Method for production of sterilized microcrystalline cis-dichlorodiamineplatinum (ii)
FIELD: pharmaceuticals, organic chemistry.
SUBSTANCE: invention relates to method for production of sterilized microcrystalline cis-dichlorodiamineplatinum (II). Claimed method includes heat treatment of microcrystalline cis-dichlorodiamineplatinum (II) salt of high purity (not less than 99.5 mol %) at 160°C for 6 hours.
EFFECT: new method for production of sterilized microcrystalline cis-dichlorodiamineplatinum (II).
2 ex, 3 tbl
The invention relates to a method of obtaining a national patent-friendly dosage forms "CIS-platinum sterilized, ready to use in chemotherapy of malignant diseases.
There are several ways to get sterilized CIS-platinum [1, 2]. They are based on dissolved salts of CIS-dichlorodiammineplatinum (II) in dimethylformamide followed by the addition of hydrochloric acid and the allocation of microcrystalline CIS-[Pt(NH3)2Cl2]. The resulting product is subjected to high-vacuum drying for 24 hours at a temperature of up to 42°C.
Closest to the claimed is a method for preparing a sterile CIS-platinum for injection .
To 90 ml of dimethylformamide is slowly added 10 ml of concentrated HCl at t=20-27°and With intensive stirring, add 4 g of salt CIS-dichlorodiammineplatinum (II) under the current N2for 1 hour, then the solution is filtered, and under sterile conditions to the filtrate for 5 min add 200 ml of sterilized-free About2of 0.1 N HCl, heated to 20-27°C. the Resulting thick yellow microcrystalline precipitate is filtered off, sucked off to apparent dryness", washed on the filter with sterile solutions of 10 ml free O2of 0.1 N HCl and 20 ml of acetone at t=20-27°C. Microcrystalline CIS-dichlorodiammineplatinum (II) dried the high-vacuum drying Cabinet at t=37-42° With in 24 hours. The output is 3.3-3.5 g (80-86%).
The disadvantage of this method  sterilization CIS-platinum is a relatively low yield of the main product, and is also quite lengthy, complicated and expensive procedure sterilization of the drug.
The aim of the invention is to increase the release of "CIS-platinum sterilized, eliminating complicated and costly procedure sterilization of the product.
This goal is achieved using a really high-purity substances, high temperature sterilization up to 160°C. Thus time is reduced and simplified processing procedure of the original salt, and eliminates the use of expensive drugs.
The essence of the invention consists in the following.
Microcrystalline salt of CIS-dichlorodiammineplatinum (II) is subjected to heat treatment at a temperature of 160°C for 6 hours (the time necessary and sufficient for the sterilization of dry products).
The basis of the proposed method to obtain the dosage form "CIS-platinum sterilized" based on these new results. Under normal conditions, long-term (5 years) and when heated in the temperature range up to 240°studied With "aging" antitumor substance, complex salts of CIS-dichlorodiammineplatinum (II) different degrees of purity [1, 2,3]. Found an increase in the resistance of a substance to the ageing depending on the purity of the drug. Defined temperature range stability up to 160°With antitumor substance satisfying the requirements of the temporary monograph .
The proposed method of obtaining drug CIS-platinum sterilized, ready to use, differs simplicity and accessibility implementation on a laboratory scale in comparison with commonly used pharmaceutical companies ways [1, 2]. But the proposed method is applicable only for really high-purity substances, containing, according to the requirements of the temporary monograph not less than 99,5% (mol.) salt of CIS-dichlorodiammineplatinum (II). Ways of microcrystalline salt of CIS-dichlorodiammineplatinum (II) [5, 6] satisfy these requirements. Samples obtained by other means, thermally unstable due to the decomposition of the essential organic impurities, in particular of dimethylformamide, and the recovery of platinum compounds to metal. That is why in pharmaceutical practice long-term low-temperature and costly sterilization ingredients. Instability is not quite pure drugs likely complicated catalyzed microdispersed decomposition products is torigny chemical and phase transformations and, consequently, changes in the phase and component compositions, including without heating.
The results are shown in examples 1 and 2 and in tables 1-3.
Example 1. 4 g of microcrystalline salt of CIS-dichlorodiammineplatinum (II)obtained by the method [5, 6], in a drying Cabinet was subjected to heat treatment at t=160°C for 6 hours. The obtained sample 1 after the heat treatment is a microcrystalline yellow substance, the weight of the substance remained unchanged. A comparative analysis of the original CIS-platinum and sample 1 different physico-chemical methods (XRF, UV spectroscopy, IR spectroscopy, elemental analysis) shows that the substance by heat treatment has not changed. The comparative analysis are shown in tables 1, 2, 3.
