USOO6407079B1 (12) United States Patent (10) Patent No.: US 6,407,079 B1 Miller et al. (45) Date of Patent: Jun. 18, 2002
(54) PHARMACEUTICAL COMPOSITIONS (52) U.S. Cl...... 514/58 CONTAINING DRUGS WHICHARE (58) Field of Search ...... 514/58; 536/46, INSTABLE OR SPARINGLY SOLUBLE IN 536/103 WATER AND METHODS FOR THEIR PREPARATION (56) References Cited (75) Inventors: Bernd W. Miller, Flintbek; Ulrich U.S. PATENT DOCUMENTS Brauns, Kiel, both of (DE) 3,459,731. A 8/1969 Gramera et al...... 260/209 4,371,673 A 2/1983 Pika ...... 525/426 (73) Assignee: Janssen Pharmaceutica N.V., Beerse 4,383,992 A * 5/1983 Lipari ...... 424/238 (BE) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this FR 2484252 * 12/1981 patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. * cited by examiner Primary Examiner Elli Peselev (21) Appl. No.: 07/264,726 (57) ABSTRACT (22) Filed: Oct. 31, 1988 Pharmaceutical compositions comprising inclusion com Related U.S. Application Data pounds of Sparingly water-Soluble or water-instable drugs with B-cyclodextrin ethers or B-cyclodextrin esters and (63) Continuation of application No. 06/756,498, filed on Jul. 3, process for the preparation thereof. 1985, now abandoned. (51) Int. Cl...... A61K 31/70 35 Claims, 2 Drawing Sheets U.S. Patent Jun. 18, 2002 Sheet 1 of 2 US 6,407,079 B1 MG/ML FIG. 1 45 4 3,5 3 2.5 2 15 1 0,5
O 1 2 3 4 5 6 7 8 9 10 %CD
MG/ML FIG. 2 45 4 3,5 3 2,5 2 15 1 0,5 O O 1 2 3 4 5 6 7 8 9 10 %CD U.S. Patent Jun. 18, 2002 Sheet 2 of 2 US 6,407,079 B1 MG/ML FIG. 3 1,75 15
1,25
0.75
0.5 0.25
O 1 2 3 4 5 6 7 8 9 1 O %CD
MG/ML FIG. 4
O 1 2 3 4 5 6 7 8 9 10 %CD US 6,407,079 B1 1 2 PHARMACEUTICAL COMPOSITIONS erable toxicity of the unsubstituted f-cyclodextrin. It is a CONTAINING DRUGS WHICHARE further Serious disadvantage for the practical application that INSTABLE OR SPARINGLY SOLUBLE IN the solubility of the dimethyl 3-cyclodextrin and its com WATER AND METHODS FOR THEIR plexes Suffers a Steep decrease at higher temperatures So that PREPARATION crystalline dextrin precipitates upon heating. This phenom enon makes it very difficult to sterilize the solutions at the This is a continuation of application Ser. No. 06/756,498, usual temperatures of 100 to 121 C. filed Jul. 3, 1985, now abandoned. Quite Surprisingly it has now been found that certain The invention relates to pharmaceutical compositions other B-cyclodextrin derivatives can form inclusion com containing drugs which are instable or only sparingly pounds which also considerably increase the water Soluble in water, and methods for their preparation. The Solubility of Sparing water-Soluble and instable drugs with compositions are characterized by increased water Solubility out showing the advantages described above. and improved stability. Subject of the invention are therefore novel pharmaceu A large number of drugs is only poorly or sparingly tical compositions comprising inclusion compounds of only Soluble in water So that Suitable application forms like drop 15 sparingly water-Soluble and in water instable drugs with a Solutions or injection Solutions are being prepared using partially etherified B-cyclodextrin of the formula other polar additives like propylene glycol etc. If the drug molecule has basic or acidic groups there exists the further (B-CD-9R (I), possibility of increasing the water Solubility by Salt forma in which the residues R are hydroxyalkyl groups and part of tion. As a rule this results in decreased efficacy or impaired the residues R may optionally be alkyl groups, the chemical stability. Due to the shifted distribution equilib B-cyclodextrin ether having a water-Solubility of more than rium the drug may penetrate the lipophilic membrane only 1.8 g. in 100 ml water. Slowly corresponding to the concentration of the non A partially etherified B-cyclodextrin of formula I is pref dissociated fraction while the ionic fraction may be Subject erably used in which the residues R are hydroxyethyl, to a rapid hydrolytic decomposition. 