NL8204122A - GAMMA-CYCLODEXTRINE-INCLUDED COMPOSITION COMPLEXES OF STEROID COMPOUNDS, METHOD FOR THE PREPARATION THEREOF, AND MEDICINAL PRODUCT PREPARATIONS CONTAINING THESE INCLUSION COMPLEXES. - Google Patents

Description

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Inclusion complexes of steroid compounds formed with γ-cyclodextrin, process for their preparation, as well as drug preparations containing these inclusion complexes.

The invention relates to inclusion complexes of water-poorly soluble steroid compounds formed with γ-cyclo-dextrin, further to a process for their preparation and finally to drug preparations containing these inclusion complexes as active substance.

The cyclodextrins are formed by the action of the enzyme cyclodextrin transglycosilase on starch. The cyclo-dextrin molecules are composed of 6, 7 or 8 glucopyranose units and accordingly ¢¢, p- and γ-10 cyclodextrins are distinguished. Their molecules enclosed within a hollow space have the shape of a truncated cone. The outer surface of the hollow truncated cone structure is hydrophilic - for which reason the cyclodextrins are water-soluble - while the inner cavity wall has an apolar character for which reason the cyclodextrins with non-polar so-called guest molecules in aqueous medium can form inclusion complexes, which can also be isolated in microcrystalline form.

The inclusion complex formation influences the physical and resp. chemical stability of the entrapped guest molecule and numerous cases were observed, thereby also increasing solubility.

For α-cyclodextrin, the following solubility enhancing effects are known and described: According to Lautsch, Rauchut, Grimm and Broeser (Z. Naturforsch.

12.b., 307-314 from 1957), the solubility of acetylene in aqueous α-cyclodextrin solution increases to 1.2-fold;

Cohen and Lach (J. Pharm. Sci., 52, 132-136-196737) observed that the solubility of hydroxybenzoic acids and parabens in α-cyclodextrin solution rises to 1.25-6 fold; Lach and Cohen (J..Pharm. Sci., 52_, 137 ^ 19637) report the increase in the solubility of 11 compounds of different types to the 1.1-3.4 fold in α-cyclodextrin-8204122 «« - 2 solution; Lach and Chin (J. Pharm. Sci., 53, 69-73 / 19647) observed an increase in solubility to 1.1-10 fold for substituted benzoic acids; according to Uekama, Hiramama, Matsuo and Koinuma (Chem. Lett., 1978, 703-706), the solubility of tolbutamide increases to the 2-fold in α-cyclo-dextrin solution; Uekama and Hirayama (Chem. Bull, £ 2, 1195-1200 / 19787) observed an increase in the solubility of prostagrandin-F0 to 2.8-fold? according to Uekama, Hirayama, Yamada, Inaba and Ideda (J. Pharm. Sci. 6j3, 1059 10/19797) the solubility of the prostaglandin E. methyl ester derivatives by .alpha.-cyclodextrin increases to 27.5-fold.

In β-cyclodextrin solutions, significant effects with regard to the increase in solubility were also achieved.

15 For example, Lautsch, Bandel and Broeser (Z.

Naturforsch., Lib, 282-291 / 19567) increase the solubility in water of the azo dye designated "Buttergelb" to 6-fold; Cohen and Lach (J. Pharm. Sci. 52_, 132-136 / 19637) have reported an increase in the solubility of hydroxybenzoic acids and parabens to 1.1-2 fold,

Lach and Cohen (J. Pharm. Sci. 52_, 137/19637) in the case of various compounds, an increase in solubility to 1.03-3.6 fold; Lach and Chin (J. Pharm. Sci. 53, 69-73 / 19647) found an increase in solubility to 1.1-9 fold for substituted benzoic acids; likewise, Lach and Chin (J. Pharm. sci., 5, 924-927 / 19647) directed the increase in solubility of benzocaine to 2-fold; Thakkar, Kuehn, Perrin and Wilham (J. Pharm. Sci., J51, 1841-1843 / 1912 /) have described a 1.3-3.3-fold increase in solubility for barbitals; Uekama, Matsuo, Hirayama, Yamaguchi, Imamura, and Ichibagase (Chem. Pharm. Bull, 21, 398-402 / 19727) observed a 3-fold increase in solubility with acetohexamide; Ikeda, Uekama and Otagiri (Chem. Pharm. Bull., 23_201-208 / 19757) an increase in the solubility of flufenamic acid to 6.6-fold; according to Uekama, Hirayama, Matsuo and Koinuma (Chem. Lett., 1978, 703-706) the solubility of tolbutamide in β-cyclodextrin solution increases to 2.75-fold; Frank and Cho (J. Pharm. Sci., 8204122-9-367, 1665-1668 / 19787) were able to increase the solubility of prostaglendine E2 to 4-fold; Uekama and Hirayama (Chem. Bull. / 26_, 1195-1200 / 19787) report an increase in the solubility of prostaglandin F2a to 3.8-5 fold; according to Uekama, Hirayama, Yamada, Inaba and Ikeda (J. Pharm. Sci., 68_, 1059/19797), the water solubility of prostaglandin-E-methyl ester derivatives increases to 7.5 fold; Pauli and Lach (J. Pharm. Sci., S4, 1745-1750 / 19657) were able to increase the solubility of seven aromatic carboxylic acid derivatives to 1.05-4.2 fold in 3-cyclodextrin solution.

