Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation

The invention relates to pharmaceutical compositions con- taining drugs which are instable or only sparingly soluble in water, and methods for their preparation. The compo¬ sitions are characterized by increased water solubility and improved stability.

A large number of drugs is only poorly or sparingly soluble in water so that suitable application forms ^" like drop solutions or injection solutions are being prepared using other polar additives like propylene glycol etc. If the drug molecule has basic or acidic groups there exists the further possibility of increasing the water solubility by salt formation. As a rule this results in decreased efficacy or impaired chemical stability. Due to the shifted distribution equilibrium the drug may penetrate the lipophilic membrane only slowly corresponding to the concentration of the non-dissociated fraction while the ionic fraction _may be subject to a rapid hydrolytic decomposition.

Additional "water-like" solvents like low molecular poly- ethylene glycols or 1 ,2-propylene glycol are therefore used in the preparation of aqueous solutions of sparingly water-soluble drugs which glycols, however, cannot be considered pharmacologically inert, or the drug is solubi- lized using surfactants so that the drug molecules are occluded in micells. This solubilization has numerous

disadvantages: The surfactant molecules used have frequent¬ ly a strongly haemolytic effect and the drug needs to pass out of the micell by diffusion after the application. This results in a retard effect (compare B.W. Muller, Gelbe Reihe, Vol. X, pages 132ff (1983)).

Accordingly it may be stated that there exists no satis¬ factory and generally applicable method of solubilization.

For solid drugs it is also important to render the sparingly water-soluble drug water-soluble since a good solubility increases the bioavailability of the drug. It has been described that inclusion compounds, e.g. with μrea or complexes of polyvinyl pyrrolidone may improve the solubility of a compound but in aqueous solution they are not stable. Such inclusion compounds are therefore at ^' best suitable for solid application forms of drugs.

This is different when using -, a-, and γ-cyclodextrin which can bind a drug in its ring also in aqueous solution (W. Sanger, Angewandte Chemie , 343 (1980)). However, it is disadvantageous that the S-cyclodextrin itself is only poorly water-soluble (1.8 g/100 ml) so that the therapeuti- cally necessary drug concentrations are not achieved.

If a derivative is formed of the cyclodextrin its solubili¬ ty and therefore the amount of dissolved drug may be considerably increased. Thus, German Offenlegungsschrift 31 18 218 discloses a solubilization method using methylat- ed β-cyclodextrin as monomethyl derivative with 7 methyl groups and especially as dimethyl derivative with 14 methyl groups. With the 2,6-di-O-methyl derivative it is for instance possible to increase the water solublity of indometacin 20.4-fold and that of digitoxin 81.6-fold.

However, for therapeutical use the methyl derivatives of β-cyclodextrin show serious draw backs. Due to their increased lipophility they have a haemolytic effect and they further cause irritations of the mucosa and eyes. Their acute intravenous toxicity is still higher than the already considerable toxicity of the unsubstituted β-cyclo¬ dextrin. It is a further serious disadvantage for ^' the practical ^" application that the solubility of the dimethyl β-cyclodextrin and its complexes suffers a steep decrease at higher temperatures so that crystalline dextrin precipi¬ tates upon heating. This phenomenon makes it very diffi¬ cult to sterilize the solutions at the usual temperatures of 100 to 121°C.

Quite surprisingly it has now been found that certain other β-cyclodextrin derivatives can form inclusion ^' com¬ pounds which also considerably increase the water-solubili¬ ty of sparingly water-soluble and instable drugs without showing the advantages described above.

Subject of the invention are therefore novel pharmaceuti¬ cal compositions comprising inclusion compounds of only sparingly water-soluble and in water instable drugs with a partially etherified β-cyclodextrin of the formula

( ^β -CD*0R (I),

in which the residues R are hydroxyalkyl groups and part of the residues R may optionally be alkyl groups, the β-cyclodextrin ether having a water-solubility of more than 1.8 g in 100 ml water.

A partially etherified β-cyclodextrin of formula I is preferably used in which the residues R are hydroxyethyl, hydroxypropyl or dihydroxypropyl groups. Optionally part of the residues R may for instance be methyl or ethyl

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groups; the use of partially ^• methylated β-cyclodextrin ethers with 7 to 14 methyl groups in the β-cyclodextrin molecule, as they are known from German Offenlegungs- schrift 31 18 218 do not come under the present invention. Partial ethers of β-cyclodextrin comprising only alkyl groups (methyl, ethyl) may be suitable in accordance with the invention if they have a low degree of substitution (as defined below) of 0.05 to 0.2.