25 hydroxypropyl or dihydroxypropyl groupS. Optionally part Additional “water-like” solvents like low molecular of the residues R may for instance be methyl or ethyl groups, polyethylene glycols or 1,2-propylene glycol are therefore the use of partially methylated B-cyclodextrin ethers with 7 used in the preparation of aqueous Solutions of Sparingly to 14 methyl groups in the B-cyclodextrin molecule, as they water-Soluble drugs which glycols, however, cannot be are known from German Offenlegungsschrift 31 18 218 do considered pharmacologically inert, or the drug is Solubi not come under the present invention. Partial ethers of lized using Surfactants So that the drug molecules are f-cyclodextrin comprising only alkyl groups (methyl, ethyl) occluded in micells. This Solubilization has numerous dis may be suitable in accordance with the invention if they advantages: The Surfactant molecules used have frequently have a low degree of Substitution (as defined below) of 0.05 a strongly haemolytic effect and the drug needs to pass out to 0.2. of the micell by diffusion after the application. This results 35 B-cyclodextrin is a compound with ring Structure consist in a retard effect (compare B. W. Miller, Gelbe Reihe, Vol. ing of 7 anhydro glucose units, it is also referred to as X, pages 132ff (1983)). cycloheptaamylose. Each of the 7 glucose rings contains in Accordingly it may be Stated that there exists no Satis 2-, 3-, and 6-position three hydroxy groups which may be factory and generally applicable method of Solubilization. etherified. In the partially etherified f-cyclodextrin deriva For Solid drugs it is also important to render the Sparingly 40 tives used according to the invention only part of these water-Soluble drug water-Soluble Since a good Solubility hydroxy groups is etherified with hydroxyalkyl groups and increases the bioavailability of the drug. It has been optionally further with alkyl groups. When etherifying with described that inclusion compounds, e.g. with urea or com hydroxy alkyl groups which can be carried out by reaction plexes of polyvinyl pyrrollidone may improve the Solubility with the corresponding alkylene oxides, the degree of Sub of a compound but in aqueous Solution they are not stable. 45 stitution is stated as molar substitution (MS), viz. in mole Such inclusion compounds are therefore at best Suitable for alkylene oxide per anhydroglucose unit, compare U.S. Pat. Solid application forms of drugs. No. 3,459,731, column 4. In the hydroxyalkyl ethers of This is different when using Cl-, 3-, and Y-cyclodextrin B-cyclodextrin used in accordance with the invention the which can bind a drug in its ring also in aqueous Solution (W. molar substitution is between 0.05 and 10, preferably Sanger, Angewandte Chemie 92,343 (1980)). However, it is 50 between 0.2 and 2. Particularly preferred is a molar substi disadvantageous that the B-cyclodextrin itself is only poorly tution of about 0.25 to about 1. water-soluble (1.8 g/100 ml) so that the therapeutically The etherification with alkyl groups may be Stated directly necessary drug concentrations are not achieved. as degree of Substitution (DS) per glucose unit which—as If a derivative is formed of the cyclodextrin its solubility stated above-is 3 for complete substitution. Partially and therefore the amount of dissolved drug may be consid 55 etherified B-cyclodextrins are used within the invention erably increased. Thus, German Offenlegungsschrift 31 18 which comprise besides hydroxyalkyl groups also alkyl 218 discloses a Solubilization method using methylated groups, especially methyl or ethyl groups, up to a degree of B-cyclodextrin as monomethyl derivative with 7 methyl substitution of 0.05 to 2.0, preferably 0.2 to 1.5. Most groupS and especially as dimethyl derivative with 14 methyl preferably the degree of Substitution with alkyl groups is groups. With the 