HU190356B - Process for preparing steroid-gamma-cyclodextrin inclusion complexes with high water-solubility - Google Patents

Abstract

The invention relates to a process for the preparation of gamma-cyclodextrin-containing inclusion complexes of water-soluble steroid compounds, in particular methylestosterone, spironolactone, pregnene triolone triacetate, hydrocortisone, prednisolone, dexamethasone and triamcinolone for use as medicaments. The aim of the invention is to provide aqueous injection solutions of previously unachieved steroid concentration. According to the invention, the poorly water-soluble, hydrophilic steroids take on a hydrophilic character as a result of the complex formation with the hollow gamma-cyclodextrin molecules, which are nonpolar on their inner surface and hydrophilic on their outer surface. As a result, both the solution speed and the solubility (Saettigungskonzentration) by 1-2 orders of magnitude larger. It is characteristic of the process for the preparation of the inclusion complexes according to the invention that the solution prepared with C 1 to 3 alkanols, ether or acetone is mixed with the aqueous solution of gaseous cyclodextrin which is poorly soluble in water, the mixture is cooled and the precipitate is cooled isolated crystalline complex in a conventional manner.

Description

The present invention relates to a process for the preparation of 9a-fluoro-11β, 17,21-trihydroxy-16a-methyl-pregna, 4-diene-3,20-dione, 11β, 17,21-trihydroxypregn-4 3,20-dione, 17? -Hydroxy-17-methyl-androst-4-en-3-one, 17? -Hydroxy-estr-4-en-3-one, 3-hydroxy-estra-1,3,5 (10) -1 rhenium-17-one, 11 β, 17,21-trihydroxypregna-1,4-diene-3,20-dione, pregn-4-ene-3,20-dione,

17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-enecarboxylic acid γ-lactone-7-acetate, 9α-fluoro-11β, 16α,

17,21-Tetrahydroxy-pregna-1,4-diene-3,20-dione - hereinafter referred to as "water-soluble steroids", which are poorly soluble in water, for the preparation of the new γ-cyclodextrin inclusion complex.

It is known that α- and β-cyclodextrin can form inclusion complexes with many molecules. The physical properties of the complexed materials, such as their solubility in water, are different from that of uncomplexed materials (M. L. Bender, M. Komiyama, Cyclodextrin Chemistry, Springer, Berlin, 1978).

It is also known that Chem.Ber., 91, 308 (1958) and Biochem. Biophys. Research Communs

5. II. (1961), from a prehydrolyzed starch, a cyclodextrin-glucosyl transferase enzyme can be used to produce a so-called γ-cyclodextrin consisting of eight glucose units. Γ-Cyclodextrin also possesses the complexing ability of other cyclodextrins, but its complexing properties differ slightly from those of other cyclodextrins. This is probably due to the larger inner cavity. Agr. Biol. Chem., 36.2615. (1972) describe the preparation of γ-cyclodextrin inclusion complexes of several organic materials. The inclusion complex of γ-cyclodextrin-containing digitalis glycosides containing sugar units in a glycosidic bond is described by

J. Pharm. Dyn., 4, 735 (1981), and Proceeding of the first Int. Symp. on Cyclodextrins (1981) 5.4. s. Lecture. These deal with the preparation of inclusion complexes, the solubility of the resulting inclusion complexes, and the increase in stability and absorption achieved by inclusion complexes. The above descriptions refer only to steroid glycosides and do not even mention poorly water-soluble steroids without the solubility-increasing glycosidic group.

It is also known from the literature that steroid active compounds are extremely poorly soluble in water and therefore have difficulties in their therapeutic application. Attempts have been made to improve absorption either by using an oily solution formulation (oil injections), or by using special solubility-enhancing additives or by chemical modification of the steroid molecule. [Clin. Pharmacol. Ther., 19, 170 (1975); Chem. Pharm. Bull., 26, 2832 (1978); J. Pharm. Sci., 68, 542 (1979)].

Oily injection formulations are disadvantageous both because they can cause unpleasant side effects (pain, absorption problems, irritation, etc.) and because they have poor stability. In order to increase the water solubility of unmodified steroids, additives are used which form a molecule-associated molecule having colloidal dimensions with the steroid molecule, from which the release of the steroid molecule is delayed. The solubility of solid steroids in pharmaceutical formulations also varies significantly over time, due to the variety of crystalline modifications that exist, depending on the manufacturing process, and even due to recrystallization processes during storage. In many cases, the biological activity of steroid molecules converted to water solubility is not the same as that of the parent molecule.

