Pharmaceutical composition, containing one or more fumaric acid ethers in degradable matrix

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

 

AREA of TECHNOLOGY

The present invention relates to a pharmaceutical composition comprising a degradable matrix. In particular, the present invention relates to a pharmaceutical composition containing ertirea matrix containing one or more fumaric acid esters, and one or more of controlling the speed of the agents, the decomposition of the specified biodegradable matrix provides controlled or sustained release of the aforementioned esters of fumaric acid.

The LEVEL of TECHNOLOGY

Psoriasis is a chronic skin disease with a high percentage of genetic predisposition. The disease varies from acute to periods of complete lull. Patients suffering from psoriasis can have serious physical disabilities due to external characteristics of the disease. This affects all areas of life, such as career and private life.

Treatment options available to treatment according to the present invention, is limited, particularly for patients with psoriasis with the severity from mild to severe, and many of them only provide temporary and short-term improvement, and/or have serious unwanted effects/side effects. Since psoriasis has a high recurrence rate, most patient�to have to undergo prolonged treatment.

Esters of fumaric acid used for the treatment of psoriasis with the severity from mild to severe for more than 30 years. In 1994 in Germany was approved by the particular compound of dimethylfumarate and salts of monomethylfumarate - Fumaderm® initial / Fumaderm® (Fumaderm® initial / Fumaderm®). One tablet of Fumaderm® enteric coated contains the following active ingredients: dimethyl fumarate 120 mg; acylhydrolase, calcium salt, 87 mg; acylhydrolase, magnesium salt 5 mg; acylhydrolase, zinc salt of 3 mg and the following other ingredients: croscarmellose sodium, talc, magnesium stearate, colours E171 and e, copolymer of methacrylic acid and methyl methacrylate (1:1) copolymer of methacrylic acid and ethyl acrylate (1:1), macrogol 6000 (Macrogol 6000), simethicone (simethicone is an), povidone, triethylcitrate, microcrystalline cellulose, highly dispersed silicon dioxide [summary of product characteristics of Fumaderm, revised January 2009]. Today Fumaderm® represents approximately 66% of all appointments for the systemic treatment of psoriasis in Germany. However, the high frequency of side effects is the reason for the discontinuation, some patients receiving early treatment. It is assumed that the side effects from the gastrointestinal tract and redness may be, at least partially, explained by the properties �of svobodne prescribed composition, leading to the appearance of high local concentrations in the gut.

The authors of the present invention suggest that better treatment can be achieved by the introduction of a pharmaceutical composition intended for the delivery of active substances in a controlled way, i.e. in a way that is prolonged, delayed, detained, slow and/or delayed compared with the delivery of the commercially available product.

Esters of fumaric acid such as dimethyl fumarate, can be prone to disintegration and hydrolysis. For example, it is known that dimethyl fumarate is more susceptible to hydrolysis in alkaline/less acidic environment compared to more acidic environments (Litjens et al, "In vitro pharmacokinetics of anti-psoriatic fumaric acid esters", BMC Pharmacology 2004, 4:22). Thus, it is believed that dimethyl fumarate is more susceptible to hydrolysis in the small intestine compared to the stomach. Besides the influence of pH, as described above, it is considered that the esterase contributes to the hydrolysis of the ester of fumaric acid.

In WO 2006/037342 described pharmaceutical compositions with controlled release containing the ester (esters) of fumaric acid as the active substance (substances), wherein the controlled release characteristics allow to reduce the side effects associated with the gastrointestinal tract (gastrointestinal tract).

TASK FROM�RETENU

The task of implementation variants of the present invention to provide a pharmaceutical composition with a controlled or delayed release containing the ester (esters) of fumaric acid as the active substance (substances), which shows decreased side effects associated with the gastrointestinal tract (gastrointestinal tract), and/or reduced hyperemia compared with the composition of Fumaderm®, known in the art. Another object of the present invention is to provide a pharmaceutical composition with a controlled or delayed release containing the ester (esters) of fumaric acid as the active substance (substances), which has an improved pharmacokinetic profile compared to compounds known in the art. In particular, the object of the present invention is to provide a pharmaceutical composition with a controlled or delayed release containing the ester (esters) of fumaric acid as the active substance (substances), which shows a reduced variability of CPD (AUC) and/or values Smah compared with the compositions of controlled release, known in the art. In particular, the object of the present invention to provide a pharmaceutical composition with a controlled or delayed release, containing EF�R (ethers) of fumaric acid as the active substance (substances), demonstrates sufficient relative bioavailability compared to, for example, the composition of Fumaderm®, known in the art. Specifically, the object of the present invention to provide a pharmaceutical composition with a controlled or delayed release containing the ester (esters) of fumaric acid as the active substance (substances), which shows a reduced variability of CPD and/or values of Cmaxcompared with the composition of Fumaderm®, the prior art.

BRIEF description of the INVENTION

The authors present invention found that the controlled or sustained release of one or more fumaric acid esters can be achieved through the pills with the biodegradable matrix. Extend the release of active pharmaceutical ingredient (API) can be controlled using the number controls the speed of the polymer(s) relative to other components and it is assumed that high local concentrations of the active pharmaceutical ingredients can be avoided or reduced.

It was found that the controlled or sustained release of one or more fumaric acid esters to the corresponding pharmaceutically level can be achieved, compared with Fumaderm, from small tablets to improve a patient's compliance with treatment and regimens, � high local concentrations of the API could be avoided by ensuring full delivery of the active substance within a certain period of time after reaching the site of absorption, and at the same time can be provided with reduced variability compared to Fumaderm®.

It was found that the compositions according to the present invention show a good correlation in vitro/in vivo. In accordance with one aspect, the correlation in vitro/in vivo is determined by comparing time to release 80% of the fumaric acid ester of the compounds in the test for solubility in vitro with Cmaxmeasured in vivo after administration of the compositions.

The authors of the present invention also suggest that controlled release of the API by erosion of the matrix minimizes or reduces the exposure of the API to hydrolysis in the gastrointestinal tract, thereby reducing the dissolution of the API to absorption.

In accordance with the first aspect, it is assumed that in this way can maintain the effect of treatment and at the same time significantly reduce some or several unwanted side effects or negative effects known to Fumaderm®, or to improve tolerability in comparison with Fumaderm®.

In accordance with another aspect it is assumed that in this way it is possible to achieve improved treatment effect compared with Fumaderm® and at the same time reducing the unwanted side effects which are known to occur in the treatment of psoriasis the specified known in the art by Fumaderm®.

In accordance� with another aspect of the assumed thus it is possible to achieve an improved effect of the treatment, while maintaining tolerability in comparison with Fumaderm®.

In accordance with another aspect it is assumed that in this way it is possible to achieve an improved effect of treatment while improving tolerability compared with Fumaderm®.

In accordance with the first aspect of the present invention relates to a pharmaceutical composition in form of tablet with the biodegradable matrix containing:

i) from 10 wt.% to 80 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

(ii) 1-50 wt.% one or more of controlling the speed of the agents; and the enteric coating, wherein the specified the enteric coating is applied at a rate of 1.5 to 3.5 wt.% from the mass of the nucleus, while the decomposition of the specified biodegradable matrix provides controlled or sustained release of the specified active substances.

In accordance with one aspect of the present invention relates to a pharmaceutical composition in form of tablet with the biodegradable matrix containing:

(i) from 30 wt.% to 60 wt.% one or more esters of fumaric acid, you�early from di-(C 1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

ii) 3-40 wt.% one or more of controlling the speed of the agents; and the enteric coating, wherein the specified the enteric coating is applied at a rate of 1.5 to 3.5 wt.% from the mass of the nucleus, while the decomposition of the specified biodegradable matrix provides controlled or sustained release of the specified active substances.

In accordance with one aspect of the present invention relates to a pharmaceutical composition in the form of a monolithic tablet with the biodegradable matrix containing:

i) from 10 wt.% to 80 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance and

(ii) 1-50 wt.% one or more of controlling the speed of the agents; and the enteric coating, wherein the specified the enteric coating is applied at a rate of 1.5 to 3.5 wt.% from the mass of the nucleus, while the decomposition of the specified biodegradable matrix provides controlled or sustained release of the specified active substances.