Of the steroids, only the testosterone resp. the cortisone acetate (Lach and Pauli, J. Pharm. Sci., S5, 32-38 / 19667). Where an increase in solubility to 2.7, respectively. 4.3-fold was observed.

Extensive own research up to the γ-cyclodextrin showed surprisingly high solubility-enhancing effects. In proportion dilute (displaying a few percent concentration) Y-eyelodextrin solutions, steroid solubility increased to 3-100 fold, usually to 3.4-66 fold.

In this way, aqueous injectable steroid solutions can be prepared, e.g.

methyltestosterone 7.5 mg / ml 25 spironolactone 3.0 mg / ml hydrocortisone 5.0 mg / ml prednisolone 8.2 mg / ml dexamethasone 6.0 mg / ml triamcinolone 14.6 mg / ml, etc.

These compounds could hitherto be used only in the form of oily injections, intramuscularly or in the form of solutions prepared with no doubt harmful organic solvents, or a water-soluble chemical derivative had to be prepared.

Another important aspect for the complex formation of the steroids with γ-cyclodextrin and the use of these complexes in drug preparations to be used parenterally is related to the fact that α- and 3-cyclodextrin 8204122 4 - 4 - enzymatically degrade only very slowly and therefore have a nephrotoxic effect when administered parenterally. Therefore, no injectable steroid preparations could be prepared from α- and β-cyclodextrin, if the solubility increase allowed this. The γ-cyclo-dextrin, on the other hand, has such a flexible molecular structure that it is enzymatically degraded at least 100 times faster than β-cyclodextrin / ie the cyclodextrin is broken open quickly in the organism and metabolized in exactly the same way as the one. starch, respectively. the linear dextrins. Therefore, when using γ-cyclodextrin for parenteral purposes, the danger of toxicity is virtually negligible.

The absorption of the orally or locally applied steroids can also be considerably accelerated with γ-cyclodextrin.

The inclusion complexes of the steroids formed with γ-cyclodextrin have a pronounced hydrophilic character, they are directly wetted by water and the steroid does not float directly on the surface. The saturation concentration of the solution can generally be reached in an order of magnitude less time than is the case without γ-cyclodextrin, and this saturation concentration is about 10-10 times that of the original steroid. According to the experiences made with β-cyclodextrin, it seems plausible that - since the poorly water-soluble hydrophobic substances are easily wettable and readily soluble by the complex formation - also the biological absorption, ie the biological utilization of the compound in any case is being improved.

Accordingly, the present invention relates to the complexes of water sparingly soluble steroid compounds formed with γ-cyclodextrins. By the term "sparingly soluble steroids" here is meant the water-insoluble or only in low concentration soluble steroids which are not suitable for practical purposes. Due to the complex formation, the 8204122 i «F ™ -———— · - - - 5 - poorly water soluble, pronounced hydrophobic steroids take on a hydrophilic character and thereby both the dissolution rate and the saturation concentration of the discharge 1-2 orders of magnitude greater, thereby increasing the biological processability of the compounds.

Several methods are known for the preparation of cyclodextrin inclusion complexes. E.g. in the presence of little water, the cyclodextrin can be kneaded with the substance to be included, or the solution of the substance prepared with an organic solvent is shaken with the aqueous cyclo-dextrin solution, or the complex is formed from the homogeneous solution of both components by coprecipitation. The latter method is suitable for the steroids.

The invention also extends to the preparation of the inclusion complexes of sparingly water-soluble steroids formed with γ-cyclodextrins. The inclusion complexes are prepared by mixing the solution of the steroids prepared with C 1 -6 alkanols, with ether or acetone and the aqueous solution of the γ-cyclodextrin at a temperature between room temperature and the boiling point of the solvent, the mixture cools and secretes the precipitated steroid-γ-cyclodextrin complex in a manner known per se.

Preferably, the process according to the invention is carried out in such a way that the solution of the γ-cyclodextrin is prepared at 50-70 ° C, the steroid to be included in the complex is dissolved in an identical volume of 96% ethanol at the same temperature and then brings the two components together. Under the conditions mentioned, a clear homogeneous solution is formed at 50-70 ° C, which is cooled slowly to room temperature under intensive stirring, within 3 hours.

Upon cooling, the separation of the complex crystals begins, which is completed after completion of stirring and cooling by leaving at about 0 ° C for 12 h. The precipitated product is separated from the mother liquor by filtration or centrifugation and dried under atmospheric pressure at 80 ° C or in vacuum at 40 ° C.

Solutions can also be prepared by mixing the steroid with the 1-10 wt%, preferably 3-5 wt%, aqueous solution of the γ-cyclodextrin. In this way, an injectable solution is obtained.

The invention also extends to this method.

The desired effectiveness of complex formation is generally achieved when two or more molecules of Ύ-cyclodextrin are available per steroid molecule. When the steroid is used in a larger molar ratio, only part of it is included in the complex.

