United States Patent (19) 11) Patent Number: 4,870,060 Miller (45) Date of Patent: Sep. 26, 1989

(54) DERIVATIVES OFy-CYCLODEXTRIN 4,727,064 2/1988 Pitha ...... 514/965 (75) Inventor: Bernd W. W. Miller, Flintbek, Fed. FOREIGN PATENT DOCUMENTS Rep. of Germany 1548917 10/1968 France. (73) Assignee: Janssen Pharmaceutica, Beerse, 57-200361 6/1981 Japan. Belgium 144376 2/1982 Japan . 138473 12/1985 Japan. (21) Appl. No.: 224,025 122701 11/1986 Japan. 22 Filed: Jul. 25, 1988 OTHER PUBLICATIONS Enhanced Water Solubility of Vitamins A,D,E, and K, Related U.S. Application Data by Substituted Cycloamyloses; Life Sciences, vol. 29, (62) Division of Ser. No. 833,622, Feb. 27, 1986, Pat. No. pp. 307-311 Printed in USA. 4,764,604. The Chemistry of Cyclodextrin Derivatives; I.Int. Symp. on Cyclodextrins Budapest, 1981. (51) Int, C...... as a w w w w a w a as a so C08B 37/16 (52) U.S. Cl...... 514/58; 536/103 Windholz et al, The Merck Index, an encyclopedia of Field of Search ...... 536/103; 514/58 chemicals, drugs, and biologicals, Tenth Edition, Pub (58) lished by Merck & Co., Inc., Rahway, N.J., pp. 560, 56) References Cited 592,753 and 762 (1983). U.S. PATENT DOCUMENTS Primary Examiner-Ronald W. Griffin 3,453,259 7/1969 Parmerter ...... 536/103 Attorney, Agent, or Firm-Robert L. Minier 3,459,731 10/1969 Gramera et al...... 536/103 4,054,736 10/1977 Masaki et al. . ... 536/103 57 ABSTRACT 4,371,673 2/1983 Pitha ...... 424/78 Novel derivatives of y-cyclodextrin, their preparation 4,535,152 8/1985 Szejtli et al...... 536/103 and their use as complexants and solubilizers. Composi 4,542,211 9/1985 Szejtli et al...... 53.6/03 4,596,795 6/1986 Pitha ...... 514/58 tions containing the novel y-cyclodextrin derivatives 4,609,640 9/1986 Renji et al...... 514/12 and method of preparing such compositions. 4,659,696 4/1987 Hirai et al...... 514/5 4,670,419 6/1987 Hirai et al...... 514/6 31 Claims, No Drawings 4,870,060 1. 2 y-CD does not form such inclusion complexes with DERIVATIVES OF y-CYCLODEXTRIN any given compound. Often, such complexation is onlyu established in the lower concentration range. At This is a division of application Ser, No. 833,622, filed higherr concentrations of y-CD, the formed complex is Feb. 27, 1986, now U.S. Pat. No. 4,764,604, issued Aug. 5 precipitated. 16, 1988. It has now been found that an appropriately alkyl ated, hydroxyalkylated, carboxyalkylated or (alkylox BACKGROUND OF THE INVENTION ycarbonyl)alkylated form of y-CD or a mixed ether The present invention is concerned with new ethers thereof prevents the crystallization of such complexes. of y-cyclodextrin, their preparation and their use as O The advantages of y-CD over its lower homologues, complexants for chemicals and pharmaceuticals. i.e. its larger cavity resulting in a superior propensity to ty-cyclodextrin (y-CD) is a cyclic oligosaccharide form inclusion complexes, its favourable toxicological consisting of 8 glucose units which are joined together properties and the fact that it can be cleaved enzymati by a(1-4) linkages. cally by a-amylase (in contrast with 6-CD), can there 15 fore fully be exploited.

