body. In this specification, in the above formula (I), R ¹ = His, R ² = Tyr, R ³ = D-Leu, and R ⁴ = Le.
u, an acetate of peptide is R ⁵ = NHCH ₂ -CH ₃ is referred to as "TAP-144".

The peptides include LH-RH antagonists (US Pat. Nos. 4,086,219 and 41,245).
Nos. 77, 4259397 and 431781
No. 5). Further, as the peptide, for example, insulin, somatostatin, somatostatin derivatives (U.S. Pat. Nos. 4,087,390 and 40,390)
No. 93574, No. 4100117 and No. 425
No. 3998), growth hormone, prolactin, adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone (MSH), thyroid hormone-releasing hormone (TRH), its salts and derivatives (Japanese Patent Application Laid-Open Nos. 50-112273, 52). -116465), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), vasopressin, a vasopressin derivative {desmopressin [Japan Endocrine Society, Vol. 54, No. 5, No. 676- 691 (1978)], oxytocin,
Calcitonin, parathyroid hormone, glucagon, gastrin, secretin, pancreozymine, cholecystokinin, angiotensin, human placental lactogen, human chorionic gonadotropin (HCG), enkephalin, enkephalin derivative [US Pat. No. 4,277,394, European Patent Application Publication No. 31567] and oligopeptides such as endorphin, kyotorphin,
Interferon (α type, β type, γ type), interleukin (I, II, III), tuftsin, thymopoietin, thymosin, thymostymulin, thymic humoral factor (T
HF), blood thymic factor (FTS) and its derivatives (see US Pat. No. 4,229,438), and other thymic factors
[Ayumi of Medicine, Vol. 125, No. 10, 835-84
3 (1983)], tumor necrosis factor (TNF), colony-inducing factor (CSF), motilin, dinorphin, pombesin, neurotensin, caerulein, bradykinin, urokinase, asparaginase, kallikrein,
Substance P, nerve growth factor, blood coagulation factor VI
Factor II, Factor IX, lysozyme chloride, polymyxin B, colistin, gramicidin, bacitracin, protein synthesis stimulating peptide (UK Patent No. 823,022), gastric acid secretion inhibitory polypeptide (GIP), vasoactive intestin polypeptide (vasoactive intestin)
al polypeptide: VIP), platelet-derived growth factor
Activator: PDGF, peptides such as growth hormone secreting factor (GRF, somatocrinin), bone morphagenetic protein (BMP) and epidermal growth factor (EGF).

The above antitumor agents include, for example, bleomycin hydrochloride, methotrexate, actinomycin D,
Mitomycin C, vinblastine sulfate, vincristine sulfate, daunorubicin hydrochloride, adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil,
Picibanil, lentinan, levamisole, bestatin, azimexone, glycyrrhizin, poly I: C, poly A: U, poly ICLC and the like. Examples of the above antibiotics include, for example, gentamicin, dibekacin, canedomycin, ribidomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, lolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephaloridine, Examples include cefotiam, cefsulodin, cefmenoxime, cefmetazole, cefazolin, cefataxime, cefoperazone, ceftizoxime, moxolactam, thienamycin, sulfazecin, azuleonam or a salt thereof. Examples of the above antipyretic, analgesic, and anti-inflammatory agents include, for example, salicylic acid, sulpyrine, flufenamic acid, diclofenac, indomethacin, morphine, pethidine, levorphanol tartrate, oxymorphone, and the like, as antitussive antitussives, for example, ephedrine,
Methylephedrine, noscapine, codeine, dihydrocodeine, alloclamide, chlorphedianol, picoperidamine, cloperastine, protochlorol, isoproterenol, salbutanol, terbutaline or a salt thereof, and the like, as an analgesic, for example, chlorpromazine, prochlorperazine , Trifloperazine, atropine, scopolamine or salts thereof, as muscle relaxants, for example, pridinol, tubocurarine, pancuronium and the like, as antiepileptic agents, for example, phenytoin, ethosuximide, acetazolamide, chlordiazepoxide and the like, respectively. Can be

The above-mentioned anti-ulcer agents include, for example, metoclopromide and histidine, and the antidepressants include, for example, imipramine, clomipramine, noxiptiline,
Phenelzine and the like, as anti-allergic agents, for example, diphenhydramine, chlorpheniramine, tripelenamine, methdilazine, clemizole, diphenylpyraline, methoxyphenamine and the like, as cardiotonic agents,
For example, trans-bioxo camphor, terephyllol, aminophylline, etilephrine and the like, as an arrhythmia therapeutic agent, for example, propranol, alprenolol, bufetrol oxyprenolol and the like, as a vasodilator, for example, oxyfedrine , Diltiazem, tolazoline, hexobendine, bamethane and the like, as antihypertensive diuretics, for example, hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine and the like, as antidiabetic agents, for example, glymidine, glibizide, phenformin , Buformin, metformin and the like; anticoagulants such as heparin and citrate; and hemostatic agents such as thromboplastin, thrombin, menadione, acetomenaphthone, ε- Minokapuron acid, tranexamic acid, carbazochrome sulfonate, and adrenochrome chromium mono aminoguanidine, as antituberculosis agents, for example, isoniazid, ethambutol, and p-aminosalicylic acid, as a hormonal agent such as, prednisolone,
Prednisolone, dexamethasone, betamethasone, hexestrol, methimazole, and the like; narcotic antagonists, for example, levallorphan, nalorphine, naloxone or a salt thereof; and bone resorption inhibitors, (sulfur-containing alkyl) aminomethylenebisphosphone Acids are angiogenesis inhibitors, angiogenesis inhibitors
[Science Vol. 221 p. 719 (1983)
Year)), fumagillin (European Patent Publication No. 325)
199) and fumagillol derivatives (see European Patent Publication Nos. 357061, 359036, 386667, and 415294). Of these, the present invention is more preferably applied to water-soluble drugs, since excessive initial release is often observed in the case of water-soluble drug preparations. The water solubility of a drug is defined as the oil-water partition ratio between water and n-octanol, where the n-octanol / water solubility ratio is 1
Application to the following drugs is preferred, and application to drugs below 0.1 is more preferred.

