WO2003017975A2

WO2003017975A2 - Method for producing solutions

Info

Publication number: WO2003017975A2
Application number: PCT/EP2002/009776
Authority: WO
Inventors: Ralph E. Eckert
Original assignee: Molecular And Clinical Drug Research
Priority date: 2001-08-31
Filing date: 2002-09-02
Publication date: 2003-03-06
Also published as: DE10142416A1; WO2003017975A3; AU2002340848A1

Abstract

The invention relates to methods for producing aqueous solutions of water-insoluble substances by dissolving at least one pure substance in at least one water-miscible solubilizer and diluting in water the solution so-produced by adding water and/or an aqueous buffer solution.

Description

Process for the preparation of solutions

The invention relates to processes for the preparation of aqueous solutions of poorly water-soluble or substantially water-insoluble substances. The invention further relates to aqueous solutions which are produced on the basis of such a method and the use of such solutions.

One focus of drug manufacturing is the question of the pharmaceutical formulation of pharmacologically active ingredients. In addition to the shelf life of the active ingredient and the minimization of possible side effects due to the active ingredient, the bioavailability of the active ingredient is of crucial importance: the type of dosage form and the galenical formulation must ensure that the active ingredient is used over a defined period of time in a defined area of activity (e.g. on a specific organ or the entire blood circulation system). At the same time, the aim is to achieve the lowest possible side effects through the galenical formulation and additives used.

The formulation of water-soluble drugs does not generally pose any major problems, since their bioavailability is also guaranteed when given in solid form (e.g. as a dragee or tablet) and, on the other hand, liquid water-based formulations of such drugs are biocompatible with the human or animal organism are so that no solvent-related side effects (e.g. venotoxicity when injected) are to be expected during their application. However, a large part of the known medicinally active substances is essentially insoluble in water or is so insoluble in water that aqueous solutions of such substances do not have a sufficient concentration of substances in order to obtain a sufficient medicinal effect in the target organism.

Such substances are therefore mostly used in solid form. Liquid formulations based on organic solvents or solubilizers are also known, for. B. in ethanol, oils or fats or in organic solubilizers. It is also known to use mixtures of different organic solvents and / or solubilizers in order to produce liquid or viscous formulations of water-insoluble active substances. However, such formulations can predominantly be administered orally (e.g. in gelatin capsules). However, oral administration is not suitable for all indications.

Furthermore, it is known to use liquid organic solvent-based formulations (e.g. ethanol) as injection solutions. However, injections of such formulations are associated with severe pain due to tissue damage caused by the solvent.

There is therefore a need for novel liquid formulations of poorly water-soluble or essentially water-insoluble substances which can be used for the production of medicaments without the disadvantages known in the prior art.

^" This object is achieved according to the invention by a process for the preparation of aqueous solutions of sparingly water-soluble and essentially water-insoluble substances, in which the substance is first dissolved in at least one water-miscible solubilizer and then converted into aqueous solution by adding water and / or an aqueous buffer solution becomes.

The invention is based on the surprising result that, using at least one solubilizer which is miscible with H ₂ O, aqueous, Highly concentrated formulations of sparingly water-soluble or essentially water-insoluble substances which are soluble in the water-miscible solubilizer are available. Surprisingly, the sparingly water-soluble or essentially water-insoluble substances remain in solution even after the aqueous dilution of the substance-solubilizer mixture and do not precipitate out even with strong dilution (and thus low concentration of solubilizer in the final dilution). In addition, the substances remain pharmacologically active even after aqueous dilution.

The aqueous solutions prepared in this way can be used to produce a wide variety of pharmaceuticals based on known and previously unknown substances. The new formulation of known substances is expected to improve efficacy in known indications. In addition, pharmaceuticals can be manufactured on the basis of known active substances, which are used for a much wider range of indications. For example, in the case of essentially water-insoluble or sparingly water-soluble active substances which have hitherto been predominantly used in solid form, it can now also be assumed that these can be used for the production of eye drops or injection solutions.

