JP6972623B2 - Base for solid dispersion, method for producing solid dispersion using it, and solid dispersion - Google Patents

Description

The present invention relates to a base for a solid dispersion using a polyvinyl alcohol-based resin (hereinafter, may be abbreviated as PVA-based resin), and more particularly to a base for solid-dispersing a drug. Further, the present invention relates to a method for producing a solid dispersion using it and a solid dispersion.

In designing a pharmaceutical product for oral administration, designing a sufficiently high bioavailability is regarded as important from the viewpoint of efficacy and safety.
One of the important factors affecting the bioavailability of pharmaceuticals is the solubility of drugs, and many studies have been conducted on the relationship between solubility and gastrointestinal absorption. Especially for poorly soluble drugs, it is known that the dissolution rate is the rate-determining step of absorption. Various methods are known as a pharmaceutical method for improving the solubility of a poorly soluble drug, and a solid dispersion is particularly noteworthy.
The solid dispersion is a poorly soluble drug dispersed in a base for a solid dispersion (inert carrier) in a solid state, and its production method includes a solvent method, a melting method and a mixed pulverization method (mechanochemical method). And so on.

In the solvent method, the solvent is removed after dissolving both the drug and the base for the solid dispersion which is the carrier in an organic solvent, or the drug is dissolved in the organic solvent and dispersed in the base. It is a method of producing a solid dispersion by removing the solvent later.

The melting method utilizes the melting point drop of the drug and the base for the solid dispersion, and the method of obtaining a solid dispersion by heating, melting, and then cooling, solidifying, and pulverizing both of them, or a drug. Is heated and dissolved in a water-soluble polymer having a relatively low melting point, and this is cooled, solidified, and pulverized to obtain a solid dispersion.

In the mixed pulverization method, the poorly soluble drug and the base for a solid dispersion are mixed and pulverized by a ball mill without heating, or mixed and pulverized by roll mixing or the like to amorphize the poorly soluble drug to form a solid dispersion. It is a manufacturing method.
Mechanochemicals are phenomena in which mechanical energy (compression, shear, friction) changes the physicochemical properties of a substance. In this method, various factors such as lattice defects, lattice irregularities, and increase in specific surface area / surface energy due to mechanical operation improve the activity of the solid, promote the amorphization of the solid, and in the carrier of the amorphized drug. It is thought that it will promote dispersion in the area.

Conventionally, a base for a solid dispersion using a compound having a specific water solubility and an ionic or nonionic polymer has been studied (see, for example, Patent Document 1).
Particularly in recent years, since the glass transition temperature of the PVA-based resin is high, it is expected that the stability of the amorphous portion of the drug will be high, and the use of the PVA-based resin has been studied. For example, a base for a solid dispersion composed of a PVA-based copolymer has been proposed (see, for example, Patent Document 2).

Special Table 2010-536848 Gazette International Publication No. 2008/133102

However, the bases for solid dispersions disclosed in Patent Documents 1 and 2 are insufficient in terms of the dissolution rate of the drug, and further improvement is desired.

Therefore, it is an object of the present invention to provide a base for a solid dispersion for obtaining a solid dispersion having an excellent drug elution rate and a small coloration under such a background.

However, as a result of diligent studies, the present inventors have obtained a solid dispersion having an excellent drug elution rate by using a PVA-based resin containing a small amount of a carboxylic acid metal salt as a base for a solid dispersion. We have found that we can do this, and have completed the present invention.
That is, the present invention relates to the following <1> to <5>.
<1> A base for a solid dispersion, which comprises a polyvinyl alcohol-based resin having a carboxylic acid metal salt content of 0.8% by weight or less.
<2> The base for a solid dispersion according to <1>, wherein the polyvinyl alcohol-based resin has a saponification degree of 80 to 95 mol%.
<3> The base for a solid dispersion according to <1> or <2>, wherein the polyvinyl alcohol-based resin has an average degree of polymerization of 200 to 2500.
<4> A method for producing a solid dispersion, which comprises melting and kneading a mixture of a base for a solid dispersion and a drug according to any one of <1> to <3> and then cooling the mixture.
<5> A solid dispersion containing the base for the solid dispersion and the drug according to any one of <1> to <3>.

According to the present invention, a base for a solid dispersion for obtaining a solid dispersion having a high dissolution rate of a drug can be obtained, and the solid dispersion using such a base for a solid dispersion can be absorbed by a living body. The amount of the active ingredient is increased, and a solid dispersion with less coloring can be obtained, which is highly expected.

Here, the greatest feature of the present invention is the use of a PVA-based resin containing a small amount of a carboxylic acid metal salt.
Generally, PVA-based resins available on the market have a carboxylic acid metal salt (generally sodium acetate) content of more than 1% by weight. The carboxylic acid metal salt is a by-product in the manufacturing process of the PVA-based resin, but since it has advantages that the melt viscosity can be stabilized and an antiseptic effect can be obtained by containing it in the PVA-based resin. The content of the carboxylic acid metal salt has not been reduced more than necessary. However, in the object of the present invention, it has been found that a solid dispersion can be obtained as a base for a solid dispersion, which does not impair the above-mentioned merits, is difficult to color, and has an improved drug elution rate. Is.