The advantages of the invention can be summarized as follows: a) the preparation of aqueous injection solutions with a hitherto unattainable steroid concentration is enabled; B) the Ύ-cyclodextrin is enzymatically metabolized two orders of magnitude faster than the ct or 3-cyclodextrin, for which reason the solutions can be injected parenterally; c) the solid γ-cyclodextrin complexes of the ste-20 grids are easily and quickly wettable with water, their dissolution rate - and often also their solubility limit - orders of magnitude improve (powder ampoules, injections, etc. can be prepared), a faster and more complete absorption of the active substance from tablets, resp. ointments is to be expected.

The invention also extends to the drug preparations containing steroid complexes formed with Ύ-cyclodextrin. In addition to the inclusion complexes, these drug preparations contain the usual carriers, extenders and diluents and, if necessary. other substances customary in the pharmaceutical preparation. They are produced in the manner customary for the preparation of drug preparations, according to their known technology.

The invention is further elucidated by the following exemplary embodiments, but is not limited to these examples.

EXAMPLE I

Preparation of aqueous steroid solutions.

In Ύ-cyclodextrin solutions with different 8204122 IF1 '' '' 1 'Jl ..................

Concentrations were shaken at 25 ° C in a shaker for 3 hours for different steroids. The steroids were used in excess, so that solid steroid was also still present in the solution at the end of the test. This solid steroid was filtered off, then the amount of the steroid that had gone into solution was determined. As Tables A-G show, solubility generally does not increase monotonically with the concentration of γ-cyclodextrin, but a more or less sharp maximum can be observed. Depending on the steroid, the concentration range of the Ύ-cyclodextrin in which the greatest increase effect on solubility was observed is larger or smaller. After exceeding this optimum value, the solubility of the steroid drops again, but in this case too it is substantially greater than in the absence of cyclodextrin.

Tables A-G show the water solubility of various steroids as a function of the γ-cyclodextrin concentration. According to these tables, the highest solubility can generally be achieved in 3-5% γ-cyclodextrin solutions. In order to compare the individual steroids with respect to the solubility enhancing effect, the steroids were shaken in 10% (ie 7.51 x 10 mol / l) Y-cyclodextrin solution at 25 ° C for 3 h and then the amount of steroid that had gone into solution was determined. The results are shown in Table H.

30 8204122 - 8 -

TABLE A

The solubility of methyltestosterone (S) as a function of the γ-cyclodextrin concentration

γ-cyclodextrin conc. dissolved methyltestosterone S / SQ

5% mol / 1 mg / ml mol / 1 0 0 (S = 0.070 2.35.10-4) 1 1.58 0.0093 3.2 1.06.10-2 45.7 3.16 0.0186 5.3 1.75.10-2 75.7 4.74 0.0279 7.5 2.48.10-2 107.1 10 6.32 0.0372 6.3 2.08.10-2 90.0 7.9 0.0465 5 , 6 1.85.10-2 80.0 9.48 0.0558 3.75 1.24.10-2 53.6 11.06 0.0651 2.95 9.69.10-3 42.1 12.64 0.0744 1.00 3.31.10-3 14.3 15 14.22 0.0837 0.95 3.14.10-3 13.6 15.8 0.0930 0.80 2.65.10-3 11.4 SQ = solubility without γ- cyclodextrin S = the solubility measured each time

TABLE B

20 The solubility of spironolactone as a function of the γ-cyclo-dectrin concentration

γ-cyclodextrin conc. dissolved spironolactone S / S

% mol / 1 mg / ml mol / 1 0 0 SQ = 0.06 1.44x10-4 1 25 1.6 0.0104 1.342 3.23.10-3 22.4 3.2 0.0208 2.288 5.5. 10-3 38.1 4.8 0.0312 2.816 6.77.10-3 46.9 6.4 0.0416- 2,992 7.19.10-3 49.9 8.0 0.0520 2.99 7.19.10- 3 49.9 30 9.6 0.0624 2.73 6.59.10-3 45.5 11.2 0.0728 2.66 6.40.10-3 44.4 12.8 0.0832 2.62 6.29.10- 3 43.6 14.4 0.0936 2.82 6.77.10-3 46.9_16Ζ0 ________ 0A104 _____________ 2 ^ 00 _______ 4jL81ilO-3 ______ 33z4_ 8204122 P ':' ............... .... .................................. .............

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TABLE C

Solubility of pregnene triolone triacetate (prolac) as a function of γ-cyclodextrin concentration

γ-cyclodextrin conc. premium prolac S / S

5% mol / 1 mg / ml mol / 1 ° 0 0 S_ = 0.010 2.1.10-5 1 0 -5 0.5 0.00295 0.036 7.59.10 ° 3.6 1.0 0.0059 0.047 9.92.10-5 4.7 2.0 0.0118 0.061 1.29.10-4 6.1 10 5.0 0.0295 0.154 3.25.10-4 15.4 10.0 0.0590 0.227 4.79.10-4 22.7 15.0 0.0885 0.291 6.14.10-4 29.1 20.0 0.1180 0.280 5.9 .10-4 28.0

