KR920008700B1 - Process for preparing pharmaceutical preparation containing drugs which are instable or sparingly soluble in water - Google Patents

Abstract

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Description

Method for preparing water-soluble complex of water-soluble or water-labile agent and β-cyclodextrin ether

1 shows Indomethacin.

FIG. 2 shows the results obtained for indomethacin with respect to 2,6-di-0-methyl-β-cyclodextrin ether in JP 31 18 218.

3 is a diagram showing pyroxicam.

4 shows diazepam.

The present invention relates to a pharmaceutical composition containing a water-insoluble or poorly water-soluble agent and a water-soluble complex of β-cyclodextrin ether, and a method for preparing the same. The composition of the present invention is characterized by water solubility and improved stability.

Many drugs are poorly soluble in water and are therefore prepared using other polar additives such as propylene glycol in suitable applications such as drop solutions or injections. If the drug molecule has a basic or acidic group, there is a possibility that the water solubility may be increased by the formation of a salt. In general, these methods reduce efficacy or compromise chemical stability. Because of the shift of the distribution equilibrium, the medicament passes very slowly through the lipophilic membrane depending on the concentration of the non-dissociative moiety, while the ionic, moiety can undergo rapid hydrolysis.

ller, Gelbe Reihe, Vol. X, pages 132ff(1983)참조).Thus, additional water-like solvents, such as low molecular weight polyethyleneglycol or 1,2-propylene glycol, are used to prepare aqueous solutions of poorly water-soluble drugs, although these glycols are pharmaceutical It cannot be considered inert. The drug is also solubilized with a surfactant, in which case the drug molecule is blocked in the micelle. This solubilization method has many disadvantages. That is, the surfactant molecules used frequently exhibit a strong hemolytic effect and cause delays because the drug must exit the micelle by diffusion after administration (BW M

ller, Gelbe Reihe, Vol. X, pages 132ff (1983).

Therefore, it can be said that there is generally no applicable and satisfactory solubilization method.

In the case of solid medications, it is also important to make the water- poorly soluble drug water soluble, because good solubility increases the bioavailability of the drug. Encapsulated compounds, such as urea or polyvinylpipolydone complexes, can improve the solubility of the compounds, but they are unstable in aqueous solution. Therefore, these inclusion compounds are only suitable for solid dosage forms of the drug at best.

ngger, Angewandte Chemie 92, 343(1980)]. 그렇지만, β-사이클로덱스트린 자체는 단지 수-난용성이므로 (1.8g/100ml) 치료학적으로 필요한 약제농도를 얻을 수 없다는 단점이 있다.However, there is a difference in the use of α-, β- and γ-cyclodexscreens capable of binding a drug to the ring in aqueous solution [W. S.

ngger, Angewandte Chemie 92, 343 (1980)]. However, β-cyclodextrin itself is only water-soluble (1.8g / 100ml) has the disadvantage that it is not possible to obtain a therapeutically necessary drug concentration.

When derivatives of cyclodextrins are formed, their solubility and thus the amount of dissolved agent can be significantly increased. Therefore, Federal Republic of Germany Patent No.-31 18 218 describes a solubilization method using methylated β-cyclodextrins in the form of monomethyl derivatives having 7 methyl groups and especially dimethyl derivatives having 14 methyl groups. For example, a 2,6-di-0-methyl derivative can increase the water solubility of indomethacin by 20.4-fold and increase the water solubility of digitoxin by 81.6-fold. However, the methylfluid of β-cyclodextrins represents a serious decision in therapeutic use. Due to their increased lipophilic, they not only have hemolytic action, but also cause irritation to the mucous membranes and eyes. They are much higher than those of unsubstituted β-cyclodextrins, which are already known to have significant acute intravenous toxicity. Since the solubility of dimethyl β-cyclodextrin and its complex decreases rapidly at high temperatures, the precipitation of crystalline dextrin upon heating is also a very serious disadvantage in practical use. The precipitation of crystalline dextrin upon heating also makes it very difficult for practical use to sterilize the solution at normal temperatures of 100-121 ° C.

