CS237017B1 - Medicine form of anorganic complex compounds of 4valence platinum - Google Patents

Abstract

The invention relates to an inorganic dosage form complex compounds of tetravalent platinum, which is mainly used in treatment cancer applications by injection or infusion.

Description

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

Platinum complexes are a new class of potent anticancer drugs. The clinic has been widely used in the clinic for the inorganic divalent platinum complex cis-diamindichloro platinum (cis-DDPj). It is particularly effective against tumors of the urogenital tract, head and neck. These disadvantages appear to be eliminated by an analogous tetravalent platinum complex which has been described many times in the literature, the preparation of which is described, for example, in Offenlegungsschrift 27 15 492, or in journals (for example, II Cerniaiev and NN Krasnovskaya, Zhur. nieorganicheskoj chimii 3, pp. 2024-2038, 1958).

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

The disadvantages of the lyophilisate dosage form are both in manufacture and in use. The addition of mannitol is the most common source of non-standard preparation; freeze-drying is equipment and energy intensive. At the consumer, the lyophilisate should be reconstituted, which complicates the application. Therefore, even with an unstable complex of divalent platinum such as cis-DDP, an attempt is made to develop a stabilized solution to replace the lyophilisate. For example, one such experiment is described in Offenlegungsschrift 29 06 700.

The essence of the dosage form of the inorganic complexes of tetravalent platinum for the treatment of human diseases, in particular of cancerous origin by parenteral administration, is that it consists of a stable aqueous solution of an inorganic complex of tetravalent platinum of structure I

NH 3 OH Cl

NH 3 OH Cl

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

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

Investigations have shown that the aqueous solution of cis-diamine-indichloro-transdihydroxoplatinate complex is sufficiently stable to be used as an injectable dosage form. Furthermore, it has 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 to reliably sterilize.

The advantage of the dosage form according to the invention is economical manufacture, 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. Another advantage is the easy assurance of standard quality, because Table 1 that the dosage form contains only an aqueous solution of the active substance without any other additions. The advantage of the dosage form for the user is that it is easy to apply the solution directly from the vial.

The invention will now be described by way of example and not by way of limitation.

Example 1

Cis-diamminedichloro-trans-dihydroxoplatinate 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 S4 porosity sintered glass filter and uniformly filled into glass vials. The sealed vials were stored in the dark at 45 ° C, 60 ° C and 90 ° Celsius. After 100 days, the vials were opened and measured spectrophotometrically. The spectra from 280 nm to 500 nm were registered. The deviations of the curves at the three temperatures of the maintained solutions from those obtained with the fresh solution did not differ by more than + 3 ° / 0. 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-resolution liquid chromatography (HPLC). Spectra Physics 8000, Laboratory Instrument Sl VSK C-18 column, mobile phase H2O, methanol 60:40, flow rate 1.6 ml / min, detection at 225 nm, injection 10 were used. Results are shown in the table.

Results of chromatographic analysis of 100 days of incubated aqueous solutions of complex I

Temperature incub. Elution time Areas under ° C with% total

Fresh solution 87 99.56 Fresh solution 87 99.45 zahř. 30 min 100 ° C High: 32 ° 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

A solution of complex I was prepared as in Example 1 and stored at 60 ° C for 100 days. The thus incubated solution (P) was compared in toxicity with the freshly prepared solution (S) by the Czechoslovak Pharmacopoeia Quantum Test, 3rd edition, p. 114 et seq. The results are shown in Table 2. Table 2

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

Exam:

Toxicity

Object:

mouse, male weight 19 + 1 g

Application:

intravenous

Number of doses: 6

Number of animals per group: 10

Dose range: 50 to 250 mg / kg

Efficiency: R (% j 101.73)

Lower limit: R1 (% j 92.0

Upper limit: Rž (% j 112.7 e - 10.18%

Prescribed maximum value for e (%):

Prescribed Interval for R1 and R2 100 R2

Example 4

A solution of Complex I was prepared as in Example 1 except that the water contained 2 mmol of 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 pages 158-161. The contents of the vial were found to be sterile. Manganometric control showed the absence of H2O2.

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.