FI86507B - Method for the production of therapeutic compositions containing &gamma-cyclodextrin derivatives - Google Patents

Abstract

The invention relates to the production of pharmaceutical compositions which contain a therapeutically active compound and, as a vehicle, γ -cyclodextrin derivatives. In the compositions, the said γ- cyclodextrin derivatives act as complex-forming and solubility-improving agents. These new derivatives consist of γ-cyclodextrin ethers and mixed ethers in which the ether substituents are C1-6-alkyl, hydroxy-C1-6- alkyl, carboxy-C1-6-alkyl or (C1-6-alkyloxycarbonyl)-C1- 6-alkyl.

Description

1 86507

A process for the preparation of therapeutic compositions containing γ-cyclodextrin derivatives

Divided by application 861 064 5

The present invention relates to the preparation of therapeutic compositions containing novel γ-cyclodextrin ethers.

γ-cyclodextrin (γ-CD) is a cyclic oligosaccharide comprising 8 glucose units linked together by β (1-4) bonds.

CHaOH

hJt \ h 15 JSOHH / [SKIN J, - - - ____ γ-CD is prepared by enzymatic digestion and re-binding of starch-20 lys, followed by separation of the resulting cyclodextrin mixture containing e.g. α-cyclodextrin (containing 6 glucose units), β-cyclodextrin (β-CD) (7 glucose units) and γ-cyclodextrin (γ-CD).

. 25 Cyclodextrins are known in the art to be able to form inclusion complexes and to have related solubilizing properties. A thorough review describing such complexes and their properties can be found in the journal article W. Sänger, 30 Angewandt Chemie, 92, 343-361 (1981).

::: Derivatives of cyclodextrins are also known to have the above properties. The above-mentioned. : women are A.P. Croft and R.A. Bartsch described the era. ··. in the journal article Tetrahedron, 39, 1417-1474 (1983). German Offenlegungsschrift DE 3 118 218 describes in particular 2,6-dimethyl derivatives of • · • · 1 • 4 * 2 86507 / '- CD, while U.S. Pat. No. 3,459,731 describes hydroxyethyl, hydroxypropyl and hydroxypropyl / hydroxyethyl ethers. In addition, U.S. Patent 4,596,795 describes the use of certain derivatives of cycl-5 lodextrins to enhance the systemic delivery of sex hormones. Most of the cyclodextrin derivatives currently known in the art are derived from / 'CD, while the derivatives of ot-CD, and in particular γ-CD, are relatively unknown.

| The use of J-CD derivatives has the following advantages. p-CD is only poorly soluble in water and is therefore disadvantageous of being used as a complexing and solubility enhancing agent. Derivatives of β-CD, on the other hand, are more suitable complexing and solubility enhancers due to their improved solubility. In contrast, Qt-CD and ΊΓ-CD, which are excellently soluble in water, do not require such substitutions.

Therefore, it is natural to use an unsubstituted Y-CD compound (and a tf-CD compound) as a complexing agent and a solubility enhancer. In the case of γ-CD in particular, a number of complexes formed with various useful compounds can be found, for example, in the following publications: 25 Int. J. Pharm. 10, 1-15 (1982), with steroid hormones,

Acta Pharm. Seuc. 20, 11-20 (1983), with flurtripofen, Chem. Pharm. Bull. 31, 286-291 (1983), spirolactone. . with, and Acta Pharm. Suec. 20, 287-294 (1983), with proskil- * / laridine.

30 γ-CD does not form such inclusion complexes with any of said compounds. Such complexation often occurs only in the low concentration range.

Complex formed at higher concentrations of Y-CD · precipitates.

3 86507

It has now been found that a suitably alkylated, hydroxyalkylated, carboxyalkylated or (alkyloxycarbonyl) alkylated form of γ-CDr or a mixed ether thereof prevents the crystallization of such complexes. advantages of γ-CD over its lower homologues, i. its larger cavity, which results in a better tendency to form inclusion complexes, its favorable toxicological properties and the fact that it can be enzymatically degraded by cl-amylase (as opposed to β-CD), can therefore be fully exploited.