TABLE D

15 Solubility of hydrocortisone as a function of γ-cyclodextrin concentration

γ-cyclodextrin conc. dissolved hydrocortisone S / SQ

% mol / 1 mg / ml mol / 1 0 0 S_ = »0.36 9.9 .10-4 1 -3 ° -3 20 1.59 9.38.10 -3 3.25 8.97.10 -3 9, 06 3.18 1.88.10-2 5.14 1.42.10-2 14.34 4.77 2.81.10-2 4.78 1.32.10-2 13.33 6.36 3.75.10-2 3.65 1.01.10-2 10.20 7.95 '4.70.10-2 3.30 9.1 .10-3 9.19 25 9.54 5.63.10-2 4.00 1.1 .10-2 11 , 11 11.13 6.57.10-2 4.20 1.16.10-2 11.72 12.72 7.51.10-2 3.20 8.83.10-3 8.92 14.31 8.45.10-2 2, 22 6.12.10-3 6.18 15.9 9.38.10-2 2.00 5.52.10-3 5.59 30 8 204 122 - 10 -

TABLE E

Solubility of prednisolone as a function of γ-cyclodextrin concentration

γ-cyclodextrin conc. dissolved prednisolone S / S

5% mol / 1 mg / ml mol / 1 ° 0 0 SQ = 0.610 1.7 .10-3 1 1.29 9.95.10-3 3.18 8.82.10-3 5.19 2.57 1.98.10 -2 5.54 1.54.10-2 9.06 3.86 2.98.10-2 8.23 2.28.10-2 13.41 10 5.15 3.97.10-2 5.62 1.56.10-2 9 , 18 6.43 4.96.10-2 5.33 1.48.10-2 8.71 7.72 5.96.10-2 5.38 1.49.10-2 8.76 9.00 6.94.10-2 4, 81 1.34.10-2 7.88 10.30 7.95.10-2 4.45 1.23.10-2 7.24 15 11.58 8.94.10-2 4.22 1.17.10-2 6.88 12, 9 9.95.10-2 4.02 1.11.10-2 6.53 t

TABLE F

solubility of dexamethasone as a function of γ-cyclodextrin concentration

20 y cyclodextrin conc. dissolved dexamethasone S / S

% mol / 1 mg / ml mol / 1 ° 0 0 SQ = 0.11 3.43.10-4 l 1.275 9.84.10-3 2.88 7.33.10-3 26.2 2.55 1.97.10-2 4 , 97 1.27.10-2 45.2 25 3.825 2.95.10-2 5.99 1.52.10-2 54.5 6.375 4.92.10-2 4.91 1.25.10-2 44.6 7.65 5, 90.10-2 4.40 1.12.10-2 40.0 8.925 6.89.10-2 5.46 1.39.10-2 49.6 10.20 7.87.10-2 6.40 1.63.10-2 58.2 30 11.475 8.85.10-2 6.05 1.54.10-2 55.0 12.75 9.84.10-2 5.06 1.29.10-2 46.0 35 8 204 122 - 11 -

TABLE G

solubility of tramcinolone base as a function of γ-cyclodextrin concentration

γ-cyclodextrin conc. dissolved triamcinolone base S / S

5% mol / 1 mg / ml mol / 1 0 0 S = 0.21 4.8 .10-4 1 -2 0 -3 1.32 1.02.10 * 3.05 7 .10 J 14.5 2, 65 2.04.10-2 5.56 1.28.10-2 26.5 3.97 3.06.10-2 8.25 1.90.10-2 39.3 10 5.30 4.08.10-2 10.25 2, 36.10-2 48.8 6.62 5.10.10-2 12.44 2.86.10-2 59.2 7.94 6.12.10-2 13.44 3.09.10-2 64.0 9.27 7.14.10 -2 13.50 3.11.10-2 64.3 10.59 8.16.10-2 13.69 3.15.10-2 65.2 15 11.91 9.18.10-2 14.63 3.37.10-2 69 .7 13.23 1.02.10-1 12.06 2.78.10-2 57.4 20 8 204 122 »ft.

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EXAMPLE II

Preparation of spironolactone-Y-cyclodextrin complex with 1: 2 molar ratio

At 60 ° C, 1531 mg (1.03.103 mol) of γ-cyclodextrin, containing 15% inclusion and crystal water, was dissolved in -4 ml of water. At 60 ° C, 213 mg (5.1.10 mol) of spironolactone was dissolved in 4 ml of 96% ethanol. The two solutions were mixed together under intensive stirring. Within a short time the complex started to collapse. With continued intensive stirring, the solution was cooled to room temperature within 3 hours and then stored at about 0 ° C for 12 hours. The crystalline product was filtered off and dried. 1476 mg of product were obtained, the spironolactone content of which was 12%.

Thermoanalytical examination showed that the product was an inclusion complex. X-ray diffraction measurements also confirmed the complex character: in the polar diffractogram of the complex, at one of those deviating angular values characteristic of the physical mixture, reflective peaks appear.

Preparation of the same complex with the mol ratio 1: 3.

-3 1539 mg (1.03.10 mol) of the 15% moisture-containing γ-cyclo--4 dextrin was dissolved in 4 ml of water at a temperature of 60 ° C. Furthermore, 140 mg (3.34.10 mol) of spironolactone was dissolved in 4 ml of 96% ethanol at 60 ° C. The two solutions were brought together in the manner described, stirred, the product was filtered and dried. 1342 mg of product with a spironolactone content of 8.25% were obtained. Thermoanalytical research proved the complex character.

79.3% of the steroid introduced into the reaction mixture was bound in the complex. The theoretical spironololactone content of the 1: 3 molar ratio complex would have been 9.7%.

