JP2023057068A - Base for solid dispersion - Google Patents

Abstract

To provide a base for a solid dispersion, which gives a solid dispersion having a favorable elution rate of an agent.SOLUTION: A base for a solid dispersion contains a polyvinyl alcohol resin, the polyvinyl alcohol resin having a degree of saponification of 70-85 mol%, and the polyvinyl alcohol resin having an average degree of polymerization of 1000 or more.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to a solid dispersion base using a polyvinyl alcohol resin (hereinafter sometimes abbreviated as PVA resin).

In the design of formulations for oral administration, designing bioavailability to be sufficiently high is emphasized in terms of efficacy and safety.

One of the important factors affecting the bioavailability of pharmaceuticals is drug solubility, and many studies have been conducted on the relationship between drug solubility and gastrointestinal absorption. Especially for poorly soluble drugs, it is known that the dissolution rate is the rate-limiting step for absorption. Various formulation methods are known for improving the solubility of poorly soluble drugs, and solid dispersions are particularly noteworthy.

A solid dispersion is obtained by dispersing a sparingly soluble drug in a solid dispersion base (inert carrier) in a solid state. etc.

In the solvent method, the drug and the solid dispersion base (carrier) are dissolved in an organic solvent and then the solvent is removed, or the drug is dissolved in an organic solvent and dispersed in the base. In this method, the solvent is removed later to produce a solid dispersion.

The melting method utilizes the melting point depression of the drug and the base for solid dispersion. is heated and dissolved in a water-soluble polymer having a relatively low melting point, which is then cooled, solidified and pulverized to obtain a solid dispersion.

In the mixed pulverization method, the poorly soluble drug and the solid dispersion base are mixed and pulverized by a ball mill without heating, or mixed and pulverized by roll mixing, etc., to make the poorly soluble drug amorphous and form a solid dispersion. It is a method of manufacturing a body.

Mechanochemicals are phenomena in which mechanical energy (compression, shear, friction) causes changes in the physicochemical properties of matter. In this method, various factors such as lattice defect, lattice mismatch, increase in specific surface area and surface energy due to mechanical manipulation improve the activity of the solid, promote the amorphization of the drug, and promote the amorphization of the drug. It is thought that it will bring about the promotion of dispersion to

Technologies related to such solid dispersions include, for example, Patent Document 1, which contains one or more sparingly soluble active pharmaceutical ingredients uniformly dispersed in a polyvinyl alcohol (PVA) matrix as a functional excipient. A composition, wherein a) PVA, at least one sparingly soluble active pharmaceutical ingredient, and optionally at least one treating agent are placed in a chamber of a thermokinetic mixer; The mixer is thoroughly compounded for a residence time of less than 300 seconds, preferably 5-180 seconds, more preferably 7-60 seconds, most preferably 10-30 seconds to minimize heat exposure of the compounded material. , whereby the temperature of the chamber of the thermokinetic mixer is reduced by rotational shear forces and frictional energy to a temperature in the range 100-200°C, preferably in the range 100-150°C, especially in the range 100-130°C. and c) thereby forming a melt-blended pharmaceutical composition of the active pharmaceutical ingredient, functional excipients and optional processing agents. A composition is disclosed.

US Pat. No. 5,300,003 discloses the use of spray dried sorbitol as a plasticizer in polymer-containing compositions for hot melt extrusion (HME) or melt extrusion processes.

In WO 03/031003, an extrudable polyvinyl alcohol (PVA) powder with improved flowability, which is milled and has a thickness in the range of 45-1400 μm, preferably in the range of 45-1000 μm, most preferably in the range of 50 Said powders are disclosed having particle sizes in the range of -300 μm.

US Pat. No. 6,200,401 discloses direct molded tablets produced from polyvinyl alcohol (PVA)-based extrudates with an anti-alcoholic dose-dumping effect.