Hereinafter, the base for a solid dispersion of the present invention will be described in more detail.
The base for a solid dispersion of the present invention comprises a PVA-based resin having a carboxylic acid metal salt content of 0.8% by weight or less.

<PVA resin>
First, a PVA-based resin will be described.
The PVA-based resin is a resin mainly composed of a vinyl alcohol structural unit obtained by saponifying a polyvinyl ester-based resin obtained by polymerizing a vinyl ester-based monomer, and is a vinyl alcohol structural unit and a vinyl ester corresponding to the degree of saponification. It consists of structural units.

The PVA-based resin used in the present invention has a carboxylic acid metal salt content of 0.8% by weight or less.
Examples of the carboxylic acid of such a carboxylic acid metal salt include formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, capric acid, pelargonic acid, capric acid, lauric acid, mistylic acid, palmitic acid and margarine. Acids, stearic acids, oleic acids, sorbic acids, oxalic acids, malonic acids, succinic acids, glutaric acids, adipic acids, fumaric acids, maleic acids, etc., among others, formic acid, acetic acid, propion from the viewpoint of solubility in water. Acid and capric acid are preferable, and acetic acid is particularly preferable.
Examples of the metal salt include alkali metal salts such as sodium and potassium, and divalent metal salts such as magnesium and calcium. Among them, alkali metal salts are preferable because they have a large effect on the amount used, and particularly sodium. Salt is preferred.
Specifically, sodium acetate is most preferable.

The base for a solid dispersion of the present invention contains the above-mentioned carboxylic acid metal salt in an amount of 0.8% by weight or less in a PVA-based resin, preferably 0.4% by weight or less, and particularly preferably 0.2. It is less than% by weight. If the content is too large, it becomes difficult to obtain the effect of the present invention. Further, from the viewpoint of stability of the melt viscosity, the lower limit of the content is preferably 0.01% by weight, particularly 0.02% by weight, and more preferably 0.03% by weight.

Regarding the method of containing the carboxylic acid metal salt, since a carboxylic acid metal salt such as sodium acetate is usually contained in an amount of about 1.0 to 2.0% by weight as a by-product during saponification, the content is 0.8. A method of washing with an alcohol-based organic solvent such as methanol is preferable so that the weight is less than% by weight.

The saponification degree of the PVA-based resin used in the present invention is preferably 80 to 95 mol%, more preferably 83 to 93 mol%, and even more preferably 85 to 90 mol%. If the saponification degree of the PVA-based resin is too low or too high, the dissolution rate of the drug tends to decrease.
In the present invention, the saponification degree of the PVA-based resin is a value obtained by a method conforming to JIS K 6726.

The average degree of polymerization of the PVA-based resin used in the present invention is preferably 200 to 2500, more preferably 400 to 1500, and particularly preferably 300 to 1000.
If the average degree of polymerization of the PVA resin is too low, the strength tends to decrease and the resin tends to become brittle. If the average degree of polymerization is too high, the melting point becomes high and it tends to be difficult to produce a solid dispersion by the melting method. There is.
In the present invention, the average degree of polymerization of polyvinyl alcohol shall be the average degree of polymerization obtained by a method according to JIS K 6726.

Here, the method for producing the PVA-based resin used in the present invention will be described in more detail.
The PVA-based resin can be obtained, for example, by saponifying a polyvinyl ester-based polymer obtained by polymerizing a vinyl ester-based monomer.
Examples of such vinyl ester-based monomers include vinyl formate, vinyl acetate, vinyl propionate, vinyl valerate, vinyl butyrate, vinyl isobutyrate, vinyl pivalate, vinyl capricate, vinyl laurate, vinyl stearate, and vinyl benzoate. , Vinyl acetate and the like, and vinyl acetate is preferable from the viewpoint of economic efficiency.

Further, a monomer having copolymerizability with the vinyl ester-based monomer can be copolymerized to the extent that the effect of the present invention is not impaired, and examples of such a copolymerizable monomer include ethylene, propylene, isobutylene, and α. -Esters such as octene, α-dodecene, α-octadecene, 3-butene-1-ol, 4-pentene-1-ol, 5-hexene-1-ol, 3,4-dihydroxy-1-butene and the like. Derivatives such as hydroxy group-containing α-olefins and acylated products thereof, unsaturated acids such as acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itaconic acid, and undecylenic acid, salts thereof, monoesters, or dialkyls. Esters such as esters, nitriles such as acrylonitrile and metaacrylonitrile, amides such as diacetone acrylamide, acrylamide and methacrylamide, olefin sulfonic acids such as ethylene sulfonic acid, allyl sulfonic acid and methallyl sulfonic acid, salts thereof and alkyls. Vinyl ethers, dimethylallyl vinyl ketone, N-vinylpyrrolidone, vinyl chloride, vinylethylene carbonate, 2,2-dialkyl-4-vinyl-1,3-dioxolane, vinyl compounds such as glycerin monoallyl ether, isopropenyl acetate, 1 -Substituted vinyl acetates such as methoxyvinyl acetate, vinylidene chloride, 1,4-diacetoxy-2-butene, 1,4-dihydroxy-2-butene, vinylene carbonate, 1,3-diacetoxy-2-methylenepropane, 1, Examples thereof include hydroxymethylvinylidene diacetates such as 3-dipropionyloxy-2-methylenepropane and 1,3-dibutyronyloxy-2-methylenepropane. The content of the copolymerized monomer is usually 10 mol% or less, preferably 5 mol% or less, and particularly preferably 1 mol% or less, based on the total amount of the polymer. In the present invention, from the viewpoint of safety, unmodified PVA consisting of only a vinyl alcohol structural unit and an unsaponified portion of the vinyl ester structural unit is preferable.