y-CD contains three free hydroxy functions per glu cose unit which can completely or partially be deriva tized. In view of this, the average degree of substitution (D.S.) is introduced, which is the average number of 20 substituted hydroxy functions per glucose unit. Said D.S. can vary from its minimal value 0.125 up to its maximal value 3. In the latter case all 24 hydroxy groups are substituted, while in the former case only one is substituted. A minimal D.S. is especially pre 25 ferred when y-CD is used as solubilizer of pharmaceuti ty-CD is prepared by the enzymatic cleavage and religa cals for use in parenteral applications, while a higher tion of starch and a subsequent separation from the thus D.S. is preferred when used in technical applications, obtained cyclodextrin mixture containing i.a. a such as, for example, for pesticides or enzymes. In the cyclodextrin (containing 6 glucose units), g-cyclodex latter instance, the higher D.S. causes that also those trin (3-CD) (7 glucose units) and y-cyclodextrin 30 hydroxy groups are functionalized which are located in (y-CD). the cavity of the y-CD molecule. Consequently, the Cyclodextrins are known in the art to possess the diameter of the cavity is decreased. By selecting the ability to form inclusion complexes and to have con appropriate D.S. the size of the cavity can be adapted in comitant solubilizing properties. An exhaustive review order to obtain the optimum space required for a certain which describes such complexes and their properties 35 molecule to appropriately fit into the cavity of the cy can be found in W. Sanger, Angewandte Chemie, 92, clodextrin. 343-361 (1981). When introducing hydroxyalkyl substitutions on Derivatives of cyclodextrins are also known to pos y-CD, the hydroxy function of the thus obtained hy sess the above-mentioned properties. Said derivatives droxyalkyl ether group can further be hydroxyalk have been reviewed in an article by A. P. Croft and R. ylated, generating multiple substitutions on one particu A. Bartsch in Tetrahedron, 39, 1417–1474 (1983). More lar OH-group. In such cases the term average molar particularly, the German Offenlegungsschrift DE No. substitution (M.S.) is introduced. Said M.S. is defined as 31 18218 discloses the 2,6-dimethyl derivatives of 6-CD, the average number of moles of the substituting agent while in U.S. Pat. No. 3,459,731 there are described per glucose unity. In view of this, it is evident that the hydroxyethyl, hydroxypropyl and hydroxypropyl/hy 45 M.S. can be greater than 3 and has, theoretically, no droxyethyl ethers of (3-CD. Furthermore, in U.S. patent upper limit. application Ser. No. 6-603, 839 there is described the use of specific derivatives of cyclodextrines to improve the DESCRIPTION OF THE PREFERRED systemic administration of sex hormones. Most of the EMBODIMENTS cyclodextrin derivatives presently known in the art are 50 The present invention is concerned with novely-CD derived from 3-CD, while the derivatives of a-CD and derivatives, said novel y-CD derivatives being y-CD particularly of y-CD remain relatively unknown. substituted with C1-C6 alkyl, hydroxy C1-C6 alkyl, The use of derivatives of 6-CD has the following carboxy C1-C6 alkyl or C1-C6 alkyloxycarbonylc1-C6 advantages. (3-CD is only poorly water soluble and alkyl or mixed ethers thereof. therefore it is disadvantageous to use it as a complexant 55 In the foregoing definitions the term “C1-C6-alkyi' is and solubilizer. Derivatives of 3-CD on the other hand, meant to include straight and branched saturated hy due to their increased solubility, are more suitable com drocarbon radicals, having from 1 to 6 carbon atoms, plexants and solubilizers. In