In US Pat. No. 5,230,000, after extrusion and milling to a particle size in the range of ≦200 μm (d50), preferably in the range of 60-120 μm (d50), most preferably in the range of 70-110 μm (d50) Disclosed is a polyvinyl alcohol (PVA) containing powder characterized by exhibiting improved flowability and feasibility in direct compression into tablets.

Japanese Patent Publication No. 2018-502160 Japanese translation of PCT publication No. 2019-515006 Japanese Patent Publication No. 2019-520325 Japanese Patent Publication No. 2019-533699 Japanese Patent Publication No. 2019-534293

However, according to the studies of the present inventors, there is room for further improvement in the drug elution rate in the techniques disclosed in Patent Documents 1 to 5.

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned conventional circumstances, and an object of the present invention is to provide a base for a solid dispersion that provides a solid dispersion having an excellent drug elution rate.

The present inventors have made intensive studies to achieve the above objects, and as a result, have found that the above problems can be solved by the following solid dispersion base, and have completed the present invention.

That is, the present invention relates to the following <1> to <3>.
<1> A solid dispersion base containing a polyvinyl alcohol resin,
The degree of saponification of the polyvinyl alcohol resin is 70 to 85 mol%,
A base for solid dispersion, wherein the polyvinyl alcohol-based resin has an average degree of polymerization of 1,000 or more.
<2> A method for producing a solid dispersion, comprising the step of melt-kneading the mixture of the base for solid dispersion and the drug according to <1> and then cooling the mixture.
<3> A solid dispersion containing the base for solid dispersion according to <1> and a drug.

By using the solid dispersion base of the present invention, a solid dispersion having an excellent drug elution rate can be obtained.

FIG. 1 is a graph showing the results of dissolution rate evaluation performed in Examples.

Although the present invention will be described in detail below, these show examples of preferred embodiments, and the present invention is not limited to these contents.

The solid dispersion base of the present invention contains a PVA-based resin.

<PVA-based resin>
PVA-based resin is a resin mainly composed of vinyl alcohol structural units obtained by saponifying a polyvinyl ester-based resin obtained by polymerizing a vinyl ester-based monomer. Consists of structural units.

The degree of saponification of the PVA-based resin used in the present invention is 70-85 mol %. If the degree of saponification of the PVA-based resin is less than 70%, the water-solubility tends to be remarkably lowered and the dissolution rate tends to be low. When the degree of saponification of the PVA-based resin exceeds 85 mol %, the compatibility with the drug decreases, making it difficult to maintain the drug in an amorphous state, which tends to lower the dissolution rate. If the degree of saponification of the PVA-based resin is too low or too high, the elution rate of the drug tends to decrease.

The degree of saponification of the PVA-based resin is preferably 72-85 mol %, more preferably 75-80 mol %.
In the present invention, the degree of saponification of the PVA-based resin is a value obtained by a method conforming to JIS K6726.

Moreover, the average degree of polymerization of the PVA-based resin used in the present invention is 1000 or more. If the average degree of polymerization of the PVA-based resin is less than 1000, the strength tends to decrease and the resin tends to become brittle.

The average degree of polymerization of the PVA-based resin is preferably 1,000 to 3,000, more preferably 1,500 to 2,700, and even more preferably 2,000 to 2,500.
In addition, in this invention, the average degree of polymerization calculated|required by the method based on JISK6726 shall be used for the average degree of polymerization of PVA-type resin.

Here, the method for producing the PVA-based resin used in the present invention will be described in more detail.
A PVA-based resin is obtained, for example, by saponifying a polyvinyl ester-based polymer obtained by polymerizing a vinyl ester-based monomer.

Examples of such vinyl ester monomers include vinyl formate, vinyl acetate, vinyl propionate, vinyl valerate, vinyl butyrate, vinyl isobutyrate, vinyl pivalate, vinyl caprate, vinyl laurate, vinyl stearate, and vinyl benzoate. , vinyl versatate, etc., and vinyl acetate is preferred from the viewpoint of economy.

