Pharmaceutical composition for pain management

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a pharmaceutical composition for control of pain accompanying individual's joint diseases containing hyaluronic acid, which is cross-linked by cycling a double bond in a group of cinnamic acid in partially amidated hyaluronic acid presented by formula (1) to form a cyclobutane cycle, wherein in the above formula, Ar represents a phenyl group, n is equal to an integer 2 or 3; HA represents a carboxy residue of hyaluronic acid, and m represents a relation of amidation of hyaluronic acid to all the carboxyl groups and is equal to 3-50% in relation to all the carboxyl groups, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition represents a product for injection, wherein the pharmaceutical composition represents the product for injection, wherein the amount of the cross-linked hyaluronic acid makes 1 wt % at the total amount of the product for injection, wherein a single dose of the product for injection makes 2-3 ml, wherein the pharmaceutical composition represents a single-use preparation, which is administered every 13 weeks and more.

EFFECT: invention provides the extremely long analgesic action after the single administration, earlier onset of the analgesic action.

15 cl, 1 dwg, 5 tbl, 1 ex

 

Area of technology

The invention relates to pharmaceutical compositions for the relief of pain in joint disease comprising crosslinked hyaluronic acid and a pharmaceutically acceptable carrier.

The level of technology

In an ageing modern society osteoarthritis (hereinafter in this description referred OA), which is a pain and functional disorder peculiar degeneration of the joints, is the most common joint disorder worldwide and is a leading cause of disability in elderly people in everyday life.

Currently the treatment of OA includes, for example, treatment by oral administration of analgesic medications such as nonsteroidal anti-inflammatory drug which is widely used in the case of a variety of pain, and treatment by intraarticular injections of hyaluronic acid solution.

The first method of treatment is a symptomatic therapy for easing joint pain with the use of synthetic drugs with strong anti-inflammatory effect.

On the other hand, the latter method of treatment is a therapy for the treatment of joint disease that impairs the function of the joints and the related reduction in the production of the Sino�ialei fluid and cartilage degeneration, due to the lubricating action of the shock absorber action, improving actions on cartilage metabolism, which are provided by hyaluronic acid.

Hereinafter in this description hyaluronic acid or its derivative can be denoted as AT.

Currently intraarticular composition with the use of hyaluronic acid or its derivative (hereinafter in this description referred to as the product of IA-HA) commercially available as products obtained from the solution of sodium hyaluronate, and the products obtained from the solution of crosslinked derivative of hyaluronic acid. Examples of products IA-HA, obtained from the solution of sodium hyaluronate, include ARTZ (registered trademark), SYNVISC (registered trademark), HYALGAN (registered trademark), and ORTHOVISC (registered trademark). Examples of products IA-HA, obtained from the solution of crosslinked derivative of hyaluronic acid include SYNVISC (registered trademark) and DUROLANE (registered trademark). SYNVISC (registered trademark) consists of a derivative of hyaluronic acid, cross-linked by a covalent bond with a small amount of aldehyde, and a derivative of hyaluronic acid obtained through additional crosslinking derived by diphenylsulfone. DUROLANE (registered trademark) represent�t a stitched epoxypropane protecting tool joints (see the publication of the patent application U.S. No. 2006/0148755).

Such products IA-HA is administered mostly every 1-2 weeks in order to obtain the desired therapeutic effect (see "The Journal of Rheumatology", 2004, 31: 4, pp. 775-782); and "Current Medical Research and Opinion", 11: 205-213, 1988). Since hyaluronic acid has viscoelastic properties, intraarticular injection of such products IA-HA performed using needles for injection thicker of the drug than normal injection. Therefore, intraarticular injection of such products IA-HA gives the feeling stronger invasion of drilling and pain than the injection and the introduction of such products IA-HA in one cycle of treatment in Japan is limited, in principle, up to 5 times. However, traditional products require continuous injection every week that could be a big difficulty for patients who are away from the hospital, or are difficult weekly visits because of their work. Accordingly, a search for products that require administration less often, and showing an equal or better therapeutic effect than conventional products IA-HA.

Recently reported about the product (SYNVISC-ONE (registered trademark)), which is a new scheme of using SYNVISC (registered trademark), and allows a one-time injection of conventional products with dosiro�Oh, above normal (2 ml) three times. According to this report believe that in such a case, therapeutic effect lasts for 26 weeks after a single injection (see "ARD Online First, published on March 19, 2009 as 10. 1136/ard. 2008. 094623). However, this therapeutic effect is the result of a single injection of three doses (6 ml) of the common product. In addition, there is the disadvantage that the load on patients by intraarticular injection of three doses at once increased compared with the conventional product.

In addition, in international publication no WO 2008/069348 reported therapeutic agent against diseases of the joints for intraarticular injections with a derivative of hyaluronic acid, cross-linked under the action of light, which is crosslinked form, which differs from commercially available crosslinked hyaluronic acid and has long-term effect after a single dose. However, there is no specific disclosure or assumptions concerning the long duration in the treatment of OA in humans.

In addition, the products IA-HA focus on long-term strengthening of patient QOL by improving the comprehensive functions of the joints, and it is difficult to expect the presence of rapid analgesic action, what is expected, for example, from non-steroidal anti-inflammatory drug CP�of DSTV (see "The Journal of Rheumatology", 2004, 31: 4, PP. 775-782; "OsteoArthritis and Cartilage" (2004), 12, 642-649; "ARD Online First, published on March 19, 2009 as 10. 1136/ard. 2008. 094623; "Arthritis & Rheumatism", Vol.43, No.9, pp. 1905-1915 (2000)).

As described above, there are a number of products IA-HA, but there are no messages on intraarticular composition, which shows an equal or better effect after a single dose, than the action, prominent when multiple introductions of any of the usual products IA-HA, without raising a single dose and over a long period, in particular, more than half a year, from the point of view of invasion.

Therefore, we need products that can have early onset of a pronounced analgesic action with a lower frequency of implementation and less as far as possible, the dosage after a single dose, and show an equal or better therapeutic effect than conventional products IA-HA.

Summary of the invention

The problem solved by the invention

The aim of the present invention is intraarticular composition, which exhibits rapid analgesic effect after administration and which shows an extremely long lasting effect against joint disease with only a single dose rather than multiple injections, and the dosage after a single dose, in substance, does not change compared to the dosage of p�and a single dose of conventional products IA-HA, which serve multiple introductions, etc.

Ways of solving problems

The authors of the present invention have conducted extensive studies to solve the above problems and as a result have found that when using crosslinked hyaluronic acid with a short-chain amino as a spacer, it shows the early action mitigation of pain, while conventional products IA-HA not show such early action to mitigate pain. In addition, the inventors found that such a product shows extremely long lasting action, for example, in six months, against joint disease with only a single administration of the dosage, which is almost indistinguishable from a dose of conventional products IA-HA, which are used for multiple injections, whereby the invention is implemented.