In con�accordance with one aspect of the present invention relates to a pharmaceutical composition in the form of a monolithic tablet with the biodegradable matrix containing:

(i) from 30 wt.% to 60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

ii) 3-40 wt.% one or more of controlling the speed of the agents; and the enteric coating, wherein the specified the enteric coating is applied at a rate of 1.5 to 3.5 wt.% from the mass of the nucleus, while the decomposition of the specified biodegradable matrix provides controlled or sustained release of the specified active substances.

In accordance with one aspect of the present invention relates to a pharmaceutical composition in form of tablet with the biodegradable matrix containing:

A) a tablet core containing:

(i) 40-60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substances,

(ii) 4-6 wt.% controlling the speed of the agent;

(iii) 35-55 wt.% binders;

B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable Matri�s leads to the release of the fumaric acid ester - when exposed to the test on solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% the fumaric acid ester contained in the composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% the fumaric acid ester contained in the composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% the fumaric acid ester contained in the composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

In accordance with one aspect of the present invention relates to a pharmaceutical composition in form of tablet with the biodegradable matrix containing:

A) a tablet core containing:

(i) 30-60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or and� pharmaceutically acceptable salt as the active substance,

ii) 3-6 wt.% controlling the speed of the agent;

(iii) 35-65 wt.% binders;

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable matrix leads to the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% the fumaric acid ester contained in the composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% the fumaric acid ester contained in the composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% the fumaric acid ester contained in the composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

In accordance with one aspect of the present invention relates to FA�maceutical composition in the form of a monolithic tablet with the biodegradable matrix containing:

A) a tablet core containing:

(i) 40-60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substances,

(ii) 4-6 wt.% controlling the speed of the agent;

(iii) 35-55 wt.% binders;

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable matrix leads to the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% the fumaric acid ester contained in the composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% the fumaric acid ester contained in the composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% ester of fumaric acid, �of derashos as above specified, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

In accordance with one aspect of the present invention relates to a pharmaceutical composition in the form of a monolithic tablet with the biodegradable matrix containing:

A) a tablet core containing:

(i) 30-60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substances,

ii) 3-6 wt.% controlling the speed of the agent;

(iii) 35-65 wt.% binders;

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable matrix leads to the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% ester of fumaric acid�you contained in the specified composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% the fumaric acid ester contained in the composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% the fumaric acid ester contained in the composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

In accordance with one aspect of the present invention relates to a pharmaceutical composition in form of tablet with the biodegradable matrix containing:

A) a tablet core containing:

(i) 30-60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substances,

ii) 3-6 wt.% controlling the speed of the agent;

(iii) 35-65 wt.% binders;

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable matrix leads to the release of the fumaric acid ester - when subjected to humiliating�rgani test on solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to less than about 10 wt.% the fumaric acid ester contained in the composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% the fumaric acid ester contained in the composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% the fumaric acid ester contained in the composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

In accordance with one aspect of the present invention relates to a pharmaceutical composition in the form of a monolithic tablet with the biodegradable matrix containing:

A) a tablet core containing:

(i) 30-60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substances,

ii) 3-6 wt.% controlling the speed of the agent;

(iii) 35-65 wt.% binder�about substances;

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable matrix leads to the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to less than about 10 wt.% the fumaric acid ester contained in the composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% the fumaric acid ester contained in the composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% the fumaric acid ester contained in the composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

In accordance with one aspect of the present invention relates to a pharmaceutical composition in form of tablet with the biodegradable matrix containing

A) a tablet core containing:

(i) 30-60 wt.% dimethylfumarate,

ii) 3-6 wt.% the hydroxypropyl cellulose;

(iii) 35-65 wt.% lactose;

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable matrix leads to the release of dimethylfumarate - exposure test on solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% dimethylfumarate contained in the specified composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% dimethylfumarate contained in the specified composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% the fumaric acid ester contained in the composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% the total number of dimethylfumarate contained in the specified composition.

In accordance with one aspect of the present invention �tositsa pharmaceutical composition in the form of a monolithic tablet with the biodegradable matrix containing:

A) a tablet core containing:

(i) 30-60 wt.% dimethylfumarate,

ii) 3-6 wt.% the hydroxypropyl cellulose;

(iii) 35-65 wt.% lactose;

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable matrix leads to the release of dimethylfumarate - exposure test on solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% dimethylfumarate contained in the specified composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% dimethylfumarate contained in the specified composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% the fumaric acid ester contained in the composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% the total number of dimethylfumarate contained in the specified composition.

In the present context, the term "wt.%" relative�tsya to the percentage by weight of each component in the tablet core, that, therefore, excludes any external coating or film.

In accordance with another aspect of the present invention relates to a method for producing the composition according to the present invention, comprising the following steps:

(a) Dissolving or suspending either one or both of the ester of fumaric acid, and controlling the speed of the agent in the form of a polymer matrix substance in water to obtain an aqueous suspension of said substances;

(b) Applying a specified water slurry spray into pellets ester of fumaric acid and/or binder during the period of time that is sufficient for obtaining uniform coatings;

c) drying the obtained granules;

d) Possibly, sieving or grinding of these granules;

e) preparation of the mixture with any pharmaceutically acceptable excipients and additives essentially known method of obtaining the composition in the form of pills;

f) Applying enteric coating on said composition is in tablet form essentially known manner;

while any or all of the above steps is carried out at this temperature to product temperature did not exceed 45 º C.

It is known that, for example, dimethyl fumarate can be preserved during sublimation, and sublimation are more pronounced at higher temperatures.

In accordance with�tvii with some aspects of the manufacture of compositions according to the present invention is carried out at a relatively low temperature to minimize or reduce sublimation, and including several intermediate stages and minimal involvement of non-motorized stages. These factors contribute to ensuring that the manufacturing process was scalable and feasible in an industrial environment and in an industrial scale. In accordance with some aspects, it was found that the compositions according to the present invention can be manufactured on a larger scale, such as at least 15 kg, such as at least 20 kg, such as at least 30 kg.

In accordance with another aspect of the present invention relates to a method for producing the composition according to the present invention, comprising the following steps:

(a) Dissolving or suspending controlling the speed of the agent in the form of a polymer matrix substance in water to obtain an aqueous suspension of a specified substance;

(b) Applying a specified water slurry spray into pellets ester of fumaric acid during the period of time that is sufficient for obtaining uniform coatings;

c) drying the obtained granules;

d) Possibly, sieving or grinding of these granules;

e) preparation of the mixture with any pharmaceutically acceptable excipients and additives essentially known method of obtaining the composition in the form of pills;

(f) Applying the enteric coating on ukazannayav tablet form essentially in a known manner;

while any or all of the above steps is carried out at this temperature to product temperature did not exceed 45 º C.

In accordance with another aspect of the present invention relates to a method for producing the composition according to the present invention, comprising the following steps:

a) Possibly, sieving or grinding of crystals of the ester of fumaric acid;

(b) Mixing the above crystals of fumaric acid ester, which controls the speed of the agent in the form of a polymer matrix substance and any pharmaceutically acceptable excipients and additives by direct compression with obtaining a composition in the form of pills;

(C) the Application of enteric coating on said composition is in tablet form essentially known manner;

while any or all of the above steps is carried out at this temperature to product temperature did not exceed 45 º C.

In accordance with another aspect of the pharmaceutical composition according to the present invention is intended for use for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (PC), juvenile diabetes, Hashimoto's thyroiditis, grave's disease, SLE (systemic lupus of volcha�CI), sjögren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/isiana pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or anulyarnaya granuloma.

Another aspect of the present invention is a pharmaceutical composition according to the present invention for obtaining a medicinal product for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (PC), juvenile diabetes, Hashimoto's thyroiditis, grave's disease, SLE (systemic lupus erythematosus), sjögren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis, pain such as radicular pain, pain associated with RA�isolatie, neuropathic pain or sciatica/isiana pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or anulyarnaya granuloma.

Another aspect of the present invention is a method of treating psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (PC), juvenile diabetes, Hashimoto's thyroiditis, grave's disease, SLE (systemic lupus erythematosus), sjögren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis, pain, such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/isiana pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or anulyarnaya granuloma, wherein said method comprises the oral administration to a patient in need this, the effective dose of the pharmaceutical composition according to the present invention.

Explanation of DRAWINGS

Fig.1 shows the characteristics of dissolution in vitro at 37º using Primorac blade for dissolution at 100 rpm using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the test, and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution for the remaining period of the test film-coated or enteric-coated tablets with the biodegradable matrix according to the present invention, as described in Examples 16, 18, 20 and 22.