[0011] The measurement of the oil-water partition ratio is performed by the "physical chemistry experiment method".
The method may be in accordance with the method described in Jimaburo Samejima, published by Shokabo, 1961. That is, first, a buffer solution of n-octanol and pH 5.5 (a 1: 1 equivalent mixture) is placed in a test tube. As the buffer, for example, Zelensen (Sφer
enzen) buffer [Ergeb. Physiol. 12 , 393 (191)
2)], Clark-Lubs buffer [J. Bact.
2 (1), 109, 191 (1917)], Macllvaine buffer [J. Biol. Chem. 49 , 183].
(1921)], Michaelis buffer [Die W
asser-stoffionenkonzentration. p. 186 (191
4)], Kolthoff buffer [Biochem. Z. 17
9 , 410 (1926)]. These drugs are added in appropriate amounts, and further stoppered, and a thermostat (25 ° C.)
And often shake vigorously. When the drug dissolves between the two liquid layers and seems to have reached equilibrium, the liquid is allowed to stand or centrifuged, and a certain amount of liquid is separately taken from each of the upper and lower layers with a pipette. By determining the concentration of the drug in the solution and taking the ratio of the concentration of the drug in the n-octanol layer / the concentration of the drug in the aqueous layer, the oil-water distribution ratio is obtained. The drug may be itself or a pharmaceutically acceptable salt. As the pharmaceutically acceptable salt, for example,
When the drug has a basic group such as an amino group, salts with inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, etc.) and organic acids (eg, carbonic acid, citric acid, etc.) can be mentioned. When it has an acidic group, such as an inorganic base (eg, an alkali metal such as sodium or potassium), a basic organic compound (eg, triethylamine, pyridine, etc.), a salt with a basic amino acid (eg, arginine, histidine, etc.) Is mentioned.

The amount of the drug used depends on the kind of the drug, the desired pharmacological effect and the duration of the effect, and can be appropriately selected depending on the use of each fine particle preparation. For example,
In the production of a fine particle preparation, the drug concentration is usually about 0.001% to 70% (W / W), more preferably about 0.001% to 70% (W / W).
It is selected from the range of 01% to 50% (W / W). The high molecular weight polymer used in the fine particle preparation of the present invention is a poorly water soluble or insoluble high molecular weight polymer that is biocompatible. The term “slightly water soluble” means that the solubility in water is 3% (w / w) means: The amount of the polymer used depends on the strength of the pharmacological activity of the drug, the rate and duration of drug release, and the like. For example, the polymer is prepared in an amount of about 0.5 to 10,000 times (weight ratio) to the drug, and preferably about 1 to 100 times (weight ratio) of the polymer is used.

The number average molecular weight of the high molecular weight polymer is about 3.0
The thing of 00-30,000 is preferable. About 5,000
0 to 25,000, preferably about 5,000 to 2
The one of 000 is particularly preferred. As used herein,
The weight average molecular weight and the degree of dispersion were determined by gel permeation chromatography (G
PC). For the measurement, GPC column KF804 × 2 (manufactured by Showa Denko) was used, and chloroform was used as a mobile phase. Examples of the high molecular weight polymer include, for example, a polyfatty acid ester [eg, a homopolymer of fatty acid (eg, polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, etc.) as a biodegradable type; Copolymers (eg, lactic acid / glycolic acid copolymer, 2-hydroxybutyric acid / glycolic acid copolymer, etc.), and mixtures thereof (eg, mixtures of polylactic acid and 2-hydroxybutyric acid / glycolic acid copolymer) Here, as the fatty acid, for example, α-hydroxy fatty acid (eg, glycolic acid, lactic acid,
Hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methylbutyric acid, 2-hydroxycaproic acid, 2-
Hydroxyisocaproic acid, 2-hydroxycapric acid, etc.) Cyclic dimers of α-hydroxy fatty acids (eg, glycosides, lactides, etc.), hydroxydicarboxylic acids (eg, malic acid, etc.), hydroxytricarboxylic acids (eg, citric acid, etc.) )], Poly-α-cyanoacrylate,
Poly-hydroxybutyric acid, polyalkylene oxalate
(Eg, polytrimethylene oxalate, polytetramethylene oxalate, etc.), polyorthoester, polyorthocarbonate or other polycarbonate
(E.g., polyethylene carbonate, polyethylene propylene carbonate, etc.), polyamino acids (e.g., poly-γ-
Benzyl-L-glutamic acid, poly-L-alanine, poly-γ-methyl-L-glutamic acid and the like). Furthermore, as other high molecular weight polymer having biocompatibility, polystyrene, polyacrylic acid, polymethacrylic acid, a copolymer of acrylic acid and methacrylic acid,
Silicone polymer, dextranstearate, ethylcellulose, acetylcellulose, nitrocellulose,
Examples thereof include polyurethane, maleic anhydride copolymer, ethylene vinyl acetate copolymer, polyvinyl acetate, polyvinyl alcohol, and polyacrylamide. These polymers may be of one kind,
It may be a copolymer of two or more kinds or a simple mixture, or a salt thereof.

