JPS62123196A - Prednisolone inclusion compound - Google Patents

Abstract

NEW MATERIAL:An inclusion compound of prednisolone with heptakis (2,6-di-O- methyl)-beta-cyclodextrin. External appearance; white crystalline powder. solubility; greatly soluble in water. USE:Water-solubility of an adrenal cortex steroid prednisolone useful as an anti- inflammatory agent is enhanced and absorbability thereof by the oral and percutaneous administration is improved. Since the dose of prednisolone can be reduced, side reaction can be suppressed and the use thereof is economically advantageous. PREPARATION:Prednisolone and keptakis(2,6-di-O-methyl)-beta-cyclodextrin are mixed together, for example, at 1:1-1:5 molar ratio of the former to the latter and purified water is added to knead the mixture. Thus obtained pasty mixture is dried such as under reduced pressure to obtain the aimed powdery compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel prednisolone [(11β)-11゜1
Regarding the cyclodextrin clathrate compound of 7.21-trihydroxypregna-1,4-diene-3,20-dione, it is more specifically an adrenal corticosteroid, a leafy vegetable involved in anti-inflammatory drugs, and used for medical purposes. Concerning a prednisolone-hebutakis(2,6-di-0-methyl)-β-cyclodextrin clathrate compound that increases the total water solubility of prednisolone and improves its oral and transdermal absorption, which is used as an oral or external preparation. It is something. Prednisolone is a substance with anti-inflammatory properties that comes as a white crystalline powder.
It is slightly soluble in methanol or ethanol, slightly less soluble in acetone or dioxane, less soluble in ethyl acetate or chloroform, and extremely less soluble in water.

Since it is extremely poorly water-soluble, there are large individual differences in bioavailability upon oral administration, and side effects are also severe, so a preparation that can provide the same effect with a small amount is desired. Furthermore, while it is expected to have a long-lasting effect, it is possible that it may have an adverse effect on the kidneys and other organs. Therefore, so-called transdermal absorption, in which the drug is absorbed locally into the affected area, has been devised and studied, but it is not practical because general cartilage has low permeability to the skin.

The present inventors combined predniso o7 with heptakis (2,6-
It has been found that absorption, especially transdermal absorption, is improved by inclusion with dimethyl-β-cyclodextrin (DM-β-CyD). 1. The present invention has been completed.

Prednisolone, which is used as a drug, has extremely high side effects, and great care must be taken when administering it, but it is possible that by increasing its absorption, the dose may be reduced, and side effects may be reduced. . It is also economically advantageous.

However, when prednisolone is clathrated with DM-β-CyD and solubilized, its solubility in water increases, and its application to injections and the like can be expected. Furthermore, when this prednisolone clathrate is orally administered as a liquid or solid preparation, its absorption rate increases dramatically.

Therefore, it was suggested that prednisolone has increased bioavailability and can be used advantageously for treatment. Inclusion compounds also change the physicochemical properties of prednisolone and further promote its full transdermal absorption.

Dimethyl-β-cyclodextrin (DM-β-CyD) used in the present invention has a methyl group introduced into the 2- and 6-position hydroxyl groups of glucose, which is a constituent unit of β-cyclodextrin, and has a melting point of 295 to 600. ℃, it is extremely easy to bathe in water, has low hygroscopicity and high surface activity, and has the property of being well soluble in Ariso bath media.

Generally known clathration methods include a kneading method, a bath solution method, and a freeze-drying method, and any of these methods can be used in the present invention. The invention will now be explained on the basis of the crosstalk method as an example.

In the crosstalk method, prednisolone and DM-β-CyD are weighed out at a molar ratio of 1 to 1:5, and after adding enough ice cubes to form a sol, mix thoroughly until the mixture becomes a star. The clathrate compound is then dried under reduced pressure to obtain a powdery clathrate compound. There is no particular restriction on the number of kneading times, and room temperature is sufficient, and the kneading time of 0.5 to 2 hours is sufficient depending on the amount of the sample to be prepared. The clathrate compound thus obtained can be subjected to am treatment, if necessary.

DM-β of prednisolone obtained by the above method
The -CyD clathrate is a white crystalline powder that significantly increases its solubility in water. The formation of the clathrate compound was confirmed by various means such as dispersion phase diagram, ultraviolet absorption spectrum (UV), and circular dichroism spectrum (CD).

The solubility phase diagram of prednisolone and various cyclodextrins at 25°C is shown in Figure 1.

