JP2805539B2 - Poly-γ-cyclodextrin inclusion compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION "Industrial application field" The present invention relates to glucocorticoids having a degree of polymerization of 2 to 4 poly-γ.
The present invention relates to an inclusion compound which is included in cyclodextrin and an anti-inflammatory aqueous preparation containing the same as an active ingredient.

"Prior art" Research on application of a substance which is hardly soluble in water to an aqueous preparation has been conducted for a long time, and a method of solubilizing with various cyclodextrins has been studied as one of them.

Α-, β
-And γ-types, each of which has a different property and is used in various technologies. Numerous studies have also been made on application to the pharmaceutical field for the purpose of solubilizing poorly water-soluble substances and improving drug stability. Although those studies mainly use β-cyclodextrin,
Since a high concentration of β-cyclodextrin has a hemolytic effect, studies using γ-cyclodextrin having a low hemolytic effect have also been reported (Japanese Patent Publication No. 64-9996).
issue). On the other hand, in addition to these natural cyclodextrins, marcitr cyclodextrin obtained by chemically modifying cyclodextrin (JP-A-62-281855), glucosylcyclodextrin (JP-A-63-27440), and hydroxypropylcyclodextrin Dextrin (JP-A-61-275301)
No.) has been reported. Further, studies using a cyclodextrin polymer include a β-cyclodextrin polymer (Japanese Patent Application Laid-Open No. 61-97025) and a γ-cyclodextrin high polymer (Japanese Patent Application Laid-Open No. 60-11961) which is not applied as a medicine. ) Have been reported.

"Problems to be Solved by the Invention" Glucocorticoids are widely used as pharmaceuticals as anti-inflammatory drugs, but are practically used as suspension-type preparations in the case of aqueous preparations which are hardly soluble in water. Solubilizing this glucocorticoid is a major problem, and methods using various cyclodextrins have been studied.

However, the selection of the size of the guest molecule and the type of cyclodextrin are important points for making an inclusion compound. In addition, the nature of the clathrate compound produced depends greatly on the type.

Furthermore, in order to be applied as a medicine, the problems of stability and side effects must be solved.

"Means for Solving the Problems" The present inventors have studied intensively a cyclodextrin having high solubility in water, excellent stability, and few side effects upon studying an inclusion compound of glucocorticoid. It has been found that these problems can be solved at once by using poly-γ-cyclodextrin having a degree of 2 to 4.

"Constitution of the Invention" The present invention relates to a method of preparing a glucocorticoid from poly-γ
The present invention relates to an inclusion compound encapsulated in cyclodextrin and its application to an aqueous preparation.

Glucocorticoids include fluorometholone, dexamethasone, betamethasone, hydrocortisone, prednisolone and the like.

Poly-γ-cyclodextrin having a degree of polymerization of 2 to 4
1 shows a polymer containing 2 to 4 γ-cyclodextrins obtained by crosslinking γ-cyclodextrin with epichlorohydrin.

Although various studies have been made on cyclodextrin inclusion compounds of glucocorticoids, α-cyclodextrin has a low inclusion ability and is not suitable for molecules such as glucocorticoids. β-cyclodextrin is a cyclodextrin that has been used in many studies, but when applied to glucocorticoids as shown in the test examples below,
The solubility is not sufficiently increased, and it cannot be said that β-cyclodextrin is appropriate in terms of the hemolytic action. Although the problem of hemolysis can be solved by using γ-cyclodextrin, there is room for improvement in terms of solubility.

As for the cyclodextrin polymer, β-
Satisfactory cyclodextrin polymers cannot be obtained, and γ-cyclodextrin having a high degree of polymerization results in poor solubility in water.

Although the details will be described in the test examples described below, the present inventors use poly-γ-cyclodextrin having a degree of polymerization of 2 to 4,
It has been found that an inclusion compound of glucocorticoid which has excellent solubility and stability and has few side effects can be obtained.

This inclusion compound can be made into an aqueous preparation by using a commonly used technique. Taking eye drops as an example, sodium chloride, potassium chloride, isotonic agents such as boric acid, buffering agents such as sodium hydrogen phosphate, which are commonly used in eye drops,
Preservatives such as benzalkonium chloride and p-hydroxybenzoate, thickeners such as polyvinyl alcohol and carboxyvinyl polymer, and a pH adjuster such as hydrochloric acid and sodium hydroxide may be added as necessary, and formulated as eye drops. Good.

Also, when preservatives are prescribed in eye drops, it is necessary to consider the preservative effect. It is said that when cyclodextrin is used, preservatives are included and the preservative effect is generally reduced. However, poly-γ-cyclodextrin has the merit that the preservative effect is less reduced.

Further, in the case of an aqueous preparation, it is necessary to prevent the danger that the clathrate once dissolved will precipitate again. The use of poly-γ-cyclodextrin increases the viscosity as described later, and also has the effect of preventing the reprecipitation. Of course, the viscosity can be increased by using a thickener in combination.

Fluorometholone is used as a representative example of the glucocorticoid, and will be described in detail in the following examples.

"Example" (Production Example) Production of poly-γ-cyclodextrin (degree of polymerization 3) inclusion compound of fluorometholone Sodium borohydride (0.4 g) was dissolved in a 20% aqueous sodium hydroxide solution (90 ml), and water was added. (50 ml) and γ-cyclodextrin (100 g), and the mixture is stirred at 50 ° C.
After the γ-cyclodextrin is completely dissolved, epichlorohydrin (30 ml) is added dropwise in 30 minutes. After completion of the dropwise addition, the mixture is further stirred at 50 ° C. for 3 hours and neutralized with dilute hydrochloric acid. It is desalted using an ion exchange resin, concentrated under reduced pressure, and then powdered using spray drying to obtain poly-γ-cyclodextrin. A small amount of water is added to the poly-γ-cyclodextrin (3.8 g) thus obtained to form a paste, to which fluorometholone (0.38 g) is added and kneaded sufficiently. After kneading, the paste is dried to obtain a powdery clathrate compound (quantitative).