There are no particular restrictions on the polymerization of the vinyl ester-based monomer and the copolymerization monomer, and known methods such as bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, and emulsion polymerization can be adopted, but usually. Solution polymerization is performed.

Examples of the solvent used in such polymerization usually include aliphatic alcohols having 1 to 4 carbon atoms such as methanol, ethanol, isopropyl alcohol, n-propanol and butanol, and ketones such as acetone and methyl ethyl ketone, which are industrially used. Methanol is preferably used.
Further, the polymerization reaction is carried out using, for example, known radical polymerization catalysts such as azobisisobutyronitrile, acetyl peroxide, benzoyl peroxide, and lauroyl peroxide, and various known low temperature active catalysts. The reaction temperature is selected from a range of 35 ° C. or higher and lower than the boiling point of a known radical polymerization catalyst or various known low temperature active catalysts.

The obtained polyvinyl ester-based polymer is then saponified by a continuous method or a batch method. For such saponification, either alkaline saponification or acid saponification can be adopted, but industrially, alkaline saponification performed by dissolving the polymer in alcohol and performed in the presence of an alkaline catalyst is preferable.
As the alcohol, for example, aliphatic alcohols having 1 to 4 carbon atoms such as methanol, ethanol, isopropyl alcohol, n-propanol and butanol are preferable, and methanol and ethanol are more preferable. The concentration of the polymer in the alcohol is selected from the range of 20-60% by weight. Further, if necessary, about 0.3 to 10% by weight of water may be added, and further, various esters such as methyl acetate and various solvents such as benzene, hexane and DMSO (dimethyl sulfoxide) are added. You may.

Specific examples of the above-mentioned alkaline catalyst include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethyllate, and potassium methylate, and alkali catalysts such as alcoholate. The amount of such a catalyst used is preferably 1 to 100 mmol equivalent with respect to the monomer.

After saponification, the obtained PVA-based resin is washed with a washing liquid. Examples of the cleaning liquid include alcohols such as methanol, ethanol, isopropyl alcohol and butanol, and methanol is preferable from the viewpoint of cleaning efficiency and drying efficiency.

Examples of the cleaning method include a batch type cleaning method and a continuous type cleaning method, and a batch type cleaning method is usually adopted. Examples of the stirring method (device) during cleaning include screw blades, ribbon blenders, kneaders and the like.
In addition, examples of the cleaning device include a cylindrical cleaning device, a countercurrent contact type cleaning device, and a centrifugal cleaning device.
The bath ratio (mass of cleaning liquid / mass of polyvinyl ester-based polymer particles) is usually 1 to 30, and particularly preferably 2 to 20. If the bath ratio is too large, a large cleaning device is required, which tends to increase the cost, and if the bath ratio is too small, the cleaning effect tends to decrease and the number of cleanings tends to increase.

The temperature at the time of washing is usually 10 to 80 ° C, particularly preferably 20 to 70 ° C. If the temperature is too high, the amount of volatilization of the cleaning liquid increases, which tends to require a reflux facility. If the temperature is too low, the cleaning efficiency tends to decrease. The washing time is usually 5 minutes to 12 hours, particularly preferably 30 minutes to 4 hours. If the washing time is too long, the production efficiency tends to decrease, and if the washing time is too short, the washing tends to be insufficient and a large amount of carboxylic acid metal salt tends to remain. The number of washings is usually 1 to 10 times, and particularly preferably 1 to 5 times. Too many washes tend to reduce productivity and increase costs.

The washed particles of the polyvinyl ester-based polymer kenmono are dried by hot air or the like in a continuous or batch manner to obtain a powder of the PVA-based resin used in the present invention. The drying temperature is usually 50 to 150 ° C., particularly preferably 60 to 130 ° C., particularly preferably 70 to 110 ° C. If the drying temperature is too high, the PVA-based resin tends to be thermally deteriorated, and if the drying temperature is too low, it tends to take a long time to dry. The drying time is usually 1 to 48 hours, particularly preferably 2 to 36 hours. If the drying time is too long, the PVA-based resin tends to be thermally deteriorated, and if the drying time is too short, the drying tends to be insufficient or high temperature drying tends to be required.