Surprisingly, it has been found that water-poorly soluble steroid molecules can be made highly water-soluble by converting them to inclusion complexes with γ-cyclodextrin. The inclusion complex is highly soluble in water and dissociates in the body with γ-cyclodextrin and free steroid. Thus, the use of γ-cyclodextrin inclusion complexes provides a good opportunity for the preparation of biologically useful pharmaceutical compositions containing a steroid. A particular advantage is that the solid steroid-γ-cyclodextrin inclusion complexes are easy-to-handle powders that are easily miscible with other materials to minimize the difference in drug content between low-active tablets.

The highly hydrophilic, water-soluble steroid γ-cyclodextrin inclusion complexes of the present invention are prepared by mixing a solution of the steroid to be complexed with a C 1-2 alkanol and an aqueous solution of γ-cyclodextrin at a temperature below the boiling point of the alkanol used. and recovering the resulting steroid γ-cyclodextrin inclusion complex from the resulting homogeneous solution.

Methanol or ethanol can be used as the C 1 -C 2 alkanol in the process of the present invention. Ethanol is preferably used. The steroid is preferably mixed with the γ-cyclodextrin solution while warm, for example 50-70 ° C. The solutions are preferably adjusted to 60 ° C prior to mixing. In this case, the easiest way to ensure a homogeneous solution after mixing is achieved.

The molar ratio of reactants reacted is preferably from 1: 2 to 1: 3.

There are several ways to obtain the inclusion complex from the homogenous solution obtained after mixing. It is possible to cool the homogeneous solution and separate the precipitated complex crystals by filtration, centrifugation and decantation from the mother liquor. The complex may be recovered either by spray drying the homogeneous solution or by freeze-drying the residue after distillation of the alkanol.

The high solubility of the complexes of the present invention is illustrated in Table 1. The assay was performed by equilibrating 100 mg of free steroid or equivalent in 10 ml of distilled water at 25 ° C for 24 hours. The steroid concentration of the solutions was then determined by UV spectrophotometry.

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Table 1

Name Steroid concentration (mg / ml) free in the case of a complex steroid spironolactone 0.06 2.7 nortestosterone 0.31 1.06 Methyl-testosterone 0.07 1.4 progesterone 0,016 0,095 hydrocortisone 0.36 4.3 dexamethasone 0.11 6.0 estrone 0.03 0.355 prednisolone 0.61 4.6 triamcinolone 0.21 9.0

Given that one of the most important characteristics of solid pharmaceutical formulations is the rate at which the active ingredient is released, comparative experiments were conducted with the inclusion complexes of the invention and free steroids to determine dissolution rates. The experiments were carried out by spraying 50 ml of distilled water at 25.0 ° C with a content (complex or free steroid) well in excess of the saturation concentration, and measuring the steroid concentration in samples taken at specified times with constant mixing. The data obtained is shown in Figures 2-6. tables.

Table 2

Spironolactone and its γ-cyclodextrin complex

Spironolactone Concentration Time (min) _ (Mg / ^m ') _ of steroid complex

1 8 30 3 14 43 5 20 43 10 30 44 15 35 43 20 39 44 30 42 44 60 44 43

Table 3 Prednisolone and γ-cyclodextrin complex Time (minutes) Prednisolone concentration (pg / ml) steroid complex 1 39 350 3 130 400 5 170 413 10 260 410 15 300 407 30 340 414 60 380 410 90 417 414

Table 4

Complexes of dexamethasone and γ-cyclodextrin

Dexamethasone Concentration Time (minutes) precipitated lyophilized

steroid complex 1 21 107 103 3 44 111 100 5 52 105 105 10 83 108 103 20 85 106 106 30 95 105 103 45 99 109 104 90 104 103 105

Table 5 Complex of methyl testosterone and γ-cyclodextrin Time (minutes) Methyl Testosterone Concentration (pg / ml) steroid complex 1 9 52 3 15 70 5 20 68 10 25 72 20 40 71 30 51 72 45 65 69 60 71 71

Table 6 Complex of hydrocortisone and γ-cyclodextrin Time (minutes) Hydrocortisone Concentration (G / ml) steroid complex 1 33 304 3 80 352 5 123 359 10 197 360 20 264 355 30 305 358 45 331 354 60 357 359

As can be seen from the data in the tables above, the γ-cyclodextrin complexes produced by the present invention achieve a steroid concentration corresponding to a saturation concentration in a significantly shorter time than using the free steroid. This is important because it also reaches the concentration needed to produce a therapeutic effect in the body faster.

