JP2000239152A - Method for removing organic solvent remaining in fine particle - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently and almost completely remove an organic solvent remaining in fine particles in a short time by heating the fine particles in which an organic solvent having a lower boiling point than water is contained in a water phase at a temperature higher than the boiling point of the organic solvent. SOLUTION: An organic solvent (preferably an organic solvent having a boiling point >=10 deg.C less than that of water, e.g. a halogenated aliphatic hydrocarbon-based solvent) remaining in fine particles consisting of an agent and a polymer (e.g. the polyester of a hydroxyfatty acid) hardly soluble in water is removed by heating the fine particles in a water phase at a temperature higher than the boiling point of the organic solvent (preferably at a temperature >=5 deg.C higher than the boiling point). The initial residual amount of the organic solvent in the fine particles is preferably <=40 wt.%. The ratio of the fine particles to the water phase is preferably 0.1-1000 g per 1 litter of the water phase without containing the fine particles. Thus, highly safe fine particle formulations are easily provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for removing an organic solvent remaining in fine particles comprising a drug and a poorly water-soluble polymer.

[0002]

2. Description of the Related Art A fine particle preparation containing a drug in a poorly water-soluble biodegradable polymer such as polylactic acid and lactic acid-glycolic acid copolymer is administered once to a living tissue such as muscle by administering the drug. The drug treatment becomes possible for a long period of time by administration of.

[0003] Such fine particle preparations are prepared, for example, by dissolving or dispersing a drug in a polymer organic solvent solution, emulsifying the drug in an aqueous phase, distilling off the organic solvent in the aqueous phase, and solidifying the polymer. (In-liquid drying method).

In this preparation method, it is essential to use an organic solvent that dissolves the polymer and is hardly soluble in water, and halogenated aliphatic hydrocarbon solvents such as dichloromethane and chloroform are widely used. However, it is known that a considerable amount of these solvents remain in the prepared fine particle preparation.

[0005] However, there is a concern that halogenated aliphatic hydrocarbon solvents have an effect on the human body.
In the case of dichloromethane, the remaining amount in the preparation was 600 p.m. at the International Conference on Harmonization (ICH)
pm.

In order to reduce the residual organic solvent, it is conceivable to distill off the organic solvent at a temperature higher than the boiling point of the organic solvent in the above-mentioned in-liquid drying method to solidify the polymer. Since the organic solvent evaporates rapidly on the way, abnormalities occur on the surface of the fine particles, resulting in a decrease in the drug uptake rate and a deterioration in the elution characteristics.

As a method for removing the residual organic solvent from the fine particle preparation, it is conceivable to distill the organic solvent from the fine particle preparation under reduced pressure at room temperature, but it takes several days to one week or more. When the temperature is increased to shorten the temperature, the glass transition point of the polymer forming the fine particles is exceeded, the polymer is softened, and the fine particles aggregate.

As a method for solving these problems, Japanese Patent Application Laid-Open No. 9-221417 describes a method in which fine particles are covered with a high melting point additive such as mannitol and then dried under reduced pressure while heating. There is a problem that an extra step is required and unnecessary additives remain in the resulting fine particle preparation.

[0009]

SUMMARY OF THE INVENTION The present invention provides a method for efficiently removing an organic solvent remaining in fine particles comprising a drug and a poorly water-soluble polymer without affecting the quality of the fine particle preparation. It is.

[0010]

Means for Solving the Problems As a result of intensive studies to solve the above problems, fine particles comprising a drug and a poorly water-soluble polymer in which an organic solvent having a boiling point lower than that of water remains,
By heating above the boiling point of the organic solvent in the aqueous phase,
Organic solvent remaining in the microparticles in a very short time
It has been found that the residual organic solvent) can be almost completely removed, and the present invention has been completed.

In the method of the present invention, the heating to a temperature higher than the boiling point of the organic solvent is carried out not after the step of forming the fine particles but after the formation of the fine particles, so that there is substantially no effect on the drug uptake rate and release characteristics of the fine particles. Without removing the residual organic solvent. Further, even if the temperature is raised above the glass transition point of the poorly water-soluble polymer constituting the fine particles, the fine particles do not agglomerate because they are in the aqueous phase.

That is, the present invention provides an organic solvent having a boiling point lower than that of water and remaining in fine particles comprising a drug and a poorly water-soluble polymer, by heating the fine particles in an aqueous phase to a temperature higher than the boiling point of the remaining organic solvent. It relates to the method of removing.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the method of the present invention, fine particles comprising a drug from which a solvent is removed and a poorly water-soluble polymer are
Any particle having a particle diameter of 1000 μm or less may be used. For example, microparticles, microcapsules, microspheres, nanoparticle,
Nanocapsules and nanospheres are included. Among these fine particles, it is preferable to apply to particles having a particle diameter of 0.01 to 300 μm.

