Solubilizing agent for producing a solid dispersion and a solid dispersion containing the same

Abstract

The present invention provides a solubilizer for producing a solid dispersion. This solubilizer comprises a copolymer of 2-methacryloyloxyethyl phosphorylcholine and a methacrylic acid ester, said copolymer having a repeating unit represented by general formula (I) (wherein: n:m falls within the range of from 0.25:0.75 to 0.95:0.05; and R represents a hydrogen atom, an alkyl group having 1-6 carbon atoms, an alkyl group having 1-6 carbon atoms and containing a urethane bond, or an alkyl group having 1-6 carbon atoms, containing a urethane bond and also containing an optionally substituted aryl group at one end) and having a molecular weight of 5000 or greater.

Description

Technical Field

[0001] The present invention relates to a solubilizing agent for producing a solid dispersion and a solid dispersion containing the same.

Background Art

[0002] As a technique for improving the solubility of poorly soluble drugs, solid dispersions are known. A solid dispersion is a technique in which a drug is dispersed in an amorphous state in a polymer carrier, and the solid dispersion is required to have rapid drug elution at the initial stage of elution and the ability to maintain supersaturation to keep its dissolved state. Currently, as the polymer carrier of the solid dispersion, it is common to use polyvinylpyrrolidone (PVP) (Non-Patent Documents 1 to 3).

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0004] The inventors of the present invention have made it an object to develop a polymer carrier suitable for the production of solid dispersions in addition to PVP, which is a currently commonly used polymer carrier for solid dispersions. [Means for Solving the Problems]

[0005] In view of the above problems, the present inventors have conducted intensive studies and found that a copolymer having a specific structure described below is suitable for the production of solid dispersions and has properties more suitable for the production of solid dispersions than PVP, thus completing the present invention.

[0006] That is, the present application provides the following inventions in summary. [1] A solubilizing agent for producing a solid dispersion, comprising a copolymer of 2-methacryloyloxyethyl phosphorylcholine and a methacrylic acid ester, having a repeating unit represented by the general formula (I) [Chemical Formula] (wherein n:m is in the range of 0.25:0.75 to 0.95:0.05, and R is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms containing a urethane bond, or an alkyl group having 1 to 6 carbon atoms containing a urethane bond and an aryl group which may be substituted at the terminal) and having a molecular weight of 5000 or more. [2] The solubilizing agent according to [1] above, wherein R is a linear alkyl group having 1 to 6 carbon atoms, a linear alkyl group having 1 to 6 carbon atoms containing a urethane bond, or a linear alkyl group having 1 to 6 carbon atoms containing a urethane bond and an aryl group which may be substituted at the terminal. [3] The solubilizing agent according to [1] above, wherein R is a linear alkyl group having 1 to 6 carbon atoms containing a urethane bond and an aryl group which may be substituted at the terminal. [4] The linear alkyl group having 1 to 6 carbon atoms containing a urethane bond and an aryl group which may be substituted at the terminal is represented by the following formula -X-NHC(=O)-O-Y-Z (wherein X and Y may be the same or different and each represents a linear alkylene group having 1 to 6 carbon atoms, and Z represents an aryl group which may be substituted). The solubilizing agent described in the above [3], represented by [5] The solubilizing agent described in the above [4], wherein the carbon numbers of X and Y may be the same or different, and each is 1 to 3. [6] The solubilizing agent described in the above [4], wherein X and Y may be the same or different, and each represents a methylene group or an ethylene group. [7] The solubilizing agent according to any one of the above [4] to [6], wherein Z represents a phenyl group which may be substituted. [8] The solubilizing agent according to any one of the above [4] to [6], wherein Z is an unsubstituted phenyl group or a phenyl group substituted with a methyl group. [9] A solid dispersion comprising the solubilizing agent according to any one of the above [1] to [8] and a poorly water-soluble drug.

[10] The solid dispersion described in the above [9], wherein the solubility of the poorly water-soluble drug in water is 10 μg / mL.