β-cyclodextrin is a compound with ring structure consist¬ ing of 7 anhydro glucose units; it is also referred to as cycloheptaamylose. Each of the 7 glucose rings contains in 2-,3-, and 6-position three hydroxy groups which may be etherified. In the partially etherified β-cyclodextrin derivatives used according to the invention only part of these hydroxy groups is etherified with hydroxyalkyl groups and optionally further with alkyl groups. When etherifying with hydroxy alkyl groups -which can be carried out by reaction with the corresponding alkylene oxides, "the degree of substitution is stated as molar substitution (MS), viz. in mole alkylene oxide per anhydroglucose unit, compare US patent specification 34 59 731, column 4..In the hydroxyalkyl ethers of β-cyclodextrin used in accor¬ dance with the invention the molar substitution is between 0.05 and 10, preferably between 0.2 and 2. Particularly preferred is a molar substitution of about 0.25 to about 1.

The etherification with alkyl groups may be stated direct- ly as degree of substitution (DS) per glucose unit which - as stated above - is 3 for complete substitution. Partial¬ ly etherified β-cyclodextrins are used within the in¬ vention which comprise besides hydroxyalkyl groups also alkyl groups, especially ^" methyl or ethyl groups, up to a degree of substitution of 0.05 to 2.0, preferably 0.2 to 1.5. Most preferably the degree of substitution with alkyl groups is between about 0.5 and about 1.2.

The molar ratio of drug to β-cyσlodextrin ether is preferably about 1:6 to 4:1, especially about 1:2 to 1:1. As a rule it is preferred to use the complex forming agent in a molar excess.

Useful complex forming agents are especially the hydroxy- ethyl, hydroxypropyl and dihydroxypropyl ether, their corresponding mixed ethers, and further mixed ethers with methyl or ethyl groups, such as methyl-hydroxyethyl, methyl-hydroxypropyl, ethyl-hydroxyethyl and ethyl-hydroxy¬ propyl ether of β-cyclodextrin.

The preparation of the hydroxyalkyl ethers of β-cyclo¬ dextrin may be carried out using the method of US patent specification 34 59 731. Suitable preparation methods for β-cyclodextrin ethers may further be found in J. Szejtli et al., Starke 3_2., 165 (1980) und A.P. Croft and R.A. Bartsch, Tetrahedron 3_9_, 1417 (1983). Mixed ethers of β-cyclodextrin can be prepared by reacting β-cyσlodextrin in a basic liquid reaction medium comprising an akali metal hydroxide, water and optionally at least one organic solvent (e.g. dimethoxyethane or isopropanol) with at least two different hydroxyalkylating and optionally al- kylating etherifying agents (e.g. ethylene oxide, propy- lene oxide, methyl or ethyl chloride).

Drugs exhibiting a significantly increased water-solubili¬ ty and improved stability, respectively, after having been transferred into inclusion compounds with the above- en- tioned β-cyclodextrin ethers are those having the required shape and size, i.e. which fit into the cavity of the β-cyclodextrin ring system. This includes for instance non-steroid anti-rheumatic agents, steroids, cardiac glyco- sides and derivatives of benzodiazep ^' ine, beήzimidazole, piperidine, piperazine, imidazole or triazole.

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Useful benzimidazole derivatives are thiabendazole, fuberi- dazole, oxibendazole, parbendazole, cambendazole, mebenda- zole, fenbendazole, flubendazole, albendazole, oxfenda- zole, nocodazole and astemisole. Suitable piperadine deri- vatives are fluspirilene, pimozide, penfluridole, loperamide, astemizole, ketanserine, levocabastine, cisa- pride, altanserine, and ritanserine. Suitable piperazine derivatives include lidoflazine, flunarizine, mianserine, oxatomide, mioflazine and cinnarizine. Examples of suitable imidazole derivatives are metronidazole, ornidazole, ipronidazole, tinidazole, isoconazole, nimora- zole, burimamide, metiamide, metomidate, enilconazole, etomidate, econazole, clotrimazole, carnidazole, cimetidine, docodazole, sulconazole, parconazole, orconazole, butocona- zole, triadiminole, tioconazole, valconazole, fluotrimazole, ketoconazole, oxiconazole, lombazole, bifonazole, oxmeti- dine, fenticonazole and tubulazole. As suitable triazole derivatives there may be mentioned virazole, itraconazole and terconazole.

Particularly valuable pharmaceutical compositions are ob¬ tained when converting etomidate, ketoconazole, tubulazole, itraconazole, levocabastine or flunarizine into a water-so¬ luble form using the complex forming agents of the invention. Such compositions are therefore a special subject of the present invention.

The invention is further directed to a method of preparing pharmaceutical compositions of sparingly water-soluble or water-instable drugs which is characterized by dissolving the β-cyclodextrin ether in water and adding thereto the selected drug as well as optionally drying the solution of the formed inclusion compound using methods known per se.

Formation of the solution may take place at temperatures between 15 and 35 C.

