DK175288B1 - Pharmaceutical agents containing drugs which are unstable or sparingly soluble in water, and methods for their preparation - Google Patents

Abstract

Novel pharmaceutical compositions comprise inclusion compounds of drugs, which are instable or only sparingly soluble in water, with partially etherified beta -cyclodextrin derivatives having hydroxyalkyl and optionally additional alkyl groups.

Description

DK 175288 B1

The invention relates to pharmaceutical agents containing drugs which are unstable or only sparingly soluble in water, and methods for their preparation. The agents are characterized by increased water solubility and improved stability.

A large number of drugs are only poorly soluble or sparingly soluble in water, so that suitable application forms such as drip solutions or injection solutions are prepared using other polar additives such as propylene glycol, etc.

If the drug molecule has basic or acidic groups, there is the further possibility of increasing the water solubility by salt formation. As a rule, this leads to diminished efficiency or loss of chemical stability. Because of the offset equilibrium, it is possible that the drug only slowly penetrates the lipophilic membrane, corresponding to the concentration of the undissociated fraction, while the ionic fraction can undergo rapid hydrolytic decomposition.

Further "aqueous" solvents such as low molecular weight polyethylene glycols or 1,2-propylene glycol are therefore used to prepare aqueous solutions of sparingly water-soluble drugs, which, however, cannot be considered pharmacologically inert or the drug is solubilized using surfactants, occluded in micelles. This solubility has numerous drawbacks: the molecules of the surfactant used frequently have a strong hemolytic effect and the drug has to leave the micelle upon diffusion after application. This results in a delayed effect (cf. B. W. Muller, Gelbe Reihe, Vol. X, p. 132 et seq. (1983)).

25 It can therefore be said that there is no satisfactory and generally applicable solubilization process.

For solid drugs, it is also important to make the sparingly water-soluble drug water-soluble, because good solubility increases the bioavailability of the drug.

It has been described that inclusion compounds, e.g. with urea or complexes of polyvinylpyrrolidone can improve the solubility of a compound but in aqueous solution.

I DK 175288 B1 I

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In solution, they are not stable. Such inclusion compounds are therefore best suited for use in phases

In first application forms of pharmaceuticals. IN

This is different when Οί-, β- and γ-cyclodextrin is used, which can bind a physician.

In 5 medium in its ring, also in aqueous solution (W. Sanger, Angewandte Chemie 92, 343 I

I (1980)) However, it is a disadvantage that the β-cyclodextrin itself is only poorly water-soluble.

I corpus (1.8 g per 100 ml) so that the therapeutically needed drug concentrations I

You are not achieved. IN

If a derivative of the cyclodextrin is formed, its solubility and therefore the amount of I

The dissolved drug increases significantly. German Publication Publication 31 18 218 Description

Thus, a solubilization method is employed using methylated β-cyclodextrin I

I as monomethyl derivative with 7 methyl groups and especially as dimethyl derivative with 14 L

In methyl groups. With the 2,6-di-Omethyl derivative, e.g. possible to increase water dissolution

In the solubility of indomethacin 20.4 times and the water solubility of digitoxin 81.6 times. IN

In E. Fenyvesi et al. (Proceedings of the first International Symposium on Cyclodextrins; I

In Budapest 1981, pages 345-356) describe the preparation of cyclodextrin polymers by I

In reaction with epichlorohydrin, which exhibits a high water solubility and is suitable for I

In increasing the solubility in water of highly soluble compounds. The polymers become you

I made of monomeric β- and γ-cyclodextrin and the polymers selected for use I

You have an average molecular weight of 4000 to 6000, with an average molecular I

In weight Mw of 5300. I

In IWO-A-820051, encapsulated compounds of cyclodextrin and eye retinoids

In lodextrin derivatives described. The fundamental problem in writing is the reduction of I

In the toxic side effects of retinoids through modification of the molecular structure I

In and / or complexation with cyclodextrins. The fat solubility of the substances I

You need to decrease, and thus their propensity for concentration in adipose tissue decreases

In 30 set or avoided. In the specification, α-, β- and γ-cyclodextrins as well as their derivatives I

You designate as equally suitable for complex formation, while as the only example like I

Applicable first-line derivatives are mentioned methoxy derivatives of α, β and γ-cyclodex steps.

