JPH1059862A - Cyclosporin preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an easily takable powdery or solid preparation having high stability, safety and quality and free from the deterioration of the quality in distribution and storage by adding relatively small amounts of different kinds of surfactants to cyclosporin. SOLUTION: The objective preparation is produced by finely pulverizing cyclosporin, adding an anionic surfactant, thoroughly mixing the mixture and adding a nonionic surfactant to the mixture. The anionic surfactant is preferably sodium laurylsulfate and the nonionic surfactant is preferably a glycerol fatty acid ester or glycerol monostearate. The total amount of the surfactants is preferably 0.5-3 pts.wt. based on 1 pt.wt. of cyclosporin and the amount of the nonionic surfactant is preferably 0.5-2 pts.wt. based on 1 pt.wt. of the anionic surfactant. Cyclosporin A is widely used among the cyclosporin group as an immunosuppressing agent mainly for improving the percentage of success of organ transplantation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a powdery or solid preparation having enhanced dissolution by mixing different kinds of surfactants with cyclosporin.

[0002]

2. Description of the Related Art Cyclosporin is known as Tolypocladium infla
It is a fermentation product produced by fungi such as tum, and nine types of A to I are known. Among them, cyclosporin A is widely used, and is mainly used as an immunosuppressant for the purpose of increasing the survival rate of organ transplantation. Cyclosporin is a cyclic polypeptide composed of 11 amino acids and has poor solubility in water. For this reason, a formulation in which cyclosporin is dissolved in an organic solvent such as vegetable oil or ethanol, and emulsified when administered in vivo to absorb the main drug has been developed. However, since it is a liquid type preparation, it is supplied as a soft capsule or as a liquid for internal use as it is. The soft capsule contains ethanol, and is packaged in a double-sided aluminum blister to prevent volatilization of the ethanol. The contents are invisible and inconvenient. In addition, these preparations have a unique odor derived from the oil and surfactant contained therein, and are accompanied by discomfort when taken. Furthermore, when stored at a high temperature because of the gelatin capsule, there is a concern that the quality may be degraded due to denaturation of the gelatin. In the case of a liquid preparation for internal use, it is used as it is or diluted with an appropriate beverage, but the discomfort at the time of taking it is the same, and it is extremely inconvenient to use, such as the need to measure each time. Was.

[0003]

A number of powder-type preparations have been studied to solve the problems of liquid preparations. For example, there are reports of a soluble powdery preparation of cyclosporin (Japanese Patent Publication No. 64-38029), a cyclosporin preparation (Japanese Patent Publication No. 64-85921) and a novel cyclosporin preparation (Japanese Patent Publication No. 2-235817). However, since an organic solvent is used at the time of preparation, there is a concern that the organic solvent remains, which is not preferable in terms of safety. Although the solubility of cyclosporin is increased by adding cyclodextrin, the amount of cyclodextrin is large, and it is not practical as an oral preparation. In addition, although the solubility of cyclosporin is increased by using a fatty acid saccharide monoester as a surfactant, the two are melted to form a solid solution, and there is a concern over stability over time. As described above, the preparations conventionally devised as the powder type have some disadvantages, and none of them have been put to practical use. Therefore, development of a powder type formulation that solves these problems is desired. Further, the preparation is required to be stable enough to withstand severe storage conditions, to be free from side effects of additives, and to be safe. Cyclosporine is poorly soluble in water, so it is necessary to incorporate a solubilization method, but generally this requires the use of a large amount of surfactants and additives, resulting in an increase in dosage and difficulty in taking it At the same time, there are concerns about side effects due to the additives. On the other hand, it is difficult to improve the solubility of cyclosporin in water only by adding an additive, and it is necessary to use a special method such as a solid dispersion. However, the solid dispersion is generally unstable compared to the crystalline state, and there is a concern that there is a danger that the quality will deteriorate when stored under severe temperature and humidity conditions. Therefore, in the case of using cyclosporin as a powder-type preparation, a technique for solubilizing cyclosporin with as small an additive as possible and formulating the preparation without changing the crystalline state of cyclosporin has been desired.