Γ-Cyclodextrin is metabolised in the body by two orders of magnitude faster than α- or β-cyclodextrin and can be used parenterally. At 37 ° C, As3

After 24 hours, 98% of α-cyclodextrin and 83% of β-cyclodextrin are present, whereas γ-cyclodextrin is not found in the enzymatic reaction mixture. This is beneficial because it prevents the accumulation of γ-cyclodextrin in the body and avoids the effects of β-cyclodextrin on the kidneys.

Chemical differences between the complexes, the γ-cyclodextrin and the individual steroid-γ-cyclodextrin mixtures were confirmed by thermoanalytical and X-ray diffractometry. While the mechanical mixtures show the thermoanalytical behavior typical of the free steroid, the complexes show only a change consistent with the degradation of γ-cyclodextrin.

The characteristic peaks of the X-ray powder diagrams in mechanical mixtures are additive from those of the free steroid and γ-cyclodextrin (20 = 5,2,6,3,3, 12,4, 15,4, 16,7, 18), in the case of complexes the appearance of the new crystal structure is illustrated by the simplification of the diagram, where the new peaks cannot be derived from any of the components.

The steroid names used in this description are replaced by the following chemical names:

dexamethasone = 9α-fluoro-11β, 17,21-trihydroxy16α-methyl-pregna-1,4-diene-3,20-dione;

hydrocortisone = 11 β, 17,21-trihydroxypregn-4en-3,20-dione;

methyl testosterone = N-hydroxy-17-methylandrost-4-en-3-one;

nortestosterone = 17β-hydroxy-estr-4-en-3-one; estrone = 3-hydroxy-estra-1,3,5 (10) -trien-17-one; prednisolone = 11 β, 17,21-trihydroxy-pregna-1,4-diene-3,20-dione;

progesterone = pregn-4-ene-3,20-dione; spironolactone = 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-enecarboxylic acid γ-lactone-7-acetate; triamcinolone = 9α-fluoro-11β, 16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione.

The invention is illustrated by the following non-limiting examples.

Example 1: 2 molar ratio spironolactone-γ-cyclodextrin complex

1531 mg (1.03 mmol) of γ-cyclodextrin containing 15% water are dissolved in 4 ml of water at 60 ° C. A solution of spironolactone (213 mg, 0.51 mmol) in 4 mL of 96% ethanol at 60 ° C was also prepared. The two solutions were mixed with vigorous stirring. The complex begins to precipitate within a short time. Stirring is continued for 3 hours while the solution is allowed to cool slowly to room temperature. After stirring, the reaction mixture containing the crystals was allowed to stand for 12 hours at 0 ° C, and the crystals were filtered off and dried. 1476 mg of the title compound are obtained in the form of a white crystalline powder. The complex contains 12% spironolactone. Given that the 1: 2 molar complex has a calculated spironolactone content of 13.8%, the resulting product also contains, in addition to spironolactone, free γ-cyclodextrin. The complex lex contains 90.9% of the spironolactone reacted.

Thermoanalysis of the title product and a mechanical mixture of the same spironolactone content confirms the complexity of the product. While the mechanical mixture exhibits an endothermic peak at 203 ° C for the melting of spironolactone, it does not occur in the complex.

Example 2

I: 3 Molar ratio of spironolactone-γ-cyclodextrin complex

1539 mg (1.03 mmol) of γ-cyclodextrin containing 15% water are dissolved in 4 ml of water at 60 ° C. A solution of spironolactone (140 mg, 0.334 mmol) in 4 mL of 96% ethanol at 60 ° C was prepared. The two solutions were mixed, stirred, cooled, filtered as in Example 1. 1342 mg of the title inclusion complex are obtained. The product had a spironolactone content of 8.25%. Since the complex has a theoretical spironolactone content of 1: 3 molar ratio of 9.7%, this means that the resulting product also contains free γ-cyclodextrin. The complex contains 79.3% of the spironolactone reacted.

Thermoanalysis of the title product and a mechanical mixture of the same spironolactone content confirms the complexity of the product. While the mechanical mixture exhibits an endothermic peak at 203 ° C for melting spironolactone, it does not occur in the complex.