According to one aspect of the present invention relates to pharmaceutical compositions for the relief of pain in joint disease, including a hyaluronic acid and pharmaceutically acceptable media in which the hyaluronic acid is crosslinked by cyclization of the double bond in the group of cinnamic acid in a partially amidinophenoxy hyaluronic acid, represented by formula (1)

with the formation of cyclobutanones cycle, where Ar represents optionally samisen�Yu phenyl group, n is an integer 2 or 3, represents carboxylate hyaluronic acid, and m represents the ratio of the hyaluronic acid amidation to all carboxyl groups and equal 3-50% relative to all the carboxyl groups.

The content of the crosslinked hyaluronic acid in such pharmaceutical composition is preferably 0.5 to 3.0 wt.% in volume relative to the whole product.

In addition, this pharmaceutical composition is preferably in the drug at one time. In this case, such a pharmaceutical composition preferably is administered with an interval of introduction of 13 weeks or longer.

In addition, this pharmaceutical composition is preferably used for long-term operation up to at least 13 weeks, more preferably for a long period of operation until at least 26 weeks.

The present invention is more specifically described below.

(1) Pharmaceutical composition for the relief of pain in joint disease, including a hyaluronic acid and a pharmaceutically acceptable carrier and hyaluronic acid crosslinked by cyclization of the double bond in the group of cinnamic acid in a partially amidinophenoxy hyaluronic acid, represented by formula (1)

(where Ar represents an optionally substituted phenyl group, n Rav�n an integer 2 or 3, ON is carboxylato hyaluronic acid, and m represents the ratio of the hyaluronic acid amidation to all carboxyl groups and equal 3-50% relative to all the carboxyl groups, with the formation of cyclobutanones cycle.

(2) the Pharmaceutical composition described above in (1) and the proportion (degree of crosslinking) double bond in the group of cinnamic acid, which forms cyclobutanones cycle by cyclization equal 5-40%.

(3) the Pharmaceutical composition described above in (1) or (2), wherein the content of the crosslinked hyaluronic acid is 0.5-3.0 wt.% the volume of the entire product.

(4) the Pharmaceutical composition described above in any of (1) to(3), wherein the pharmaceutical composition is a product for injection.

(5) the Pharmaceutical composition described above in (4), wherein a single dosage of the product for injection is 2-3 ml.

(6) the Pharmaceutical composition described above in any of (1) to(5), wherein the pharmaceutical composition is a drug at one time.

(7) the Pharmaceutical composition described above in (6), wherein the drug is a single dose administered at intervals introduction in 13 weeks or longer.

(8) the Pharmaceutical composition described above in any of (1) to(7), wherein the pharmaceutical composition is used for long-term action on m�Nisha least 13 weeks.

(9) the Pharmaceutical composition described above in (8), wherein the pharmaceutical composition is used for a long period of validity at least up to 26 weeks.

(10) Hyaluronic acid, crosslinked by cyclization of the double bond in the group of cinnamic acid in a partially amidinophenoxy hyaluronic acid, represented by formula (1)

[Ar-CH=CH-COO-(CH2)n-NH-]m-HA (1),

(where Ar represents an optionally substituted phenyl group, n is an integer 2 or 3, represents carboxylate hyaluronic acid, and m represents the ratio of the hyaluronic acid amidation to all carboxyl groups and equal 3-50% relative to all the carboxyl groups, with the formation of cyclobutanones cycle, for use as pharmaceutical compositions for the relief of pain in joint disease.

(11) Hyaluronic acid described above in (10) and the proportion (degree of crosslinking) double bond in the group of cinnamic acid, which forms cyclobutanones cycle by cyclization equal 5-40%.

(12) Hyaluronic acid described above in (10) or (11), wherein the content of the crosslinked hyaluronic acid in the pharmaceutical composition is 0.5-3.0 wt.% on the whole volume of the pharmaceutical composition.

(13) Hyaluronic acid described above in any of (10)-(12), wherein the pharmaceutical composition is used ka� product for injection.

(14) Hyaluronic acid described above in (13), wherein a single dosage of the product for injection is 2-3 ml.

(15) Hyaluronic acid described above in any of (10) to(14), wherein the pharmaceutical composition is a drug at one time.

(16) Hyaluronic acid described above in (15), wherein the drug is a single dose administered at intervals introduction in 13 weeks or longer.

(17) Hyaluronic acid described above in any of (10) to(16), wherein the pharmaceutical composition is used for a long period of operation until at least 13 weeks.

(18) Hyaluronic acid described above in (17), wherein the pharmaceutical composition is used for a long period of operation until at least 26 weeks.

(19) a Method of reducing pain in a patient in need of relief of pain in joint disease, comprising administering to a patient in need of relief of pain with joint disease, an effective dose of hyaluronic acid and pharmaceutical compositions comprising a pharmaceutically acceptable carrier and hyaluronic acid crosslinked by cyclization of the double bond in the group of cinnamic acid in a partially amidinophenoxy hyaluronic acid, represented by formula (1)

(where Ar represents an optionally substituted phenyl group, n is an integer 2 and�and 3, ON is carboxylato hyaluronic acid, and m represents the ratio of the hyaluronic acid amidation to all carboxyl groups and equal 3-50% relative to all the carboxyl groups, with the formation of cyclobutanones cycle.

(20) the Method described above in (19) and the proportion (degree of crosslinking) double bond in the group of cinnamic acid, which forms cyclobutanones cycle by cyclization equal 5-40%.

(21) the Method described above in (19), wherein the content of the crosslinked hyaluronic acid in the pharmaceutical composition is 0.5-3.0 wt.% on the whole volume of the pharmaceutical composition.

(22) the Method described above in (19), wherein the pharmaceutical composition is a product for injection.

(23) the Method described above in (22), wherein a single dosage of the product for injection is 2-3 ml.

(24) the Method described above in (19), wherein the pharmaceutical composition is a drug at one time.

(25) the Method described above in (24), wherein the drug is a single dose administered at intervals introduction in 13 weeks or longer.

(26) the Method described above in (19), wherein the pharmaceutical composition is used for a long period of operation until at least 13 weeks.

(27) the Method described above in (19), wherein the pharmaceutical composition is used for a long period of operation up to at least 26 weeks.

The effect of inventions

The present invention relates to a product based on hyaluronic acid, which has an earlier start improving actions in case of pain in joint disease. In addition, the present invention relates to the drug at once, in which the dosage is, in essence, is the same as the usual dosage in the drug. Pharmaceutical composition according to the invention shows a fast improving action at pain after injection. Because of this rapid effectiveness, not observed in conventional products IA-HA, it is possible that the active ingredient according to the invention has a mechanism of action different from the mechanisms of action of conventional products IA-HA. In other words, in the invention it was found that crosslinked hyaluronic acid used in the invention has such potential.

