JPH04364129A - 6-substituted alkoxyquinoxaline derivative-containing medicinal composition and its production - Google Patents

Abstract

PURPOSE:To provide the subject composition substantially improved in the solubility in water, giving sustainable supersaturated phenomena, containing a noncrystallizingly treated product from a 6-substituted alkoxyquinoxaline derivative and hydroxypropyl cellulose. CONSTITUTION:The objective composition containing either (A) a noncrystallizingly treated product from both (1) a 6-substituted alkoxy-2-oxo-1,2- dihydroquinoxaline derivative of the formula (R is methyl or ethyl; (n) is 3 or 4), e.g. 6-[3-(N-cyclohexyl-Nmethyl-aminocarbonyl)propoxy]-2-oxo-1,2- dihydroquinoxaline (2) hydroxypropyl cellulose(HPC) or (B) a noncrystallizingly treated product from the compound of the formula and HPC. Said noncrystallizingly treated product can be prepared by drying (a) a volatile organic solvent solution of the compound of the formula and HPC or (b) a volatile organic solvent solution of both the compound of the formula and HPC; in this process, it is preferable that a noncrystalline matter stabilizer such as hydroxypropylmethyl cellulose, a methacrylic copolymer or bile acid be made to coexist.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention is based on the general formula

The present invention relates to a pharmaceutical composition of a poorly soluble drug represented by the following formula (wherein R represents a methyl or ethyl group, and n represents 3 or 4) and a method for producing the same.

0002

[Prior Art] The above-mentioned 6-substituted alkoxy-2-oxo-1,2-dihydroquinoxaline derivative [I] has platelet aggregation inhibitory activity and/or cyclic-AMP phosphodiesterase inhibitory activity, and is used as an antithrombotic agent, a circulating It is a drug useful as an ameliorating drug (Japanese Unexamined Patent Publication No. 2-76860).

[0003] The drug [I] has extremely low solubility in water, and even when improved by ordinary dissolution means,
Its solubility in water is low, and a method of adding cyclodextrins to slightly improve the solubility in water has been disclosed (Japanese Patent Application Laid-Open No. 2-221223
Publication No.). However, even with this method, a sufficiently satisfactory improvement in solubility has not been shown.

[0004] In general, poorly soluble drugs are difficult to absorb in the gastrointestinal tract and cannot exhibit effective medicinal effects when administered orally. It has long been believed that increasing the solubility of poorly soluble drugs is particularly important for increasing bioavailability and maintaining effective drug efficacy. , various reports have been made. for example,

(1) A method of adding a poorly soluble drug to β-1,4-glucan and co-pulverizing it to make it amorphous (Japanese Patent Publication No. 1983-2
9565), (2) A method in which a soluble protein such as gelatin and a hydrophilic polymer substance such as methyl cellulose, hydroxypropyl cellulose, or polyvinylpyrrolidone are added to a poorly soluble drug and co-pulverized until it becomes amorphous.
4-6174),

(3) A method of mixing and pulverizing poorly soluble drugs and quinoxaline to such an extent that they exist in an amorphous state (Japanese Patent Publication No. 63-28414); (4) highly water-soluble drugs such as polyvinylpolypyrrolidone and methylcellulose; A method of dispersing a poorly soluble drug in a non-crystalline state in a mixture with a molecular substance (Japanese Patent Publication No. 63-60010);

(5) A method of kneading and kneading a poorly soluble drug and a water-soluble polymeric substance such as polyvinylpyrrolidone using a roll mixer under heating at room temperature or at a temperature lower than the melting point of the poorly soluble drug (Japanese Patent Application Laid-open No. 1986 -190723 Publication), (6) Dissolve a poorly soluble substance and a polymeric substance such as hydroxypropyl cellulose in an organic solvent, add powder or granules insoluble in the solvent to this solution, knead, and then remove the solvent. Method (Japanese Unexamined Patent Publication No. 61-249914),