Example 3: Prednisol 2: olone-γ-cyclodextrin complex

1550 mg (1.02 mmol) of γ-cyclodextrin containing 15% water are dissolved in 5 ml of water at 60 ° C. A solution of 185 mg (0.51 mmol) of prednisolone and 5 ml of 96% ethanol at 60 ° C was prepared and the two solutions were slowly mixed with constant stirring. Stirring was continued until the reaction mixture cooled to room temperature. The reaction mixture, which also contains crystals, was allowed to stand at 0 ° C for 12 hours, then filtered and the resulting crystalline product dried in an oven at 80 ° C. 1366 mg of the title complex are thus obtained in the form of a white crystalline powder. The product has a prednisolone content of 11.2%. The 1: 2 molar complex has a calculated prednisolone content of 12.2% and thus the product also contains free γ-cyclodextrin. The product contains 82.7% of the prednisolone reacted.

Differential thermogravimetric analysis of the product and the mechanical composition of the same composition show significant differences. The mechanical mixture at 278 ° C exhibits a high weight loss due to steroid degradation compared to the complex, which does not exhibit weight loss. In a differential scanning calorimetric assay, the mechanical mixture exhibits a large exothermic peak at 243 ° C corresponding to the oxidation of free prednisolone. This is not detectable in the complex.

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Example 4: 2 molar ratio of dexamethasone-γ-cyclodextrin complex

Following the procedure of Example 3, 1388 mg of the title complex was obtained from γ-cyclodextrin containing 1496 mg (0.98 mmol) of 15% water and 196 mg (0.49 mmol) of dexamethasone. The product has a dexamethasone content of 10.6% (calculated 13.3%). This means that the product also contains free γ-cyclodextrin and contains 75% of the dexamethasone reacted.

Example 5 1: 2 Mole ratio dexamethasone-γ-cyclodextrin complex

In each case, the procedure of Example 4 was repeated, except that the reaction mixture obtained by mixing the aqueous and ethanolic solutions was still hot distilled from the ethanol and then freeze-dried. 1400 mg of the title complex is obtained with a dexamethasone content of 13.3%. This corresponds to the theoretical composition.

The thermal evolution analyzer (TEA) of the product of Examples 4 and 5 and of the mechanical mixture showed that large amounts of organic material from the decomposition of free dexamethasone were removed from the mechanical mixture at 250-290 ° C, whereas It occurs.

Example 6: 2 molar ratio of methyl testosterone-γ-cyclodextrin complex

All of the procedures of Example 3 were repeated except that 1497 mg (1 mmol) of γ-cyclodextrin containing 13.6% water and 160 mg (0.53 mmol) of methyl testosterone were used. This gives 1270 mg of the title complex having a methyl testosterone content of 10.1% (theoretical 10.45%). The yield for methyl testosterone was 81%.

Thermal analysis of the title product and a mechanical mixture of the same methyl testosterone content confirmed the complexity of the product. While the mechanical mixture exhibits an endothermic peak at 163 ° C, which is characteristic of methyltestosterone melting, it is undetectable at copmlex.

Example 7.

: 2 Mole ratio hydrocortisone-γ-cyclodextrin complex

All of the procedures of Example 3 were repeated except that 1514 mg (1.01 mmol) of γ-cyclodextrin containing 13.6% water and 185 mg (0.51 mmol) of hydrocortisone were used. 1311 mg of the title complex is obtained having a hydrocortisone content of 11.8% (theoretical 12.3%). The yield based on hydrocortisone was 83.7%.

Thermoanalytical analysis of the title product and a mechanical mixture of the same hydrocortisone content confirm the complexity of the product. While the decomposition of the mechanical mixture starts at 220 'C and has a maximum around 260' C, according to the thermal evolution analyzer (TEA), the decomposition of the complex is only significant around 270 'C.

Example 8: 2 molar ratio progesterone-γ-cyclodextrin complex

Each was prepared as in Example 3, except that 1532 mg (1.02 mmol) of γ-cyclodextrin containing 13.6% water and 1 58 mg (0.504 mmol) of progesterone were used. 1220 mg of the title compound are thus obtained in the form of a white crystalline powder. The progesterone content of the products is 10.2% (theoretical 10.82%). The yield of progesterone was 78.7%.

Thermoanalysis of the title product and a mechanical mixture of the same progesterone content confirmed the complexity of the product. While the mechanical mixture exhibits a 121 'C endothermic peak typical for melting progesterone, this is not detectable in the complex.

