RU2128042C1 - Antitumor agent - Google Patents

Abstract

FIELD: medicine, oncology. SUBSTANCE: invention proposes an agent that has chelate substance as a main component. The latter is a lyophilized substance of S-malatoammine-(cyclo-pentylamino)-platinum (II) and water for injection as an additional agent. The proposed agent shows high antitumor activity and low toxicity. EFFECT: enhanced effectiveness, simplified technology, decreased cost. 6 tbl, 3 ex

Description

The invention relates to medicines, namely to antitumor drugs, and can be used in chemical therapy for the treatment of malignant neoplasms
A lyophilized preparation from the class of platinum compounds is known which is manufactured by Lahema in the Czech Republic under the name Platidiam at 0.01.0.025 and 0.05 g in vials (Platidiam. Primary documentation Lahema, National enterprise, g Brno, Czech Republic). The composition of the drug "Platidiam" includes: cis-diammine dichloroplatin, mannitol, sodium chloride, 0.1 N. hydrochloric acid solution and water for injection.

 Also known is a drug from the class of platinum compounds for the treatment of ovarian cancer, metastases of testicular tumors, breast cancer, prostate cancer, etc. Specific name: cis-diammine dichloroplatin (Cisplatin, Directory "Medicines" M.D. Mashkovsky, ed. "Medicine" Moscow, 1987, vol. 2, p. 450.). The well-known drug called "Cisplatin lyophilized" at 0.01 g in ampoules per 10 ml was produced by the Association "Moskhimpharmpreparaty" im. N.A.Semashko in the following composition: cis-diammine dichloroplatin, D (-) - mannitol, D-sorbitol, sodium chloride, 0.1 N solution of hydrochloric acid, water for injection. (VFS 42-1797-88. Cisplatin 0.01 g lyophilized for injection).

The antitumor agents described above have several disadvantages.
1. Very poorly soluble in water (0.1 g in 100 ml of water).

 2. The multicomponent composition of the recipe.

 3. A large volume of lyophilization concentrate (10 ml in a single package).

4. Very complex (eutectic - 45 ^o C) and a long process of lyophilization.

 5. The drugs are very expensive.

 6. High nephrotoxicity, ototoxicity, neurotoxicity, large toxic manifestations from the gastrointestinal tract.

 7. A narrow spectrum of antitumor activity.

 The disadvantages listed above do not allow the wide and risk-free use of these effective drugs in wide medical practice. Currently, cisplatin is not produced by the domestic industry.

Currently, drugs based on platinum complex compounds are used as antitumor agents. The closest of them to the claimed is an antitumor agent, which is a complex compound of "second generation" platinum based on cyclobutane-1,1-dicarboxolate diammineplatinum, sold under the name - "Carboplatin". This drug is produced by various companies in the world in the form of a dry powder of 0.05, 0.15 and 0.45 g in a vial, as well as in the form of an aqueous concentrate for infusions of 5, 15 and 45 ml in vials (1 ml of water contains 0, 01 g of active substance). (Vidal Handbook "Medicinal Products in Russia", 1996, p. B 291-292.). Carboplatin is not reproduced by domestic industry and also has a number of disadvantages:
1. Not high enough carboplatin activity. (Table N 1,2,3,4).

 2. Lack of selectivity of antitumor action.

3. Has nephrotoxicity, ototoxicity, neurotoxicity, pronounced inhibits hematopoiesis. (Medicines in Russia. VIDAL'S HANDBOOK, 1996)
4. The drug is very expensive (0.1 g of the drug costs $ 30- $ 36).

 The anticancer agent for injection "Carboplatin" is accepted by us as a prototype.

In this regard, the developers faced the challenge - to create a domestic drug from this class of compounds with less side effects, eliminating all of the listed disadvantages of the prototype, while maintaining pharmacological activity
The proposed tool contains S-malatoammine (cyclopentylamine) platinum (II) lyophilized. This is a new domestic antitumor drug from the class of second-generation platinum complex compounds.

 The aim of the invention is to eliminate the disadvantages of the prototype.

This goal is achieved in that the injectable antitumor solution containing the platinum complex compound and water as the platinum complex compound contains the lyophilized substance S-malatoammine (cyclopentalamine) platinum (II) in the following ratio, wt.%: S-malatoammine (cyclopentylamine) platinum (II) - 9.5-10.5 Water for injection up to 100.0 ml
The inventive antitumor injection solution is obtained by dissolving S-malatoammine (cyclopentylamine) platinum (II) by the volumetric method in water for injection, after which the solution is subjected to sterile filtration through 0.22 μm Millipor filters, dispensed into 10 ml vials, frozen to temperature - 45-50 ^o C, maintained at this temperature for about 3 hours and sublimated (total drying time about 24 hours). As a result, a lyophilized form of the drug is obtained in vials of 0.05, 0.1, 0.15 g.

The invention is illustrated by the following examples:
Example 1

Lyophilized substance
S-malatoammine (cyclopentylamine) platinum (II) - 9.50 g
Water for injection up to 100.0 ml
Example 2

Lyophilized substance
S-malatoammine (cyclopentylamine) platinum (II) - 10.0 g
Water for injection up to 100.0 ml
Example 3

Lyophilized substance
S-malatoammine (cyclopentylamine) platinum (II) - 10.5 g
Water for injection up to 100.0 ml
The advantages of the claimed antitumor agent.