The Y-CD contains 3 free hydroxy functions per unit of glucose which can be reacted in whole or in part to form derivatives. Therefore, the term average degree of substitution (D.S.) is used, which is the average number of substituted hydroxy functions per unit glucose. Said D.S. can vary from a minimum value of 0.125 to a maximum value of 3. In the latter case, all 24 hydroxy groups are substituted, whereas in the former case only 20 l of the hydroxy group are substituted. A minimum value of D.S is particularly advantageous in the case where Y-CD is used as a solubilizer for pharmaceuticals for use in parenteral applications, while a high D.S. is preferred for use in technical applications such as plant protection products or enzymes. In the latter case, a high D.S. causes them to be hydroxy as well. . groups become functional located in the cavity of the γ-CD molecule. As a result, the cavity diameter ·; - 30 decreases. By selecting the appropriate D.S. the size of the cavity can be adjusted to obtain the optimal level required to properly attach a particular molecule to the cyclodextrin cavity.

- By introducing hydroxyalkyl substitutions into the Y-CD compound, the hydroxy function of the hydroxyalkyl ether group thus obtained can be further hydroxyalkylated, thereby creating multiple substitutions for one particular OH group. In such cases, the term mean molar substitution (M.S.) is used. Mentioned-5 tu M.S. is determined as the average molar number of substituting agent per unit of glucose. In this case, it is obvious that M.S. can be greater than 3 and theoretically has no upper limit.

The present invention relates to a process for preparing a pharmaceutical composition comprising a therapeutically active ingredient and a γ-cyclodextrin ether or mixed ether by dissolving the β-cyclodextrin ether or mixed ether in water and adding the therapeutically active ingredient, followed by adding the thus obtained solution. 15 may be dried. The process is characterized in that the N-cyclodextrin ether or mixed ether used is a N-cyclodextrin ether or mixed ether in which the ether substituents are C1-6-alkyl, hydroxy-C1-8-alkyl, carboxy-C1-8-alkyl or carbonyl) -C ^ _G alkyl. and wherein the degree of substitution is 0.125-3 and the average molar substitution is 0.125-10, except for octacis- (2,6-di-O-methyl) -T-cyclodextrin and per-O-methylated γ-cyclodextrin.

In the above definitions, the term "C 1-8 alkyl" means straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl,. : propyl, 2-methylpropyl, butyl, pentyl, hexyl and the like.

Preferred compounds are those γ-CD derivatives. . in which γ-CD is substituted by C 1-4 alkyl, hydroxy-C 1-2 alkyl, carboxy-C 1-2 alkyl or C 1-2 alkyloxycarbonyl) C 1-2 alkyl or its mixed ethers. Particularly preferred are methyl-, ethyl-, isopropyl-, hydroxyethyl-, hydroxypropyl-, hydroxybutyl-, carboxymethyl- and carboxyethyl-substituted cyclodextrins, and in addition (methyl) (hydroxymethyl) -5,8507 substituted V-cyclodextrins DS this is the M.S. is between 0.125-3, preferably between 0.3-2.

The cyclodextrin derivatives used in the methods of the invention can generally be prepared by reacting the starting f-CD with a suitable O-alkylating agent or a mixture of such agents at a concentration selected to achieve the desired D.S. Said reaction is preferably carried out in a suitable solvent in the presence of a suitable base. Suitable O-alkylating agents are, for example, alkyl, hydroxyalkyl, carboxyalkyl or (alkyloxycarbonyl) alkyl halides or sulfonates, e.g. methyl chloride, ethyl bromide, propylmethylsulfonate, ethyl chloroacetate, α-chloroacetic acid; or an oxirane, e.g. oxirane or methyloxirane. Suitable solvents are, for example, water; an alcohol or polyalcohol, e.g., methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 1,2-ethanediol, 1,2-propanediol, and the like; a ketone, e.g. 2-propanone, 2-buta-20-non, 4-methyl-2-pentanone and the like; ethers or polyethers, e.g. ethoxyethane, 2- (2-propyloxy) -propane, tetrahydrofuran, 1,2-dimethoxyethane and the like; and C 1-4 alkyloxy-C 2-3 alkanol and mixtures of such solvents. A suitable base is, for example, an alkali or alkaline earth metal hydroxide, e.g. sodium hydroxide, potassium hydroxide; or an alkali or alkaline earth metal hydride or amide, e.g. sodium hydride, calcium •; hydride, sodium amide and the like bases.