Example 9: 2 molar ratio of nortestosterone-γ-cyclodextrin complex

All of the procedures of Example 3 were followed except that 1493 mg (0.995 mmol) of γ-cyclodextrin containing 13.6% water and 136 mg (0.495 mmol) of nortestosterone were used. 1307 mg (9.2%) of the nortestosterone-containing title complex are obtained. The theoretical content of nortestosterone is 9.57%. The product contains 88.4% of the reacted nortestosterone.

Thermoanalytical analysis of the title product and a mechanical mixture of the same nortestosterone content confirm the complexity of the product. While the mechanical mixture exhibits a 122'C endothermic peak typical for the melting of nortestosterone, this is not detectable in the complex.

Example 10: A 2 molar estrone-γ-cyclodextrin complex

All of the procedures of Example 3 were repeated except that 1504 mg (1 mmol) of γ-cyclodextrin containing 13.6% water and 130 mg (0.48 mmol) of estrone were used. 1190 mg of the title complex containing 9.25% estrone are obtained. The theoretical estrone content is 9.45%. The product contains 84.7% of the estrone reacted.

The complex is characterized by an X-ray diffraction port5

-5190 356 agram peaks that differ from the mechanical mixture: 20 = 6.9, 13.1, 15.8

Example 11: Triamcinolone 2-molar base-γ-cyclodextrin complex

Each was prepared as in Example 3, except starting from 1498 mg (0.997 mmol) of 13.6% water containing γ-cyclodextrin and 213 mg (0.49 mmol) of triamcinolone base. 1247 mg of the title complex containing 13.9% triamcinolone base are obtained. The theoretical triamcinolone base content is 14.39%. Yield 81.4% relative to triamcinolone base.

Complex X-ray powder diffraction pattern peaks that differ from mechanical blend: 20 = 7.5, 12.1, 15.9

Example 12 Tablet containing mg spironolactone

In a manner known per se, tablets are prepared with the following composition:

200 mg of the spironolactone-γ-cyclodextrin complex prepared according to Example 1, mg lactose, mg potato starch, mg talc, mg magnesium stearate.

Each tablet weighs 300 mg.

Example 75 Tablet containing prednisolone mg

In a manner known per se, tablets are prepared with the following composition:

mg of prednisolone-cyclodextrin complex prepared according to Example 3,

120 mg microcrystalline cellulose,

31.5 mg of starch,

1.5 mg colloidal silica,

2m 'magnesium stearate.

The tab ate about 200 mg.

Example 16

0.5% prednisolone ointment

4,777; Contains 6% lanakol, 3% cetylstearyl alcohol and 12% ophthalmic white petroleum jelly according to FoNo V for "Unguentum simplex" ointment base

0.223 of the prednisolone-cyclodextrin complex prepared in Example 3 was mixed and the mixture was uniformly worked up.

Example 17

1% hydrocortisone ointment

4.576 g for "Unguentum simplex" base ointment according to FoNo V

0.424 g of the hydrocortical-γ-cyclodextrin complex prepared according to Example 7 are mixed and the mixture is worked up well.

Example 13 Tablet containing mg hydrocortisone

In a manner known per se, tablets are prepared by the dry granulation process with the following composition:

mg, hydrocortis-γ-cyclodextrin complex prepared according to Example 7, mg carboxymethyl starch,

135 mg microcrystalline cellulose, mg stearic acid, mg talc.

Each tablet weighs 250 mg.

Example 14! , Tablets containing 5 mg estrone

In a manner known per se, tablets are prepared with the following composition:

mg, estrone-γ-cyclodextrin complex prepared according to Example 10,

120 mg microcrystalline cellulose, mg starch, mg stearic acid, mg colloidal silica, mg vinylpyrrolidine-vinyl acetate copolymer,

The tablets weigh 180 mg.

Example 18

0.5% hydrocortisone eye ointment

4, for "Oculentum simplex" base ointment according to FoNo V, containing 5% lacquered, 25% liquid paraffin and 70% ophthalmic vaseline

0.212 g of hydrocortisone-γ-cyclodextrin complex prepared according to Example 7 and

Chloramphenicol (0.01 g) was added and the mixture was homogenized.

Example 19

0.5 mg aqueous dexamethasone injection

Prepare a solution for injection with the following composition:

47.2 mg of the dexamethasone-γ-cyclodextrin complex prepared according to Example 4

21.0 g of sodium chloride, pyrogen-free, distilled water for injection, is given in 3 ml.

