WO2003072085A1

WO2003072085A1 - Solid preparations with improved absorbability of hardly water-soluble drug

Info

Publication number: WO2003072085A1
Application number: PCT/JP2003/001965
Authority: WO
Inventors: Takashi Hayashi; Asako Takakura
Original assignee: Shionogi & Co., Ltd.
Priority date: 2002-02-27
Filing date: 2003-02-24
Publication date: 2003-09-04
Also published as: JPWO2003072085A1; AU2003211267A1; JP4632288B2

Abstract

It is intended to improve the dissolution properties of a hardly water-soluble drug and thus provide solid preparations with improved drug absorbability in oral administration. Namely, solid preparations containing a hardly water-soluble drug, a surfactant and a solid excipient, characterized in that the composition ratio of the hardly water-soluble drug to the surfactant is 25% (W/W) or less.

Description

Description Solid preparations with improved absorption of poorly water-soluble drugs

The present invention relates to a solid preparation, specifically, a solid preparation comprising a poorly water-soluble drug, a surfactant and a solid forming agent, and more specifically, a drug is rapidly dissolved from the preparation to maintain a supersaturated dissolved state for a long time. In addition, the present invention relates to a solid preparation having improved absorption when orally administered. Background art

Poorly water-soluble drugs are often poorly absorbed when administered orally because the drugs are not sufficiently dissolved in the gastrointestinal tract. With these drugs, the absorption rate of the drug decreases as the dose increases, and digestive activity during eating (mechanical stimulation due to contraction of the gastrointestinal tract, increased secretion of digestive juice, prolonged gastrointestinal residence time) The absorption rate tends to fluctuate more than on an empty stomach.

It is known that a solution in which a poorly water-soluble drug is dissolved in a certain surfactant or an emulsion containing a poorly water-soluble drug temporarily increases the solubility of the drug when mixed with an aqueous solution. . However, liquids dissolved in surfactants are inconvenient to handle at the time of administration due to their high viscosity, and it is also difficult to process them into tablets and other preparations. In the case of emulsions, the stability of the drug is generally poor in a solution state. Therefore, solidification of these solution components is desired, and various techniques have been found. A technique for solidifying a surfactant solution is disclosed in Japanese Patent Application Laid-Open (JP-A) No. 62-242,13, and a technique for solidifying an emulsion is disclosed in Japanese Patent Application Laid-Open No. 60-224246. And JP-A-60-239417, JP-A-4-2752166 and WO 00/0179.

However, the solubility of poorly water-soluble drugs is increased in any of the above-mentioned preparations. There is no mention of what was done. In the case of emulsion, an oily drug must be used as a poorly water-soluble drug, or the drug must be once dissolved in an oily base or the like, which limits the drug. Therefore, there has been a demand for a solidified preparation which does not use an emulsion, increases the solubility of the drug, and furthermore, is solid. Disclosure of the invention

The present inventors mixed a solution in which a sparingly water-soluble drug was dissolved in a surfactant and a solution in which a solid forming agent as an aqueous gel was dissolved, and dried the solution to make the water solubility of the drug equal to or higher than the solubility. It has been found that a solid preparation in which the so-called supersaturated dissolution state is maintained for a long time can be obtained, and the following invention has been completed.

(1) Improves the solubility of a drug containing a poorly water-soluble drug, a surfactant, and a solid-forming agent, wherein the compounding ratio of the poorly water-soluble drug to the surfactant is 25 (W / W)% or less. Solid preparation.

(2) The preparation according to the above (1), wherein the compounding ratio of the poorly water-soluble drug to the surfactant is 3 to 25 (W / W)%.

(3) The preparation according to the above (1) or (2), wherein the blending ratio of the surfactant to the total amount of the preparation is 20 (W / W)% or more.

(4) The preparation according to any one of the above (1) to (3), wherein the surfactant is HLB 8 or more.

(5) The surfactant is one or more selected from the group consisting of polyethylene glycol, polyoxyethylene sorbin fatty acid ester, polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester, and sucrose fatty acid ester The preparation according to any one of the above (1) to (4).

(6) The preparation according to the above (5), wherein the surfactant is polyethylene glycol and / or polyoxyethylene sorbitan fatty acid ester.

(7) The solid-forming agent according to any one of (1) to (6) above, wherein the solid forming agent is one or more selected from the group consisting of gelatin, polysaccharides, celluloses, and polyvinyls. The listed formulation.

(8) The solid forming agent is gelatin, agar, sodium alginate, pectin, pullulan, hexane gum, gum arabic, carrageenan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium. The preparation according to the above (7), which is one or more selected from the group consisting of lium, polyvinyl alcohol and polyvinyl pyrrolidone.

(9) The preparation according to the above (7), wherein the solid forming agent is one or more selected from the group consisting of gelatin, agar, pectin and gum arabic.

(10) The solid forming agent is one or two or more selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose and cellulose acetate phthalate The preparation according to the above (7).

(11) The preparation according to the above (7), wherein the solid forming agent is hydroxypropylmethylcellulose acetate succinate.

(12) A preparation obtained by adding sucrose as an excipient to the preparation according to any one of the above (1) to (11).

(13) From the above (1), wherein the water solubility of the poorly water-soluble drug is 100 g / mL or less.

The preparation according to any one of (1 2).

(14) The poorly water-soluble drug is

Equation (I):

R ¹

R ° -R ⁴ -R ° -S0 ₂ -N 'ヽ COY (I)

R ²

(Wherein, R ¹ is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted Heteroarylalkyl; R ² is hydrogen, substituted Lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, R ³ is a single bond, substituted Optionally substituted arylene or substituted arylene; R ⁴ is a single bond, one (CH ₂ ) m—, —CH = CH—, — C —C-I, —CO—, —CO— NH—, -N = N- -N (R ^A ) —, -NH—CO—NH—, one NH—CO—, one hundred one, one S—, one S 0 ₂ NH—, —SO ₂ — NH — N = CH—, oxaziazole or tetrazolediyl; R ⁵ is an optionally substituted lower alkyl, an optionally substituted C ₃ -C ₈ cycloalkyl, an optionally substituted aryl, a substituted non-aromatic heterocyclic group may be heteroaryl or substitution also to good; R ^A is hydrogen or Grade alkyl; Y is N 11_Rei_11 or 01 ^ 1 ^ or 1 or 2 A compound represented by R ² is hydrogen when the wherein Y is NH_〇 H, an optically active form thereof, or their pharmaceutically The preparation according to the above (13), which is an acceptable salt or a solvate thereof.

