Cyclosporin-containing and practically oil-free compositions
SUBSTANCE: the present innovation deals with cyclosporin-containing and practically oil-free compositions being of immunosuppressive action. The composition contains a hydrophilic surface-active substance, a lipophilic component, a lipophilic surface-active substance and ethanol. As a hydrophilic surface-active substance this composition contains ether of fatty acid and polyoxyethylene sorbitane and product of either natural or hydrogenised castor oil and ethylenoxide; as a lipophilic component and lipophilic surface-active substance it contains ether of fatty acid and sorbitane. The suggested composition has been designed as a gelatinous capsule with solid covering. The present innovation solves the problem dealing with stability of galena compositions with cyclosporin: at treating with water the composition develops practically stable microemulsion.
EFFECT: higher efficiency of application.
11 cl, 2 ex
The present invention relates to new Galanova compositions, for example to Galanova compositions, containing no oils that as the active substance include cyclosporine, and also contain a number of alkanols.
At present, the use of cyclosporine have significant specific difficulties associated with their introduction in General, and with the preparation of galenic compositions, which, in particular, include problems of stability, bioavailability of drugs and the problems associated with the variability of response to injected dose as between different patients, so the individual patient. The present invention provides the ability to get the most convenient form, namely the capsule.
One of the objects of the invention is comprising a cyclosporin composition in the form of a capsule, which contains a fatty acid ester and polyoxyethylenesorbitan, for example polyoxyethylene (20) servicemanual, which, for example, available under the trademark Tween®80; a reaction product of a natural or hydrogenated castor oil and ethylene oxide, for example an ether of polyethylene glycol and castor oil, for example, commercially available under the trademark Cremophor®RH40 or Cremophor®EL (EL); ester of fatty acid and sorbitan, for example, Span®80 (servicemanual) and ethanol. Next, the context of the present description, these include cyclosporine composition with particular reference to compositions for filling capsules (e.g., at the mention of their mass and number) is designated as the composition of the invention.
Capsule, including composition, preferably represents a gelatin capsule with a hard surface.
As should be obvious to the person skilled in the art, the present invention also includes a variety of options.
For example, the composition of the invention may contain (ness.)the alkanols, for example propylene glycol and polyethylene glycol.
Including cyclosporine composition according to the invention in the form of a capsule, if necessary, may contain:
(a) a hydrophilic surfactant,
(b) a lipophilic component,
(C) lipophilic surfactant,
and it differs by the presence of fatty acid ester and polyoxyethylenesorbitan, the reaction product of a natural or hydrogenated castor oil and ethylene oxide and a fatty acid ester and sorbitan.
Specialist in this field should also be obvious that the same component can serve as a lipophilic component and a lipophilic surfactant.
If necessary, the composition according to the invention can be prepared so that when processing water it forms a practically stable emulsion, for example almost stable microemulsion, or e is ulsio, for example, the microemulsion.
The composition of the invention may have the preferred characteristics of biological availability and reduced variability parameters bioavailability between different patients, and the individual patient. Preferably the composition has the form of a "pre-prepared emulsion, for example of the microemulsion concentrate making it possible to obtain emulsions of the type oil/water emulsion of the type oil-in-water), such as microemulsions.
The concept of "pre-prepared emulsion, for example of the microemulsion concentrate" in the context of the present description refers to a composition which spontaneously forms an emulsion, such as a microemulsion in an aqueous environment, such as water, for example, preferably upon dilution of the composition for filling capsules in a ratio of from 1:1 to 1:10, for example in the ratio 1:10, or in the gastric juices after oral administration.
The microemulsion is thermodynamically stable and contains dispersed particles with an average size of less than approximately 200 nm. Usually micro-emulsions containing droplets or particles having an average diameter of less than approximately 150 nm; normal less than 100 nm, typically more than 10 nm, and they remain stable for periods of time exceeding 24 hours "Mi who Roumelia" may not be opaque or almost opaque, alternatively, it may be a translucent colloidal dispersion, which is formed spontaneously or substantially spontaneously when its components are brought into contact with each other. Other characteristics can be found in the patent application GB 2222770, which is incorporated into this description by reference.