In addition, the pharmaceutical composition according to the invention shows an extremely long lasting effect in the case of joint disease in humans, only just in a single dose, which does not differ almost from a dose of conventional products IA-HA, which require multiple injections. The treatment is carried out with a single introduction without increasing injection pressures for the patients, and thus, the risk of infection by microorganisms during the injection is reduced, and PA�anti also spared from drilling pain. In addition, such action shall be prolonged for an extremely long period, which reduces the burden of hospital visits and costs in patients on treatment. In addition, thus allowed long-term treatment products IA-HA.

In addition, the pharmaceutical composition according to the invention detects fewer side effects and is particularly preferable as a pharmaceutical composition.

Brief description of the drawings

Fig.1 is a graph illustrating the debilitating pain from 1 to 13 weeks after the introduction the group of patients derived crosslinked hyaluronic acid and the introduction of a group of patients with PBS. The horizontal axis represents weeks after injection, and the vertical axis represents a difference (mm) between the value for comparison to injection (baseline) and the value of VAS in each week. Vertical lines on the chart, which go up and down at points corresponding to weeks 1, 3, 6, 9 and 13 represent the standard deviation. Icons "•" represent the results for the group derived from crosslinked hyaluronic acid, and the icons"present the results for the group with PBS.

Method of carrying out the invention

1. Active ingredient

The active ingredient according to the invention is a hyaluronic acid, which�traveler stitched by cyclization of the double bond in the group of cinnamic acid in a partially amidinophenoxy hyaluronic acid, represented by the formula (1)

[Ar-CH=CH-COO-(CH2)n-NH-]m-HA (1),

(where Ar represents an optionally substituted phenyl group, n is an integer 2 or 3, represents carboxylate hyaluronic acid, and m represents the ratio of the hyaluronic acid amidation to all carboxyl groups and equal 3-50% relative to all the carboxyl groups, with the formation of cyclobutanones cycle. Further, in this specification, such a connection is called "cross-linked derivative".

ON which is stitched a derivative, not particularly limited as long as it has a disaccharide element as a constituent element, in which N-acetyl-D-glucosamine and D-glucuronic acid linked by the relation β1,3, and it represents glycosaminoglycans, composed of repeating links disaccharide such communication links β1,4. IN addition, may form a salt, or may form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include salts with alkali earth metal ion, such as sodium salts and potassium salts, salts with ion alkaline-earth metal such as magnesium salts and calcium salts, salts with inorganic base, such as ammonium salts, and salts with organic base such as diethanolamine, cyclohexylamine and am�nakilat. More preferable examples of salts are salts with alkali earth metal ion. A particularly preferred example is a salt with a sodium ion.

AT can be any of the acids obtained from natural products by extraction parts of living organisms, such as cockscomb, umbilical cord, cartilage and skin; chemically synthesized; or acids, which are obtained by cultivation or by genetic engineering procedures using microorganisms such as yeast. Since the crosslinked derivative IN the invention is administered to a living organism, made derived IN is preferably of high purity, which almost does not contain substances of which inclusion is pharmaceutically acceptable.

The average molecular weight is not particularly limited and is, for example, 10000-5000000. The average molecular weight is preferably AT 200000-3000000 and more preferably 500000-2500000.

In crosslinked derivative of a substance in which a carboxyl group in such ON and aminoalkylated cinnamic acid amide linked relationship with each other (hereinafter in this description called "photoreactive derived"), exists as above. Such substances are crosslinked with each other or intermolecular and/or intramolecular through education cyclobutanones cycle in the field of the double bond of the residue aminoalkyl�Fira cinnamic acid.

In the formula (1) n represents the length alkalinous group aminoalkylation cinnamic acid and preferably equal to 2 or 3. In other words, the carbon is preferably present in an amount of 2 or 3 atoms and, in particular, is a linear structure. Examples of such structure include ethylene group or trimethylene group. Examples of cinnamate in the invention include 2-aminoethylamide the cinnamate and 3-aminopropionic the cinnamate. A preferred example cinnamate is a 3 aminopropionic the cinnamate. In the description below the 3 aminopropionic the cinnamate for brevity called aminopropionic the cinnamate, and explanations will be given on that basis. Will just have to understand that instead aminopropionic cinnamate can be used aminoacylase the cinnamate, which will be explained below.

Photoreactive derivative FOR can be obtained by allowing the linking of an amino group formed from aminopropanol, which is part aminopropionic cinnamate, with a carboxyl group by amide bond formation.

This aminopropionic ester of cinnamic acid is an ester in which the carboxyl group of cinnamic acid and hydroxyl group of 3-aminopropanol products�s with each other ester bond. This aminopropionic the cinnamate can form cyclobutanone cycle by binding together vinelinux groups are cinnamic acid. Venelinova group in cinnamic acid, has the ability to react to photodimerizable or photo-polymerization reaction when exposed to light (ultraviolet). Therefore, cyclobutanones the loop is formed from two vinelinux groups upon irradiation with light. In addition, cinnamic acid which is 3-aminopropionic the cinnamate, can be a substituted cinnamic acid, having a Deputy.

Ar in the formula (1) represents an optionally substituted phenyl. When Ar in the formula (1) represents a phenyl group that has no Deputy, the compound of formula (1) is an ester of cinnamic acid. Meanwhile, when Ar is a phenyl group having a Deputy, it is a substituted cinnamate. Examples of such Deputy, which means it substitutes one or two hydrogen atoms in the benzene ring of cinnamic acid include linear or branched lower With1-8-alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), linear or branched lower With1-8-alkoxygroup (for example, methoxy, ethoxy, Ministers�si isopropoxy, butoxy, etc.), an amino group, an optionally substituted alkyl group, a hydroxyl group, a halogen atom, etc.

All of a carboxyl group in IN in photoreactive derived ON are not necessarily bound by amide coupling with aminopropylene ester of cinnamic acid, but only some of the carboxyl groups may be linked amide bond with aminopropylene ester of cinnamic acid.

In the formula (1) m represents the ratio (%) amide bond with aminoalkylation cinnamic acid to all carboxyl groups. Hereinafter in this description m carboxyl groups which form an amide bond to all the hydroxyl groups present in ON is called the "degree of substitution" (DS). DS is calculated in respect of implementation (%) balance aminopropionic cinnamate at the disaccharide level, amounting TO. For example, DS photoreactive derived, in which is introduced one rest aminopropionic cinnamate on constituent disaccharide unit, or DS photoreactive derived, in which is introduced one rest aminopropionic cinnamate 200 constituting disaccharide units, is 100% and 1%, respectively.