Very surprisingly, it has been found that certain other β-cyclodextrin ethers according to the present invention can form inclusion compounds that significantly increase the water solubility and water solubility of unstable drugs without exhibiting the above-mentioned disadvantages.

It is therefore an object of the present invention to provide a novel pharmaceutical composition containing a water-soluble and water-labile agent and an inclusion compound of a partially etherified β-cyclodextrin ether of general formula (I) It is.

(β-CD) -OR

Wherein the residue R is a hydroxyalkyl group, some of the R residues may optionally be alkyl groups, and the β-cyclodextrin ether has a water solubility of at least 1.8 g in 100 ml of water.

As the partially etherified β-cyclodextrin of general formula (I), those in which the residue R is a hydroxyethyl, hydroxypropyl or dihydroxypropyl group are preferably used. Optionally, some of the residues R may be methyl or ethyl groups, for example, but are known in Federal Republic of Patent No. 31 18 218 and β-methylated into portions having 7 to 14 methyl groups in the β-cyclodextrin molecule. Cyclodextrin The use of ethers is not included in the present invention.

Partial ethers of β-cyclodextrins containing only alkyl groups (methyl, ethyl) may be suitable for the present invention if they have a low degree of substitution (defined below) of 0.05 to 0.2.

β-cyclodextrin is a cyclic compound composed of seven anhydroglucose units, and is also called cycloheptimyrose. Each of the seven glucose rings contains three hydroxy groups which can be ederized at the 2-, 3- and 6- positions.

In the partially etherified β-cyclodextrin derivatives used according to the invention, only some of their hydroxy groups are etherified with hydroxyalkyl groups, and optionally further alkyl groups. In etherification with a hydroxy alkyl group, which may be carried out by reaction with the corresponding alkylene oxide, the degree of substitution is in terms of molar substitution (MS), ie in moles of alkylene oxide per anhydroglucose unit. (See column 4 of US Pat. No. 34 59 731). In the hydroxyalkyl ethers of β-cyclodextrins used according to the invention, the molar substitution degree is from 0.05 to 10, preferably from 0.2 to 2. Particularly preferred molar substitution degrees are from about 0.25 to about 1.

Etherification by alkyl groups can be directly expressed in degrees of substitution per unit of glucose (DS), with a degree of substitution of 3 for complete substitution as described above. In addition to the hydroxyalkyl groups also partially etherified β-cyclodextrins containing 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, are used in the present invention. Most preferred alkyl group substitution is about 0.5 to 1.2.

The molar ratio of drug to β-cyclodextrin ether is preferably from about 1: 6 to 4: 1, in particular about 1: 2 to 1: 1. Generally, it is preferable to use the complex former in a molar excess.

Useful complex formers are in particular hydroxyethyl, hydroxypropyl and dihydroxypropyl ethers of β-cyclodextrins, additional mixed ethers in which they have corresponding mixtures, ethers, and methyl or ethyl groups, for example β-cyclo Methyl-hydroxyethyl, methyl-hydroxypropyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ether of dextrin.

The preparation of hydroxyalkyl ethers of β-cyclodextrins can be carried out using the method of US Pat. No. 34 59 731. Suitable methods for preparing β-cyclodextrin ethers are described in J. Chem. Starke 32, 165 (1980) by Szejtli et al. And Tetrahedron 39, 1417 (1983) by A. P. Croft and R. A. Bartsch. Mixed ethers of β-cyclodextrins may be selected from at least two different hydrides of β-cyclodextrin ethers in a basic liquid reaction medium containing alkali metal hydroxides, water and optionally at least one organic solvent such as dimethoxyethane or isopropanol. It can be prepared by reacting with an oxyalkylated etherification agent and any alkylation etherification agent (eg ethylene oxide, propylene oxide, methyl or ethyl chloride).