However, for therapeutic use, the methyl derivatives of β-cyclodextrin exhibit disadvantages, because of their increased lipophilicity, they have a haemolytic effect and further cause irritation of the mucosa and eyes. Their acute intravenous toxicity is even higher than the already significant toxicity of the unsubstituted β-cyclodextrin. It is a further serious disadvantage of the practical application that the solubility of dimethyl-3-cyclodextrin and its complexes undergoes a sharp decrease at higher temperatures, so that crystalline dextrin precipitates upon heating. This phenomenon makes it very difficult to sterilize the solutions at the usual temperatures of 100 to 121 ° C.

Surprisingly, it has now been found that certain other β-cyclodextrin derivatives can form inclusion compounds which also significantly increase the water solubility of sparsely water-soluble and unstable drugs without the disadvantages described above.

The invention therefore relates to novel pharmaceutical agents comprising inclusion compounds of only sparingly water-soluble or water-unstable drugs with a partially etherified / S-cyclodextrin, wherein the ether substituent is hydroxyethyl, hydroxypropyl, or dihydroxypropyl groups, whereby some of be methyl or ethyl groups and the β-cyclodextrin ether exhibits a water solubility of more than 1.8 g in 100 ml of water, thereby encapsulating compounds of retinoids with β-cyclodextrin ethers insofar as their ether substituents are methyl, ethyl-25 and 2-hydroxyethyl groups, as well as encapsulating compounds of sparingly water-soluble or water-unstable drugs with mixtures of β-cyclodextrin-epichlorohydrin derivatives having a medium molecular weight Mw are excluded

The use of partially methylated β-cyclodextrin ethers with 7 to 14 methyl groups in the β-cyclodextrin molecule, as known from DE-A-31 18 218, does not fall within the scope of the present invention. Furthermore, encapsulating compounds of retinoids are included

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I / 3-cyclodextrin ethers of the invention insofar as their ether substituents are methyl,

In ethyl and 2-hydroxyethyl groups (cf. WO-A-820051), and encapsulating compounds of I

In sparingly water-soluble or water-unstable drugs with mixtures of / 3-cyclo-I

In dextrin epichlorohydrin derivatives with a mean molecular weight Mw 5300, omitted. IN

I 5 I

I / 3-cyclodextrin is a compound having a ring structure consisting of 7 anhydroglucose

In honor. It is also referred to as cycloheptaamylose. Each of the 7 glucosings contains I

In the 2, 3, and 6 positions, three hydroxy groups may be etherified. In the partially for- I

In etherated / 5-cyclodextrin derivatives used according to the invention, only part of these

In 10 hydroxy groups etherified with the indicated hydroxyalkyl residues, as well as in given I

In cases etherified with methyl or ethyl esters. When etherified with 5-hydroxyalkyl radical

Substances which can be carried out by reaction with suitable alkylene oxides are substituted

In the degree of molar substitution degree (MS), namely in moles of alkylene oxide per anhydro-I

In glucose unit, cf. US-A-34 59 731, column 4. For hydroxyalkyl ethers of / 3-cyclodextrin, I

In the present invention, the molar degree of substitution is between 0.2 and 10.1

Preferably between 0.2 and 2. Particularly preferred is a degree of molar substitution of approx. IN

For 0.25 to approx. 1. I

In the etherification with alkyl groups can be stated directly as degree of substitution (DS) per glu- I

In 20 unit of unit, as mentioned above, 3 is at complete substitution. Part I is used

In some etherated β-cyclodextrins of the invention, which, in addition to hydroxyalkyl groups I

You also include alkyl groups, especially methyl or ethyl groups up to a degree of substitution I

of from 0.2 to 2.0, preferably from 0.2 to 1.5. Most suitable is the degree of substitution I

I with alkyl groups between ca. 0.5 and approx. 1.2. IN

I 25 I

Preferably, in the molar ratio of drug to β-cyclodextrin ether, approx. 1: 6 to 1

In 4: 1, especially approx. 1: 2 to 1: 1. As a rule, it is preferred to use the complexing I

In the mean in a molar excess. IN

In particular, useful complexing agents are hydroxyethyl, hydroxypropyl and dihydro-I

In the xypropyl ether, their corresponding mixed ethers and further mixed ethers with I

Methyl or ethyl groups such as methyl hydroxyethyl, methyl hydroxypropyl, ethyl hydroxyethyl and ethyl hydroxypropyl ether of β-cyclodextrin.