Specific forms of the fine particles include mononuclear fine particles having one drug-containing nucleus in a poorly water-soluble polymer, and polynuclear fine particles having many drug-containing nuclei in a poorly water-soluble polymer. And dispersion-type fine particles in which finer drug particles are substantially uniformly dispersed throughout the poorly water-soluble polymer. The method of the present invention can be suitably applied to any type of fine particles.

The method of the present invention can be applied to those in which the organic solvent used in the production of the fine particles remains in the fine particles. Examples of such fine particles include a submerged drying method, a phase separation method, and a spraying method. Fine particles prepared by a method such as a drying method can be given.

In particular, the method of the present invention is preferably applied to fine particles comprising a drug and a poorly water-soluble polymer containing a residual organic solvent at a concentration higher than the concentration affecting the living body. Concentration of the residual organic solvent (initial residual organic solvent concentration) in the fine particles before the treatment is 40% by weight
In the following cases, in particular, it can be suitably applied to the case of 30% by weight or less.

The residual organic solvent concentration can be determined by a known method,
For example, the measurement may be performed using gas chromatography or the like.

As the poorly water-soluble polymer which forms fine particles together with the drug, any of the poorly water-soluble polymers generally used in the field of pharmaceutical preparations can be used, and both those of natural origin and those of synthetic origin can be used. Although it is possible, those having biocompatibility are preferred.

Examples of biocompatible polymers include polyesters of hydroxy fatty acids (eg, polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, poly-β-hydroxybutyric acid, ε-caprolactone ring-opening polymer, lactic acid -Glycolic acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer, etc.), polymers of alkyl α-cyanoacrylates (eg, polybutyl-2-cyanoacrylate, etc.), polyalkylene oxalates (eg, polytriacrylate). Methylene oxalate,
Polytetramethylene oxalate), polyorthoester, polycarbonate (eg, polyethylene carbonate, polyethylenepropylene carbonate, etc.), polyorthocarbonate, polyamino acid (eg, poly-γ-L-alanine, poly-γ-benzyl-L)
-Glutamic acid, poly-γ-methyl-L-glutamic acid, etc.), biodegradable polymers such as hyaluronic acid ester, polystyrene, nylon, tetron, silicone polymer, polyurethane, dextranstearate, acrylic acid polymer ( Polyacrylic acid, polymethacrylic acid, acrylic acid-methacrylic acid copolymer, etc.), cellulose derivatives (ethyl cellulose, acetyl cellulose, nitrocellulose, etc.), maleic anhydride copolymer, ethylene vinyl acetate copolymer, Examples include polyvinyl acetate and polyacrylamide. These polymers may be used alone or in combination of two or more.

Particularly preferred among these biocompatible polymers are those which are biodegradable, and among them, polyesters of hydroxy fatty acids are particularly preferred. The preferred average molecular weight of the hydroxy fatty acid polyester is in the range of about 2,000 to about 800,000, more preferably in the range of about 5,000 to about 200,000.

Further, among the above-mentioned polyesters of hydroxy fatty acids, more preferred are polylactic acid, lactic acid-glycolic acid copolymer, and 2-hydroxybutyric acid-glycolic acid copolymer. The molar ratio of lactic acid / glycolic acid in the lactic acid-glycolic acid copolymer is preferably 90/10
30/70, more preferably 80/20 to 40/60. On the other hand, the molar ratio of 2-hydroxybutyric acid / glycolic acid in the 2-hydroxybutyric acid-glycolic acid copolymer is preferably 90/10 to 30/70, and more preferably 80/20 to 40/60.

In the method of the present invention, fine particles composed of a drug and a poorly water-soluble polymer are heated in an aqueous phase. Therefore, even if the temperature is raised to a temperature exceeding the glass transition point of the poorly water-soluble polymer contained in the fine particles, No aggregation of fine particles due to softening occurs, and the residual organic solvent can be efficiently removed from the fine particles containing various polymers regardless of the height of the glass transition point.