Fig.2 shows characteristics of dissolution in vitro at 37º with the use of the device with the blade for dissolution at 100 rpm using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution for the remaining period of the test film-coated tablets with the biodegradable matrix according to the present invention, as described in Example 23.

DETAILED description of the INVENTION

In the present context the term "API" is an abbreviation of "active pharmaceutical ingredient" and the term "active substance" are used interchangeably and refer to an ester (esters) of fumaric acid, which must be released from the pharmaceutical composition according to the present invention.

In the present context, the term "controlled or sustained release" refers to release from the composition is designed to release the fumaric acid ester prolonged, retardirovannah, slow and/or from�rucenim way compared to the release of the commercially available product of Fumaderm when tested under comparable conditions (e.g., in vivo: the equivalent doses to the standardized or without food, etc., or for in vitro studies: equivalent doses, the device for carrying out the test on the solubility and conditions, including, for example, composition, volume, and temperature of your environment for dissolution, rotation speed, etc.).

The release in vivo can be tested by measuring plasma concentrations at pre-defined time periods and, thus, by obtaining the graph of the dependence of the concentration in plasma from time to time for the ester of fumaric acid or, if necessary, its metabolite. In addition, it is assumed that metabolism occurs in the GI tract or with the passage of the mucous membrane of the gastro-intestinal tract, or the first passage through the hepatic circulation. Accordingly, with the introduction of dimethylfumarate relevant component for detection in plasma may be monomethyl ether, instead of the dimethyl ester of fumaric acid.

Can also be used other tests to determine or measure the release of active agent in vivo. Thus, animals (for example, dwarf pigs, dogs, etc.) can be used as a model. These animals get studied composition and after certain periods of time W�gathered blood samples and determine the content of the active component (or its metabolite, if necessary) in plasma or specific organs, or extracted from the contents of the intestine.

Another test involves the use of a particular segment of the intestine of an animal or human. The specified segment is placed in a suitable device comprising two cameras (donor and recipient), separated by a segment, and studied the composition is placed in a suitable environment in one cell (donor cell). The composition will release the active substance, which is then transferred through the segment of the intestine. Accordingly, at suitable time intervals the concentration of the active substance (or, if necessary, metabolite) was measured in the cell-recipient.

Specialist in the art will be able to apply the above method to a specific track.

Regarding the in vitro methods available methods are known, in particular, the methods described in an official pharmacopoeial articles, such as, for example, the United States Pharmacopoeia (USP) or European Pharmacopoeia. Specialist in the art knows which method to choose and how to choose the specific conditions for conducting the test in vitro. For example, USP prescribes the tests in vitro at 37+/-1,0, for example, 37+/-0,5 degrees Celsius/centigrade scale. In accordance with one aspect of suitable test solubility is a test in which characteristics�and dissolution determine as described in the US Pharmacopoeia in 37º with the use of the device with the blade for dissolution at 100 rpm using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 in the medium to dissolve in the remaining period of the test. Specialist in the art knows how to adjust the applied conditions, such as temperature, pH, speed of the blade, length, etc. In accordance with another aspect of the testing in vitro dissolution as follows:

using the instrument II (blades) USP vessels with a volume of 1 liter. The temperature of the bath is mounted on 37º OF±0.5 º C, and the speed of the blade at 100 rpm. One tablet is placed in one vessel containing 750 ml of 0.1 N HC1 (pH of 1.2) for 2 hours. After this pH change to 6.8 by adding 220 ml of 0.2 M sodium phosphate buffer. Selected samples 1.5 ml each time of sampling and analyzed by HPLC on DMF. The HPLC parameters set as follows: Column: Phenomenex Luna C18, 50×4.6 mm, 3 µm; column thermostat temperature 30 º C,: mobile phase: Methanol: 20 mm phosphate buffer pH 3.0 (35:65 vol./vol.), injection volume: 5 µl, flow rate: 0.8 ml/min, wavelength of detection: 210 nm; chromatography time of 5 minutes, the retention time of the DMF 3.5 minutes.

In the present context the term "�oxytelinae bioavailability" refers to the comparison of the quantity of the drug, absorbed (expressed as the area under the curve) after administration of two different formulations or reference product. In this context, the amount of absorbed drug, expressed as AUC, can be detected in the form of the actual input of the drug or its metabolite. Relative bioavailability can be expressed as the percentage of reference of CPD, i.e. % ACC.

In the present context, the term "variability" refers to the variability of FC parameters (e.g., Cmaxand control panel) after administration of the pharmaceutical composition or the reference composition. Variability can be expressed in terms of coefficient of variation (CV) for the FC parameter, i.e. the ratio of standard deviation and mean value.

In the present context the term "portability" refers to the action of the drug, hyphenated subjects and/or patients. In accordance with one aspect of "tolerance" is defined as the action of the drug, tolerated by the subjects and/or patients in the early stages of treatment, for example, during the first three months after the start of treatment, for example, in the first month after the start of treatment, for example, during the first two weeks after the start of treatment, for example, in the first week after the start of treatment, for example, during TRANS�'s three days after the start of treatment, for example, during the first days after the start of treatment, for example, after the first dose of treatment. The drug, with better tolerability, produce fewer side effects in a subject and/or patient in comparison to the medicine having more poor tolerability.

In the present context, the term "essentially no" refers to the level of less than about 1%, such as less than about 0.5%, such as less than about 0.3%, such as about 0.0 per cent.

In the present context, the terms "controlling the speed of the agent" and "controlling the speed of the agent in the form of a polymeric matrix substances" are interchangeable and refer to the agent that might delay/slow down and/or to prolong the release of active substances in vivo and/or in vitro.

As indicated above, the release in vivo and/or in vitro of the active substance is prolonged, slow and/or delayed compared with the composition of commercially available Fumaderm. In the present context the term "prolonged" means that the active substance is released over a longer period of time than Fumaderm®, for example, at least during the time period that is at least 1.2 times, such as at least 1.5 times, at least 2 times in at least 3 times, in less�St least 4 times or at least 5 times more than Fumaderm®. Thus, if, for example, 100% of dimethylfumarate released from tablets of Fumaderm® 3 hours after the start of a suitable test, 100% of dimethylfumarate in the composition according to the present invention is released at least 3.6 hours after the start of a suitable test.

In the present context the term "deferred" means that the release of the active substance starts at a later point in time compared to Fumaderm® (for example, after 30 minutes or later, as for example 45 minutes or 1 hour or more later or 1.5 hours or later).

In the present context, the term "monolithic" refers to consisting of one unit or constituting a single unit.

It is assumed that the composition according to the present invention provides an improved tolerability, such as fewer and/or less severe side effects such as gastro-intestinal tract (GIT), such as fewer and/or less severe cases of redness, such as fewer and/or less severe cases of hyperemia.

According to the present invention a side effect gastro-intestinal tract (GIT) may include, but are not limited to, diarrhea, stomach pain, abdominal pain, abdominal cramps, nausea, bloating, tenesmus, flatulence, increased frequency of stool, feeling of fullness and cramping upper� abdomen.

In this context, reduction of side effects from the gastrointestinal tract means a reduction in severity and/or frequency of occurrence among cure this group of patients when compared side effects from the blood observed after administration of the composition according to the present invention, with side effects from the blood observed after the introduction of Fumaderm®. Thus, the decrease associated with gastrointestinal side effects according to this definition can be regarded as a significant decrease in the frequency of the occurrence of any of the side effects from the gastrointestinal tract listed above, such as at least 10% decrease in the frequency of occurrence, or more preferably at least 20% decrease in the frequency of occurrence or even more preferably more than 30% decrease in the frequency of occurrence. Reduction associated with gastrointestinal side effects can also be expressed as a significant reduction of the severity of any side effects from the gastrointestinal tract listed above, such as a reduction in severity and/or frequency of diarrhea, stomach pain, abdominal pain, stomach cramps, nausea, bloating, tenesmus, flatulence, increased frequency of defecation, feeling of fullness or cramps upper abdomen. Reduction associated with gastrointestinal side effects described above can be observed in the clinical �direction, or comparing the introduction of the composition according to the present invention directly with Fumaderm® or placebo. In the case of placebo controlled studies the frequency of occurrence associated with gastrointestinal side effects in patients receiving the composition according to the present invention, compared with the placebo group, can be compared with previous studies comparing Fumaderm with placebo (see, for example, Altmeyer et al, J. Am. Acad. Dermatol. 1994; full reference: Altmeyer PJ et al, Antipsoriatic effect offumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J. Am. Acad. Dermatol. 1994; 30:977-81).