DS in photoreactive derived TO the invention, i.e., the ratio m is not particularly limited, but is preferably equal to 3% -50%, �more preferably 5%-30% and most preferably 10%-25%.

Stitched derived TO be used in the invention can be obtained according to methods described in publications with an open display of patent applications in Japan (JP-A) No. 2002-249501 and international publication no WO 2008/069348.

Method of obtaining is not particularly limited as long as he gives aminopropionic ester of cinnamic acid and chemically connected with each other amide bond. Examples of the method include a method using water-soluble condensing agent such as water-soluble carbodiimide (for example, hydrochloride 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl∙HCl) and meto-p-toluensulfonate 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide); a method using an auxiliary condensing agent, such as N-hydroxysuccinimide (HOSu) and N-hydroxy-benzotriazole (HOBt), with the above-mentioned condensing agent; a method using a condensation agent, as chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine (DMT-MM); active method of esterification and an acid anhydride.

Photoreactive derivative FOR can be obtained by introducing into the interaction of cinnamic acid and aminopropanol (for example, 3-aminopropanol, below which is the same) in order to obtain aminopropionic the cinnamate (for example, 3-aminopropionic the cinnamate, below which is the same), and for�eat a linking amide bond to the amino group obtained aminopropionic cinnamate and a carboxyl group ON each other. On the other hand, photoreactive derivative FOR can be obtained by linking the amine bond to the amino group of aminopropanol and a carboxyl group ON each other to get ON with embedded aminopropanol, and then linking to each other carboxyl group of cinnamic acid and hydroxyl group of aminopropanol as received ON embedded aminopropanol ester bond.

Crosslinked derivative is a compound in which photoreactive ON derivatives described above are connected with each other due to the formation cyclobutanones cycle at the place of double bonds in the residue propyl cinnamate, existing in such a derivative.

Method of education cyclobutanones cycle at the place of the double bond, this residue propyl cinnamate is not particularly limited and is, for example, the method of implementation of the exposure light on the solution photoreactive derived ON the conditions in which such residues propyl cinnamate come into photodimerization or photopolymerization with each other. In respect of lighting, the type, wavelength, etc. of light special restrictions are, if light can cause photochemical reaction residue propyl cinnamate without cleavage of glycosidic bonds. Light ameri� a, for example, ultraviolet radiation with a wavelength of 200-400 nm. The light intensity can be respectively selected depending on properties required for crosslinked derivative FOR. The lighting device is preferably an ultraviolet lamp, a mercury lamp high pressure or metal halide lamp or similar device. The unnecessary wavelength of light from the light source is preferably removed by, for example, a cut-off filter, etc.

As for crosslinked derivative ON, it is not necessary that all double bonds in the residue propyl cinnamate in photoreactive derivative ON associated with the formation of cyclobutanone cycles, but only some of these groups can contact the education cyclobutanone cycles.

Hereinafter in this description in stitched derived ON the ratio (%) residues propyl cinnamate, contributing to education cyclobutanone structures, to balances propyl cinnamate present in photoreactive derived, is called the "degree of crosslinking". For example, if 20 residues propyl cinnamate (monomer) timeresults in photoreactive derived, which includes 100 residues propyl cinnamate, get 10 dimaro�, and the degree of crosslinking is 20%.

The degree of crosslinking in crosslinked derivative TO be used in the invention is not particularly limited, but is preferably 5%-40%, more preferably 7%-35%, and most preferably 10%-30%.

When education cyclobutanone cycles is carried out by crosslinking through exposure to light, the concentration of the reaction solution when performing the cross-linking preferably is 0.5%-3,0%, most preferably from 0.7% to 2%.

Stitched derived ON can be freely mesolevel form or can form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of crosslinked derivative FOR include sodium salts, potassium salts, magnesium salts and calcium salts.

2. The content of the crosslinked derivative according to the invention ON

Stitched derived AT has a three-dimensional structure. Consequently, the solution in which the crosslinked derivative dissolved in an aqueous medium, has a physical property of a hydrogel having viscoelastic properties and in particular, detects a higher viscoelasticity than finds a solution of sodium hyaluronate, obtained in the same concentration.

The content of the crosslinked derivative in the pharmaceutical composition of the invention preferably is 0.5-3.0 wt.% on volume, preferably 0.7 to 2.0 wt.% �and the volume and more preferably 1.0 wt.% on the volume.

Pharmaceutical composition according to the invention can be obtained in various dosage forms, but usually it is obtained in the form of the product for injection, which is a liquid preparation for injection.

The content of active ingredient as described above, allows the injection according to the invention to have suitable fluidity for intraarticular injections using needles for injection of size 18 to 25. Accordingly, the pharmaceutical composition according to the invention is used as a product for injection by intraarticular injections.

3. Dosage and other pharmaceutical compositions according to the invention

A pharmaceutical composition according to the invention is injected into the joint, particularly the knee joint of man. For example, in the case of a single injection into the knee joint of the pharmaceutical composition is preferably administered in a dosage of 2-5 ml and more preferably in a dosage of 2-3 ml. a Pharmaceutical composition according to the invention can be administered in the same dosage or almost the same dosage as a single dose usual products IA-HA for multiple introductions.

In addition, in relation to a single injection into the knee joint dosage (volume of solution) of the pharmaceutical compositions also can be reduced, so that the mass photoreactive derived ON INTA is in�Vale 15-60 mg, preferably in the range of 25-35 mg and particularly preferably is 30 mg per adult patient (50-70 kg).

A pharmaceutical composition according to the invention can be entered with an interval between doses of 1 week or more, like usual products IA-HA. Pharmaceutical composition according to the invention has facilitate early action in pain, and the effect lasts for a long period, and thus, the interval between doses can be increased compared with conventional products IA-HA. Pharmaceutical composition according to the invention has a lasting effect for up to 13 weeks or longer, and more specifically, from 13 to 26 weeks. Based on this, the interval between doses can be installed in 13 weeks or more, and besides, in the period of 13-26 weeks. A pharmaceutical composition according to the invention can be used for a long period of operation until at least 13 weeks, and moreover, for long-acting to 26 weeks. Taking into account that a number of ways to treat existing products IA-HA perform in the course of every 26 weeks, the pharmaceutical composition according to the invention can be a product of IA-HA continuous type, which can be continuously enter one injection every 26 weeks.

4. The zone of action of the pharmaceutical composition of the invention

Pharmaceutical composition�I according to the invention has an action debilitating pain, or the effect of improvement in pain in the case of joint disease in humans. Pharmaceutical composition according to the invention has an early onset of therapeutic action after injection. At the beginning of this maximum effect occurs between 1 week and 3 weeks after administration and the effect lasts for 13 weeks or longer, and furthermore, to 26 weeks. Such "therapeutic effect" is not particularly limited as long as it is an effect of improving symptoms of joint disease in humans, but, as his examples, includes an action to improve the physical function, the effect of improving stiffness, the effect of pain relief, etc., and preferably the action of relief of pain.