Further, a monomer having copolymerizability with the vinyl ester monomer can be copolymerized to the extent that the effect of the present invention is not impaired. Examples of such copolymerizable monomers include olefins such as ethylene, propylene, isobutylene, α-octene, α-dodecene and α-octadecene, 3-buten-1-ol, 4-penten-1-ol, 5 - hydroxy group-containing α-olefins such as hexen-1-ol and 3,4-dihydroxy-1-butene, derivatives such as acylated products thereof, acrylic acid, methacrylic acid, crotonic acid, maleic acid, maleic anhydride, itacon acids, unsaturated acids such as undecylenic acid, salts thereof, esters such as monoesters or dialkyl esters, nitriles such as acrylonitrile and methacrylonitrile, amides such as diacetone acrylamide, acrylamide, and methacrylamide, ethylenesulfonic acid, Olefinsulfonic acids such as allylsulfonic acid and methallylsulfonic acid, salts thereof, alkyl vinyl ethers, dimethyl allyl vinyl ketone, N-vinyl pyrrolidone, vinyl chloride, vinyl ethylene carbonate, 2,2-dialkyl-4-vinyl-1, Vinyl compounds such as 3-dioxolane and glycerin monoallyl ether, substituted vinyl acetates such as isopropenyl acetate and 1-methoxyvinyl acetate, vinylidene chloride, 1,4-diacetoxy-2-butene, 1,4-dihydroxy-2- Hydroxymethyl vinylidene diacetate such as butene, vinylene carbonate, 1,3-diacetoxy-2-methylenepropane, 1,3-dipropionyloxy-2-methylenepropane, 1,3-dibutyronyloxy-2-methylenepropane, etc. is mentioned. The content of such copolymerizable monomers is usually 10 mol % or less, preferably 5 mol % or less, particularly preferably 1 mol % or less, based on the total amount of the polymer. In the present invention, unmodified PVA consisting only of vinyl alcohol structural units and unsaponified vinyl ester structural units is preferred from the viewpoint of safety.

There are no particular restrictions on the polymerization of the vinyl ester-based monomers and copolymerizable monomers, and known methods such as bulk polymerization, solution polymerization, suspension polymerization, dispersion polymerization, or emulsion polymerization can be employed. Solution polymerization is carried out.

Solvents 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. Methanol is preferably used.

The polymerization reaction is carried out using known radical polymerization catalysts such as azobisisobutyronitrile, acetyl peroxide, benzoyl peroxide and lauroyl peroxide, and various known low temperature active catalysts. Also, the reaction temperature is selected from the range of 35° C. or higher and the boiling point of known radical polymerization catalysts and various known low-temperature active catalysts or lower.

The obtained polyvinyl ester polymer is then saponified in a continuous or batch manner. For such saponification, either alkali saponification or acid saponification can be employed, but industrially, alkali saponification in which the polymer is dissolved in alcohol and carried out in the presence of an alkali catalyst is preferred.

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 among these, methanol and ethanol are more preferable. The concentration of polymer in alcohol is selected from the range of 20-60% by weight. In addition, if necessary, about 0.3 to 10% by mass of water may be added, and further, various esters such as methyl acetate, benzene, hexane, and various solvents such as DMSO (dimethyl sulfoxide) are added. You may

Examples of the alkali catalyst include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate and potassium methylate, and alkali catalysts such as alcoholates. The amount of such catalyst used is preferably 1 to 100 millimol equivalents relative to the monomer.

After saponification, it is preferable to wash the obtained PVA-based resin 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.

The cleaning method includes a batch type cleaning method and a continuous type cleaning method, and usually a batch type cleaning method is adopted. Examples of the stirring method (apparatus) for washing include a screw blade, a ribbon blender, and a kneader.