Another object of the present invention is the composition according to the present invention, characterized in that the relative content of cyclosporine, lipophilic component, hydrophilic surfactants, lipophilic surfactants and ethanol in the composition is such that after dilution with water at a ratio of 1 wt. part of the composition for filling capsules preferably 1-100, for example, 10-100 wt. parts of water, spontaneously form a microemulsion of the type oil-in-water, having an average particle size less than 200 nm.
In the composition for filling capsules cyclosporine may be present in an amount up to 20 wt.% in terms of the weight of the composition of the invention. Preferably, the cyclosporine is present in an amount of from 1 to 15% based on the weight of the composition, for example from about 2 to 10%.
According to another variant implementation of the lipophilic component may be present in an amount of 5 to 35 wt.% in re the couple on the weight of the composition for filling capsules, for example from 10 to 30%, preferably from 15 to 25 wt.%, more preferably about 20 wt.% or 30 wt.%.
According to alternative implementation in the composition of the present invention adopted the mass ratio of lipophilic component and cyclosporine is preferably 1-30:1 and more preferably 2-30:1.
According to another variant implementation of the hydrophilic surfactant can be present in an amount of from 25 to 70 wt. % calculated on the weight of the composition for filling capsules; preferably from 30 to 60 wt.%; more preferably from 40 to 60 wt.% and even more preferably about 50 wt.%
According to alternative implementation in the composition of the present invention adopted the mass ratio of the hydrophilic surfactant and cyclosporine is preferably 1-60:1 and more preferably 2-60:1.
According to another variant implementation of the lipophilic surfactant may be present in an amount of 5 to 35 wt.% in terms of the weight of the composition for filling capsules; for example from 5 to 30 wt.%, preferably from 5 to 20 wt.%, more preferably about 10 wt.%
According to alternative implementation in the composition of the present invention adopted the mass ratio of the lipophilic surfactant and cyclosporine is preferably 1-30:1 and more preferably 2-30:1.
According to another variant of implementation, the ethanol may be present in an amount of from 1 to 20 wt. % calculated on the weight of the composition for filling capsules, for example from 5 to 10 wt.%, preferably about 10 wt.%.
According to alternative implementation in the composition of the present invention adopted the mass ratio of ethanol and cyclosporine is preferably from 10:1 to 1:10 and more preferably from 5:1 to 1:5.
Another object of the present invention is a capsule comprising a composition for filling capsules, which contains 1-20 wt.% cyclosporine A, 5-35 wt.% lipophilic component, for example Migliol®812 or Span®80, 25-70 wt.% hydrophilic surfactants such as Cremophor®RH40 or EL and Tween®80, 5-35 wt.% lipophilic surfactants, such as Span®80, 1-20 wt.% of ethanol.
Cyclosporine, which include the present invention, are any cyclosporine, used in the pharmaceutical industry, for example, immunosuppressants, anti-parasitic agents, and agents to overcome multiple drug resistance, are known and described in the field, especially cyclosporin a, cyclosporin G, [0-(2-hydroxyethyl)-(D)Ser]8-cyclosporine or [3’-deshidrate-3’-keto-mt]1-[Val]2-cyclosporine. Preferred assetcategory A.
One of the objects of the present invention is a composition in which ciclosporin is the cyclosporin A.
Esters of polyoxyethylenesorbitan and fatty acids may constitute, for example, mono - and trilaurylamine, palmately, stearyl and alerby esters, known and marketed under the trademarks Tween®, for example, which are produced by the company ICI, UK, including the products Tween®:
The most preferred products of this class are Tween®40 (value hydrophilic-lipophilic balance (products HLB) of about 15-16) and Tween®80 (products HLB value of about 15).
Upon receipt of products of interaction of natural or hydrogenated castor oil and the ethyl the oxide natural or hydrogenated castor oil may be subjected to interaction with ethylene oxide in a molar ratio of from about 1:35 to about 1:60 with optional removal of the product polietilenglikoli component. Commercially available variety of such surfactants. Most useful are the hydrogenated products of hydrogenated castor oil, which are commercially available under the trademark Cremophor®. Most preferred are Cremophor® RH40, having a saponification number of approximately 50-60, an acid number less than about 1, a water content (Fischer) less than about 2%,approximately 1,453-1,457 and products HLB value of approximately 14-16; and Cremophor® RH60, having a saponification number of approximately 40-50, acid number less than about 1, an iodine number less than about 1, a water content (Fischer) about 4.5 to 5.5%,approximately 1,453-1,457 and products HLB value of approximately 15-17. The most preferred product of this class is Cremophor® RH40. Also suitable are esters of polyethylene glycol and castor oil, commercially available under the trademark Cremophor®EL, molecular weight (determined by the method of steam osmometry) is approximately 1630, a saponification number of approximately 65-70, an acid number of about 2, an iodine number of approximately 28-32 andapproximately 1,471.