(7) A method of adding partially α-starch to a poorly soluble drug and spray-drying it (Japanese Patent Laid-Open No. 101333/1983), (8) Adding a partially α-starch to a poorly soluble drug, and (8) Adding a partially α-starch to a poorly soluble drug, hydroxypropyl cellulose, sodium carboxymethyl starch, and partially Water-swellable polymeric substances such as α-starch and organic solvents such as hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, etc., and any buffer in the pH range of 1 to 9. Polymer substances and/or
or a method of uniformly mixing a water-soluble polymer substance with a monovalent metal salt (Japanese Unexamined Patent Publication No. 1-156909);

0
(9) From a solution or suspension in which a poorly soluble drug and a hydrophilic polymer substance such as polyvinylpyrrolidone, crystalline cellulose, crosslinked carboxymethyl cellulose, etc. and/or hydrophilic inorganic fine particles are dissolved in an organic solvent. Examples include a method of rapidly removing the solvent (Japanese Unexamined Patent Publication No. 2-49720).

0010

[Problems to be Solved by the Invention] As mentioned above, the drug represented by the general formula [I] has extremely low solubility in water, and when made into an oral preparation, it has poor bioavailability due to poor dissolution in the gastrointestinal tract. They have the disadvantage of low E, and as a means to improve this, compositions containing cyclodextrins have been prepared, but they have the disadvantage that the solubility in water has not been improved to a sufficiently satisfactory degree.

[0011] In order to solve the above-mentioned drawbacks, the present inventors have conducted various studies on methods for improving the solubility of conventional poorly soluble drugs. The method of co-pulverizing a soluble drug and a polymeric substance using a grinder such as a ball mill to amorphize the drug requires grinding for several tens of hours before amorphizing, which not only lacks convenience but also
There are drawbacks such as the possibility of drug deterioration.

[0012] Furthermore, with the methods of prior art techniques (5) to (8), it was not possible to significantly improve the solubility of the present drug [I]. Furthermore, we tried the method of prior art (9) in which the poorly soluble drug and polymeric substance were dissolved in a solvent and rapidly removed from the solution, but even if the polymeric substance described in (9) was used, It was found that the effect of significantly improving the solubility of the drug [I] was small, and the supersaturation state did not last long, resulting in only a so-called transient increase in solubility.

Therefore, even if known methods are applied as they are, the results will be greatly affected by the type of poorly soluble drug, its properties, the type of polymeric substance used, and the solubility improvement treatment method. I learned that the solubility was not significantly improved regardless of the amount.

[0014]

[Means for Solving the Problems] With the aim of solving the above problems, the present inventors, as a result of various studies, have solved the drug represented by the general formula [I] in a volatile organic solvent, The drug [I] is obtained only when the solution is rapidly dried by a spray drying method or a fluidized bed granulation drying method, and the resulting amorphized product contains hydroxypropylcellulose among various polymeric substances. The present inventors have found that a pharmaceutical composition in which the solubility of the compound is significantly improved is obtained, and that the use of polymeric substances other than those mentioned above does not significantly improve the solubility of the compound.

Furthermore, when the drug [I] is dissolved in an organic solvent, a pharmaceutical composition obtained by dissolving it together with the above-mentioned hydroxypropyl cellulose and drying it by a spray drying method or a fluidized bed granulation drying method may also be used. It has been found that the solubility of [I] is significantly improved. Furthermore, the inventors have also discovered that a pharmaceutical composition exhibiting a sustained supersaturation phenomenon can be efficiently produced in a short period of time, thereby completing the present invention.

The present invention is characterized in that it contains an amorphized product of the drug represented by the general formula [I] and hydroxypropylcellulose, or an amorphized product of the drug [I] and hydroxypropylcellulose. At least the drug [
A pharmaceutical composition obtained by improving the water solubility of [I] and a method for producing the same.

[0017] The present invention also provides a method for determining the solubility in water of the drug [I], which is characterized by containing an amorphous product of the drug [I], hydroxypropyl cellulose, and an amorphous stabilizer. An improved pharmaceutical composition and a method for producing the same.