Substances which are practically insoluble in water (such as, for example, dihydropyridine derivatives) or which dissolve so little that such aqueous solutions are not or only to a very limited extent for the production of medicaments based are understood as essentially water-insoluble substances of these substances (because, for example, the medicinal effect of such solutions is too low due to the low concentration of active substance). The term "poorly water-soluble substance" includes substances that are poorly soluble in water and more readily soluble in organic solvents (eg moxaverine hydrochloride). With these substances, the method according to the invention enables the production of highly concentrated aqueous solutions of the respective substance for the first time. The term "substance" includes the respective active substance in pure form, for. B. as a free base, free acid or as a pharmaceutically acceptable salt, ester or amide. Pharmaceutically acceptable salts are salts which are produced from pharmaceutically acceptable, non-toxic acids of the respective active substance.

Solubilizers are substances that improve the solubility of other substances. The solution can be mediated on the basis of complexation, by molecular variation and salt formation, by micelle formation (solubilization) or by improving the solution conditions as a result of structural changes in the solvent (cosolvation). According to the invention, cosolvents of water (i.e. organic solvents which can be mixed with water as desired) are preferably used as solubilizers, with the exception of ethanol. In principle, all solubilizers suitable for the production of pharmaceuticals in which the water-insoluble substances are readily soluble (i.e. more soluble than in water) and which are miscible with water can be used as solubilizers.

According to a further advantageous embodiment, aqueous polyvinylpyrrolidone (PVP) solutions with PVP concentrations suitable for the production of medicaments can also be used as solubilizers.

According to a preferred embodiment, by adding water or an aqueous buffer solution, the content of solubilizer in the finished aqueous solution is reduced to such an extent that it does not exceed 50% by volume,

^'is preferably less than 30%, particularly preferably less than 20% and in particular less than 10% by volume. Aqueous solutions with a content of 30 vol.% Or more of solubilizers are suitable as stock solutions for the manufacture of medicinal products which have to be further diluted, since only small concentrations of solubilizers (e.g. a maximum of 30 vol. % of polyethylene glycols) are allowed. Aqueous dilutions with less than 30% by volume of solubilizer can be used as a medicament or for the production of medicaments without further dilution. According to a further preferred embodiment, one or a mixture of different polyalkylene glycols are used as solubilizers. Because of their physiological compatibility, polypropylene glycols or polyethylene glycols are particularly suitable. The use of polyethylene glycols is particularly preferred. Polyethylene glycols are characterized by good solubility with unlimited miscibility with water and good compatibility.

In the process according to the invention, polyethylene glycols with an average molecular weight (weight average) between 200 and 2000 are particularly suitable, since they are essentially liquid at room temperature. In addition, polyethylene glycols in this molecular weight range are distinguished by the fact that they are particularly suitable for the preparation of highly concentrated solutions of poorly water-soluble substances. It is possible with polyethylene glycols with an average molecular weight in the range from 200 (PEG 200) to 1000 (PEG 1000) to produce particularly highly concentrated substance solutions. The use of PEG 400 as a solubilizer is particularly preferred.

According to a further preferred embodiment, the process according to the invention includes a process step in which a desired pH value is set. The type of pH desired depends on the type of use of the aqueous solution to be prepared. The pH is expediently adjusted by adding a suitable buffer (usually in

^{* '"Form} the base of a weak acid or a weak base of the ^{acid)' •} and setting the desired pH value z by adding a suitable acid or base (. B. HCI, NaOH or KOH). Since the inventive method is particularly Suitable for the production of injection solutions is the setting of an essentially physiological pH (that is in the range from 7.0 to 8.0, preferably between 7.3 and 7.5) and in particular a physiological pH of approx. 7 , 4 particularly preferred.

The addition of other substances which do not serve as active substances is also expedient, for example in addition to the substances mentioned further customary formulations and additives (depending on the particular determination of the aqueous solution) are added. Since the use of the smallest possible number of additives minimizes the risk of side effects, the number of additives is kept as low as possible. This purpose also benefits if the aqueous solution according to the invention contains only a single solubilizer, preferably polyethylene glycol (in particular PEG 400). Optionally, the addition of active ingredient stabilizers may be necessary in order to increase the stability of the essentially water-insoluble or sparingly water-soluble substances (for example physiologically compatible dyes in the case of light-sensitive substances). The type of such formulations and additives is generally known to the person skilled in the art.