As shown in FIG. 1, DM-β-CYD solubilized prednisolone to a greater degree than natural α-1β-2r-cyclodextrin, and also suppressed the formation of higher-order water-soluble complexes. The solubility of prednisolone in water is significantly increased by the addition of DM-β-CYD. In contrast, β-CYD, γ-
The solubility of CYD decreases dramatically above a certain level. Also α
-CyD cannot be expected to improve di-solubility. For example, the solubility of prednisolone in a 0.1 M DM-β-CYD water bath solution was 6.4 p/-.

In addition, the U of the DM-β-CyD envelope H of prednisolone
The full image quotient of the V and CD spectra is shown in Figure 6. As is clear from these, it was confirmed that prednisolone was clathrated. In addition to these, thermal analysis, X-ray diffraction, N
MRl was performed and physicochemical differences were observed, suggesting inclusion.

Note that the molar ratio of DM-β-CyD and prednisolone in the clathrate compound of the present invention was 2:1 on average. Therefore, the clathrate compound of the present invention, compared to other natural cyclodextrin clathrate compounds and prednisolone alone,
It has excellent solubility in water, maintains the original activity of prednisolone, and has a remarkable effect of increasing skin permeability (permeability). Therefore, using rabbits, the uptake of prednisolone into the back skin was determined from the drug residual rate, and the total skin absorption of the drug was evaluated. Figure 4 shows the results. From this figure, it can be seen that the DM-
It was found that prednisolone was significantly consumed in the β-CyD clathrate compared to the natural cyclodextrin clathrate and prednisolone alone, and thus the uptake of prednisolone into the skin was significantly improved compared to the conventional method. .

From this, it is expected that the drug will have the same efficacy at lower doses than conventionally used drugs, and that there will be fewer side effects.

Prednisolone-DM-β-CYD encapsulating compound of the present invention!
12! I has unique characteristics both physiologically and physicochemically.1 For example, it has been suggested that improved fermentability in water may facilitate the application of prednisolone to injectable preparations and improve the absorption of oral preparations. It was done. Furthermore, it becomes possible to improve the effectiveness and safety of external preparations such as patches that are applied locally.

Next, we will discuss Example 2 of the present invention.

Example DM-β-CyD for 1.00 fI
7, 38.9 Place in a mortar, add an appropriate amount of distilled water to make a sol, and mix for about 30 minutes to prepare prednisolone DM-β-
A CyD clathrate was obtained. This product was pressure dried for 3 days, passed through a 100 mesh sieve, and used in the following formulation examples.

Formulation N is shown below.

Formulation Example 1 (Patch) Hydrophilic ointment base Contains the following ingredients: 185.24 wNJ.

White petrolatum 25wt thistearyl alcohol 22wt tibropylene glycol 12wt% sodium lauryl sulfate
i, 5 wt% ethyl paraoxybenzoate
0.025wt% paraoxybenzoic late propyl 0゜015wt%ff Water suitable
Hydrophilic desire/q group 41 in the 200 da clathrate compound? Add, homogenize, and evenly spread and mold this into a thin plastic film.

Formulation Example 2 (Cream) Water-absorbing ointment Made from the following ingredients: 9581.

White petrolatum 40wt% cetanol 18wt% sesquioleic sorbitan 5wt% lauromacrogol
0.5wt% ethyl paraoxybenzoate
Q, jwt% propyl oxybenzoate
Q, jwt% pure water Appropriate amount 1000.0 Hi Used as a cream.

Formulation example 3 (tablet) Crystalline cellulose 32.0 kg milk
Sugar 1050■
Corn starch 12.a
m9 carboxymethyl cellulose calcium 10.
0~Magnesium stearate 1
．． 1■200.01n9 Add excipients, disintegrants, binders, and lubricants to the clathrate compound, mix evenly, and then compress and mold using a tablet machine.

Formulation Example 4 (Granule) Corn Tenbun 2501
1v breasts Kinuta 1
88.1 ~ Polyvinylpyrrolidone
20.0×500.0η After adding excipients, disintegrating Ml, and a binder to the clathrate compound and mixing them evenly, the mixture is granulated at the granulation limit, and then dried and sieved to produce granules.

[Brief explanation of drawings]

Figure 1 is a solubility phase diagram of the clathrate compound of the present invention, and Figure 2 is a solubility phase diagram of the clathrate compound of the present invention.
The figure is an ultraviolet absorption spectrum diagram, Figure 3 is a circular dichroism diagram, and Figure 4 is a diagram showing percutaneous absorption in terms of residual rate.

Claims (1)

[Claims] Heptakis(2,6-di-O-methyl)-β-cyclodextrin clathrate of prednisolone.