Pharmaceutical composition according to the invention shows the beginning of such improvement actions 1 week - 3 weeks after a single injection, which usually lasts for a long period, such as at least 13 weeks, and moreover, up to 26 weeks.

Pharmaceutical composition according to the invention may include additives such as a solvent, a pH Adjuster, a means for regulating toychest and stabilizer, which are used in conventional products for injection, if they do not cause loss of desirable actions and side effects. For example, when�trollers solvent for the crosslinked derivative TO include water for injection, saline and phosphate-buffered saline. Further, examples of the additives include sodium dihydrogen phosphate, sodium hydrogen phosphate and sodium chloride, are used as pH regulators or means for regulating toychest when receiving a normal product for injection.

In addition, the pharmaceutical composition according to the invention reaches the early start of Express therapeutic effect after a single injection. As shown in the Examples described below, with regard to action features, debilitating pain, about 90% or more than the maximum therapeutic effect is achieved within 3 weeks after administration of the pharmaceutical compositions according to the invention. Such rapid onset and relief as the pharmaceutical compositions according to the invention can not be detected with conventional products IA-HA, and thus, it is also believed that the active ingredient according to the invention has the potential for mechanisms of action that are different from the mechanisms of action of conventional products IA-HA, through which such action is manifested as a rapid analgesic effect. In other words, in the invention it was found that crosslinked derivative according to the invention ON has the potential for mechanisms of action that are different from the mechanisms of action of a component of hyaluronic acid in �conventional products IA-HA, under the action of improvement with pain.

In addition, as shown in the Examples described below, in the group administered the pharmaceutical composition according to the invention, there are considerably fewer patients who experience pain and require re-treatment within 26 weeks after the initial single injection than in the control group for comparison, which is administered PBS. From this it follows that the introduction of the pharmaceutical compositions according to the invention leads to a significantly delayed relapse of pain.

For reference, ARTZ (registered trademark, manufacturer SEIKAGAKU Corporation), which is one of the commercially available products IA-HA, is a liquid for intraarticular injection volume of 2.5 ml per vial, or syringe, and the main requirement for it is one vial or one syringe for one injection a week 5 times in a row. Therefore, the dose ARTZ used in a single treatment, is 12.5 ml. in addition, Synvic-One (registered trademark, manufacturer Genzyme Co.) used in an amount of 6 ml per administration in a single injection as directed for him.

In General, the pharmaceutical composition according to the invention has three major advantages: a single injection; small dosage and prolonged therapeutic effect, and can also be used, for example, � the quality of the drug for a single injection every 3 months - six months in the case of chronic joint disease. Needless to add that the pharmaceutical composition according to the invention can also be used as a drug, which is administered at intervals of 6 months or longer, given the length improves action in patients and how the patients according to the level of symptoms, etc. As a matter of course, also possible only one introduction, i.e., only a single treatment.

Hereinafter the present invention will also be explained with reference to examples, but the technical scope of the invention is not restricted by them.

Example get

Getting stitched derived ON

According to the method described in international publication WO 2008/069348, otherwise than by using as starting materials sodium hyaluronate with an average molecular weight 900000-1000000 hydrochloride and 3-aminopropionic cinnamate, respectively receive crosslinked derivative of hyaluronic acid having a degree of substitution of 10%-25% and the degree of crosslinking 10%-30%, and receive a solution crosslinked derivative of hyaluronic acid at a concentration of 1.0 wt.% on the volume. This solution below is called the "test substance".

Example 1

Research methods

Conduct multi-pole controlled trial double-blind parallel groups of patients with osteoar�Triton knees, and verify the effectiveness of a single injection of crosslinked derivative according to the invention ON. Phosphate-buffered saline (PBS) is used to control how the placebo.

The selection of patients was made on the basis of inclusion criteria and exclusion criteria, described below, for 1-2 weeks prior to the introduction of the test substance. Patients who meet the criteria, randomly distributed in the group administered crosslinked derivative IN the present invention, or the group injected with PBS. The group receiving stitched derived, consists of 249 patients, and the group receiving PBS, includes 128 patients (a total of 377 patients).

Each patient in the group, which is introduced into crosslinked derivative IN the present invention, the test substance once injected into one of the affected knee in a dosage of 3 ml/knee. Each patient in the group injected with PBS in the same manner once injected PBS. The doctors who perform the introduction, check the affected knee in patients and aspirate the fluid from the knee, if prior to the introduction of effusion is present.

The effect of the improvement is assessed on the basis of the assessment method, described below, in the moments week 1, week 3, week 6, week 9 and week 13, respectively, after injection.

In addition, as a means of emergency medical care in each valuation day distribute �cetaminophen, and allow patients to take up to 4000 mg of acetaminophen a day. In addition to acetaminophen during the study to allow patients to take non-steroidal anti-inflammatory analgesic drugs, medicines, over-the-counter (OTC), medical product from herbs and protective agents, only if the patients continued to take this drug at a constant dose for more than four weeks before the introduction of the test substance. In addition, during the study also allowed the periodic use of opioid pain medicines. However, 24 hours before each day of the evaluation of any prohibited concomitant therapy.

Inclusion criteria and exclusion criteria

(1) inclusion Criteria

Patients who meet all of these further criteria, you can prepare for such examinations, except those who meet any one of the exclusion criteria listed below.

Patients aged 40-80 years who have a symptom of knee osteoarthritis.

Patients with pain in the knees when standing or when walking with a duration of at least 4 weeks.

Patients with the degree of Kellgren-Larence 1-3 according to x-ray.

Patients with a pain rating index of osteoarthritis Western Ontario and McMaster Universities (WOMAC (registered tov�n-car mark)) ≥40 mm in the affected knee and ≤20 mm in the other knee. In this case, WOMAC (registered trademark) measured using a 100-mm visual analog scale (VAS).

Patients ready for preryvayuscheesya modern treatment of OA other than allowed as concomitant therapy.

(2) exclusion Criteria

Patients with the degree of Kellgren-Larence 4 according to x-ray.

Patients, in addition to having OA inflammatory disease of the knee in the affected knee; patients with severe effusion in the knee joint, or patients with significant wrong direction of the axis of the knee.

Patients with joint replacement of the knee or hip; patients with knee surgery in the previous 12 months; patients with arthroscopy within 3 months or patients who were injected intraarticular product of hyaluronic acid in the previous 6 weeks.

Patients with severe systemic arthropathy/infectious diseases of the skin in the affected knee for evaluation.