It may also be expedient to add one or more electrolytes to the aqueous solution. The type of electrolytes added and their concentration in the finished aqueous solution depend on the particular determination of the aqueous solution. These can differ in the case of aqueous solutions which are used as drops to be administered orally or serve as the basis of an aqueous active ingredient gel from those of aqueous solutions which are expedient for intravenous injection solutions. According to a particularly expedient embodiment, the finished aqueous solution has an essentially isotonic and preferably isotonic setting (ie an at least essentially isotonic electrolyte concentration and / or an at least essentially isotonic electrolyte composition. For aqueous solutions which are used as stock solutions to be diluted it is against it

^• expedient if these have a correspondingly higher concentration

Have electrolyte content.) This can be done, for example, by setting

Table salt, with conventional Tyrode buffers or other buffers suitable for the preparation of medicinal solutions, as is known to the person skilled in the art.

It is also expedient to use buffer substances or buffer solutions which serve to set a suitable pH value and a suitable electrolyte concentration. It has been found that the solution of the water-insoluble substance or substances in the undiluted solubilizer in the temperature range between 15 and 50 ° C and preferably between 20 and 40 ° C, particularly preferably between 35 and 39 ° C and in particular at about 37 ° C is useful is. At these temperatures, the difficult to dissolve or essentially water-insoluble substances dissolve particularly well in the solubilizer, which is particularly true for polyethylene glycols and especially for polyethylene glycols in the range of average molecular weight between 200 and 600. At the same time, the temperatures are low enough so as not to have a negative effect on the stability of most substances which are poorly or substantially water-insoluble, so that a loss of activity in the end product is avoided. (For polyethylene glycols with average molecular weights in the upper range of the range given above, a solution of the water-insoluble substances at temperatures above 20 ° C is advisable due to their higher and temperature-dependent viscosity.)

The process is particularly suitable for the preparation of aqueous solutions of sparingly or substantially water-insoluble substances which are soluble in alcohols, preferably in ethanol, for example alkaloids and their salts. Isoquinoline derivatives, in particular moxaverine, are particularly suitable here. Dihydropyridine derivatives, in particular nifedipine or nifedipine analogs, preferably nitrendipine, nimodipine, nisoldipine or felodipine, are also particularly suitable. The invention further relates to aqueous solutions of poorly or substantially water-insoluble substances which are produced by the process according to the invention. "^'' In a preferred embodiment, the invention relates • • aqueous solutions of isoquinoline derivatives and / or dihydropyridine Deriväten relates, in particular those listed above.

The invention also relates to the use of the aqueous solutions according to the invention for the production of medicaments.

Depending on the indication, it may be appropriate for a mixture of several poorly or substantially water-insoluble substances or a mixture of one or several poorly or substantially water-insoluble substances are contained with one or more water-soluble substances as active ingredients. The medicinally active constituents can (eg in the case of gel capsules which contain, inter alia, an aqueous formulation of poorly or substantially water-soluble and / or water-soluble substances) be contained in a formulation other than the aqueous formulation. However, all of the pharmaceutical constituents are preferably present in the aqueous formulation. In principle, all substances which are not contraindicated when the active ingredient (s) which are difficult or essentially water-soluble are applied and which have drug effects which are additive or synergistic to the action of the difficultly or essentially water-insoluble substance in which the substance is active can be used Active ingredients contained in the solution behave. In particular, the invention also relates to the use of the aqueous solutions according to the invention for the production of injection solutions.

The invention will be explained in more detail below with the aid of examples.