An example of the drug [I] is 6-[3-(
N-cyclohexyl-N-methyl-aminocarbonyl)
propoxy]-2-oxo-1,2-dihydroquinoxaline (compound A), 6-[3-(N-cyclohexyl-
N-ethyl-aminocarbonyl)propoxy]-2-oxo-1,2-dihydroquinoxaline (compound B), 6
-[4-(N-cyclohexyl-N-methyl-aminocarbonyl)butoxy]-2-oxo-1,2-dihydroquinoxaline (compound C), 6-[4-(N-cyclohexyl-N-ethyl-aminocarbonyl) )butoxy]−
2-oxo-1,2-dihydroquinoxaline (compound D
), but these are known substances, and the method for producing them is disclosed in JP-A-2-76860.

[0019] In order to produce the present pharmaceutical composition, first, the present drug [I] is dissolved in an appropriate amount of a volatile organic solvent. The organic solvent to be used is not particularly limited as long as it dissolves the drug [I] and has volatility, and examples include alcohols, ketones, ethers, chlorinated hydrocarbons, etc. Of these, ethanol and methylene chloride are preferred. The concentration of the drug [I] in the solvent is not particularly limited, but is usually about 1-2% to 10%.

[0020] The solution obtained above is rapidly dried to obtain an amorphized product, and this drying treatment is carried out by a rapid drying method such as a spray drying method or a fluidized bed granulation drying method. In the above-mentioned fluidized bed granulation drying method, the carrier may be sprayed onto a carrier such as lactose or starch in a fluidized bed granulation dryer. Such amorphization treatment improves the solubility of the drug [I], but the increase in solubility is only temporary.

In the present invention, hydroxypropyl cellulose (H
PC), the object of the present invention is achieved and the pharmaceutical composition of the present invention is obtained. The amount of HPC to be used may be about 0.25 parts by weight or more based on the drug [I], but the upper limit is about 3 times as much, considering the convenience of formulation. There are four grades of HPC, SL, L, M, and H, depending on their viscosity, and any of them may be used, but L is the most effective.

Furthermore, in the present invention, even when the drug [I] is dissolved in an organic solvent, even if it is dissolved together with HPC, the object of the present invention is achieved and the desired pharmaceutical composition of the present invention can be obtained. . It goes without saying that the obtained amorphized product containing the present drug [I] and HPC may further contain HPC. When this drug [I] and HPC are dissolved together, the total amount of HPC used is the HP
The range of the amount used may be the same as that of C.

[0023] When implementing the pharmaceutical composition of the present invention, the higher the amorphous rate of the drug [I], the better, so an amorphous treated product with as high an amorphous rate as possible is blended. Needless to say, this is preferable.

[0024] The pharmaceutical composition of the present invention thus obtained not only significantly improves the solubility of the drug [I] in water, but also maintains the supersaturation phenomenon for 120 to 180 minutes. . The continuation of such a supersaturation phenomenon means that crystal precipitation is prevented for a long period of time, and for drugs that are poorly soluble in water, such as this drug [I], absorption from the gastrointestinal tract is significantly reduced. It will be improved.

[0025] The above pharmaceutical composition shows almost no decrease in amorphousness even when stored for a long time under normal storage conditions, but when stored under harsh storage conditions, for example, at 40°C and 75% humidity. If stored for a long period of time under low temperatures, the degree of amorphism decreases (crystallization progresses) and the solubility in water decreases.

In order to maintain the above-mentioned amorphous stability, when dissolving the present drug [I] together with HPC in an organic solvent, one or more amorphous stabilizers must be dissolved together. It is preferable to carry out the amorphization treatment by the drying step.

Examples of the amorphous stabilizer include hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, ethylcellulose, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, polyvinyl acetal diethylaminoacetate,
Includes bile acids or their non-toxic salts. The amount of amorphous stabilizer to be used should be about 0.25 parts by weight or more based on the drug [I], but the upper limit should be about 3 times as much, considering the convenience of formulation. be.