In accordance with another aspect of the composition according to the present invention is by oral administration and compared with those obtained after oral administration of tablets of Fumaderm in equivalent dose reduces side effects from the gastrointestinal tract (frequency and/or severity).

In one embodiment, the implementation of specified clinical study can be conducted as described below under the heading "Clinical study on the patients." In another embodiment, the implementation of specified clinical study can be conducted as described below under the heading "Clinical study on healthy volunteers."

A clinical study on patients: As a rule, in the study include patients who suffer from psoriasis, and as a rule, more than 10% of the power�of the body will be affected with psoriasis (severe psoriasis). However, can also be included, patients whose affected from 2 to 10 percent of the surface area of the body (secondary psoriasis). Patients can also be selected on the basis of the index of the scope and severity of psoriasis (PASI). As a rule, include patients within a certain range of indicators PASI, such as from 10 to 40, or such as from 12 to 30, or such as from 15 to 25. In another embodiment include patients with a certain minimum PASI, such as the index of PASI equal to at least 8, such as at least 10, such as at least 12, such as at least 15. Can be included patients with any type of psoriasis (chronic plaque type, essentally teardrop type, pustular type, psoriatic erythroderma or Palmar-plantar type), but in some cases include only patients with chronic plaque type. In most cases, it helps to about 15 to 20 patients in each treatment group (the composition according to the present invention, Fumaderm® or placebo), but more preferably includes from about 30 to 50 patients in each study group. The total duration of the study may be from one day to one week, but more preferably, the study will take place over 8 weeks to 12 weeks or up to 16 weeks, or longer. �obecnie effects can be for example, estimated as the total number of times a certain side effect reported in each group (regardless of how many patients experienced a listed side effect), or side effects may be estimated as the number of patients who have experienced a particular side effect a certain number of times, e.g., at least once or at least twice or at least three times during the duration of the study. In addition, it is possible to observe the severity of the side effect, or a certain severity of side effects may be necessary as a side effect in the study. A convenient way of assessing the severity of a side effect is to use a visual analogue scale (VAS).

Clinical study in healthy volunteers: This study typically will be a single-centre study after open, randomized, "inverted" design for the study of plasma concentrations, pharmacokinetics, safety and tolerability of the pharmaceutical compositions according to the present invention, it is possible with the use of market composition Fumaderm® as a reference. The study can be conducted as described in example 25 below.

In accordance with another aspect of the composition according to�ACLs to the present invention - after oral administration and compared with those obtained after oral administration of tablets of Fumaderm® equivalent dose decreases hyperemia (frequency and/or severity).

In the present context the term "hyperemia" describes episodic attacks of redness of the skin along with the sensation of warmth or burning of the face and/or neck, and less frequently the upper body and abdomen or the whole body. Short-term nature of the attacks that distinguishes flushing from the constant erythema of photosensitivity or acute reactions to contact. Repeated flushing over a long period of time can lead to telangiectasia and occasionally to classical rosacea of the face (Greaves MW. Flushing and flushing syndromes, rosacea and perioral dermatitis. B: Champion RH, et al, eds. Rook/Wilkinson/Ebling textbook of dermatology, 6th ed., vol.3. Oxford, UK: Blackwell Scientific, 1998: 2099-2104).

In this context, reducing congestion means reducing the severity and/or frequency of occurrence/frequency of hyperemia among cure this group of patients is observed after administration of the composition according to the present invention, compared with hyperemia observed after the introduction of Fumaderm®, and can be measured, for example, as described by O'toole et al. Cancer 2000, 88(4): p.770-776. Thus, reducing congestion according to this definition can be seen as a decrease in the frequency of occurrence and/or severity of hyperemia. In accordance� with one aspect of the present invention, the frequency of occurrence of congestion is reduced by at least about a quarter, in accordance with another aspect of the present invention, the frequency of occurrence is reduced by at least about a third, in accordance with another aspect of the present invention, the frequency of occurrence is reduced by at least half and in accordance with another aspect of the present invention, the frequency of occurrence of congestion has been reduced by approximately two-thirds or more. Similarly, heaviness in accordance with one aspect of the present invention is reduced by at least about a quarter, in accordance with another aspect of the present invention, at least about a third, in accordance with another aspect of the present invention at least about half and in accordance with another aspect of the present invention at least about two-thirds. One hundred percent decrease in the frequency of occurrence and severity of hyperemia is most preferable, but is not necessary. Reducing congestion, as described above, can be observed in the clinical studies, for example, by comparing the introduction of the compounds according to the present invention, for example, with the introduction of Fumaderm®. In the case of controlled Fumaderm study to compare the incidence and severity defined as mild, moderate or severe, hyperemia in patients receiving �the connection according to the present invention in comparison with a group of Fumaderm.

In accordance with one aspect of the severity of congestion is defined as the affected area of the body surface.

In one embodiment, the implementation of specified clinical study can be conducted as described above under the heading "Clinical study on the patients." In another embodiment, the implementation of specified clinical study can be conducted as described above under the heading "Clinical study on healthy volunteers."

In accordance with another aspect of the composition according to the present invention is by oral administration and compared with those obtained after oral administration of tablets of Fumaderm® in equivalent dose - reduces redness (frequency and/or severity).

In the present context the term "flushing describes episodic attacks of redness of the skin. In accordance with one aspect of the redness occurs on the face, neck, and less frequently in the upper body and abdomen.

In this context, the reduction of redness means reducing the severity and/or frequency of occurrence/frequency of redness among cure this group of patients is observed after administration of the composition according to the present invention, compared with the reddening observed after the introduction of Fumaderm, and can be assessed, for example, by a Clinician or nurse. Thus, the mind�isenia redness according to this definition can be seen as a decrease in the frequency of occurrence and/or severity of redness. In accordance with one aspect of the present invention, the frequency of occurrence of redness is reduced at least about a quarter, in accordance with another aspect of the present invention, the frequency of occurrence is reduced by at least about a third, in accordance with another aspect of the present invention, the frequency of occurrence is reduced by at least half and in accordance with another aspect of the present invention, the frequency of occurrence of redness is reduced by about two-thirds or more. Similarly, heaviness in accordance with one aspect of the present invention is reduced by at least about a quarter, in accordance with another aspect of the present invention, at least about a third, in accordance with another aspect of the present invention at least about half and in accordance with another aspect of the present invention at least about two-thirds. One hundred percent decrease in the frequency of occurrence and the severity of the redness is most preferable, but is not necessary. Reducing redness, described above, can be observed in the clinical studies, for example, by comparing the introduction of the compounds according to the present invention, for example, with the introduction of Fumaderm®. In the case of controlled Fumaderm�m® research you can compare the frequency of occurrence and severity defined as mild, moderate or severe, redness in patients receiving the compound according to the present invention in comparison with a group of Fumaderm®.

In accordance with one aspect of severity defined as redness of the affected area of the body surface.

In one embodiment, the implementation of specified clinical study can be conducted as described above under the heading "Clinical study on the patients." In another embodiment, the implementation of specified clinical study can be conducted as described above under the heading "Clinical study on healthy volunteers."

In one embodiment, the implementation of the relative bioavailability of the composition according to the present invention compared with Fumaderm® is at least about 75%, e.g., at least about 80%, e.g., at least about 85%, e.g., at least about 90%, e.g., at least about 95%, e.g., about 100%.

In one embodiment, the implementation of the relative bioavailability of the composition according to the present invention compared with Fumaderm® is at least about 100%, e.g., at least about 110%, for example at least about 120%, e.g., at least about 125%, n�example, at least about 130%.

In one embodiment, the implementation of the relative bioavailability of the composition according to the present invention compared with Fumaderm® is not more than about 130%, e.g., less than about 125%, e.g., less than about 120%, e.g., less than about 110%, e.g., less than about 100%.

In the present context, the term "degradable matrix refers to a matrix in which the release of the API is not dependent on the internal processes of diffusion, but rather is the result of the rate of erosion of the specified matrix. By removing erodynamic layers of the matrix is well controlled, and the method will be obtained predetermined number of APIs, with the release of the API depends on the rate of swelling and dissolution or erosion of the matrix and the dissolution rate, solubility and diffusion rate of the API.