After conversion to inclusion compounds with β-cyclodextrin ethers described above, agents exhibiting significantly increased water solubility and improved stability have the required shape and size, i.e., agents suitable for the cavity of the β-cyclodextrin ring system. to be. Such agents include, for example, non-steroidal antirheumatic agents, steroids, cardiac glycosides, and derivatives of benzodiazepines, benzimidazoles, piperidine, pepperazine, imidazoles or triazoles.

Useful benzimidazole derivatives include thiabendazole, fuberidazole, oxybendazole, pavevenazole, cambendazole, mebendazole, penbendazole, flubendazole, albendazole, oxpendazole, nocodazole and Astelmisol. Suitable piperidine derivatives are flupyrrylene, pimozide, fenfluridol, loperamide, astemizol, ketanserine, levocarbastine, cisapride, altanserine and ritanserine. Suitable piperazine derivatives include lidofrazine, flunarizine, myanserine, oxatomid, myoflavin and sanarizine. Examples of suitable imidazole derivatives are metronidazole, ornidazole, ipronidazole, tinidazole, isoconazole, nimorazol, burimidamide, methamide, metomidate, enilconazole, ethomidate, echonazol , Clotrimazole, canidazole, cimetidine, docodazole, sulfonazole, paconazole, orconazole, butoconazole, triadiminol, thiocazole, valconazole, fluorotrimazole, ketoconazole, oxyconazole , Rollbazole, biponazole, oxymethidine, pantyconazole and tubulazole. Suitable triazole derivatives may be mentioned virazole, itraconazole and terconazole.

Particularly useful pharmaceutical compositions are those obtained by converting ethomidate, ketoconazole, tubulazole, itraconazole, levocarbastin or flunarizine into water soluble forms using the complex former of the invention. Therefore, in particular, the provision of the composition is an object of the present invention.

The present invention is also characterized by dissolving β-cyclodextrin in a mole and adding a selective agent thereto, and then drying a solution of an optionally formed encapsulating compound by a method known per se, which is poorly water-soluble or water-labile. It relates to a method for preparing a pharmaceutical composition of a medicament. Formation of the solution in the above method can be carried out at a temperature of 15 to 35 ℃.

Agents are added in batches as appropriate. The water may further contain physiologically suitable compounds, for example sodium chloride, potassium nitrate, glucose, mannitol, sorbitol, xylitol, or buffers such as phosphate, acetate, or citrate.

In the case of medicaments, the use of β-cyclodextrin ether ethers in accordance with the present invention, in case of unspecified or topical application, such as infusions and injections, drops (such as eye drops or nasal drops), sprays, aerosols, syrups and baths. It is possible to manufacture a medical bath.

The aqueous solution may also contain a suitable physiologically acceptable preservative such as quaternary ammonium soap or chlorbutanol.

For the preparation of solid preparations, the solution of the encapsulating compound is dried in a conventional manner, which can be evaporated by evaporation in a rotary evaporator or by lyophilization. The obtained residue is ground and optionally added with additional inert ingredients and then formulated with tablets, suppositories, capsules, creams or ointments with or without coating.

The following examples are presented to illustrate the present invention, but the present invention is not limited to these examples.

The phosphate buffer mentioned in the examples has a pH of 6.601 and has the following composition:

KH ₂ PO ₄ 68.05g

NaOH 7.12g

Distilled water is added to make 5000.0 g. All percentages below are in weight percent.

Using a 7% master solution of hydroxyethyl β-cyclodextrin (MS 0.43) in phosphate buffer as a starting material, a series of dilutions were prepared to increase the concentration of the complex former in 1% steps. do. 3 ml of these solutions are transferred to 5 ml snap-top-glasses containing the test agent using a pipette. After shaking for 24 hours at 25 ° C., the solution is filtered through a membrane filter (0.22 microns) and the dissolved drug content is determined spectrophotometrically. Figures 1, 3 and 4 show the increase in drug concentration in solution with the concentration of the complexing agent in the case of indomethacin (Figure 1), pyroxicam (Figure 3) and diazepam (Figure 4), respectively. Indicates. The highest drug concentration is limited by the saturated solubility of the cyclodextrin derivatives in the buffer, reaching 7.2 g / 100 ml for hydroxyethyl-β-cyclodextrin (MS 0.43).