Similar or identically the e products which can also be used according to the invention, are commercially available under trademarks Nikkol®(for example, Nikkol® HCO-40 and HCO-60), Mapeg® (for example, Mapeg® CO-40h), Incrocas® (for example, Incrocas® 40), Tagat® (for example, mixed fatty acid esters and polyoxyethylene-glycerol, such as, for example, Tagat® RH 40; and Tagat® THEN, polyoxyethyleneglycol with products HLB value of 11.3; preferred is Tagat® RH 40) and Simulsol OL-50 (Paglinawan using PEG-40 castor oil having a saponification number of approximately 55-65, an acid number of at most 2, iodine number 25-35, the water content of a maximum of 8% and the products HLB value of about 13, marketed by the company Seppic). These surfactants are also described in Fiedle in: "Lexicon der Hilfstoffe für Pharmazie, Kosmetik und angrenzende Gebiete", published by Cantor Verlag Aulendorf, Aulendorf, 4th revised and expanded edition (1996); and "Handbook of Pharmaceutical Excipients", 2nd ed., A.Wade and P.J.Weller (ed-s), Joint publication of American Pharmaceutical Association, Washington, USA and The Pharmaceutical Press, London, England.
Preferably the ester of polyoxyethylenesorbitan and fatty acids and the product of the interaction of natural or hydrogenated castor oil and ethylene oxide may, for example, be 25-70 wt.% composition for filling capsules.
Preferred esters sorbitan and fatty acids include monetary sorbitan and C12-C18fat is Oh acid or truefire sorbitan and C 12-C18fatty acids, known and marketed under the trademark Span® from the company ICI. The most preferred product of this class is Span®20 (sorbitanoleat, products HLB value of about 8) or Span®80 (servicemanual, products HLB value of about 4) (Fiedler, loc. cit (a specified place), volume 2, str; Handbook of Pharmaceutical Exipients, loc. cit., str).
Esters sorbitan and fatty acids can for example be 10-70 wt.% composition for filling capsules.
Examples polyalkyleneglycols products are polyethylene glycols, in particular polyethylene glycols having a molecular weight of from about 500 to about 4000, for example from about 1000 to about 2000.
Another object of the invention are a variety of alkanols. For example, ethanol can be replaced or partially replaced by alkanol, which may be hydrophilic, for example, can be selected from a range that includes Transcutol (which has the formula C2H5-[O-(CH2)2]2-HE), Glycofurol (also known as the simple ether tetrahydrofurfuryl alcohol and polyethylene glycol and 1,2-propylene glycol.
In the composition according to the invention can also be incorporated numerous liquid and/or solid polyethylene glycols, such as polyethylene glycol (PEG) 3350 or PEG 1450, which is producing the by the company Union Carbide.
In GB I described a wide variety of lipophilic components, which can be used in compositions according to the invention. Typical examples of the lipophilic components are:
(I) a triglyceride of fatty acids with medium chain length, for example, With6-C12for example Migliol® 812, and/or
(II) mixed mono-, di-, triglycerides, for example With6-C20for example , C16-C18for example Maisine®and/or
(III) transesterification ethoxylated vegetable oils, such as Labrafil®and/or
(IV) monoether of propylene glycol and fatty acids, for example, C14-C18for example hydroxystearate propylene glycol, isostearic propylene glycol, ricinoleic propylene glycol, propylene glycol stearate, and/or
(V) the diesters of propylene glycol and fatty acids, for example With6-C20for example , C8-C12for example dicaprylate propylene glycol, for example Migliol® 840, or dilaurate propylene glycol, and/or
(VI) esterified derivatives of fatty acid and primary alcohol, for example With8-C20fatty acids and C2-C3alcohols, such as ethyllinoleate, and/or
(VII) mono - and/or diglycerides, for example a mixture of mono - and diglycerides, for example, monoglyceride18fatty acids as its main component, for example GMOrphic®-80 or Tegin® O.
