RU2060031C1 - Method of sarcolysin preparing for intravenous injection - Google Patents

Abstract

FIELD: chemical-pharmaceutical industry. SUBSTANCE: sarcolysin hydrochloride is dissolved in the solvent at the definite ratio. Solvent is prepared from ascorbic, glutamic (or aspartic), hydrochloric acids, ethanol, polyvinylpyrrolidone, D-mannitol or sorbitol and water for injection. Obtained solution is purified from mechanical inclusions, subjected for sterile filtration, dosing, freezing at temperature from -40 to -45 C and sublimating drying. EFFECT: enhanced quality of the pharmaceutical preparation, its safety. 1 dwg, 2 tbl

Description

 The invention relates to pharmaceutical technology and relates to the production of a sterile lyophilized dosage form for intravenous administration of an antitumor drug sarcolysin, a derivative of bis-β-chloroethylamine, which belongs to the class of alkylating compounds.

N

C

COOH
(C₁₃H₁₈Cl₂N₂O₂·HCl), мол. м. 341,67 один из наиболее активных противоопухолевых препаратов высокой избирательности и широкого спектра противоопухолевого действия.Sarcolysin D, L, α-aminoβ- [p-bis- (β-chloroethyl) aminophenyl] propionic acid hydrochloride

N

C

Cool
(C ₁₃ H ₁₈ Cl ₂ N ₂ O ₂ · HCl), mol. m. 341.67 is one of the most active antitumor drugs with high selectivity and a wide spectrum of antitumor effects.

 It is used for testicular seminoma and its metastases, reticulosarcoma, malignant angioendothelioma, Ewing's tumor and myeloma. It is widely used in combination with other anticancer drugs.

As a prototype, a method for producing sarcolysin for intravenous administration was selected, according to which the dry powder of the substance sarcolysin is dosed by weight to 0.02-0.04 g into bottles with a capacity of 10-20 ml, corked with rubber stoppers and sealed with aluminum caps. Before use, the vial is administered 10-20 ml isotonic sodium chloride solution and warmed on a steam bath to 60-70 ^{° C,} cooled and introduced into the patient intravenously.

 The disadvantages of the method are the following: lack of guarantee of sterility of the drug; the inability to ensure a sufficient degree of mechanical purity of the solution intended for intravenous administration; the absence in domestic practice of disposable filter nozzles to ensure the mechanical purity of solutions and their sterility in clinical conditions.

Sarkolizin for intravenous administration as a dry powder, the substance is poorly soluble in water at room temperature to dissolve it in the sodium chloride isotonic solution required warming to 60-70 ^{° C,} except that the inconvenience of use, leads to hydrolysis and other irreversible physical-chemical transformations antitumor drug, which can cause weakening and worsening of its pharmacotherapeutic action. For this reason, the English firm "Wellcome" eliminated the need for a heating process by using special solvents and diluents.

 In addition, it is impossible to ensure the complete dissolution of sarcolisin and the manifestation of a spontaneous gelation process under clinical conditions in a drug intended for intravenous administration is possible, which can lead to tragic consequences.

 It is extremely difficult to observe all the precautions against the toxic effects of the dust of an easily electrified preparation in the industrial production of sarcolysin for intravenous administration in the form of dry powder, which is why plants are reluctant to take on the production of such drugs.

 A well-known foreign preparation “Alkeran” is obtained from a dry powder of a substance-analogue of sarcolysin melphalan by dosing into vials with a capacity of 25 ml of 0.1 g each (Wellcome, England).

 In order to dissolve melphalan under clinical conditions, Wellcome company proposes to use a specially developed solvent from an acid-alcohol solution and a diluent from an aqueous solution of potassium dihydrogen phosphate with propylene glycol, which are supplied to the preparation in two ampoules.

 To ensure sterility and exemption from mechanical impurities, this company offers a solution of the drug before administration to the patient to filter through a special disposable syringe nozzle.