Method of evaluation

Efficiency stitched derived TO assess using assessment by WOMAC (The Journal of Rheumatology, 1988, 15: 12, p. 1833-1840), developed by Dr. Nicholas Bellamy. WOMAC is a registered trademark. Further, in this specification, the indication of the trademark will be omitted.

Assessment by WOMAC used in this description, represents the way in which interviewing patients generally 24 times (total) 3 PT�Yam: pain, stiffness and physical function and make an assessment based on the answers.

In this study, the first dimension is sobottka WOMAC pain, and second dimensions are Sobieski stiffness in WOMAC, Sobieski physical function and WOMAC total score WOMAC.

The implementation of the assessment by WOMAC is the result reported by the patient, which is installed as a method of evaluating OA, which consists of all 24 questions about pain, physical function and stiffness as described above. Method of answering the questions, include 2 kinds: VAS (visual analogue scale and Likert scale. VAS is a method in which patients in the case of each question shows the extent of his own feelings on a 100-mm line, and the degree is determined by the position. The position can be represented by the distance from the left end of the scale. On the other hand, the Likert scale is a method in which patients in the case of each question indicate the degree of their own feelings using a 5 category scale. In this study, when assessing the degree of pain, physical function and stiffness in patients using VAS.

For example, patients are asked the same question about pain during every assessment before and after administration, and patients respond, indicating the position (degree) on the scale. On the basis of differences IU�do the distance, shown by the patient prior to the introduction (reference value before injection (baseline)), and the distance shown by the patient at each assessment after the introduction, improving action translate into figures.

Average WOMAC widely used as an index of therapeutic action in OA, and also recognized the validity and reliability of assessment by WOMAC therapeutic action of OA (The Journal of Rheumatology, 2000, 27: 11, R. 2635-2641).

Analyses of the effectiveness is carried out using a set of relations of healing to treatment (ITT set) and the set of protocols (a set of RR). In the ITT population of all 375 patients, of which 247 patients administered crosslinked derivative IN the present invention, and 128 patients administered PBS. Exclude two patients that came after the injection.

In aggregate, the overall RR 344 patients, of whom 229 patients administered crosslinked derivative IN the present invention, and 115 patients administered PBS. Patients who violated the Protocol of this study, exclude.

Results

The results of the analysis of the PP population for Sobieski WOMAC pain are shown in table 1, and the results of the analysis of the ITT population are presented in table 2.

Table 1
Ned�blah 1 Week 3Week 6Week 9Week 13
The average crosslinked derivative ON (standard deviation)20,8 mm (you € 24.50)28.9 mm (25,52)31,7 mm (28,00)31,7 mm (28,47)27.8 mm (29,84)
The average PBS (standard deviation)19.1 mm (24,71)20,9 mm (you € 24.50)23,4 mm (26,64)25,7 mm (25,93)20,5 mm (28,66)
Table 2
Week 1Week 3Week 6Week 9Week 13
The average crosslinked derivative ON (standard deviation)(20.7 mm 24,09)28,7 mm (25,23)31,2 mm (by 27.61)31,7 mm (27,91)27.8 mm (29,26)
The average PBS (standard deviation) 19.8 mm (24,61)21.3 mm (25,00)24,7 mm (27,31)27,4 mm (26,46)22.6 mm (29,31)

The group treated with crosslinked derivative IN the present invention, shows a statistically significant improvement in time week 3 after injection compared with the group receiving PBS, and also the effect continues after the 3rd week. The combination of PP shows a statistically significant difference from the group treated with PBS, with a p value of 0.05 or less in the moments week 3, week 6 and week 13. Such analyses show a trend towards improvement for the treated group crosslinked derivative IN the present invention, although there are no significant differences by week 9.

In addition, in Fig.1 shows a graph representing the results of the model estimation of the regression analysis in the ITT population. In the analysis of improvement in pain during the 13 weeks after administration in the group administered crosslinked derivative IN the present invention, improvement in pain was statistically significant compared with the group which was administered PBS, from week 1 to week 13 and week 3 to week 13. P value between week 1 and week 13 after the introduction of equal 0,0483, and p value between week 3 and week 13 after the introduction of equal 0,0495, and they both show statistical significance compared with group �otoroy PBS was injected.

In addition, the improvement of each assessment by WOMAC at time week 13 analyzed by regression models using the PP population. The results are shown in table 3. At the time week 13 after the introduction of the group treated with crosslinked derivative IN the present invention, shows a statistically significant improvement in pain compared with the group treated with PBS. The group treated with crosslinked derivative IN the present invention, shows a statistically significant improvement in the overall assessment by WOMAC and subatance physical function on the WOMAC, which are secondary performance metrics, and shows a statistically significant difference with the group receiving PBS. Sobottka stiffness in WOMAC shows a favorable trend in the group treated with crosslinked derivative FOR, although a statistically significant difference.

Below are the estimated difference is the difference, calculated using a regression model.

7,41
Table 3
The estimated differenceThe 95 percent confidence interval (CI), lower value, upper valueP value
Sobottka pain on WOMAC0,54, of 14.280,035
Total score WOMAC7,270,60, 13,950,033
Sobottka physical function on the WOMAC7,300,54, 14,050,035
Sobottka stiffness in WOMACAbout 6,82-0,22, 13,860,058

In addition, to confirm the clinical applicability analyze the Strict answer OMERACT-OARSI. A statistically significant improvement demonstrated in the group treated with crosslinked derivative ON (see table 4).

The answer is Strict OMERACT-OARSI identifies patients who report not less than 50%, and at least improve by 20 mm from baseline in subatance pain on WOMAC or subatance physical function, as great of respondents. In General, these groups of respondents called the Respondent Strict OMERACT-OARSI.

1,74
Table 4
Attitude differencesP value
Strict OMERACT-OARSI0,012

In addition, a relatively early start improving actions in the groups receiving stitched derived ON PBS and, in week 3 compare the average improvement relative to the baseline of Sobieski WOMAC pain, General assessment by WOMAC, Sobieski physical function on the WOMAC and Sobieski stiffness by WOMAC. Sobottka pain on WOMAC shows in week 3 improving action of more than 90% of the maximum improvement actions, and estimate the value of R, which represents the statistical significance of differences between groups treated with stitched derived ON and PBS (table 5). The p value is less than 0.05 (p<0.05) in any of the estimates, which show a statistically significant difference.

Table 5
P value at week 3
Sobottka pain on WOMAC0,0065
Total score WOMAC0,0129
Sobottka physical function on the WOMAC0,0205
Sobottka stiffness in WOMAC0,0336

In addition, p� completion of the 13-week observation in connection with the introduction of stitched derived ON or PBS I keep checking back in for 13 weeks to evaluate the effectiveness of the group entered with stitched derived FOR up to 26 weeks from baseline introduction.