Predpochtite lname lipophilic components are triglycerides of fatty acids with medium chain length, mixed mono-, di-, triglycerides, esters of fatty acids and sorbitan and transesterification ethoxylated vegetable oil.
Thus, another object of the present invention is the composition according to the invention, in which the lipophilic component is a triglyceride of fatty acids with medium chain length or ether fatty acids and sorbitan.
According to another variant implementation of the lipophilic component can be a triglyceride of fatty acids with medium chain length and/or mono - and diglyceride or their mixture.
As the triglyceride fatty acids with medium chain length in the lipophilic component can be used triglyceride of saturated fatty acid having 6 to 12, for example 8 to 10 carbon atoms. Suitable triglycerides of fatty acids with medium chain length are the products known and marketed under the trademarks Acomed®, Myritol®, Captex®, Neobee® M 5F, Migliol® 810, Migliol® 812, Migliol® 818, Mazol®, Sefsol® 860, Sefsol® 870; most preferred is Migliol® 812. Migliol® 812 is a fractionated coconut oil comprising triglycerides of Caprylic-capric acid and has a molecular mass of approximately 520 Yes. It has the following fatty acid composition: C6a maximum of approximately 3%, With8PR is approximately 50-65%, C10approximately 30-45%, With12a maximum of 5%; acid number of approximately 0.1; number of saponification of approximately 330-345; iodine number of at most 1. Migliol® 812 is made by the company Condea. Neobee® M 5F is a fractionated triglyceride Caprylic-capric acid derived from coconut oil; acid number max 0,2; saponification number of approximately 335-360; iodine number a maximum of 0.5, the water content of a maximum of 0.15%, D20is 0,930-0,960,is 1,448-1,451 (according to manufacturer). Neobee® M 5F is made by the company Stepan Europe.
These triglycerides are described in H.P. Fiedler, loc. cit., the contents of the document are included in the present description by reference.
According to another alternative implementation of triglycerides preferably comprise at least 5%but less than about 25%, calculated on the total weight of lipophilic component. More preferably, the triglyceride is present in an amount of from about 7.5 to about 20% (e.g. from about 9%to 12%).
Suitable mixed mono-, di-, triglycerides are the products known and marketed under the trademark Maisine® from the company Gattefossé. They are products of transesterification of corn oil and glycerol.
According to another volume is the invention in the compositions according to the invention is adopted, the mass ratio of lipophilic component and cyclosporine is preferably 1-30:1 and more preferably 2-30:1.
It should be understood that the components may represent a complex mixture comprising by-products or unreacted starting materials used for their production, for example surface-active substances obtained by polyoxyethylene may contain other by-product, such as polyethylene glycol.
Typically, the composition is a surfactant having the value hydrophilic-lipophilic balance (products HLB) ranging from 8 to 17. The products HLB value preferably represents the average value of the products HLB.
According to the invention the hydrophilic surfactant can be mixed with a lipophilic surface-active agent. Under hydrophilic surface-active agent understand surfactant, products HLB value greater than or equal to 10 and under lipophilic surface-active agent understand surfactant, products HLB value below 10.
Selected for the composition of the hydrophilic surfactant preferably has a value of hydrophilic-lipophilic balance (products HLB)greater than or equal to 10, for example it is a Cremophor® RH40 or EL.
One of the selected for the composition of components is set to the hydrophilic-lipophilic balance (products HLB below 10, such as Span®8.
If necessary, the relative content of the lipophilic component, a surfactant and ethanol are in the area of microemulsions on the standard three-dimensional chart. Thus obtained compositions are highly stable pre-cooked microemulsion concentrates, which are capable after adding water to form a microemulsion with an average particle size <200 nm.
Standard three-dimensional graphics, such as the phase diagram can be constructed in the conventional method described, for example, in published patent application GB 2222770 or in WO 96/13273.
Compositions representing a previously prepared emulsion, for example of the microemulsion concentrates, for example, which are described below in the examples, can have very good characteristics of stability, demonstrated in standard experiments on stability studies, for example, they can maintain stability during storage up to one, two or three years and even for a longer period of time.