Examples of the drug include, but are not limited to, antitumor agents, bioactive peptides, antibiotics, antipyretic / analgesic / inflammatory agents, antitussive expectorants, sedatives, muscle relaxants, antiepileptic agents, antiulcer agents, antiulcer agents, Depressants, antiallergic agents, inotropic agents, antiarrhythmic agents, vasodilators, antihypertensive diuretics, antidiabetic agents, antilipidemic agents, anticoagulants, hemostatic agents, antituberculous agents, hormonal agents, narcotic antagonists, Examples include bone resorption inhibitors, bone formation promoters, and angiogenesis inhibitors.

Examples of the antitumor agent include paclitaxel, bleomycin, methotrexate, actinomycin D, mitomycin C, vinblastine sulfate, vincristine sulfate, daunorubicin, doxorubicin, neocarzinostatin, cytosine alibinoside, fluorouracil and tetrahydrofuryl-5- Fluorouracil, krestin, picibanil, lentinan, tamoxifen, levamisole, bestatin, azimexone, glycyrrhizin, cisplatin, carboplatin, irinotecan hydrochloride and the like.

As the physiologically active peptide, insulin,
Somatostatin, sandostatin, growth hormone, prolactin, adrenocorticotropic hormone (ACTH), ACT
H derivatives, melanocyte stimulating hormone (MSH), thyroid hormone releasing hormone (TRH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), vasopressin, desmopressin,
Oxytocin, calcitonin, elcatonin, parathyroid hormone (PTH), glucagon, gastrin, secretin, panclayozymine, cholecystokinin, angiotensin, human placental lactogen, human chorionic gonadotropin (HCG), enkephalin, enkephalin derivative, endorphin, kyo Tolphin, interferons (eg, α, β, γ type, etc.), interleukins (eg, 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12), tuftsin, thymopoietin, thymosin, thymostimulin, thymic factor (THF), blood thymic factor (FTS) and its derivatives, and other thymic factors, tumor necrosis factor (TN
F), colony-inducing factors (CSF, GCSF, GMCS
F, MCSF, etc.), motilin, dynorphin, bombesin, neurotensin, caerulein, bradykin, urokinase, asparakinase, kallikrein, substance P, insulin-like growth factor (IGF-I, IGF
-II), nerve growth factor (NGF), cell growth factor (E
GF, TGF-α, TGF-β, PDGF, FG hydrochloride
F, basic FGF, etc.), bone morphogenetic factor (BMP), neurotrophic factor (NT-3, NT-4, CNTF, GDNF, B
Blood coagulation factors, such as DNF, factor VIII, IX, lysozyme chloride, polymyxin B, colistin, gramicidin, bacitracin, erythropoietin (EP
O), thrombopoietin (TPO) and the like.

Examples of antibiotics include gentamicin, dibekacin, canendomycin, lividomycin,
Tobramycin, Amikacin, Fradiomycin, Sisomycin, Tetracycline hydrochloride, Oxytetracycline hydrochloride, Lolitetracycline, Doxycycline hydrochloride, Ampicillin, Piperacillin, Ticarcillin, Aspoxycillin, Cephalotin, Cephaloridin, Cefotiam, Cefsulodin, Cefmenoxime, Cefmetosefosem, Cefazocefosem
Ceftizoxime, moxalactam, thienamycin, sulfazecin, azuleonam and the like.

Examples of antipyretic, analgesic and anti-inflammatory agents include salicylic acid, sulpyrine, flufenamic acid, diclofenac, indomethacin, morphine, pethidine hydrochloride, levorphanol tartrate, oxymorphone and the like.

Examples of antitussive expectorants include ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, allochloramide hydrochloride, clofedanol hydrochloride, picoperidamine hydrochloride, cloperastine, protochlorol hydrochloride, isoproterenol hydrochloride , Salbutamol sulfate, terbutaline sulfate and the like.

Examples of the sedative include chlorpromazine, prochlorperazine, trifluoroperazine, atropine sulfate, methylscopolamine bromide and the like.

Examples of the muscle relaxant include pridinol methanesulfonate, tubocurarine chloride, pancuronium bromide and the like.

Examples of antiepileptic agents include phenytoin, ethosuximide, sodium acetazolamide, chlordiazepoxide and the like.

Examples of the anti-ulcer agent include metoclopromide, histidine hydrochloride and the like.

Examples of antidepressants include imipramine,
Clomipramine, noxiptiline, phenelzine sulfate and the like.

Examples of the antiallergic agent include diphenhydramine hydrochloride, chlorpheniramine maleate, tripelenamine hydrochloride, methdilamine hydrochloride, clemizole hydrochloride, diphenylperalin hydrochloride, methoxyphenamine hydrochloride and the like.

The cardiotonic agents include, for example, transpioxocamphor, theophyllol, aminophylline, ethylefrin hydrochloride and the like.