contrast herewith, a-CD such as, methyl, ethyl, 1-methylethyl, 1,1-dime and y-CD having an excellent water solubility do not thylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl need such substitutions. Hence, it is obvious to use un and the like. substituted y-CD (and a-CD) as complexant and solubi Preferred compounds are those y-CD derivatives lizer. Particularly for y-CD, a number of such com being y-CD substituted with C1-C3 alkyl, hydroxy plexes with various useful compounds can be found in C2-C4 alkyl, carboxy C1-C2 alkyl or (C1-C2 alkylox e.g. Int. J. Pharm. 10, 1-15 (1982) with steroid hor ycarbonyl)C1-C2 alkyl or mixed ethers thereof. mones, in Acta Pharm. Suec. 20, 11-20 (1983) with 65 Particularly preferred new compounds are the furtripofen, in Chem. Pharm. Bull. 31, 286-291 (1983) methyl, ethyl, isopropyl, hydroxyethyl, hydroxypropyl, with spirolacton and in Acta Pharm. Suec. 20, 287-294 hydroxybutyl, carboxymethyl and carboxyethyl substi (1983) with proscillaridin. tuted y-cyclodextrins and further the (methyl)(hydrox 4,870,060 3 4. yethyl), (methyl)(hydroxpropyl) and (methyl)(hydrox zinedione or 2,3,5,6-tetrahydro-imidazo2, 1-bithiazoles, yethyl)(carboxymethyl) substituted y-cyclodextrins or amides, hydratropic acid derivatives or trialkyla having a D.S or M.S. of from 0.125 to 3, more prefera mines, whereby the derivatives of benzodiazepine, bly of from 0.3 to 2. benzimidazole, piperidine, piperizine, imidazole, tri The compounds of the present invention can gener- 5 azole, pyridazine, 1,2,4-triazinedione or 2,3,5,6-tetrahy ally be prepared by reacting the starting y-CD with an dro-imidazo2, 1-bithiazole, or amides, hydratropic acid appropriate O-alkylating agent or a mixture of such derivatives or trialkylamines are preferred. agents in a concentration being selected so that the Useful benzimidazole derivatives are thiabendazole, desired D.S. is obtained. The said reaction is preferably fuberidazole, ciclobendazole, oxibendazole, parben conducted in a suitable solvent in the presence of an 10 dazole, cambendazole, mebendazole, fenbendazole, flu appropriate base. An appropriate O-alkylating agent is, bendazole, albendazole, oxfendazole, nocodazole and for example, an alkyl, hydroxyalkyl, carboxyalkyl or astemizole. (alkyloxycarbonyl)alkyl halide or sulfonate, e.g. methyl Suitable piperidine derivatives are diphenoxylate, chloride, ethyl bromide, propyl methylsulfonate, ethyl phenoperidine, haloperidol, haloperidol decanoate, chloroacetate, a-chloroacetic acid; or an oxirane, e.g. 15 bromperidol decanoate, bromperidol, moperone, tri oxirane, methyloxirane. Suitable solvents are, for exam fluperidol, pipamperone, piritramide, fentanyl, ben ple, water; an alcohol or polyalcohol, e.g. methanol, ethanol, l-propanol, 2-propanol, 1-butanol, 1,2- peridol, droperidol, benzitramide, benzetimide, dom ethanediol, 1,2-propanediol and the like; a ketone, e.g. peridone, sufentanil, carfentanil, alfentanil, dexetimide, 2-propanone, 2butanone, 4-methyl-2-pentanone, and the 20 milenperone, difenoxin, fluspirilene, penfluridol, pimo like; an ether or polyether, e.g. ethoxyethane, 2-(2- zide, lorcainide, loperamide, astemizole, ketanserine, propyloxy)propane, tetrahydrofuran, 1,2-dimethoxye levocabastine, cisapride, altanserin, ritanserin, 3-2-4- thane and the like; and C1-C4-alkyloxy-C2-C3-alkanol (4-fluorobenzoyl)-1-piperidinyl)ethyl)-2,7-dimethyl-4H and mixtures of such solvents. An appropriate base is, pyrido,2-alpyrimidin-4-one, 3-2-4-bis(4-fluoro for example, an alkali or earth alkaline metal hydroxide, 25 phenyl)methylene-1-piperidinyl)ethyl)-2methyl-4H e.g. sodium hydroxide, potassium hydroxide; or an al pyrido1,2-alpyrimidin-4-one and 3-2-4-3-(2-furanyl kali or earth alkaline metal hydride or amide, e.g. so methyl)-3H-imidazo[4,5-blpyridin-2-yl)amino)-1- dium hydride, calcium hydride, sodium amide and the piperidinyl)ethyl)-2-methyl-4H-pyrido1,2-alpyrimidin like bases. 