(15) The preparation according to (13), wherein the poorly water-soluble drug is a nitrophenylviridine carboxylic acid drug or a hydantoin drug.

(16) The preparation according to any one of (1) to (15), wherein the drug is rapidly dissolved and the supersaturated dissolved state is maintained for a long time.

(17) The drug described in (8) above, in which the drug dissolves at a temperature of 37 ° C higher than the drug solubility by 10 minutes after the start of the dissolution test, and maintains a supersaturated dissolved state for at least 120 minutes thereafter. Formulation.

(18) The drug did not dissolve in the dissolution test solution with a pH of less than 37 ° C at pH 5 and the drug was not dissolved in the dissolution test solution with a pH of 37 or more at 37 ° C by 10 minutes after the start of the dissolution test. (10) The preparation according to the above (10), wherein the drug is dissolved at a higher solubility than the above, and the supersaturated solution is maintained for 90 minutes or more thereafter.

(19) The preparation according to any one of the above (1) to (18), wherein the poorly water-soluble drug absorbability in oral administration is increased as compared with the case where an aqueous suspension of the drug is administered.

(20) Use poorly water-soluble drugs, surfactants and solid formers in water, alcohol and water. The method according to any one of the above (1) to (19), comprising dissolving in one or more solvents selected from the group consisting of seton, and drying the solution. .

(21) The following solutions:

1) a solution of a poorly water-soluble drug dissolved in a surfactant; and

2) A solution in which a solid former is dissolved in one or more solvents selected from the group consisting of water, alcohol and acetone.

And drying the mixture.

(22) The compounding ratio of the poorly water-soluble drug to the surfactant is 25 (W / W)% or less, and the poorly water-soluble drug, the surfactant and the solid forming agent are composed of water, alcohol, and acetone. A solid preparation in which the solubility of a drug produced by dissolving in one or more solvents selected from the group and then drying the solution is improved. BRIEF DESCRIPTION OF THE FIGURES

Figure 1: Dissolution behavior of Compound A in Examples 1, 3 and Comparative Example 1. The vertical axis represents the drug dissolution rate (%), and the horizontal axis represents the time (minutes) after the start of the dissolution test.

Figure 2: Dissolution concentration of Compound A in Examples 2 and 4 and Reference Examples 1 and 2. The vertical axis represents the drug dissolution concentration (jug / ml), and the horizontal axis represents the time (minute) after the start of the dissolution test.

Figure 3: Dissolution concentration of Compound A in the formulation of Example 5. The vertical axis represents the drug dissolution concentration (g / mL), and the horizontal axis represents the time (minutes) after the start of the dissolution test.

Figure 4: Dissolution concentration of compound B in the formulation of Example 6 and the formulation of Comparative Example 2. The vertical axis represents the drug dissolution concentration (g / mL), and the horizontal axis represents the time (minutes) after the start of the dissolution test. Figure 5: Dissolution concentration of phenytoin in the formulation of Example 7 and the formulation of Reference Example 3. The vertical axis represents the drug dissolution concentration (/ g / mL), and the horizontal axis represents the time (minute) after the start of the dissolution test. Figure 6: Dissolution concentration of difludipine in the formulation of Example 8 and the formulation of Reference Example 4. The vertical axis represents the drug dissolution concentration (Ad g / mL), and the horizontal axis represents the time (minute) after the start of the dissolution test. Figure 7: Shows a one-hour blood concentration curve after oral administration of the compound of Example 4 and a drug suspension equivalent to 50 mg of Compound A. The vertical axis represents the drug concentration in blood (g / mL), and the horizontal axis represents the time (hour) after the start of the test.

FIG. 8 shows a one-hour blood concentration curve after oral administration of the preparation and the drug suspension of Example 4 in an amount equivalent to 200 mg of compound A. The vertical axis represents the drug concentration in blood (gZmL), and the horizontal axis represents the time (hour) after the start of the test. BEST MODE FOR CARRYING OUT THE INVENTION

The poorly water-soluble drug in the present invention is not particularly limited, such as pharmaceuticals, quasi-drugs, veterinary drugs, etc., but preferably, the water solubility of the poorly water-soluble drug at 37 ° C is 100 jUL g / ταL or less. . More preferably, the following formula (I)

R ¹

R ° -R ⁴ -R ° -S0 ₂ -N 'ヽ COY (I)

R ²

(Wherein, R ¹ is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted Heteroarylalkyl; R ² is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted Good heteroarylalkyl; R ³ is a single bond, optionally substituted arylene or optionally substituted heteroarylene; R ⁴ is a single bond, one (CH ₂ ) m—, one CH = CH—, One C≡C—, One CO—, One CO—NH—, — N = N—, One N (R ^A ) —, One NH—CO—NH—, One NH—CO—, One 0—, One S - one S 0 ₂ NH-, one SO ₂ - NH- N = CH-, Okisajiazoru Others tetrazole Jiiru; R ⁵ is optionally substituted lower alkyl, optionally substituted C ₃ -C ₈ cycloalkyl, optionally substituted § Li Ichiru, the optionally substituted Teroariru Or an optionally substituted non-aromatic heterocyclic group; R ^A is hydrogen or lower alkyl; Y is N 11〇11 or 011;] 1 is 1 or 2; provided that when Y is NH 0 H, R ² is hydrogen.], An optically active form thereof, or a pharmaceutically acceptable salt thereof; Or their solvates. More preferably, the following formula (II)

R ¹ '

R ⁵ -R ⁴ — R ³ — SO. One N ', COOH (II)

H

[Wherein R ¹ ′ is benzyl, (indole-3-yl) methyl, (1-methylindole-3-yl) methyl, (5-methylindole-3-yl) methyl, (5— Fluoroindole-3-yl) methyl, (1-acetylethyl-3-yl) methyl, (1-methylsulfonylindole-3-yl) methyl, (1-alkoxycarbonyl-3-yl) methyl R) methyl (eg, ethoxycarbonylmethyl), or i-propyl; R ³ , R ⁴ and R ⁵ are as defined above], an optically active form thereof, or a pharmaceutically acceptable salt thereof, Or solvates thereof. Particularly preferably, the following formula (III)

(III)

[Wherein, R ¹ "is benzyl, (indole-3-yl) methyl or (1-methylindole-3-yl) methyl, R is one CH = CH— or one C≡C-one, and R ⁵ 'is Phenyl, 4-methylphenyl or 4-fluorophenyl], an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or the following formula (IV)

(IV)

[Wherein, R ⁶ is an optionally substituted arylene or an optionally substituted heteroaryl. R ¹ "and R ⁵ 'are as defined above, an optically active form thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. Useful as an antineoplastic agent.