35 Attempt to prepare a complex in the molar ratio 1: 1.

At 60 ° C, 660 mg (4.43.10 4 mol) of the 15% 8204122-14-moisture-containing γ-cyclodextrin was dissolved in 5 ml of water. At o -460 C, 200 mg (4.8.10 mol) of spironolactone was dissolved in 5 ml of 96% ethanol. Both solutions were brought together as described, stirred, the product filtered and dried. 634.2 mg of product containing 22.7% spironolactone was obtained. The theoretical spironolactone content of the complex with the 1: 1 molar ratio is 24.3%. However, only 69% of the spironolactone introduced into the reaction mixture was present in the solid product and thermoanalytical studies showed that a significant amount of the spironolactone was not complex-bound, but was present as a component of a mechanical mixture.

Spironolactone-γ-cyclodextrin complex with the mol ratio 1: 2, prepared by kneading in 50% ethanol.

-4 In a mortar, 1486 mg (9.8.10 mol) of -4 the 15% moisture containing γ-cyclodextrin and 203 mg (4.9.10 mol) spironolactone with 2 ml 50% ethanol were cross-linked. The evaporation loss was compensated for by adding 1 ml of 50% ethanol. The mass was dried in a drying cabinet at 60 ° C. The complex obtained in this way was homogeneous, the active substance content was 13.55% (the calculated value is 13.85 S). The material loss during the process is minimal.

In general, thermoanalytical methods can be used well in the solid phase to prove that a cyclodextrin inclusion complex has been formed. However, in the case of the steroids, the existence of the complex can only be demonstrated in this way because the steroids and the 7-cyclodextrin undergo thermal decomposition in the same temperature range. In spironolactone, complex formation can be proven by differential scanning calorimetry (DSC), because while in the case of the physical mixture at 203 ° C the endothermic peak characteristic of melting the spironolactone appears, it is in the sample of the complex not present. Therefore, in the complexes described in the previous examples with the molar ratios 1: 2, respectively. 1: 3, it is admitted that no free spironolactone is present; however, whether 8204122-15 contains the complex with the molar ratio 1: 3 free cyclodextrin or whether a complex having a deviating crystal structure has been formed, cannot be determined on the basis of said test.

The complex formation accelerates the dissolution of the steroids to a substantial degree. This effect is demonstrated by the following tests.

The dynamic solubility study of the spironolactone-γ-10 cyclodextrin complex formed in the 1: 2 molar ratio was conducted in the following manner. In 50 ml thermostated distilled water at 25/0 ° C, 6 mg spironolactone, resp. 18.6 mg complex, with an active substance content of 12%, sprinkled. Samples were taken with continuous stirring, filtered and the concentration of the dissolved spironolactone was measured UV photometrically. In these measurements, the free steroid was added in a larger amount than can be dissolved. The complex was added to a mixture which, after complete dissolution of the complex in the solution, yields the saturation concentration (the limit value) of the free steroid. The results are shown in Table I.

EXAMPLE III

Inclusion complex from prednisolone and γ-cyclodextrin in the molar ratio of 1: 2.

At 60 ° C, 1550 mg (1.02.10 ^ mol) 15% containing γ-cyclodextrin was dissolved in 5 ml of distilled water.

This solution was combined with the solution of 185-4 mg (5.1.10 mol) prednisolone in 5 ml 96% ethanol prepared at 60 ° C. The mixture was cooled slowly with continuous stirring. To complete the crystallization, the mixture was placed in a refrigerator for 12 h, the product was filtered off and dried in a drying cabinet at 80 ° C. 1366 mg of complex were obtained, the active substance content was 11.2% (the calculated active substance content of the complex prepared in the molar ratio 1: 2 is 12.2 SO. Of the prednisolone introduced into the reaction mixture 82.7% was built into the complex.

The differential thermogravimetric curve of the product shows only a small peak (slight 8204122 - 16 - mass loss) at 278 ° C, while a mechanical mixture with the same active substance content at this temperature has a marked, above the decomposition of shows the steroid protruding peak. Curves 5 of the thermal evolution analyzer (TEA) also lead to the same conclusion: only a small amount of organic decomposition products separate from the complex at 285 ° C, while in the case of the mixture the curve at this temperature shows a major peak. The differential scanning calorimetric (DSC) curve of the. The mechanical mixture shows a large exothermic peak at 243 ° C, which can be explained from the oxidation of the prednisolone. The DSC curve of the complex shows only a slight effect at this point. The complexity of the crystalline product has also been proven by X-ray diffraction studies.

In the manner described in Example I, the dissolution rate of the prednisolone (30 mg) and that of the prednislon-Y-cyclodextrin complex (188 mg, 11.2% active substance content) prepared in the 1: 2 molar ratio was measured. The 20 results are shown in Table J.