[11] The solid dispersion described in the above [9], wherein the poorly water-soluble drug is selected from the group consisting of indomethacin, nifedipine, danazol, itraconazole, probucol, and troglitazone.

[12] General formula (I) [Chemical formula] (wherein, n:m is in the range of 0.25:0.75 to 0.95:0.05, R is the following formula -X-NHC(=O)-O-Y-Z (wherein X and Y may be the same or different, and each represents a linear alkylene group having 1 to 6 carbon atoms, and Z represents an aryl group which may be substituted)) A copolymer of 2-methacryloyloxyethyl phosphorylcholine and a methacrylic acid ester, having a repeating unit represented by and having a molecular weight of 5000 or more.

[13] The copolymer described in the above

[12] , wherein the carbon numbers of X and Y may be the same or different, and each is 1 to 3.

[14] The copolymer according to

[12] above, wherein X and Y may be the same or different and each represents a methylene group or an ethylene group.

[15] The copolymer according to any one of

[12] to

[14] above, wherein Z represents a phenyl group which may be substituted.

[16] The copolymer according to any one of

[12] to

[14] above, wherein Z is an unsubstituted phenyl group or a phenyl group substituted with a methyl group.

Advantages of the Invention

[0007] The copolymer according to the present invention is suitable for the production of solid dispersions, and is particularly suitable for solubilizing poorly soluble drugs in solid dispersions. Therefore, according to a preferred embodiment of the present invention, a solid dispersion comprising a solubilizer containing a copolymer having a specific structure and a poorly soluble drug can be provided.

Brief Description of the Drawings

[0008]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Modes for Carrying Out the Invention

[0009] In one embodiment, the general formula (I)

Chemical Formula

[0010] Here, "having a repeating unit represented by the general formula (I)" means a random copolymer composed of 2-methacryloyloxyethyl phosphorylcholine and a methacrylic acid ester and formed in a molar ratio of n:m by an arbitrary polymerization reaction. Here, the "solid dispersion" is a dispersion in which a drug is dispersed in a solid inert carrier in the form of fine particles or molecules, and is used for solubilizing poorly soluble drugs. Here, the "solubilizer" refers to an additive used or formulated to increase the solubility of a drug. Since a drug needs to be dissolved in gastric juice or intestinal juice in order to be absorbed in the stomach or intestine, a solubilizer is used to improve solubility. Here, examples of the "alkyl group having 1 to 6 carbon atoms" include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. Here, the "alkyl group having 1 to 6 carbon atoms containing a urethane bond" includes cases where a urethane group is present at the terminal of an alkyl group having 1 to 6 carbon atoms or where a urethane group is present in the middle of an alkyl group having 1 to 6 carbon atoms, and may include cases such as a (propoxycarbonylamino)ethyl group. Here, the "alkyl group having 1 to 6 carbon atoms containing a urethane bond and an aryl group which may be substituted at the terminal" includes cases where a urethane group is present at the terminal of the alkyl group having 1 to 6 carbon atoms containing an aryl group which may be substituted at the terminal, and cases where a urethane group is present in the middle of the alkyl group having 1 to 6 carbon atoms containing an aryl group which may be substituted at the terminal. For example, cases such as (benzyloxycarbonylamino)ethyl group, (phenylethoxycarbonylamino)ethyl group, (4-tolylmethoxycarbonylamino)ethyl group, etc. may also be included.

[0011] Among the copolymers represented by the above general formula (I), when R is a compound represented by the following formula -X-NHC(=O)-O-Y-Z (wherein X and Y may be the same or different and each represents a linear alkylene group having 1 to 6 carbon atoms, and Z represents an aryl group which may be substituted) is a novel compound.

[0012] n:m is preferably in the range of 0.25:0.75 to 0.90:0.10, more preferably in the range of 0.30:0.70 to 0.80:0.20, and particularly preferably 0.30:0.70.