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The drug is suitably added batchwise. The water may further comprise physiologically compatible compounds such as sodium chloride, potassium nitrate, glucose, mannitole, sorbitol, xylitol or buffers such as phosphate, acetate or citrate buffer.

Using β-cyclodextrin ethers in .accordance with the in¬ vention it is possible to prepare application forms of drugs for oral, parenteral or topical application, e.g. infusion and injection solutions, drop solutions (e.g. eye drops or nasal drops), sprays, aerosols, sirups, and medical baths.

The aqueous solutions may further comprise suitable physio- logically compatible preserving agents such as quarternary ammonium soaps or chlorbutanol.

For the preparation of solid formulations the solutions of the inclusion compounds are dried using conventional methods; thus the water may be evaporated in a rotation evaporator or by lyophilisation. The residue is pulverized and, optionally after addition of further inert ingre¬ dients, converted into uncoated or coated tablets, supposi¬ tories, capsules, creams or ointments.

The following examples serve to illustrate the invention which, however, is not restricted to the examples.

The phosphate buffer solution mentioned in the examples had a pH of 6.6 and the following composition:

KH ₂ P0 ₄ 68,05 g

NaOH 7,12 g

Aqua demin. ad. 5000,0 g

All percentages are percent by weight.

Example 1

Starting from a 7% master solution of hydroxyethyl β-cyclo¬ dextrin (MS 0.43) in phosphate buffer solution a dilution series was prepared so that the complex forming agent concentration was increased in steps of 1%. 3 ml of these solutions were pipetted into 5 ml snap-top-glasses contain¬ ing the drug to be tested. After shaking for 24 hours at

25°C the solution was filtered through a membrane filter (0.22 microns) and the dissolved drug content was determin¬ ed spectrophotometrically. Figures 1, 3 and 4 show the increase of the drug concentration in solution in relation to the concentration of the complex forming agent for indometacin (figure 1) , piroxicam (figure 3) and dia'zepam (figure 4) . The maximum drug concentration is limited by the saturation solubility of the cyclodextrin derivative in the buffer which in case of hydroxyethyl-β-cyclodextrin (MS 0.43) is reached at 7.2 g/100 ml.

When comparing for instance the results obtained with indometacin to those given in German Offenlegungsschrift 31 18 218 for 2,6-di-0-methyl-β-cyclodextrin (figure 2) it will be observed that the hydroxyethyl derivative has a significantly higher complex formation constant (compare the different slopes in figures 1 and 2) .

Example 2

A. The saturation solubility at 25°C of different drugs was determined using a 10% hydroxypro- pyl- ^β -cyclodextrin solution (MS 0.35) in phosphate buffer solution under the same conditions as in example 1. The saturation solubilities S.. in phosphate buffer solution and

S- in phosphate buffer solution and 10% added hydroxypropyl-β-cyσlodextrin are given in table 1.

Table 1

Drugs S- _j (mg/ml) S ₂ (mg/ml) Ratio S ₁ :S_

Indometacine 0,19 5 , 72 30,1

Digitoxine 0,002 1 , 685 842,5

Progesterone 0,0071 7 , 69 1083,0

Dexamethasone 0,083 14 , 28 172,0

Hydrocortisone 0,36 21 , 58 59,9 Diazepame 0,032 0 , 94 29,4

B. The solubility of drugs in a 4% aqueous solution of hydroxypropyl-methyl-β-cyclodextrin (DS 0.96; MS 0.43) was determined in a similar manner. The results obtained are summarized in the following table 2 in which the ratio R of the saturation solubility in water or at the stated pH, re¬ spectively, with an without addition of β-cyclo¬ dextrin derivative is stated for each drug. The solutions prepared according to the invention were further found to be significantly more stable when compared with aqueous solutions.

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Table 2

Drug R

Itraconazole at pH 5 96 at pH 2 , ■ 5 75

Flunarizine 18

Levocabastine at pH 9, .5 81 at pH 1 , ,4 8

Ketoconazole 85

Flubendazole 30

Tubulazole 43

Cisapride 3

Loperamide 62

Etomidate 8,5

Cinnarizine at pH 5 28 at pH 3 12

Example 3

In 10 ml phosphate buffer solution 0.7 g hydroxyethyl-β-cy¬ clodextrin (MS 0.43) were dissolved together with 0.04 g indometacin at 25 C until a clear solution was formed. This solution was filtered through a membrane filter (0.22 microns) and filled under laminar flow into a pre-steriliz- ed injection bottle which was stored at 21°C (B). In a parallel test a saturated indometacin solution in a phosphate buffer solution (0.21 mg/ml) was stored under the same conditions (A) . The drug concentrations determin¬ ed by high pressure liquid chromatography are given in table 3. The great improved stability of the composition according to the invention is apparent.