4-one. Suitable piperazine derivatives include azaper Preferably the said O-alkylation reaction is con- 30 one, fluanisone, lidoflazine, flunarizine, mianserine, ox ducted with 0.1 to 3 parts by weight of water per part atomide, mioflazine, clocinizine and cinnarizine. by weight y-CD in case there is no organic solvent Examples of suitable imidazol derivatives are metro used, and with 1 to 40 parts by weight organic solvent nidazole, ornidazole, ipronidazole, tinidazole, isocona per part by weight y-CD in case no water is used. zole, nimorazole, miconazole, burimamide, metiamide, In a particularly preferred way of preparing the com- 35 metomidate, enilconazole or imazalil, etomidate, econa pounds of the present invention, the reaction mixture zole, clotrimazole, carnidazole, cimetidine, doconazole, containing the starting y-CD, the solvent, base and sulconazole, parconazole, orconazole, butoconazole, O-alkylating agent is heated in an autoclave at a temper triadiminole, tioconazole, valconazole, fluotrinazole, ature comprised between 30' and 200° C. Depending on ketoconazole, oxiconazole, lombazole, bifonazole, ox the reactivity of the O-alkylating agent, the reaction 40 metidine, fenticonazole, tubulazole and (Z)-1-(2-chloro mixture is allowed to react at this temperature for 15 2-(2,4-dichlorophenyl)ethenyl)-1H-imidazole. minutes up to 24 hours. Subsequently, the mixture is As suitable triazole derivatives there may be men acidified and the reaction product is isolated and puri tioned virazole, azaconazole, etaconazole, propicona fied by standard separation and purification procedures zole, penconazole, itraconazole, and terconazole. such as, for example, column chromatography, ultra 45 Useful pyridazine derivatives are, for example, 3 filtration, centrifugation, and dried. chloro-6-3,6-dihydro-4-(3-methylphenyl)-1(2H)- The compounds of the present invention can also be pyridinylpyridazine, 3-methoxy-6-4-(3-methyl converted into each other. For example, the (alkylox phenyl)-1 piperazinylpyridazine and the compounds of ycarbonyl)alkyl substituted y-cyclodextrines may con Publ. Eur. Pat. Appl. No. 0,156,433. veniently converted to the corresponding carboxyalkyl 50 Useful 1,2,4-trizinediones are, for example, 2-chloro substituted y-cyclodextrines following art-known sa ot-(4-chlorophenyl)-4-(4,5dihydro-3,5-dioxo-1,2,4-tria ponification procedures, e.g. by treating the starting zin-2(3H)-yl)benzeneacetonitrile, 2,6-dichloro-O-(4- compounds with an aqueous acidic or basic solution. chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin The compounds of the present invention are useful 2(3H)-yl)benzeneacetonitrile and the compounds of due to their ability to form inclusion complexes having 55 Publ. Eur. Pat. Appl. No. 0,170,316. a stabilizing effect on the complexed compounds, and Useful trialkylamines are, for example, diisopromine, due to their concomitant solubilizing activity. Com prozapine. pounds exhibiting a significantly increased water solu Useful 2,3,5,6-tetrahydro-imidazo[2,1-bithiazoles bility and improved stability after having been trans comprise, for example, tetramisole or levamisole. ferred to inclusion complexes with the above-men- 60 Useful amides are, for example, closantel, ambuceta tioned y-CD derivatives, are those having the required mide, isopropamide, buzepide metiodide, dextromora shape and size, i.e. which fit into the cavity. The size of mide. the cavity can be adapted by