The distilled water is first dissolved in sodium chloride, then the complex, filtered and filled into an ampoule. After soldering, sterilize by autoclaving at 120 ° C for 20 minutes.

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Example 4

I: 2 Mole ratio dexamethasone-γ-cyclodextrin complex

Following the procedure of Example 3, 1388 mg of the title complex was obtained from γ-cyclodextrin containing 1496 mg (0.98 mmol) of 15% water and 196 mg (0.49 mmol) of dexamethasone. The product has a dexamethasone content of 10.6% (calculated 13.3%). This means that the product also contains free γ-cyclodextrin and contains 75% of the dexamethasone reacted.

Example 5: 2 molar ratio of dexamethasone-γ-cyclodextrin complex

In each case, the procedure of Example 4 was repeated, except that the reaction mixture obtained by mixing the aqueous and ethanolic solutions was still hot distilled from the ethanol and then freeze-dried. 1400 mg of the title complex is obtained with a dexamethasone content of 13.3%. This corresponds to the theoretical composition.

The thermal evolution analyzer (TEA) of the product of Examples 4 and 5 and of the mechanical mixture showed that large amounts of organic material from the decomposition of free dexamethasone were removed from the mechanical mixture at 250-290 ° C, whereas It occurs.

Example 6 1: 2 Molar ratio of testosterone-γ-cyclodextrin complex

All of the procedures of Example 3 were repeated except that 1497 mg (1 mmol) of γ-cyclodextrin containing 13.6% water and 160 mg (0.53 mmol) of methyl testosterone were used. This gives 1270 mg of the title complex having a methyl testosterone content of 10.1% (theoretical 10.45%). The yield for methyl testosterone was 81%.

Thermoanalytical analysis of the title product and a mechanical mixture of the same methyl testosterone content confirmed the complexity of the product. While the mechanical mixture exhibits a 163 'C endothermic peak typical for melting methyl testosterone, this is not detectable in copmlex.

Example 7: Hydrocortisone-γ-cyclodextrin complex in molar ratio

All of the procedures described in Example 3 were repeated except that 1514 mg (1.01 mmol) of γ-cyclodextrin containing 13.6% water and 185 mg (0.51 mmol) of hydrocortisone were used. 1311 mg of the title complex is obtained having a hydrocortisone content of 11.8% (theoretical 12.3%). The yield based on hydrocortisone was 83.7%.

Thermoanalysis of the title product and a mechanical mixture of the same hydrocortisone content confirms the complexity of the product. While the decomposition of the mechanical mixture begins at 220 ° C and has a maximum of about 260 ° C according to the thermal evolution analyzer (TEA), the decomposition of the complex is only significant around 270 ° C.

Example 8: 2 molar ratio progesterone-γ-cyclodextrin complex

Each was prepared as in Example 3, except that 1532 mg (1.02 mmol) of γ-cyclodextrin containing 13.6% water and 158 mg (0.504 mmol) of progesterone were used. 1220 mg of the title compound are thus obtained in the form of a white crystalline powder. The product had a progesterone content of 10.2% (theoretical 10.82%). The yield of progesterone was 78.7%.

Thermoanalysis of the title product and a mechanical mixture of the same progesterone content confirmed the complexity of the product. While the mechanical mixture exhibits a 121 'C endothermic peak typical for melting progesterone, this is not detectable in the complex.

Example 9: 2 molar ratio of nortestosterone-γ-cyclodextrin complex

All of the procedures of Example 3 were followed except that 1493 mg (0.995 mmol) of γ-cyclodextrin containing 13.6% water and 136 mg (0.495 mmol) of nortestosterone were used. 1307 mg (9.2%) of the nortestosterone-containing title complex are obtained. The theoretical content of nortestosterone is 9.57%. The product contains 88.4% of the reacted nortestosterone.

Thermoanalytical analysis of the title product and a mechanical mixture of the same nortestosterone content confirmed the complexity of the product. While the mechanical mixture exhibits a 122'C endothermic peak typical for the melting of nortestosterone, this is not detectable in the complex.

Example 10 1: 2 Molar ratio estrone-γ-cyclodextrin complex

All of the procedures of Example 3 were repeated except that 1504 mg (1 mmol) of γ-cyclodextrin containing 13.6% water and 130 mg (0.48 mmol) of estrone were used. 1190 mg of the title complex containing 9.25% estrone are obtained. The theoretical estrone content is 9.45% The product contains 84.7% of the estrone reacted.