An example of hydroxypropyl methyl cellulose is TC-5 (manufactured by Shin-Etsu Chemical Co., Ltd.), and an example of hydroxypropyl methyl cellulose phthalate is HP-5.
50, HP-55 (manufactured by Shin-Etsu Chemical Co., Ltd.), examples of ethyl cellulose include EC (manufactured by Dow Chemical Company), examples of aminoalkyl methacrylate copolymers include Eu
Examples of methacrylic acid copolymers include dragitE and EudragitRS (manufactured by Rohm and Haas); examples of methacrylic acid copolymers include EudragitL and EudragitS (manufactured by Rohm and Haas); and examples of polyvinyl acetal diethylamino acetate include AEA (manufactured by Sankyo).
, Examples of bile acids include dehydrocholic acid, deoxycholic acid, and the like.

[0029] The drug [I] and H obtained in this way
A pharmaceutical composition containing an amorphous product of PC and an amorphous stabilizer not only improves the solubility of the drug [I] in water, but also improves the solubility of the drug [I] under long-term storage conditions. Also, the amorphous stability of the pharmaceutical composition is improved.

The pharmaceutical composition of the present invention can be prepared into oral preparations such as tablets, capsules, and granules according to known formulation techniques together with other excipients such as fillers, disintegrants, lubricants, and stabilizers. , syrup, etc. can be adjusted.

[0031]

[Effects of the Invention] Regarding the pharmaceutical compositions of the present invention obtained in the Examples described later and the control products obtained in the Comparative Examples, the solubility in water (37°C) and the degree of amorphism determined by X-ray diffraction images were determined. The results of the investigation are as follows.

Pharmaceutical composition 3 (-□-), pharmaceutical composition 4 (...+...) and pharmaceutical composition 5 (...◇...) of the present invention
) are shown in FIG. 1, all of which show good curves, and a sustained supersaturation phenomenon can be seen.

Furthermore, the X-ray diffraction image of the pharmaceutical composition 3 of the present invention is shown in FIG.
This shows that the degree of amorphism is significantly increased compared to that obtained through a sieve of 0 mesh (FIG. 5).

[0034] Furthermore, the pharmaceutical composition 1 of the present invention (...◇...
), Pharmaceutical composition 2 (--△--), Raw material compound (-□
Figure 2 shows the solubility curves of the amorphized product of Compound A (-) and Compound A (-x-), and it can be seen that the solubility of Pharmaceutical Compositions 1 and 2 is significantly increased compared to the raw material Compound A. .

Pharmaceutical composition 6 (-□-), pharmaceutical composition 7 (...+...), pharmaceutical composition 8 (...◇...) and pharmaceutical composition 9 (--△--) of the present invention The solubility curves of ) are shown in FIG. 3, and the same effects can be seen in both cases. The solubility curves of Control Product 1 (--◇--), Control Product 2 (-□-), and Control Product 3 (...+...) are shown in Figure 4, and Control Product 1 shows sustained solubility. However, its value is low.

Although an initial effect was observed on the solubility of Control Products 2 and 3, it was temporary, and the X-
The line diffraction image is shown in FIG. 7, and shows that the degree of amorphism is lower than that of Pharmaceutical Composition 3 of the present invention.

[0037] Furthermore, pharmaceutical composition 10 of the present invention (... +
The solubility curves of Compound D(-□-) and raw material are shown in FIG.
It can be seen that the solubility of the powder is significantly higher than that of the untreated bulk powder.

[0038] Control product 4 (-□-), control product 5 (... +
Figure 9 shows the solubility curves of control product 6 (...) and control product 6 (...◇...).
It can be seen that the increase is only about 4 times.

[0039] From the above facts, the pharmaceutical composition of the present invention:
In the manufacturing process, the present drug [I] is subjected to an amorphization treatment, and a specific hydroxypropylcellulose is used as a carrier, thereby obtaining a composition in which the solubility of the poorly soluble drug is improved. The present pharmaceutical composition can be easily produced without causing deterioration of the drug [I], and not only brings about a remarkable effect of improving the dissolution of the drug [I] compared to conventional methods, but also brings about a sustained supersaturation phenomenon. be able to.

Furthermore, the solubility curves of pharmaceutical compositions 11 to 19 containing amorphous products of the present drug [I], HPC, and an amorphous stabilizer are shown in FIGS. 10 to 12, and In both cases, the solubility was significantly increased compared to the raw material Compound A and the amorphized product of Compound A (Figure 2), and the drug [I ] Not only can it bring about a remarkable elution improvement effect, but it can also bring about a sustained supersaturation phenomenon.