The content of the solvent contained in the powder of the PVA-based resin after drying is usually 0 to 10% by weight, particularly 0.01 to 5% by weight, particularly 0.1 to 1% by weight. Is preferable.

Thus, the PVA-based resin used in the present invention is obtained, and by containing this, it becomes the base for the solid dispersion of the present invention.
In the base for a solid dispersion of the present invention, the content of the PVA-based resin is preferably 20% by weight or more, more preferably 30 to 90% by weight, and 40 to 40% by weight with respect to the entire base for a solid dispersion. 80% by weight is more preferable. If the content is too low, the amorphous state of the drug tends to be unmaintainable. If the content of the PVA-based resin is too large, the content of the drug tends to decrease, and the amount of the drug to be administered in order to exert the medicinal effect tends to increase.

Further, the solid dispersion of the present invention comprises the base for the solid dispersion of the present invention and a drug.
<Drug>
Next, the drug will be described.
Examples of the drug contained in the solid dispersion of the present invention include the following.
(1) Antifever, analgesic, anti-inflammatory agents For example, salicylic acid, sulpyrine, flufenamic acid, diclofenac, indomethacin, atropin, scopolamine, morphine, petidin, levorphanol, ketoprofen, naproxen, ibuprofen, oxymorphon, aspirin, aminopyrine, phenacetin, Acetaminophenone, phenylbutazone, ketophenylbutazone, mefenamic acid, bucolome, benzydamine, mepyridamine, thialamide, tynolysine, xylocaine, pentazocin, dexamethacin, hydrocortisone, prednisolone, azulene, isopropylantipyrine, sazapyrin, clofezone, etodrug or itss. Examples include salt.

(2) Psychotropic agents Examples thereof include diazepam, lorazepam, oxazepam, oxazolam, clotiazepam, medazepam, temazepam, fludiazepam, meprobamate, nitrazepam, and chlordiazepamide.

(3) Antipsychotic agents For example, chlorpromazine, prochlorperazine, triflorazine, sulpiride, clocapramine hydrochloride, zotepine, haloperidol and the like can be mentioned.

(4) Antibacterial agents For example, griseofulvin, lancasidins [J. Antibiotics, 38,877-885 (1985)], azole compounds [2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1) , 2,4-Triazole-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl-3- (2H, 4H) -1,2,4-triazolone, Fluconazole, itraconazole, etc.], nalidixic acid, pyromidic acid, pipemidic acid trihydrate, enoxacin, cinoxacin, ofloxacin, norfloxacin, cyproxacin hydrochloride, sulfamethoxazole / trimethoprim and the like.

(5) Antibiotics For example, gentamicin, dipecacin, canendamicin, ribidomycin, topramycin, amicacin, dibecacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, loritetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalotin, cephalotin. , Cefotaxime, cefothium hexethyl, cefthrosin, cefmenoxime, cefmethazole, cefazoline, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamicin, sulfazecin, azthreonum, amoxylin, cephalexin, erythromycin Be done.

(6) Antineoplastic agents For example, 6-O- (N-chloroacetylcarbamoyl) fumaguilol, bleomycin, methotrexate, actinomycin D, mitomycin C, doxorubicin, adriamycin, neocarmustine, cytosine aradinoside, fluorouracil, tetrahydrofuryl. -5-Fluorouracil, pisibanil, lentinan, levamizol, bestatin, azimexone, glycyrrhizin, HER2 inhibitor (heterocyclic compound described in International Publication No. 01/77107, etc.), taxol, doxorubicin hydrochloride, etoposide, mitoxanthrone, mesna , Dimesna, aminoglutetimide, tamoxifen, acroline, cisplatin, carboplatin, cyclophosphamide, lomustine (CCNU), carmustine (BCNU) and the like.

(7) Antihyperlipidemic agents For example, clofibrate, 2-chloro-3- [4- (2-methyl-2-phenylpropoxy) phenyl] ethyl propionate [Chem. Pharm. Bull. , 38, 2792-2996 (1990)], clinofibrate, cholestyramine, soysterol, tocopherol nicotinate, nicomol, niceritrol, probucol, elastase and the like.

(8) Antitussives and expectorants For example, ephedrine, methylephedrine, noscapine, codeine, dihydrocodeine, allocramide, cloperastine, picoperidamine, cloperastine, protochilol, isoproterenol, salbutamol, tereptalin, bromhexine, carbocystin, ethylcystine, Examples include methylcystine or salts thereof.

(9) Muscle relaxants For example, pridineol, tuboclarine, pancronium, chlorphenesin carbamate, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, mephenesine, chlorzoxazone, fenprobamate, metcarbamol, chlormesanone, pridinor mesylate, afroqualon, baclofen. , Dantrolene sodium and the like.

(10) Antiepileptic drugs Examples thereof include phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, phenobarbital, carbamazepine, primidone and the like.