The complex is characterized by an X-ray diffraction port5

190 356 agram peaks which differ from the mechanical mixture: 20 = 6.9, 13.1, 15.8

Example 11: Triamcinolone 2-molar base-γ-cyclodextrin complex

All of the procedures of Example 3 were followed except that 1498 mg (0.997 mmol) of γ-cyclodextrin containing 13.6% water and 213 mg (0.49 mmol) of triamcinolone base were used. 1247 mg of the title complex containing 13.9% triamcinolone base are obtained. The theoretical triamcinolone base content is 14.39%. The triamcinolone base is 81.4%.

Complex X-ray powder diffraction pattern peaks that differ from mechanical blend: 20 = 7.5, 12.1, 15.9

Example 12 Tablet containing mg spironolactone

In a manner known per se, tablets are prepared with the following composition:

200 mg of the spironolactone-γ-cyclodextrin complex prepared according to Example 1, mg lactose, mg potato starch, mg talc, mg magnesium stearate.

Each tablet weighs 300 mg.

Example 75 Tablet containing prednisolone mg

In a manner known per se, tablets are prepared with the following composition:

mg of prednisolone-cyclodextrin complex prepared according to Example 3,

120 mg microcrystalline cellulose,

31.5 mg of starch,

1.5 mg colloidal silica, magnesium stearate.

The tab ate about 200 mg.

Example 16

0.5% prednisolone ointment

4,777; "Unguentum simplex" ointment with FoNo V content of 6% lanakol, 3% cetylstearyl alcohol and 12% ophthalmic white petroleum jelly

0.223; the prednisolone γ-cyclodextrin complex prepared according to Example 3 was mixed and the mixture was uniformly worked up.

Example 17

1% hydrocortisone ointment

4,576 g for "Unguentum simplex" base ointment according to FoNo V.

0.424 g of the hydrocortical-γ-cyclodextrin complex prepared according to Example 7 are mixed and the mixture is worked up well.

Example 13 Tablet containing mg hydrocortisone

In a manner known per se, tablets are prepared by the dry granulation process with the following composition:

mg, hydrocortis-γ-cyclodextrin complex prepared according to Example 7, mg carboxymethyl starch,

135 mg microcrystalline cellulose, mg stearic acid, mg talc.

Each tablet weighs 250 mg.

Example 14

Tablets containing 1.5 mg estrone

In a manner known per se, tablets are prepared with the following composition:

mg of estrone-γ-cyclodextrin complex prepared according to Example 10,

120 mg microcrystalline cellulose, mg starch, mg stearic acid, mg colloidal silica, mg vinylpyrrolidine - vinyl acetate copolymer.

The tablets weigh 180 mg.

Example 18

0.5% hydrocortisone eye ointment

For 4,778 g of "Oculentum simplex" base ointment according to FoNo V, 5% lacquered, 25% liquid paraffin and 70% ophthalmic vaseline

0.212 g of the hydrocortical-γ-cyclodextrin complex prepared according to Example 7 and

Chloramphenicol (0.01 g) was added and the mixture was homogenized.

Example 19

0.5 mg aqueous dexamethasone injection

Prepare a solution for injection with the following composition:

47.2 mg of dexamethasone-γ-cyclodextrin complex prepared according to Example 4

21.0 g of sodium chloride, pyrogen-free, distilled water for injection, is given in 3 ml.

The distilled water was first dissolved in sodium chloride, then the complex, filtered and filled into an ampoule. After soldering, sterilize by autoclaving at 120 ° C for 20 minutes.

Claims (18)

