DD295987A5 - 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 pursues the goal of providing highly effective and effectively usable agents for the therapy of such diseases in humans and possibly also in livestock. Since this ielstellung associated task is in each case solved in their various variants by a platinum coordination compound of the general formula (formula) is mixed with conventional carriers and / or auxiliaries. The injectable or infusible therapeutic agents obtainable by using active substances from this class of substances, such as cis-DDP, iproplatin and carboplatin, in the preferred embodiments of the invention are distinguished by high activity and bioavailability with tolerable toxicity in the abovementioned application.

Description

cis-diammine-platinum (II) dichloride (-cis-DDP-),

cis-diammine-trans-dihydroxy-PlatindVl dichloride,

cis-diisopropylamine-trans-dihydroxy-platinil VJ-dichloride (-Iproplatin -), cis-diammine-platinum (II) - (1,1-cyclobutanedicarboxylate) (-carboplatinum), cis-diammine-platinum D-dilactate,

cis-diammine-platinum (II) lactate or

cis-diammine-platinum (II) malonate

as an active ingredient entält.

9. Composition according to claim 7 or 8, characterized in that it contains an active ingredient olbigert characterization in conjunction with conventional carriers and / or excipients.

10. A composition according to claim 7 to 9, characterized in that it is used in dimensioning an active ingredient content of 0.1 wt .-% bis2,0Gew .-% of the patient as a tablet, dragee, granules, gelatin capsule or as suppositories.

11. Composition according to claim 7 to 9, characterized in that it is in dimensioning of an active substance content of 0.1 wt .-% to 2.0Gew .-% at pH values between pH 2.5 and pH 7.5 on the patient used as injection or infusion solution.

12. Composition according to claim 9 and 11, characterized in that said injection or infusion solutions sterile aqua dist. or sterile physiological saline solution as a carrier.

13. Composition according to claim 9 and 11 and 12, characterized in that said injection or infusion solutions in sterile aqua dist. or in sterile physiological saline, an addition of a sodium salt of a mineral or carboxylic acid as a stabilizing adjuvant.

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 producing such agents for this purpose, in which high efficacy and good bioavailability are advantageously associated with a tolerable specific toxicity, ie, where there is 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-I and HIV-2), efforts are being made worldwide with enormous financial efforts as well as powerful personal potentials to find or develop therapeutics with which this pandemic, which is still spreading steadily, can be counteracted successfully. For example, on the one hand, the search for substances which can prevent or at least significantly inhibit an infection by these viruses or then a replication thereof, has been extremely intensively intensified. However, at present 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. However, even in this area can not be achieved any major success Against AIDS comes so far on a larger scale, but only with varying degrees of success, only one means of application - the 1- (3'-azido-2 ', 3'-dideoxy- ß-D-erythro-pentofuranosylthymidine With this therapeutic agent, however, only a temporary postponement of the mentioned disease can be achieved.Also shows this difficult and expensive to produce substance AZT significant toxic side effects and

Resistance phenomena, both of which sustainably limit their use. This disadvantage could not be overcome by a combination therapy (including this active ingredient).

In other active substances, which included both currently in clinical trials as are also expected to Nikleosidanaloga or the anticoagulants, there is the same disadvantage: None of these active ingredients, with none of created them combination a) has a permanent cure can be achieved still b) a longer treatment is feasible.

P.S.Sarin, Y.Taguchi et al. has recently been reported (see Chemical Abstracts, Vol 107, 1987, Unit 108862) for in vitro studies in which (in cell culture) the possible inhibitory influence of a number of selected chemical substances on the replication of the retrovirus HTLV-3 was tested , As can be seen from a secondary reference in Chemical Abstracts, these investigations also include the neutral complex known under the name carboplatin, i. The cis-diammine-platinum (II) - (1,1-cyclobutanedicarboxylate) has been included.

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.

Explanation of the essence 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

(L _a Pt " ^lv R ₂ X ₂ ), where

L = ammin or diisopropylamine, if a = 2,

L = diaminocyclohexane, if a = 1,

R = OH group or "-"

X = radical of a monovalent mineral or carboxylic acid, if b = 2 or

X = bivalent acid residue. Hydroxy carboxylic acid radical when b = 1,

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

This displacement of an active substance of the above characterization with customary carriers and / or excipients is carried out in a 1-process variant in such a way that each of the basic masses obtained is calculated to be tablets when the active substance content is from 0.1% by weight to 2.0% by weight Dragees, granules, 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 auxiliaries is carried out such that each of the use solutions obtained likewise has an active ingredient content of 0.1% by weight to 2% , 0Gew .-% can be converted into a directly applicable to the patient injection or infusion solution.