Further, examples of the cleaning device include a cylindrical cleaning device, a countercurrent contact type cleaning device, a centrifugal separation cleaning device, and the like.
The bath ratio (mass of cleaning solution/mass of polyvinyl ester polymer particles) is usually 1-30, preferably 2-20. If the bath ratio is too large, a large washing apparatus is required, which tends to lead to an increase in cost.

The temperature during washing is usually 10 to 80°C, preferably 20 to 70°C. If the temperature is too high, the amount of volatilization of the cleaning liquid increases, and there is a tendency to require a reflux facility. If the temperature is too low, cleaning efficiency tends to decrease.

The washing time is usually 5 minutes to 12 hours, preferably 30 minutes to 4 hours. If the washing time is too long, the production efficiency tends to decrease.

The number of times of washing is usually 1 to 10 times, preferably 1 to 5 times. Too many washes tend to reduce productivity and increase costs.

The washed particles of the saponified polyvinyl ester polymer are dried continuously or batchwise with hot air or the like to obtain the PVA resin powder used in the present invention. The drying temperature is generally 50 to 150°C, 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, drying tends to take a long time.

The drying time is usually 1 to 48 hours, preferably 2 to 36 hours. If the drying time is too long, the PVA-based resin tends to be thermally deteriorated.

The content of the solvent contained in the dried PVA-based resin powder is usually 0 to 10% by mass, preferably 0.01 to 5% by mass, more preferably 0.1 to 1% by mass.

In this way, the PVA-based resin used in the present invention is obtained, and by containing it, it becomes the base for the solid dispersion of the present invention.

In the solid dispersion base of the present invention, the content of the PVA-based resin is preferably 50% by mass or more, more preferably 60% by mass or more, more preferably 80% by mass with respect to the entire solid dispersion base. The above is more preferable. If the content of the PVA-based resin is too low, the drug tends to be unable to maintain its amorphous state.

Moreover, the solid dispersion base of the present invention may contain a resin generally used as a solid dispersion base, other than the PVA-based resin, to the extent that the effects of the present invention are not impaired. Examples of such resins include polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer, polyvinyl alcohol-polyethylene glycol-graft copolymer, polyvinylpyrrolidone, copolyvidone, hypromellose phthalate, hydroxyethylmethylcellulose, hypromellose acetate succinate. Ester, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose and the like are exemplified, but are not limited to these, and can be used in combination as appropriate.

In the solid dispersion of the present invention, the content of the PVA-based resin is preferably 20% by mass or more, more preferably 30 to 90% by mass, and even more preferably 40 to 80% by mass with respect to the entire solid dispersion. . If the content of the PVA-based resin is too low, the drug tends to be unable to maintain its amorphous state. If the content of the PVA-based resin is too high, the content of the drug tends to decrease, and the amount of the formulation to be administered tends to increase in order to exert its efficacy.

Moreover, the solid dispersion of the present invention contains the solid dispersion base of the present invention and a drug.

<Drugs>
Drugs contained in the solid dispersion of the present invention include the following.

(1) antipyretic, analgesic, anti-inflammatory drugs, e.g., salicylic acid, sulpyrine, flufenamic acid, diclofenac, indomethacin, atropine, scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen, ibuprofen, oxymorphone, aspirin, aminopyrine, phenacetin, Acetaminophenone, phenylbutazone, ketophenylbutazone, mefenamic acid, bucolome, benzydamine, mepyrizole, thiaramide, tinoridine, xylocaine, pentazocine, dexamethasone, hydrocortisone, prednisolone, azulene, isopropylantipyrine, sazapyrine, clofezone, etodrug or its Examples include salt.

(2) Tranquilizers Examples include diazepam, lorazepam, oxazepam, oxazolam, clotiazepam, medazepam, temazepam, fludiazepam, meprobamate, nitrazepam, chlordiazepoxide and the like.

(3) Antipsychotics Examples include chlorpromazine, prochlorperazine, trifluoperazine, sulpiride, clocapramine hydrochloride, zotepine, haloperidol and the like.