(11) Anti-ulcer agents Examples thereof include lansoprazole, metoclopramide, famotidine, omeprazole, sulpiride, trepibutone, cetraxate hydrochloride, gefernato, irsogladine maleate, cimetidine, ranitidine hydrochloride, nizatidine, and roxatidine acetate.

(12) Antidepressants For example, imipramine, clomipramine, noxiptiline, phenelzine and the like can be mentioned.

(13) Antiallergic agents Examples thereof include diphenhydramine, chlorpheniramine, triperenamine, methodiramine, cremizol, diphenylpyraline, methoxyphenamine, clemastine fumarate, cyproheptadine hydrochloride, mequitazine, and alienmemazine tartrate.

(14) Cardiotonic agents For example, transbioxocamphor, terephyllol, aminophylline, etilefrine and the like can be mentioned.

(15) Antiarrhythmic agent For example, propranolol, alprenolol, pfetrol, oxprenolol, procainamide hydrochloride, disopyramide, azimarin, quinidine sulfate, aprindine hydrochloride, propafenone hydrochloride, mexiletine hydrochloride and the like can be mentioned.

(16) Vasodilators For example, oxyfedrin, diltiazem, trazoline, hexobendin, bamethane, nifedipine, nilvadipine, isosorbit dinitrate, diltiazem hydrochloride, trapidil, dipyridamole, dilazep hydrochloride, verapamil, nicardipine hydrochloride, ifenprodil tartrate, cinepaside maleate. , Cyclanderate, sinnaridine, pentoxyphyllin and the like.

(17) Antihypertensive diuretics For example, hexamethonium bromide, pentrinium, mechamilamine, ecarazine, chronidine, zirthiazide, nifedipine, furosemide, trichlormethiazide, methiclotiazide, hydrochlorothiazide, hydroflumethiazide, ethiazide, cyclopentiazide, fluorothiazide, ethacrine. Examples include acid.

(18) Diabetes therapeutic agent For example, glymidin, glypzide, fenformin, pformin, metformin, glibenclamide, tolbutamide and the like can be mentioned.

(19) Anti-tuberculosis drug For example, isoniazid, ethambutol, para-aminosalicylic acid and the like can be mentioned.

(20) Drug antagonists For example, levallorphan, nalorphine, naloxone or salts thereof may be mentioned.

(21) Hormonal agents Examples thereof include steroid hormones such as dexamesazone, hexestrol, methimazole, petamesazone, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, prednisolone, hydrocortisone and estriol.

(22) bone and cartilage disease preventive and therapeutic agents for example, prostaglandin A1 derivative, vitamin D derivative, vitamin K ₂ derivative, eicosapentaenoic acid derivative, benzylphosphonic acid, bisphosphonic acid derivative, sex hormone derivative, phenol sulfonium phthalein Examples thereof include non-peptide bone formation promoting agents such as derivatives, benzothiopyran or benzothiepine derivatives, thienoindazole derivatives, menatetrenone derivatives, helioxanthin derivatives, and peptide bone formation promoting substances.

(23) Therapeutic agents for joint diseases For example, p38MAP kinase inhibitors (thiazole compounds described in International Publication No. 00/6894, etc.), matrix metalloprotease inhibitors (MMPI), prednisolone, hydrocortisone, methylprednisolone, dexabetamethasone, etc. Examples thereof include anti-inflammatory steroids such as betamethasone, non-steroidal anti-inflammatory analgesics such as indomethacin, diclofenac, loxoprofen, ibuprofen, pyroxicum and slindac.

(24) Therapeutic agent for pollakiuria Hydrochloric acid For example, flavoxate, oxybutynin hydrochloride, terolidin hydrochloride and the like can be mentioned.

(25) Anti-androgen agent Examples thereof include oxendolone, allylestrenol, chlormadinone acetate, guestnolone caproate, osapron acetate, flutamide, bicalutamide and the like.

(26) Fat-soluble vitamin drugs For example, vitamin Ks: vitamins K ₁ , K ₂ , K ₃ and K ₄ , folic acid (vitamin M) and the like can be mentioned.

(27) Vitamin Derivatives For example, various derivatives of vitamins, for example, vitamin D ₃ derivatives such as 5,6-trans-choleciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, 5, _{Examples thereof include vitamin D 2} derivatives such as 6-trans-ergocalciferol.

(28) Others Hydroxycam, diaserine, megestrol acetate, fake rogulin, prostaglandins, etc., as well as ischemic disease therapeutic agents, immune disease therapeutic agents, Alzheimer's disease therapeutic agents, osteoporosis therapeutic agents, angiogenesis therapeutic agents, retina Disease treatment drug, retinal vein occlusion treatment drug, senile discoid leukoplakia treatment drug, cerebrovascular spasm treatment drug, cerebral thrombosis treatment drug, cerebral infarction treatment drug, cerebral occlusion treatment drug, intracerebral hemorrhage treatment drug, spider membrane Lower bleeding drug, hypertensive encephalopathy drug, transient cerebral ischemic attack drug, multiple infarct dementia drug, arteriosclerosis drug, Huntington disease drug, brain tissue disorder drug, optic neuropathy drug , Glaucoma, hypertension, retinal detachment, arthritis, anti-rheumatic, anti-septic, anti-septic shock, anti-asthma, atopic dermatitis, allergic rhinitis And so on.