Compositions representing a pre-prepared microemulsion concentrates according to the present invention allow to obtain stable micro-emulsions that remain stable over a period of time up to one day or bol is e, for example, one day.
The composition according to the invention may also include other additives or ingredients, such as antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA)that is equivalent (OSH) and Tocopherols) and/or preservatives. In another alternative embodiment, these additives or ingredients may be about 0.05-1 wt.% in terms of the total weight of the composition for filling capsules. The composition may also include sweeteners or corrigentov in the amount of approximately 2.5 or 5 wt.% in terms of the total weight of the composition for filling capsules. Preferably the antioxidant is α-tocopherol (vitamin E).
Excipients according to the invention described in Fiedler, loc. cit.: in "Handbook of Pharmaceutical Exipients", loc. cit. or the required information can be obtained from the respective manufacturers, the content of these publications and documents included in the present description by reference.
Any carbon chain, unless otherwise stated, usually contains 1-18 carbon atoms, for example 10-18 carbon atoms, if it is a terminal group, or 2 or 3 carbon atoms if it is a fragment of a polymer.
The composition according to the invention possess a particularly preferred characteristics when ingested by; for example, in classified and consistency and high bio-availability, shown in standard experiments for the investigation of biological availability, for example, greater than 2-4 times relevant characteristics of known emulsions. These experiments are performed on animals, such as rats or dogs, or in healthy volunteers using GHUR or set of specific or nonspecific monoclonal antibodies to determine the level of cyclosporine in the blood. For example, for the composition of example 1, administered to dogs by mouth with an ELISA assay using specific monoclonal antibodies were suddenly revealed a very high value Withmax.
One of the objects of the present invention is a method of oral administration the pharmaceutical compositions involving oral administration to a patient in need of treatment with cyclosporine, the composition of the invention.
Pharmacokinetic parameters, such as levels of absorption and concentration in blood, also suddenly become more predictable, and problems of introduction associated with erroneous absorption, can be eliminated or reduced. In addition, the composition according to the invention remain effective in environments in which there are surface-active substances, such as salts of bile acids present in the gastrointestinal tract. This means that the composition of the image the structure are fully dispersible in aqueous systems, include natural surfactants and are therefore able in situ to form a microemulsion systems that are stable and in which there is no deposition of the active substance or other destruction of the fine structure. The functional activity of the compositions according to the invention by oral administration remains almost unchanged and/or it does not deteriorate in the presence of salts of bile acids or in its absence at any particular time or for a particular patient.
The composition of the invention can reduce the variability of responses depending on the dose between different patients and the individual patient.
One of the objects of the invention is a method of reducing the variability of the levels of the bioavailability of cyclosporine for patients treated with cyclosporine, introducing oral and intended for oral administration the pharmaceutical compositions of the present invention.
Another object of the invention is also a method of preparation of the compositions according to the invention, providing a thorough mixing of cyclosporine, ethanol and other components. If necessary, the composition may be prepared in a standard dosage forms, for example the composition may be the ü made in gelatin capsules.
With these components in the process of adding the active substance or after optionally can be mixed with other components or additives.
The composition can be combined with water or with a solvent system of water to obtain an emulsion, such as microemulsions.
The suitability of all the pharmaceutical compositions according to the invention may be demonstrated in standard clinical tests in, for example, with the definition of the doses of cyclosporine, giving equivalent levels of cyclosporine in the blood; for example, using doses ranging from 2.5 mg to 1000 mg of active ingredient per day to the mammal weighing 75 kg, for example, an adult mammal, as well as in standard models with animals. Increased bioavailability of cyclosporine, provided compositions may be detected in a standard animal experiments and in clinical trials, for example, as described above.
The optimal dose of cyclosporine, which should be introduced to a particular patient should be carefully specified, taking into account individual reactions and metabolism of cyclosporine, and it can vary. It is advisable to monitor the levels of the active substance in the serum using radioimmunoassay analysis using monoclonal antibodies or other with the appropriate methods.
Typically, the dose of cyclosporine in the range from 25 mg to 1000 mg per day (preferably from 50 mg to 500 mg).