[0004]

Means for Solving the Problems The present inventors have intensively studied an additive for improving the solubility of cyclosporin in water, and as a result, after effectively blending an anionic surfactant, a non-ionic surfactant was added. The inventors have found that the desired effects can be obtained by adding an ionic surfactant, and have completed the present invention. That is, the present invention relates to a formulation in which cyclosporine and two kinds of surfactants are effectively blended to improve the dissolution property. Many surfactants have been known to improve the solubility of cyclosporin in water. However, in the present invention, by combining two different types of surfactants and further devising a compounding method, the crystal state of cyclosporin is improved. Has succeeded in increasing the solubility without changing the solubility.

BEST MODE FOR CARRYING OUT THE INVENTION

There are various anionic surfactants that can be used in the present invention, such as N-acyl amino acid salts, ether carboxylate salts, alkyl phosphate salts, N-acyl taurate salts, alkyl sulfate salts, and the like. In consideration of safety to the human body, sodium lauryl sulfate is particularly preferable.

[0006] The nonionic surfactants which can be used in the present invention include glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene. There are copolymers, polyoxyethylene sorbitan fatty acid esters and the like, and glycerin fatty acid esters are preferred. Also,
Examples of the fatty acid ester include myristic acid ester, stearic acid ester, oleic acid ester and isostearic acid ester. Therefore, glyceryl monostearate is more preferable.

The total amount of the anionic surfactant and the nonionic surfactant used in the present invention is preferably 0.5 to 3 relative to 1 cyclosporin. If the ratio is 0.5 or less, the effect of solubilization is insufficient, and if it is 3 or more, there is a concern about side effects due to the surfactant.

Although the ratio of the anionic surfactant to the nonionic surfactant is not particularly limited, the ratio of the anionic surfactant to 1 and the ratio of the nonionic surfactant to 0.5 to 2 are set. It is more preferable that the ratio of the anionic surfactant to the nonionic surfactant is 1: 0.5.

[0009] Excipients, binders, disintegrants and the like can be added to the preparation of the present invention as pharmaceutically acceptable additives. Examples of the excipient include D-mannitol, lactose, sucrose, starch, crystalline cellulose and the like, with D-mannitol being particularly preferred. Also, as a binder,
Examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, and gum arabic, but are not particularly limited. Further disintegrants include croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium carboxymethyl starch,
Examples include calcium carboxymethylcellulose, but are not particularly limited. In addition, additives used for pharmaceuticals, for example, lubricants, coloring agents, flavoring agents and the like may be used, but are not particularly limited.

[0010] One method of producing the preparation of the present invention is to pulverize a cyclosporine drug substance finely, add an anionic surfactant, mix well, further add a nonionic surfactant and an appropriate additive. To make a powder. By mixing cyclosporine and an anionic surfactant, aggregation of the cyclosporine drug substance is suppressed, and the surface of the cyclosporine drug substance is covered with the anionic surfactant. Water wettability and dispersibility are improved, and dissolution is improved. Further, due to the lubricant-like effect of the anionic surfactant, the flowability of the powder is improved, and the mixing property with other agents and the improvement of the ingestibility are simultaneously achieved.

The composition of the present invention can be formulated as a powder as it is as a powder. However, the powder may be granulated by adding water or the like to form a granule, or it may be tabletted to form a tablet. Is also possible. Powders and granules can also be filled into capsules and formulated.

[0012]

The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited to these examples.

Example 1 With the following composition, cyclosporine and sodium lauryl sulfate were taken and thoroughly mixed in a mortar to obtain a powdery preparation. Cyclosporine 50.0% by weight Sodium lauryl sulfate 50.0% by weight 100.0% by weight

Test Example 1 With respect to the preparation prepared in Example 1, 25 mg of cyclosporine was filled in a gelatin hard capsule, and a dissolution test was carried out. The method of the dissolution test is as follows. The test solution is
Using 900 ml of a 0.05% sucrose fatty acid ester solution, the test was performed at 50 revolutions per minute according to the Japanese Pharmacopoeia dissolution test method 2 (paddle method). 3 ml of eluate at a certain time after the start of the test
Was filtered through an acetyl cellulose filter having a pore size of 0.2 μm. Using 30 μl of the filtrate as a sample, the elution rate was determined by liquid chromatography. The method is the titer test method (liquid chromatography method) described in the Japanese Antibiotic Drug Standards
According to. Table 1 shows the results.