Among these high molecular weight polymers, polyfatty acid esters and poly-α-cyanoacrylates are preferred. Furthermore, poly fatty acid esters are particularly preferred. Among the polyfatty acid esters, a homopolymer of α-hydroxy fatty acid or a cyclic dimer of α-hydroxy fatty acid, a copolymer of two or more α-hydroxy fatty acids or a cyclic dimer of α-hydroxy fatty acid, or a mixture thereof Are preferred. Furthermore, a homopolymer of an α-hydroxy fatty acid, a copolymer of two or more α-hydroxy fatty acids, or a mixture thereof is more preferable. In particular, polylactic acid, lactic acid /
Glycolic acid copolymer, 2-hydroxybutyric acid / glycolic acid copolymer or a mixture thereof is particularly preferred.
In these α-hydroxycarboxylic acids, a D-form,
When the L-form and the D, L-form are present, any of them may be used, but the D, L-form is preferred. When a lactic acid / glycolic acid copolymer is used as the above polymer, the composition ratio is preferably about 100/0 to 50/50. When a butyric acid-glycolic acid copolymer is used, the composition ratio is about 100/0 to 50/50. 100/0 to 25/75 are preferred. The weight average molecular weight of the lactic acid / glycolic acid copolymer is about 5,000
To about 30,000 are preferred. About 5,000
Those from 0 to 20,000 are particularly preferred. Examples of the high molecular weight polymer include polylactic acid (A) and glycolic acid / 2.
When a mixture with the hydroxybutyric acid copolymer (B) is used, the mixing ratio represented by (A) / (B) is used in a range of about 10/90 to about 90/10 (weight ratio). Preferably it is in the range of about 25/75 to about 75/25 (weight ratio).

The weight average molecular weight of polylactic acid is about 5,000
To about 30,000 are preferred. About 6,000
Those from 0 to about 20,000 are particularly preferred. The glycolic acid / 2-hydroxybutyric acid copolymer preferably has a composition in which glycolic acid is about 40 to about 70 mol and the remainder is 2-hydroxybutyric acid. The weight average molecular weight of the glycolic acid / 2-hydroxybutyric acid copolymer is about 5,000.
To about 25,000 are preferred. About 5,000
Those from 0 to about 20,000 are particularly preferred. In the fine particle preparation of the present invention, as a water-soluble inorganic salt, an organic acid and an organic acid salt used as an anti-agglomeration agent, a non-adherent substance that can be administered to the human body and is a solid at room temperature is not particularly limited. Absent. Examples of the inorganic salt include alkali metal halides (eg, sodium chloride, potassium chloride, sodium bromide, potassium bromide, etc.), alkaline earth metal halides (eg, calcium chloride, magnesium chloride, etc.), ammonium halides (E.g., ammonium chloride, ammonium bromide, etc.), alkali metal carbonates or bicarbonates (e.g., sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.), and alkaline earth metal carbonates (e.g., Calcium carbonate, magnesium carbonate, etc.), ammonium carbonate, ammonium bicarbonate, and alkali metal phosphates (eg, trisodium phosphate, tripotassium phosphate, disodium hydrogenphosphate,
Dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.), diammonium hydrogen phosphate,
Examples thereof include ammonium dihydrogen phosphate, alkaline earth metal oxides (eg, magnesium oxide, calcium oxide, etc.), and alkaline earth metal hydroxides (eg, magnesium hydroxide, calcium hydroxide, etc.). Examples of the water-soluble organic acid include citric acid, tartaric acid, malic acid, succinic acid, benzoic acid, chondroitin sulfate, dextran sulfate, carboxymethylcellulose, alginic acid, pectic acid, and the like. Examples of the water-soluble organic acid salts include, for example, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, benzoic acid, chondroitin sulfate, dextran sulfate, carboxymethylcellulose, alginic acid, pectic acid, carbonic acid, bicarbonate, and alkali metals (eg, , Sodium, potassium, etc.), ammonia, salts with basic amino acids or alkaline earth metals (eg, calcium, magnesium, etc.).

Of these, water-soluble inorganic salts are particularly preferred. These water-soluble inorganic salts, organic acids and organic acid salts can be used alone or in combination of two or more at an appropriate ratio. The mixing ratio of the water-soluble inorganic salt, organic acid or organic acid salt to the high molecular weight polymer may be within a range in which the aggregation preventing effect is recognized. Specifically, the weight ratio is about 0.001 to 100 times, and more preferably about 0.0 to 100 times.
It is selected from 1 to 50 times. More preferably about 0.1 to 0.1
10 times is chosen. Further, in the present invention, a surfactant is mixed with a water-soluble inorganic salt, an organic acid or an organic acid salt solution, or sprayed simultaneously with a drug polymer solution with a nozzle different from the aggregation preventing agent. In this case, the surfactant is dispersed or coated on the surface of the fine particle preparation, and exhibits extremely excellent dispersibility when the fine particle preparation is dispersed in a dispersion medium. Preferred specific examples of the surfactant include, for example, alkylene glycols (eg, propylene glycol and the like),
Polysorbates (eg, polysorbate 40, polysorbate 60, polysorbate 80, etc.), macrogol (eg, macrogol 300, macrogol 400, macrogol 600, macrogol 1500, macrogol 4000, macrogol 6000, etc.), polyoxy Ethylene hydrogenated castor oils (eg, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 50,
Non-ionic surfactants such as polyoxyethylene hydrogenated castor oil 60) can be used, and one or more of them can be used in combination at an appropriate ratio. The compounding ratio of the surfactant to the high molecular weight polymer may be within a range in which an improvement in dispersibility is recognized. Specifically, a weight ratio of about 0.0000011 to 10 times, more preferably 0.00000005 to 5 times is selected. More preferably, 0.0001 to 0.01 times is selected.