 1. High antitumor effect and a wide range of antitumor effects (Table 1, 2, 3, 4, 5).

 2. It is soluble in water.

 3. Small lyophilization volume per unit of packaging.

 4. The lyophilization process is simple and takes only 22-24 hours.

 5. A sufficiently high selectivity of antitumor activity compared with the prototype.

 6. Does not have nephrotoxicity, ototoxicity, neurotoxicity.

 7. The inventive drug is 3 times cheaper than the prototype.

 8. Providing the domestic market with a highly effective, domestic, antitumor agent.

When evaluating the antitumor effect of the claimed drug in comparison with the prototype (carboplatin), the following models of transplantable tumors of mice and rats were used:
Tumor strains - Type, line and sex of animals
a) Hemoblastoses - mice
P388 - lymphocytic leukemia - DBA ₂ , BDF ₁ , males, females
L1210 - lymphoblastic leukemia - DBA ₂ , BDF ₁ , males, females
La - hemoblastosis - C ₅₇ BL ₆ males, females
MOPC406 - Plasmocytoma - BalB / c males, females
b) ascites forms of tumors
Hep. 22 - hepatoma 22 - C ₃ HA males, females
S 37 - sarcoma 37 - SHK males, females
AOE - Ehrlich ascites tumor - SHK males, females
LMTK - lymphogenous metastatic teratocarcinoma - F ₁ males, females
LMEK - lymphogenous metastatic embryocarcinoma - F ₁ males, females
c) Solid forms of tumors
CA 755 - breast adenocarcinoma - C ₅₇ Bl ₆ females
B16 - melanoma - C ₅₇ Bl ₆ WDR ₁ males
LLC - Lewis Epidermoid Lung Cancer - C ₅₇ Bl ₆ VDR ₁ males
Cervical cancer-5 - cervical cancer - female CBA
ACATOL - Colon Adenocarcinoma - Balb / c
C45 - Sarcoma - Outbred males, females
Leukemia and ascites forms of tumors were transplanted intraperitoneally, dosed at 1.0-1.2 x 10 cells / mouse in 0.3 ml of medium 199. Solid tumors were transplanted under the skin of the flank (closer to the armpit), introducing 50 mg of tumor suspension into each mouse (dilution 1:10) in 0.5 ml of 199 medium.

 Treatment was started 48 hours after tumor inoculation. When studying the effect of drugs on developing tumors, treatment was started on days 5–7 or 11 after tumor transplantation.

 The drugs were administered to animals in optimal therapeutic doses once, daily for 5 days or at intervals of 48-96 hours and 7 days. Used intravenous (iv), intramuscular (i / m), subcutaneous (s / c), and mainly intraperitoneal (i / b) methods of drug administration.

Criteria for evaluating the antitumor effect
The therapeutic effect was evaluated by the following indicators inhibition of tumor growth (T.R. O), increase in life expectancy (VL), and cure of animals (% of control).

У_к и Y_о - средние объемы опухолей в контроле и опыте (см³)

где СПЖ - средняя продолжительность жизни животных в контроле и опыте (дни)
Излечение животных представлено в процентах или в виде отношения числа выживших животных в группе (п/п₁).

U _to and Y _about - the average volume of tumors in the control and experiment (cm ³ )

where LNG is the average life span of animals in control and experiment (days)
The cure of animals is presented as a percentage or as a ratio of the number of surviving animals in the group (n / a ₁ ).

 Minimum criteria of activity: UPZ = 25%, T.R.O. = 50%. Animals were considered cured without relapse for at least 2-3 months after the end of treatment.

 Note: x) - resistant strains of leukemia L1210 to compounds of the nitrosoalkylurea group obtained in the experimental chemotherapy department of the ONC RAMS.

 xx) - resistant strains of leukemia L-1210 and P 388 obtained in the same place.

или

где ЛД - доза, вызывающая гибель указанного процента животных, а ЕД - доза, вызывающая УПЖ указанного процента животных.Chemotherapy index was defined as the ratio

or

where LD is the dose that causes the death of the specified percentage of animals, and ED is the dose that causes the VL of the specified percentage of animals.

 All therapeutic experiments were repeated at least 2-3 times. Statistical processing of experimental data was carried out on a Iskra 1030 microcomputer at a probability level of 95% and using Student's criterion. The difference was considered significant at P = 0.05.

 Thus, from the presented biological materials it can be seen that the proposed tool is a highly active drug in the treatment of a large number of transplanted tumors. It significantly exceeds carboplatin in the efficiency and breadth of its antitumor spectrum.

 The prototype carboplatin is significantly inferior to the claimed agent in terms of efficacy on all solid tumors used in animals and leukemia L1210, P388, La used in our experiments (Tables 2, 4, 5).

 From the data of table 6 it is seen that the antitumor activity of the inventive means obtained by freeze drying, corresponded to that in the substance on the basis of which it was prepared.

 Thus, the combination in the claimed antitumor agent of such positive properties as the manifestation of greater biological activity, significantly less side effects and lower toxicity, as well as the simplicity and speed of preparation, its significantly lower cost compared to existing foreign counterparts, will provide the domestic market with new effective antitumor drug from complex compounds of platinum "second generation".

Claims (1)

 Injection antitumor solution containing a complex compound of platinum and water, characterized in that as a complex compound of platinum it contains 0.05, 0.10 and 0.15 g of the lyophilized substance S-malatoammine (cyclopentylamine) platinum (II).

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