[0041] Figure 13 shows the solubility curves of control products 7 to 11 obtained by spray drying a solution obtained by dissolving the drug [I] and the amorphous stabilizer in an organic solvent without using HPC. As shown in
There was no significant increase in solubility seen with pharmaceutical compositions containing HPC.

Pharmaceutical composition 2 and pharmaceutical compositions 11 to 19
The results of testing the amorphous stability of each pharmaceutical composition after 4 weeks of storing it under harsh conditions of 40°C and 75% humidity are shown in Table 1 below. The solubility of Pharmaceutical Composition 2, which does not use an amorphous stabilizer, after storage under harsh conditions is significantly lower than that at the time of preparation, but all of Pharmaceutical Compositions 11 to 19, which use an amorphous stabilizer, have a lower solubility than that at the time of preparation. Compared to this, it is significantly improved and the degree of amorphism is maintained.

Instead of the amorphous stabilizer used in the present invention, vinyl acetate resin (manufactured by Tanabe Seiyaku Co., Ltd., food additive),
Control products 12 and 13 manufactured using sucrose fatty acid SEL (manufactured by Daiichi Kogyo Seiyaku Co., Ltd., DK-Ester F160)
In the amorphization stability test, the solubility after storage under harsh conditions was significantly lower than that at the time of preparation, indicating that vinyl acetate resin and sucrose fatty acid ester are ineffective as amorphous stabilizers.

From the above facts, the present pharmaceutical composition using an amorphous stabilizer can maintain amorphous stability even during long-term storage under harsh conditions.

[0045]

EXAMPLES Next, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

Example 1 2 g of compound A was dissolved in 200 ml of methylene chloride, and the solution was dried using a spray dryer (YAMATO, Pul.
visGB22 type) using spray drying (intake air temperature 70℃
, exhaust temperature 45° C.) to obtain a powder of the amorphized compound A. Add 1 part by weight of HPC-L to 1 part by weight of this powder.
The mixture was thoroughly mixed using a mold mixer (15 minutes) to obtain Pharmaceutical Composition 1.

Example 2 2 g of Compound A was dissolved in 200 ml of methylene chloride, 2 g of HPC-L was added to this solution and dissolved, and then spray-dried using a spray dryer (intake temperature 70°C, exhaust temperature 45°C) to obtain a pharmaceutical product. Composition 2 was obtained.

Example 3 In Example 1, HPC-SL was used instead of HPC-L.
Pharmaceutical composition 3 was obtained by the same treatment using .

Example 4 In Example 2, HPC-L was replaced with HPC-L.
Pharmaceutical compositions 4 and 5 were obtained by similar treatment using M and HPC-H, respectively.

Example 5 In Example 2, 0.25, 0.5, 2 and 3 parts by weight of HPC-L were used instead of 1 part by weight, and the same procedure was repeated to prepare pharmaceutical compositions 6 and 6. , 7, 8 and 9 were obtained.

Comparative Example 1 5 g of compound A and 5 g of HPC were mixed in a ball mill (capacity 3.
6 liters and a ball weighing 1 kg), and mixed and pulverized for 12 hours to obtain Control Product 1.

Comparative Example 2 Compound A 2g and polyvinylpyrrolidone (K-30)
2 g was dissolved in 200 ml of methylene chloride, and this solution was spray-dried according to Example 2 to obtain Control Product 2.

Comparative Example 3 In Comparative Example 2, polyvinylpyrrolidone (K-30)
Control product 3 was obtained by using polyethylene glycol (6000) instead of.

Example 6 Pharmaceutical composition 10 was obtained in the same manner as in Example 2, except that Compound D was used as a drug instead of Compound A.

Comparative Example 4 Compound D and 2 g of HPC-L were placed in a ball mill,
Control product 4 was obtained by mixing and pulverizing for 12 hours.