The excipients which are to be incorporated into the novel therapeutic agents which can be prepared according to the present invention are generally non-toxic mediators for drug uptake in the organism and formulation auxiliaries, sweeteners and, if desired, dyes, if appropriate the first variant of the present invention is used, d. H. a medium of firm consistency is obtained. As auxiliaries in this process variant, the known per se, pharmaceutically acceptable stabilizing agents (other name:

Preservative).

If, according to the second variant of the method, the new agents for the treatment of retroviral diseases are provided as use solutions for injection or infusion, the carrier used is a pharmaceutically acceptable solvent (preferably sterile sterile or sterile physiological saline solution) and pharmaceutically acceptable stabilizing agents 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 coordination compounds with o.g. Structure each one substance from the compounds

cis-diammine-platinum (II) dichloride (-cis-DDP-),

cis-diammine-trans-dihydroxy-PlatindVl dichloride,

cis-diisopropylamine-trans-dihydroxy-platinum VJ-dichloride (-Iproplatin -),

cis-diammine-PIatin (II) - (1,1-cyclobutanedicarboxylate) (-Carboplatin-),

cis-diammine-platinum (II) -dilaktat,

cis-diammine-platinum (II) lactate or

cisw-diammine-platinum (II) malonate

All these substances have been well known to the art for many years, so that cis-DDPs, for example, since 1844, have also been known for a number of years, the most effective methods of preparing these coordination compounds

Preferably, the above-mentioned therapeutic agents are further provided within the scope of the present invention as use solutions to be administered to the patient for both injection and infusion. To obtain such dosage forms, an active ingredient of the above characterization will be at pH's between pH 2.5 and pH 7.5 in sterile aqua least or in sterile physiological saline solution with customary stabilizing and / or pH regulating adjuvants, wherein in each so obtained use solution, the active ingredient content is measured to an amount between 0.1 wt .-% and 2.0Gew -% Particularly useful Therapeutic agents of said indication are obtained, for example, if sterile aqueous formulations (with water for injections, 5% glucose for injection or 0.9% saline solution for injections as a carrier) with

Ice DDP at pH 3 5 and an (active) content of 0.1% by weight,

- Iproplatm at pH 3.5 and a (active substance) content of 0.5% by weight or

Carboplatin at pH 7.5 and (active ingredient) content of 1.4% by weight

be prepared as injection or infusion solutions

It is further characteristic of the preferred embodiments of the invention that the sodium salts of mineral or of selected carboxylic acids are used in each case as stabilizing auxiliaries for the production of said injection or infusion solutions

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

be resorted to

In the preferred Austaukungsformen of the invention, it has also proven to be useful to pass the procedurally obtained use solutions in a conventional manner initially in intermediate forms of higher durability and from these at the respective time of use with the addition of sterile aqua dest, 5% sterile glucose solution or of 0.9% sterile saline solution then to prepare injection or infusion solutions, each having an active substance content in the above-disclosed standard ranges. As has been found, the so-called ready-to-use solution and the dry ampoule with active ingredient / stabilizer lyophilizate can become very are well used as such intermediate forms of higher durability

An excellent anti-retroviral effect of the therapeutic agents prepared with the preferred platinum coordination compounds of the above characterization has been verified in selected in vivo test systems (sucker test models) (see table annex)

The therapeutically prepared therapeutic agents offer, on the basis of their good bioavailability, the ability to significantly reduce the viremia, ie the virus content in the patient's blood and to significantly reduce the degeneration of normal tissues under certain conditions. With the active ingredients tested in the context of the present invention This advantageous viramic status, combined with a surprisingly pronounced long-term influence, is also achieved even at low dosage. In addition, selected representatives of this class of active ingredients only show themselves to be resistant to all other previously tested substances with regard to the sustained anti-retroviral action in the regimen "Therapy for the infected mammals These findings are of importance in human medicine especially for the treatment of HIV infections, leading to an outbreak of the resulting diseases shortly before the death of the control animals (AIDS, ARC) to prevent or to slow the pathogenesis of these diseases significantly

In these indications, on the basis of the procedural provided funds in particular also the various variants of a combination therapy with other, already known agents against retroviral infections or diseases (eg with the AZT mentioned above) into consideration, so that despite the comparatively low specific toxicity, which characterizes the above-disclosed active compounds from the family of platinum coordination compounds or the use of which can be prepared with therapeutic agents, especially in long-term treatments still non-negligible undesirable side effects can be further reduced

embodiments

example 1

1 injection bottle, as lyophilisate containing 10 mg ice DDP, 90 mg sodium chloride (low HCl addition, pH 3.5) as a stabilizer and 100 mg mannitol as Oberflachengerust-Tragerstoff is included in the following infusion scheme

- Infusion of ca 11 electrolyte infusion solution with glucose

- Infusion of ice DDP in 500 ml of electrolyte solution for infusion with glucose, whereby the dry ampoule is previously dissolved in 10 ml of water for injection