Compositions according to the invention is preferably prepared in the form of standard dosage forms, for example by filling them shells of capsules intended for oral administration. Shell capsules can be a hard or soft gelatin shell capsule. If the composition according to the invention is a standard dosage form, it is advisable that each standard dosage form contains from 10 to 100 mg of cyclosporine, more preferably from 10 to 50 mg; for example, 15, 20, 25, or 50 mg standard dosage forms suitable for introduction 1-5 times a day depending on the specific treatment goals, phase, etc.
However, if necessary, the pharmaceutical compositions may take the form of a solution for drinking and may include water or any other water system for the formation of the emulsion, for example of the microemulsion systems, suitable for drinking.
The composition of the invention is most suitable for:
a) treatment and prevention of transplant rejection of an organ or tissue, for example, for the treatment of recipients of heart transplants, lung, combination heart-lung, liver, kidney, pancreatic, skin or corneal. The composition of izobreteniya can be used to prevent the reaction of graft-versus-host, which sometimes occurs after bone marrow transplantation;
b) treatment and prevention of autoimmune disease and of inflammatory conditions, the etiology of which primarily includes autoimmune component such as arthritis (for example rheumatoid arthritis, a chronic progressive arthritis and arthritis deformans) and rheumatic disorders; and
in the treatment of multiple drug resistance (MDR).
Another object of the present invention is the use of a composition according to the invention for preparing a medicinal product intended for the treatment and prevention of autoimmune disease or inflammatory condition, or for the treatment and prevention of transplant rejection or for the treatment of multiple drug-resistance.
The following describes compositions according to the invention, given only as an example. Unless otherwise noted, the content of the components is given in wt.% in terms of the mass of each compound for filling capsules.
Miglyol®812 is made by the company Condea Company, Germany.
Cremophor®RH40 produced by BASF, Germany.
Span®80 is made by the company ICI, UK.
Tween®80 is made by the company ICI, UK.
Prepare a composition with the following components:
40% vol. Cremophor®RH0
32 vol.% Miglyol®812
8% vol. Span®80
10% vol. cyclosporine And
10% vol. ethanol
Prepare a composition with the following components:
56 wt.% Cremophor®EL
10% cyclosporin a
Other examples include compositions prepared by removing Miglyol®812 and replacement Miglyol®812 on Span®80.
Additional examples of compositions prepared by replacing a part (for example, 30-70%) Cremophor®EL on an equivalent amount of Tween®80.
These compositions can be enclosed in gelatin capsules, hard and soft cover.
The examples illustrate the compositions are suitable, for example, to prevent transplant rejection or to treat autoimmune disease by introducing 1-5 standard dosage forms per day in a dose of from 2 to 5 mg/kg/day.
According to visual inspection of each composition after dilution forms a transparent and stable emulsion or microemulsion.
1. Containing cyclosporine a composition having immunosuppressant action, in the form of a capsule comprising a fatty acid ester and polyoxyethylenesorbitan, the reaction product of a natural or hydrogenated castor oil and ethylene oxide, ester of fatty acid and sorbitan and ethanol.
2. Containing cyclosporine to notice, with immunosupressants action, in the form of capsules, including:
(a) a hydrophilic surfactant,
(b) a lipophilic component,
(C) lipophilic surfactant and
characterized in that the hydrophilic surface-active substances it contains a fatty acid ester and polyoxyethylenesorbitan and the reaction product of a natural or hydrogenated castor oil and ethylene oxide, as a lipophilic component and a lipophilic surface-active substances it contains a fatty acid ester and sorbitan.
3. Gelatin capsule with a hard coating containing composition according to claim 1 or 2.
4. The composition according to claim 1 or 2, or 3, comprising a cyclosporin in an amount of 1-20% based on the weight of the composition for filling capsules.
5. The composition according to claim 1, comprising a lipophilic component in an amount of 5-35% in recalculation on weight of the composition for filling capsules.
6. The composition according to claim 1, comprising a hydrophilic surfactant in an amount of 25-70% in recalculation on weight of the composition for filling capsules.
7. The composition according to claim 1, comprising a lipophilic surfactant in the amount of 5-35% in recalculation on weight of the composition for filling capsules.
8. The composition according to claim 1, including ethanol inthe number of 1-20% based on the weight of the composition for filling capsules.