2,6-di-O-methyl derivative it is for instance 60 between about 0.5 and about 1.2. possible to increase the water Solubility of indometacin The molar ratio of drug to B-cyclodextrin ether is pref 20.4-fold and that of digitoxin 81.6-fold. erably about 1:6 to 4:1, especially about 1:2 to 1:1. As a rule However, for therapeutical use the methyl derivatives of it is preferred to use the complex forming agent in a molar B-cyclodextrin show serious draw backs. Due to their CXCCSS. increased lipophility they have a haemolytic effect and they 65 Useful complex forming agents are especially the further cause irritations of the mucosa and eyes. Their acute hydroxyethyl, hydroxypropyl and dihydroxypropyl ether, intravenous toxicity is still higher than the already consid their corresponding mixed ethers, and further mixed ethers US 6,407,079 B1 3 4 with methyl or ethyl groups, Such as methyl-hydroxyethyl, The aqueous Solutions may further comprise Suitable methyl-hydroxypropyl, ethyl-hydroxyethyl and ethyl physiologically compatible preserving agents Such as quar hydroxypropyl ether of B-cyclodextrin. ternary ammonium Soaps or chlorbutanol. The preparation of the hydroxyalkyl ethers of For the preparation of solid formulations the solutions of B-cyclodextrin may be carried out using the method of U.S. the inclusion compounds are dried using conventional meth Pat. No. 3,459,731. Suitable preparation methods for ods; thus the water may be evaporated in a rotation evapo B-cyclodextrin ethers may further be found in J. Sziejtli et rator or by lyophilisation. The residue is pulverized and, al., Starke 32, 165 (1980) und A. P. Croft and R. A. Bartsch, optionally after addition of further inert ingredients, con Tetrahedron 39, 1417 (1983). Mixed ethers of verted into uncoated or coated tablets, Suppositories, B-cyclodextrin can be prepared by reacting B-cyclodextrin in capsules, creams or ointments. a basic liquid reaction medium comprising an akali metal The following examples serve to illustrate the invention hydroxide, water and optionally at least one organic Solvent (e.g. dimethoxyethane or isopropanol) with at least two which, however, is not restricted to the examples. different hydroxyalkylating and optionally alkylating etheri The phosphate buffer Solution mentioned in the examples fying agents (e.g. ethylene oxide, propylene oxide, methyl or had a pH of 6.6 and the following composition: ethyl chloride). 15 Drugs exhibiting a significantly increased water-Solubility and improved Stability, respectively, after having been trans KHPO 68.05 g ferred into inclusion compounds with the above-mentioned NaOH 7.12 g B-cyclodextrin ethers are those having the required shape Aqua demin. ad. 5000.0 g and size, i.e. which fit into the cavity of the B-cyclodextrin ring System. This includes for instance non-Steroid anti All percentages are percent by weight. rheumatic agents, Steroids, cardiac glycosides and deriva tives of benzodiazepine, benzimidazole, piperidine, EXAMPLE 1. piperazine, imidazole or triazole. Starting from a 7% master solution of hydroxyethyl Useful benzimidazole derivatives are thiabendazole, 25 f3-cyclodextrin (MS 0.43) in phosphate buffer solution a fuberidazole, OXibendazole, parbendazole, cambendazole, dilution Series was prepared So that the complex forming mebendazole, fenbendazole, flubendazole, albendazole, agent concentration was increased in Steps of 1%. 