Step Example! 1 :

Preparation of a solution for injection containing nitrendipine

10 to 500 mg of nitrendipine (Sigma company) were dissolved in 10 ml of PEG 400 (Sigma company) with constant stirring on a hot plate at 37 ° C. After the solution was complete, 10 to 90 ml of 10 × concentrated Tyrode solution were added and 2M NaOH were then added dropwise until the pH was adjusted while stirring and with constant pH control until a pH of 7.4 was reached. The volume was then made up to a concentration of 1 to 10 mg / ml with H ₂ O bd. The finished stock solution with 1 to 10 mg / ml nitrendipine, pH = 7.4 and isotonic electrolyte concentration could be used directly after sterile filtration or further diluted with 1 x Tyrode solution to a desired nitrendipine concentration. Clinically 1 to 10 mg nitrendipine / ml are applied. Example 2:

Solubility of nitrendipine in aqueous solutions containing polyethylene glycol

Nitrendipine was completely dissolved as a pure substance in increasing proportions in 10 ml of commercially available polyethylene glycol with an average molecular weight of 200 or 400 (Sigma company, <1% H ₂ O) with constant stirring at a temperature of 37 ° C. Nitrendipine concentrations of up to 60 mg / ml could be achieved in undiluted polyethylene glycol. (For comparison: A maximum of 5 mg / ml can be dissolved in EtOH. Nitrendipine is practically insoluble in H ₂ O, <1 mg / ml.) The results are summarized in Table 1.

The dissolved nitrendipine was then transferred into aqueous solution with constant stirring by adding 1 x Tyrode solution with normal extracellular electrolyte composition and concentration. The solutions could be diluted as desired without the dissolved nitrendipine failing.

In order to determine the pH dependence of the dissolution behavior of nitrendipine, a pH of 7.4 was set in a further series of tests after the complete dissolution in undiluted PEG by adding NaOH. There were no precipitations.

The pH-neutral nitrendipine solutions prepared in this way could also be diluted as desired. The nitrendipine did not precipitate even at low PEG concentrations of 5% or less. The nitrendipine dissolved in it was active. The solutions remained stable for 3 months without the nitrendipine failing.

In comparison, attempts were made to dissolve nitrendipine in 5 - 10% PEG diluted with H ₂ 0 or with Tyrode solution under the same conditions. (I.e., analogous to the series of experiments shown in Table 1, 1 to 50 mg Nitrendipine (i.e. 1/10 of the amount dissolved in undiluted PEG) in 10 ml 10% PEG 400 or 0.5 to 25 mg nitrendipine (i.e. 1/20 of the amount dissolved in undiluted PEG) in 10 ml 5% PEG 400 and stirred at 37 ° C.) The direct solution of the pure substance in diluted PEG was however not possible in either diluted PEG 400 or diluted PEG 200. The solubility essentially corresponded to that in water.

Example 3:

Preparation of a solution for injection containing moxaverin

400 mg of moxaverin hydrochloride were dissolved in 10 ml of PEG 400 (Sigma) with constant stirring on a hot plate at 37 ° C. After the solution was complete, 4 ml of 10 × concentrated Tyrode solution were added and then 2M NaOH was added dropwise until the pH was adjusted while stirring and constant pH control until a pH of 7.4 was reached. The volume was then made up to 40 ml with H ₂ O bd. The finished stock solution with 10 mg / ml moxaverin-HCl, pH = 7.4 and isotonic electrolyte concentration could be used directly after sterile filtration or further diluted with 1 x Tyrode solution to a desired moxaverin concentration.

Example 4:

Solubility of moxaverin hydrochloride in aqueous solutions containing polyethylene glycol.

Moxaverin hydrochloride was used as a pure substance in increasing proportions (see Table 1) in 10 ml of commercially available polyethylene glycol with an average molecular weight of 200 or 400 (PEG 200 or PEG 400, Sigma company, <1% H ₂ 0) with constant stirring at Temperature of 37 ° C completely dissolved. Moxaverin concentrations of up to 40 mg / ml could be achieved in undiluted polyethylene glycol. (For comparison: A maximum of 200 mg / ml in EtOH and less than 1 mg / ml moxaverin hydrochloride in H ₂ O can be dissolved.) The dissolved moxaverin was then converted into an aqueous solution with constant stirring by adding 1 x Tyrode solution with normal extracellular electrolyte composition. The solutions could be diluted as desired without the dissolved moxaverin precipitating.