The preparation of the hydroxyalkyl ethers of β-cyclodextrin can be carried out using the method of US Patent No. 3,459,731. Suitable methods of preparation for β-cyclodextrin ethers can be further found in J. Szejtli et al., Starkke 32, 165 (1980) and A.P. Croft and R.A. Bartsch, Tetrahedron 39, 1417 (1983). Mixed ethers of β-cyclodextrin may be prepared by reaction of β-cyclodextrin in a basic liquid reaction medium comprising an alkali metal hydroxide, water and optionally at least one organic solvent (e.g. dimethoxyethane or isopropanol) with at least two various hydroxyalkylating agents and optionally alkylating etherifying agents (e.g., ethylene oxide, propylene oxide, methyl or ethyl chloride).

Drugs that exhibit significantly increased water solubility and improved stability, respectively, after being converted to inclusion compounds with the above-mentioned 3-cyclodextrin ethers, are those having the necessary shape and size, i. which fits into the cavity of the / 3-cyclodextrin ring system. This includes e.g. non-steroidal antirheumatic agents, steroids, cardiac glycosides, and derivatives of benzodiazepine, benzimidazole, piperidine, piperazine, imidazole or triazole.

20

Useful benzimidazole derivatives are thiabendazole, fuberidazole, oxybendazole, parbendazole, cambendazole, mebendazole, fenbendazole, flubendazole, albendazole, oxfendazole, nocodazole and astemisole. Suitable piperadine derivatives are fluospiril, pimozide, penfluridol, lope-ramide, astemizole, ketanserin, levocabastine, cisapride, altanserin and ritanserin. Suitable piperazine derivatives include lidoflazine, flunarizine, mianserin, oxatomide, myoflazine and cinnarizine. Examples of suitable imidazole derivatives are metronidazole, omidazole, ipronidazole, tinidazole, isoconazole, nimorazole, burimamide, methiamide, metomidate, enilconazole, etomidazole, econazole, clotrimazole, camidazole, cimetidine, cimetidine, cimetidine, , thioconazole, valconazole, fluotrimazole, ketoconazole, oxiconazole, lombazole, bifonazole, oxmetidine, fenticonazole and tubulazole. Suitable triazole derivatives include virazole, itraconazole and terconazole.

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Particularly valuable pharmaceutical agents are obtained by conversion of etomidate, ketoconazole, I

In tubulazole, itraconazole, levocabastine or flunarizine, in a water-soluble form under

Turning on the complexing agents of the invention. Such pharmaceutical I

In particular, there is a particular object of the present invention. IN

I 5 I

The invention also relates to a process for the preparation of pharmaceutical agents I

I of sparingly water-soluble or water-unstable drugs which are peculiar to I

In solution of the β-cyclodextrin ether in water and addition thereto of the selected drug.

In part, and optionally drying the solution of the inclusion compound formed under I

In the use of methods known per se. The formation of the solution can take place at temp

At temperatures between 15 and 35 ° C. IN

The portion of the drug is conveniently added portionwise. The water may further comprise physical

In logically compatible compounds such as sodium chloride, potassium nitrate, glucose, mannite, I

In sorbit, xylite or buffer such as phosphate, acetate or citrate buffer. IN

I Using β-cyclodextrin ethers according to the invention, it is possible to prepare I

In application forms of drugs for oral, parenteral or topical application, e.g. infil- I

In solution and injection solutions, drip solutions (eg eye drops or nasal drops)

In 20 ber), spray fluids, aerosols, syrups and medical baths. IN

The aqueous solutions may further comprise suitable physiologically useful concentrates

In preservatives such as quaternary ammonium soaps or chlorobutanol. IN

For the preparation of solid compositions, the solutions of the inclusion compounds become dry

In court using usual methods. Thus, the water can be evaporated in a rotary I

In evaporator or lyophilization. The residue is pulverized and optionally after addition

In addition of additional inert constituents, it is transformed into uncoated or coated

In laid tablets, suppositories, capsules, creams or ointments. IN

I 30 I

7 DK 175288 B1

The following examples serve to illustrate the invention, but not limited to the examples.