9. The composition according to claim 1, in which ciclosporin is the cyclosporin A.
10. The composition according to claim 1, in which there is an additional hydrophilic component.
11. The method of preparation of the composition according to any one of claims 1 to 10, providing a mixture of cyclosporine, ethanol, and other specified components.
FIELD: coordination compounds synthesis.
SUBSTANCE: invention provides complex comprising calcium and [[(4R)-4[bis[carboxy.kappa.O)methyl]amino-.kappa.N]-6,9-bis[carboxy-.kappa.O)methyl]-1-[(4,4-diphenylcyclohexyl)oxy]-1-hydroxy-2-oxa-6,9-diaza-1-phosphaundecane-11-ylic acid-.kappa.N6,.kappa.N9,-kappa.011]-oxydato(6-)]-,6H, (MS-325) or its salt with physiologically acceptable cation in each case containing essentially no Gf-MS-325. Also described are pharmaceutical agent based on compounds according to claim 1 and a method for preparing galena composition, complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent reducing effect produced by heavy metals as well as complex or its salt with physiologically acceptable cation according to claim 1 intended for preparation of pharmaceutical agent suitable for NMR diagnostics and/or diagnostic radiology, a method for amplifying patient's image in NMR tomography based on compounds according to claim 1 and above defined complex or its salt with physiologically acceptable cation in each case containing essentially no visualizing metal chelates and MS-325.
EFFECT: increased assortment of complexes with useful medicine-destination properties.
14 cl, 4 dwg, 30 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to biologically active compounds. Agent represents 3,6-dioxocyclohexa-1,4-diene-1,2,4,5-tetrasulfonate sodium. The new agent elicits antioxidant properties and therefore it can be used in food industry, in pharmaceutical compositions and cosmetic products. Also, the new agent elicits antiviral activity owing to it can be used as both the independent medicinal agent and in compositions with other preparations used for treatment of viral infections.
EFFECT: expanded assortment of medicinal agents and antioxidants, realization of indicated prescription.
1 tbl, 8 dwg
FIELD: medicine, toxicology.
SUBSTANCE: invention proposes applying 15% aqueous solution of 1-methyl-5-[2'-(benzyldimethylammonio)ethyl]carbamoyl pyridinium-2-aldoxime dichloride that exceeds the 15% solution of dipiroxime (TMB-4, trimedoxime bromide) used in native medicinal practice by the curative effectiveness. Invention can be used in urgent treatment of acute poisoning with organophosphorus poisonous substances eliciting neuroparalytic effect.
EFFECT: enhanced effectiveness, valuable medicinal properties of agent.
FIELD: antibiotics, pharmacy.
SUBSTANCE: invention relates to stabilization of rapamycin or rapamycin derivative with immunosuppressive properties and sensitive to oxidation. Method for stabilization involves addition of antioxidant to the purified rapamycin in small concentrations - below 1% as recalculated for rapamycin mass. Also, invention relates to a solid mixture containing rapamycin and antioxidant taken in the catalytic amount. Antioxidant represent preferably 2,6-di-tert.-butyl-4-methylphenol. The stabilized rapamycin shows high stability against oxidation, it can be stored as formulation without package before it's the following treatment and can be used in an unmodified form for preparing the required galenic composition.
EFFECT: improved stabilizing method.
14 cl, 3 dwg, 2 ex
where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl; R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II
where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6)alkyl or halogen, or R1presents arylamination-2-methylprop-1-ilen group, or R and R1together with the nitrogen atom to which IGN="ABSMIDDLE">
where R7denotes phenyl or pyridinyl; R2means (C1-C6)alkyl, which optionally contains a phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium residue; R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)alkyl, or R3is cyclopentanecarbonitrile; Z denotes Oh, and alkyl, alkoxy or alkylamino mean as an unbranched group, such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and branched alkyl groups such as isopropyl or tert-butylene group; halogen means fluorine, chlorine, bromine or iodine and alkoxygroup means methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan, and their pharmaceutically acceptable salts with acids
FIELD: organic chemistry, steroids, medicine, pharmacy.
SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):
wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.
EFFECT: valuable medicinal properties of compounds, improved method for treatment.
38 cl, 1 tbl, 18 ex