[0015]

[Table 1]

Although the dissolution rate was low until 15 minutes after the start of the test, the dissolution rate was 80% or more after 20 minutes, suggesting that sodium lauryl sulfate is suitable as a solubilizing agent for cyclosporin. However, it was considered that it was necessary to further increase the elution rate up to 15 minutes in order to quickly absorb cyclosporin.

Example 2 Cyclosporine, sodium lauryl sulfate, and sorbitan monopalmitate as a nonionic surfactant were taken in the following mixing ratio and mixed well in a mortar to obtain a powdery preparation. Cyclosporine 25.0% by weight Sodium lauryl sulfate 37.5% by weight Sorbitan monopalmitate 37.5% by weight 100.0% by weight

Example 3 Cyclosporine, sodium lauryl sulfate, and glyceryl monostearate as a nonionic surfactant were taken in the following mixing ratio and mixed well in a mortar to obtain a powdery preparation. Cyclosporine 25.0% by weight Sodium lauryl sulfate 37.5% by weight Glycerin monostearate 37.5% by weight 100.0% by weight

Test Example 2 With respect to the preparations prepared in Examples 2 and 3, 25 mg of cyclosporine was filled in a gelatin hard capsule, and a dissolution test was carried out. The test method was the same as in Test Example 1.

[0020]

[Table 2]

As a result, as shown in Table 2, by adding sorbitan monopalmitate or glyceryl monostearate as a nonionic surfactant, a high dissolution rate was obtained immediately after the start of the test, and sodium lauryl sulfate alone was used. Was superior to the formulation of Example 1 blended with

Examples 4 to 7 Cyclosporine, sodium lauryl sulfate and glyceryl monostearate were taken at the mixing ratio (unit:% by weight) shown in Table 3 and mixed well in a mortar to obtain a powdery preparation.

[0023]

[Table 3] (Blending ratio: wt%)

Test Example 3 For the preparations of Examples 4 to 7, 25% as cyclosporin
mg was filled in a gelatin hard capsule, and a dissolution test was performed. The test method was the same as in Test Example 1.

[0025]

[Table 4]

As a result, as shown in Table 4, Examples 4 to
No. 7 were found to exhibit good dissolution properties. The ratio of cyclosporin to the surfactant (total amount) is preferably 1 to 3 with respect to cyclosporin 1, and the ratio of the anionic surfactant to the nonionic surfactant is preferably 1: 0.5 to 2. Was.

Example 8 Cyclosporine, sodium lauryl sulfate and glyceryl monostearate were taken at the following compounding ratios. First, cyclosporine was finely pulverized in a mortar, and then sodium lauryl sulfate was added. Separately, glycerin monostearate was placed in a mortar, pulverized finely, added to a mixture of cyclosporine and sodium lauryl sulfate, and further mixed to obtain a powdery preparation. Cyclosporin 25.0% by weight Sodium lauryl sulfate 50.0% by weight Glycerin monostearate 25.0% by weight 100.0% by weight

Example 9 Cyclosporine, sodium lauryl sulfate, glyceryl monostearate and croscarmellose sodium were taken at the following compounding ratios. First, cyclosporin was finely ground in a mortar, and sodium lauryl sulfate was added.
Both were mixed well. Separately, glycerin monostearate was placed in a mortar, ground finely, added to a mixture of cyclosporine and sodium lauryl sulfate, and further mixed with croscarmellose sodium to form a powdery preparation. Cyclosporine 12.5 wt% Sodium lauryl sulfate 25.0 wt% Glycerin monostearate 12.5 wt% Croscarmellose sodium 50.0 wt% 100.0 wt%