(4) antibacterial agents such as griseofulvin, lankacidins [J. Antibiotics, 38, 877-885 (1985)], an azole compound [2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1 ,2,4-triazol-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, ciproxacin hydrochloride, sulfamethoxazole/trimethoprim, and the like.

(5) Antibiotics such as gentamicin, dipekacin, kanendomycin, lividomycin, topramycin, amikacin, dibekacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephalolysine , cefotiam, cefotiam hexetil, cefsulodin, cefmenoxime, cefmetazole, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, azthreonam, amoxicillin, cephalexin, erythromycin, bacampicin, minocycline, chloramphenicol or salts thereof, etc. be done.

(6) anti-tumor drugs such as 6-O-(N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine alazinoside, fluorouracil, tetrahydrofuril -5-fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexone, glycyrrhizin, HER2 inhibitors (such as heterocyclic compounds described in WO 01/77107), taxol, doxorubicin hydrochloride, etoposide, mitoxantrone, mesna , dimesna, aminoglutethimide, tamoxifen, acroline, cisplatin, carboplatin, cyclophosphamide, lomustine (CCNU), carmustine (BCNU) and the like.

(7) antihyperlipidemic drugs such as clofibrate, ethyl 2-chloro-3-[4-(2-methyl-2-phenylpropoxy)phenyl]propionate [Chem. Pharm. Bull. , 38, 2792-2796 (1990)], clinofibrate, cholestyramine, soysterol, tocopherol nicotinate, nicomol, niceritrol, probucol, elastase and the like.

(8) Antitussives/expectorants For example, ephedrine, methylephedrine, noscapine, codeine, dihydrocodeine, alloclamide, chlorphedianol, picoperidamine, cloperastine, protochirol, isoproterenol, salbutamol, tereptaline, bromhexine, carbocysteine, ethylcysteine, Examples include methylcysteine and salts thereof.

(9) muscle relaxants, e.g., pridinol, tubocurarine, pancuronium, chlorphenesin carbamate, tolperisone hydrochloride, eperisone hydrochloride, tizanidine hydrochloride, mephenesin, chlorzoxazone, fenprobamate, methocarbamol, chlormezanone, pridinol mesylate, afloqualone, baclofen , dantrolene sodium, and the like.

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

(11) Antiulcer drugs Examples include lansoprazole, metoclopramide, famotidine, omeprazole, sulpiride, trepibutone, cetraxate hydrochloride, gefernate, irsogladine maleate, cimetidine, ranitidine hydrochloride, nizatidine, and roxatidine hydrochloride.

(12) Antidepressants Examples include imipramine, clomipramine, noxiptiline, and phenelzine.

(13) Antiallergic drugs Examples include diphenhydramine, chlorpheniramine, tripelennamine, methdilamine, clemizole, diphenylpyraline, methoxyphenamine, clemastine fumarate, cyproheptadine hydrochloride, mequitazine, and alimemazine tartrate.

(14) Cardiotonics Examples thereof include trans-bioxocamphor, terephyllol, aminophylline, etilephrine and the like.

(15) Antiarrhythmic drug Examples thereof include propranolol, alprenolol, pfetrol, oxprenolol, procainamide hydrochloride, disopyramide, ajmaline, quinidine sulfate, aprindine hydrochloride, propafenone hydrochloride, and mexiletine hydrochloride.

(16) Vasodilators For example, oxyfedrine, diltiazem, tolazoline, hexobenzine, bamethane, nifedipine, nilvadipine, isosorbitol dinitrate, diltiazem hydrochloride, trapidil, dipyridamole, dilazep hydrochloride, verapamil, nicardipine hydrochloride, ifenprodil tartrate, sinepaside maleate , cyclanderate, cinnarizine, pentoxifylline and the like.