Examples of the therapeutic agent for arrhythmia include azimilide, propranolol, alprenolol, bufetrol, oxyprenolol and the like.

Examples of the vasodilator include oxyfedrine hydrochloride, diltiazem hydrochloride, trazoline hydrochloride, hexobendine, bamethane sulfate and the like.

Examples of high pressure diuretics include hexamethonium bromide, pentolinium, mecamylamine hydrochloride,
Ecarazine hydrochloride, clonidine and the like can be mentioned.

Examples of the therapeutic agent for diabetes include glymidine sodium, glipizide, phenformin hydrochloride, buformin hydrochloride, metformin and the like.

Examples of antilipidemic agents include mevalotin,
Pravastatin sodium, simvastatin, clinofibrate, clofibrate, simfibrate, bezafibrate and the like.

Examples of the anticoagulant include sodium heparin and the like.

Examples of the hemostatic agent include thromboplastin, thrombin, sodium menadione bisulfite, acetomenaphthone, ε-aminocaproic acid, tranexamic acid, sodium carbazoclob sulfonate, adrenochrome monoaminoguanidine methanesulfonate and the like.

Examples of antituberculous agents include isoniazid,
Ethambutol, para-aminosalicylic acid and the like.

Examples of hormonal agents include prednisolone, sodium prednisolizolone phosphate, dexamethasone sodium hydrochloride, hexestrol phosphate, methimazole and the like.

Examples of the narcotic antagonist include levallorphan tartrate, nalorphine hydrochloride, naloxone hydrochloride and the like.

Examples of the bone resorption inhibitor include ipriflavone and the like.

Examples of the bone formation promoter include BMP, P
And polypeptides such as TH, TGF-β, and IGF-I.

Examples of the angiogenesis inhibitor include angiogenesis inhibitor steroids, fumagillin, fumagillol derivatives, angiostatin, endostatin and the like.

The above drug may be free or a pharmacologically acceptable salt thereof. For example, when the drug is a compound having a basic group such as an amino group, a salt with an inorganic acid (eg, hydrochloric acid, sulfuric acid, nitric acid, etc.) or an organic acid (eg, carbonic acid, succinic acid, etc.) is used. Also,
When the drug has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium)
Alternatively, a salt with an organic base compound (for example, an organic amine such as triethylamine, or a basic amino acid such as arginine) is used.

According to the method of the present invention, the residual organic solvent that can be removed from the fine particles composed of the drug and the poorly water-soluble polymer is not particularly limited as long as it has a boiling point lower than that of water. As described above, those having a boiling point lower than that of water by 15 ° C. or more are particularly preferable.

The organic solvent having a boiling point lower than that of water is an organic solvent that boils at a temperature lower than that of water when the temperature is increased under a certain pressure. Upon heating, the remaining organic solvent can be removed. Further, for example, a boiling point lower than water by 20 ° C. or more means that, at a certain atmospheric pressure, the residual organic solvent is 20 times lower than water.
Boiling at a temperature lower than or equal to ° C.

When the method of the present invention is used, a poorly water-soluble polymer usually used for preparing fine particles can be dissolved, and any organic solvent having a boiling point lower than that of water can be easily removed from the fine particles. Water-immiscible organic solvents commonly used in the above can also be easily removed.

Specific examples of the residual organic solvent removed from the fine particles by the method of the present invention include, for example, dichloromethane,
Halogenated aliphatic hydrocarbon solvents such as chloroform, chloroethane, dichloroethane, trichloroethane and carbon tetrachloride; fatty acid ester solvents such as methyl acetate, ethyl acetate and butyl acetate; ether solvents such as ethyl ether, isopropyl ether and tetrahydrofuran Solvents: ketone solvents such as acetone and 2-butanone; aromatic hydrocarbon solvents such as benzene; cyanated aliphatic hydrocarbon solvents such as acetonitrile; mixed solvents thereof. Of these, halogenated aliphatic hydrocarbon solvents are preferred, and dichloromethane is particularly preferred.

Even when two or more kinds of the above-mentioned organic solvents remain in the fine particles in a mixed state, any of these solvents can be efficiently removed by the method of the present invention.

According to the method of the present invention, the residual organic solvent can be removed by heating the fine particles in the aqueous phase to a temperature higher than the boiling point of the residual organic solvent.