- then infusion of 150ml mannitol infusion solution so *. ~>

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

The thus-prepared infusion solution containing ice DDP is to be protected from daytime and fluorescent lamp light and has a shelf life of 8 hours

Bdlb / c mice infected with Rauscher leukemia virus were found to contain the spleen weight and reverse transcriptase findings reported in the Ta jel! Enaniiang

Example 2

To an aqueous solution of 180 mg of sodium chloride in 15 ml of water for injection is added while n / 10HCl (adjuvant) until a pH of 3.5 is reached. 10 mg of cis-DDP are added to this solution and the batch is stirred until complete dissolution. Subsequently, the pH is checked again and optionally corrected with n / 10 HCl to pH 3.5. The volume is then adjusted to 20 ml. Finally, it is sterilized by filtration.

The ready-to-spray solution obtained in this way is incorporated into the infusion scheme according to Example 1. The light protection against daylight and fluorescent lamp light must be observed in all reaction steps in which cis-DDP is in aqueous solution. As particularly suitable for this purpose, the light emitted by conventional high-pressure sodium vapor lamps has proven.

Balb / c mice infected with Rauscher leukemia virus were treated with this agent (shelf life of the use solution:

8 hours) obtained in the table annex findings with regard to spleen weight and reverse transcriptase.

Example 3

The procedure is as in Example 2, but with the difference that the drug solution is prepared with 50 mg of iproplatin.

The shelf life of the working solution is 8 hours.

Example 4

An injection vial containing 50 mg carboplatin as lyophilisate is diluted with one of the following solvents to a concentration of 10 mg carboplatin per ml:

- sterile water for injections;

- 5% glucose solution for injections;

- 0.9% NaCl solution for injection.

The solutions thus prepared, when dissolved in 5% glucose solution or 0.9% NaCl solution, can be further diluted with the same solutions to a final concentration of 0.5 mg / ml. When using water for injections as solvent, 5% glucose solution for injection or 0.9% NaCI solution for injection must be used for further dilution to the same final concentration (0.5 mg / ml).

Solutions of carboplatin prepared according to this protocol are stable for 8 hours.

In Balb / c mice infected with Rauscher leukemia virus, this agent was used to obtain the results in regard to spleen weight and reverse transcriptase indicated in the table annex.

Example 5

The procedure is as in Example 2, but with the difference that the drug solution with 20 mg cis-diammine-trans-hydroxy-platinum (IV) dichloride prepared wild. The shelf life of the working solution is 6 hours.

In Balb / c mice infected with Rauscher leukemia virus, this agent was used to obtain the results in regard to spleen weight and reverse transcriptase indicated in the table annex.

Example 6

1 injection bottle, containing as lyophilisate 50 mg of cis-diammineplatinum (II) dilactate, 50 mg of sodium lactate as stabilizer and 100 mg of mannitol as surface scaffold carrier, is incorporated into the infusion scheme explained in Example 1 (shelf life of the obtained use solution: 6 hours).

Example 7

1 injection bottle, containing as lyophilisate 50 mg of cis-diammineplatinum (II) lactate, 50 mg of sodium lactate as stabilizer and 100 mg of mannitol as surface scaffold carrier, is incorporated into the infusion scheme explained in Example 1 (shelf life of the use solution thus prepared: 6 hours).

Example 8

1 injection bottle, containing as lyophilisate 50 mg of cis-diammineplatinum (II) malonate, 50 mg of sodium malonate as stabilizer and 100 mg of mannitol as surface scaffold carrier, is incorporated into the infusion scheme explained in Example 1 (shelf life of the obtained use solution: 6 hours).

Table 1

Animal group treatment scheme Spleen weight g / animal Reverse transcriptase (dpm / μΙ serum) Control group 8 animals infected with RLV 1.7 ± 0.6 75000 Carboplatin in PBS i. p .: for 6 animals: 250 mg; 9. + 12. d. 500mg; 15.d. 0.4 ± 0.1 8,500 cis-diammine-trans-dihydroxy-platinum (IV) dichloride in PBS i. p .: for animals: 150 pg; 5th, 10th, 15th. 0.3 ± 0.06 11000

Test animals: mice of the strain Balb / c / Bln (Bockchen) All animals were infected with the virus of the Rauscher leukemia (RLV) on the first day of the experiment and killed on the 24th day.

The mean spleen weights and serum reverse transcriptase (RT) activity as a measure of viremia were determined.

