CS237017B1 - Drug form of inorganic complex compounds of tetravalent platinum - Google Patents

Abstract

The invention relates to a pharmaceutical form of inorganic complex compounds of tetravalent platinum, which is used in particular in the treatment of cancer by administration in the form of injection or infusion.

Description

The invention relates to a pharmaceutical form of inorganic complex compounds of tetravalent platinum, which is used in particular in the treatment of cancer by administration in the form of injection or infusion.

Platinum complexes are a new class of effective anticancer drugs. For several years now, the inorganic divalent platinum complex cis-diaminidichloroplatinum complex (cis-DDP) has been widely used in the clinic. It is particularly effective against tumors of the urogenital tract, head and neck. However, new areas of application are constantly emerging. Its main disadvantages are that it damages the kidneys and is relatively poorly soluble. This means that it must be administered to the patient in a long-term infusion during hydration. These disadvantages seem to be eliminated by the analogous tetravalent platinum complex, which has been described many times in the literature and the preparation of which is described, for example, in patent Offenlegungsschrift 27 15 492, or in journals (for example, I. I. Cherniayev and N. N. Krasnovskaya, Zh. něorganicheskoj khimii 3, pp. 2024 to 2038, 1958).

Platinum complexes used in the clinic are supplied as a lyophilisate, where usually in addition to the active substance, mannitol or other substances are added. For example, the cis-DDP dosage form under the name Platinol (Bristol Myers), and analogous preparations from other companies (Roger-Bellon, Lachema, Farmitalia, etc.) contain 10 milligrams of cis-DDP, 90 mg of NaCl and 100 mg of mannitol in a lyophilisate. The dosage form of cis-diaminecyclobutane-1,1-dicarboxylate platinum complex (CBDCA) is also in the form of a lyophilisate, containing 150 mg of the active substance and 150 mg of mannitol. This type of dosage form was chosen because solutions of divalent platinum complexes are unstable. An aqueous solution of cis-DDP undergoes hydrolysis, forming toxic aquo- and hydroxo-complexes. The CBDCA solution releases reduced platinum metal over time.

The disadvantages of the lyophilisate dosage form are both in production and in use. The addition of mannitol is the most common source of non-standardity of the preparation; lyophilization is demanding on equipment and energy. The lyophilisate needs to be reconstituted by the consumer, which complicates the application. Therefore, even for unstable divalent platinum complexes such as cis-DDP, an attempt is made to develop a stabilized solution that would replace the lyophilisate. One such attempt is described, for example, in patent Offenlegungsschrift 29 06 700.

The essence of the dosage form of inorganic complex compounds of tetravalent platinum intended for the treatment of human diseases, especially of cancer origin, by parenteral administration is that it consists of a stable aqueous solution of an inorganic complex compound of tetravalent platinum with the structure I

NH3 OH Cl

NHs OH Cl

I in sterile pyrogen-free water at a concentration of 0.1 mg/ml to 25 mg/ml.

The dosage form of inorganic complex compounds of tetravalent platinum according to the invention is prepared in such a way that the inorganic complex compound of tetravalent platinum is dissolved in sterile pyrogen-free water optionally containing hydrogen peroxide H2O2 in a concentration of up to 5 mmol, preferably 1.5 to 2.5 mmol per liter, and sterilized at a temperature of 100 °C to 120 °C, preferably by immersion in a boiling water bath for 20 to 50 minutes.

Research has shown that an aqueous solution of cis-diamminedichloro-transdihydroxoplatinum complex is sufficiently stable to be used as a dosage form for injection. It has also been shown that the stability of this solution is sufficient for heat sterilization and that heating the solution in a boiling water bath is sufficient for reliable sterilization.

The advantage of the dosage form according to the invention is its economical production, since the active substance is dissolved in sterile, pyrogen-free water to the desired concentration, usually 20 milligrams per milliliter, filtered to ensure clarity, and the solution is uniformly filled into ampoules, which are heated in a boiling water bath after sealing. Another advantage is the ease of ensuring standard quality, since the dosage form contains only an aqueous solution of the active substance without any other additives. The advantage of the dosage form from the user's point of view is the easy application of the solution directly from the ampoule.