In order to produce the fine particle preparation of the present invention, as described above, (1) a solution containing a drug and a high molecular weight polymer,
(2) a liquid in which a part or all of a drug or a polymer or both are in a dispersed state; and (3) a liquid containing a drug or a polymer or both thereof is O / W, W / O, W / O
/ W, O / W / O type emulsion, (4) Drug or high molecular weight polymer or liquid containing both is in the emulsified state of (3), and is one of drug or high molecular weight polymer or both. A part or all of the liquid in a dispersed state is atomized and sprayed from a spray dryer nozzle, and a water-soluble inorganic salt, organic acid or organic acid salt solution is sprayed from another nozzle. If desired, a nonionic surfactant may be added to a water-soluble inorganic salt, organic acid or organic acid salt solution, or a nonionic surfactant solution may be separately sprayed. The solution of the water-soluble inorganic salt, organic acid or organic acid salt is preferably an aqueous solution. More specifically, for example, in the case of a water-soluble drug, first, the water-soluble drug is dissolved in water to obtain an aqueous solution for an internal aqueous phase. The aqueous solution may contain, as a pH adjuster for maintaining the stability or solubility of the water-soluble drug, for example, an inorganic acid (eg, carbonic acid,
Phosphoric acid), organic acids (eg, acetic acid, oxalic acid, citric acid, tartaric acid, succinic acid, etc.) or their inorganic acids, alkali metal salts of organic acids, hydrochloric acid, alkali metal hydroxide (eg,
Sodium hydroxide, etc.) may be added. Further, as a water-soluble drug stabilizer, for example, albumin, gelatin, citric acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, and the like,
Alternatively, as a preservative, for example, paraoxybenzoic acid esters (eg, methyl paraben, propyl paraben), benzyl alcohol, chlorobutanol, thimerosal, and the like may be added.

The aqueous solution for the internal aqueous phase thus obtained is added to a solution (oil phase) containing a high molecular weight polymer, and then an emulsifying operation is performed to prepare a W / O emulsion. As the polymer solution, a solution obtained by dissolving a polymer in an organic solvent is used. The organic solvent has a boiling point of about 120.
Any material that dissolves a high molecular polymer at a temperature of not more than ° C may be used.
Specific examples thereof include, for example, halogenated alkanes
(E.g., dichloromethane, chloroform, chloroethane,
Trichloroethane, carbon tetrachloride, etc.), esters (eg, ethyl acetate, etc.), ethers (eg, ethyl ether, tetrahydrofuran, etc.), alcohols (eg,
Methanol, ethanol, propanol, isopropanol, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.),
Examples thereof include hydrocarbons (eg, n-hexane, cyclohexane, etc.), aromatic hydrocarbons (benzene, toluene, etc.), and the like. These organic solvents may be used as a mixture of two or more kinds at an appropriate ratio. For the emulsification operation, a known dispersion method is used. Examples of the method include an intermittent shaking method, a method using a mixer such as a puller-type stirrer or a turbine-type stirrer, a colloid mill method, a homogenizer method, and an ultrasonic irradiation method.

When the liquid containing the polymer or the drug or both is an emulsion, the ratio of the aqueous phase is preferably about 5 to 95%, more preferably about 10 to 30%.
%, But the ratio can be freely changed depending on the solvent used and the nature of the drug. In addition, a drug (which may be water-soluble or fat-soluble) and a high molecular weight polymer are dissolved in a mixture of an organic solvent or a water-miscible solvent and water, and if the drug is insoluble, a suspending operation is performed. To make an S / O suspension. As the organic solvent in this case, in addition to those described above, those having a property of being easily miscible with water may be used. Examples thereof include acetone, acetonitrile, tetrahydrofuran, dioxane, pyridine, and alcohols. You may mix and use more than types. Alternatively, a mixed solution of the above-mentioned organic solvent and water, which can uniformly dissolve the drug and the polymer, may be used in an appropriate ratio. At this time, the ratio of water is about 1 to 99%, preferably about 5 to 90%, and more preferably about 10 to 30%. You can change it freely.

Next, the emulsion, suspension, solution or suspension emulsion thus prepared is sprayed into a drying chamber of a spray drier using a nozzle, and the organic solvent in the atomized droplets is extremely shortly discharged. And water are volatilized to prepare a particulate fine particle preparation. Nozzles include a two-fluid nozzle type, a multi-fluid nozzle type, a pressure nozzle type, a rotating disk type, and the like. In the present invention, a water-soluble inorganic salt, organic acid, or organic acid salt solution is sprayed simultaneously from another nozzle or in advance from the same nozzle or another nozzle for the purpose of preventing aggregation of the fine particle preparation. Preferably,
Two nozzles are installed, one of which sprays an emulsion, suspension, aqueous solution or suspension emulsion of a drug and a polymer, and the other from which a water-soluble inorganic salt, organic acid or organic acid salt is sprayed. To uniformly disperse the water-soluble inorganic salt, organic acid or organic acid salt on the surface of the fine particle preparation. When a two-fluid nozzle or a pressure nozzle is used as the nozzle, two nozzles may be installed at the center of the spray dryer, but a liquid of a polymer of a drug and a water-soluble inorganic salt, organic acid or organic acid salt may be used. So that they can be sprayed separately without mixing in the nozzle
Various nozzles having a structure for spraying liquid may be used. At this time, a nonionic surfactant may be added to the water-soluble inorganic salt, organic acid or organic acid salt as described above. In addition, a water-soluble inorganic salt, an organic acid or an organic acid salt solution and a non-ionic surfactant in water or an organic solvent solution or dispersion as described above are combined with a drug polymer polymer solution. Spray at the same time.