IR spectrum In the case of fluorometholone alone, three peaks (1718, 1660, 1618 cm ^-1 ) based on the carbonyl stretching vibration are observed, but in the case of the clathrate compound, the low frequency was shifted from 1718 cm ^-1 to 1716 cm ^-1 . . In the case of a physical mixture of fluorometholone and poly-γ-cyclodextrin 1: 1 (molar ratio), no change was observed in these peaks. FIG. 1 shows the spectra of fluorometholone alone and the clathrate.

Differential thermal analysis In the case of fluorometholone alone, an endothermic peak due to melting of the drug was observed at around 293 ° C, but in the case of the inclusion compound, this endothermic peak completely disappeared.

In the case of a physical mixture of fluorometholone and poly-γ-cyclodextrin 1: 1 (molar ratio), an endothermic peak at 293 ° C. was observed as a shoulder.

FIG. 2 shows the results of analysis of fluorometholone alone and the inclusion compound.

(Test Example) Fluorometrone as a glucocorticoid, poly-
The following tests were performed using γ-cyclodextrin (Poly-γ-CyD) having a degree of polymerization of 3.

1. Using various cyclodextrins, the inclusion ability of fluorometholone was examined and the stability constant (Kc) was calculated.

The results are shown in FIG. 3, where γ-cyclodextrin (γ
-CyD), β-cyclodextrin (β-CyD), poly-
β-cyclodextrin (Poly-β-CyD), hydroxypropyl-γ-cyclodextrin (HP-γ-CyD)
As compared with D) and dihydroxypropyl-γ-cyclodextrin (DHP-γ-CyD), the inclusion ability of Poly-γ-CyD was particularly excellent.

2. The solubility of various cyclodextrin inclusion compounds of fluorometholone was investigated.

The results are shown in the table, γ-CyD, β-CyD, Poly-β-Cy
D, HP-γ-CyD, Po compared to the case using DHP-γ-CyD.
The solubility using ly-γ-CyD was particularly excellent.

3. Viscosity increasing ability of Poly-γ-CyD Since the increase in viscosity of an aqueous preparation has the effect of preventing re-precipitation of an inclusion compound, the viscosity increasing ability of Poly-γ-CyD was examined.

The results are shown in FIG. 4, where the same polymer, Poly-β
The viscosity increasing ability of Poly-γ-CyD was much better than that of -CyD.

(Prescription example) An example of the prescription is shown below.

Formulation Example 1 Fluoromethorone 0.02 (wt%) Poly-γ-CyD 0.2 Sodium chloride 0.8 Sodium hydrogen phosphate 0.4 Benzalkonium chloride 0.005 Dilute hydrochloric acid qs Sterile purified water qs Formula 2 Fluorometrone 0.02 (wt%) Poly-γ-CyD 0.2 Boric acid 1.8 Methyl parahydroxybenzoate 0.026 Propyl parahydroxybenzoate 0.014 Appropriate amount of sodium hydroxide Appropriate amount of sterilized purified water According to the present invention, a glucocorticoid which is useful as an anti-inflammatory drug but is sparingly soluble in water is used. The excellent effect of solubilization can be obtained.

[Brief description of the drawings]

FIG. 1 shows the IR spectra of the fluorometholone alone and the fluoro-metholone poly-γ-cyclodextrin inclusion compound. FIG. 2 shows the results of differential thermal analysis of fluorometholone alone and fluorometholone poly-γ-cyclodextrin inclusion compound. FIG. 3 is a graph showing the stability constants (Kc) of fluorometholone and various cyclodextrin derivatives in 10 mM phosphate buffer (pH 7.4) at 25 ° C., wherein the horizontal axis represents the concentration of cyclodextrin. , The vertical axis represents the concentration of fluorometholone,
-○-is Poly-γ-CyD,-■-is γ-CyD,-□-is HP
-Γ-CyD,-●-is Poly-β-CyD,-△-is DHP-γ
-Data of CyD is shown. FIG. 4 shows the viscosity of the cyclodextrin polymer in a 10 mM phosphate buffer (pH 7.4) at 25 ° C., wherein the horizontal axis represents the concentration of the cyclodextrin polymer and the vertical axis represents the viscosity. Indicates data for Poly-γ-CyD, and -−- indicates data for Poly-β-CyD.

──────────────────────────────────────────────────続 き Continued on front page (51) Int.Cl. ⁶ Identification code FI C08B 37/16 C08B 37/16

Claims (5)

(57) [Claims] (1) a glucocorticoid having a degree of polymerization of 2 to 4;
An anti-inflammatory aqueous preparation comprising, as an active ingredient, an inclusion compound that is included in γ-cyclodextrin. 2. The anti-inflammatory aqueous preparation according to claim 1, wherein the glucocorticoid is fluorometholone. 3. The anti-inflammatory aqueous preparation according to claim 1, wherein the dosage form is an eye drop. 4. A glucocorticoid having a degree of polymerization of 2-4.
Inclusion compound included in γ-cyclodextrin. 5. The clathrate compound according to claim 4, wherein the glucocorticoid is fluorometholone.