Further, other more preferable poorly water-soluble drugs include nitrophenylpyridine carboxylic acid drugs or hydantoin drugs. Specific examples of the nitrophenylpyridine carboxylic acid-based drug include diphdinapine and the like, and specific examples of the hydantoin-based drug include phenytoin. Difludipine is used as a calcium antagonist, and phenytoin is used as an antiepileptic drug.

Other drugs that can be used in this formulation include antipyretic analgesics, such as phenacetin, indomethacin, and flurbiprofen; inotropics such as digitoxin; antiepileptic drugs such as diazepam and pheno Antibiotics such as barbital, for example, chloramphenicol, 7/5 — [(Z) —2- (2-amino-4-thiazolyl) -12-hydroxyhydroxyminoacetamide] 13— (1,2,3- Triazole-4-ylthiomethylthio) 1-l-carper 3-sefume 4 rubonic acid, (+)-(6R, 7R) -7-[(Z) —2- (2-amino-4-thiazolyl )-2-pentenamide]-3-Carpamoyloxymethyl-8-year old 5-thia 1-1-azabicyclo [4. 2. 0] oct 1-2-2- pivaloyl carboxylate Xymethyl ester or its manufacture (+) — (Z)-7-[(1 R, 2 S, 3 S) as anti-allergic drugs such as the above acceptable salts and their hydrates (eg, hydrochloride · 1-hydrate) , 4 S) — 3-benzenesulfonamidobicyclo [2.2.1] hept-2-yl] -15-heptenoic acid calcium dihydrate, etc. As an anti-histamine, such as diphenhydramine Anti-fungal agents, such as fluconazole, clotrimazole, isoconazole nitrate, econazole nitrate, miconazole nitrate, bifonazole, griseofulvin, etc.Synthetic antibacterial agents, such as ofloxacin, hydrochloric acid Cyproxasin, tosfloxacin tosylate, nofloxacin, lomefloxacin hydrochloride, pazufloxacin, etc. Shiros Evening Zoe Al blockers, such as prazosin hydrochloride, terazosin hydrochloride, and brazosin hydrochloride; carbonic anhydrase inhibitors; e.g., acetazolamide and methazolamide; adrenal cortical steroids; e.g., difluprednate, butesonide Diflucortron valerate, hydrocortisone butyrate propionate, clobezone butyrate, fluorometholone and the like, and pharmaceutically acceptable salts of these drugs.

The compounding ratio of the drug may be any compounding ratio in which the drug can be dissolved in the surfactant in order to increase the solubility of the drug, and preferably, the compounding ratio of the drug to the surfactant is 25 (W / W W)% or less, more preferably 1 to 25 (W / W)%, and still more preferably 3 to 25 (W / W)%. In this case, the drug can be completely dissolved in the surfactant, and the solubility of the drug can be increased. The compounding ratio of the drug to the total amount of the preparation is 0.5 (W / W)% or more, preferably 0.5 (W / W)% to 30 (W / W)%, more preferably 0.75 (W / W)%. (W / W) -27.5 (W / W)%, more preferably 1 (W / W)% to 25 (W / W)%.

The surfactant used in the present invention may be any semi-solid or liquid surfactant that dissolves a poorly water-soluble drug and is physiologically acceptable.For example, Pharmaceutical Excipient Standard 1998 (hereinafter referred to as “ Semi-solid or liquid surfactants listed in the Pharmaceutical Additive Regulations) and the 7th Edition of the Official Addendum of Food Additives (hereinafter sometimes abbreviated as “food additives”) can be used. However, even a solid surfactant can be used if it becomes liquid by heating. The HLB (hydrophilic hydrophobic ratio) of the surfactant is preferably 8 or more, more preferably 8 to 20, more preferably 12 to 20, and particularly preferably 14 to 20, for example, polyethylene. Glycols, polyoxetylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, glycerin fatty acid esters and sucrose fatty acid esters.

Specifically, as the polyethylene glycol, Macrogol 200 (PE G200), Macrogol 300 (PEG300), Macrogol 400 (PEG400), McGoal 600 ( PEG 600) can be used. Polyoxyethylene sorbitan fatty acid esters include polyoxyethylene sorbitan monoester. Palmitate (Tween 40), polyoxyethylene sorbitan monostearate (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80) and the like can be used. Examples of glycerin fatty acid esters include decaglycerin stearate monoester, decaglycerin stearate triester, hexaglycerin stearate monoester, hexaglycerin stearate sesquiester, tetraglycerin stearate monoester, and hexaglycerine stearic acid. Triester, Hexaglycerin monostearate, Decaglycerinoleic acid monoester, Hexaglycerinoleic acid monoester, Tetraglycerinoleic acid monoester, Decaglycerin caprylic acid monoester, Decaglycerin lauric acid monoester, Hexaglycerin Monolaurate, Monoester tetraglycerin Laurate, Condensed ricinoleate Tetraglycerin Kisaguriseri down condensed ricinoleic acid ester, polyglycerol condensed ricinoleic acid ester, etc. can be used to. Polyoxyethylene hardened castor oil includes polyoxyethylene hardened castor oil 5, polyoxyethylene hardened castor oil 10, polyoxyethylene hardened castor oil 20, polyoxyethylene hardened castor oil 40, polyoxyethylene hardened Castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 100 E.0., Etc. can be used. Particularly preferably, one or two kinds of macrogol 400 (PEG 400) which is polyethylene glycol and / or polyoxyethylene sorbitan monooleate (Tween 80) which is a fatty acid ester of polyoxetylene sorbitan You may use it combining the above. Further, the mixing ratio thereof is preferably 1: 1 to 1:10, more preferably 1: 2 to 1: 8, and further preferably 1: 3 to 1: 7.