The phosphate buffer solution mentioned in Examples had a pH of 6.6 and 5 of the following composition: KH2PO4 68.05 g

NaOH 7.12 g

Aqua demin.ad. 5000.0 g 10

All percentages are weight percentages.

Example 1 Starting from a 7% stock solution of hydroxyethyl / 3-cyclodextrin (MS 0.43) in phosphate buffer pad, a dilution series was prepared so that the concentration of complexing agent was incrementally increased by 1% 3 ml of these solutions. in 5 ml glass with removable top containing drug to be tested. After shaking for 24 hours at 25 ° C, the solution was filtered through a 20 membrane filter (0.22 micron) and the dissolved drug content was determined spectrophotometrically. FIG. Figures 1, 3 and 4 show the increase in drug concentration in solution relative to the concentration of the complexing agent for indomethacin (Fig. 1), pyroxicam (Fig. 3) and diazepam (Fig. 4). The maximum drug concentration is limited by the saturation solubility of the cyclodextrin derivative in the buffer which, in the case of hydroxyethyl / 3-cyclodextrin (MS 0.43), is reached at 7.2 g / ml. 100 ml.

When comparing e.g. the results obtained with indomethacin with those disclosed in German disclosure 31 18 218 for 2,6-di-0-methyl-5-cyclodextrin (Fig. 2), it will be seen that the hydroxyethyl derivative has a significantly higher complex formation constant 30 (compare the different slopes of Figures 1 and 2).

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In Example 2 I

In A. The saturation solubility at 25 ° C of various drugs was determined under I

Turning to a 10% hydroxypropyl-β-cyclodextrin solution (MS 0.35) in phosphate buffer I

In 5 cushion solution under the same conditions as in Example 1. The saturation solubilities I

I Si in phosphate buffer solution and S2 in phosphate buffer solution and 10% added hy-I

The droxypropyl-β-cyclodextrin is listed in Table 1. I

In Table 1 I

I 10 I

In Drugs S) (ng / ml) S2 (mg / ml) Ratio S): S2 I

In Indomethacin 0.19 5.72 1: 30.1 I

I Digitoxin 0.002 1.685 1: 842.5 I

I Progesterone 0.0071 7.69 1: 1083.0 I

I Dexamethasone 0.083 14.28 1: 172.0 I

I Hydrocortisone 0.36 21.58 1: 59.9 I

In Diazepam 0.032 0.94 1: 29.4 I

I R The solubility of drugs in a 40% aqueous solution of hydroxypropyl methyl I

20 µl cyclodextrin (DS 0.96; MS 0.43) was similarly determined. The results obtained I

Iter is summarized in the following Table 2, in which the ratio R of saturation solubility I

In the water or at the indicated pH with and without the addition of β-cyclodextrin I

The derivative is listed for each drug. The solutions prepared according to the invention showed I

In addition, being significantly more stable compared to aqueous solutions. IN

I 25 I

I 30 I

9 DK 175288 B1

Table 2

Drug_R

Itraconazole at pH 5 96 5 at pH 2.5 75

Flunarizin 18

Levocabastine at pH 9.5 81 at pH 7.4 8

Ketoconazole 85 10 Flubendazole 39

Tubulazole 43

Cisapride 3

Loperamide 62

Etomidate 8.5 Cinnarizine at pH 5 28 at pH 3 12

Example 3

In 10 ml of phosphate buffer solution was dissolved 0.7 g of hydroxyethyl - / - cyclodextrin (MS 0.43) together with 0.04 g of indomethacin at 25 ° C until a clear solution was formed. This solution was filtered through a membrane filter (0.22 micron) and loaded under a laminar flow into a pre-sterilized vial stored at 21 ° C.