PBS = phosphate buffered saline

Table 2

Animal group treatment scheme Spleen weight g / animal Reverse transcriptase (dpm / μΙ serum) Control group 10 animals infected with RLV 2.4 ± 0.4 143,000 Carboplatin in PBS i. p .: for 8 animals: 3 x 500μg, 11., 14., 18.d. 0.2 ± 0.06 0 cis-diammine-trans-dihydroxy-platinum (IV) dichloride in PBS i. p .: for animals: 3x150μg; 7th, 11th, 17thd. 0.4 ± 0.1 2000 cis-diammine-platinum (II) malonate in PBSi. p .: for 8 animals: 2x200μg; 11th, 17.d. 0.15 ± 0.02 0

Test animals: Balb / c / Bln mice (females) All animals were infected on the first day of the experiment with the Rauscher leukemia virus (RLV).

The mean spleen weights and serum reverse transcriptase (RT) activity as a measure of viremia were determined.

PBS = phosphate buffered saline

Table 3 a

Animal Group Spleen Weight Reverse transcriptase

Treatment regimen g / animal (dpm / μΙ serum)

Control group 10 animals infected with RLV

Killing of 6 animals on the 22nd d. 1.1 ± 0.5 10000

mean survival time of the 4 animals: 29 days p.i.

cis-DDPinPBSi. p .: , 19th d. 0.135 ± 0.01 1000 for 10 animals: 3x 80μg; 2., 9. d. Killing of 6 animals on 22.

Test animals: Balb / c / Bln mice (females) All animals were infected on the first day of the experiment with the Rauscher leukemia virus (RLV).

The mean spleen weights and serum reverse transcriptase (RT) activity as a measure of viremia were determined.

Untreated Balb / c mice have spleen weights between 0.09 g and 0.12 g.

PBS = phosphate buffered saline solution

Table 3 b

Animal group treatment scheme Spleen weight g / animal Reverse transcriptase (dpm / μΙ serum) Control group 8 animals infected with RLV leukocytes: 26,000 1.3 ± 0.5 100000 cis-DDPinPBSi.p .: for 7 animals: 3 x 50 μg; 11th, 15th, 19th d. Leucocytes: 6500 0.12 ± 0.035 6000

cis-diammine-trans-dihydroxy-platinum (IV) dichloride in PBS i. p .:

for 8 animals: 3 x200pg; 11., 15., 19.d. 0.14 ± 0.02 4000

Leucocytes: 9,800

Laboratory animals: mice of strain Balb / c / Bln (female, 8 weeks) All animals were infected on the first day of the experiment with the virus of Rauscher leukemia (RLV).

The mean spleen weights and serum reverse transcriptase (RT) activity as a measure of viremia were determined.

The killing of all animals took place on the 22nd day.

Leukocyte normal values: 4000 to 10,000.

PBS = phosphate buffered saline

Claims (3)

A process for the preparation 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 (L _a Pt ^luv R ₂ X _b ),
in which mean: L = ammin or diisopropylamine, if a = 2, L = diaminocyclohexane, if a = 1, R = OH group or "-" X = remainder of a monovalent mineral or. Carboxylic acid, when b = 2 or X = divalent acid radical or hydroxy-carboxylic acid radical, if b = 1, mixed with conventional carriers and / or excipients. 2. The method according to claim 1, characterized in that a platinum Koo.-dination compound from the collection cis-diamine-platinum (II) dichloride (-cis-DDp-), cis-diammine-trans-dihydroxy-PlatinflVJ dichloride, cis-diisopropylamine-trans-dihydroxy-platinum OVI dichloride (-Iproplatin -), cis-diammine-platinum (II) - (1,1-cyclobutanedicarboxylate) (- carboplatinum), cis-diammineplatinum (II) -dilactate, cis-diammine-platinum (II) -laktatbzw. cis-diammine-platinum (II) -manolat 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 of the base materials thus obtained formulated with an active ingredient content of 0.1 wt .-% to 2.0Gew .-% to tablets, dragees, granules, 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 of the use solutions thus 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 substance of the above characterization at pH values between pH 2.5 and pH 7.5 in sterile distilled water. or in sterile physiological saline solution with customary stabilizing and / or pH-regulating adjuvants and - Provides each of the use solutions thus 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 for the preparation of said injection or infusion solutions as a stabilizing excipient, the sodium salt of a mineral or a carboxylic acid. 7. Agents against retroviral diseases, in particular against HIV infections, with high bioavailability and tolerable toxicity, characterized in that it contains a platinum coordination compound of the general structure (L _a Pt "' ^lv R ₂ X _b )
contains as active ingredient, wherein L = ammin or diisopropylamine, if a = 2, L = diaminocyclohexane, if a = 1, R = OH group or "-" X = radical of a monovalent mineral or carboxylic acid, if b = 2 or X = divalent acid radical or hydroxy-carboxylic acid radical if b = 1. 3. Composition according to claim 7, characterized in that it has a platinum coordination compound of the collection