In addition, sparingly soluble drugs are preferable from the viewpoint of improving solubility, and examples of such sparingly soluble drugs include carbamatepine, indomethacin, naproxen, ibuprofen, phenacetin, phenylbutazone, glyceofrubin, azole compounds, phenytoin, isosorbit dinitrate, and the like. Examples thereof include nitrophenylpyridine compounds. The nitrophenylpyridine-based compound includes a sparingly soluble compound having a nitrophenyl group and a pyridine ring structure. As the nitrophenylpyridine compound, a compound having a structure in which a nitrophenyl group is bonded to any of the 2-position to 4-position of the pyridine ring is preferable. Specific examples thereof include nifedipine and nilvadipine.

The content of the above drugs is appropriately adjusted according to bioavailability. The drug may be diluted with a diluent generally used in the medical and food fields. Further, those treated for the purpose of masking the bitterness of the drug may be used.

<Other additives>
Various additives can be added to the solid dispersion of the present invention as long as the effects of the present invention are not impaired. Examples of the additive include excipients, disintegrants, pH adjusters, fluidizers, surfactants, colorants, sweeteners and coating agents.

As the excipient, for example, one or more components selected from sugar alcohols, sugars, calcium phosphates, crystalline celluloses, starches, sodium phosphates, gelatin and the like are used. Preferred excipients include sugar alcohols and sugars.
Examples of sugar alcohols include mannitol, erythritol, xylitol, sorbitol and maltitol. Examples of sugars include glucose, fructose, lactose, sucrose, trehalose, maltose and oligosaccharides.

Examples of the disintegrant include carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, cellulose or a derivative thereof, starch or a derivative thereof, and the like.

Examples of the pH adjuster include citric acid and its salt, phosphoric acid and its salt, carbonic acid and its salt, tartrate acid and its salt, fumaric acid and its salt, acetic acid and its salt, amino acids and its salt, succinic acid and its salt. Examples thereof include salt, lactic acid and its salt.

Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, stearic acid, corn gel and heavy anhydrous silicic acid.

Examples of the surfactant include phospholipid, glycerin fatty acid ester, polyoxyethylene fatty acid ester, sorbitan fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, sucrose fatty acid ester, and lauryl sulfate. Examples thereof include sodium, polysorbates, sodium hydrogen phosphates and potassium hydrogen phosphates.

Examples of the colorant include iron sesquioxide, yellow iron sesquioxide, edible yellow No. 5, edible yellow No. 4, aluminum chelate, titanium oxide and talc.

Examples of the sweetener include saccharin, aspartame, acesulfame potassium, thaumatin and sucralose.

Examples of the coating agent include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, ethyl polyvinylpyrrolidone acrylate, methyl methacrylate copolymer dispersion, hydroxypropylmethyl cellulose acetate succinate and methacrylic acid copolymer.

<Manufacturing method of solid dispersion>
Examples of the method for producing a solid dispersion of the present invention include the following methods.
(I) Solvent method: A method of dissolving a drug and a base in an organic solvent and then removing the solvent.
(Ii) Melting method: A method in which a drug and a base are heated, melted and kneaded, and then cooled and solidified.
(Iii) Mixed pulverization method (mechanochemical method): A method of atomizing or dispersing a drug in a base using mechanical energy such as compression, shearing, and friction.
Among the above, the melting method of (ii) is preferable from the viewpoint of crystal control.
The melting method will be described in detail below.

The melting method is a method of obtaining a solid dispersion by heat-treating a mixture of a drug and a base for a solid dispersion and adjusting the form of the heat-treated product (crushing, powdering, molding, etc.) as necessary. be.

The heat treatment of the mixture of the drug and the base for the solid dispersion of the present invention may be performed at a temperature at which the entire mixture is melted, a temperature at which a part of both is melted, or even if the mixture is not melted. Depending on the temperature conditions, the temperature condition at which part or all of the drug is amorphized can be selected.
Even if melting does not occur, a solid dispersion can be obtained by amorphizing a part or all of the drug, and in the present invention, this case is also included in the melting method. ..

The mixture of the drug and the base for the solid dispersion is a mixture obtained by mixing the drug with the base for the melted solid dispersion, or the base for the solid dispersion and the drug are dry-blended and then melt-kneaded. It contains a mixture obtained by the above method.

The heating means used for the heat treatment is not particularly limited, and an appropriate heating means available by those skilled in the art can be adopted, and more specifically, a dryer, an oil bath, an electric furnace, or the like can be used. Heating, heating by ultrasonic irradiation, heating by biaxial kneading treatment, heating by uniaxial and biaxial melt extrusion treatment (extruder), heating by microwave irradiation, etc.