In accordance with one aspect of the present invention relates to a pharmaceutical composition comprising a degradable matrix, which contains:

i) from 10 wt.% to 80 mass%, for example, from 20 wt.% to 70 mass%, for example, from 20 wt.% to 60 mass%, for example, from 30 wt.% to 60 mass%, for example, from 35 wt.% to 60 mass%, for example, from 35 wt.% to 55 mass%, for example, from 40 wt.% to 55 mass%, for example, from 44 wt.% to 55 mass%, for example, from 40 wt.% to 50 wt.%, for example, from 42 wt.% to 48 wt.% one or more esters of Fuma�acid type, selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

ii) from about 1 wt.% to 50 wt.% one or more of controlling the speed of the agents; and the enteric coating, as defined above, wherein the decomposition of the specified biodegradable matrix provides controlled or sustained release of the specified active substances.

In accordance with one aspect of the present invention relates to a pharmaceutical composition comprising a degradable matrix, which contains:

(i) from 30 wt.% to 60 mass%, for example, from 35 wt.% to 60 mass%, for example, from 35 wt.% to 55 mass%, for example, from 40 wt.% to 55 mass%, for example, from 40 wt.% to 50 wt.%, for example, from 44 wt.% to 55 mass%, for example, from 42 wt.% to 48 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylamino fumaric acid, or their pharmaceutically acceptable salts as active substance;

ii) from 3 wt.% to 40 wt.% one or more of controlling the speed of the agents; and the enteric coating, as defined above, wherein the decomposition of the specified biodegradable matrix provides controlled or sustained release of the decree�x active substances.

In some embodiments, implementation of the present invention, it was found that it is possible to achieve sustained release by using a relatively low amount of controlling the speed of the agent and at the same time still receive sufficient exposure to the drug in a narrow "window of absorption in the small intestine and, thus, provide favorable pharmacokinetic properties, such as sufficient relative bioavailability in comparison, for example, the composition of Fumaderm, known in the art.

In some additional embodiments, the implementation, it was found that it is possible to obtain coated enteric-coated formulations with slow release according to the present invention and at the same time to obtain sufficient exposure to the drug in a narrow "window of absorption in the small intestine and, thus, provide favorable pharmacokinetic properties, such as sufficient relative bioavailability in comparison, for example, the composition of Fumaderm®, known in the art.

In accordance with one aspect of the present invention controls the speed of the agent is a water-soluble polymer.

In the present description, the term "water soluble polymer" means a traditional polymer for pharmaceutical Prim�tion, having the solubility of more than 10 mg/ml in water. Suitable water soluble polymers include, but not limited to, for example, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and carboxymethylcellulose. In accordance with one aspect of the water-soluble polymer is a hydroxypropyl cellulose.

In the present description, the term "water soluble polymer" means a traditional polymer for pharmaceutical use, having a solubility of not more than 10 mg/ml in water.

In accordance with another aspect of the present invention, the biodegradable matrix essentially does not contain water-insoluble polymer. In accordance with another aspect of degradable matrix does not contain water-insoluble polymer.

In the present context, the term "essentially" refers to the level of less than about 1%, e.g., less than about 0.5%, e.g., less than about 0.3%, e.g., about 0.0 per cent.

In accordance with one aspect of the present invention controls the speed of the agent is a water-soluble polymer, and the biodegradable matrix essentially does not contain water-insoluble polymer.

In accordance with one aspect of the present invention controls the speed of the agent is a water-soluble polymer and biodegradable Mat�Itza does not contain water-insoluble polymer.

In one variant of implementation of the present invention controls the speed of an agent is a cellulose polymer or a cellulose derivative, or a mixture of these substances. As non-limiting examples of cellulosic polymer or a cellulose derivative, or mixtures of these substances can indicate hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, carboxymethylcellulose and mixtures of these substances.

In one variant of implementation of the present invention controls the speed of an agent is a hydroxypropyl cellulose. There are many different grades of hydroxypropyl cellulose, depending on, for example, its molecular weight, degree of esterification, viscosity, etc. typical non-limiting commercially available hydroxypropylcellulose can be obtained, for example, from Aqualon or Nippon Soda under the trade names of Klucel® (Klucel®) HPC-L, HPC-SL, HPC-SSL, HPC-M, HPC-H, etc., In one embodiment, implementation of the present invention controls the speed of an agent is a hydroxypropyl cellulose having a viscosity (MPa. s) component of 3.0 to 5.9, measured in aqueous solution, containing 2 wt.% dry HPC at 20 ° C. In one variant of implementation of the present invention controls the speed of an agent is a GOC-SL.

In one� variant implementation of the present invention controls the speed of the agent is present in a quantity equal 1-40 wt.%, for example, about 3-35 wt.%, for example, about 4-15 wt.%, for example, about 4-10 wt.%, for example, about 3-15 wt.%, for example, about 3-10 wt.%, for example, about 3-6 wt.%, for example, about 3-5,5 wt.%, for example, about 4-6% by weight.

In one variant of implementation of the present invention controls the speed of the agent is present in an amount equal to 1-40 wt.%, for example, about 3-35 wt.%, for example, about 4-15 wt.%, for example, about 4-10 wt.%, for example, about 3-15 wt.%, for example, about 3-10 wt.%, for example, about 3-6 wt.%, for example, about 3-5,5 wt.%, for example, about 4-6% by weight.

In another embodiment of the present invention controls the speed of the agent is present in an amount equal to 15-40 wt.%, for example, approximately 15-25 weight%.

In another embodiment of the present invention controls the speed of the agent is present in an amount equal to 25-40 wt.%, for example, about 35 to 40 mass%.

In another embodiment of the present invention controls the speed of the agent is present in an amount equal to 0-5 wt.%, for example, about 0-3 wt.%, for example, the absence of essentially any controlling speed of the agent.

In accordance with one aspect of the present invention relates to a pharmaceutical composition comprising a degradable matrix, Kotor�I contains:

i) from 10 wt.% to 80 mass%, for example, from 20 wt.% to 70 mass%, for example, from 20 wt.% to 60 mass%, for example, from 30 wt.% to 60 mass%, for example, from 35 wt.% to 60 mass%, for example, from 35 wt.% to 55 mass%, for example, from 40 wt.% to 55 mass%, for example, from 40 wt.% to 50 wt.%, for example, from 44 wt.% to 55 mass%, for example, from 42 wt.% to 48 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substances; and

ii) from 0 wt.% to 40 mass%, for example, from 0 wt.% to 20 mass%, for example, from 0 wt.% to 10 mass%, for example, from 0 wt.% to 5 mass%, for example, from 0 wt.% to 1 mass%, one or more of controlling the speed of the agents; and the enteric coating, as defined above, wherein the decomposition of the specified biodegradable matrix provides controlled or sustained release of the specified active substances.

The amount, if any, controlling the speed of the agent varies depending on the specific controls the speed of the agent, the directional characteristics of the release, the level and nature of any excipients and additives present in the tablet core, etc.

In one embodiment, the implementation of the present invention, the composition additionally contains� binder. Non-limiting examples of specified substances include water soluble sugars and sugar alcohols such as lactose, sucrose, glucose, sorbitol, mannitol, etc., In one embodiment, said binder substance is a lactose. Lactose is commercially available in several different varieties based (including) used from the production method, resulting in a range of particle sizes, particle sizes, etc. Examples of lactose include, but are not limited to, anhydrous lactose, lactose monohydrate obtained from alpha-lactose, agglomerated lactose, granulated lactose, crystalline lactose, crystalline, sieved lactose (for example, Primalac® (PrismaLac®), such as Primalac® 40), crystalline, abrasive lactose (for example, Granules® (GranuLac®), like Granola® 70, Granular® 140, Granular® 200, Granular® 230 and Granular® 400), improved lactose, agglomerated lactose (for example, Tablettose® (Tablettose®), such as Tablettose® 70, Tablettose® 80 and Tablettose® 100), improved lactose, spray dried lactose (Flolan® (FlowLac®), such as Flolan® 90 and Flolan® 100). Lactose is available, for example, from Meggle Pharma under the trade names Primalac, Capsules® (Capsulac®), such as Capsular® 60, Saelac® (SacheLac®), Spheromak® (SpheroLac®), Ingalik® (Inhalac®), Granola®, such as Granular® 70, Granular� 140, Granular® 200, Granular® 230 and Granular® 400, Sorbulak® (SorboLac®), Tablettose®, such as Tablettose® 70, Tablettose® 80 and Tablettose® 100, Flolan® (FlowLac®), such as Flolan® 90 and Flolan® 100.

