DD293496A5 - METHOD FOR THE PRODUCTION OF AGENTS AGAINST RETROVIRAL DISEASES - Google Patents

Abstract

The invention relates to a production process for agents against retroviral diseases, in particular against HIV infections. It aims to provide highly effective and effective means for the therapy of such diseases in humans and, where appropriate, in livestock. The task associated with this objective is in each case solved in its various variants by adding a * of the general formula (LaPtIIXZ) with customary carriers and / or auxiliaries. The injectable or infusible therapeutic agents, which are based on active substances from this class of substances and are thus obtainable in the preferred embodiments of the invention, exhibit high efficacy and bioavailability with tolerable toxicity in the abovementioned application {anti-retroviral agents, cf. HIV infections; * including * injectable or infusible solution; Therapy in humans and possibly also in farm animals; high effectiveness; high bioavailability}

Description

Field of application of the invention

The invention relates to a method for the production of therapeutic agents against retroviral diseases, primarily against HIV infections. In particular, the invention relates to a method for preparing such agents for this purpose, in which high efficacy and good bioavailability are advantageously associated with a tolerable specific toxicity, in which there is thus a sufficient therapeutic index.

The field of application of the invention lies in the pharmaceutical research and industry, the field of application of the products according to the method, however, in human and possibly in veterinary medicine.

Characteristic of the known state of the art

It has since been recognized that retroviruses can cause malignant and other destructive diseases in the mammal, and in humans the causative agent for certain leukemias (abbreviated to these viruses: HTLV-1 to HTLV-3) and Acquired Immunodeficiency Syndrome (AIDS); HIV-1 and HIV-2), efforts are being made throughout the world with tremendous financial efforts as well as high-performance personal potentials to find or develop therapeutics with which this pandemic - which is still spreading - can be counteracted successfully. For example, on the one hand, the search for substances that can prevent or at least significantly inhibit an infection by these viruses or even a replication of the same, has been extremely intensified. At present, however, there is still no way for a vaccine to protect other individuals from infection.

Another focus of the effort is focused on providing effective agents for therapeutic agents against manifest diseases following a retroviral infection. But just in this area could not be achieved any major successes. Against AIDS comes so far on a larger scale, but only with varying success, only one means of application - the 1- (3'-azido-2 ', 3'-dideoxy-ß-D-erythro-pentofuranosythymidine.) With this therapeutic In addition, this difficult and expensive to produce substance AZT shows considerable toxic side effects and resistance phenomena, both of which limit their use lasting.This disadvantage could not be overcome by a combination therapy (including this drug).

The same drawback exists with other active substances which are currently being included in clinical trials as well as nucleoside analogues or anticoagulants: none of these active substances, even with any combination of them, has been able to achieve a) permanent healing still b) a longer-term treatment is feasible.

Object of the invention

The aim of the invention is to provide highly effective and effectively usable agents for the therapy of retroviral diseases, in particular of HIV infections, in humans and optionally also in livestock.

Representing the nature of the invention

The invention has for its object to describe a simple method, can be produced with the highly effective and effective means for the therapy of retroviral infections in humans and possibly also in farm animals.

According to the invention, this object is achieved in its basic feature by in each case a platinum coordination compound having the general structure

(LPt ¹¹ XZ) ⁺ ,

in which mean:

L = ammin or diisopropylamine, if a = 2, L = diaminocyclohexane, if a = 1, X = remainder of a monovalent mineral or. Carboxylic acid, Z = coordinatively unsaturated organic solvent of the alkyl sulfoxide type,

is added as active ingredient with conventional tröger and / or excipients.

This displacement of a material of the above characterization with customary carriers and / or auxiliaries is carried out in a 1-variant process in such a way that each of the basic masses obtained has a drug content of 0.2% by weight to 2.0% by weight to dragees , Gelatin capsules or suppositories can be formulated. On the other hand, in a second process variant, the addition of an active substance of the above characterization in aqueous solution with customary carriers and / or excipients is carried out so that each of the use solutions obtained when dimensioning an active substance content of also 0.1 wt .-% to 2 , 0 wt .-% can be converted into a directly applicable to the patient injection or infusion solution.

The excipients which are incorporated into the novel therapeutic agents preparable according to the present invention are usually non-toxic mediators for drug uptake in the organism known per se, as well as formulation auxiliaries, sweetening or flavoring agents and optionally Dyes, if the procedure according to the 1st method variant is used, ie a medium of firm consistency is obtained.

As excipients in this variant the known pharmaceutically acceptable stabilizing agents (alternative name: preservative) are used. If the new agents for the treatment of retroviral diseases, however, provided by the second variant of the method as use solutions for injection or infusion, come as a carrier, a pharmaceutically acceptable solvent (preferably sterile sterile or sterile physiological saline) and as excipients pharmaceutically acceptable stabilizing and pH-adjusting additives for use.

The therapeutic agents produced in this way are distinguished by a high specific anti-retroviral activity, coupled with a good bioavailability, with tolerable side effects (primarily with regard to nephrotoxicity, myelosuppression and anorexia) in combating the diseases mentioned.