Example 2. 2 g of microcrystalline salt of CIS-dichlorodiammineplatinum (II)obtained by the method [5, 6], was subjected to heat treatment at t=190°C for 2 hours. The obtained sample 2 was a microcrystalline substance yellow-green color, the weight of the substance remained unchanged. A comparative study of the above physico-chemical methods indicates that sample 2 has a substance related to TRANS-[Pt(NH3)2Cl2]. That is at a higher temperature sterilization process is accompanied by the I-isomerization. Comparative data supporting this fact are given in tables 1, 2, 3.
X-ray data for the initial CIS-, TRANS-[Pt(NH3)2Cl2] and sterilized sample
|CIS-[Pt(NH3)2Cl2] source ||TRANS-[Pt(NH3)2Cl2] source ||Sample 1||Sample 2|
|d A||J/J0100%||d A||J/J0100%||d A||J/J0100%||d A||J/J0100%|
The characteristic frequency of deformation vibrations of ammonia source CIS-, TRANS-[Pt(NH3)2Cl2] and sterilized sample
|CIS-[Pt(NH3)2Cl2] source||TRANS-[Pt(NH3)2Cl2] source||Sample 1||Sample 2||Assignment|
Thus, the use of the proposed method to obtain domestic pharmaceutical form "CIS-platinum sterilized, ready to use for injection with a large output, using a simple procedure that has been heated to 160°C for 6 hours.
Sources of information:
1. U.S. patent No. 4302446, 01 F 15/00, 1981.
2. the Federal Republic of Germany patent No. 3133443, class C 01 G 55/00, 1988.
3. Jelihovsky N.N., Markov, V.F., Samatov A.G., Krasovskaya Apposes obtain CIS-diamminedichloroplatinum (II) A.S. No. 991705, class C 01 G 55/00, 1982.
4. Temporary pharmacopoeial article on pharmacological agent Cisplatinum FMS No. 42-1790-88, KTD No. 48.0572.008.86.
5. Starkov, A., Kirik S. D., Kabanov VI Bis-(μ-oxalato)tetraammineplatinum(II) as an intermediate product in the synthesis of CIS-platinum and method of reception. A.S. No. 1445144 the USSR, CL With 071 15/00, 1988.
6. Starkov, A., Kabanov V., Karpov, N., Borisov V.V., Malinovskaya L.M. Method of purification of CIS-dichlorodiammineplatinum(II) A.S. No. 1640920, CL 01 G 55/00, 1990.
7. ICPDS Data card 25-0610. USA, 1997.
8.ICPDS Data card 25-0609. USA, 1997.
The method of obtaining sterilized microcrystalline CIS-dichlorodiammineplatinum (II), characterized in that the microcrystalline salt of CIS-dichlorodiammineplatinum (II) not less than 99,5 mol.% purity to the main component is subjected to heat treatment at a temperature of 160°C for 6 hours
SUBSTANCE: preparation belongs to gestagen class as 17α-acetoxy-3β-butanoyloxy-6-methyl-pregna-4,6-dien-20-on allowing peroral application. The compound shows no toxic activity and has no androgenic side effect. It is found to be better than Depo-Provera gestagen used in clinical practice and possesses chemosensitizing activity. The preparation is obtained by megestrol acetate reduction with sodium borohydride with following product etherification with butyric acid anhydride. The reaction mixture is treated with ammonia solution after etherification with butyric acid excess being removed to increase output and target product separation.
EFFECT: enhanced effectiveness of treatment.
3 cl, 3dwg, 1 tbl
SUBSTANCE: method involves applying chlorocholine chloride as antitumor means.
EFFECT: enhanced effectiveness of treatment; reduced risk of adverse side effects manifestation; low toxicity.
SUBSTANCE: method involves preparing composition comprising epotilone analogs by dissolving said epotilone analog in aqueous butanol. The produced solution is dried in two stages to produce lyophilized product being lyophilized epotilone analog and pharmacological means for treating cancer diseases containing lyophilized epotilone analog.
EFFECT: high solubility of obtained product.
20 cl,1 tbl
FIELD: chemistry of metalloorganic compounds, medicine, oncology.
SUBSTANCE: invention relates to novel chemical compounds, namely, to complexes of palladium with heterocyclic ligands of the general formula (I): wherein R1 means-NH, oxygen atom (O), -CH2; R2 means two hydrogen atoms (2H), O; R3 means hydrogen atom H, CH3, CH2-CH2-NH2,-(CO)-CH3; X means chlorine (Cl), bromine (Br) atom; n = 1; m = 1 if R1 means -NH, O; R2 means 2H; R3 means H, CH3, CH2-CH2-NH2, -(CO)-CH3; n = 2; m = 1 if R1 means O, -CH2; R2 means O, 2H; R3 means H, CH3, -(CO)-CH3; n = 2; m = 3 if R1 means -NH; R2 means 2H; R3 means CH2-CH2-NH2 eliciting pharmacological, in particular, anti-tumor activity. Proposed compounds possess high activity and characterized by reduced toxicity as compared with anti-tumor preparations with platinum complexes.