The means for adjusting the form of the heat-treated product is not particularly limited, and appropriate means available to those skilled in the art can be adopted, and for example, crushing means, molding means and the like can be adopted. Examples of the molding means include extrusion molding (for example, single-screw extrusion, twin-screw extrusion, multi-screw extrusion, hot melt calendar method), injection molding (for example, twin-screw extruder), and compression molding (for example, tableting and granulation). Etc. are exemplified.

When the production of the solid dispersion by the heat treatment and the adjustment of the form of the solid dispersion are performed at the same time, a device for adjusting the form of the heat-treated product provided with the heating means may be adopted.

The temperature of the heat treatment does not necessarily have to be the temperature at which the object to be heated melts. It is known that a solid dispersion can be produced at a heating temperature lower than the melting temperature, and in the present invention as well, by producing a solid dispersion at a temperature as low as possible, a drug that decomposes or deteriorates at a high temperature is also solid-dispersed. Can be a body. It is usually 80 to 220 ° C, preferably 120 to 200 ° C, and more preferably 150 to 200 ° C. In the ultrasonic irradiation, ultrasonic waves are applied to the powder mixture, and in the case of heating by ultrasonic irradiation, the ultrasonic irradiation energy is usually 600 to 2000 J, preferably 700 to 1800 J, and more preferably 800 to 1300 J. .. As such an apparatus, an ultrasonic molding machine USTM / L20 manufactured by Technea Engineering Co., Ltd. can be used. In such a device, a powder mixture of a drug, a base for a solid dispersion and, if necessary, an additive is filled in a mortar provided in the device, and the mixture is compression-molded while being irradiated with ultrasonic waves. ..

Further, some twin-screw extruders, twin-screw extruders, and the like are provided with heating means, and as the heat treatment in the present invention, twin-screw extrusion provided with means for compression molding while irradiating ultrasonic waves and heating means. Manufacture by a twin-screw extruder equipped with a molding machine and heating means is preferable.

Thus, a solid dispersion using the base for a solid dispersion of the present invention can be obtained, and the obtained solid dispersion has an excellent drug elution rate and is less colored.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples as long as the gist of the present invention is not exceeded.
In the example, "part" and "%" mean the weight standard.

Example 1 [Preparation of base for solid dispersion]
280 parts of vinyl acetate, 300 parts of methanol, and 0.10 mol% of azobisisobutyronitrile (against charged vinyl acetate) were charged in a reaction can equipped with a reflux cooler, a dropping funnel, and a stirrer, and under a nitrogen stream. The temperature was raised with stirring until reflux started, and 30 minutes after reflux started, 720 parts of vinyl acetate was added dropwise at a constant velocity for 9.5 hours to carry out polymerization. After the completion of the dropping, when the polymerization rate of vinyl acetate reaches 92%, m-dinitrobenzene is added to complete the polymerization, and then the unreacted vinyl acetate monomer is removed from the system by a method of blowing methanol vapor. It was removed to obtain a methanol solution (resin content 53%) of the vinyl acetate polymer.

Subsequently, the methanol solution was further diluted with methanol to adjust the concentration to 50%, and the solution was charged into the kneader. While maintaining the solution temperature at 35 ° C., a 4% methanol solution of sodium hydroxide was added at a ratio of 6.0 mmol to 1 mol of the vinyl acetate structural unit in the polymer to perform keratinization. As the saponification progressed, the saponified product was precipitated, and when it became particulate, it was separated by solid-liquid separation and dried.
The degree of saponification of the obtained dry powder of the PVA-based resin was 88 mol% when analyzed by the amount of alkali consumed for hydrolysis of the residual vinyl acetate, and the viscosity of the 4% aqueous solution was 5.6 mPa. The average degree of polymerization was 600.

The dry powder of the PVA-based resin obtained above was put into methanol having a bath ratio of 10 and stirred for 3 hours for washing. Then, solid-liquid separation was performed, and the obtained PVA-based resin powder was vacuum-dried at 90 ° C. until the volatile content became 1% or less to obtain a dry powder of PVA-based resin, which was used as a base for a solid dispersion. ..
The sodium acetate content was determined by dissolving a dry powder of a PVA-based resin in water, using methyl orange as an indicator, and neutralizing and titrating with hydrochloric acid. The content of sodium acetate was 0.1%.

The method of neutralization titration will be described in detail below.
First, 3.00 g of the dry powder of the PVA-based resin and 100 ml of water were put into the Erlenmeyer flask, placed in a heating / stirring / dissolving machine, and heated and stirred until the dry powder of the PVA-based resin was completely dissolved. Next, the air-cooling tube was removed and left for 30 minutes to expel the residual solvent in the dry powder of the PVA-based resin and cool it to room temperature.
Three drops of methyl orange were added dropwise to 100 ml of the obtained PVA-based resin aqueous solution and 100 ml of pure water (blank test, standard color). 0.1N-HCl was dropped drop by drop into the PVA-based resin aqueous solution, titration was continued until the same color as pure water was obtained, and the amount of sodium acetate was calculated from the amount of 0.1N-HCl required for neutralization. ..