(B). In a parallel sample, a saturated indomethacin solution in a phosphate buffer solution (0.21 mg per ml) was stored under the same conditions (A). The drug concentrations determined by high pressure liquid chromatography are given in Table 3. The much improved stability of the agent according to the invention is clearly evident.

30

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In Table 3 I

Shelf life in weeks Indomethacin content (%) I

I _A_B I

I 100 100.1 99.7 'I

I 2 91.2 99.9. IN

I 4 79.1 98.1 I

I 6 69.8 98.6 I

I 8 64.8 98.4 I

I 10 I

In Example 4 (injectable preparation) I

In 0.35 g of hydroxypropyl / 3-cyclodextrin (MS 0.35) was dissolved in 5 ml of physiological sodium I

In chloride solution and heated to approx. 35 ° C, then 3 mg of diazepam was added. Ef- I

For 15 h of storage for a short time, a clear solution was obtained which was filled into a vial after filtering.

In the ring through a membrane filter (0.045 micron). IN

In Example 5 (tablet) I

Dissolve 7 g of hydroxyethyl / 3-cyclodextrin (MS 0.43) and 0.5 g of medium in 20 liters of water.

In xyprogesterone acetate. The water was then evaporated in a rotary evaporator. The residue I

I (75 mg) was pulverized and after addition of 366 µg calcium hydrogen phosphate, I

In 2H 2 O, 60 mg corn starch, 120 mg cellulose powder (microcrystalline), 4.2 mg high

In purple silica (AEROSIL®200) and 4.8 g of magnesium stearate, tabs were prepared.

I 25 facilitates with a weight of 630.0 mg and comprising 5 mg of drug per day. unit dose. Up in

At the dissolution rate of the medroxyprogesterone acetate of this preparation is 21 times higher

In re of a tablet comprising the same inert ingredients without the addition of β-cycl I

In the lodextrin ether. IN

I 30 I

11 DK 175288 B1

Example 6 55 g of hydroxyethyl / 3-cyclodextrin (MS 0.43) and 14 mg of vitamin A acetate were dissolved with stirring in 100 ml of water or sugar solution (5% aqueous solution) over 2.5 hours under a nitrogen atmosphere. . After filtration through a membrane filter (0.45 micron), the solution was filled into ampoules and sterilized or filled in drip bottles with the addition of 0.4% chlorobutanol as a preservative.

Example 7 10 5 or 7.5 g of hydroxyethyl / 3-cyclodextrin (MS 0.43) and 0.5 or 0.75 g of lidocaine were dissolved in 100 ml of physiological sodium chloride solution at 30 ° C (B). Injection solutions, eye drops and topical solutions were prepared therefrom as described in Example 6. By comparing the anesthetic effect of these solutions.

In animal experiments with an aqueous lidocaine HCl solution (A), an extension of the duration of action was observed by 300%. Sample: rats, 0.1 ml injection into the tail root near the right or left nerve filaments and electrical irritation. The experimental results are summarized in Table 4.

20 Table 4 Drug concentration Duration of action (min) Extension (%) _ A_B _ (%} 0.5 56 163 291 25 0.75 118 390 330

Example 8 6 mg of dexamethasone and 100 mg of hydroxyethyl-E-cyclodextrin (MS 0.43) were dissolved in 5 ml of water, sterilized by filtration through a membrane filter (0.22 micron) and packed in an aerosol container allowing dispense 0.1 ml per dosage.

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In Example 9 I

The acute intravenous toxicity of some β-cyclodextrins was tested in rats with I

In the following results. Surprisingly, it was found that the toxicity of the derivatives used

By December 5 according to the invention, an entire order of magnitude is lower. IN

In Table 5 I

In LP ™ in rats (i.v.l in mg / kg body weight I

I 10 I

I / 3-cyclodextrin 453 I

I Dimethyl / 3-cyclodextrin (DS 2.0) 200-207 I

In Hydroxypropyl-methyl-E-cyclodextrin> 2000 * I

I (DS 0.96; MS 0.43) (I

I 15 I

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

I The hemolytic effect of the methyl ether according to German publication 31 31 I