The spraying conditions are not particularly limited, and are appropriately selected according to the individual fine particle preparation and the spray dryer used. The microparticle preparation thus obtained is heated, if necessary, and the water in the microparticle preparation and the solvent in the microparticle preparation membrane are completely removed under reduced pressure. The particle size of the fine particle preparation of the present invention is appropriately selected depending on the degree of sustained release and the type of preparation. For example, when used as a suspension for injection, it may be in a range that satisfies dispersibility and needle penetration. Specifically, as an average particle, about 0.5 to 40
0 μm, more preferably in the range of about 2 to 200 μm. Thus, according to the present invention, non-adhesive water-soluble inorganic salts, organic acids or organic acid salts are dispersed on the surface of the fine particle preparation, so that the fine particle preparations have less aggregation in the production process, It is possible to obtain a well-formed spherical fine particle preparation, and when a nonionic surfactant is sprayed simultaneously with a drug polymer solution, it is extremely excellent when dispersing the fine particle preparation in a dispersion medium. It has advantages such as improved dispersibility. Further, the rate of incorporation of the drug into the fine particle preparation can be increased to almost 100% without losing the main drug which cannot be avoided by the underwater drying method. Furthermore, the present invention is based on the fact that the amount of the organic solvent to be used is smaller than that in the in-oil drying method, and the solvent removal in the in-water drying method requires a very long time. Is extremely advantageous in industrial production.

The fine particle preparation of the present invention has low toxicity and can be used safely. The fine particle preparation of the present invention is used for the prevention or treatment of various diseases depending on the pharmacological activity of the main drug contained therein. For example, when the main drug is an LH-RH derivative, for treating prostate cancer and endometriosis, for example, when the main drug is TRH, for treating senile dementia and spinocerebellar degeneration, for example, when the main drug is (sulfur-containing alkyl) aminomethylene In the case of bisphosphonic acid, it is used for the prevention or treatment of osteoporosis. The fine particle preparation of the present invention can be directly administered to a living body as fine granules, but can also be formed into various preparations and administered, and is used as a raw material when producing such preparations. obtain. Examples of the above preparations include parenteral preparations [eg, injections, external preparations (eg, nasal preparations, transdermal preparations, etc.), suppositories (eg, rectal suppositories, vaginal suppositories).
Etc.), oral administration preparations (eg, powders, granules, capsules,
Tablets and the like). The amount of the drug contained in these preparations can vary depending on the type of the drug, the dosage form, the disease to be treated, and the like, but is usually about 0.0 per preparation.
It is from about 0.01 mg to about 5 g, preferably from about 0.01 mg to about 2 g. For example, in the case of TRH salts and derivatives thereof, usually about 0.1 mg to about 1 g, preferably about 1 mg to about 500 mg, particularly preferably about 3 mg to about 60 mg per preparation.
mg.

These preparations can be produced by a method known per se usually used in the preparation process. For example, the microparticle preparation of the method of the present invention may be a dispersant (eg, Tween 80 (manufactured by Atlas Powder Co., USA), HCO60 (manufactured by Nikko Chemicals), carboxymethylcellulose, sodium alginate, etc.),
Preservatives (eg, methylparaben, propylparaben, benzyl alcohol, chlorobutanol, etc.) and isotonic agents (eg, sodium chloride, glycerin, sorbitol, glucose, etc.) and the like in aqueous suspension or olive oil, sesame oil, peanut It can be dispersed in oil, vegetable oils such as cottonseed oil and corn oil, propylene glycol and the like, formed into an oily suspension, and used as an injection. For example, in order to prepare a preparation for oral administration, the fine particle preparation of the present invention can be prepared by, for example, excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.), binders according to a method known per se. (Eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) and the like, and then compression-molded. Oral preparations can be prepared by coating in a manner known per se for taste masking, enteric coating or long-lasting purposes. As the coating agent, for example, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose,
Hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Bluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm,
(Germany, methacrylic acid / acrylic acid copolymerization) and dyes such as titanium oxide and red iron oxide are used.

For example, in order to prepare an external preparation, the fine particle preparation of the present invention can be made into a solid, semi-solid or liquid external preparation according to a method known per se. For example, as the solid, the fine particle preparation may be used as it is, or excipients (eg, glucose, mannitol, starch, microcrystalline cellulose, etc.), thickeners (eg, natural gums, cellulose derivatives, acrylic acid) And the like to form a powdery composition. The liquid form is almost the same as the injection form, and is an oily or aqueous suspension. In the case of semi-solid, an aqueous or oily gel or an ointment is preferred. Also, all of these are p
An H regulator (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), a preservative (eg, paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.) may be added.

For example, in order to prepare a suppository, the fine particle preparation of the present invention may be prepared in an oily or aqueous solid form according to a method known per se.
It can be a semi-solid or liquid suppository. The oily base used in the composition may be any one that does not dissolve the fine particle preparation, such as a glyceride of a higher fatty acid.
[Examples: cacao butter, witepsols (Dynamite Nobel), etc.], intermediate fatty acids [eg, miglyols (Dynamite Nobel), etc.], and vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). As the aqueous base, for example, polyethylene glycols,
Examples of the propylene glycol and aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers and the like. The dosage of the fine particle preparation of the present invention is determined by the type and content of the main drug, the dosage form, the duration of drug release, the animal to be administered (eg, a warm-blooded mammal such as a mouse, rat, horse, cow, or human), and the purpose of administration. , But may be any effective amount of the active ingredient. For example, the dosage of the fine particle preparation can be appropriately selected from the range of about 1 mg to 10 g, preferably about 10 mg to 2 g, as a single dose per adult (body weight: 50 kg). For example, in the case of a fine particle preparation containing TRH salt or a derivative thereof, the weight of the fine particle preparation is about 5 mg to 5 g, preferably about 30 mg to 2 g, particularly preferably about 30 mg per adult (body weight: 50 kg) per administration. It can be appropriately selected from the range of 50 mg to 1 g. The volume of the suspension when administered as an injection can be appropriately selected from the range of about 0.1 to 5 ml, preferably about 0.5 to 3 ml.