[0013] In a preferred embodiment, R is a linear alkyl group having 1 to 6 carbon atoms, a linear alkyl group having 1 to 6 carbon atoms containing a urethane bond, or a linear alkyl group having 1 to 6 carbon atoms containing a urethane bond and an aryl group which may be substituted at the terminal.

[0014] In another preferred embodiment, R is a linear alkyl group having 1 to 6 carbon atoms containing a urethane bond and an aryl group which may be substituted at the terminal.

[0015] In a more preferred embodiment, the linear alkyl group having 1 to 6 carbon atoms containing a urethane bond and an aryl group which may be substituted at the terminal of R is the following formula -X-NHC(=O)-O-Y-Z (In the formula, X and Y may be the same or different, each representing a linear alkylene group having 1 to 6 carbon atoms, and Z represents an optionally substituted aryl group) It is represented by. Examples of the linear alkylene group having 1 to 6 carbon atoms include a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group, and a hexylene group.

[0016] In a particularly preferred embodiment, X and Y may be the same or different, and each is a linear alkylene group having 1 to 3 carbon atoms. Examples of such a linear alkylene group having 1 to 3 carbon atoms include a methylene group, an ethylene group, and a propylene group, and preferably each is either a methylene group or an ethylene group.

[0017] In a particularly preferred embodiment, Z represents an optionally substituted phenyl group, and preferably Z is an unsubstituted phenyl group or a phenyl group substituted with a methyl group.

[0018] In one embodiment, the linear alkyl group having 1 to 6 carbon atoms containing a urethane bond of R and an optionally substituted aryl group at the terminal is represented by the following formula.

[0019] [Chemical formula]

[0020] The above copolymer can be produced, for example, by a method according to the method described in Polymer Journal, Vol 22, No. 5, pp355-360 (1990). Specifically, 2-methacryloyloxyethyl phosphorylcholine and a hydrophobic monomer are used preferably in a molar ratio of 0.25:0.75 to 0.90:0.10, preferably in a mixed solvent of tetrahydrofuran and ethanol, in the presence of an initiator, preferably α,α'-azobisisobutyronitrile, and preferably reacted at 60 to 65 ° C for 4 to 20 hours, but it is not limited to this production method.

[0021] Since the solubilizing agent according to the present invention is suitable for solubilizing a poorly soluble drug into a solid dispersion, one embodiment provides a solid dispersion comprising the solubilizing agent and a poorly soluble drug.

[0022] Here, the degree of "poor solubility" of a "poorly soluble drug" can be determined, for example, by the solubility of the drug in water.

[0023] When poor solubility is determined by the solubility of a drug in water, the water solubility of a poorly soluble drug can be, for example, about 10 μg / mL or less, about 9 μg / mL or less, about 8 μg / mL or less, about 7 μg / mL or less, about 6 μg / mL or less, about 5 μg / mL or less, about 4 μg / mL or less, about 3 μg / mL or less, about 2 μg / mL or less, or about 1 μg / mL or less, preferably about 8 μg / mL or less, and more preferably about 1 μg / mL or less. Here, the solubility is defined as the concentration of a drug measured by adding an excess amount of the drug to a container containing 20 mL of water at 37° C. and stirring, and measuring the concentration with an ultraviolet spectrophotometer after 120 minutes.

[0024] In one embodiment, the poorly soluble drug is selected from the group consisting of indomethacin, nifedipine, danazol, itraconazole, probucol, and troglitazone, preferably indomethacin, nifedipine, danazol, itraconazole, probucol, or troglitazone.

[0025] The amount of the solubilizer according to the present invention used when producing a solid dispersion varies depending on the amount of drug (preferably a poorly soluble drug) to be dispersed in the solid dispersion and the degree of poor solubility, and therefore it is difficult to determine a general amount. However, the mass ratio of drug:solubilizer is preferably about 0.10:0.90 to 0.90:0.10, preferably about 0.10:0.90 to 0.70:0.30, and more preferably about 0.10:0.90 to 0.50:0.50.