In 218 was compared with the effect of an ether used according to the invention. For this I

For 20 purposes, 100 μΐ of a physiological sodium chloride solution with a cyclodextrin indi-

In hold of 10%, 800 μΐ of a buffer (400 mg MOPS, 36 mg Na2HP04, 2 H2O, 1.6 g I

In NaCl in 200 ml of H2 O) and 100 μΐ of a suspension of human red blood cells (three times I)

Washed with sodium chloride solution) mixed for 30 minutes at 37 ° C. Then became

The mixture was centrifuged and the optical density determined at 540 nm. IN

I 25 I

I Controls: I

(A) 100 μΐ sodium chloride solution + buffer -> 0% hemolysis I

(B) 900 μΐ water - * 100% hemolysis I

I 30 The results obtained are summarized in the following Table 6, which lists the cons

In traces at which 50% and 100% hemolysis occurred. IN

13 DK 175288 B1

Table 6

Stof_c50% _c100%

Dimethyl / 5-CD 0.33% 0.5% 5 (DS 2.0)

Methyl / 3-CD 0.53% 0.8% (DS 1.79)

Hydroxypropyl methyl / 3-CD 1.5% 4% (DS 0.96; MS 0.43%)

The results show that the hemolytic effect of the hydroxypropyl methyl ether is approx.

S to 8 times weaker than the action of the known dimethyl ether. Animal studies have further shown that the hydroxyalkyl ethers do not cause irritation of the mucosa and eyes as opposed to the methyl etheme.

15

Claims (14)

Pharmaceutical agent containing inclusion compounds of drugs which are unstable or sparingly soluble in water, with a cyclodextrin, characterized in that the and a portion of the ether substituents II may optionally be methyl or ethyl groups, and the etherated / 3-cyclodextrin has a II water solubility of more than 1.8 g in 100 ml of water, inclusion compounds of retinoids with / 3-cyclodextrins in to the extent that their ether substituents are methyl, ethyl II or 2-hydroxyethyl groups, as well as inclusion compounds of drugs which are II sparingly water-soluble or unstable in water, with mixtures of / 5-cyclodextrinepi-II chlorohydrin derivatives having an intermediate molecular weight of (Mw) 5300, is excluded. I I 15 Agent according to claim 1, characterized in that the partially etherated β-cyclodextrin has an I molar degree of substitution for hydroxyalkyl groups of 0.2 to 10 and a degree of substitution for alkyl groups of 0.2 to 2.0. IN An agent according to claim 1 or 2, characterized in that it comprises drug and β-I to 20 cyclodextrin ethers in a molar ratio of 1: 6 to 4: 1. IN An agent according to claims 1 to 3, characterized in that it contains as a drug an I I non-steroidal anti-rheumatic agent, a steroid, a cardiac glycoside or derivatives of benz I, ziaziazepine, benzimidazole, piperidine, piperazine, imidazole or triazole. I I 25 I An agent according to any one of claims 1 to 4, characterized in that it contains, as a drug 11, etomidate. IN An agent according to any one of claims 1 to 4, characterized in that it contains as ketoconazole as a medicament I 30. In DK 175288 B1 An agent according to any one of claims 1 to 4, characterized in that it contains as itraconazole as a medicament. An agent according to any one of claims 1 to 4, characterized in that, as a medicament '5, it contains levocabastine. An agent according to any one of claims 1 to 4, characterized in that it contains as a drug flunarizine. An agent according to any one of claims 1 to 4, characterized in that it contains as a drug tubulazole. Process for the preparation of a pharmaceutical according to any one of claims 1 to 10, characterized in that the β-cyclodextrin ether is dissolved in water and the selected drug is then added, whereupon the solution of the inclusion compound thus obtained is optionally dried. using methods known per se. Process according to claim 11, characterized in that the residue obtained after removal of the solvent is pulverized and, optionally, after addition of additional excipients, is converted into a solid, administrable form. Process according to claim 11 or claim 12, characterized in that additional physiologically compatible substances are added to the water. 1 30 Process according to claim 13, characterized in that sodium chloride, glucose, mannitol, sorbitol, xylitol or a phosphate or citrate buffer are added to the water.