As the aqueous phase, both water and an aqueous solution obtained by adding an additive such as an emulsifier to water can be used. As the emulsifier, for example, anionic surfactant (for example,
Sodium oleate, sodium stearate, sodium lauryl sulfate, etc., nonionic surfactants (for example, polyoxyethylene sorbitan fatty acid ester,
Polyoxyethylene castor oil derivatives), polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, carboxymethylcellulose, lecithin, gelatin, hyaluronic acid and the like can be used, and among them, polyvinyl alcohol is particularly preferable. Further, these emulsifiers may be added by mixing two or more kinds at an appropriate ratio.

The concentration of the emulsifier in the aqueous phase is 0.00
Within the range of 1 to 20% by weight, preferably 0.01 to 20% by weight.
In the range of 10% by weight, particularly preferably 0.0%
It is in the range of 5-5% by weight.

The ratio of the fine particles to the aqueous phase is not particularly limited as long as the fine particles are not in contact with the aqueous phase. 0.1-1000 g per liter,
Preferably from 0.5 to 500 g, particularly preferably 1.
Fine particles are preferably contained in the range of 0 to 300 g.

The heating in the aqueous phase can be carried out by heating the fine particles so that the fine particles have a boiling point equal to or higher than the boiling point of the residual organic solvent lower than water.
It is preferable to heat to a temperature higher than 5 ° C., preferably higher than 10 ° C. Here, the boiling point of the residual organic solvent is a temperature at which the residual organic solvent boils when the temperature is increased under a certain atmospheric pressure. The removal can be carried out at a temperature lower than the boiling point of the residual organic solvent in the above.

Since the removal of the residual organic solvent is carried out in the aqueous phase, the temperature can be raised to the boiling point of water at the pressure at which the removal operation is performed, and the removal can be carried out while azeotroping the water and the residual organic solvent. It is efficient to remove the residual organic solvent by heating the mixture to a temperature lower than the boiling point of water at the pressure at which the operation is performed, in particular, to a temperature lower than the boiling point of water by 10 ° C. or more.

The temperature for removing the residual organic solvent can be determined in consideration of the temperature stability of the drug contained in the fine particles, the type of the poorly water-soluble polymer, the type and amount of the residual organic solvent, the pressure at the time of performing the removing operation, and the like. When the drug is easily decomposed or denatured at a high temperature, it is preferable to reduce the pressure to reduce the boiling point of the remaining organic solvent.

It is not always necessary to keep the temperature constant above the boiling point of the remaining organic solvent when heating, and the operation of raising the temperature above the boiling point of the remaining organic solvent and the operation of lowering the temperature below the boiling point are repeated. Alternatively, the temperature of the fine particles may be changed at a temperature equal to or higher than the boiling point of the remaining organic solvent.

Since the method of the present invention removes the residual organic solvent from the fine particles in the aqueous phase, even if the fine particles are heated to a temperature higher than the glass transition temperature of the poorly water-soluble polymer constituting the fine particles together with the drug, Can remove the residual organic solvent without causing aggregation.

When the method of the present invention is carried out industrially, it is desirable to flow an aqueous phase in order to efficiently remove the residual organic solvent from the fine particles. The flow of the aqueous phase can be carried out by circulation or stirring. However, it is preferable that the aqueous phase be flowed with vertical movement so that the water pressure applied to the particles in the aqueous phase is averaged. Circulation can be performed by sucking a part of the aqueous phase from the lower part of the aqueous phase using a pump and returning it to the upper part of the aqueous phase through a pipe. Further, the stirring can be performed by stirring the aqueous phase horizontally or vertically by a usual stirring means such as a stirring blade or a magnet stirrer.

The heating time, that is, the time for heating the fine particles above the boiling point of the residual organic solvent, depends on the type and amount of the residual organic solvent in the fine particles, the type of the poorly water-soluble polymer in the fine particles, the type of the drug, The temperature, the flow means of the aqueous phase, the removal amount of the residual organic solvent and the like may be appropriately determined, but usually 0.5
２４24 hours, preferably 0.5-10 hours.

The fine particles from which the residual organic solvent has been removed by the method of the present invention can be recovered from the aqueous phase by a conventional method such as centrifugation or filtration. If necessary, the collected fine particles may be washed and removed of an additive contained in an aqueous phase such as an emulsifier adhering to the surface of the fine particles with distilled water.

As described above, by applying the method of the present invention, the residual organic solvent in the fine particles composed of the drug and the poorly water-soluble polymer can be almost completely removed.
For example, in the case of dichloromethane, I
It can be reduced to less than the allowable amount of CH of 600 ppm.

The fine particles to which the method of the present invention is applied include:
It can be prepared by a conventionally known method, for example,
Fine particles obtained by a submerged drying method, a phase separation method, a spray drying method, and the like described below are exemplified.