The high molecular weight polymer used as a base for the fine particle preparation is prepared by a known method, for example, JP-A-50-17525, JP-A-56-45920, JP-A-57-118512, and JP-A-57-185512.
-150609, 61-28521, 62-5
It can be produced according to the method described in 4760, European Patent Publication 481732 or a method analogous thereto. Thus, the microparticle preparation of the present invention has, for example, the following features. (1) Sustained release of a drug can be obtained in various dosage forms. Particularly, in the case of injections, if long-term administration is required to perform the expected treatment, instead of daily administration, 1-weekly Times,
The desired pharmacological effect can be stably obtained by injection once a month or once a year, and a longer-term sustained release can be obtained as compared with conventional sustained-release preparations. (2) When administered as an injection using a biodegradable polymer, no surgical operation such as implantation is required, and it can be easily administered subcutaneously and intramuscularly just like a normal suspension injection. No need to take it out again. In addition, it can be directly administered to tumors, inflammation sites or local areas where receptors are present, reduces systemic side effects, allows the drug to act on its target organ efficiently over a long period of time, and is expected to enhance its action . Furthermore, vascular embolization therapy for kidney cancer, lung cancer, etc. [Lancet (L
ancet II), pp. 479-480, (1979)].

(3) The main drug is continuously released, and in the case of a hormone antagonist or a receptor antagonist, a stronger pharmacological effect can be obtained than in the case of daily frequent administration. (4) It is possible to incorporate a drug into a fine particle preparation more efficiently than in a production method in which a conventional W / O / W type three-phase emulsion is prepared and subjected to drying in water, and a fine, spherical form is obtained. A fine-particle preparation having a uniform particle size can be obtained. (5) It is possible to obtain microcapsules having a drug content of 10 to 50%, which was impossible by the underwater drying method. (6) Since the removal rate of the solvent is faster than in the underwater drying method, the solidification rate of the fine particle preparation is high, and the fine particle preparation having a strong structure can be obtained, so that the initial release amount of the drug after administration can be reduced. . (7) Aggregation and adhesion of the microparticle preparation are significantly less than in the method of spray-drying only a liquid containing a drug and a polymer. (8) Spraying a water-soluble inorganic salt, organic acid or organic acid salt dispersion or solution as an anti-aggregation agent in advance or simultaneously with a drug polymer solution further reduces adhesion and aggregation between the fine particle preparations. And the adhesion to the spray dryer main body and the pipe section can be reduced. (9) Further, by spraying the nonionic surfactant simultaneously with the high molecular weight polymer, a very good dispersibility can be obtained when the fine particle preparation is dispersed in the dispersion medium.

[0028]

EXAMPLES The present invention will be described more specifically with reference to experimental examples and examples, but the present invention is not limited to these examples. In the following experimental examples and examples, the percentage (%) representing the concentration represents the weight / volume percent (W / V%). Experimental Example 1 5 g of leuprorelin acetate was dissolved in 50 ml of water at 60 ° C., and a lactic acid / glycolic acid copolymer (lactic acid / glycolic acid = 75/25, polystyrene equivalent average molecular weight of 13,00)
0) A solution prepared by dissolving 45 g of methylene chloride in 75 ml was added and emulsified with a small homogenizer (Polytron, manufactured by Kinematica, Switzerland) to obtain a W / O emulsion. (1) Underwater drying method (conventional method, abbreviated as method A) The above W / O type emulsion was prepared by adding 0.5% PVA aqueous solution 20
A (W / O) / W emulsion was prepared using a homogenizer in 00 ml. Thereafter, the mixture was slowly stirred with an ordinary propeller stirrer, collected from a (W / O) type microcapsule with a centrifugal separator after solidification with the volatilization of methylene chloride, and simultaneously washed with purified water. The collected microcapsules were obtained as a powder by freeze-drying overnight. (2) Spray-drying method (abbreviated as the method of the present invention, method B) The above W / O emulsion was simultaneously applied to one of two two-fluid nozzles at a flow rate of 10 ml / min, and 2% from the other nozzle.
The salt solution was sprayed into the drying chamber of the spray dryer at a flow rate of 10 ml / min to obtain powder microcapsules. At this time, the drying chamber inlet temperature was 95 ° C, the outlet temperature was 40 ° C, and the air volume was 8 ° C.
The test was performed at 0 kg / hour. Table 1 shows the results of comparing various characteristics of the microcapsules produced by both the method A and the method B.

[0029]

[Table 1] Comparison of characteristics of microcapsules Release fraction ²⁾ particle size distribution of the surface state drug uptake rate ¹⁾ 1 day ³⁾ A method stoma often 5.2% 77% 5~200μm B method stoma less 100% 24% 5 to 40 m 1) drug Measurement method of uptake ratio The content of leuprorelin acetate in the microcapsules was determined by high performance liquid chromatography (HPLC, apparatus: Hitachi L
-6300 type device, manufactured by Hitachi). The microcapsules (50 mg) were dissolved in 10 ml of methylene chloride, and 1/30 molar phosphate buffer (pH 6.0, 20 ml).
And leuprorelin acetate extracted in the buffer layer was quantified by HPLC. The detection was performed using an ultraviolet absorption detector under the following conditions. Column: Lichrosorb RP · 15, length 250 mm, diameter 4 mm Column temperature: 30 ° C. Moving layer: 0.25 mol / mixture of acetonitrile (100 ml) and methyl alcohol (150 ml) Flow rate: 0.7 ml / min. Detector wavelength: 280 nm The drug uptake rate was calculated by the following equation.