TABLE I

The dissolution rate of the spironolactone in free form and as a complex in water at 25 ° C

time concentration of the dissolved spironolactone µg / ml 25 min. spironolactone complex '18 30 3 14 43 limit value after 3 5 20 43 reached 10 30 44 30 15 35 43 20 39 44 30 42 limit value after 30- 44 60 min reached 60 44 43 35 8204122 - 17 -

TABLE J

The dissolution rate of the prednisolone in free form and as a complex, in water at 25 ° C

time concentration of the dissolved prednisolone, µg / ml 5 min. prednisolone complex 1 39 350 3 130 400 limit value after 3 - 2 4i3 5 min reached 10 260 410 10 15 300 407 30 340 414 60 380 410 90 417 limit value after 90 414 min reached

EXAMPLE IV

Complex from dexamethasone and Y-cyclodextrin in the molar ratio of 1: 2

In the manner described in Example III, from 1464 mg (9.8.10 mol) 15% water-containing γ-cyclodextrin -4 20 and 196 mg (4.9.10 mol) dexamethasone were obtained 1388 mg of a 10.6% achieve substance complex prepared. (For the complex with the 1: 2 molar ratio, the calculated value is 13.1%).

The yield based on dexamethasone was 75%.

The complex of the above composition 25 can also be prepared by freeze drying. At room temperature, 104 mg (2.65.10 4 mol) dexamethasone and 912 mg (6.2.10 4 mol) γ-cyclodextrin (water content 13.6%) were dissolved in 40 ml 50% ethanol. The opalescent solution was filtered through a glass filter and then lyophilized. The product had an active substance content of 11.5%, the yield was almost quantitative. When the product was heated, considerably less organic matter separated off at 250-290 ° C than in the case of the mechanical mixture or of the pure dexamethasone. From this it can be concluded that the majority of the dexamethasone is present in complex bound form.

In the manner described in Example II, the dissolution rate of 7.6 mg dexamethasone, 47.3 mg 10.6% 8204122-18 active complex and 43.3 mg 11.5% active lyophilized complex was determined. The results are summarized in Table K.

TABLE K

5 The dissolution rate of dexamethasone in free form and as a complex, in water at 25 ° C

time concentration of the dissolved dexamethasone ug / ml • · η freeze-dried dexamethasone complex complex 101 21 107 limit value 103 limit value 1 min the range in 1 min 3 44 111 100 reaches 15 5 52 105 105 10 83 108 103 20 85 106 106 30 95 105 103 45 99 109 104 20 90 104 limit value 103 105 - after 90 min

FOREVIEW V

Complex of methyltestosterone and γ-cyclodextrin in the molar ratio of 1: 2 In the manner described in example III, γ-cyclodextrin (water content 13.6%) and -4 160 mg (5, 3.10 mol) methyltestosterone 1270 mg complex. The active substance content was 10.1% (theoretical value: 10.45%). Relative to methyltestosterone, the yield was 81%.

In the manner described in Example II, the dissolution rate of 7 mg of methyltestosterone and of 35.2 mg of the above complex was investigated. The results are shown in Table L.

35 8204122 IP '"- 19 -

TABLE L

The dissolution rate of methyltestosterone in free form and as a complex, in water at 25 ° C

time concentration of the dissolved methyltestosterone 5 min. µg / ml methyltestosterone complex 19 52 3 15 70 limit value reached after 5 20 63 3 min 10 10 25 72 20 40 71 30 51 72 45 65 69 60 71 limit value reached after 71 15 60 min

EXAMPLE VI

Complex of hydrocortisone and γ-cyclodextrin in the molar ratio of 1: 2.

In the manner described in example III, from 1514 mg (1.01.10 mol) 13.6% water-containing γ-cyclodextrin -4 and 185 mg (5.1.10 mol) hydrocortisone 1311 mg complex with an active substance content of 11 .8% (theoretical value: 12.3%). The yield based on hydrocortisone was 83.7%.

In the manner described in Example II, the dissolution rate of 28 mg hydrocortisone, resp. 151 mg of the above complex, determined. The results are shown in Table M.

82 0 4 1 2 2 30 - 20 - TABLE Μ

The dissolution rate of hydrocortisone in free form and as a complex, in water at 25 ° C

time concentration of the dissolved hydrocortisone, µg / ml min. hydrocortisone complex '5 1 33 304 3 80 352 limit after 5 123 359 3 ^ reached 10 197 360 20 264 355 10 30 305 358 45 331 354 60 357 limit after 60 359 min reached

A simple qualitative method can also be called upon to prove complex formation. Each 50 ml of 100 ml distilled water-containing beakers were placed on a black paper background. About 3 mg steroid resp. approx. 30 mg steroid Y-cyclodextrin complex, resp. a physical mixture with the same active substance content sprinkled. The steroid floats on the surface of the water in the form of hydrophobic lumps and remains on the surface as a white deposit even after strong shaking. of the water. In its behavior, the physical mixture hardly deviates from the free steroid. However, the complex scattered on the water surface sinks to the bottom of the beaker within 3-5 seconds and disintegrates, or disintegration still occurs on the surface of the water. To accelerate and complete dissolution, it is also sufficient to move the beaker slightly. Without exception the complexes prepared in the following Examples II-XI could be observed without exception with the described differences.

EXAMPLE VII

Complex from progesterone and Y-cyclodextrin in the 35 molar ratio of 1: 2 8204122 pr—. ........ ..........; - 21 -

In the manner described in example III, from -3 -4 1532 mg (1.02.10 mol) γ-cyclodextrin and 158 mg (5.04.10 mol) progesterone 1220 mg complex with an active substance content of 10.2% (theoretical value : 10.82%). The yield based on pro-5esterone was * 78.7%.