(1) Drying method in liquid A solution in which a poorly water-soluble polymer is dissolved in an organic solvent having a boiling point lower than that of water and immiscible with water (a poorly water-soluble polymer solution)
The organic phase thus obtained is dispersed in an aqueous phase to prepare an O / W emulsion, and the organic solvent is distilled off at a temperature lower than the boiling point of the organic solvent.

In the present method, the preparation method varies depending on the form of the organic phase, but any of them can be prepared by a conventional method.

The form of the organic phase containing the drug includes:
Includes the following:

(A) An organic phase in which a drug is directly dissolved or dispersed in a poorly water-soluble polymer solution (Japanese Patent Laid-Open No. 49-1).
2024, JP-A-63-91325, JP-A-8-151
321, Drug Development and Industrial Pharmacy [Drug Development]
ment and Industrial Pharm
acy], 24 (8), 703-727, 1998.
Year (hereinafter simply referred to as Document 1), etc.).

(B) A W / O emulsion in which an aqueous drug solution is dispersed in a poorly water-soluble polymer solution. The organic phase,
That is, when the W / O emulsion is dispersed in the aqueous phase,
More specifically, a (W / O) / W type emulsion is obtained (Japanese Patent Application Laid-Open No. 60-100516, Japanese Patent Application Laid-Open No. 62-201816, Japanese Patent Application Laid-Open No. Hei 9-221417, Reference 1).

(C) An O / O emulsion in which two or more types of poorly water-soluble polymers are used, and the drug is dissolved or dispersed in one of the poorly water-soluble polymer solutions dispersed in the other poorly water-soluble polymer solution. . When the organic phase, that is, the O / O emulsion is dispersed in the aqueous phase, the emulsion becomes (O / O) / W emulsion in detail (JP-A-6-21).
1648).

(2) Phase Separation Method (Coacervation Method) A coacervation agent is stirred in an organic phase in which a drug or a drug aqueous solution is dispersed in a solution in which a poorly water-soluble polymer is dissolved in an organic solvent having a boiling point lower than water. The mixture is gradually added to the bottom to precipitate and solidify (JP-A-60-67417, JP-A-8-151).
321, Japanese Unexamined Patent Publication No. 9-221417, the above-mentioned document 1, etc.).

(3) Spray drying method: A drug is dissolved or dispersed in a solution in which a poorly water-soluble polymer is dissolved in an organic solvent having a boiling point lower than that of water, or an organic phase in which a drug aqueous solution is dispersed is sprayed with a spray nozzle. And spray it into the drying chamber of a spray dryer (spray dryer) to volatilize the organic solvent in the spray droplets in a very short time (Japanese Patent Application Laid-Open No. 1-15).
5942, JP-A-8-151321, JP-A-9-221
417, Reference 1 etc.).

The fine particles obtained by the above methods (1) to (3) each contain a considerable amount of the residual organic solvent as it is, but by applying the method of the present invention, the fine particles in the fine particles The residual organic solvent can be significantly reduced.

When the fine particles are prepared by the submerged drying method among the fine particle preparation methods described above, the fine particles are preferably prepared by dissolving a poorly water-soluble polymer in an organic solvent having a boiling point lower than that of water and immiscible with water. A drug is contained, and the organic phase thus obtained is dispersed in an aqueous phase to prepare an O / W emulsion,
From this, fine particles are prepared by distilling off the organic solvent at a temperature lower than the boiling point of the organic solvent, and the fine particles are heated in the aqueous phase to a temperature higher than the boiling point of the organic solvent to remove the residual organic solvent. Fine particles from which the residual organic solvent has been removed can be produced.

In this method, the removal of the organic solvent from the O / W emulsion and the removal of the residual organic solvent from the fine particles can be carried out in the same aqueous phase. May be used to reduce the amount of the aqueous phase. When the process is carried out in the same aqueous phase, the fine particles obtained in the in-liquid drying step are once separated from the aqueous phase, and after washing, the trouble of dispersing in the aqueous phase again can be omitted. When the organic solvent is distilled off from the O / W emulsion and the residual organic solvent is removed from the fine particles in the same aqueous phase, it can be performed as a continuous process.