[Preparation of solid dispersion]
44 parts of the above base for solid dispersion and 11 parts of carbamazepine as a drug are mixed, melt-kneaded with a twin-screw kneader (Plastograph manufactured by Brabender) under the following conditions, and melt-kneaded from the inside after the kneading is completed. The substance was taken out and cooled at room temperature to obtain the solid dispersion of the present invention.

(Melting and kneading conditions)
Screw rotation speed: 50 rpm
Set temperature: 200 ° C
Preheating time: 3 minutes Kneading time: 5 minutes The obtained solid dispersion was evaluated as follows.

[Elution rate evaluation]
The dissolution rate was measured according to the second method of the dissolution test in accordance with the third part of the Japanese Pharmacopoeia Pharmaceutical Standards "Carbamazepine Fine Granules". In order to calculate the elution rate, the absorbance was measured with a UV absorbance meter (ultraviolet visible spectrophotometer, "V-560" manufactured by Shimadzu Corporation). Specifically, 900 mL of water was put into a glass container with a stirring blade, 1.2 g of the solid dispersion obtained above was put into the container, and the mixture was stirred. After 180 minutes, 20 mL of the sample was withdrawn, and a membrane filter (DISMIC 0. The mixture was filtered through a 45 μm φ25 mm ADVANTEC company), 2 mL of which was collected, and further diluted to 50 mL to prepare a measurement sample.

Separately, a known carbamazepine (manufactured by Wako Pure Chemical Industries, Ltd.) with a purity of 98% or more is dried at 105 ° C. for 2 hours, about 0.022 g thereof is weighed, dissolved in 10 mL of methanol, and water is added to make exactly 100 mL. I made it. 4 mL of this solution was diluted with water to 100 mL to make a standard solution. Using the standard solution, sample solution, and water as a reference, the ultraviolet-visible absorbance measurement method (ultraviolet-visible spectrophotometer, "V-560" manufactured by Shimadzu Corporation) was used to measure the wavelength at 285 nm, and the absorbances At and As were measured. ..

The elution rate of carbamazepine was calculated by the following formula. The results are shown in Table 1.
Elution rate (%) = (Ws / Wt) x (At / As) x (1 / C) x 900
Ws: Collection amount (mg) of carbamazepine standard product
Wt: Sample collection amount (g) at the time of elution rate measurement
C: Amount of carbamazepine in 1 g of sample (mg)
At: Absorbance of the sample at 285 nm (abs.)
As: Absorbance of carbamazepine standard solution at 285 nm (abs.)

[Coloring evaluation]
Under the following conditions, the above solid dispersion was formed into a plate and the YI (yellow index) value was measured to evaluate the coloring. (Plate making method)
Equipment: NSF-37 type single-acting compression molding machine (manufactured by Shinto Metal Industry Co., Ltd.)
Temperature: 220 ° C
Preheating: 8 minutes Press time: 10 minutes Plate size: 30 mm x 50 mm x 0.8 mm

(YI measurement conditions)
Equipment: Spectral color difference meter SE-6000 (manufactured by Nippon Denshoku Industries Co., Ltd.)
Measurement method: Reflection method Number of measurements: 2 times

Example 2
In Example 1, the evaluation was carried out in the same manner as in Example 1 except that the washing bath ratio of PVA was 5 and the washing time was 1 hour. The results are shown in Table 1.

Comparative Example 1
In Example 1, the evaluation was carried out in the same manner as in Example 1 except that the cleaning step of the PVA-based resin was eliminated. The results are shown in Table 1.

In the solid dispersion (Examples 1 and 2) using the base for the solid dispersion of the present invention, the elution rate was high and the bioavailability was excellent. On the other hand, Comparative Example 1 having a high sodium acetate content had a low elution rate and low bioavailability.
Further, in the solid dispersion using the base for the solid dispersion of the present invention, the YI value was small and the coloring was small. On the other hand, Comparative Example 1 having a high sodium acetate content was highly colored.

The solid dispersion of the present invention is useful for pharmaceutical preparations because it has a high drug elution rate, high bioavailability, and low coloring.

Claims (3)

Contains a polyvinyl alcohol-based resin having a carboxylic acid metal salt content of 0.8% by weight or less ,
The degree of saponification of the polyvinyl alcohol-based resin is 80 to 95 mol%, and the saponification degree is 80 to 95 mol%.
The polyvinyl alcohol-based resin has an average degree of polymerization of 200 to 2500, and has an average degree of polymerization of 200 to 2500.
A base for a solid dispersion, wherein the content of the polyvinyl alcohol-based resin is 20% by weight or more with respect to the entire base for the solid dispersion. A method for producing a solid dispersion, which comprises melting and kneading a mixture of a base for a solid dispersion and a drug according to claim 1 and then cooling the mixture. A solid dispersion containing the base for a solid dispersion and a drug according to claim 1.