selecting the appropriate A useful hydratropic acid derivative is, for example, y-CD derivatives having a suitable D.S. Examples of suprofen. such compounds are, for example, non-steroid anti- 65 Particularly valuable pharmaceutical compositions rheumatic agents, steroids, cardiac glycosides and de are obtained when converting etomidate, ketoconazole, rivatives of benzodiazepine, benzimidazole, piperidine, tubulazole, itraconazole, levocabastine or flunarizine piperazine, imidazole, triazole, pyridazine, 1,2,4-tria into a water-soluble form using the complex forming 4,870,060 5 6 agents of the invention. Such compositions are there fore a special subject of the present invention. EXAMPLE 2 The invention is further directed to a method of pre In an autoclave there were mixed 2.5 parts of 1,2- paring compositions of sparingly water-soluble or wa dimethoxyethane. 1 part of y-CD and a solution of 1 ter-instable compounds which method is characterized part of sodium hydroxide in 1.2 parts of water. To this by dissolving the y-cyclodextrin ether in water and mixture, there were added 2 parts of oxirane and the adding thereo the selected compound as well as option whole was heated to 110° C. for 5 hours. After cooling, ally drying the solution of the formed inclusion com the remaining oxirane was expelled and the reaction pound using methods known per se. Formation of the O mixture was neutralized with hydrochloric acid. The solution may preferably take place at temperatures be volatile components were evaporated and the remain tween 15 and 35 C. der was filtered. The filtrate was subsequently liberated The drug is suitably added batchwise. The water may from sodium chloride over an ion exchanger and subse further comprise physiologically compatible con 15 quently freeze-dried, yielding the hydroxyethyl deriva tive of y-CD with a M.S. of 0.77. pounds such as sodium chloride, potassium nitrate, glu Following the same procedures and using the appro cose, mannitol, sorbitol, xylitol or buffers such as phos priate starting materials there was also prepared the phate, acetate or citrate buffer. 2-hydroxypropyl derivative of y-CD with a M.S. of Using y-cyclodextrin ethers in accordance with the 20 invention it is possible to prepare commonly known 0.66. application forms of drugs for oral, parenteral, topical, EXAMPLE 3 rectal or vaginal application, e.g. infusion and injection 1 Part of y-CD, 3 parts of 1,2-dimethoxyethane and solutions, drop solutions (e.g. eye drops or nasal drops), 25 1.5 parts of sodium hydroxide in 1.5 parts of water were sprays, tablets, powders, capsules, aerosols, sirups, mixed in an autoclave. Subsequently, there were added jellies, ointments, medical baths, rectalia and vaginalia. 4 parts of chloromethane and the whole was heated at The aqueous solutions may further comprise suitable 120° C. for 4 hours. After cooling the reaction mixture physiologically compatible preserving agents such as, was neutralized with hydrochloric acid and the volatile for example, quaternary ammonium soaps, chlor 30 components evaporated. The remainder was filtered butanol, phenoxetol, bromopol, and the like, and also and the filtrate was liberated from sodium chloride over antioxidantia, such as, for example, ascorbic acid. an ion exhanger and subsequently freeze-dried, yielding For the preparation of solid formulations the solu the methyl derivative of y-CD with a D.S. of 1.49. tions of the inclusion compounds are dried using con 35 Following the same procedures and using the appro ventional methods; thus the water may be evaporated in priate starting materials there were also prepared the a rotation evaporator or by lyophilisation. The residue