For example, the results obtained in the case of indomethacin are compared with those presented for 2,6-di-0-methyl-β-cyclodextrin ether in Federal Republic of Germany Patent No. 31 18 218 (Figure 2). It can be seen that the hydroxyethyl derivative has a much larger complex formation constant (compare the different slopes of FIG. 1 and FIG. 2).

Example 2

A. Saturated solubility of several agents is measured at 25 ° C. using a 10% hydroxypropyl-β-cyclodextrin solution (MS0.35) in phosphate buffer under the same conditions as in Example 1. The saturation solubility, and phosphate buffer solutions S ₁ and 10% hydroxypropyl -β- cyclodextrin addition of saturated solubility S ₂ of from the in phosphate buffer are shown in Table 1.

TABLE 1

B. Drug solubility is measured in a similar manner in 4% aqueous solution of hydroxypropyl-methyl-β-cyclodextrin (DS 0.96: MS 0.43). The results obtained are summarized in Table 2 below, where the ratio R of solubility in the presence and absence of the added β-cyclodextrin derivatives, respectively, in water or at the indicated pH for each agent is indicated.

It has also been found that solutions prepared according to the invention are much more stable compared to aqueous solutions.

TABLE 2

Example 3

0.7 g of hydroxyethyl-β-cyclodextrin (MS 0.43) are dissolved with 0.04 g of indomethacin in 10 ml of phosphate buffer solution at 25 ° C. until a clear solution is formed. The resulting solution is filtered through a membrane filter (0.22 micron), filled in a pre-sterilized injection bottle in a linear flow manner and stored at 21 ° C. (B), saturated in phosphate buffer for parallel test. Indomethacin solution (0.21 mg / ml) is stored under the same conditions (A). The drug concentration measured by high pressure liquid chromatography is shown in Table 3. The composition according to the invention has been shown to significantly improve the stability.

TABLE 3

Example 4

(Injection type)

0.35 g of hydroxyrophyll-β-cyclodextrin (MS 0.35) is dissolved in 5 ml of physiological saline, cooled to about 35 ° C., and 3 mg of diazepam is added. If a clear solution is formed after storage for a short time, it is filtered through a membrane filter (0.45 micron) and then filled into ampoules.

Example 5

(refine)

In 100 ml of water, 7 g of hydroxyethyl-β-cyclodextrin (MS 0.43) and 0.5 g of hydroxyprogesterone acetate are dissolved. The water is then evaporated in a rotary evaporator. The residue (75 mg) was ground, and after adding 366 mg of calcium hydrogen phosphate 2H ₂ O, 60 mg of corn starch, 120 mg of cellulose powder (microcrystalline), 4.2 mg of highly dispersed silica (AEROSIL _L 200) and 4.8 mg of magnesium stearate, A tablet is prepared that weighs 630.0 mg and contains 5 mg of drug per unit formulation. The dissolution rate of hydroxyprogesterone acetate from this formulation is 21 times greater compared to tablets containing the same inactive ingredients without the addition of β-cyclodextrin ether.

Example 6

5 g of hydroxyethyl-β-cyclodextrin (MS 0.43) and 14 mg of vitamin A-acetate are dissolved in 2.5 ml of water or sugar solution (5% aqueous solution) within 2.5 hours under nitrogen atmosphere. After filtration through a membrane filter (0.45 micron), the resulting solution is filled into ampoules and sterilized or into a dropper bottle with 0.4% chlorobutanol added as preservative.

Example 7

5 g or 7.5 g of hydroxyethyl-β-cyclodextrin ether (MS 0.43) and 0.5 g or 0.75 g of lidocaine are dissolved in 100 ml of physiological saline at 30 ° C. (B). From this solution, injection solutions, eye drops and topical solutions are prepared according to the method described in Example 6. When the anesthetic effect of these solutions was compared with lidocaine HC1 aqueous solution (A) in animal tests, the duration of the effect was observed to be extended to 300%. Animal testing is performed by injecting 0.1 ml into the tail root of the rat near the left or right nerve fibers and subjecting them to electric shock. The test results are summarized in Table 4.

