WO2003017991A2

WO2003017991A2 - Injection solution containing a dihydropyridin derivative

Info

Publication number: WO2003017991A2
Application number: PCT/EP2002/009778
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: AU2002331101A1; DE10142417A1; WO2003017991A3

Abstract

The invention relates to a drug containing an aqueous formulation of dihydropyridin derivatives with at least one water-miscible solubilizer.

Description

drug

The invention relates to a medicament which contains a dihydropyridine derivative as an active ingredient. The invention further relates to formulations of dihydropyridine derivatives and the use of dihydropyridine derivatives for the production of medicaments.

The substance class of the dihydropyridine derivatives comprises compounds which are known as substances with a variety of medicinal effects. So come dihydropyridine derivatives of the general structural formula

-. where R = CH ₃ or CH (CH ₃ ) 2; R ₂ = H, NO ₂ or Cl; R ₃ = NO ₂ , H, Cl; ^" and R ₄ = CH _3l CH ₂ -CH _3l CH ₂ -CH (CH ₃ ) ₂ , (CH ₂ ) ₂ -0-CH ₃ (in particular nifedipine, nimodipine, nisoldipine, nitrendipine and felodipine) are known to be coronary therapeutic agents, in particular with the treatment and long-term therapy of coronary heart failure and angina pectoris as well as in general in the treatment of peripheral and central arterial and coronary circulatory disorders. The substances mentioned are practically insoluble in water and are therefore mostly used in solid form or based on ethanolic formulations. The disadvantage of solid dosage forms is the comparatively poorer bioavailability compared to liquid formulations. In addition, these are mainly administered orally. However, oral administration is not suitable for all indications. However, the known liquid formulations based on ethanol are problematic because of the ethanol they contain: injections of these formulations are associated with venotoxicity and pain caused by the low pH and the ethanol.

Aqueous formulations of the substances mentioned with a physiological pH cannot be prepared because of their extremely poor solubility in water. The associated extremely low active ingredient concentrations could not be compensated for even by administering correspondingly large volumes.

There is therefore a need for pharmaceuticals based on the dihydropyridine derivatives mentioned, without the disadvantages associated with the formulations known in the prior art.

This object is achieved according to the invention by a medicament which contains, as an active ingredient, an aqueous formulation of at least one dihydropyridine derivative with at least one solubilizer which is miscible with H ₂ O.

The invention encompasses both medicinal products for treating humans and veterinary medicinal products. The number and type of the dihydropyridine derivatives contained in the aqueous formulation depend on the type of drug and the particular indication.

The invention is based on the surprising result that aqueous, highly concentrated formulations of dihydropyridine derivatives can be obtained using at least one H ₂ O-miscible solubilizer. The dihydropyridine derivative becomes miscible with H ₂ O. Solubilizer added, brought into solution and then adjusted to the desired dihydropyridine derivative concentration with H ₂ O or aqueous buffer solution. Surprisingly, the dihydropyridine derivatives remain in solution even after dilution of the solubilizer with water or aqueous buffer solution and maintain their activity. Moreover, unexpectedly, aqueous solutions of the dihydropyridine derivatives can be produced which have even higher concentrations of dihydropyridine derivatives than is possible in ethanolic solution.

The injection of the aqueous formulations according to the invention of the dihydropyridine derivatives mentioned is physiologically more tolerable than the ethanolic formulations of comparable concentrations, so that no painful tissue damage caused by ethanol occurs when the medicament according to the invention is administered parental (e.g. intravenous injection).

Since the administration of the medicament according to the invention does not cause any pain, larger volumes of liquid formulations of dihydropyridine derivatives, which also have higher concentrations of dihydropyridine derivatives, can be applied compared to ethanolic solution. Overall, much higher single doses can be administered.

A significant increase in the therapeutic benefit in the known indications of dihydropyridine derivatives, such as peripheral arterial or coronary occlusive disease, coronary heart failure, angina pectoris, etc., can thus be assumed.