The mixing ratio of the surfactant of the present invention varies depending on the content of the main drug in the preparation, but is not less than 20 (W / W)% based on the total amount of the preparation, preferably 20 (W / W) based on the total preparation. W)% to 70 (W / W)%, more preferably 20 (W / W)% to 65 (W / W)%, still more preferably 30 (W / W)% to 62.5 (W / W)%. Above the upper limit of this range, the drug product cannot be prepared, and below the lower limit, the solubility of the drug does not improve.

The solid forming agent used in the present invention is physiologically acceptable and may be any compound that dissolves in water and forms a gel in water. Examples of the solid forming agent include gelatin, polysaccharides, celluloses, and polyvinyls. preferable. Specifically, gelatin, agar, sodium alginate, pectin, pullulan, xanthan gum, gum arabic, carrageenan, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, polyvinyl alcohol And polyvinylpyrrolidone, more preferably gelatin, agar, pectin and gum arabic. One or more of these may be used in combination. Examples thereof include gelatin and agar, agar and pectin, agar and acacia, but are not limited to combinations thereof. Preferably, agar and gelatin are used, and the mixing ratio thereof is preferably 1: ;! To 1:20, more preferably 1: 5 to 1:15, even more preferably 1: 7.5 to 1: 12.5.

In addition, if a solid forming agent that dissolves at a pH of 5 or more is used, an enteric formulation that does not dissolve in the stomach but dissolves in the intestine can be prepared. Specific examples of the solid forming agent in this case include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and cellulose acetate phthalate, and more preferably hydroxypropylmethylcellulose. Methyl cell mouth is acetate succinate.

The mixing ratio of the solid forming agent of the present invention varies depending on the content of the active ingredient in the preparation and the like, but is at least 20 (W / W)%, preferably 20 (W / W)% to 7 to the total amount of the preparation. 0 (W / W)%, more preferably 22.5 (W / W)% to 62.5 (W / W)%, still more preferably 25 (W / W)-60 (W / W )%.

The preparation of the present invention may contain a physiologically acceptable excipient depending on the poorly water-soluble drug, surfactant and solid forming agent. Specifically, sucrose, lactose, silica (silicon dioxide), synthetic aluminum silicate and crystalline cellulose can be used. And preferably sucrose.

The mixing ratio of the above-mentioned excipient of the present invention varies depending on the content of the active ingredient in the preparation and the like, but is preferably 0.5 (W / W)% to 5 (W / W)% based on the total amount of the preparation. It is preferably 0.75 (W / W) to 4.5 (W / W)%, more preferably 1 (W / W)% to 4 (W / W)%.

In the preparation of the present invention, the compounding ratio of the drug to the surfactant is preferably 25 (W / W)% or less, and the compounding ratio of each component to the total amount of the preparation is 0.5 (W / W) for the poorly water-soluble drug. ) To 30 (W / W)%, surfactant is 20 (W / W)% to 70 (W / W)%, solid forming agent is 20 (W / W)% to 70 (W / W) W)%, and 0.5 (W / W) to 5 (W / W)% if an excipient is added. More preferably, the compounding ratio of the drug to the surfactant is 1 to 25 (W / W)%, and the compounding ratio of each component to the total amount of the preparation is 0.75 (W / W) for the poorly water-soluble drug. ~ 27.5 (W / W)%, surfactant 20 (W / W)% ~ 65 (W / W)%, solid forming agent 22.5 (W / W)% -62.5 (W / W)%, and 0.75 (W / W)% to 4.5 (W / W)% if an excipient is added. More preferably, the compounding ratio of the drug to the surfactant is 3 (W / W)% to 25 (W / W)%, and the compounding ratio of each component to the total amount of the preparation is 1 (W / W) of the poorly water-soluble drug. W)% to 25 (W / W)%, surfactant is 30 (W / W)% -62.5 (W / W)%, solid forming agent is 25 (W / W)% to 6 0 (W / W)%, and 1 (WZW)% to 4 (W / W)% if an excipient is added.

When the preparation of the present invention is produced, it is not particularly limited, but preferably, a poorly water-soluble drug, a surfactant, and a solid-forming agent are one or more solvents selected from the group consisting of water, alcohol, and acetone. Then, the aqueous solution, alcohol solution or acetone solution may be dried to produce the compound. For example, first, 1) dissolve a poorly water-soluble drug in a surfactant (after melting in the case of a semi-solid or solid surfactant). On the other hand, 2) the solid former is dissolved in one or more solvents selected from the group consisting of water, alcohol or acetone. The solutions of 1) and 2) may be mixed and dried to prepare a solid preparation. After drying, mortar, hammer mill, sample This product is ground with a mill, ditto mill, etc., and sieved to obtain the preparation. The drying method may be a method known to those skilled in the art. For example, there is a method of drying all over the desiccator, drying in a tray dryer, or drying by a spray dryer. The form of the preparation is not particularly limited, but is preferably granules, powders and fine granules, and more preferably granules.

Since the preparation of the present invention is solidified, it can be easily taken as it is, and it is convenient to carry. It is also possible to prepare granules, powders and fine granules, then blend them into tablets, granules, capsules and the like and form them. At this time, the tablets and granules may contain pharmaceutically acceptable additives such as excipients, binders and lubricants. In the case of a capsule, it can be filled into a hard capsule and a soft capsule. After forming these tablets, granules or capsules, gastric-soluble film base, hydrophobic film base, and enteric film base are coated on these preparations to produce gastric-, sustained-release, and enteric-coated preparations. You can also.