[0030]

(Equation 1) 2) Method of measuring release rate per day Microcapsules (50 mg) were added to 0.05% Tween-
10 ml of 1 / 30M phosphate buffer (pH 80)
7.0). This suspension was placed in a shaking vessel for 1
Shake the day. After shaking, the microcapsules were collected by filtration with a 0.8 μm millipore filter, and leuprorelin acetate remaining in the microcapsules was quantified by the method described in the above 1) Method for measuring drug uptake rate. Similarly, the amount of leuprorelin acetate in the microcapsules before shaking was determined.
The release rate per day was calculated by the following equation.

[0031]

(Equation 2) 3) Measurement method of particle size distribution The microcapsules (10 mg) were placed in Isoton II solution (250 m
l, manufactured by Nikkaki Co., Ltd.). This dispersion is added to 10
The particle size distribution was measured by analysis using a multi-riser (manufactured by Coulter, USA) equipped with a 0 μm or 280 μm aperture tube. On the surface of the microcapsules observed by a scanning electron microscope, the microcapsule obtained by the method A had very many small holes, and the microcapsule obtained by the method B showed almost no small holes, and the salt was uniformly dispersed on the surface. The uptake rate of the drug leuprorelin acetate was higher in Method B than in Method A. Drug release amount per day in release test (initial release amount)
Was lower in the B method. As for the particle size distribution, the distribution by the method B was sharper. The time required for the production was about 24 hours in Method A, whereas it was as short as about 10 minutes in Method B. As described above, the method B was a more useful method for producing sustained-release microcapsules than the method A when compared comprehensively.

Experimental Example 2 0.5 g of thyroid stimulating hormone releasing hormone (TRH) and a lactic acid / glycolic acid copolymer (lactic acid / glycolic acid = 75 /
25, average molecular weight 14000) 9.5 g of acetone 30 ml
And 2 ml of water uniformly and sprayed at a flow rate of 10 ml / min from one of two two-fluid nozzles set at the center of the spray dryer, and at the same time, 4% sorbitol to prevent microcapsules from adhering. The liquid was sprayed from the other nozzle to obtain powder microcapsules.
(This is referred to as method C.) Further, a 3% saline solution was sprayed from the other nozzle as an adhesion preventive agent for the microcapsules to obtain powdered microcapsules. (This is referred to as Method D.) Further, a 3% saline solution containing 0.0005% polysonebate 80 was sprayed from one nozzle to obtain powder microcapsules. (This is referred to as Method E.) Table 2 shows the results of comparing various characteristics of the microcapsules produced by the methods C, D, and E.

[Table 2] Comparison of characteristics of microcapsules Drug uptake rate Release rate per day Average particle size Residual moisture C method 99% 6% 45μm 0.9% D method 100% 5% 23μm 0.3% E method 100% 6% 24μm 0.3%

The content of TRH in the microcapsules is 9.9.
-10,0% (uptake rate 99-100%), C, D, E
The initial release rate in M / 30 phosphate buffer (37 ° C.) at pH 7.0 was 5 to 6%, and C, D, E
No difference in law was observed. Particle size distribution is 5 to 90 μm by C method
m (average 45 μm), 5 to 40 μm (average 23 μm) in Method D,
In Method E, the average particle diameter was 5 to 40 μm (average 24 μm), and no difference was observed between Methods D and E. The water content was 0.9% in Method C,
The methods D and E were 0.3%, but the result was less than 1.0% of the moisture of the freeze-dried microcapsules after drying in water. On the surface of the microcapsules observed with a scanning electron microscope, almost no small pores were observed in any of C, D and E. However, in the preparation of the method C, aggregation of the microcapsules was observed due to sorbitol, and the average particle diameter was increased. It is thought that it is. Looking at the dispersibility of the microcapsules in the dispersion medium containing polysorbate 80 and mannitol, the formulation of the method C has poor dispersibility, and a particle mass that does not disperse even when shaken is observed. Did not disperse. On the other hand, although the preparation of Method D had relatively good dispersibility, particles that did not disperse were slightly observed, and were easily dispersed by applying ultrasonic waves. After standing for 24 hours, the particles that settled out were dispersed by simple shaking. The preparation of Method E had good dispersibility in a dispersion medium and was easily dispersed, and was easily redispersed even after standing for 24 hours.

EXAMPLE 1 0.4 g of thyroid stimulating hormone releasing hormone (TRH) and a lactic acid / glycolic acid copolymer (lactic acid / glycolic acid = 7)
(5/25, average molecular weight 14000) 4.6 g is uniformly dissolved in a mixed solvent of 9.5 ml of methylene chloride, 10 ml of acetonitrile and 0.5 ml of ethanol, or a mixed solvent of 12 ml of methylene chloride, 7.5 ml of acetonitrile and 0.5 ml of ethanol. Then, from one of the two two-fluid nozzles set in the center of the spray dryer, the flow rate was 10 ml /
And spray 1 / 5M phosphate buffer (disodium hydrogen phosphate / sodium dihydrogen phosphate, pH 7.4) from the other nozzle to prevent microcapsule adhesion. Capsules were obtained. Each of the microcapsules obtained had a drug uptake rate of 100% and an initial release amount in a release test of 15%. The dispersibility was good, and the average particle size was 22 μm. Example 2 0.8 g of thyroid stimulating hormone releasing hormone (TRH) and a lactic acid / glycolic acid copolymer (lactic acid / glycolic acid = 7)
(5/25, average molecular weight 14000) 9.2 g was uniformly dissolved in a mixed solvent of 34.6 ml of acetonitrile and 5.3 ml of water, and the flow rate was 10 ml from one of two two-fluid nozzles set at the center of the spray dryer. Per minute,
At the same time, 1 / 5M
Phosphate buffer (disodium hydrogen phosphate / phosphoric acid 2)
Sodium hydrogen (pH 7.4) was sprayed from the other nozzle to obtain powdered microcapsules. The drug uptake was 100%, and the initial release in the release test was 10%. The dispersibility was good, and the average particle size was 23 μm.