In accordance with one aspect of lactose is an agglomerated lactose. In accordance with another aspect of the lactose is a spray-dried lactose. In accordance with another aspect of the lactose is an abrasive lactose.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

i) from 40 wt.% to 60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

(ii) 4-6 wt.% controlling the speed of the agent;

(iii) 35-55 wt.% binder

and the enteric coating, as defined above.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

i) from 40 wt.% to 60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts in quality�ve active substances;

(ii) 15-50 wt.% controlling the speed of the agent;

(iii) 5-30 wt.% binder

and the enteric coating, as defined above.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

(i) from 30 wt.% to 60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

ii) 3-6 wt.% controlling the speed of the agent;

(iii) 35-65 wt.% binder

and the enteric coating, as defined above,

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

(i) from 35 wt.% to 55 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

ii) 3-6 wt.% controlling the speed of the agent;

(iii) 40-60 wt.% binder

and the enteric coating, as defined above.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

i) from 40 wt.% to 50 wt�.% one or more fumaric acid esters, selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

ii) 3-6 wt.% controlling the speed of the agent;

(iii) 45-55 wt.% binder

and the enteric coating, as defined above.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

i) of 42 wt.% to 48 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

(ii) 3-5,5 wt.% controlling the speed of the agent;

(iii) 45-52 wt.% binder

and the enteric coating, as defined above.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

(i) from 30 wt.% to 60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

ii) 3-6 wt.% controlling the speed of the agent;

(iii) 35-65 wt.% binder substances�VA;

(iv) 0.15 to 0.7 wt.% lubricants;

and the enteric coating, as defined above;

and perhaps of 0.05-0.25 wt.% controlling agent turnover.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

(i) from 35 wt.% to 55 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

ii) 3-6 wt.% controlling the speed of the agent;

(iii) 40-60 wt.% binders;

(iv) 0.15 to 0.7 wt.% lubricants;

and the enteric coating, as defined above;

and perhaps of 0.05-0.25 wt.% controlling agent turnover.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

i) from 40 wt.% to 50 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

ii) 3-6 wt.% controlling the speed of the agent;

(iii) 45-55 wt.% binders;

(iv) 0.15 to 0.7 wt.% lubricants;

and enteric-coated�Thiais, as defined above;

and perhaps of 0.05-0.25 wt.% controlling agent turnover.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

i) of 42 wt.% to 48 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substance;

(ii) 3-5,5 wt.% controlling the speed of the agent;

(iii) 45-52 wt.% binders;

(iv) 0.2 to 0.5 wt.% lubricants;

and the enteric coating, as defined above;

and perhaps 0.05 to 0.2 wt.% controlling agent turnover.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

(i) from 30 wt.% to 60 wt.% dimethylfumarate;

ii) 3-6 wt.% The GOC;

(iii) 35-65 wt.% lactose;

and the enteric coating, as defined above;

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

(i) from 35 wt.% to 55 wt.% dimethylfumarate;

ii) 3-6 wt.% The GOC;

(iii) 40-60 wt.% lactose;

and the enteric coating, as defined above.

In one embodiment, the implementation of the present invention, the composition according to the present invented�Yu contains:

i) from 40 wt.% to 50 wt.% dimethylfumarate;

ii) 3-6 wt.% The GOC;

(iii) 45-55 wt.% lactose;

and the enteric coating, as defined above.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

i) of 42 wt.% to 48 wt.% dimethylfumarate;

(ii) 3-5,5 wt.% The GOC;

(iii) 45-52 wt.% lactose;

and the enteric coating, as defined above.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

(i) from 30 wt.% to 60 wt.% dimethylfumarate;

and) 3-6 wt.% The GOC;

(iii) 35-65 wt.% lactose;

(iv) 0.15 to 0.7 wt.% magnesium stearate;

and perhaps of 0.05-0.25 wt.% silicon dioxide;

and the enteric coating, as defined above.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

(i) from 35 wt.% to 55 wt.% dimethylfumarate;

ii) 3-6 wt.% The GOC;

(iii) 40-60 wt.% lactose;

(iv) 0.15 to 0.7 wt.% magnesium stearate;

and perhaps of 0.05-0.25 wt.% silicon dioxide;

and the enteric coating, as defined above.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

i) from 40 wt.% to 50 wt.% dimethylfumarate;

ii) 3-6 wt.% The GOC;

(iii) 45-55 wt.% lactose;

(iv) 0.15 to 0.7 wt.% magnesium stearate;

and who�one of 0.05-0.25 wt.% silicon dioxide;

and the enteric coating, as defined above.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

i) of 42 wt.% to 48 wt.% dimethylfumarate;

(ii) 3-5,5 wt.% The GOC;

(iii) 45-52 wt.% lactose;

(iv) 0.2 to 0.5 wt.% magnesium stearate;

and perhaps 0.05 to 0.2 wt.% silicon dioxide;

and the enteric coating, as defined above.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

A) the tablet core, consists of:

(i) from 30 to 60 wt.% dimethylfumarate as active ingredients having a distribution of particle sizes such that 0-5% of the particles have a size of >500 μm and 45-53% of the particles have a size of >250 microns, and 7-15% of the particles have a size of <100 μm;

ii) 3-6 wt.% The GOC;

(iii) 35-65 wt.% lactose;

(iv) 0.15 to 0.7 wt.% magnesium stearate, and 0.05-0.25 wt.% silicon dioxide;and

B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

A) the tablet core, consists of:

(i) from 35 to 55 wt.% dimethylfumarate as active ingredients having a distribution of particle sizes such that 0-5% of the particles have a size of >500 μm and 45-53% of the particles have a size of >250 μm, and 7-15% of the particles have a size of <100 μm;

ii) 3-6 wt.% The GOC;

(iii)40-60 wt.% lactose;

(iv) 0.15 to 0.7 wt.% magnesium stearate, and 0.05-0.25 wt.% silicon dioxide; and

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

A) the tablet core, consists of:

i) from 40 to 50 wt.% dimethylfumarate as active ingredients having a distribution of particle sizes such that 0-5% of the particles have a size of >500 μm and 45-53% of the particles have a size of >250 microns, and 7-15% of the particles have a size of <100 μm;

ii) 3-6 wt.% The GOC;

(iii)45-55 wt.% lactose;

(iv) 0.15 to 0.7 wt.% magnesium stearate, and 0.05-0.25 wt.% silicon dioxide; and

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

A) the tablet core, consists of:

(i) from 42 to 48 wt.% dimethylfumarate as active ingredients having a distribution of particle sizes such that 0-5% of the particles have a size of >500 μm and 45-53% of the particles have a size of >250 microns, and 7-15% of the particles have a size of <100 μm;

(ii) 3-5,5 wt.% The GOC;

(iii)45-52 wt.% lactose;

(iv) 0.2 to 0.5 wt.% magnesium stearate, and 0.05-0.2 wt.% dioxidine; and

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

A) the tablet core, consists of:

(i) from 30 to 60 wt.% dimethylfumarate as active ingredients having a distribution of particle sizes such that 0-7% of the particles have a size of >500 μm and 42-59% of the particles have a size of >250 microns, and about 3-12% of the particles have a size of <100 μm;

ii) 3-6 wt.% The GOC;

iii) 35-B5 wt.% lactose;

(iv) 0.15 to 0.7 wt.% magnesium stearate, and 0.05-0.25 wt.% silicon dioxide; and

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

A) the tablet Core, consists of:

(i) from 35 to 55 wt.% dimethylfumarate as active ingredients having a distribution of particle sizes such that 0-7% of the particles have a size of >500 μm and 42-59% of the particles have a size of >250 microns, and about 3-12% of the particles have a size of <100 μm;

ii) 3-6 wt.% The GOC;

(iii) 40-60 wt.% lactose;

(iv)0.15 to 0.7 wt.% magnesium stearate, and 0.05-0.25 wt.% silicon dioxide; and

B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel.