In addition, the medicament according to the invention can be used on the basis of the novel formulation with a much wider range of indications. Highly concentrated water-based dihydropyridine derivative solutions can also be safely administered orally to alcohol addicts. Above all, however, there is now the possibility of parenteral and, in particular, intravascular application, e.g. B. systemic administration by intravenous injection. The medicament according to the invention thus makes it possible for the first time to use dihydropyridine derivatives in the intravascular therapy of coronary heart diseases or the peripheral one Application of dihydropyridine derivatives in the treatment of myocardial infarctions.

The medicament according to the invention can in principle be used in any dosage form which is suitable for the administration of aqueous dihydropyridine derivative solutions. For example, pharmaceuticals for oral, ocular, rectal and parentalaral (e.g. subcutaneous, intramuscular, intravenous, intracavernous, etc.) application are possible; however, the most suitable dosage form depends on the type and severity of the pathological condition to be treated. For example, drops for oral administration or eye drops are just as possible as ointments on an aqueous basis or soft capsules with at least partially liquid content. Injection solutions are particularly preferred embodiments, since the ethanolic solutions of dihydropyridine derivatives known in the prior art are of limited use as injection solutions.

The term dihydropyridine derivative includes the active ingredient as a free base and as a pharmaceutically acceptable salt, ester or amide. Pharmaceutically acceptable salts are salts which are prepared from pharmaceutically acceptable, non-toxic acids of the dihydropyridine derivatives.

Solubilizers are substances that improve the solubility of other substances. The solution can be mediated based on the complex

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

Solubilizers are preferably cosolvents of water (i.e. water-miscible organic solvents) with the exception of ethanol. As a solution broker, everyone can in principle

Suitable drug mediators in which the dihydropyridine derivatives are readily soluble (i.e. more soluble than in

Water, preferably at least as readily soluble as in ethanol) and which are miscible with water. According to a preferred embodiment of the invention, one or more of the following substances are used as dihydropyridine derivatives: nifedipine, nisoldipine, nitrendipine, nimodipine or felodipine. The use of nitrendipine (often also referred to as WL-nifedipine) is particularly preferred due to the good pharmaceutical effectiveness and stability.

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 preferred. Polyethylene glycols are characterized by their good compatibility and their excellent solution properties with unlimited miscibility with water.

Polyethylene glycols with an average molecular weight (weight average) between 200 and 2000 are particularly suitable for the production of the medicament according to the invention, since these 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 dihydropyridine derivative solutions. It is possible to produce particularly highly concentrated dihydropyridine derivative solutions with polyethylene glycols with an average molecular weight of 400 (PEG 400). Accordingly, the use of PEG 400 as a solubilizer is particularly preferred.

The use of aqueous polyvinylpyrrolidone (PVP) solutions with PVP concentrations, which are suitable for the production of medicaments, can also be expedient as solubilizers.

In addition to the substances mentioned, the medicinal product according to the invention may also contain other customary formulations and additives (depending on the particular form of the medicament and the particular indication). Since the use of the smallest possible number of additives minimizes the risk of side effects, the medicament according to the invention has the smallest possible number of additives. It is for this purpose it also benefits if the aqueous formulation of the medicament according to the invention contains only a single solubilizer, preferably polyethylene glycol (in particular with an average molecular weight of 400). It may be necessary to add physiologically compatible dyes to increase the stability of the dihydropyridine derivative or derivatives.

In order to minimize the risk of undesirable effects and to obtain formulations which are as thin as possible, it is advisable for the solubilizer content in the finished aqueous formulation to be as low as possible. According to a preferred embodiment, the content of polyethylene glycol in the aqueous formulation is at most 30% by volume, preferably less than 20% by volume and particularly preferably less than 10% by volume.