Said O-alkylation reaction is preferably carried out using 0.1 to 3 parts by weight of water in one portion; 'no part per γ-CD in the case where no organic solvent is used and 1 to 40 parts by weight of organic solvent per part by weight of Y-CD in the case where no water is used .

Particularly preferably, the reaction mixture containing the starting 1T-CD, the solvent, the base and the O-alkylating agent is heated in an autoclave at a temperature of between 30 and 200 ° C. Depending on the reactivity of the O-alkylating agent, the reaction mixture is allowed to react at this temperature for 15 minutes to 24 hours. The mixture is then acidified and the reaction product is isolated and purified by standard separation and purification methods such as column chromatography, ultrafiltration and centrifugation and dried.

Cyclodextrin derivatives can also be interchanged. For example, β-cyclodextrins substituted with (alkyloxycarbonyl) -10 alkyl can be suitably converted to the corresponding carboxyalkyl-substituted γ-cyclodexins following saponification procedures known in the art, e.g., by treating the starting materials with an acidic or basic aqueous solution.

Said γ-cyclodextrin derivatives are useful due to their ability to form inclusion complexes having a stabilizing effect on complexed compounds and their concomitant solubilizing activity. Compounds that show markedly increased water solubility and improved stability after being converted to inclusion complexes with the aforementioned Y-CD derivatives are those of the required shape and size, i. which adhere to the cavity. The size of the cavity can be adjusted by selecting suitable Y-CD derivatives with a suitable D.S. Examples of such compounds are, for example: - non-steroidal anti-rheumatic agents, steroids, cardiac glycosides and benzodiazepines, benzimidates, sol, piperidine, piperazine, imidazole, triazoline, pyridazine, 1,2,4-triazine, 1,2,4-triazine, Derivatives of 3,5,6-tetrahydroimidazo [2,2-b] thiazoles, or amides, derivatives of hydratropic acid or trialkyl-. amines, with benzodiazepine, benzimidazole, piperidine, piperazine, imidazole, triazole, pyridazine, 1,2,4-triazinedione or 2,3,8,6,6-tetrahydroimidazo [2,1-b] triazole derivatives being preferred, or amides, hydratropic acid derivatives or trialkylamines.

Useful benzimidazole derivatives include thiabenzol, fuberidazole, cyclobenzene, oxybendazole, parbendazole, cambendazole, mebendazole, fenbendazole, flubendazole, albendazole, oxfendazole, nocodazole and astemizole.

Suitable piperidine derivatives include diphenoxylate, enoperidine, haloperidol, haloperidolidecanoate, bromiperdolidecanoate, bromiperidol, moperone, trifluorididol, pipamperon, pyritramide, carfentilide, fentanyl, benperidol, droperidol, benzitramide, benzitramide, 15 milenperone, diphenoxine, fluspirilene, penfluridol, pimozide, lorcainide, loperamide, estemizole, ketanserin, levocabastine, cisapride, altanserin, ritanserin, 3- / 2- / 4- (4-fluorobenzoyl) -1-piperidinyl] ethyl , 7-dimethyl-4H-pyrido [1,2-a] pyrimidin-4-one, 3- [2- [4- (bis-20 (4-fluorophenyl) methylene] -1-piperidinyl) li] ethyl-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one and 3- (2- [4- [C3- (2-furanylmethyl) -3H-imidazo [4,5-b] pyridin-2-one); -yl-7-amino-1-piperidinyl-ethyl-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one. Suitable piperazine derivatives include azaperone, fluanisone, lidoflazine, flunarizine, mianseri. ni, oxatomide, myoflazine, closinicin: and cinnarizine.