When the preparation of the present invention is added to water, the drug in the preparation dissolves promptly and maintains a so-called supersaturated dissolution state in which the drug dissolves over a long period of time in excess of the solubility of the drug. Preferably, the paddle method according to the 14th revised Japanese Pharmacopoeia [paddle stirring speed 50 rpm, test solution temperature 37 ± 0.5 ° C] should be less than the solubility of the drug by 10 minutes after the start of the dissolution test. The drug dissolves highly, and after 60 minutes, dissolves the drug 1.5 times or more, more preferably 3 times or more, more preferably 4 times or more the solubility of the drug. After 60 minutes from the start of the dissolution test, the supersaturated dissolution state is maintained for preferably 60 minutes or more, more preferably 90 minutes or more, and even more preferably 120 minutes or more. In a preferred embodiment, the drug does not dissolve in a dissolution test solution at a pH of less than 37 ° C and a supersaturated dissolution for a long time in a dissolution test solution at a pH of 37 or more. Maintain state. Preferably, in the paddle method described above, after the preparation is poured into a dissolution test solution having a pH of 5 or more, the drug dissolves higher than the solubility of the drug by 10 minutes, and the solubility of the drug is 60 minutes after 60 minutes. It dissolves a drug by 5 times or more, more preferably 3 times or more, and still more preferably 4 times or more. 30 minutes after the start of drug elution The falling and supersaturated dissolution state is maintained for preferably 30 minutes or more, more preferably 60 minutes or more, and even more preferably 90 minutes or more. In this case, a solid forming agent that dissolves at a pH of 5 or more may be used.

As described above, due to the improved solubility, the maximum blood concentration (C max) of the present formulation when orally administered to an animal differs depending on the dose and the drug, but it is preferably that when the drug suspension is administered. It is at least 1.2 times, more preferably at least 2 times, even more preferably at least 2.5 times. The area under the blood concentration curve (AUC) also varies depending on the dose and the drug, but is preferably at least 1.2 times, more preferably at least 2.5 times, more preferably at the time of administration of the drug suspension. Is more than 3.5 times.

This formulation is basically composed of a drug, a surfactant and a solid forming agent, but a drug and a surfactant or a drug and a solid forming agent may form a complex. The cause of the increase in water solubility of the drug included in this drug product is estimated as follows. That is, when the drug substance is dissolved in a surfactant and dried with a solid former, the drug substance is present in the drug substance in the surfactant dispersed in molecular units. When this is added to water, it is thought that micelles containing the drug substance in high concentration are rapidly formed in the water and dissolved in the water. Example

Hereinafter, the present invention will be described more specifically with reference to Examples, but this is merely an example and does not limit the present invention.

(Examples 1-4, Comparative Example 1, Reference Examples 1-2)

Using the formulations shown in Table 1, the solid preparations of Examples 1 to 4 and Comparative Example 1 and the solutions of Reference Examples 1 and 2 were prepared. Example 1 The production method of the preparation is shown below. Other Examples, Comparative Examples and Reference Examples were manufactured in the same manner. The preparation of the reference example was a solution in which the drug was dissolved in the indicated surfactant.

Manufacturing method

The raw materials used for the preparation are listed. The drug is compound A (N ^α- [2- [5-[[4-Methylphenyl] ethynyl] ceryl]] sulfonyl] -D-triptophan) was used after pulverization. Polyethylene glycol is Macrogol 400 (PEG 400), polyoxyethylene sorbitan fatty acid ester is polyoxyethylene sorbitan monooleate (Tween 80), and sucrose, gelatin, and agar are pharmaceutical products Was used.

The compound A10Omg is dissolved in a solution obtained by mixing PGE4001400mg and Tween8506mg heated to about 60 ° C. This solution is referred to as “surfactant solution”. On the other hand, 80 mg of gelatin and 80 mg of agar are added to 12 mL of distilled water and kept at around 100 ° C. This solution is referred to as “solid forming agent solution”.

Mix the surfactant solution and the solid former solution, leave the solution at room temperature, put it in a desiccator overnight, and store it under vacuum and vacuum overnight. The obtained solid was pulverized with a tablet pulverizer to obtain a 24 mesh commercial product.

(Table 1) (Unit: mg)

• Compound A: { ^α- [2- [5-[[4-methylphenyl] ethynyl] phenyl]] sulfonyl〗 -D-tributane

• P E G4 0 0: Mcmouth goal 4 0 0

• Twe e η80: Polyoxyethylene sorbitan monoester

Dissolution test and drug concentration measurement

The dissolution test was performed in accordance with the method prescribed in the Japanese Pharmacopoeia 14th Edition. The amount of the drug in the formulation injected into the test solution was 90 mg.

Test method: Japanese Pharmacopoeia Dissolution test method 2nd method (paddle method) Stirring speed 50 rpm Test solution: 90 OmL of distilled water, water temperature 37 ± 0.5 ° C, Sample volume of test solution: 2 mL Test liquid sampling time: 10, 20, 30, 60, 90, 120, 180 minutes after the start of test

Drug concentration measurement method: The collected liquid was filtered through a 0.45 / zm filter, and the filtrate was diluted with acetonitrile. HPLC method for the drug concentration in the diluted solution [wavelength: 3 15 nm, mobile phase: acetonitrile / 1% acetic acid aqueous solution = 6/4 (volume ratio), power column: YM C— CDS—AM AM— 3 0 2 S—5 m (150.times.4.6 mm I.D., manufactured by JM Corporation)].

The elution rate was calculated by substituting each value into the following equation.

Dissolution rate (%)

1 (/ ~

: Ws X—— X 900 (900- (ί-ΐ) χ2) + Ϋ ri-1 χ2 χ χ--xlOO

As 100 B (mg) ¥, ： Compound A standard (mg)

A _Ti , A _Ti-1 : Peak area of the sample sampled at the i-th and i-th first 1/100: dilution factor, S: drug amount in drug (mg)

Dissolution test results

FIG. 1 shows the measurement results of the dissolution rates of Examples 1, 3 and Comparative Example 1. As a result, in Examples 1 and 3, the drug eluted more rapidly than after the start of the test, and reached a dissolution rate of 100% 90 minutes after the start of the test. In contrast, in Comparative Example 1, only about 60% of the drug was eluted even after 180 minutes. In Examples 1 and 3, the ratio of the drug to the surfactant was 14 and 20 (W / W)%, respectively, and the drug was completely dissolved in the surfactant at the time of preparation. Had dissolved. In contrast, in Comparative Example 1, the compounding ratio of the drug to the surfactant was 33 (W / W)%, and the drug was not completely dissolved in the surfactant at the time of preparation.