3 ml of Oxfendazole, nocodazole and astemisole. Suitable pipera these Solutions were pipetted into 5 ml Snap-top-glasses dine derivatives are fluspirilene, pimozide, penfluridole, containing the drug to be tested. After Shaking for 24 hours loperamide, astemizole, ketanserine, levocabastine, at 25 C. the solution was filtered through a membrane filter cisapride, altanserine, and ritanserine. Suitable piperazine (0.22 microns) and the dissolved drug content was deter derivatives include lidoflazine, flunarizine, mianserine, mined spectrophotometrically. FIGS. 1, 3 and 4 show the oxatomide, mioflazine and cinnarizine. Examples of Suitable increase of the drug concentration in Solution in relation to imidazole derivatives are metronidazole, ornidazole, the concentration of the complex forming agent for ipronidazole, tinidazole, isoconazole, nimorazole, 35 indometacin (FIG. 1), piroxicam (FIG. 3) and diazepam burimamide, metiamide, metomidate, enilconazole, (FIG. 4). The maximum drug concentration is limited by the etomidate, econazole, clotrimazole, carnidazole, cimetidine, saturation solubility of the cyclodextrin derivative in the docodazole, Sulconazole, parconazole, orconazole, buffer which in case of hydroxyethyl-f-cyclodextrin (MS butoconazole, triadiminole, tioconazole, Valconazole, 0.43) is reached at 7.2 g/100 ml. fluotrimazole, ketoconazole, oxiconazole, lombazole, 40 When comparing for instance the results obtained with bifonazole, OXmetidine, fenticonazole and tubulazole. AS indometacinto those given in German OffenlegungSSchrift suitable triazole derivatives there may be mentioned 31 18 218 for 2,6-di-O-methyl-f-cyclodextrin (FIG. 2) it Virazole, itraconazole and terconazole. will be observed that the hydroxyethyl derivative has a Particularly valuable pharmaceutical compositions are Significantly higher complex formation constant (compare obtained when converting etomidate, ketoconazole, 45 the different slopes in FIGS. 1 and 2). tubulazole, itraconazole, levocabastine or flunarizine into a water-Soluble form using the complex forming agents of the EXAMPLE 2 invention. Such compositions are therefore a special Subject A. The Saturation solubility at 25 C. of different drugs of the present invention. was determined using a 10% hydroxypropyl-B- The invention is further directed to a method of preparing 50 cyclodextrin solution (MS 0.35) in phosphate buffer pharmaceutical compositions of sparingly water-Soluble or Solution under the same conditions as in example 1. water-instable drugs which is characterized by dissolving The saturation solubilities S in phosphate buffer solu the B-cyclodextrin ether in water and adding thereto the tion and S in phosphate buffer solution and 10% added Selected drug as well as optionally drying the Solution of the hydroxypropyl-3-cyclodextrin are given in table 1. formed inclusion compound using methods known per Se. 55 Formation of the Solution may take place at temperatures TABLE 1. between 15 and 35° C. The drug is suitably added batchwise. The water may Drugs S (mg/ml) S2 (mg/ml) Ratio S:S further comprise physiologically compatible compounds Indometacine O.19 5.72 1:30.1 Such as Sodium chloride, potassium nitrate, glucose, 60 Digitoxine O.OO2 1685 1842.5 mannitole, Sorbitol, Xylitol or bufferS Such as phosphate, Progesterone O.OO71 7.69 1:1083.0 acetate or citrate buffer. Dexamethasone O.083 14.28 1:172.O Using B-cyclodextrin ethers in accordance with the inven Hydrocortisone O.36 21.58 1:59.9 tion it is possible to prepare application forms of drugs for Diazepame O.O32 O.94 1:29.4 oral, parenteral or topical application, e.g. infusion and 65 injection Solutions, drop Solutions (e.g. eye drops or nasal B. The solubility of drugs in a 4% aqueous solution of drops), sprays, aerosols, Sirups, and medical baths. hydroxypropyl-methyl-3-cyclodextrin (DS 0.96; MS US 6,407,079 B1 S 6 0.43) was determined in a similar manner. The results rator The residue (75 mg) was powdered and after addition obtained are Summarized in the following table 2 in of 366 mg calcium hydrogen phosphate.2H2O, 60 mg corn which the ratio R of the Saturation solubility in water or Starch, 120 mg cellulose powder (microcrystalline), 4.2 mg at the Stated pH, respectively, with an without addition highly dispersed silica (AEROSIL(R) 200) and 4.8 mg mag of B-cyclodextrin derivative is stated for each drug. The nesium stearate tablets with a weight of 630.0 mg and Solutions prepared according to the invention