*: * Examples of suitable imidazole derivatives are metronidazole, ornidazole, ipronidazole, tinidazole-30, isoconazole, nimorazole, miconazole, burimamide, methamide, methomidate, enilconazole or imazalil,; etomidate, econazole, clotrimazole, carnidazole, cimetidine, doconazole, sulconazole, parkonazole, orconat, sol, butoconazole, triadiminol, thioconazole, whiteazole, fluorotrimazole, ketoconazole, oxiconazole, bifonazole, oxmetidine, fenticonazole, tubulazole and (Z) -1- [2-chloro-2- (2,4-dichlorophenyl) ethenyl] -1H-imidazole.

Suitable triazole derivatives include virazole, azaconazole, ethaconazole, propiconazole, penconazole, itraconazole and terconazole.

Useful pyridazine derivatives include, for example, 3-chloro-6- [3,6-dihydro-4- (3-methylphenyl) -1 (2H) -pyridinyl] pyridazine, 3-methoxy-6- [4- (3-methyl-10-phenyl) ) -1-piperazinyl / pyridazine and the compounds of published European Patent Application No. 0 156 433.

Useful 1,2,4-triazinediones include, for example, 2-chloro-d- (4-chlorophenyl) -4- (4,5-dihydro-3,5-dioxo-1,2-4, triazine-2 (3H ) -yl) benzeneacetonitrile, 2,6-15 dichloro-1- (4-chlorophenyl) -4- (4,5-dihydro-3,5-dioxo-1,2,4-triazin-2 (3H) -yl) ) benzene acetonitrile and compounds of published European Patent Application No. 0 170 336.

Useful trialkylamines include, for example, diisoprromine and procapine.

Useful 2,3,5,6-tetrahydroimidazo [2,1-b] thiazoles are, for example, tetramisole or levamisole.

Useful amides include, for example, closantel, ambusetamide, isopropamide, butepeptide, methiodide and dextromamide.

A useful hydratropic acid derivative is, for example, suprofen.

Particularly valuable pharmaceutical compositions are obtained by converting etomidate, ketoconazole, tubulazole, itraconazole, levocabastine or flunarizine into aqueous form using the complexing agents described above.

9 86507

Pharmaceutical compositions of the sparingly water-soluble or water-impermeable compounds of the invention are prepared by dissolving β-cyclodextrin ether or mixed ether in water and adding to it a selected therapeutically active compound and optionally drying the solution of the resulting inclusion compound using methods known per se. The formation of the solution preferably takes place at temperatures between 15 and 35 ° C.

The drug is suitably added intermittently. The water may further contain physiologically miscible compounds such as sodium chloride, potassium nitrate, glucose, mannitol, sorbitol, xytol, or buffering agents such as phosphate, acetate, or citrate buffer.

By using said β-cyclodextrin ethers it is possible to prepare generally known forms of administration of drugs for oral, parenteral, topical, rectal or vaginal use, e.g.

20 solutions for infusion or injection, drops (eg eye drops or nasal drops), sprays, tablets, granules, capsules, aerosols, syrups, gels, ointments, baths for rectal and vaginal use.

Aqueous solutions may additionally contain suitable physiologically acceptable preservatives, such as quaternary ammonium soaps, chlorobutanol, phenoxanol, bromopoly and the like, as well as antioxidants, such as ascorbic acid.

: 30 For the preparation of solid preparations::: solutions of inclusion compounds are dried using conventional methods; thus, the water can be evaporated on a rotary evaporator or by drying with cooling. The residue is ground finely. and converted into uncoated or coated tablets or suppositories, suppositories, capsules, creams or ointments after any addition of inert excipients.

examples

The following examples are intended to illustrate the present invention in all its aspects, but not to limit it. All parts are by weight unless otherwise indicated.

A. Examples for the preparation of γ-cyclodextrin derivatives

Example 1 10 parts of γ-CD and a solution containing 1.5 parts of sodium hydroxide in 1.5 parts of water were mixed in an autoclave. Then 3 parts of methyl chloride were added to 0.5 parts of methyloxirane. The mixture was heated at 65 ° C for 1 hour and then at 100 ° C for 2 hours.