Table 3 •

Storing time Indometacin content (%) in weeks A B

0 100,1 99,7

2 91,2 99,9

4 79,1 98,1

6 69,8 98,6

8 64,8 98,4

Example 4 (Injectable formulation)

0.35 g hydroxypropyl-β-cyclodextrin (MS 0.35) were dissolv¬ ed in 5 ml of physiological sodium chloride solution and warmed to about 35°C whereafter 3 mg diazepam were added. After storing for a short time a clear solution was obtained which was filled into an ampule after filtration through a membrane filter (0.45 microns).

Example 5 (Tablet)

In 100 ml water 7 g hydroxyethyl-β-cyclodextrin (MS 0.43) and 0.5 g medroxyprogesterone acetate were dissolved. The water was then evaporated in a rotation evaporator. The residue (75 mg) was powdered and. after addition of 366 mg calcium hydrogen phosphate.2H.-0, 60 mg corn starch, 120 mg cellulose powder (microcrystalline) , 4.2 mg highly dispers- ed silica (AEROSIL 200) and 4.8 mg magnesium stearate tablets with a weight of 630.0 mg and comprising 5 mg drug per unit dose were made. The dissolution rate of the medroxyprogesterone acetate from this formulation is 21 times higher when compared to a tablet comprising the same inert ingredients without addition of the β-cyclodextrin ether.

Example 6

5 g hydroxyethyl-β-cyclodextrin (MS 0,43) and 14 mg vitamin A-acetate were dissolved with stirring in 100 ml water or sugar solution (5% aqueous solution) within 2.5 hours under a nitrogen atmosphere. After filtration through a membrane filter (0.45 microns) the solution was filled into ampules and sterilized or filled into dropper bottles with addition of 0.4% chlor butanol as preserving agent.

Example 7

5 or 7.5 g hydroxyethyl β-cyclodextrin (MS 0.43) and 0.5 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 prepared therefrom as described in example 6. When compar¬ ing the anaethesic effect of these solutions in animal tests with an aqueous lidocain HC1 solution (A) one observes an extension of the duration of the effect by 300%. Test: rats, injection of 0.1 ml into the tail root in the vicinity of the right or left nerve fillaments and electrical irritation. The test results are summarized in table 4.

Table 4

Drug concentration Duration of effect (min) Extension (%) A B (%)

0,5 56 163 291

0,75 118 390 330

Example 8

6 mg dexamethasone and 100 mg hydroxyethyl-β-cyclodextrin (MS 0.43) were dissolved in 5 ml water, sterilized by filtration through a membrane filter (0.22 microns) and packed into an aerosol container allowing to dispense 0.1 ml per dose.

Example 9

The acute intravenous toxicity of some β-cyclodextrins was tested on rats with the following results. It was sur¬ prisingly found that the toxicity of the derivatives used according to the invention is lower by an entire order of magnitude.

Table 5

LD ₅₀ in rats (i.v.) in mg/kg bodyweight

β-cyclodextrin 453 dimethyl-β-cyclodextrin 200-207

(DS 2.0) hydroxypropyl-methyl- β-cyclodextrin > 2000*

(DS 0.96; MS 0.43)

* a higher dose has not been tested. In mice the value was > 4000 mg/kg.

The haemolytic effect of the methylether according to German Offenlegungsschrift 31 18 218 was compared to that of an ether used according to the invention. To this end 100 μl of a physiological sodium chloride solution with a cyclodextrin content of 10%, 800 μl of a buffer (400 mg MOPS, 36 mg Na ₂ HP0 ₄ . 2 H ₂ 0, 1,6 g NaCl in 200 ml H ₂ 0) and 100 μl of a suspension of human red blood cells (three times washed with sodium chloride solution) were mixed for 30 minutes at 37°C. Thereafter the mixture was centrifuged and the optical density was determined at 540 nm.

Controls: a) 100 μl sodium chloride solution + buffer -* ^■ 0% haemo¬ lysis b) 900 μl water →- 100% haemolysis

The results obtained are summarized in the following table 6 in which the concentrations are stated at which 50% and 100% haemolysis occurred.

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Table 6

Substance ^C 50 ^{% C} 100 ^%

Dimethyl-β-CD 0,33% 0,5%

(DS 2.0)

Methyl-β-CD 0,53 0,8%

(DS 1.79)

Hydroxypropyl- methyl-β-CD 1,5% 4 %

(DS 0.96; MS 0. .43%)

The results show that the haemolytic effect of the hydroxypro pylmethyl ether is about 5 to 8 times weaker than that of th dimethyl ether according to the prior art. Animal tests hav further shown that the hydroxyalkyl ethers do not caus irritation of the ucosa and eyes in contrast to the methy ethers.