were comprising 5 mg drug per unit dose were made. The further found to be significantly more stable when dissolution rate of the medroxyprogesterone acetate from this formulation is 21 times higher when compared to a compared with aqueous Solutions. tablet comprising the Same inertingredients without addition TABLE 2 of the B-cyclodextrin ether. Drug R EXAMPLE 6 Itraconazole at pH 5 96 5 g hydroxyethyl-B-cyclodextrin (MS 0.43) and 14 mg at pH 2.5 75 vitamin A-acetate were dissolved with stirring in 100 ml Flunarizine 18 15 water or Sugar Solution (5% aqueous Solution) within 2.5 Levocabastine at pH 9.5 81 hours under a nitrogen atmosphere. After filtration through at pH 7.4 8 Ketoconazole 85 a membrane filter (0.45 microns) the solution was filled into Flubendazole 3O ampules and sterilized or filled into dropper bottles with Tubulazole 43 addition of 0.4% chlor butanol as preserving agent. Cisapride 3 Loperamide 62 EXAMPLE 7 Etomidate 8.5 Cinnarizine at pH 5 28 5 or 7.5g hydroxyethyl B-cyclodextrin (MS 0.43) and 0.5 at pH 3 12 or 0.75 g Lidocaine were dissolved in 100 ml of physiologi cal sodium chloride solution at 30° C. (B). Injection Solutions, eye droplets and Solutions for topical use were 25 prepared therefrom as described in example 6. When com EXAMPLE 3 paring the anaethesic effect of these Solutions in animal tests In 10 ml phosphate buffer solution 0.7 g hydroxyethyl with an aqueous lidocain HCl Solution (A) one observes an f3-cyclodextrin (MS 0.43) were dissolved together with 0.04 extension of the duration of the effect by 300%. Test: rats, g indometacin at 25 C. until a clear Solution was formed. injection of 0.1 ml into the tail root in the vicinity of the right This solution was filtered through a membrane filter (0.22 or left nerve filliaments and electrical irritation. The test microns) and filled under laminar flow into a pre-sterilized results are Summarized in table 4. injection bottle which was stored at 21 C. (B). In a parallel test a saturated indometacin solution in a phosphate buffer TABLE 4 Solution (0.21 mg/ml) was Stored under the same conditions (A). The drug concentrations determined by high pressure 35 Drug concentration Duration of effect (min Extension liquid chromatography are given in table 3. The great improved Stability of the composition according to the (%) A. B (%) invention is apparent. 0.5 56 163 291 0.75 118 390 330 TABLE 3 40
Indometacin EXAMPLE 8 Storing time content (% 6 mg dexamethasone and 100 mg hydroxyethyl-3- in weeks A. B 45 cyclodextrin (MS 0.43) were dissolved in 5 ml water, O 100.1 99.7 sterilized by filtration through a membrane filter (0.22 2 91.2 99.9 microns) and packed into an aerosol container allowing to 4 79.1 98.1 dispense 0.1 ml per dose. 6 69.8 98.6 8 64.8 98.4 EXAMPLE 9 50 The acute intravenous toxicity of Some B-cyclodextrins was tested on rats with the following results. It was Surpris EXAMPLE 4 ingly found that the toxicity of the derivatives used accord Injectable Formulation ing to the invention is lower by an entire order of magnitude. 55 0.35 g hydroxypropyl-B-cyclodextrin (MS 0.35) were TABLE 5 dissolved in 5 ml of physiological sodium chloride solution and warmed to about 35 C. whereafter 3 mg diazepam were LDso in rats (i.v.) in mg/kg bodyweight added. After Storing for a short time a clear Solution was f-cyclodextrin 453 obtained which was filled into an ampule after filtration dimethyl-f-cyclodextrin 2OO-2O7 through a membrane filter (0.45 microns). 