To determine the pH dependency of the dissolving behavior of moxaverin hydrochloride, in a further series of experiments after the complete dissolution in undiluted PEG, a pH of 7.4 was set by adding NaOH.

As can be seen from Table 2, the moxaverin-HCl dissolved in PEG 200 precipitated at concentrations of 35 mg / ml and more after neutralization. In contrast, the moxaverin dissolved in PEG 400 remained in solution even at high concentrations even after pH neutralization. The pH-neutral moxaverin solutions prepared in this way could also be diluted as desired. The moxaverin did not precipitate even at low PEG concentrations of 5% or less. The moxaverin HCI dissolved in it was active. The solutions remained stable for more than 6 months without the moxaverin failing.

For comparison, attempts were made to dissolve moxaverin-HCl in 5-10% PEG diluted with H ₂ O or with Tyrode's solution under the same conditions. (In other words, analogously to the series of tests shown in Table 2, 15 to 40 mg of moxaverin-HCl in 10 ml of 10% PEG 400 or 7.5 to 20 mg of moxaverin-HCl in 10 ml of 5% PEG 400 were added and stirred at 37 ° C.) However, the direct solution of the pure substance in diluted PEG was not possible in either diluted PEG 400 or diluted PEG 200.

Table 1

nitrendipine

A. dest

Ethanol 90%

PEG 200

PEG 400

Table 2

moxaverin

Solubility in 10 ml PEG 200. Temperature 37 ° C

Solubility in 10 ml PEG 400, temperature 37 ° C

Solubility of moxaverin in ethanol, temperature 26.6 ° C, pH meter calibrated, moxaverin-HCI, ethanol (pharmacy) 90%

Claims

claims

1. Process for the preparation of aqueous solutions of poorly water-soluble or essentially water-insoluble substances, the process steps

a) dissolving at least one water-insoluble substance in at least one water-miscible solubilizer and

b) Dilution by adding water and / or an aqueous buffer solution.

2. The method according to claim 1, characterized in that one or more polyalkylene glycols are used as solubilizers.

3. The method according to claim 2, characterized in that the polyalkylene glycols are polypropylene glycols and / or polyethylene glycols.

4. The method according to claim 3, characterized in that

Polyethylene glycols with an average molecular weight of 200 to 2000 can be used.

5. The method according to claim 4, characterized in that polyethylene glycol with an average molecular weight of 400 (PEG 400) is used.

6. The method according to any one of the preceding claims 1 to 5, characterized by the step of setting a desired pH.

7. The method according to claim 5, characterized in that the pH is adjusted by adding a suitable buffer and pH settings by adding a suitable acid or base.

8. The method according to any one of the preceding claims, characterized by setting a desired electrolyte concentration.

9. The method according to any one of the preceding claims, characterized in that the solution of the pure substance in or

Solubilizers at temperatures between 20 and 40, particularly preferably between 35 and 39 and in particular at about 37 °.

10. The method according to any one of the preceding claims, characterized in that the sparingly water-soluble or substantially water-insoluble substance is a substance soluble in ethanol.

11. The method according to claim 10, characterized in that the substance is an isoquinoline derivative.

12. The method according to claim 11, characterized in that the water-insoluble substance is moxaverin.

13. The method according to claim 10, characterized in that the

Substance is a dihydropyridine derivative.

14. The method according to claim 13, characterized in that the water-insoluble substance is nifedipine or a nifedipine analogue, preferably nitrendipine, nimodipine, nisoldipine or felodipine.

15. The method according to claim 14, characterized in that the substance is nitrendipine.

16. Aqueous solution of at least one water-insoluble substance, produced by a method according to one of the preceding claims.

17. Aqueous solution of at least one isoquinoline derivative, produced by a process according to one of claims 11 or 12.

18. Aqueous solution of at least one dihydropyridine derivative, prepared according to one of claims 13 to 15.

19. Use of an aqueous solution according to one of the preceding claims 16 to 18 for the manufacture of medicaments.

20. Use according to claim 19, characterized in that the medicaments are injection solutions.