EFFECT: valuable medicinal properties of complexes.
4 cl, 2 tbl, 10 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to derivatives of quinazoline of the formula (I): m means a whole number from 1 to 3; R1 represents halogen atom or (C1-C3)-alkyl; X1 represents -O-; R2 represents (C1-C5)-alkyl-R3 wherein R3 represents piperidine-4-yl that can comprise one or two substitutes chosen from (C1-C4)-alkyl and to their salts. Also, invention relates to methods for synthesis of these compounds and pharmaceutical compositions comprising compound of the formula (I) or its pharmaceutically acceptable salts as an active component. Compounds of the formula (I) and their pharmaceutically acceptable salts inhibit effect of VEGF that is a valuable property in treatment of different pathological states including cancer and rheumatic arthritis.
EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.
28 cl, 14 ex
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to using compound of the formula (I) as the first anti-tumor agent for preparing a medicinal preparation that in administration with the second anti-tumor agent prevents development of resistance of malignant cells to apoptosis as result of activation of NFKB by the indicated second anti-tumor agent. Invention provides enhancing effectiveness of treatment.
EFFECT: improved and valuable medicinal properties of agent.
15 cl, 4 tbl, 3 ex
FIELD: medicine, pharmacology.
SUBSTANCE: agent represents flavolignans chosen from silybinine, silydianine, silycrystine, dehydrosilybinine, their mixtures or extracts prepared from plant spotted milk thistle (Silybium marianum (L.) Gaertn) containing these components. Agent is used for inhibition of excessive or pathological proliferation of vascular endothelium. Proposed agent expands assortment of agents directed for treatment pathologies associated with angiogenesis disorders. Invention can be used in development of medicinal preparations used in therapy of pathologies associated with angiogenesis disorders, namely, for inhibition of excessive or pathological proliferation of vascular endothelium.
EFFECT: valuable medicinal properties of agent.
1 tbl, 2 dwg, 2 ex
FIELD: medicine, pharmacology, pharmacy.
SUBSTANCE: invention relates to a method for enhancing availability of epotilone analog. Method involves oral administration of epotilone analog or its pharmaceutically acceptable salt, solvate, clathrate, hydrate or a prodrug in mammal in combination with pharmaceutically acceptable buffer neutralizing acid in the amount providing at least 20 mequiv. of capacity for acid neutralization that results to improving bioavailability of epotilone.
EFFECT: improved properties of formulations of drug.
20 cl, 5 tbl, 2 dwg, 9 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to a composition used in solubilization of paclitaxel. The composition comprises the following components, wt.-%: monoolein, 40-89.99 (or 40-64.7 as variants); oil, 10-59.99 (or 25-49.7 as variants), and paclitaxel, 0.3-4 (or 0.01-10 as variants), and to a method for preparing such composition. Paclitaxel-containing compositions don't comprise potentially toxic surface-active substances, show stability for prolonged time and possess high mucoadhesive capacity and high bioavailability.
EFFECT: valuable medicinal and pharmaceutical properties of composition.
22 cl, 5 tbl, 3 dwg, 19 ex
SUBSTANCE: method involves carrying out combined chemotherapy according to AC-scheme of adriamycin+cyclophosphane. Bioorganic preparation of animal origin is intramuscularly introduced in parallel to chemotherapy to a group of rats at a dose of 0.3 ml/100 g of body weight every day during 30 days.
EFFECT: enhanced effectiveness of treatment.
FIELD: biotechnological processes.
SUBSTANCE: invention relates to anaerobic fermentation of manure, energetic biomass, and similar organic substrates. Method envisages providing organic material containing solid and/or liquid fraction and treating this organic material with lime at pressure and temperature between 100 and 220°C, which results in hydrolysis of organic material. Lime is composed of Ca(OH)3 and/or CaO and being added to trap evolving ammonia and to disinfect organic material it also precipitates dissolved orthophosphate.
EFFECT: reduced amount of viable microorganisms.
125 cl, 6 dwg, 1 tbl
SUBSTANCE: claimed preparation contains (mass %): disodium or dipotassium salt of ethylenediamine-N,N'-disuccinic acid 15.0-35.0; iron (III) 0.6-4.0; manganese (II) 0.5-2.5; copper (II) 0.05-0.25; zinc (II) 0.3-2.5; cobalt (II) 0.005-0.05; selenium (IV) 0.01-0.03; iodine (I) 0.03-0.08; vitamins: A 0.006-1.2; D3 0.00006-0.0015; E 0.1-3.5; B1 0.005-0.2; B2 0.01-0.25; B3 0.02-0.03; B4 5.5-20.0; B5 0.04-1.4; B6 0.005-1.2; and balance: water.
EFFECT: improved antianemic and growth stimulating preparation for veterinary.
6 cl, 6 tbl