60 (DS 2.0) hydroxypropyl-methyl- >2OOO* EXAMPLE 5 f-cyclodextrin (DS 0.96; MS 0.43) Tablet *a higher dose has not been tested. In mice the value was >4000 mg/kg. In 100 ml water 7 g hydroxyethyl-B-cyclodextrin (MS 65 0.43) and 0.5 g medroxyprogesterone acetate were dis The haemolytic effect of the methylether according to Solved. The water was then evaporated in a rotation evapo German Offenlegungsschrift 31 18 218 was compared to US 6,407,079 B1 7 8 that of an ether used according to the invention. To this end 9. Composition according to claim 1, wherein Said drug is 100 ul of a physiological sodium chloride solution with a levocabastine. cyclodextrin content of 10%, 800 ul of a buffer (400 mg 10. Composition according to claim 1, wherein Said drug MOPS, 36 mg NaHPO.2H2O, 1.6 g NaCl in 200 ml HO) is flunarizine. and 100 ul of a suspension of human red blood cells (three 11. Composition according to claim 1, wherein Said drug times washed with sodium chloride solution) were mixed for is tubulazole. 30 minutes at 37 C. Thereafter the mixture was centrifuged 12. Pharmaceutical composition comprising an inclusion and the optical density was determined at 540 nm. compound of (i) a drug which is instable or only sparingly Controls: soluble in water and which is capable of fitting into the a) 100 ul sodium chloride solution+buffer+0% haemoly cavity of the B-cyclodextrin ring System and Sis (ii) a B-cyclodextrin derivative of the formula: b) 900 ul water->100% haemolysis The results obtained are summarized in the following (B-CD)-OR table 6 in which the concentrations are stated at which 50% 15 wherein f3-CD represents f-cyclodextrin and the residue(s) and 100% haemolysis occurred. R is Selected from hydroxyethyl, hydroxypropyl, dihydroxypropyl, methyl, and ethyl or mixtures thereof; TABLE 6 provided that; Substance Cso% Coo% (a) the molar substitution by hydroxyethyl, hydroxypropyl, and dihydroxypropyl is from 0.05 to Dimethyl-f-CD O.33% O.5% (DS 2.0) 10, and Methyl-p-CD O.53 O.8% (b) the degree of Substitution by methyl and ethyl is from (DS 1.79) O to 2.0 and Hydroxypropyl methyl-f-CD 1.5% 4% (c) the molar ratio of Said drug to said f-cyclodextrin (DS 0.96; MS 0.43%) 25 derivative is from 1:6 to 4:1, and (d) the water solubility of said B-cyclodextrin derivative The results show that the haemolytic effect of the hydrox is greater than 1.8 g. in 100 ml of water. ypropylmethyl ether is about 5 to 8 times weaker than that 13. The composition of claim 12 wherein said molar of the dimethyl ether according to the prior art. Animal tests Substitution is from 0.2 to 2. have further shown that the hydroxyalkyl ethers do not cause 14. The composition of claim 12 wherein said molar irritation of the mucosa and eyes in contrast to the methyl Substitution is from about 0.25 to about 1. ethers. 15. The composition of claim 12 wherein said molar ratio We claim: is from 0.2 to 2. 1. Pharmaceutical composition comprising an inclusion 35 16. The composition of claim 12 wherein said molar ratio compound of (i) a drug capable of fitting into the cavity of is from about 0.5 to about 1.2. the cyclodextrin ring System which is instable or only 17. The composition of claim 12 wherein said drug is sparingly soluble in water with (ii) a partially etherified Selected from etomidate, ketoconazole, tubulazole, B-cyclodextrin of the formula: itraconazole, levacabastine, and flunarizine. 18. A method of producing a Stabilizing amorphous com (B-CD)-OR (I) 40 plex of a drug and mixture of beta-cyclodextrin derivatives wherein the residues R are hydroxyalkyl groups and part of comprising the Steps of: Said residues R may optionally be alkyl groups, the Bcyclo (1) dissolving the intrinsically amorphous mixture of dextrin ether having a water Solubility of greater than 1.8 g. beta-cyclodextrin derivatives which are water soluble in 100 ml water, wherein said composition has considerably 45 and capable of forming inclusion complexes with drugs increased water Solubility and Stability relative to Said drugs, in water, and with very low toxicity. (2) Solubilizing sparingly water-soluble drugs into the 2. Composition according to claim 1 wherein Said resi aqueous media to form a Solution and form a Solubi dues R are hydroxyethyl, hydroxypropyl, dihydroxypropyl, lized drug/cyclodextrin complex. methyl or ethyl groups. 