Example 3 1.6 g of thyrotropin-releasing hormone (TRH) and a lactic acid / glycolic acid copolymer (lactic acid / glycolic acid = 7)
(5/25, average molecular weight 14000) 18.4 g was uniformly dissolved in a mixed solvent of 50 ml of acetonitrile and 10 ml of ethanol, and sprayed at a flow rate of 10 ml / min from one of two two-fluid nozzles set at the center of the spray dryer. And at the same time, to prevent the attachment of microcapsules,
/ 30M phosphate buffer (disodium hydrogen phosphate
Sodium dihydrogen phosphate, pH 7.4) was sprayed from the other nozzle to obtain powder microcapsules. The drug uptake was 100%, and the initial release in the release test was 10%. Good dispersibility, average particle size is 22μ
m. Example 4 0.8 g of thyrotropin-releasing hormone (TRH) and a lactic acid / glycolic acid copolymer (lactic acid / glycolic acid = 7)
(5/25, average molecular weight 14000) 9.2 g was uniformly dissolved in a mixed solvent of 24 ml of methylene chloride, 14 ml of ethanol and 2 ml of water, and the flow rate was 10 ml from one of two two-fluid nozzles set at the center of the spray dryer. /
And 1/10 M phosphate buffer (disodium hydrogen phosphate / sodium dihydrogen phosphate, pH 7.4) and 2/1
A mixture of 0 M saline was sprayed from the other nozzle to obtain powder microcapsules. The drug uptake was 100%, and the initial release in the release test was 18%. The dispersibility was good, and the average particle size was 23 μm.

Example 5 0.8 g of thyrotropin-releasing hormone (TRH) and a lactic acid / glycolic acid copolymer (lactic acid / glycolic acid = 7)
(5/25, average molecular weight 14000) 9.2 g of methylene chloride 10.6 ml, acetonitrile 25.5 ml and water 3.
Dissolve uniformly in 9 ml of the mixed solvent, and from one of the two two-fluid nozzles set in the center of the spray dryer,
Spraying is performed at a flow rate of 10 ml / min. At the same time, a 1/5 M phosphate buffer (disodium hydrogen phosphate / sodium dihydrogen phosphate, pH 7.
4) was sprayed from the other nozzle to obtain powder microcapsules. The drug uptake was 100%, and the initial release in the release test was 18%. Good dispersibility,
The average particle size was 23 μm. Example 6 A solution obtained by dissolving 1 g of cefotiam dihydrochloride in 3 ml of water, adding a solution of 9 g of polylactic acid (molecular weight: 21,000) in 20 ml of methylene chloride and mixing with a polytron for 20 seconds to form a double-structured rotation. Inject and spray from one side (inner side) of the disk type nozzle, and add 3% sodium dihydrogen phosphate solution containing 0.0001% polyoxyethylene hydrogenated castor oil 60 to the other side.
(Outside) and sprayed at the same time, and powder microcapsules were obtained with a spray dryer.

Example 7 1 g of bleomycin hydrochloride and a butyric acid / glycolic acid copolymer (butyric acid / glycolic acid = 50/50, average molecular weight 10
000) 9 g was dissolved in a mixture of 5 ml of water, 30 ml of acetonitrile and 5 ml of ethanol, sprayed from the innermost side of a three-fluid nozzle configured to spray two liquids, and a 2% sodium bicarbonate solution was placed secondarily from the inner side. Microcapsules were obtained by flowing compressed air on the outermost side.

[0038]

According to the present invention, it becomes possible to mass-produce a sustained-release fine particle preparation containing a drug in a short time and continuously, which was impossible with the conventional in-water drying method. In addition, by uniformly dispersing the non-adhesive substance on the surface of the fine particle preparation, it is possible to remarkably prevent adhesion and aggregation of the fine particle preparations, which were unavoidable in the conventional spray drying method. By dispersing or coating with a nonionic surfactant, the dispersibility of the fine particle preparation can be remarkably improved.

Continuation of the front page (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 9/58 A61K 9/52 A61K 47/34

Claims (7)

(57) [Claims] (1) a drug-containing polymer-containing polymer fine particle preparation which is at least partially or completely coated with a water-soluble inorganic salt, a water-soluble organic acid or a water-soluble organic acid salt (where the polymer is A polyfatty acid ester or a poly-α-cyanoacrylate, wherein the water-soluble organic acid is not carboxymethylcellulose or an amino acid, and the water-soluble organic acid salt is not a carboxymethylcellulose salt). 2. The preparation according to claim 1, which is at least partially or completely coated with a water-soluble inorganic salt. 3. The preparation according to claim 2, wherein the water-soluble inorganic salt is sodium chloride. 4. A high molecular weight polymer solution containing a drug and a solution of a water-soluble inorganic salt, a water-soluble organic acid or a water-soluble organic acid salt are sprayed using separate nozzles in a spray drier. A method for producing a drug-containing polymer fine particle preparation which is at least partially or completely coated with a water-soluble inorganic salt, a water-soluble organic acid or a water-soluble organic acid salt, which is characterized by being brought into contact with the solution (however, , The high molecular weight polymer is a polyfatty acid ester or a poly-α-cyanoacrylate, the water-soluble organic acid is not carboxymethylcellulose or an amino acid, and the water-soluble organic acid salt is not a carboxymethylcellulose salt). 5. The method according to claim 4, wherein the solution of the water-soluble inorganic salt, water-soluble organic acid or water-soluble organic acid salt is an aqueous solution. 6. The method according to claim 4, wherein the solution of a water-soluble inorganic salt, a water-soluble organic acid or a water-soluble organic acid salt contains a nonionic surfactant. 7. The method according to claim 4, further comprising spraying and contacting a nonionic surfactant solution.