After cooling, the remaining methyl oxirane was removed and the reaction mixture was neutralized with hydrochloric acid. The volatile components were evaporated and the remaining portion was filtered. Sodium chloride was removed from the filtrate by means of an ion exchanger, and then the filtrate was freeze-dried. to give a (methyl) - (hydroxypropyl) derivative of / "- CD. Following the same procedure and using appropriate starting materials, a derivative of •" "- CDin (ethyl) (hydroxyethyl) was also prepared.

Example 2 In an autoclave, 2.5 parts of 1,2-dimethoxyethane, 1 part of lf-CD and a solution containing. . one part of sodium hydroxide in 1.2 parts of water. To this mixture was added 2 parts of oxirane and the whole was heated at 110 ° C for 5 hours. After cooling, the remaining oxirane was removed and the reaction mixture was neutralized with hydrochloric acid. The volatile components were evaporated and the residue was filtered. Sodium chloride was then removed from the filtrate by means of an ion exchanger, and then the filtrate was dried by cooling to give a hydroxyethyl derivative of γ-CD having an MS of 0.77.

11 86507

Following the same procedures and using the appropriate starting materials, a 2-hydroxypropyl derivative of γ-CD was also prepared by M.S. was 0.66.

Example 3 1 part of f-CO, 3 parts of 1,2-dimethoxyethane and 1.5 parts of sodium hydroxide were mixed in an autoclave with 1.5 parts of water. Then 4 parts of chloromethane were added to the batch and the whole mixture was heated at 120 ° C for 4 hours. After cooling, the reaction mixture was neutralized with hydrochloric acid and the volatile components were evaporated. The remaining portion was filtered and the sodium chloride was removed from the filtrate by means of an ion exchanger, and the filtrate was then freeze-dried to give the methyl derivative of β-CD, which D.S. was 1.49.

Following the same procedures and using the appropriate starting materials, a methyl derivative of T-CD was also prepared by D.S. was 0.13; a carboxymethyl derivative of γ-CD, which D.S. was 0.86: and a (ethoxycarbonyl) methyl derivative of γ-CD; an ethyl derivative of γ-CD; Y-CD 20 butyl derivative; T-CD isobutyl li derivative; / "- CDm isopropyl derivative; /" - CD carboxyethyl derivative; γ-CD 3 hydroxypropyl derivative; and β-CD 4-hydroxybutyl derivative.

B.Examples describing the properties of Y "CD derivatives _ 25

Example 4. . j Starting from a 5% stock solution of the Τ'-CD derivative in question in phosphate buffer (pH 7.4) ·. a dilution series was obtained with concentrations ranging from 0-5% in 0.5% increments. 3 ml of these solutions were pipetted into a sealed container containing an appropriate amount of progesterone. After shaking for 5 days at 25 ° C, the resulting mixture was filtered through a membrane filter (pore diameter 0.22 μιη) and the progesterone content was determined by high performance liquid chromatography (using a 25 cm long column; inner diameter 5 cm 2). mm; packed with 5 μm ODS-hypersil (RP-18; eluent: acetonitrile / water; UV detection). The results of these concentration measurements performed on several T 1 CD derivatives and unsubstituted γ CD according to the present invention are summarized in the following table.

progesterone content μg / ml X-CD derivative -N-substimethylmethylcarboxyhydroxyhydroxy-linked conjugated substituent-methylethylpropyl concentration f-CD derivatized substituted. subst. subst.

% (w / w = 0.13 DS = 1.49 MS = 0.86 MS = 0.77 MS = 0.66 by volume) 0 5.9 5.9 5.9 5.9 5.9 5 .9 0.5 425 488 379 102 234 302 1 343 972 748 209 452 582 1.5 275 1458 1144 313 673 872 2 203 1902 1470 417 860 1165 2.5 163 2149 1888 517 1055 1431 3 93 2258 2260 610 1291 1704 3.5 60 2392 2686 79 1472 1987 4 54 2592 3050 796 1722 2287 4.5 46 2627 3411 891 1817 2595 5 45 2602 3876 979 2065 2865

Table: Progesterone content in solutions containing different concentrations of β-CD derivative and γ-CD.