50 19. A method of claim 18 wherein the cyclodextrins used 3. Composition according to claim 2, wherein Said par are substituted by the following substituents: hydroxyalkyl. tially etherified f-cyclodextrin of formula I has a molar 20. A method of claim 18 wherein the drug is progester substitution by hydroxyalkyl groups of 0.05 to 10 and a OC. degree of Substitution by alkyl groups of 0 to 2.0. 21. A composition of matter which contains a water 4. Composition according to claim 1, wherein Said drug 55 Soluble amorphous complex of beta-cyclodextrin derivatives and Said B-cyclodextrin ether are in a molar ratio of 1:6 to and a drug. 4:1. 22. A composition of claim 21 wherein the drug is 5. Composition according to claim 1, wherein Said drug is progesterOne. a non-Steroid anti-rheumatic agent, a Steroid, a cardiac 23. A composition of matter for use in the process of claim glycoside or derivatives of benzodiazepine, benzimidazole, 60 18 containing a mixture of substituted beta-cyclodextrin piperidine, piperazine, imidazole or triazole. ethers in amorphous form. 6. Composition according to claim 1, wherein Said drug is 24. A composition of matter in Solid form comprising etomidate. progesterone as an inclusion complex with hydroxypropyl 7. Composition according to claim 1, wherein Said drug is beta-cyclodextrin adapted for administration by the oral ketoconazole. 65 rOute. 8. Composition according to claim 1, wherein Said drug is 25. The composition of claim 12 wherein the residue R is itraconazole. selected from hydroxyethyl with a molar substitution of US 6,407,079 B1 9 10 from 0.2 to 2, and methyl and ethyl with a degree of 31. Pharmaceutical composition comprising an inclusion Substitution of 0 to 2.0. compound of (i) a drug capable of fitting into the cavity of 26. The composition of claim 12 wherein the residue R is the B-cyclodextrin ring System which is instable or only selected from hydroxypropyl with a molar substitution of sparingly Soluble in water and (ii) a partially etherified from 0.2 to 2, and methyl and ethyl with a degree of B-cyclodextrin derivative of the formula: Substitution of 0 to 2.0. 27. Pharmaceutical composition comprising an inclusion (B-CD)-OR compound of (i) a drug capable of fitting into the cavity of wherein B-CD represents B-cyclodextrin and the residues R the B-cyclodextrin ring System which is instable or only are in part hydroxyalkyl groupS and in part alkyl groups, Said sparingly Soluble in water and (ii) a partially etherified alkyl groups being present up to a degree of Substitution B-cyclodextrin derivative of the formula: between about 0.05 to 2. 32. Composition according to claim 31 wherein the alkyl (B-CD)-OR groups hydroxyalkyl groups are Selected from hydroxyethyl, hydroxypropyl and dihydroxypropyl having a molar Substi wherein B-CD represents B-cyclodextrin and the residue R is 15 tution of about 0.2 to 2, and the alkyl groups are methyl or a hydroxyalkyl group and the B-cyclodextrin has a molar ethyl being present up to a degree of Substitution between substitution by hydroxyalkyl of about 0.25 to about 1. about 0.5 and 1.2. 28. Composition according to claim 27 wherein the 33. Composition according to claim 32 wherein the hydroxyalkyl group is Selected from hydroxyethyl, hydrox hydroxyalkyl group is hydroxyethyl having a molar Substi ypropyl and dihydroxypropyl. tution of about 0.25 to about 1. 29. Composition according to claim 27 wherein the 34. Composition according to claim 32 wherein the hydroxyalkyl group is hydroxyethyl and the molar ratio of hydroxyalkyl group is hydroxpropyl having a molar Substi Said drug to Said 3-cyclodextrin derivative is from about 1:6 tution of about 0.25 to about 1. to 4:1. 35. Composition according to claim 32 wherein the ratio 30. Composition according to claim 27 wherein the 25 of Said drug to Said B-cyclodextrin derivative is from about hydroxypropyl group is hydroxyethyl and the molar ratio of 1:6 to 4:1. Said drug to Said 3-cyclodextrin derivative is from about 1:6 to 4:1.