[0026] The method for producing the solid dispersion according to the present invention is not particularly limited, and any method generally used in this technical field can be used. Generally, it can be prepared by dissolving a poorly water-soluble drug and a polymer as a solubilizer in an organic solvent and then removing the solvent. Examples of methods for removing the solvent include heating and spray drying. In addition, a solid dispersion can be prepared without using a solvent by dry mixing and pulverization, melting method, or the like.

Examples

[0027] Hereinafter, the present invention will be described in more detail using examples, but the present invention is not limited to the embodiments described in these examples.

[0028] Synthesis Example 1 2-Methacryloyloxyethyl phosphorylcholine (MPC) was used as a hydrophilic monomer, and butyl methacrylate (BMA) was used as a hydrophobic monomer. These monomers were dissolved in methanol and mixed so that their respective concentrations were 0.3 mol / L and 0.7 mol / L. Copper(I) bromide and 2,2'-bipyridyl were added to the monomer solution as a catalyst and a ligand, respectively, so that their concentrations were 0.01 mol / L and 0.02 mol / L. Nitrogen was blown into this solution for 20 minutes, and ethyl α-bromoisobutyrate was added as a polymerization initiator so that its concentration was 0.01 mol / L. After sealing the reaction system, it was subsequently stirred at 25 °C for 24 hours to carry out a polymerization reaction. This solution was dropped into diethyl ether, and the precipitate was recovered by a reprecipitation method. The recovered product was dissolved in water, inserted into a dialysis membrane (manufactured by Spectrum Medical Industries, trade name Spectra / por 7, MWCO 3500), and dialysis was carried out using water. Solvent exchange was continued twice a day for 5 days to obtain an aqueous polymer solution. Furthermore, the obtained aqueous solution was freeze-dried to obtain a polymer powder.

[0029] <Molecular weight measurement (GPC)> The obtained polymer was dissolved in methanol:water = 7:3 (v:v) containing 10 mmol / L lithium chloride to a concentration of 1 mg / mL to prepare a sample solution. The analysis conditions for GPC were as follows: eluent, methanol:water = 7:3 (v:v) containing 10 mmol / L lithium chloride; flow rate, 0.5 mL / min; column temperature, 40 °C; column, OHpak LB-806M manufactured by Shodex; detector, differential refractive index detector; standard substance, polyethylene oxide.

[0030] <Measurement of monomer ratio( 1 H-NMR)> 10 mg of the obtained polymer was dissolved in 0.65 mL of deuterated ethanol. The obtained deuterated ethanol solution was subjected to 1 1H-NMR analysis using JEOL α-500 to determine the molar ratio of the hydrophilic monomer to the hydrophobic monomer. The obtained polymer poly(MPC-co-BMA) is hereinafter referred to as PMB. The analysis results of the polymer are shown in Table 1.

[0031] Synthesis Examples 2 to 6 Using the hydrophobic monomers and composition ratios shown in Table 1, polymers were synthesized and analyzed in the same manner as in Synthesis Example 1. In Table 1, MEBU is 2-methacryloyloxyethyl butyl urethane, MEBZU is 2-methacryloyloxyethyl benzyl urethane, MEPU is 2-methacryloyloxyethyl phenyl urethane, MEPEU is 2-methacryloyloxyethyl phenethyl urethane, MEMBZU is 2-methacryloyloxyethyl 4-methylbenzyl urethane is shown.

[0032]

Table 1

[0033] Example 1-1 <Preparation of solid dispersion> 0.25 g of the polymer obtained in the synthesis example and 0.25 g of indomethacin were dissolved in 10 mL of ethanol:acetone = 1:1 (v:v). Using a rotary evaporator, the solvent was evaporated from the solution to obtain a powder of the solid dispersion. The conditions of the evaporator were temperature: 40 °C, pressure: 20 mmHg.

[0034] <Dissolution profile measurement (μDiss)> The powder of the obtained solid dispersion was weighed so that the amount of the drug contained was 2.5 mg. The weighed solid dispersion powder was put into a container containing 20 mL of water, and the dissolution profile was measured. The measurement conditions of μDiss were test solution: water, test solution temperature: 37 °C, detector: ultraviolet absorptiometer. The results are described in the drawings.