K

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Example 5

Following the procedures described in Example 4, the concentration of 3-chloro-6- [3,6-dihydro-4- (3-methylphenyl) -1 (2H) -pyridinyl / pyridazine in solutions containing various concentrations of / -CD derivatives was determined. . Said pyridazine compound is disclosed in published EP Patent Application No. 0 156 433 as a useful antiviral agent.

Concentration of 3-chloro-6- [3,6-dihydro-4- (3-methylphenyl) -110 (2H) -pyridinyl] pyridazine in ug / ml γ-CD derivative non-substituent-methyl-hydroxypropyl substituted y-CD substituted i substituted concentration DS = 1.49 μM.S. = 0.66% (w / v) j 15 0 0.4 ÖTi ÖTi 1 2.0 2.0 j 1, 5 2.5 0.8 8.0 4.5 3.5 - 12.6 7.0 5 0.8 20.0 10.0 20 Examples illustrating the preparation of pharmaceutical compositions containing novel β-cyclodextrin derivatives C. Examples of the composition of matter

Example 6 7 g of hydroxyethyl N-CD (M.S. = 0.77) and 0.5 g of medroxyprogesterone acetate were dissolved in 100 ml of water. The water was evaporated. 75 mg of the residue was ground finely and mixed with 366 mg of CaHPO 4 .2H 2 O,: 60 mg of corn starch, 120 mg of cellulose powder 30 (microcrystalline), 4.2 mg of very fine silicic acid - (Aerosii0 ^ 200) and 4.8 mg magnesium stearate and a mixture of pu; . was crossed into tablets.

Example 7 5 g of hydroxyethyl - / - cyclodextrin (MS = 0.77) • Y ·: 35 and 0.5 g of lidocaine were dissolved in 100 ml of physiological Y: sodium chloride solution at 30 ° C and filtered through a membrane filter (0.45 microns). through. The solution was filled into ampoules ’···. and sterilized.

Claims (8)

A process for preparing a pharmaceutical composition comprising a therapeutically active ingredient 5 and a γ-cyclodextrin ether or mixed ether by dissolving the 7-cyclodextrin ether or mixed ether in water and adding the therapeutically active ingredient as an ether, optionally drying the solution thus obtained, characterized in that or 7-cyclodextrin ether or mixed ether is used as the c-ether, in which the ether substituents are C 1-6 alkyl, hydroxy-C 1-6 -alkyl, carboxy-C 1-6 -alkyl or (C 1-6 -alkyloxycarbonyl) -C 1-6 -alkyl , and wherein the degree of substitution is 0.125-3 and the average molar substitution is 0.125-10, except for octacis- (2,6-di-O-methyl) -7-cyclodextrin and per-O-methylated 7-cyclodextrin. Process according to Claim 1, characterized in that the degree of substitution is 0.3 to 3 and the average molar substitution is 0.3 to 3. Process according to Claim 1 or 2, characterized in that the substituents are C 1-3 alkyl, hydroxy-C 1-4 alkyl or carboxy-C 1-2 alkyl. Process according to Claim 1 or 2, characterized in that the substituents are methyl, ethyl, isopropyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl and carboxyethyl. Process according to Claim 1, characterized in that the degree of substitution is 0.3 to 2 and the average molar substitution is 0.3 to 3. Process according to one of Claims 1 to 5, characterized in that the therapeutically active ingredient is a non-steroidal antirheumatic agent, a steroid, a cardiac glycoside or a benzodiazer. silicon, benzimidazole, piperidine, piperazine, iridazole, triazole, pyridazine, 1,2,4-triazine 86507 dione, 2,3,5,6-tetrahydroimidazo [2,1-b] thiazole - or a hydratropic acid derivative or an amide or a trialkylamine derivative. Process according to Claim 1, characterized in that the residue obtained after removal of the solvents is ground and, if appropriate, other ingredients are added, after which it is converted into a solid form suitable for pharmaceutical administration. Process according to Claim 1, characterized in that sodium chloride, glucose, mannitol, sorbitol, xylitol or phosphate or citrate buffer are added to the water. ♦ * ie 86507