Sobolenko pain on WOMAC performed at weeks 16, 19, 22 and 26 from the first injection, and patients who do not meet the criteria specified below, taken as a group with a long performance from the first injection, and carry out a duration analysis using a model of risk for pelvic joint for each treatment group.

Endpoint a: sobottka WOMAC pain ≥ 40 mm.

Endpoint: sobottka WOMAC pain ≥ 40 mm, and the improvement of < 20 mm from the baseline of the first injection.

Analysis of risk for pelvic joint shows performance for the group, which is introduced into crosslinked derivative FOR up to 26 weeks in both end points (end point A: p=0.019, endpoint: p=0,027).

Conclusion

Discovered that a single injection of a crosslinked derivative ON shows for a long period of improving action until at least 26 weeks after injection.

Stitched derived ON shows marked improvement not only in subatance pain, but also in subatance physical function and other assessments compared with the group receiving PBS, and, thus, shows a multidimensional effectiveness of joint diseases.

In addition, crosslinked derivative FOR shows rapid onset of improvement in pain at week 3 after injection and also shows a statistically significant difference when compared with PBS.

In addition, crosslinked derivative FOR shows a significant improving effect for up to 13 weeks, and moreover, up to 26 weeks. In addition, crosslinked derivative FOR does not have a statistically significant difference from PBS in the rate of expression of deleterious events and has severe side effects. It means high security crosslinked derivative FOR as intraarticular injection.

Industrial applicability

The present invention relates to novel means for the relief of pain in joint disease that shows early onset of the debilitating pain of action after administration, which has a long length of up to 13 weeks or up to 26 weeks, and is a therapeutic means of continuous type against diseases of the joints, considerably reducing the burden on patients and thus has applicability in industries such as medical industry.

1. Pharmaceutical composition for attenuating pain at joint disease in humans that contains
hyaluronic acid, which is crosslinked by cyclization of the double bond in the group of cinnamic acid in a partially amidinophenoxy hyaluronic acid, represented by formula (1), with the formation of cyclobutanones cycle

where Ar represents a phenyl group, n is an integer 2 or 3, HA represents Soboh� carboxylato hyaluronic acid, and m represents the ratio of the hyaluronic acid amidation to all carboxyl groups and equal 3-50% relative to all the carboxyl groups; and
pharmaceutically acceptable carrier,
where the pharmaceutical composition is a product for injection, where the content of the crosslinked hyaluronic acid is about 1 wt.% in the calculation of the total volume of the product for injection, where a single dosage of the product for injection is 2-3 ml, where the pharmaceutical composition is a tablet single dose, which is administered with an interval of introduction of 13 weeks or more.

2.Pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used for a long period of operation, at least up to 13 weeks.

3. Pharmaceutical composition according to claim 2, where the pharmaceutical composition is used for a long period of operation, at least up to 26 weeks.

4. Pharmaceutical composition for attenuating pain at joint disease in humans that contains
hyaluronic acid, which is crosslinked by cyclization of the double bond in the group of cinnamic acid in a partially amidinophenoxy hyaluronic acid, represented by formula (1), with the formation of cyclobutanones cycle

where Ar represents a phenyl group, n is an integer 2 or 3, HA represents carboxyla�OK hyaluronic acid, and m represents the ratio of the hyaluronic acid amidation to all carboxyl groups and equal 3-50% relative to all the carboxyl groups; and
pharmaceutically acceptable carrier,
where the pharmaceutical composition is a product for injection, where the content of the crosslinked hyaluronic acid is about 1 wt.% in the calculation of the total volume of the product for injection, where a single dosage of the product for injection is 2-3 ml, where the pharmaceutical composition is used for a long period of operation, at least up to 13 weeks.

5.Pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is a drug at one time.

6. Pharmaceutical composition according to claim 4 or 5, where the pharmaceutical composition is used for a long period of operation, at least up to 26 weeks.

7. Method for relief of pain in a patient in need of relief of pain in joint disease in humans, including:
introduction the effective dose of the pharmaceutical composition to the patient at intervals the introduction of 13 weeks or more,
where the pharmaceutical composition contains
hyaluronic acid, which is crosslinked by cyclization of the double bond in the group of cinnamic acid in a partially amidinophenoxy hyaluronic acid, represented by formula (1), with the formation of cyclobutanones cycle

where Ar represents a phenyl group, n is an integer 2 or 3, HA represents carboxylate hyaluronic acid, and m represents the ratio of the hyaluronic acid amidation to all carboxyl groups and equal 3-50% relative to all the carboxyl groups; and
pharmaceutically acceptable carrier,
where the pharmaceutical composition is a product for injection, where the content of the crosslinked hyaluronic acid is about 1 wt.% in the calculation of the total volume of the product for injection, where a single dosage of the product for injection is 2-3 ml, where the pharmaceutical composition is a drug at one time.

8. A method according to claim 7, where the mass of hyaluronic acid for a single injection into the knee joint is 30 mg per adult patient.

9. A method according to any one of claim 7 or 8, in which the pharmaceutical composition is used for a long period of operation, at least up to 13 weeks.

10. A method according to claim 9, in which the pharmaceutical composition is used for a long period of operation, at least up to 26 weeks.

11. A method according to claim 7 or 8, in which the patient suffers defeat joint.

12. A method according to claim 7 or 8, in which the patient suffers from pain in disease of the joint.

13. A method according to claim 7 or 8, in which the patient suffers from osteoarthritis of the knee.

14. Pharma�the algebraic composition for attenuating pain in humans with diseases of the joints, contains
hyaluronic acid, which is crosslinked by cyclization of the double bond in the group of cinnamic acid in a partially amidinophenoxy hyaluronic acid, represented by formula (1), with the formation of cyclobutanones cycle

where Ar represents a phenyl group, n is an integer 2 or 3, HA represents carboxylate hyaluronic acid, and m represents the ratio of the hyaluronic acid amidation to all carboxyl groups and equal 3-50% relative to all the carboxyl groups; and
pharmaceutically acceptable carrier,
where the pharmaceutical composition is a product for the injections, weight hyaluronic acid for a single injection into the knee joint is in the range from 25 to 35 mg per adult patient, where the pharmaceutical composition is a tablet single dose, which is administered with an interval of introduction of 13 weeks or more.

15. Method for relief of pain in a patient in need of relief of pain in joint disease in humans, including:
introduction the effective dose of the pharmaceutical composition to the patient at intervals the introduction of 13 weeks or more,
where the pharmaceutical composition contains
hyaluronic acid, which is crosslinked by cyclization of the double bond in the group of cinnamic acid in frequent�chno amidinophenoxy hyaluronic acid, represented by the formula (1), with the formation of cyclobutanones cycle,

where Ar represents a phenyl group, n is an integer 2 or 3, HA represents carboxylate hyaluronic acid, and m represents the ratio of the hyaluronic acid amidation to all carboxyl groups and equal 3-50% relative to all the carboxyl groups; and
pharmaceutically acceptable carrier,
where the pharmaceutical composition is a product for the injections, weight hyaluronic acid for a single injection into the knee joint is in the range from 25 to 35 mg per adult patient, where the pharmaceutical composition is a drug at one time.