 The above disadvantages of sarcolisin obtained by the prototype method negatively affected the wider use of this highly active antitumor drug in domestic medical practice, which necessitated the purchase of its expensive analogue Alkeran abroad (the cost of one unit of packaging of the proposed drug would be at 1992 prices 4.4 rub.). Its production sharply decreased and practically stopped, while oncology clinics and dispensaries with a limited arsenal of funds, especially in the periphery, are in need of highly active and relatively inexpensive domestic antitumor drugs.

The proposed method for producing sarcolysin for internal injection by dissolving the substance of sarcolisin in a solvent is that the substance of sarcolisin hydrochloride is dissolved in a ratio of 1:50 in a solvent prepared from 0.48-0.52 g of ascorbic acid, 0.48-0.50 g of glutamic acid (or 0.44-0.46 g of aspartic acid), 0.806-0.810 g of hydrochloric acid (ρ 1.1837), 2.036-2.056 g of 95% ethyl alcohol, 9.9-10.1 g of polyvinylpyrrolidone , m.m 12500 ± 300 (or iol.m. 25000-35000), 2.27-3.33 g of D-mannitol (or sorbitol) and 90-92 g of water for injection, the solution is purified from mechanical impurities, sterile filtration, dosing during bottles with a capacity of 10 ml, freezing at (-40) - (- 45) ^о С and freeze-drying.

 Before use in a clinical setting, 10 ml of injection water is added to the vial with the drug. The drug dissolves almost instantly (without heating).

Sarkolizin and excipients ascorbic acid, glutamic acid, ethyl alcohol, polyvinylpyrrolidone must meet the requirements of the State Pharmacopoeia X ed. pharmacopeia articles and relevant GOSTs;
Aspartic acid, D-mannitol or sorbite qualifications ChP; hydrochloric acid qualifications of special grade, regulated for medical substances by the relevant GOST or OST.

PRI me R 1. 2.0 g of sarcolysin hydrochloride-substance is dissolved in a solvent prepared from the following components, g: ascorbic acid 0.48-0.52, aspartic acid 0.44-0.46, hydrochloric acid ( ρ = 1.1837) 0.806-0.810, 95% ethyl alcohol 2.036-2.056, polyvinylpyrroliditone mol.m. 12500 ± 300) 9.9-10.1, D-mannitol 2.27-3.33, water for injection 90-92, subjected to purification from mechanical impurities, sterile filtration, dosing in bottles with a capacity of 10 ml, freezing at (- 40) - (- 45) ^about C and freeze-drying.

PRI me R 2.d 2.0 g of sarcolysin hydrochloride-substance is dissolved in a solvent prepared from the following components, g: ascorbic acid 0.48-0.52, glutamic acid 0.48-0.50, hydrochloric acid (ρ = 1.1837) 0.806-0.810, 95% ethyl alcohol 2.036-2.056, polyvinylpyrrolidone (mol.m. 25000-35000) 9.9-10.1, D-mannitol 2.27-3.33, water for injection 90-92, subjected to purification from mechanical impurities, sterile filtration, dosing in vials with a capacity of 10 ml, freezing at (-40) - (- 45) ^о С and freeze-drying.

PRI me R 3. 2.0 g of sarcolysin hydrochloride-substance is dissolved in a solvent prepared from the following components, g: ascorbic acid 0.48-0.52, glutamic acid 0.48-0.50, hydrochloric acid ( ρ = 1.1837) 0.806-0.810, 95% ethyl alcohol 2.036-2.056, polyvinylpyrrolidone (mol.m. 12500 ± 300) 9.9-10.1, sorbitol 2.27-3.33, water for injection 90-92, subjected to cleaning from mechanical impurities, sterile filtration, dosing in vials with a capacity of 10 ml, freezing at (-40) - (-45) ^about C and freeze-drying.