In one Varian�s implementation of the present invention, the composition according to the present invention contains:

A) the tablet core, consists of:

i) from 40 to 50 wt.% dimethylfumarate as active ingredients having a distribution of particle sizes such that 0-7% of the particles have a size of >500 μm and 42-59% of the particles have a size of >250 microns, and about 3-12% of the particles have a size of <100 μm;

ii) 3-6 wt.% The GOC;

(iii) 45-55 wt.% lactose;

(iv) 0.15 to 0.7 wt.% magnesium stearate, and 0.05-0.25 wt.% silicon dioxide; and

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

A) the tablet core, consists of:

(i) from 42 to 48 wt.% dimethylfumarate as active ingredients having a distribution of particle sizes such that 0-7% of the particles have a size of >500 μm and 42-59% of the particles have a size of >250 microns, and about 3-12% of the particles have a size of <100 μm;

(ii) 3-5,5 wt.% The GOC;

(iii) 45-52 wt.% lactose;

(iv) 0.2 to 0.5 wt.% magnesium stearate, and 0.05-0.2 wt.% silicon dioxide; and

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

A) the tablet core, consists of:

(i) from 30 to 60 wt.% dimethylfumarate as the active substance, with distribution h�STIC size, that 0-10% of the particles have a size of >500 μm and 40-65% of the particles have a size of >250 microns, and about 2-10% of the particles have a size of <100 μm;

ii) 3-6 wt.% The GOC;

(iii) 35-65 wt.% lactose;

(iv) 0.15 to 0.7 wt.% magnesium stearate, and 0.05-0.25 wt.% silicon dioxide; and b) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

A) the tablet core, consists of:

(i) from 35 to 55 wt.% dimethylfumarate as active ingredients having a distribution of particle sizes such that 0-10% of the particles have a size of >500 μm and 40-65% of the particles have a size of >250 microns, and about 2-10% of the particles have a size of <100 μm;

ii) 3-6 wt.% The GOC;

(iii) 40-60 wt.% lactose;

(iv) 0,l 5-0,7 wt.% magnesium stearate, and 0.05-0.25 wt.% silicon dioxide; and

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

A) the tablet core, consists of:

i) from 40 to 50 wt.% dimethylfumarate as active ingredients having a distribution of particle sizes such that 0-10% of the particles have a size of >500 μm and 40-65% of the particles have a size of >250 microns, and about 2-10% of the particles have a size of <100 μm;

ii) 3-6 wt.% The GOC;

(iii) 45-55 m�SS.% lactose;

(iv) 0.15 to 0.7 wt.% magnesium stearate, and 0.05-0.25 wt.% silicon dioxide; and

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains:

A) the tablet core, consists of:

(i) from 42 to 48 wt.% dimethylfumarate as active ingredients having a distribution of particle sizes such that 0-10% of the particles have a size of >500 μm and 40-65% of the particles have a size of >250 microns, and about 2-10% of the particles have a size of <100 μm;

(ii) 3-5,5 wt.% The GOC;

(iii) 45-52 wt.% lactose;

(iv) 0.2 to 0.5 wt.% magnesium stearate, and 0.05-0.2 wt.% silicon dioxide; and b) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel.

In one embodiment, the implementation of the composition according to the present invention further comprises one or more lubricants.

In one embodiment, the implementation of the composition according to the present invention further comprises one or more controlling agent turnover.

In one embodiment, the implementation of the composition according to the present invention further comprises one or more lubricants and one or more controlling agent turnover.

In one embodiment, the implementation of the composition according to the present invented�Yu further comprises pharmaceutically acceptable excipients and additives, selected from the group comprising lubricants, substances promoting sliding, leavening agents, controlling the fluidity agents, solubilization regulating pH agents, surfactants and emulsifiers.

In one embodiment, the implementation of the composition according to the present invention are made without the use of baking powder.

Some compositions according to the present invention exhibit a two-phase characteristics of dissolution in vitro, with the release of the API, such as dimethyl fumarate, is slower in the acidic environment in the first two hours in the unit USP for dissolution and faster as soon as Wednesday to dissolve the change to pH of 6.8, although the solubility of the API may be the same in acidic and alkaline medium. Thus, for drugs that require relatively low impact on the stomach, but at the same time, it should release/absorption in the small intestine, you limit the impact of APIs on the stomach and at the same time to optimize the impact of APIs on the small intestine. In one embodiment, the implementation characteristics of dissolution in vitro of the two-phase composition, i.e. the release of the API is slower in the acidic environment in the first two hours in the unit USP for dissolution and faster as soon as Wednesday to dissolve the change to pH of 6.8.

The rate of dissolution in vitro describes how the released amount of the active pharmaceutical ingredients contained in the composition according to the present invention is in the exposure test, the in vitro solubility - changing with time. The higher/faster the rate of dissolution in vitro means that more of the API is released within a certain time period, and the lower/slower the rate of dissolution in vitro means that fewer AFI released during the same time period - when exposed to the same test conditions in vitro dissolution.

In one variant of implementation of the present invention in the test for solubility in vitro, used to determine the dissolution rate in vitro, using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution.

In one embodiment, the implementation of the present invention, the dissolution rate in vitro of the active pharmaceutical ingredients contained in uncoated enteric coating composition according to the present invention when exposed to the test on solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the test and then 0.05 M phosphate buffer pH 6.8 in the medium to dissolve the above in the specified buffer (pH 6,8) phase in �the eyes with acid phase (0.1 N hydrochloric acid as the medium for the dissolution test dissolution in vitro for example, at least 10% higher, e.g. at least 20% higher, e.g. at least 30% higher, e.g. at least 40% higher, e.g. at least 50% higher, e.g. at least 60% higher, e.g. at least 70% higher, e.g. at least 80% higher, e.g. at least 90% higher, e.g. at least 100% higher for example, at least about 125% higher, e.g. at least about 150% higher, e.g. at least 200% higher, e.g. at least 250% higher, e.g. at least 300% higher, e.g. at least 350% higher, e.g. at least 400% higher in buffer (pH 6,8) phase in comparison with the acid phase (0.1 N hydrochloric acid as the medium for the dissolution test on solubility in vitro. In one implementation, the comparison is made between the dissolution rate in vitro in the first hour of the test (between time =0 and time =1 hour) and dissolution rate in vitro for 3 hours (between time =2 hours and time =3 hours) of the test. In another embodiment the comparison is made between the dissolution rate in vitro during the first two hours of the test (between time=0 and time=2 hours) and dissolution rate in vitro for 3 hours (between time =2 hours and time =3 hours) of the test. In another embodiment the comparison is made between the dissolution rate in vitro in the Techa�their first two hours of the test (between time =0 and time =2 hours) and dissolution rate in vitro, in the next 2 hours (between time =2 hours and time =4 hours) test. In another embodiment the comparison is made between the dissolution rate in vitro in the first hour of the test (between time =0 and time =1 hour) and dissolution rate in vitro between time =2 hours and time =2.5 hours of the test.

In one embodiment, the implementation of the composition according to the present invention further comprises one or more shells. In one variant of implementation of the present invention the specified one or more shells are added to improve the stability and characteristics of swallowing tablets or to delay the release of the API. In one embodiment, the implementation of these enteric coatings are coatings and possibly film coating. The coating film can improve the characteristics of swallowing, as well as stability and also can reduce the risk sublimation of the active pharmaceutical component. In addition, the coating film can improve the security aspect of the treatment of tablets. The coating film with the overlying enteric coating or the enteric coating itself may possess advantages similar to the above for film coating. However, in addition, active pharmaceutical component may not be released in the acidic environment of the stomach, potentially protects the gastric mucosa from irritation, EU�and AFI has an irritant action on the mucous membrane of the stomach.

According to the invention, the said coating is an enteric coating.

Substances enteric coating may be selected from any of a number of commercially available substances of the coating. Non-limiting examples of these substances include Eudragit® (Eudragit® E, L, S, L30D55, Kollicoat® (Kollicoat®) 30D, acetated cellulose, polyvinylacetate and phthalate hypromellose.

According to the invention, indicated the enteric coating is applied at a level of approximately 1.5 to 3.5 wt.% from the mass of the nucleus, such as about 2.0 to 3.5 wt.% from the mass of the nucleus, such as about 2-3 wt.% from the mass of the nucleus.

The enteric coating is a well-known approach to prevent or minimize the drug release in the stomach and provide release in the small intestine. These enteric polymer coatings act on the principle of pH-dependent solubility:

insoluble at low pH of the stomach, but is soluble in near-neutral pH environment of the proximal small intestine having a pH in the range 5-6.