 

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FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, and concerns using a human Annexin-1 antibody (Anx-A1), which has the sequence SEQ ID NO: 23 for treating a disease caused by abnormal T-cell activation. The group of inventions also concerns a method of treating a disease caused by abnormal T-cell activation, involving administering a therapeutic amount of the above antibody into an individual in need thereof; using the above antibody for producing a therapeutic agent for treating a disease caused by abnormal T-cell activation.

EFFECT: group of inventions provides treating the disease caused by abnormal T-cell activation.

9 cl, 11 ex, 22 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , which is a methylhydrofumarate (MHF) prodrug. In formula (I), radicals and symbols have the values specified in the patent claim. The invention also refers to a pharmaceutical composition containing the declared methylhydrofumarate drugs, to using the declared methylhydrofumarate drugs and the pharmaceutical composition containing them, for treating diseases, such as psoriasis, asthma, multiple sclerosis, inflammatory intestinal disease and arthritis, and to a method of treating the above diseases.

EFFECT: higher oral bioavailability and plasma MHF, dimethylfumarate and/or other metabolites.

47 cl, 1 tbl, 54 ex

FIELD: medicine.

SUBSTANCE: as medications administered are: methotrexate 15 mg per week intake, folic acid 5 mg per week intake, movalis 15 mg per day intake. Laser therapy is administered in differential way depending on degree of disease activity and level of glucosaminoglycanes (GAG). In case of second stage of rheumatoid arthritis - index DAS28 3.2-5.1, level of glucosaminoglycanes 0.510±0.032 g/l, 7 daily procedures of intravenous laser irradiation are carried out. Radiating head KL-VLOK with wavelength 635 nm, power at the end of disposable light guide 1.5 mW, exposure time 15 minutes and laser head KL-VLOK-365 with wavelength 365 nm, power at the end of light guide 1.0 mW, exposure time 5 minutes, are alternated. In case of third degree of activity index DAS28 is higher than 5.1, GAG level is equal or is higher than 0.618±0.069 g/l, 10 procedures are carried out Radiating head KL-VLOK with wavelength 635 nm, power at outlet of disposable light guide 1.5-2.0 mW, exposure time 15 minutes and laser head KL-VLOK-365 nm, power at outlet of disposable light guide 1.0 mW, time of exposure 5 minutes.

EFFECT: method makes it possible to reduce frequency of exacerbations, reduce expression of clinical manifestations, reduce drug load on patient, provides earlier arrest of disease symptoms due to differentiated approach in case of administration of intravenous laser irradiation of blood and its normalising action on GAG indices and reduction of disease activity degree.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel N-containing heteroaryl derivatives of formula I or II or their pharmaceutically acceptable salts, which possess properties of JAK kinase, in particular JAK3, and can be applied for treating such diseases as asthma and chronic obstructive pulmonary disease (COPD). In formulae A represents carbon and B represents nitrogen or A represents nitrogen and B represents carbon; W represents CH or N; R1 and R2, independently represent hydrogen, C1-4alkyl, halogenC1-4alkyl, -CN; R3 represents C1-4alkyl, R9-C1-4alkyl, Cy1, where Cy1 is optionally substituted with one or several substituents R10; R4 represents hydrogen, C1-4alkyl, R12R7N-C0alkyl, where one of R7 and R12 represents hydrogen, and the other represents C1-4alkyl or group R13, which is selected from C1-5alkyl, Cy2-C0alkyl; R5 represents hydrogen; R6 represents hydrogen, C1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl, R12R7N-C1-4alkyl, R16CO-C0alkyl, Cy1; R7 represents hydrogen or C1-4alkyl; R9 represents halogen, -CN, -CONR7R12, -COR13, CO2R12, -OR12, -SO2R13, -SO2NR7R12, -NR7R12, -NR7COR12; R10 represents C1-4alkyl or R9-C0-4alkyl; R11 represents C1-4alkyl, halogen, -CN, -NR7R14; R12 represents hydrogen or R13; R13 represents C1-5alkyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, Cy2-C0alkyl or R14R7N-C1-4alkyl; where Cy2 is optionally substituted with one or several constituents R11; R14 represents hydrogen or C1-4alkyl; R16 represents C1-4alkyl, halogenC1-4alkyl, C1-4alkoxyC1-4alkyl, hydroxyC1-4alkyl or cyanoC1-4alkyl; Cy1 represents monocyclic carbocyclic unsaturated or saturated ring, selected from C3-C6cycloalkyl, phenyl, or saturated monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or partially unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available C atom, and where one or several ring C or S atoms are optionally oxidised with formation of CO or SO2; and Cy2 represents monocyclic carbocyclic unsaturated ring, selected from C3-C6cycloalkyl, or aromatic monocyclic 4-6-membered heterocyclic ring, containing from 1 to 2 heteroatoms, selected from N and S, or unsaturated 10-membered bicyclic heterocyclic ring, containing oxygen atom as heteroatom, which can be substituted with group R11, where said ring is bound with the remaining part of molecule via any available atom C or N.

EFFECT: obtaining novel heteroaryl derivatives.

27 cl, 41 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition in the form of a tablet with an erodible matrix, which contains one or more fumaric acid ethers, as well as a rate-controlling agent, representing hydroxypropylcellulose and a binding agent, representing lactose, with the decomposition of the said degradable matrix providing the controlled release of the said fumaric acid ether (ethers).

EFFECT: provision of the controlled release of fumaric acid ether (ethers).

19 cl, 43 ex, 2 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the novel and unexpected application of sulphated hyaluronic acid as a cytokine activity regulator for the prevention and/or treatment of asthma and degenerative joint osteoarthritis, associated with the activation of IL-1, IL-2, IL-6, IL-7, IL-8 and IL-12, the said sulphated hyaluronic acid has a molecular weight from 10000 to 50000 Da, from 150000 to 250000 Da and from 500000 to 750000 Da and where sulphated hyaluronic acid has a sulphation degree equal to 3.

EFFECT: invention provides the extension of an arsenal of means for the prevention and/or treatment of asthma and degenerative joint osteoarthritis.

3 cl, 25 ex, 4 tbl, 12 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and represents medication, possessing virucidal activity, for preventive and therapeutic treatment of viral infections, caused by virus of herpesviridae family, characterised by the fact that said medication contains pyroxican in carrier substance.

EFFECT: invention provides extension of arsenal of means, possessing virucidal activity.

7 cl

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