Comparative Example 5 In Example 2, Compound D was used instead of Compound A, and polyvinylpyrrolidone (K-30) and polyethylene glycol (6) were used instead of HPC-L.
Control products 5 and 6 were obtained by the same treatment using 000).

Example 7 In Example 1, each of Compound B and Compound C was used in place of Compound A to obtain a pharmaceutical composition. As with Pharmaceutical Composition 1, all of these had improved solubility in water.

Example 8 In Example 2, each of Compound B and Compound C was used in place of Compound A to obtain a pharmaceutical composition. Like Pharmaceutical Composition 2, all of these had improved solubility in water.

Example 9 2 g of compound A was dissolved in 200 ml of methylene chloride, 2 g of HPC-L and 2 g of HP-5 were added and dissolved in this solution, and then this solution was spray-dried using a spray dryer (intake temperature 70°C, exhaust temperature 45° C.) to obtain Pharmaceutical Composition 11.

Example 10 In Example 9, instead of HP-55, EC,
AEA, EudragitE, EudragitS,E
Pharmaceutical compositions 12, 13, 14, 15, 16 and 17 using udragitRS, EudragitL, respectively.
I got it.

Example 11 In Example 9, HPC-L2g and HP-552
Pharmaceutical composition 18 was obtained by using 1 g of HPC-L and 1 g of TC-5 instead of g.

Example 12 2 g of compound A was dissolved in 200 ml of methylene chloride, 1 g of HPC-L, 1 g of TC-5 and 0.5 g of dehydrocholic acid were added and dissolved, and then the solution was spray-dried using a spray dryer. (Intake temperature: 70°C, exhaust temperature: 45°C) to obtain Pharmaceutical Composition 19.

Example 13 In Example 12, 1 g of dehydrocholic acid was used in place of TC-51 g and 0.5 g of dehydrocholic acid to obtain 20 g of a pharmaceutical composition.

Comparative Example 6 2 g of Compound A and 2 g of Eudragit E were dissolved in 200 ml of methylene chloride, and this solution was spray-dried using a spray dryer to obtain Control Product 7.

Comparative Example 7 In Comparative Example 6, AEA, Eudragit L, Eudragit S, and dehydrocholic acid were used in place of Eudragit E, and the same treatment was performed to obtain Control Products 8, 9, 10, and 11, respectively.

Comparative Example 8 In Example 11, vinyl acetate resin (manufactured by Tanabe Seiyaku Co., Ltd., food additive) and sucrose fatty acid ester DK-ester F160 were used in place of TC-5, and the same treatment was carried out to obtain a control. Items 12 and 13 were obtained.

Test Example Amorphous stability test of the present pharmaceutical composition 1) Test method Immediately after preparing the present pharmaceutical composition or the control product,
Measuring the solubility of the drug in water (37°C) for up to
The area under the curve from 0 to 180 minutes is calculated from the obtained solubility curve, and the area is defined as X.

[0068] Next, after storing the test sample for 4 weeks under harsh conditions of 40°C and 75% humidity, the solubility of the drug in water (37°C) from 0 to 180 minutes is measured, and the area is designated as Y. . The ratio of Y to X is determined, and the value is used as a guideline for stabilizing the amorphous state of the drug in the test sample. A value closer to 1 indicates that the amorphous state is maintained, and a smaller value indicates that crystallization of the drug occurs and the solubility in water decreases.

2) Test results: Table 1 shows the results.

[0070]

[Table 1]

[0071] From the above results, it can be seen that when stored open for 4 weeks under the harsh conditions of 40°C and 75% humidity, pharmaceutical compositions 11 to 19
Both indicate that amorphous stability is maintained compared to Pharmaceutical Composition 2.

[Brief explanation of the drawing]

FIG. 1 is a solubility curve of the present pharmaceutical compositions 3-5.

FIG. 2 shows solubility curves of the present pharmaceutical compositions 1 and 2, their raw material Compound A, and the amorphized product of Compound A.

FIG. 3 is a solubility curve of the present pharmaceutical compositions 6-9.

FIG. 4 is a solubility curve of control products 1 to 3.