FIG. 2 shows the measurement results of the drug dissolution concentration in Examples 2 and 4 and Reference Examples 1 and 2. As a result, the drug dissolution concentration became higher than the solubility of the drug by 10 minutes after the start of the dissolution test, and thereafter, the concentration was significantly higher than the solubility for more than 120 minutes, that is, the so-called supersaturated solution was maintained. . Of the formulations of Example 2 and Example 4 The dissolution behavior was almost the same as the preparations of Reference Examples 1 and 2. Stability test methods and results

A sample compound stored in a sealed container at 40 ° C for 1 month A 10 mg equivalent of Example 4 was placed in acetonitrile to extract the drug, and the drug concentration in the extract was determined by HPLC. It was measured. As a result, the drug residual ratio was 99.8%, and the drug in the preparation was stable.

(Example 5)

Manufacturing method

Solid formulations were prepared according to the formulation shown in Table 2. The production method is shown below.

The raw materials used for the preparation are listed. The drug is obtained by pulverizing compound A (N "-[2- [5-[[4-methylphenyl] ethynyl] chenyl]] sulfonyl] -D-tritophan) described in WO 97/27 174. Polyethylene glycol was Macrogol 400 (PEG 400), polyoxyethylene sorbitan fatty acid ester was polyoxyethylene sorbitan monooleate (Tween 80), and hydroxypropyl methyl cellulose acetate succinate ( HPMCAS—LF) used a drug-compliant product.

Compound A10 Omg is dissolved in a solution obtained by mixing PEG4001100 mg and Tween8000400 mg heated to about 60 ° C. This solution is referred to as “surfactant solution”. On the other hand, add 200 mg of HPMCAS-LF120 to 4.5 mL of acetone and dissolve. This solution is referred to as “solid forming agent solution”.

The surfactant solution and the solid forming agent solution are mixed, placed in a desiccator, and stored under reduced pressure under vacuum. The obtained solid was pulverized with a tablet pulverizer and sieved, and a 24 mesh live product was used as a sample.

(Table 2) (Unit: mg)

Example 5

Compound A 100

PEG 400 100

Tween 80 400

HPMCAS- LF 1200 • PE G40 0: Mak Π Goal 40 0

-T we e η 80: Polyoxyethylene sorbitan monooleate

• HPMCAS-LF: Hydroxypropyl methylcellulose acetate succinate

Dissolution test and drug concentration measurement

The dissolution test was performed in accordance with the method prescribed in the Japanese Pharmacopoeia 14th Edition. First, the preparation was put into the first liquid, and after 120 minutes, the preparation in the test liquid was taken out. The formulation was put into the second liquid, and the dissolution test was performed. In the test solution, a preparation equivalent to 125 mg of the drug was added.

Test method: Japanese Pharmacopoeia Dissolution test method 2nd method (paddle method) Stirring speed 50 rpm Test solution: 1st solution (pH 1.2) 900 mL, water temperature 37 ± 0.5 ° C

Second solution (pH 6.7) 900 mL, water temperature 37 ± 0.5 ° C

Test liquid sampling time: 120 minutes after the start of the test 120, 125, 130, 135, 150, 165, 180, 240 minutes

Test liquid collection volume: 2 mL

Drug concentration measurement method: The collected liquid was filtered with a 0.45 m pore size filter, and the filtrate was diluted with acetonitrile. The drug concentration in the diluted solution was determined by the HP LC method [wavelength: 315 nm, mobile phase: acetonitrile / 1% acetic acid aqueous solution = 6/4 (volume ratio), power ram: YMC—ODS—AM AM—30 2 S—5 m (1500 × 4.6 mm I.D., manufactured by Yemushi Corporation)].

Dissolution test results

Figure 3 shows the measurement results of drug dissolution concentration. As a result, the drug did not elute in the first solution until 120 minutes after the start of the dissolution test, and when it was subsequently poured into the second solution, the drug dissolution concentration was increased by 5 minutes after the start of the dissolution test. And maintained concentrations above solubility for over 90 minutes thereafter.

(Example 6, Comparative Example 2) Manufacturing method

According to the formulation shown in Table 3, the solid preparation of Example 6 and the solution of Comparative Example 2 were produced. The method for producing the solid preparation is shown below.

The raw materials used for the preparation are listed. The drug is the compound B ((2R) -2-[[4- [3- (4-fluorophenyl) -1,2,4-oxaziazol-5-yl] benzenesulfonyl] described in WO 01/83464] Amino] -3-phenylpropionic acid) was used after pulverization. Polyethylene glycol was Macrogol 400 (PEG 400), polyoxetylene sorbitan fatty acid ester was polyoxyethylene sorbitan monooleate (Tween 80), and sucrose, gelatin and agar were compliant with the pharmaceutical specifications. . Dissolve 60 mg of the pulverized compound B in a mixed solution of 400 mg of PEG 400 and 400 mg of Tween heated to about 60 ° C. This solution is referred to as “surfactant solution”. Meanwhile, 800 mg of gelatin and 80 mg of agar are added to 12 mL of distilled water and kept at around 100 ° C. This solution is referred to as “solid forming agent solution”. Mix the surfactant solution and the solid former solution, leave the solution at room temperature, put it in a desiccator overnight, and store it under vacuum and vacuum overnight. The obtained solid was pulverized with a tablet pulverizer and sieved to obtain a sample of 24 mesh.

(Table 3) (Unit: mg)

• Compound B: (2R) -2-[[4- [3- (4-fluorophenyl) -1,2,4-oxaziazol-5-yl] benzenesulfonyl] amino] -3-phenyl Propionic acid

• P E G40 0: Macrogol 400

• Tween 80: Polyoxyethylene sorbitan monooleate

Dissolution test and drug concentration measurement

The dissolution test was performed in accordance with the method prescribed in the Japanese Pharmacopoeia 14th Edition. The test Into the solution was added a preparation equivalent to 60 mg of the drug / product.

Test method: Japanese Pharmacopoeia Dissolution test method 2nd method (paddle method) Stirring speed 50 rpm Test solution: 900 mL of distilled water, water temperature 37 ± 0.5 ° C

Test liquid collection time: 10, 20, 30, 60, 90, 120, 180 minutes after the start of test

Test liquid collection volume: 1 mL

Drug concentration measurement method: The collected liquid was filtered with a 0.45 pore size filter, and the filtrate was diluted with acetonitrile. HPLC method for the concentration of the drug in the diluted virulent fluid [measurement wavelength: 252 nm, mobile phase: methanol / 0.1% aqueous solution of trifluoroacetic acid = 6/4, column: YMC—Pack 〇DS—AM AM— 302 S-5 zm (150 X 4.6 mm I.D., manufactured by JM Corporation)].