EXAMPLE VIII

Complex out. nortestosterone and γ-cyclodextrin in the molar ratio of 1: 2

In the manner described in example III, nortestosterone 1307 mg complex with an active ingredient content was obtained from -4 10 1493 mg (9.95.10 mol) γ-cyclodextrin (water content 13.6%) -4 and 136 mg (4.95.10 mol) substance of 9.2% prepared (theoretical value: 9.57%). The yield based on nortestosterone was 88.4%.

EXAMPLE IX

Complex of estrone and γ-cyclodextrin in the molar ratio of 1: 2

In the manner described in example III, from 3 1504 mg (10 mol) γ-cyclodextrin (water content 13.6%) and -4

130 mg (4.8.10 mol) oestrone 1190 mg complex with an active ingredient content of 9.25% (theoretical value: 9.45%). The yield based on oestrone was 84.7%. EXAMPLE 'X

Complex of triamcinolone base and γ-cyclodextrin 25 in the molar ratio of 1: 2

In the manner described in Example III, 1,498 mg (9.97.10 mol) of γ-cyclodextrin (water content 13.6%) -4 and 213 mg (4.9.10 mol) of triamcinolone base were 1247 mg complex with an active substance content of 13.9% (theoretical value: 14.39%). The yield based on triamcinolone base was 81.4%.

EXAMPLE XI

Complex of pregnancy triolone triacetate and γ-cyclodextrin in the molar ratio of 1: 2 · 35 In the manner described in example III, but using 8 ml of distilled water and 8 ml of 96% -3 ethanol, 1520 mg (1.01.10 mol) Y-cyclodextrin and -4,232 mg (4.9.10 mol) pregnenetriolone triacetate 1173 mg of com 8204122-22 plex with an active content of 15.1% (theoretical value: 15.46%). The yield based on the steroid was 76.3%.

EXAMPLE XII

Comparison of the steroid-dissolving effect of α and γ-cyclodextrin at equal cyclodextrin concentrations.

In <* and γ-cyclodextrin solutions of equal molarity, steroid was added in large excess. At room temperature, after adjusting the solution weight, the total steroid concentration of the solution phase was determined. A solution of the stated concentration (10%) cannot be prepared from β-cyclodextrin, therefore no comparative data are available for β-cyclodextrin.

The steroids tested showed a significantly better solubility in the Y-cyclodextrin solution. The results are summarized in Table N.

TABLE N

ο p 1 o sibility in '| "Γ | 20 water | a-CD solution, j γ-CD solution 1 steroid (S) i (S) (S) 1

η, \ I S / S Y,, 'S / S

mg / ml | mg / ml, a o mg / ml. γ o ---------------------------: ---------'-------- j- ---------- 1 · -------- methyltestosterone 0.071 0.430 I 6.06 1 .1,400 | 19.7

Reichstein-S 0.060. 0.675 | 11.2 ^ 2.010 I 33.5

25 Reichstein-S-17-, j I I

acetate 0.1111 0.930 8.4 j 2,400) 21.5

Reichstein-S 0.011 I 0.330 j 30 I 0.730 (66.3 monac 0.008 I 0.076 | 9.5 1 0.230 ^ 28.8 30 prolac 0.0101 0.080 8 1 0.250 j 25.0 oestrone 0.030 1 0.065 * 2.2 ^ 0.355, 11.8

III I

methylsecosion 0.057 (0.114 (2.0 ^ 0.200 (3.5 - 2 ± Concentration of the cyclodextrin solutions: 7.5.10 mol / l.

EXAMPLE XIII

Comparative solubility studies of complexes of one and the same steroid prepared with 35 different cyclodextrins.

8204122 F ------------------------ - 23 -

In the manner described in the present application, preparations were made from progesterone, methyltestosterone and triamcinolone acetonide with 3- and Ύ-cyclodextrin complexes. The complexes separating from the warm, homogeneous solution prepared with 50% ethanol were filtered off and dried. The content of achieve dust and the composition were determined. The solubility of the complexes was examined in distilled water at 37 ° C (Table 0). The solution equilibrium adjusted within 2-5 min. In order to determine the solubility limit value, an weighed amount of 10 mg active substance / ml was used in each case. The solubility of the γ-cyclodextrin complex was greatest among all steroids.

15 TABLE 0

steroid and are I.

solubility at I complex property a-CD β-CD γ-CD 3.7 ° C (mg / ml.), | .

—---- 1 ----- 1- Progesterone! active ingredient content 14.9% 10.62% 12.22% 20 0.025 mg / ml molar ratio 1: 1.58 1: 2.08 1: 1.51 I solubility (mg steroid / ml) 0.08 0.051 0.473 mm a »aw · mm mm mm mm mm mm mm mmtmmmm mm mmmJmm mm mm mm * mm mm mm mm mm mmmmmmmmmmmmm mm mm mmm ^ m mm mm mm mm ^ mwm mm mm mm ^ mmmmBmmmm ^ mmm ^ mwmmm mm ^ m mm i methyltestosterone j active substance content 12.8% 9.42% 7.8% 25 0.074 mg / ml (mol ratio 1: 2.32 1: 2.25 1: 2.28 | solubility 0.197 0.129 1.16 j (mg steroid / ml)} triamcinolone acyl active substance content 19.46% 13.93% 10.76% ^ mg / ml I molar ratio 1: 1.64 1: 2.10 1: 2.26 30 * solubility 0.156 0.962 4.174 I ( mg steroid / ml) _________________J____________________________________________

EXAMPLE XIV

The use of the inclusion complexes of the steroids formed with γ-cyclodextrin in pharmaceutical preparations.