PRI me R 4. 2.0 g of sarcolysin hydrochloride-substance is dissolved in a solvent prepared from the following components, g: ascorbic acid 0.48-0.52, aspartic acid 0.44-0.46, hydrochloric acid ( ρ = 1.1837) 0.809-0.810, 95% ethyl alcohol 2.036-2.056, polyvinylpyrrolidone (mol.m. 12500 ± 300) 9.9-10.1, sorbitol 2.27-3.33, water for injection 90-92, subjected to cleaning from mechanical impurities, sterile filtration, dosing in vials with a capacity of 10 ml, freezing at (-40) - (-45) ^about C and freeze-drying.

 The proposed method for producing sarcolysin for internal injection solves many problems that negatively affected the use of this drug obtained by the prototype method, and which has not yet allowed the production of this effective antitumor agent to be established.

 The method of obtaining sarcolysin is easily reproducible, technologically advanced and affordable; provides the necessary degree of sterility and mechanical purity of the pharmaceutical product; does not require the use of special filtering nozzles for extemporal filtration of a drug solution before administration to a patient; provides both in the process of obtaining and in the process of using the drug, the easy solubility of sarcolysin without heating (60 times greater than in ordinary water), guaranteeing high reliability of the complete dissolution; increases the stability of the unstable substance sarcolysin in aqueous solution by an average of 5.9 times in comparison with the prototype.

 The whole process of obtaining an easily-electrifying and atomizing highly toxic drug sarcolysin for intravenous injection and, in particular, its most dangerous stage of dosing, is carried out with the drug in a dissolved state (or in the form of a frozen solution), which ensures compliance with all safety measures necessary when working with highly toxic antitumor drugs.

 Biological studies conducted with sarcolysin for intravenous injection, obtained by the proposed method, confirmed its equal effectiveness with the original substance of sarcolysin.

 Data confirming the positive effect of the invention are presented in table. 1.

As a result of physico-chemical studies using HPLC Stability sarkolizina obtained by the proposed method, it was found that within 5 hours of exposure solutions at 5, 10, 23, 25 and 40 ^{° C} there is a reduction of content sarkolizina in solution 1.17; 1.02; 1.08; 1.1 and 1.39 times, respectively; during this period sarkolizina content of the solution obtained according to the prototype sposobu- (without the required heating to 60-70 ° ^C) at ²⁵ ° C decreased to 1.56 times compared with the initial concentration.

 The hydrolysis rate in the prototype solution is on average 5.9 times higher than that in the solution prepared by the proposed method.

 The data of physical and chemical studies are given in table. 2.

Kinetic curves of hydrolysis of 2% sarkolizina solution prepared according to the proposed method, and a solution of the prototype at different temperatures are shown in the drawing, where curve 1 sarcolysine a prototype solution, lot 170392 (temperature 25 ° ^C); curves 2-6 Sarcolysin prepared by the proposed method (lot 2 180 592, temperature 40 ^C, 3 180 592 series, temperature ²⁵ ° C; lot 4 180 592, the temperature ^of 5 C 5 170 392 series, temperature 23 ^{° C;} lot 6 170 392, temperature 10 ^C).

Claims (1)

A method of producing sarcolysin for intravenous injection by dissolving the substance of sarcolisin in a solvent, characterized in that the substance of sarcolisin hydrochloride is dissolved in a ratio of 1 50 in a solvent prepared from 0.48 0.52 g of ascorbic acid, 0.48 0.50 g of glutamic acid or 0.44 0.46 g of aspartic acid, 0.806 0.810 g of hydrochloric acid, p 1.1837, 2.036 2.056 g of ethyl alcohol 95% 9.9 - 10.1 g of polyvinylpyrrolidone Mm 12200 12800 or Mm 25000 35000, 2.27 3, 33 g of D-mannitol or sorbitol and 90 92 g of water for injection, the resulting solution is purified from mechanical impurities, sterile filtration, dispensing, frozen at -40 ^o C -45 ^o C and freeze-dried.

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