methyl derivative of y-CD with a D.S. of 0.13; the is pulverized and, optionally after addition of further carboxymethyl derivative of y-CD with a D.S. of 0.86; inert ingredients, converted into uncoated or coated and the (ethoxycarbonyl)methyl derivative of y-CD; tablets, suppositories, capsules, creams or ointments. the ethyl derivative of y-CD; the butyl derivative of y-CD; the isobutyl derivative of y-CD; the isopropyl EXAMPLES derivative of y-CD; the carboxyethyl derivative of The following examples are meant to illustrate and y-CD; the 3-hydroxypropyl derivative of y-CD; and not to limit the present invention in all its aspects. Un 45 the 4-hydroxybutyl derivative of y-CD. less stated otherwise, all parts therein are by weight. B. Examples Illustrating the Properties of the y-CD A. Preparation Examples Derivatives EXAMPLE 4 EXAMPLE 1 50 Starting from a 5% stock solution of a particular 1 Part of y-CD and a solution of 1.5 parts of sodium y-CD derivative in a phosphate buffer of pH 7.4, a hydroxide in 1.5 parts of water were mixed in an auto dilution series was obtained with concentrations vary clave. Then there were added 3 parts of methyl chloride ing of from 0% to 5% with 0.5% steps. 3 ml of these and 0.5 parts of methyloxirane. The mixture was heated 55 solutions were pipetted into a closed container contain for 1 hour at 65 C. and subsequently for 2 hours at 100 ing an appropriate amount of progesteron. After 5 days C. After cooling, the remaining methyloxirane was shaking at 25 C., the thus obtained mixture was filtered expelled and the reaction mixture was neutralized with over a membrane filter (pore diameter: 0.22 um), and hydrochloric acid. The volatile components were evap the content of progesteron was determined with high orated and the remainder was filtered. The filtrate was pressure liquid chromatography (using a column of 25 liberated from sodium chloride over an ion exchanger cm length; 5 mm internal diameter; packed with 5 um and subsequently freeze-dried, yielding the (methyl)- ODS-hypersil (RP-18); eluent: acetonitrile/water; U.V. (hydroxypropyl) derivative of y-CD. Following the 65 detection). The results of these concentration measure same procedures and using the appropriate starting ments for a number of the y-CD derivatives of the pres materials the (ethyl)(hydroxyethyl) derivatives of y-CD ent invention and for unsubstituted y-CD gathered in was also prepared. V the following table. 4,870,060 7 TABLE Content of progesteron in solutions containing various concentrations of Y-CD derivative and Y-CD s concentration content of progesteron in ug/n of y-CD methyi methyl carboxy- hydroxy hydroxy derivative unsubsti- substi- substi- methyl ethyl propyl in 26 (weight tuted tuted tuted subst. subst. subst. by volume) y-CD D.S. s. 0.3 D.S. is 4.9 M.S. s. 0.86 M.S. = 0.77 M.S. is 0.66 O 5.9 5.9 5.9 5.9 5.9 5.9 0.5 425 488 379 02 234 302 1 343 972 748 209 452 582 15 275 458 1144. 313 673 872 2 203 1902 1470 417 860 1165 2.5 163 2149 1888 57 1055 431 3 93 2258 2260 610 129 1704 3.5 60 2392 2686 79 1472 1987 4. 54 2592 3050 796 722 2287 4.5 46 2627 341 89 1817 2595 5 45 2602 3876 979 2065 2865