Claims A process for the preparation of 9a-fluoro-11β, 17,21-trihydroxy-16α-methyl-pregna-1,4-diene-3,20-dione, 11β, 17,21-trihydroxy-pregn-4-ene-3, poorly soluble in water. 20dione, 17β-1ιί0Γθχί-17-methyl-androst-4-en-3-one, 17β-hydroxy-estr-4-en-3-one, 3-hydroxy-estra-1,3,5 (10) -triene-17 -on, 11β, 17,21-trihydroxy-pregnal, 4-diene-3,20-dione, pregn-4-ene-3,20-dione, 17-hydroxy-7α-mercapto-3-oxo-17α pregn-4-ene-carboxylic acid γ-lactone-7-acetate, 9a-fluoro-11β, 16α, 17,21 tetrahydroxypregna-1,4-diene-3,20-dione inclusion complex of γ-cyclodextrin characterized by mixing a solution of the steroid to be complexed with a C 1-2 alkanol and an aqueous solution of γ-cyclodextrin at a temperature lower than the boiling point of the alkanol used and recovering the resulting steroid-γ-cyclodextrin inclusion complex. 2. A process according to claim 1, wherein the C 1 -C 2 alkanol is ethanol. Process according to any one of the preceding claims, characterized in that the alkanolic steroid solution and the aqueous γ-cyclodextrin solution are mixed at 50-70 ° C. 4. The process of claim 3, wherein the alkanolic steroid solution is mixed with an aqueous solution of? Cyclodextrin at 60 ° C. Process according to any one of the preceding claims, characterized in that the resulting complex is recovered by cooling the reaction mixture and filtering. 6. Process according to any one of claims 1 to 3, characterized in that the resulting complex is obtained by freeze-drying the reaction mixture. A process for the preparation of a 1: 2 molar ratio of steroid to γ-cyclodextrin according to any one of the preceding claims, characterized in that 2 moles of γ-cyclodextrin are used per mole of steroid. 8. A process for the preparation of a 1: 3 steroid-γ-cyclodextrin mole ratio complex according to any one of claims 1 to 3, characterized in that 3 moles of γ-cyclodextrin are used per mole of steroid. Process for the preparation of the 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-carboxylic acid γ-lactone-γ-cyclodextrin complex according to any one of the preceding claims, characterized in that 17-Hydroxy-7α-mercapto-3-oxo-17α-pregn-4-enecarboxylic acid γ-lactone is used. 10. A process for the preparation of the 11 β, 17,21-trihydroxy-pregna-1,4-diene-3,20-dione-γ-cyclodextrin complex according to any one of claims 1 to 4, characterized in that 11β, 17,21-trihydroxy- ⁵ diene-3,20-dione. 11. A method according to any one of claims 9a-fluoro-1β, 17,21-trihydroxy-16? -methyl-pregna-l, 4-diene-3,20-dione-y-cyclodextrin complex thereof, characterized in that the steroid 9a fluoro θ ¹ 11-β, 17,21-trihydroxy-16a-methyl-pregna-1,4-diene-3,20-dione is used. 12. A method according to any one of claims 17β-hydroxy-17-methylandrost-4-en-3-one yciklodextrin complex preparation characterized ^fifteen ve, employing ^ -hydroxy-17-methylandrost-4-en-3-one steroid. 13. A method according to any one of claims 11 β, 17,21-trihydroxy-pregn-4-ene-3,20-dione yciklodextrin complex preparation characterized ve ²⁰ to steroid 11 β, 17,21-trihydroxy-pregn-4-ene-3 , 20-dione. 14. A process for the preparation of pregn-4-ene-3,20-dione-γ-cyclodextrin complex according to any one of claims 1 to 4, wherein the steroid is ²⁵ preg-4-ene-3,20-dione. 15. Method as claimed in any one 17β-4-Ιιΐ3Γθχϊ-05ΖΐΓ έη-3-οη-γ-οϊΜοάεχΐΓίη complex preparation characterized in that the steroid ^ -hydroxy-estr-4-en-3-one ³⁰ is used. 16. A process for the preparation of a 3-hydroxyestra-1,3,5, (10) -1-rhenium-17-one-cyclodextrin complex according to any one of claims 1 to 3, wherein the steroid is 3-hydroxyestra-1,3,5, (10) ³⁵ ) trien-17-one was used. 17. A process for the preparation of a 9a-fluoro-11β, 16α, 17,21-tetrahydroxypregnal, 4-diene-3,20-dione-γ-cyclodextrin complex according to any one of claims 1 to 6, characterized in that 9a-fluoro ⁴⁰ 11β, 16a, 17 is a steroid. 21-Tetrahydroxy-pregna-1,4-diene-3,20-dione is used. 18. A process for preparing a pharmaceutical composition comprising a steroid active ingredient which is readily absorbed from an aqueous medium, characterized in that a pharmaceutical composition according to any one of claims 1 to 17 is provided. The steroid cyclodextrin complex prepared according to any one of claims ^{45 to 45} , mixed with filler, diluent, taste, odor, pH, osmotic pressure adjusting agent and other formulation auxiliaries commonly used in the preparation of pharmaceutical compositions. We make it into 50 pharmaceutical formulations.