The invention is described below by way of examples, without being limited thereto.

Example 1

Cis-diamminedichloro-trans-dihydroxoplatinum complex (complex I) was dissolved in sterile pyrogen-free water to a final concentration of 20 mg/ml. The solution was pressure-filtered through a sintered glass filter with porosity S4 and uniformly filled into glass ampoules. The sealed ampoules were stored in the dark at temperatures of 45 °C, 60 °C and 90 °C. After 100 days, the ampoules were opened and measured spectrophotometrically. The spectra from 280 nm to 500 nm were recorded. The deviations of the curves at the three temperatures of the solutions maintained from the curve obtained with the fresh solution did not differ by more than + 3 %/o O. D. The deviations were not proportional to the temperature at which the solutions were stored.

Example 2

The solution of complex I was prepared and stored as described in Example 1. After opening, the contents of the vials were analyzed by high-performance liquid chromatography (HPLC). Spectra Physics 8000 instrument was used, Laboratory Instruments Sl VSK C-18 column, mobile phase H2O, methanol 60:40, flow rate 1.6 ml/min., detection at 225 nm, injection 10 The results are shown in the table.

Results of chromatographic analysis of 100-day incubated aqueous solutions of complex I

Incubation temperature Elution time Area under the curve °C s % total

Fresh solution 87 99.56 Fresh solution 87 99.45 heat 30 min 100 °C 45°C 92 99.21 60°C 95 99.93 90°C 91 90.16 355 0.023 477 4.53 539 5.28

Example 3

The solution of complex I was prepared as in Example 1 and stored for 100 days at 60 °C. The solution (P) incubated in this way was compared in terms of toxicity with the freshly prepared solution (S) using the quantal test method of the Czechoslovak Pharmacopoeia, 3rd edition, p. 114 et seq. The results are in Table 2. Table 2

Comparison of the toxicity of a solution of complex I after incubation for 100 days at 60 °C with a fresh solution.

Exam:

Toxicity

Object:

mouse, male weight 19 + 1 g

Application:

intravenous

Number of servings: 6

Number of animals in the group: 10

Dose range: 50 to 250 mg/kg

Efficiency: R (% j 101.73

Lower limit: Rl (% j 92.0

Upper limit: Rye (% j 112.7 e — 10.18 %

Prescribed maximum value for e (%):

Prescribed Interval for Ri and R2 100 R2

Example 4

The solution of complex I was prepared as in Example 1 with the difference that the water contained 2 mmol H2O2 in 1 liter, sealed in an ampoule and immersed in a boiling water bath for 30 minutes. After cooling, the solution was tested for sterility using a membrane filter according to the Czechoslovak Pharmacopoeia 3rd edition, pp. 158 to 161. The contents of the ampoule were found to be sterile. The absence of H2O2 was demonstrated by manganometric control.

Claims (2)

SUBJECT 1. A pharmaceutical form of inorganic complexes of tetravalent platinum for the treatment of human diseases, in particular of cancerous origin by parenteral administration, characterized in that it consists of a stable aqueous solution of an inorganic complex of tetravalent platinum of the formula I NH3 OH Cl \ l / Pt / 1 \ NH 3 OH Cl (I) in sterile pyrogen-free water at a concentration of 0.1 mg / ml to 25 mg / ml. 2. A process for preparing a dosage form according to claim 1, wherein the inorganic complex of tetravalent platinum of formula I is dissolved in sterile pyrogen-free water containing optionally hydrogen peroxide H2O2 at a concentration of up to 5 mmol, preferably 1.5 to 2.5 mmol per liter. sterilized at a temperature of 100 ° C to 120 ° C, preferably by immersion in a boiling water bath for 20 to 50 minutes.