Depending on the indication, it may be expedient for the medicament according to the invention to contain one or more other active ingredients in addition to the dihydropyridine derivative. The active pharmaceutical ingredients can be contained in a different formulation than the aqueous formulation (e.g. in the case of gel capsules which contain, inter alia, an aqueous formulation of nitrendipine). However, they are preferably also present in the aqueous formulation. In principle, all substances which are not contraindicated when the dihydropyridine derivative (s) are applied and which have drug effects which are additive or synergistic can be considered as active ingredients

^'' Behavior of the dihydropyridine derivative behave. These can be substances with ^{* a} different pharmacological effect than those of the dihydropyridine derivative (in the sense of a supplement), but also those with essentially the same or similar pharmacological direction of action (e.g. active substances that promote blood circulation). One or more substances from the group of the α-receptor inhibitors and PDE inhibitors are preferably used as further active ingredients.

According to a particularly preferred embodiment of the medicament, the aqueous formulation has an essentially physiological pH between 6.0 to 8.0, preferably between 7.0 and 8.0, particularly preferably between 7.3 and 7.5 and in particular with a physiological pH of about 7.4. Such formulations with an at least essentially physiological pH are distinguished by particularly good tolerability, the injection of which is not associated with pH-related venotoxicity.

Such aqueous formulations with a physiological or at least essentially physiological pH are prepared by adjusting the pH with a conventional physiological buffer suitable for the preparation of medicinal solutions after dissolving the dihydropyridine derivative or derivatives and then diluting it to the desired final concentration. It has surprisingly been found that the dihydropyridine derivatives in such aqueous formulations are still stable and active and do not fail even after an essentially physiological pH has been set.

In this form, the medicament according to the invention is suitable for use in a particularly large spectrum of different indications. In addition to oral administration, not only intravenous injection, but also, for example, intramuscular or even intracavernous injection of dihydropyridine derivatives for local blood circulation promotion based on such an essentially pH-neutral formulation is possible without pain. In addition, such aqueous, pH-neutral formulations of dihydropyridine derivatives can also be used as eye drops without leading to local irritation.

The particular concentration of dihydropyridine derivative or derivatives in the drug and the total amount administered per dose depends in particular on the particular dosage form (gel capsule, oral drops, injection disorder, etc.), indication and the severity of the pathological condition to be treated. For intravenous systemic administration of nitrendipine, e.g. B. in the context of intravascular therapy of coronary heart disease, single doses of between 50 and 500 mg per dose with concentrations of 10 mg / ml nitrendipine and more are appropriate. With intracavernous injection as part of the erectile tissue injection therapy, single doses are from 0.5 to 15 and preferably from 1 to 10 mg nitrendipine, applied in a small volume, preferably 1 ml solution for injection, appropriately.

According to a particularly advantageous embodiment, the aqueous formulation of the medicament according to the invention has an essentially isotonic and preferably isotonic setting (i.e. an at least substantially isotonic electrolyte concentration and / or an at least substantially isotonic electrolyte composition). This can be done, for example, by adjustment with sodium chloride, with conventional Tyrode buffers or other buffers suitable for the preparation of medicinal solutions, as is known to the person skilled in the art.

A method is particularly suitable for producing the aqueous formulation of the medicament according to the invention in which the active ingredient (s) are dissolved in undiluted solubilizer, in particular in polyalkylene glycol and particularly preferably in polyethylene glycol, which is followed by the setting of a suitable pH and, if appropriate, the addition a suitable buffer to adjust an isotonic salt content based on the final dilution of the aqueous formulation, and add the addition of H ₂ O or aqueous buffer solution to the final volume.

It has been found that the preparation of the solution in the undiluted solubilizer in the temperature range between 16 and 40 ° C. and preferably at about 37 ° C. is particularly expedient. At these temperatures, the dihydropyridine derivatives dissolve particularly well in the solubilizer, which is particularly true for polyethylene glycols and especially polyethylene glycols in the range of average molecular weights between 200 and 2000; at the same time, the dihydropyridine derivatives remain stable in this temperature range, so that there is a loss of effectiveness in End product is avoided. (In the case of polyethylene glycols with average molecular weights in the upper range of the range given above, a solution of the dihydropyridine derivatives at temperatures above 20 ° C. is advisable due to their higher and temperature-dependent viscosity.) Due to the aqueous formulation of its active ingredient, the drug is basically suitable for all applications. In contrast to liquid formulations based on unphysiological solvents, it is also particularly suitable for dosage forms for which liquid formulations of dihydropyridine derivatives based on ethanol are unsuitable or have disadvantages (e.g. injection).