(17) Antihypertensive diuretics For example, hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine, furosemide, trichlormethiazide, methiclothiazide, hydrochlorothiazide, hydroflumethiazide, ethiazide, cyclopenthiazide, phlolothiazide, ethacrine acid and the like.

(18) Antidiabetic drug Examples thereof include glymidine, glipzide, phenformin, pformin, metformin, glibenclamide, and tolbutamide.

(19) Anti-tuberculosis drug Examples include isoniazid, ethambutol, para-aminosalicylic acid and the like.

(20) Narcotic antagonists Examples include levallorphan, nalorphine, naloxone, and salts thereof.

(21) Hormone drug Examples include steroid hormones such as dexamethasone, hexestrol, methimazole, petamethasone, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, prednisolone, hydrocortisone, and estriol.

(22) Bone/cartilage disease preventive/therapeutic agent For example, prostaglandin A1 derivative, vitamin D derivative, vitamin K2 derivative, eicosapentaenoic acid derivative, benzylphosphonic acid, bisphosphonic acid derivative, sex hormone derivative, phenolsulfophthalein derivative , benzothiopyran or benzothiepine derivatives, thienoindazole derivatives, menatetrenone derivatives, helioxanthine derivatives, and other non-peptidic osteogenesis-promoting substances, peptidic osteogenesis-promoting substances, and the like.

(23) therapeutic agents for joint diseases, e.g., p38MAP kinase inhibitors (thiazole compounds described in WO 00/64894, etc.), matrix metalloprotease inhibitors (MMPI), prednisolone, hydrocortisone, methylprednisolone, dexabetamethasone, Anti-inflammatory steroids such as betamethasone, non-steroidal anti-inflammatory analgesics such as indomethacin, diclofenac, loxoprofen, ibuprofen, piroxicam and sulindac.

(24) Hydrochloric acid therapeutic agents for pollakiuria Examples thereof include flavoxate, oxybutynin hydrochloride, and terolidine hydrochloride.

(25) Antiandrogen agents Examples include oxendrone, allylestrenol, chlormadinone acetate, gestonolone caproate, osaprone acetate, flutamide, and bicalutamide.

(26) Fat-soluble vitamin drugs Examples include vitamin Ks: vitamins K1, K2, K3 and K4, folic acid (vitamin M), and the like.

(27) Vitamin derivatives For example, various derivatives of vitamins, such as vitamin D3 derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, 5,6 -Vitamin D2 derivatives such as trans-ergocalciferol.

(28) Others Hydroxycam, diacerin, megestrol acetic acid, nicegoline, 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, retinal vein occlusion treatment, senile discoid macular degeneration treatment, cerebral vasospasm treatment, cerebral thrombosis treatment, cerebral infarction treatment, cerebral occlusion treatment, intracerebral hemorrhage treatment, arachnoid membrane Subhemorrhagic drug, hypertensive encephalopathy drug, transient ischemic attack drug, multi-infarct dementia drug, arteriosclerosis drug, Huntington's disease drug, brain tissue disorder drug, optic neuropathy drug , glaucoma drug, ocular hypertension drug, retinal detachment drug, arthritis drug, anti-rheumatic drug, anti-septic drug, anti-septic shock drug, anti-asthma drug, atopic dermatitis drug, allergic rhinitis drug etc.

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

The content of the above drug is appropriately adjusted according to bioavailability. The drug may be diluted with a diluent or the like generally used in the medical and food fields. In addition, the drug may be processed for the purpose of masking bitterness.

<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 additives include excipients, disintegrants, pH adjusters, fluidizing agents, surfactants, coloring agents, sweetening agents and coating agents.

As excipients, for example, one or two 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. Sugars include, for example, glucose, fructose, lactose, sucrose, trehalose, maltose and oligosaccharides.