In the case of a continuous process, the timing of heating to a temperature higher than the boiling point of the organic solvent may be any time after most of the organic solvent is distilled off from the organic phase and fine particles are formed. However, if the fine particles are heated to a temperature higher than the boiling point of the organic solvent in the aqueous phase in a state in which the fine particles are incompletely formed, the dissolution characteristics may be degraded or the drug content may be reduced. Before heating above the boiling point of the organic solvent, it is necessary to sufficiently distill off the organic solvent at a temperature below the boiling point of the organic solvent to form complete fine particles. Specifically, the amount of the organic solvent remaining in the fine particles immediately before heating to a temperature higher than the boiling point of the organic solvent is 40% by weight or less, particularly preferably 30% by weight or less.
It is preferable to heat the organic solvent to a temperature equal to or higher than the boiling point when the content of the organic solvent becomes equal to or less than the weight%.

The fine particle preparation having a significantly reduced amount of the residual organic solvent by the method of the present invention can be directly used intramuscularly, subcutaneously,
It can be easily administered as an injection or implant to blood vessels, organs, or lesions such as joint cavities, abdominal cavities, and tumors. It can also be used as a raw material for producing various preparations. Examples of such preparations include injections, oral administration preparations, transdermal preparations, suppositories, nasal administration preparations, and oral administration preparations. And intraocular administration agents.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples.

[0083]

EXAMPLES Comparative Example 1 25 mg of cisplatin was weighed into a glass test tube, and dichloromethane [boiling point: 39.75 ° C. (760 mmHg)]
0.75 g was added, and a uniform dispersion was prepared with a sonicator. Add polylactic acid (average molecular weight: about 200
00, manufactured by Wako Pure Chemical Industries) 300 mg and lactic acid-glycolic acid copolymer (average molecular weight: about 20,000, lactic acid / glycolic acid molar ratio: 50/50, manufactured by Wako Pure Chemical Industries) 150 mg
Was added and dissolved, and the mixture was sufficiently stirred to form O / O in which the cisplatin particles were localized in the dichloromethane solution of the lactic acid-glycolic acid copolymer in which microdroplets were formed by phase separation in the dichloromethane solution of polylactic acid. A type emulsion (organic phase) was obtained. The obtained O / O emulsion is
0.5% using a Pasteur pipette at a temperature of 15 ° C
(W / v) The mixture was added to 400 ml of an aqueous solution of polyvinyl alcohol (aqueous phase), and emulsified using a Polytron homogenizer (manufactured by Kinematica) (8000 rpm, 5 minutes) to obtain an (O / O) / W emulsion. This (O
/ O) / W emulsion was stirred at a temperature of 22 ° C. for 3 hours using a 4-blade paddle (400).
rpm), and dichloromethane was distilled off to form fine particles. Next, the obtained fine particles are collected by filtration with a filter having an opening of 20 μm, freeze-dried, and polynuclear fine particles having a structure in which fine regions of lactic acid-glycolic acid containing cisplatin are dispersed in polylactic acid (average particle size). Diameter: about 40μ
m) 440 mg were obtained.

Comparative Example 2 An (O / O) / W emulsion was prepared in the same manner as in Comparative Example 1, and the emulsion was stirred at a temperature of 60 ° C. for 3 hours using a paddle with four blades (400 rpm). Dichloromethane was distilled off to form fine particles. Then 30 ° C
After cooling to below, the obtained fine particles were
Was filtered and freeze-dried to obtain 350 mg of polynuclear fine particles having a structure in which microregions of lactic acid-glycolic acid containing cisplatin were dispersed in polylactic acid.

Example 1 An (O / O) / W emulsion was prepared in the same manner as in Comparative Example 1, and this emulsion was stirred at a temperature of 22 ° C. for 1 hour using a paddle with four blades (400 rpm). After dichloromethane was distilled off to form fine particles, the mixture was heated to 40 ° C. for 1 hour, and further heated to 50 ° C. and stirred for 3 hours to remove residual dichloromethane in the fine particles. Then, after cooling to 30 ° C. or lower, the obtained fine particles were filtered with a filter having a mesh size of 20 μm, and were lyophilized to disperse lactic acid-glycolic acid microdomains containing cisplatin in polylactic acid. Multinuclear fine particles 35 having
0 mg was obtained.

Experimental Example 1 The polynuclear fine particles obtained in Comparative Examples 1 and 2 and Example 1 were measured for the amount of residual organic solvent (dichloromethane), the uptake rate of drug (cisplatin), and the in vitro dissolution test (eluent: pH 7.4 isotonic phosphate buffer, 37 ° C)
The results are shown in Table 1 and FIG. The quantitative determination of the residual dichloromethane in the fine particles was performed by GC-FID method using gas chromatography (column packing: Gas Cropack 54, manufactured by GL Science), and the quantitative determination of cisplatin in the fine particles was performed by HPLC (column: TSK- GEL ODS
-120A, manufactured by Tosoh Corporation).