Due to the advantages associated with the new galenics compared to conventional ethanolic solutions of dihydropyridine derivatives, the medicament according to the invention enables the use of dihydropyridine derivative for the therapy of new indications. It is now possible to use dihydropyridine derivatives, for example, to treat erectile dysfunction.

To treat erectile dysfunction with dihydropyridine derivatives, these must be applied locally. Local injections, e.g. B. the intrauretral and especially the intracavernous. The conventional ethanolic formulations of dihydropyridine derivatives were unsuitable for this because of the pain caused by their injection. According to a preferred embodiment, the medicament according to the invention is therefore intended for the treatment of erectile dysfunction. The use of nitrendipine is particularly preferred here.

The invention further relates to the aqueous formulations of dihydropyridine derivatives described above and their use in the manufacture of medicaments. The invention also relates to injection solutions based on the aqueous formulation of dihydropyridine derivatives. With regard to the treatment of erectile dysfunction disorders, injection solutions are expedient which locally, e.g. B. are intended for intrauretral and in particular for intracavernous injection. In contrast, other injection solutions, for example for intravenous administration, may be expedient for the treatment of other pathological conditions. Due to the improved properties of the formulation of the invention compared to known formulations

Dihydropyridine derivatives can now be used in the local treatment of erectile dysfunction. The invention accordingly also relates to the use of dihydropyridine derivatives and preferably nitrendipine for the production of medicaments for the treatment of erectile dysfunction.

According to a particularly expedient embodiment, a medicament for the treatment of erectile dysfunction as an active ingredient has an aqueous formulation of between 0.5 to 15 mg and preferably between 1 and 10 mg nitrendipine per 1 ml final volume and furthermore contains in particular a maximum of 30%, but preferably less polyethylene glycol with an average molecular weight of approx. 400 and has an essentially physiological pH and an essentially isotonic electrolyte concentration.

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

Example 1:

Preparation of a solution for injection containing nitrendipine

10 to 50 mg of nitrendipine were dissolved in 10 ml of PEG 400 (Sigma) _below, with constant stirring on a hot plate at 37 ° C dissolved. After the solution was complete, 10 to 90 ml of 10 × concentrated Tyrode solution were added, and then 2M NaOH was added dropwise until the pH was adjusted with stirring and 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 shown 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 O or with Tyrode solution under the same conditions. (I.e., analogous to the series of tests shown in Table 1, 1 to 60 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.

Example 3:

Patient study: Comparison of the erectogenic potential of nitrendipine with PGE (prostaglandin E) 1 in SKAT responders

A group of 16 patients who had suffered from erectile dysfunction for one to two years and were satisfactorily adjusted with 10 to 20 μg PGE1 (erection levels in the range 4 to 5 on a scale from 0 to 5), intracavernous injections (erectile tissue injection therapy, SKAT) became more watery Solutions of nitrendipine administered. Radical prostatovisiculectomies had been performed in 8 of these patients. 6 of the patients were diabetic, 2 patients had peripheral arterial diseases.

1 to 10 mg nitrendipine was administered per injection in a solution for injection with a pH of 7.4 and isotonic salt concentration. In all of the 16 patients, the intracavernous application of nitrendipine led to the development of a complete penile erection (E5). No intrapenile pain associated with injection has been observed. Side effects such as priapism, prolonged erection or cadiovascular side effects were also not observed. The use of nitrendipine in erectile dysfunction in this study brought about the elimination of the pathological symptoms and the absence of undesirable side effects.

Claims

claims

1. Medicament, characterized in that it contains an aqueous formulation of at least one dihydropyridine derivative with at least one solubilizer which is miscible with H ₂ O.