EXAMPLE 5 20 3. A composition according to claim 1 wherein the ether substituents are methyl, ethyl, isopropyl, hydrox Following the procedures described in example 4 the yethyl, hydroxypropyl, hydroxybutyl, carboxymethyl content of 3-chloro-6-3,6-dihydro-4-(3-methylphenyl)- or carboxyethyl. 1(2H)-pyridinylpyridazine was determined in solutions 4. A composition comprising an active ingredient and containing various concentrations of y-CD derivatives. 25 a y-cyclodextrin ether or mixed ether wherein the ether Said pyridazine compound is described in Published substituents are C1-C3 alkyl, hydroxy C2-C4 alkyl or Europ. Pat. Appl. No. 0,156,433 as a useful anti-viral carboxy C1-C2 alkyl and wherein the degree of substitu agent. tion is in the range of 0.125 to less than 2. 5. A composition according to claim 4 wherein the 30 content of 3-chloro-6-3,6-dihydro-4- ether substituent is hydroxyethyl or hydroxypropyl and concentration (3-methylphenyl)-1(2H)-pyridinyl) the average molar substitution is in the range of 0.3 to of y-CD pyridazine in ug/ml less than one. derivative methyi hydroxypropyl 6. A composition according to claim 1, wherein the in % (weight unsubstituted substituted substituted active ingredient is a drug. by volume) y-CD D.S. s 49 M.S. = 0.66 35 7. A composition according to claim 4, wherein the O 0.4 0.4 0.4 active ingredient is a drug. 2.0 2.0 1.5 8. A composition according to claim 5, wherein the 2.5 0.8 8.0 4.5 3.5 w 2.6 7.0 active ingredient is a drug. s 0.8 200 10.0 9. A composition according to claim 6, wherein the 40 drug is a non-steroid anti-rheumatic agent, a steroid, a cardiac glycoside or a derivative of benzodiazepine, C. Composition Examples benzinidazole, piperidine, piperazine, imidazole, tri azole, pyridazine, 1,2,4-triazinedione, 2,3,5,6-tetrahy EXAMPLE 6 dro-imidazo[2,1-bithiazole or hydratropic acid, or an In 100 ml water 7 g hydroxyethyl-y-CD (M.S. = 0.77) 45 amide or trialkylamine derivative. and 0.5g medroxyprogesterone acetate were dissolved. 10. A composition according to claim 7, wherein the The water was evaporated. 75 mg of the residue was drug is a non-steroid anti-rheumatic agent, a steroid, a powdered and mixed with 366 mg CaHPO4.2H2O, 60 cardiac glycoside or a derivative of benzodiazepine, mg corn starch, 120 mg cellulose powder (microcrystal benzimidazole, piperidine, piperazine, imidazole, tri line), 4.2 mg highly dispersed silica (Aerosil (E) 200) and 50 azole, pyridazine, 1,2,4-triazinedione, 2,3,5,6-tetrahy 4.8 mg magnesium stearate and pressed to a tablet. dro-imidazo[2,1-bithiazole or hydratropic acid, or an amide or trialkylamine derivative. EXAMPLE 7 11. A composition according to claim 8, wherein the 5g hydroxyethyl y-cyclodextrin (M.S. = 0.77) and 0.5 drug is a non-steroid anti-rheumatic agent, a steroid, a glidocaine were dissolved in 100 ml of a physiological 55 cardiac glycoside or a derivative of benzodiazepine, sodium chloride solution at 30° C. and filtered through benzimidazole, piperidine, piperazine, imidazole, tri a membrane filter (0.45 microns). The solution was azole, pyridazine, 1,2,4-triazinedione, 2,3,5,6-tetrahy filled into ampules and sterilized. dro-imidazo[2,1-bithiazole or hydratropic acid, or an What is claimed is: amide or trialkylamine derivative. 1. A composition comprising an active ingredient and 60 12. A composition according to claim 6, wherein the a y-cyclodextrin ether or mixed ether wherein the ether drug is a derivative of benzodiazepine, benzimidazole, Substituents are C1-C6 alkyl, hydroxy C1-C6 alkyl, car piperidine, piperazine, imidazole, triazole, pyridazine, boxy C1-C6 alkyl or (C1-C6 alkyloxycarbonyl)C1-C6 1,2,4-triazinedione, 2,3,5,6-tetrahydro-imidazo[2,1- alkyl; provided that neither methyl nor hydroxypropyl bithiazole or hydratropic acid, or an amide or trialkyla is a sole substituent. 65 mine derivative. 2. A composition according to claim 1 wherein the 13. A composition according to claim 7, wherein the ether substituents are C1-C3 alkyl, hydroxy C2-C4 alkyl drug is a derivative of benzodiazepine, benzimidazole, or carboxy C1-C2 alkyl. piperidine, piperazine, imidazole, triazole, pyridazine, 4,870,060 9 10 1,2,4-triazinedione, 2,3,5,6-tetrahydro-imidazo[2,1- 22. A composition according to claim 4, wherein the bithiazole or hydratropic acid, or an amide or trialkyla drug is selected from the group consisting of etomidate, mine derivative. ketoconazole, itraconazole and flunarizine. 