Example 10 Cyclosporin, sodium lauryl sulfate, glyceryl monostearate, croscarmellose sodium and hydroxypropylcellulose were mixed in the following proportions. First, cyclosporin was finely ground in a mortar, and sodium lauryl sulfate was added. Both were mixed well. Separately, glycerin monostearate was placed in a mortar, pulverized finely, added to a mixture of cyclosporine and sodium lauryl sulfate, and further mixed with sodium croscarmellose and hydroxypropyl cellulose to obtain a powdery preparation. Cyclosporine 12.5% by weight Sodium lauryl sulfate 25.0% by weight Glycerin monostearate 12.5% by weight Croscarmellose sodium 40.0% by weight Hydroxypropylcellulose 10.0% by weight 100.0% by weight

Example 11 Cyclosporine, sodium lauryl sulfate, glyceryl monostearate, and D-mannitol were taken at the following compounding ratios. First, cyclosporine was finely ground in a mortar, and sodium lauryl sulfate was added. . Separately, glycerin monostearate was placed in a mortar, pulverized finely, added to a mixture of cyclosporine and sodium lauryl sulfate, and further mixed with D-mannitol to prepare a powdery preparation. Cyclosporine 12.5 wt% Sodium lauryl sulfate 25.0 wt% Glycerin monostearate 12.5 wt% D-mannitol 50.0 wt% 100.0 wt%

[0031]

Test Example 4 With respect to the preparations produced in Examples 8 to 11, 25 mg of cyclosporine was filled in a gelatin hard capsule, and a dissolution test was carried out. The test method was the same as in Test Example 1.

[0033]

[Table 5]

As shown in Table 5, in Example 8, by sufficiently mixing cyclosporine and sodium lauryl sulfate, aggregation of cyclosporine particles was eliminated, water wettability was improved, and high elution rate was obtained. It is thought that it has been obtained. When an additive is further added to the preparation of Example 8, the dissolution rate changes depending on the type of the additive.
As shown in the results of Example 11, when D-mannitol was added, a better dissolution property was obtained than in Example 8 where no additive was added.

Test Example 5 The preparation produced in Example 11 was examined for stability under various temperature and humidity conditions. The dissolution was measured by the method shown in Test Example 1, the titer was measured by the potency test method based on the Japanese Antibiotic Drug Standard, and the water content was measured by the water measurement method (Karl Fisher method) of the Japanese Pharmacopoeia.

[0036]

[Table 6]

As a result, as shown in Table 6, even when the preparation was stored under severe conditions, there was almost no change in potency and water, and the dissolution was slightly reduced. In a normal distribution state, the preparation is in a packaged form, which corresponds to a state of airtightness at 40 ° C. and 75% in the table, which was determined to be stable for three months. From the above results, Example 11
Was also found to be superior in stability to the conventional formulation.

[0038]

The preparation obtained by the present invention solves the problems of liquid preparations currently on the market and powder preparations which have been studied so far. That is, the commercially available preparation is a liquid in which a liquid is filled in a gelatin soft capsule or the liquid itself, and has a problem in taking and handling. On the other hand, conventional powder preparations use organic solvents in the formulation process, add large amounts of additives, or use solid dispersions, and are concerned about safety, ingestibility, stability, etc. Is done. On the other hand, the preparation of the present invention has a relatively small amount of a surfactant as an additive, is safe, has good takeability, and benefits patients. Further, the stability is good, and there is no concern about deterioration in quality under various distribution and storage conditions, and the drug can be supplied as a safe and high-quality drug.

Claims (7)

[Claims] (1) A powder or solid preparation containing cyclosporin, an anionic surfactant and a nonionic surfactant. 2. The preparation according to claim 1, which is prepared by pulverizing cyclosporin, adding an anionic surfactant, mixing well, and further adding a nonionic surfactant. 3. The preparation according to claim 1, wherein the anionic surfactant is sodium lauryl sulfate. 4. The preparation according to claim 1, wherein the nonionic surfactant is a glycerin fatty acid ester. 5. The preparation according to claim 1, wherein the nonionic surfactant is glyceryl monostearate. 6. The preparation according to any one of claims 1 to 5, wherein the total amount of the surfactant is added to cyclosporin 1 in a weight ratio of 0.5 to 3. 7. The preparation according to claim 1, wherein a nonionic surfactant is added to the anionic surfactant 1 in a weight ratio of 0.5 to 2.