2. Medicament according to claim 1, characterized in that nifedipine, nisoldipine, nitrendipine, nimodipine and / or felodipine are used as the dihydropyridine derivative.

3. Medicament according to claim 2, characterized in that the

Dihydropyridine derivative is nitrendipine.

4. Medicament according to claim 3, characterized in that it contains at least 0.5 mg / ml nitrendipine in the aqueous formulation.

5. Medicament according to one of claims 1 to 4, characterized in that the content of solubilizer in the aqueous

Formulation is at most 30 vol .-%, but preferably less.

6. Medicament according to one of claims 1 to 5, characterized in that one or more polyalkylene glycols are contained in the aqueous formulation as solubilizers.

7. Medicament according to claim 6, characterized in that the or the polyalkylene glycols are polypropylene glycols and / or polyethylene glycols.

8. Medicament according to claim 7, characterized in that the aqueous formulation contains polyethylene glycols with an average molecular weight between 200 and 2000 and preferably contains PEG 400.

9. Medicament according to one of the preceding claims, characterized in that it contains one or more other active ingredients.

10. Medicament according to claim 9, characterized in that one or more substances from the group of the α-receptor inhibitors, PDE inhibitors and / or the Ca antagonists are contained as further active ingredients.

11. Medicament according to one of the preceding claims, characterized in that the aqueous formulation has an at least substantially physiological pH and preferably a physiological pH.

12. Medicament according to one of the preceding claims, characterized in that the aqueous formulation has at least one essentially isotonic setting and preferably one isotonic setting.

13. Medicament with an aqueous formulation of a dihydropyridine derivative, which is obtained by dissolving the dihydropyridine derivative and, if appropriate, the further active ingredient (s) in undiluted solubilizer, adjusting a suitable pH and, if appropriate, diluting aqueous to the final concentration.

14. Medicament according to claim 13, characterized in that the solution of the dihydropyridine derivative and / or the other medicinally active ingredients at between 16 and 40 ° C and preferably at about 37 ° C.

15. Medicament according to one of claims 13 or 14, characterized in that a suitable buffer for isotonic adjustment of the aqueous formulation is added.

16. Medicament according to one of the preceding claims, characterized in that it is intended for parenteral administration.

17. Medicament according to claim 16, characterized in that it is intended for the treatment of erectile dysfunction.

18. Medicament according to claim 17, characterized in that it contains an aqueous formulation of nitrendipine with between 0.5 to 15 mg / ml and preferably between 1 to 10 mg / ml nitrendipine in the aqueous formulation and the aqueous formulation furthermore a maximum of 30 vol .-%, but preferably less PEG 400 and a pH between 7.3 and 7.5 and preferably of about 7.4.

19. Medicament according to claim 16, characterized in that it is intended for the intravenous treatment of peripheral arterial or coronary occlusive diseases.

20. Medicament according to claim 16, characterized in that it is intended for peripheral therapy of myocardial infarction.

21. Aqueous formulation of dihydropyridine derivatives according to one of the preceding claims 1 to 15.

22. Injection solution according to one of claims 16 to 20.

23. Solution for injection according to one of claims 17 or 18 for use in intracavernous injection.

24. Use of nitrendipine in the manufacture of a medicament for the treatment of erectile dysfunction.

25. Use of an aqueous formulation of dihydropyridine derivatives according to claim 21, for the manufacture of a medicament.

26. Use according to claim 25, characterized in that the dihydropyridine derivative is nitrendipine.

27. Use according to one of claims 25 or 26, characterized in that the medicament is a medicament for the intravenous treatment of peripheral arterial or coronary occlusive diseases.

28. Use according to claim 25 or 26, characterized in that the medicament is a medicament for peripheral therapy of myocardial infarction.

29. Use according to one of claims 25 or 26, characterized in that the medicament is a medicament for the treatment of erectile

Is malfunction.

30. Use according to one of claims 24 to 29, characterized in that the medicament is a solution for injection.