Disintegrants include, for example, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, cellulose or derivatives thereof, starch or derivatives thereof, and the like.

pH adjusters include, for example, citric acid and its salts, phosphoric acid and its salts, carbonic acid and its salts, tartaric acid and its salts, fumaric acid and its salts, acetic acid and its salts, amino acids and its salts, succinic acid and its salts salts, lactic acid and its salts, and the like.

Fluidizing agents include, for example, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, stearic acid, corn gel and heavy anhydrous silicic acid.

Examples of surfactants include phospholipids, glycerin fatty acid esters, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, sucrose fatty acid esters, and lauryl sulfate. sodium, polysorbates, sodium hydrogen phosphates and potassium hydrogen phosphates;

Examples of coloring agents include iron sesquioxide, yellow iron sesquioxide, food yellow No. 5, food yellow No. 4, aluminum chelate, titanium oxide and talc.

Sweetening agents include, for example, saccharin, aspartame, acesulfame potassium, thaumatin and sucralose.

Coating agents include, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone ethyl acrylate, methyl methacrylate copolymer dispersions, hydroxypropyl methyl cellulose acetate succinate and methacrylic acid copolymers.

<Method for producing solid dispersion>
Examples of the method for producing the solid dispersion of the present invention include the following methods.
(i) Solvent method: A method of dissolving a mixture of a drug and a solid dispersion base in an organic solvent and then removing the solvent.
(ii) Melting method: A method of melting and kneading a mixture of a drug and a solid dispersion base, followed by cooling and solidification.
(iii) Mixing pulverization method (mechanochemical method): A method of miniaturizing a drug or dispersing it in a base using mechanical energy such as compression, shearing, or friction.

Among the above, the melting method (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 solid dispersion base, and adjusting the shape of the heat-treated product (pulverization, powderization, molding, etc.) as necessary. be.

The temperature for the heat treatment of the mixture of the drug and the solid dispersion base of the present invention may be the temperature at which the entire mixture is melted, the temperature at which the two are partly melted, or even if the mixture does not melt. Depending on the properties of the drug, temperature conditions can be selected under which part or all of the drug is amorphized.

Even if the entire mixture does not melt, a solid dispersion can be obtained by amorphizing part or all of the drug, and in the present invention, this case is also included in the melting method. It is assumed that

In addition, the mixture of the drug and solid dispersion base means a mixture obtained by blending the drug into a molten solid dispersion base, or a mixture obtained by dry blending the solid dispersion base and the drug, followed by melt kneading. It includes mixtures obtained by the method of

The heating means used for the heat treatment is not particularly limited, and appropriate heating means available to those skilled in the art can be adopted. For example, heating by dryer, oil bath, electric furnace, etc., heating by ultrasonic irradiation, heating by twin-screw kneading treatment, heating by single-screw and twin-screw melt extrusion treatment (extruder), heating by microwave irradiation, etc. .

The means for adjusting the morphology of the heat-treated product is not particularly limited, and appropriate means available to those skilled in the art can be adopted. For example, crushing means, molding means, etc. can be employed. Molding means include extrusion molding (e.g., single-screw extrusion, twin-screw extrusion, multi-screw extrusion, hot-melt calendering), injection molding (e.g., twin-screw extruder), compression molding (e.g., tableting, granulation). etc. are exemplified.

When the production of the solid dispersion by heat treatment and the adjustment of the morphology of the solid dispersion are performed at the same time, an apparatus for adjusting the morphology of the heat-treated product having heating means may be employed.

As described above, 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. Also in the present invention, by producing a solid dispersion at a temperature as low as possible, even a drug that decomposes or deteriorates at high temperatures can be treated as a solid dispersion. can be a body. The temperature of the heat treatment is usually 80-220°C, preferably 120-200°C, more preferably 150-200°C.

In addition, ultrasonic irradiation is to apply ultrasonic waves 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, more preferably 800 to 1300 J. . An apparatus used for ultrasonic irradiation includes an ultrasonic molding machine USTM/L20 manufactured by Technea Engineering. A powder mixture of a drug, a base for solid dispersion and, if necessary, an additive is filled in a die provided in such a device, and the mixture is subjected to compression molding while being irradiated with ultrasonic waves.