[0087]

[Table 1]

As is clear from Table 1, the fine particles obtained in Comparative Example 1 contain a considerable amount of residual organic solvent, whereas the fine particles obtained in Comparative Example 2 and Example 1 It contained almost no residual organic solvent. Therefore, in the in-liquid drying method, by forming the fine particles at a temperature equal to or higher than the boiling point of the organic solvent, or by forming the fine particles at a temperature equal to or lower than the boiling point of the organic solvent, by heating to a temperature equal to or higher than the boiling point of the organic solvent. It was found that the organic solvent could be almost completely removed.

However, as is evident from Table 1 and FIG. 1, the fine particles of Comparative Example 2 have a markedly lower drug uptake rate and a different dissolution behavior as compared with the preparation of Comparative Example 1. I have. On the other hand, the fine particles of Example 1 have almost the same drug uptake rate and elution behavior as Comparative Example 1.
Therefore, after forming the fine particles at a temperature below the boiling point of the organic solvent, by heating above the boiling point of the organic solvent,
It has been found that the residual organic solvent can be removed without lowering the drug uptake rate or changing the elution behavior.

[0090]

According to the method of the present invention, the organic solvent remaining in the fine particles comprising a drug and a poorly water-soluble polymer can be removed in a short time, and a very safe fine particle preparation can be easily obtained. it can.

Further, in the method of the present invention, the heating to a temperature higher than the boiling point of the organic solvent is performed not after the step of forming the fine particles but after the formation of the fine particles, so that there is substantially no effect on the drug uptake rate and release characteristics of the fine particles. Do not give.

Further, even if the particles are heated above the glass transition point of the poorly water-soluble polymer constituting the fine particles, the particles are heated in the aqueous phase, so that the fine particles do not aggregate.

[Brief description of the drawings]

FIG. 1 shows fine particles formed at a temperature lower than the boiling point of the organic solvent (Comparative Example 1), fine particles formed at a temperature higher than the boiling point of the organic solvent (Comparative Example 2), and the boiling point of the organic solvent in the in-liquid drying method. 7 is a graph showing the in vitro dissolution behavior of fine particles (Example 1) formed at the following temperatures and then heated to a temperature equal to or higher than the boiling point of the organic solvent to remove the residual organic solvent.

 ────────────────────────────────────────────────── ─── Continued on front page (72) Inventor Masahiko Tanimoto 5-16-14-603 Koshienguchi, Nishinomiya-shi, Hyogo F-term (reference) 4C076 AA61 AA95 CC27 DD35 DD43 EE06 EE24 EE48 FF07 FF22 FF32 FF67 GG27 GG30 GG32

Claims (10)

[Claims] 1. A method for removing an organic solvent having a lower boiling point than water remaining in fine particles comprising a drug and a poorly water-soluble polymer by heating the fine particles in an aqueous phase to a temperature higher than the boiling point of the organic solvent. 2. The method according to claim 1, wherein the amount of the initially remaining organic solvent in the fine particles is 40% by weight or less. 3. The heating temperature is at least 5 ° C. higher than the boiling point of the organic solvent remaining in the fine particles.
The described method. 4. The method according to claim 1, wherein the ratio of the fine particles to the aqueous phase is 0.1 to 1000 g per liter of the aqueous phase containing no fine particles. 5. The method according to claim 1, wherein the organic solvent remaining in the fine particles is an organic solvent having a boiling point lower than that of water by 10 ° C. or higher. 6. The method according to claim 1, wherein the poorly water-soluble polymer is biodegradable. 7. The poorly water-soluble polymer is a polyester of a hydroxy fatty acid, and the organic solvent having a boiling point lower than that of water is a halogenated aliphatic hydrocarbon-based solvent.
The method according to claim 1. 8. The method according to claim 1, wherein the residual organic solvent is removed from the fine particles obtained by a submerged drying method, a phase separation method, and a spray drying method. 9. A solution in which a poorly water-soluble polymer is dissolved in an organic solvent having a boiling point lower than that of water and immiscible with water, the drug is contained therein, and the organic phase thus obtained is dispersed in an aqueous phase to form an O.D.
/ W-type emulsion is prepared, and the organic solvent is distilled off at a temperature lower than the boiling point of the organic solvent to prepare fine particles. A method for producing fine particles from which a residual organic solvent has been removed by removing a solvent. 10. The method according to claim 9, wherein the organic solvent is distilled off from the O / W emulsion and the solvent is removed from the fine particles in the same aqueous phase.