The inclusion complexes described in the present application may employ the inert solid or liquid carriers and, if necessary, the technologies commonly used in the drug preparation. are formulated into drug preparations using other adjuvants. Some examples are given below.

a) Spironolactone tablets containing 25 mg of active substance.

Composition: 200 mg spironolactone-γ-cyclodextrin complex 60 mg lactose 10 29 mg potato starch 9 mg talc 2 mg magnesium stearate

The indicated amount of complex is based on an active substance content of 12/5%. The tablets were manufactured in a manner known per se using the dry granulation technology. Each tablet weighed 300 mg.

b) Hydrocortisone tablets containing 10 mg of the active ingredient.

Composition: 85 mg hydrocortisone-γ-cyclodextrin complex 20 20 mg carboxymethyl starch 135 mg microcrystalline cellulose 3 mg stearic acid 7 mg talc

The indicated amount of complex is based on an active substance content of 11.8%. Each tablet weighed 250 mg.

c) Estron tablets with 1.5 mg of active substance.

Composition: 16 mg estrone-γ-cyclodextrin complex 120 mg microcrystalline cellulose 34 mg starch 30 3 mg stearic acid 5 mg vinylpyrollidinvinylacetate copolymeri-2 mg colloid silica. saat

The indicated amount of complex is based on an active substance content of 9.3%. The tablets were manufactured in a manner known per se by pressing. One tablet weighs 180 mg.

d) Prednisolone tablets with 5 mg of active substance.

Composition: 45 mg prednisolone-Y-cyclodextrin complex 120 mg microcrystalline cellulose 8204122 W - - · '' · '"------ - 25 - 31.5 mg starch 1.5 mg colloidal silica 2 mg magnesium stearate.

The amount of complex indicated is based on 11.2% active substance content. The tablets were prepared in a manner known per se. One tablet weighed 200 mg.

e) 0.5% prednisolone ointment.

To 4.777 g of base ointment unguentum simplex (containing 6% avenue alcohol, 3% cetylstearyl alcohol and 12% white petrolatum) was added 223 mg prednisolone-Y-cyclodextrin complex. The amount shown is based on an active substance content of the complex of 11.2%.

f) 1% hydrocortisone ointment.

4.576 g of unguentum simplex was mixed with 424 mg of hydrocortisone-Y-cyclodextrin com-15 plex (active substance content 11.8%).

g) 0.5% hydrocortisone eye ointment.

4.778 g of oculentum simplex 20 (composition: 5% lane alcohol, 25% liquid paraffin and 70% ophthalmic vaseline) was mixed with 10 mg of chloramphenicol and 212 mg of hydrocortisone-cyclodextrin complex. The indicated amount refers to complex with 11.8% hydrocortisone.

h) Aqueous injection with 5 mg dexamethasone.

Composition: Dexamethasone-Y-cyclodextrin complex 47.2 mg of sodium chloride 21 mg of distilled. water for injections ad 3 ml dexamethasone content of the complex: 10.6%. The sodium chloride and the dexamethasone-Y-cyclodextrin complex were dissolved in freshly distilled water suitable for injection. The volume of the solution was made up with distilled water and the solution was filtered and filled into ampoules. The filled ampoules were autoclaved at 120 ° C for 20 min.

35 8204122

Claims (9)

1. Inclusion complex of sparingly soluble steroid compounds formed with γ-cyclodextrin. Inclusion complex according to claim 1, 5, characterized in that it contains as steroid methyl testosterone, spironolactone, pregnene triolone triacetate, hydrocortisone, prednisolone, dexamethasone or triamcinolone. Inclusion complex according to claim 1 or 2, characterized in that the molar ratio of steroid compound to γ-cyclodextrin is between 1: 2 and 1: 3. 4. Inclusion complex of spironolactone and γ-cyclodextrin formed in the molar ratio of 1: 2. 5. Process for the preparation of inclusion complexes of water-insoluble steroid compounds formed with γ-cyclo-dextrin, in which the solution of the water-insoluble steroid prepared with C1-alkanols, ether or acetone is prepared at a temperature between room temperature and the boiling point of the solvent is mixed with the aqueous solution of the γ-cyclodextrin, the mixture is cooled and the precipitated steroid cy-cyclodextrin complex is isolated in a manner known per se. 6. Process according to claim 5, characterized in that the steroid and the γ-cyclodextrin 25 are used in a molar ratio of 1: 1 - 1:10, preferably 1: 2 - 1: 3. 7. Steroid-containing drug preparation, characterized in that it contains as active substance the inclusion complex of a steroid formed with γ-cyclodextrin, mixed with conventional inert carriers and diluents and any other usual auxiliary agents. 8. Process for the preparation of stable steroid injection solutions, characterized in that sparingly soluble steroids in water are dissolved in the 1-10% by weight aqueous solution of γ-cyclodextrin, Process according to claim 8, characterized in that a 3-5 wt.% Steroid is used to dissolve the 8204122 r.r "- 27 - ζϊ - - - V λ. % aqueous solution of Y-cyclodextrin. 5 r 820 4 1 22