Dissolution test results

FIG. 4 shows the measurement results of the drug dissolution concentration. As a result, the drug dissolution concentration of Comparative Example 2 became lower than the solubility 60 minutes after the start of the test. In contrast, the drug dissolution concentration in Example 6 became higher than the solubility of the drug by 10 minutes after the start of the dissolution test, and was maintained at a concentration higher than the solubility for 120 minutes or more thereafter.

(Example 7)

Manufacturing method

According to the formulation shown in Table 4, the solid preparation of Example 7 and the solution of Reference Example 3 were produced. The method for producing the solid preparation is shown below.

The raw materials used for the preparation are listed. Polyethylene glycol is Macrogol 400 (PEG 400), polyoxyethylene sorbitan fatty acid ester is polyoxyethylene sorbitan monooleate (Tween 80), phenytoin and hydroxypropyl methylcellulose TC-15EW (HPMC) are the Japanese Pharmacopoeia. One of the conforming products was used.

Dissolve 60 mg of phenytoin in a mixed solution of PEG 405 mg and Tween 800 mg heated to about 55 ° C. This solution is called “surfactant Solution ”. On the other hand, add 200 mg of HPMC to 5.2 mL of distilled water to dissolve. This solution is referred to as “solid forming agent solution”.

Mix the surfactant solution and the solid former solution, allow the solution to stand at room temperature, put it in a desiccator overnight, and store under vacuum and vacuum overnight. The obtained solid was pulverized with a tablet pulverizer and sieved to obtain a sample of 24 meshes.

(Table 4) (Unit: mg)

• P E G40 0: Macrogol 40 0

• Tween 80: Polyoxyethylene sorbitan monooleate

• HPMC: Hydroxypropyl methylcellulose TC-5EW

Dissolution test and drug concentration measurement

The dissolution test was performed in accordance with the method prescribed in the Japanese Pharmacopoeia 14th Edition. A preparation equivalent to 60 mg of drug was injected into the test solution.

Test liquid collection volume: 1 mL

Drug concentration measurement method: The collected solution was filtered through a 0.45 Aim filter, and the filtrate was diluted with methanol. The drug concentration in the diluted solution was determined by the HP LC method [measurement wavelength: 220 nm, mobile phase: methanol / water = 55Z45, column: CAP CE LL PAK C 18 UG 1 20 S—3—m (1 50 X 4.6 mm I.D., manufactured by Shiseido Co., Ltd.)].

Dissolution test results Fig. 5 shows the measurement results of the drug dissolution concentration. As a result, the drug dissolution concentration in Example 7 became higher than the solubility of the drug by 10 minutes after the start of the dissolution test, and was maintained at a concentration higher than the solubility for 120 minutes or more thereafter. The elution behavior of Example 7 was almost the same as that of Reference Example 3.

(Example 8)

Manufacturing method

According to the formulation shown in Table 5, the solid preparation of Example 8 and the solution of Reference Example 4 were produced. The method for preparing the solid preparation is shown below.

The raw materials used for the preparation are listed. Polyoxyethylene sorbitan fatty acid ester is polyoxyethylene sorbitan monooleate (Tween 80), diphedipine and hydroxypropyl methylcellulose TC-15EW (HPMC) are Japanese Pharmacopoeia compliant products. Using.

Dissolve 150 mg of diphendipine in Tween 80 210 mg heated to about 80 ° C. This solution is referred to as “surfactant solution”. On the other hand, HPMC 3150 mg is added to 7.9 mL of distilled water and dissolved. This solution is referred to as “solid forming agent solution”.

The surfactant solution and the solid former solution are mixed, and the solution is allowed to stand at room temperature, put in a desiccator overnight, and store under reduced pressure under vacuum overnight. The obtained solid was pulverized with a tablet pulverizer and sieved to obtain a sample of 24 meshes.

(Table 5)

T we en 80: Polyoxyethylene sorbitan monooleate

HPMC: Hydroxypropyl methylcellulose T C—5 EW

Dissolution test and drug concentration measurement

The dissolution test was performed according to the method specified in the 14th revised Japanese Pharmacopoeia. The test In the solution, a preparation equivalent to 100 mg of the drug was introduced.

Test liquid sampling time: 10, 20, 30, 60, 90, 120, 180 minutes after the start of test

Test liquid collection volume: 1 mL

Drug concentration measurement method: The collected liquid was filtered through a 0.45 / m pore size filter, and the filtrate was diluted with methanol. The drug concentration in the diluted solution was determined by the HPLC method [wavelength: 2

35 nm, mobile phase: methanol / water = 5/3, column: YM C—OD S—AM AM—302 S—5 jm (150 x 4.6 mm I.D. ヽ) Manufactured).

Dissolution test results

FIG. 6 shows the measurement results of the drug dissolution concentration. As a result, the drug dissolution concentration in Example 8 became higher than the solubility of the drug by 10 minutes after the start of the dissolution test, and was maintained at a concentration higher than the solubility for 120 minutes or more thereafter. The elution behavior of Example 8 was almost the same as that of Reference Example 4.

(Absorptivity test method of Example 4)

The obtained solid preparation of Example 4 was subjected to an absorption test. The absorption test was performed as follows.

The solid preparation of Example 4 was coarsely pulverized with a tablet pulverizer, and an empty gelatin capsule was filled with the preparation having a main drug amount of 5 O mg and an amount equivalent to 200 mg. The capsule was orally administered to three male Beagle dogs fasted for 24 hours before administration, and then loaded with 50 mL of distilled water via a catheter. As a control, the same 0.1% HPC-SL suspension prepared so that the active drug content in 1 OmL was 5 Omg and 200 mg was administered to the same three beagle dogs as described above before administration. After a 4-hour fast, 10 mL of the suspension sample was injected into the stomach of the dog using a gastric catheter, and then the syringe and the catheter were washed.

40 mL of distilled water was loaded and administered. Blood is collected from the forelimb vein before and after administration, The drug concentration in plasma was quantified by an HPLC method using a column switching system. HPLC conditions were as follows: Pre-column: Cosmosil 5 ph (150 mm x 4.