TABLE 4

Example 8

6 mg of dexamethasone and 100 g of hydroxyethyl-β-cyclodextrin ether (MS 0.43) are dissolved in 5 ml of water, filtered through a membrane filter (0.22 microns) and sterilized and filled in an aerosol container which disperses 0.1 ml per dose. Let's do it.

Example 9

Acute intravenous toxicity of several β-cyclodextrins was tested in rats to obtain the following results. Surprisingly, the toxicity of the derivatives used according to the invention has been significantly reduced.

TABLE 5

Note) No more than this was tested.

LD ₅₀ value in mice is> 4000 mg / kg. The hemolytic action of methyl ether according to Federal Republic of Germany Patent No. 31 18 218 was compared with the hemolytic action of the ether to be used according to the invention. For this cycle of physiological saline cyclodextrin content of 10% 100μ1, buffer solution (H ₂ O 200ml of _{MOPS 400mg, Na 2 HPO 4 .2H} 2 O 36mg, MaCL 1.6g) 800μ1 and human red blood cell suspension (washed three times with sodium chloride solution) 100 μl are mixed at 37 ° C. for 30 minutes. The mixture is then centrifuged and the absorbance measured at 540 nm.

Control bacteria: a) 100μ1 sodium chloride solution + buffer → 0% hemolysis, b) 900μ1mol → 100% hemolysis

The results obtained are summarized in Table 6 below, where the concentrations at which 50% and 100% hemolysis occurred were indicated.

TABLE 6

The above results indicate that the hemolytic action of hydroxypropylmethyl ether is about 5 to 8 times weaker than the hemolytic action of dimethyl ether of the prior art. Animal experiments have also demonstrated that hydroxyalkyl ethers, unlike methyl ethers, do not irritate mucous membranes and eyes.

Claims (14)

Pharmaceutical component in an aqueous solution of partially etherified β-cyclotextrin having a solubility of 1.8 g or more in 100 ml of water, a molar substitution degree of hydroxyalkyl substituents of 0.05 to 10, and a substitution degree of alkyl substituents of 0.05 to 2.0. A method of preparing a water-soluble complex of a poorly water-insoluble drug component and a β-cyclodextrin ether, wherein the water-soluble or water-labile pharmaceutical component is added. The method of claim 1 wherein the ether substituent of β-cyclodextrin is a hydroxyethyl, hydroxy flophyll or dihydroxypropyl group. The method of claim 2, wherein some of the ether substituents are methyl or ether groups. The method according to any one of claims 1 to 3, wherein the pharmaceutical ingredient and the β-cyclodextrin ether are used in a molar ratio of 1: 6 to 4: 1. 2. A method according to claim 1, wherein the pharmaceutical ingredient is a non-steroidal antirheumatic agent, steroid, cardiac glycoside or benzodiazepine, benzimidazole, pyreridine, piperazine, imidazole or triazole. 6. The method of claim 5, wherein the pharmaceutical ingredient is etomidate. 6. The method of claim 5, wherein the pharmaceutical ingredient is ketoconazole. The method of claim 5, wherein the pharmaceutical ingredient is itraconazole. The method of claim 5, wherein the pharmaceutical ingredient is levocarbastin. 6. The method of claim 5, wherein the pharmaceutical ingredient is flunarizine. 6. The method of claim 5, wherein the pharmaceutical ingredient is tubulazole. The method according to claim 1, wherein water is continuously removed from the obtained pharmaceutical solution, pulverized and then formulated into a solid preparation. The method of claim 1 wherein the aqueous solution of β-cyclodextrin ether contains additional physiologically acceptable components. The method of claim 13, wherein the physiologically acceptable component is saline, gurucohose, mannitol, sorbitol, xylitol, or phosphate or citrate buffer.

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