[0035] Examples 1-2 to 1-9 Using the polymers and composition ratios shown in Table 2, a solid dispersion was prepared in the same manner as in Example 1-1, and the dissolution profile was measured. The results are described in the drawings.

[0036]

Table 2

[0037] Examples 2-1 to 5-3 Using the polymers and composition ratios shown in Table 3, a solid dispersion was prepared in the same manner as in Example 1-1, and the dissolution profile was measured. The results are described in the drawings.

[0038]

Table 3

[0039] Comparative Example 1 <Preparation of solid dispersion> 0.4 g of polyvinylpyrrolidone (PVP) and 0.1 g of indomethacin were dissolved in 10 mL of ethanol:acetone = 1:1 (v:v). Using a rotary evaporator, the solvent was evaporated from the solution to obtain a powder of the solid dispersion. The conditions of the evaporator were a temperature of 40 °C and a pressure of 20 mmHg.

[0040] <Elution profile measurement (μDiss)> The powder of the obtained solid dispersion was weighed so that the amount of the drug contained was 2.5 mg. The weighed solid dispersion powder was put into a container containing 20 mL of water, and the elution profile was measured. The measurement conditions of μDiss were a test solution: water, a test solution temperature: 37 °C, and a detector: an ultraviolet spectrophotometer. The results are shown in the drawings.

[0041] Comparative Examples 2 to 5 Using the drugs and solid dispersion compositions shown in Table 4, a solid dispersion was prepared and the elution profile was measured in the same manner as in Comparative Example 1-1. The results are shown in the drawings.

[0042]

Table 4

[0043] From the results of FIGS. 1 to 6, it can be seen that the polymer copolymer of the example significantly improves the elution property of the poorly soluble drug as compared with PVP, which is a commonly used polymer.

[0044] This application is based on Japanese Patent Application No. 2020-086696 filed in Japan, the content of which is incorporated herein in its entirety.

Claims

1. General formula (I) 【Chemical 1】 (wherein n:m is in the range of 0.25:0.75 to 0.95:0.05, and R is a linear alkyl group having 1 to 6 carbon atoms containing an aryl group which may contain a urethane bond and may be substituted at the terminal) A solubilizer for producing a solid dispersion, comprising a copolymer of 2-methacryloyloxyethyl phosphorylcholine and a methacrylic acid ester, having a repeating unit represented by the formula and having a molecular weight of 5000 or more.

2. The linear alkyl group having 1 to 6 carbon atoms containing an aryl group which may contain a urethane bond and may be substituted at the terminal is represented by the following formula -X-NHC(=O)-O-Y-Z (wherein X represents a linear alkylene group having 1 to 6 carbon atoms, Y represents a linear alkylene group having 1 to 6 carbon atoms or is absent, Z represents an aryl group which may be substituted, provided that the total number of carbon atoms of X and Y is 1 to 6) The solubilizer according to Claim 1, represented by the formula.

3. The solubilizer according to Claim 2, wherein the number of carbon atoms of X and Y may be the same or different, and each is 1 to 3.

4. The solubilizer according to Claim 2, wherein X and Y may be the same or different, and each represents a methylene group or an ethylene group.

5. The solubilizer according to any one of Claims 2 to 4, wherein Z represents a phenyl group which may be substituted.

6. The solubilizer according to any one of Claims 2 to 4, wherein Z is an unsubstituted phenyl group or a phenyl group substituted with a methyl group.

7. A solid dispersion comprising the solubilizer according to any one of Claims 1 to 6 and a poorly soluble drug.

8. The solid dispersion according to Claim 7, wherein the solubility of the poorly soluble drug in water is 10 μg / mL.

9. The solid dispersion according to Claim 7, wherein the poorly soluble drug is selected from the group consisting of indomethacin, nifedipine, danazol, itraconazole, probucol, and troglitazone.

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