Some twin-screw extruders, twin-screw extruders, and the like are equipped with heating means. Production by means of a screw extruder, a twin-screw extruder equipped with heating means, is preferred.

In this manner, a solid dispersion containing the solid dispersion base of the present invention and a drug can be obtained, and the obtained solid dispersion has an excellent drug elution rate.

EXAMPLES 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 thereof is not exceeded.
In addition, "parts" and "%" in the examples mean mass standards.

[Example 1] (Preparation of base for solid dispersion)
A PVA-based resin having a degree of saponification of 80 mol % and an average degree of polymerization of 2,400 was prepared.

The dry powder of the PVA-based resin was poured into methanol having a bath ratio of 10, stirred for 3 hours, and washed. After that, 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 the PVA-based resin, which was used as a solid dispersion base. .

(Preparation of solid dispersion)
7 parts of the obtained solid dispersion base and 3 parts of indomethacin as a drug were uniformly mixed using a mortar and pestle to obtain a mixture. After filling the resulting mixture into VCM (Vacuum Compression molding, MeltPrep VCM manufactured by Nihon Validation Technologies Co., Ltd.), bubbles were removed from the powder while the pressure was reduced, and the mixture was evacuated. After that, uniform melting was performed under the following conditions.

Melting conditions Temperature: 230°C
Time: 5 min (left time)

After melting, the mixture was cooled and pulverized in liquid nitrogen under the following conditions using a freeze pulverizer (JFC-400, manufactured by Nippon Analytical Industry Co., Ltd.) to obtain a solid dispersion.

Grinding conditions Pre-cooling time/Grinding time: 5 minutes/1 minute x 1 set

[Comparative Examples 1 to 4]
A solid dispersion was obtained according to the method described in Example 1, except that the degree of saponification and the average degree of polymerization of the PVA-based resin used were as described in Table 1.

[Reference example 1]
A dissolution test was carried out using only indomethacin instead of a solid dispersion base obtained from a PVA-based resin.

[Evaluation of elution rate]
A sample containing 30 to 40 mg of indomethacin was immersed in 900 ml of distilled water, stirred at 37° C.×50 rpm, and stirred for a predetermined time (0 minutes, 30 minutes, 60 minutes, 120 minutes, 150 minutes, After 180 minutes, 210 minutes, 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes), 1 ml samples were taken. After filtering the collected sample with a 0.45 μm PTFE (Poly Tetra Fluoro Ethylene) filter, the elution rate (%) of indomethacin was quantified under the HPLC conditions shown in Table 2. The results are shown in Table 3 and FIG.

The content (%) of indomethacin was determined by the following formula.
Content (%) = (MIND/MVCM) x 100
MIND: Indomethacin mass in sample MVCM: Sample mass

Also, the content of indomethacin in the sample was quantified from a calibration curve prepared with known concentrations of indomethacin.

From the results in Table 3 and FIG. 1, it was found that the solid dispersion of Example 1 had a high dissolution rate of the final drug (indomethacin). Moreover, in Example 1, a rapid increase in the dissolution rate was confirmed, particularly after 240 minutes to 360 minutes.

The solid dispersion of the present invention is useful for pharmaceutical formulations because of its high drug elution rate.

Claims (3)

A solid dispersion base containing a polyvinyl alcohol-based resin,
The degree of saponification of the polyvinyl alcohol resin is 70 to 85 mol%,
A base for solid dispersion, wherein the polyvinyl alcohol-based resin has an average degree of polymerization of 1,000 or more. A method for producing a solid dispersion, comprising a step of cooling after melt-kneading the mixture of the solid dispersion base according to claim 1 and a drug. A solid dispersion comprising the base for solid dispersion according to claim 1 and a drug.

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