6 mm ID (manufactured by Nacalai Tesque), analytical column: J'sphere 0 DS-H80 (75 mm X 4.6 mm ID, manufactured by JEMC), mobile phase for precolumn: 0.1% trifluoroacetic acid / acetonitryl = 45:55, mobile phase for analytical column: 0.1% trifluoroacetic acid / acetonitrile = 35:65, detection wavelength: 315 nm . From the obtained blood concentrations, C max (maximum blood concentration) after administration of each administration sample and AU C (area under the blood concentration curve) calculated by the trapezoidal method were compared.

Figures 7 and 8 show the one-hour blood concentration curves when 50 mg and 200 mg of the drug were administered to the Example 4 preparation and the drug suspension, respectively.Table 6 shows Cmax and AUC Indicates a value. As a result, the blood concentration of the preparation of Example 4 was significantly increased as compared to the drug suspension, and the C max was about 2.8 times higher than that of the suspension at the time of administration of 200 mg, and the AU C was about 3.7 times.

(Table 6)

Industrial applicability

When this formulation was administered orally, the solubility of the poorly water-soluble drug was improved, so that the absorption of the drug was increased as compared with the case where the aqueous suspension of the drug was administered. The drug incorporated in this formulation was stable even after long-term storage.

Claims

The scope of the claims

1. A solid state containing a poorly water-soluble drug, a surfactant and a solid forming agent, wherein the compounding ratio of the poorly water-soluble drug to the surfactant is 25 (W / W)% or less, and the solubility is improved. Formulation.

2. The preparation according to claim 1, wherein the compounding ratio of the poorly water-soluble drug to the surfactant is 3 to 25 (W / W)%.

3. The preparation according to claim 1 or 2, wherein the mixing ratio of the surfactant to the total amount of the preparation is 20 (W / W)% or more.

4. The preparation according to any one of claims 1 to 3, wherein the surfactant is HLB 8 or more.

5. The surfactant is one or more selected from the group consisting of polyethylene glycol, polyoxyethylene sorbin fatty acid ester, polyoxyethylene hydrogenated castor oil, glycerin fatty acid ester and sucrose fatty acid ester. The preparation according to any one of claims 1 to 4.

6. The preparation according to claim 5, wherein the surfactant is a polyethylene glycol and a fatty acid ester of polyoxyethylene sorbitan.

7. The preparation according to any one of claims 1 to 6, wherein the solid forming agent is one or more selected from the group consisting of gelatin, polysaccharides, celluloses, and polyvinyls.

8. The solid former is gelatin, agar, sodium alginate, pectin, pullulan, xanthan gum, gum arabic, carrageenan, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, polyvinyl alcohol and polyvinylpyrrolidone. 8. The preparation according to claim 7, wherein the preparation is one or more selected from the group consisting of:

9. The preparation according to claim 7, wherein the solid forming agent is one or more selected from the group consisting of gelatin, agar, pectin and gum arabic.

10. The solid forming agent is hydroxypropyl permethyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, carboxymethylethyl. 8. The preparation according to claim 7, wherein the preparation is one or more selected from the group consisting of cellulose and cellulose acetate fluorophosphate.

1 1. The formulation according to claim 7, wherein the solid forming agent is hydroxypropyl methylcellulose acetate succinate.

1 2. A preparation obtained by adding sucrose as an excipient to the preparation according to any one of claims 1 to 11.

13. The preparation according to any one of claims 1 to 12, wherein the poorly water-soluble drug has a water solubility of not more than 1000 g / mL.

1. The poorly water-soluble drug

Equation (I):

R ¹

R ⁵ -R ⁴ — R ³ — SO. One N ', COY (I)

(Wherein, R ¹ is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted Heteroarylalkyl; R ² is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted Good heteroarylalkyl; R ³ is a single bond, optionally substituted arylene or optionally substituted heteroarylene; R ⁴ is a single bond, one (CH ₂ ) m-,-CH = CH —, One C≡ C—, -CO-, —CO—NH—, one N = N—, — N (R ^A ) one, one NH—CO—NH—, — NH—CO—, one 0-, ― S—, one S 0 ₂ NH—, one SO ₂ — NH— N = CH—, oxadiazole or te Torazorujiiru; R ⁵ is lower alkyl which may be substituted, an optionally substituted C ₃ ~ C ₈ cycloalkyl, optionally substituted Ariru, have been heteroaryl or substitution to an optionally substituted A non-aromatic heterocyclic group; R ^A is hydrogen or lower alkyl; Y is N H〇H or OH; m is 1 or 2; however, when Y is NH 0 H, R ² is hydrogen.], An optically active form thereof, or a pharmaceutically acceptable salt thereof, or 14. The formulation according to claim 13, wherein is a solvate thereof.

15. The preparation according to claim 13, wherein the poorly water-soluble drug is a nitrophenylpyridine carboxylic acid drug or a hydantoin drug.

1 6. The formulation according to any one of claims 1 to 15, wherein the drug dissolves quickly and maintains a supersaturated dissolved state for a long time.

The drug product according to claim 8, wherein the drug dissolves at a temperature higher than the saturated solubility of the drug by 10 minutes after the start of the dissolution test at 17.37 ° C and the supersaturated solution is maintained for at least 120 minutes thereafter. . -

18.3 The drug did not dissolve in the dissolution test solution with a pH of less than 5 at 37 ° C. 10. The preparation according to claim 10, wherein the drug dissolves at a higher than saturated solubility and maintains a supersaturated dissolved state for 90 minutes or more thereafter.

19. The preparation according to any one of claims 1 to 18, wherein the absorption of the poorly water-soluble drug in oral administration is increased as compared to when an aqueous suspension of the drug is administered.

20. The method is characterized in that a poorly water-soluble drug, a surfactant, and a solid forming agent are dissolved in one or more solvents selected from the group consisting of water, alcohol, and acetone, and then the solution is dried. A method for producing the preparation according to any one of claims 1 to 19. 2 1. The following solutions:

1) a solution of a poorly water-soluble drug dissolved in a surfactant; and

21. The method according to claim 20, wherein the mixture is dried.

22. The compounding ratio of the poorly water-soluble drug to the surfactant is 25 (W / W)% or less, and the poorly water-soluble drug, the surfactant and the solid-forming agent are composed of water, alcohol, and acetone. After dissolving in one or more solvents selected from A solid preparation with improved solubility of the drug produced by drying.