In the preferred embodiment of the invention, the active principle of the total amount of platinum coordination compounds with the o. G. Structure each one substance from the compounds

cis-diammine-PlatindD-chloro-dimethylsulfoxidbzw

 cis-diammine-PlatindD-chloro-diethyl

comprehensive collection. These substances have been well known to the art world for a number of years; Also known for a number of years, the most effective method for producing these complex compounds. Preferably, the above therapeutic agents are further provided within the scope of the present invention as use solutions to be used on the patient for both injection and infusion. In order to obtain such use solutions, an active ingredient of the above characterization at pH values between pH 6.0 and pH 8.0 in

sterile aqua dist. or in sterile physiological saline solution with customary stabilizing and / or pH value-regulating excipients, wherein in each use solution thus obtained, the active ingredient content to an amount between 0.1 wt .-% and 2.0 wt .-% is measured. Particularly advantageous therapeutic agents of said indication are obtained here, for example, if sterile aqueous solutions (with water for injections, 5% glucose solution for injection or 0.9% saline for injections as a carrier) with

cis-diammine-platinum-O-chloro-dimethyl sulfoxide at pH 6.8 to pH 7.4 and a (active) content of 1.0% by weight

be prepared as an injection or infusion solution.

It is furthermore characteristic of the preferred embodiments of the invention that the sodium salts of mineral or of selected carboxylic acids are used as stabilizing auxiliaries for the preparation of said injection or infusion solutions. In particular, beneficial in this context

Sodium chloride, rhodanide, sulfate, sodium lactate, citrate or malonate

be resorted to.

The strikingly good anti-retroviral effect of the therapeutic agents prepared with the preferred platinum coordination compounds of the above characterization has hitherto been verified on selected in vivo test systems (mammalian test models).

The therapeutic agents prepared according to the method, on the basis of their good bioavailability, offer the possibility of reducing the viremia, i. H. To significantly reduce the virus content in the patient's blood and severely limit the degeneration of normal tissues occurring under defined conditions. In human medicine, these findings are of particular importance for the treatment of HIV infections in order to prevent the onset of the resulting diseases (AIDS, ARC) or to substantially inhibit the pathogenesis of these diseases.

In this indication, on the basis of the novel agents provided according to the method, in particular the various variants of a combination therapy with other substances already known per se with an anti-retroviral spectrum of activity (for example with the already mentioned AZT) should be taken into account so that they can still be used relatively low specific 'toxicity, which distinguishes the above-disclosed active ingredients from the class of said platinum coordination compounds or the recourse to these now producible new therapeutic agents of said indication, especially in long-term treatments yet non-negligible undesirable side effects can be further reduced.

Ausführungsbelsplel

cis-diammine-platinum (II) dichloride - cis-DDP - is dissolved in a concentration of c = 50 mmol in purified dimethyl sulfoxide at a temperature of 25 ° C.

After 2 days up to 120 days, the resulting equilibrium complex solution (stock solution) is incorporated in the following infusion scheme such that a dilution ratio of 1: 200 is maintained:

- Infusion of approximately 11 electrolyte infusion solution with glucose;

- Infusion of the equilibrium complex solution in 500ml electrolyte infusion solution with glucose;

- then infusion of 150ml mannitol infusion solution as well

- final infusion of 500ml electrolyte infusion solution with glucose (post-hydration).

The stock solution should be stored at a temperature of 4 ° C, excluding direct daylight and fluorescent lamps; the working solution is stable for 6 hours.

Claims (6)

1. A method for the production of agents against retroviral diseases, in particular against HIV Infections, with high bioavailability and tolerable toxicity, characterized in that a platinum coordination compound of the general structure (UPt ¹¹ XZ) ⁺ , in which mean: L = ammin or diisopropylamine, if a = 2, L = diaminocyclohexane, if a = 1, X = remainder of a monovalent mineral or. Carboxylic acid, Z = coordinatively unsaturated organic solvent of the alkyl sulfoxide type, mixed with customary carriers and / or auxiliaries. 2. The method according to claim 1, characterized in that one comprises a platinum coordination compound from the collection
cis-diammine-platinum O-chloro-dimethyl sulfoxide or
cis-diammine-Platinlllj-chloro-diethyl mixed with conventional carriers and / or excipients. 3. The method according to claim 1 and 2, characterized in that one - Added an active ingredient of the above characterization with conventional stabilizing and / or pH-regulating excipients and - Each basic mass thus obtained formulated with a drug content of 0.1 wt .-% to 2.0Gew .-% to dragees, gelatin capsules or suppositories. 4. The method according to claim 1 and 2, characterized in that one - Added an active ingredient of the above characterization in aqueous solution with conventional stabilizing and / or pH-regulating excipients and - Provides each use solution obtained in dimensioning an active ingredient content of 0.1 wt .-% to 2.0Gew .-% for injection or infusion to the patient. 5. The method according to claim 4, characterized in that one an active ingredient of the above characterization at pH values between pH 6.0 and pH 8.0 in sterile aqua dest. or in sterile physiological saline solution with conventional stabilizing and / or pH-regulating excipients Vesetzt and - Provides each use solution obtained in dimensioning an active ingredient content of 0.1 wt .-% to 2.0 wt .-% for injection or infusion to the patient. 6. The method according to claim 4 and 5, characterized in that one uses a sodium salt of a mineral or a carboxylic acid as a stabilizing adjuvant for the preparation of sawn active ingredient-containing injection or infusion solutions.