FIG. 5 is an X-ray diffraction image of Compound A, which is a raw material for the present pharmaceutical composition.

FIG. 6 is an X-ray diffraction image of the present pharmaceutical composition 3.

FIG. 7 is an X-ray diffraction image of control product 1.

FIG. 8 is a solubility curve of the present pharmaceutical composition 10 and its raw material, Compound D.

FIG. 9 shows solubility curves of control products 4 to 6.

FIG. 10 is a solubility curve of the present pharmaceutical compositions 11-13.

FIG. 11 is a solubility curve of the present pharmaceutical compositions 14-17.

FIG. 12 is a solubility curve of the present pharmaceutical compositions 18-19.

FIG. 13 shows solubility curves of control products 7-11.

FIG. 14 is a solubility curve of the present pharmaceutical composition 20.

Claims (15)

[Claims] Claim 1: An amorphous product of a drug represented by the general formula [Formula 1] (wherein R represents a methyl or ethyl group, and n represents 3 or 4) and hydroxypropyl cellulose, or 1. A pharmaceutical composition for improving the solubility of at least the drug [I] in water, which contains an amorphized product of the drug [I] and hydroxypropylcellulose. 2. Claim 1, wherein the amorphized product is a dried product obtained by drying the drug [I] dissolved in a volatile organic solvent or a solution of the drug [I] and hydroxypropyl cellulose. Pharmaceutical compositions as described. 3. The pharmaceutical composition according to claim 2, wherein the drying is performed by a spray drying method or a fluidized bed granulation drying method. Claim 4: A combination of a drug represented by the general formula [Formula 2] (wherein R represents a methyl or ethyl group, and n represents 3 or 4), hydroxypropylcellulose, and an amorphous stabilizer. A pharmaceutical composition characterized in that it contains an amorphized product and has improved solubility in water of at least the drug [I]. 5. The amorphous stabilizer is hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, ethylcellulose, aminoalkyl methacrylate copolymer, methacrylic acid copolymer,
The pharmaceutical composition according to claim 4, which is polyvinyl acetal diethylaminoacetate, bile acid or a non-toxic salt thereof. 6. A claim in which the amorphized product is a dried product obtained by drying a solution of the drug [I], hydroxypropylcellulose, and an amorphous stabilizer dissolved in a volatile organic solvent. 4. Pharmaceutical composition according to item 4. 7. The pharmaceutical composition according to claim 6, wherein the drying is performed by a spray drying method or a fluidized bed granulation drying method. [Claim 8] Hydroxypropyl cellulose is added to an amorphous product of the drug represented by the general formula [Formula 3] (wherein R represents a methyl or ethyl group, and n represents 3 or 4). or the drug [I
] and hydroxypropylcellulose is amorphized. A method for producing a pharmaceutical composition which improves the solubility of at least the drug [I] in water. 9. The method according to claim 8, wherein the amorphized product is a dried product obtained by drying a solution of the drug [I] dissolved in a volatile organic solvent. 10. The production method according to claim 8, wherein the amorphization treatment involves drying a solution of the drug [I] and hydroxycellulose dissolved in a volatile organic solvent. 11. Claim 9 or 1, wherein the drying is performed by a spray drying method or a fluidized bed granulation drying method.
The manufacturing method described in 0. 12. A mixture of a drug represented by the general formula [Formula 4] (wherein R represents a methyl or ethyl group, and n represents 3 or 4), hydroxypropylcellulose, and an amorphous stabilizer. 1. A method for producing a pharmaceutical composition, which improves the solubility of at least the drug [I] in water, which comprises amorphizing the drug [I]. 13. A claim in which the amorphous stabilizer is hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, ethylcellulose, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, polyvinyl acetal diethylaminoacetate, bile acid or a non-toxic salt thereof. 12. The manufacturing method according to 12. 14. Claim 12, wherein the amorphization treatment involves drying a solution of the drug [I], hydroxypropylcellulose, and an amorphous stabilizer dissolved in a volatile organic solvent.
Manufacturing method described. 15. The manufacturing method according to claim 14, wherein the drying is performed by a spray drying method or a fluidized bed granulation drying method.