14. A composition according to claim 8, wherein the 23. A method of preparing a composition according drug is a derivative of benzodiazepine, benzimidazole, 5 to claim 1, characterized in that the y-cyclodextrin piperidine, piperazine, imidazole, triazole, pyridazine, ether is dissolved in water and that the active ingredient 1,2,4-triazinedione, 2,3,5,6-tetrahydro-imidazo[2,1- is added whereafter the thus obtained solution is option bithiazole or hydratropic acid, or an amide or trialkyla ally dried. mine derivative. 24. A method of preparing a composition according 15. A composition according to claim 6, wherein the 10 to claim 2 characterized in that the y-cyclodextrin ether drug is selected from the group consisting of etomidate, is dissolved in water and that the active ingredient is ketoconazole, itraconazole and flunarizine. added whereafter the thus obtained solution is option 16. A composition according to claim 7, wherein the ally dried. drug is selected from the group consisting of etomidate, 25. A method of preparing a composition according ketoconazole, itraconazole and flunarizine. 15 to claim 4 characterized in that the y-cyclodextrin ether 17. A composition according to claim 8, wherein the is dissolved in water and that the active ingredient is drug is selected from the group consisting of etomidate, added whereafter the thus obtained solution is option ketoconazole, itraconazole and flunarizine. ally dried. 18. A composition according to claim 4, wherein the 26. A method according to claim 23, wherein the active ingredient is a drug. 20 residue after removal of the solvent is pulverized and, 19. A composition according to claim 18, wherein the optionally after addition of further ingredients, con drug is a non-steroid anti-rheumatic agent, a steroid, a verted into a solid form for administration. cardiac glycoside or a derivative of benzodiazepine, 27. A method according to claim 26, wherein further benzimidazole, piperidine, piperazine, imidazole, tri physiologically acceptable substances are added to the azole, pyridazine, 1,2,4-triazinedione, 2,3,5,6-tetrahy 25 Water. dro-imidazo2, 1-bithiazole or hydratropic acid, or an 28. A method according to claim 27, wherein sodium amide or trialkylamine derivative. chloride, glucose, mannitol, sorbitol, xylitol or a phos 20. A composition according to claim 18, wherein the phate or citrate buffer are added to the water. drug is a derivative of benzodiazepine, benzimidazole, 29. A method according to claim 24, wherein the piperidine, piperazine, imidazole, triazole, pyridazine, 30 residue after removal of the solvent is pulverized and, 1,2,4-triazinedione, 2,3,5,6-tetrahydro-imidazo2, 1 optionally after addition of further ingredients, con bithiazole or hydratropic acid, or an amide or trialkyla verted into a solid form for administration. mine derivative. 30. A method according to claim 29, wherein further 21. A composition according to claim 4, wherein the physiologically acceptable substances are added to the drug is a derivative of benzodiazepine, benzimidazole, 35 Water. piperidine, piperazine, imidazole, triazole, pyridazine, 31. A method according to claim 30, wherein sodium 1,2,4-triazinedione, 2,3,5,6-tetrahydra-imidazo[2,1- chloride, glucose, mannitol, sorbitol, xylitol or a phos bithiazole or hydratropc acid, or an amide or trialkyla phate or citrate buffer are added to the water. mine derivative. s x k

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