For drugs requiring absorption in the small intestine, this leaves open only a narrow "window" of the release, such as about 5 hours, such as about 4 hours, such as about 3 hours, such as about 2½ �Asa, such as about 2 hours between solubilisate enteric coating and release of the API from the formulation. In some embodiments, implementation of the present invention, it was found that fast solubilisate enteric coating is possible by applying a relatively thin coating while still unexpected receive protection from the acidic environment of the stomach, such as that shown in the exposure test, the solubility in vitro using 0.1 And hydrochloric acid as the medium for dissolution for 2 hours to less than 10%, e.g., less than 5%, e.g., less than 2%, e.g., about 0% release of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester in vivo demonstrates earlier release than the composition of Fumaderm® prior art, for example, by at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 60 minutes of at least 70 minutes, at least 80 minutes, for at least 90 minutes, at least about 100 minutes, at least 110 minutes, or at least 120 minutes before Fumaderm® on an empty stomach.

In one embodiment, the implementation of the present invention, the composition according to the present invented�u contains the Enteric coating, and the release of the fumaric acid ester in vivo demonstrates earlier release than the composition of Fumaderm® prior art, for example, by at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 60 minutes of at least 70 minutes, at least 80 minutes, for at least 90 minutes, at least about 100 minutes, at least 110 minutes, or at least 120 minutes before Fumaderm® on an empty stomach.

In one variant of implementation of the present invention the release of the fumaric acid ester in vivo demonstrates the difference in time component from 15 minutes to 2 hours on an empty stomach, such as the difference in time, that component is not more than 120 minutes 110 minutes 100 minutes 90 minutes 80 minutes 70 minutes 60 minutes 50 minutes 40 minutes 30 minutes 20 minutes or 15 minutes on an empty stomach.

In one embodiment, the implementation of the present invention, the composition according to the present invention contains the enteric coating, and the release of the fumaric acid ester in vivo demonstrates the difference in time component from 15 minutes to 2 hours on an empty stomach, such as the difference in time, that component is not more than 120 minutes, 110 minutes, 100 minutes, 90 minutes, not more than 80 mi�ut, no more than 70 minutes, 60 minutes, 50 minutes, 40 minutes, 30 minutes, 20 minutes or 15 minutes on an empty stomach.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 50 wt.% the fumaric acid ester contained in the composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 3.5 hours after the start of the test releases not more than about 95 wt.% the total number of ester fumaric acid�, contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 4 hours after start of the test releases not more than about 98 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 60 wt.%, for example, from about 0 wt.% to about 50 wt.%, for example, from about 0 wt.% to about 40 wt.%, for example, from about 0 wt.% up to about 30 wt.%, for example, from about 0 wt.% up to about 20 wt.%, for example, from about 0 wt.% to about 10 wt.%, for example, from about 0 wt.% to about 5 wt.%, for example, p�around 0 wt.% ester of fumaric acid, contained in the composition, and/or

during the first 3 hours after start of the test is released from about 15 wt.% to about 95 wt.%, for example, from about 20 wt.% to about 95 wt.%, for example, from about 20 wt.% to about 75 wt.%, for example, from about 25 wt.% to about 75 wt.%, for example, from about 40 wt.% to about 95 wt.%, for example, from about 40 wt.% to about 75 wt.%, for example, from about 50 wt.% to about 95 wt.%, for example, from about 50 wt.% to about 75 wt.%, for example, from about 60 wt.% to about 95 wt.%, for example, from about 60 wt.% to about 75 wt.%, for example, from about 70 wt.% to about 95 wt.%, for example, from about 80 wt.% to about 95 wt.%, for example, from about 90 wt.% to about 95 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 60 wt.%, for example, from about 0 wt.% to about 5 wt.%, n�example, from about 0 wt.% to about 10 wt.%, or, for example, from about 15 wt.% to about 35 wt.%, or, for example, from about 35 wt.% to about 55 wt.% the fumaric acid ester contained in the composition, and/or

during the first 3 hours after start of the test is released from about 15 wt.% to about 95 wt.%, for example, from about 15 wt.% to about 75 wt.%, for example, from about 20 wt.% to about 75 wt.%, for example, from about 15 wt.% to about 35 wt.%, or, for example, from about 35 wt.% to about 55 wt.%, or, for example, from about 55 wt.% to about 75 wt.%, or, for example, from about 65 wt.% to about 85 wt.%, or, for example, from about 70 wt.% up to about 80 wt.%, or, for example, from about 75 wt.% to about 95 wt.%, or, for example, from about 85 wt.% to about 95 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test releases from about 1 wt.% to about 25 wt.% e�Ira fumaric acid, contained in the composition, and/or

during the first 3 hours after start of the test is released from about 15 wt.% to about 95 wt.%, for example, from about 15 wt.% to about 75 wt.%, for example, from about 25 wt.% to about 95 wt.%, for example, from about 25 wt.% to about 75 wt.%, for example, from about 40 wt.% to about 95 wt.%, for example, from about 40 wt.% to about 75 wt.%, for example, from about 50 wt.% to about 95 wt.%, for example, from about 50 wt.% to about 75 wt.%, for example, from about 60 wt.% to about 95 wt.%, for example, from about 60 wt.% to about 75 wt.%, for example, from about 70 wt.% to about 95 wt.%, for example, from about 80 wt.% to about 95 wt.%, for example, from about 90 wt.% to about 95 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test releases from about 1 wt.% to about 25 wt.% the fumaric acid ester contained in the composition, �/or during the first 3 hours after start of the test is released from about 15 wt.% to about 95 wt.%, for example, from about 15 wt.% to about 75 wt.%, for example, from about 15 wt.% to about 35 wt.%, or, for example, from about 35 wt.% to about 55 wt.%, or, for example, from about 55 wt.% to about 75 wt.%, or, for example, from about 65 wt.% to about 85 wt.%, or, for example, from about 70 wt.% up to about 80 wt.%, or, for example, from about 75 wt.% to about 95 wt.%, or, for example, from about 85 wt.% to about 95 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 3.5 hours after the start of the test releases not more than about 100 wt.%, for example, from about 30 wt.% to about 100 wt.%, for example, from about 30 wt.% to about 95 wt.%, for example, from about 40 wt.% to about 100 wt.%, for example, from about 40 wt.% to about 95 wt.%, for example, from about 50 wt.% to about 100 wt.%, for example, from about 50 wt.% to about 95 wt.%, for example, from about 60 wt.% to about 100 wt.%, for example, from approx�RNO 60 wt.% to about 95 wt.%, for example, from about 70 wt.% to about 100 wt.%, for example, from about 70 wt.% to about 95 wt.%, for example, from about 80 wt.% to about 100 wt.%, for example, from about 80 wt.% to about 95 wt.%, for example, from about 90 wt.% to about 100 wt.%, for example, from about 90 wt.% to about 95 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 3.5 hours after the start of the test releases not more than about 100 wt.%, for example, from about 30 wt.% to about 90 wt.%, for example, from about 30 wt.% to about 50 wt.%, or, for example, from about 60 wt.% up to about 80 wt.%, or, for example, from about 80 wt.% to about 95 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for rastvoreniyu for the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 4 hours after start of the test releases not more than about 100 wt.%, for example, from about 35 wt.% to about 100 wt.%, for example, from about 35 wt.% to about 98 wt.%, for example, from about 40 wt.% to about 100 wt.%, for example, from about 40 wt.% to about 98 wt.%, for example, from about 50 wt.% to about 100 wt.%, for example, from about 50 wt.% to about 98 wt.%, for example, from about 60 wt.% to about 100 wt.%, for example, from about 60 wt.% to about 98 wt.%, for example, from about 70 wt.% to about 100 wt.%, for example, from about 70 wt.% to about 98 wt.%, for example, from about 80 wt.% to about 100 wt.%, for example, from about 80 wt.% to about 98 wt.%, for example, from about 90 wt.% to about 100 wt.%, for example, from about 90 wt.% to about 98 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution occurs as �by Braz:

during the first 4 hours after start of the test releases not more than about 100 wt.%, for example, from about 35 wt.% to about 98 wt.%, for example, from about 50 wt.% to about 70 wt.%, or, for example, from about 85 wt.% to about 95 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 4 hours after start of the test releases not more than about 95 wt.%, for example, less than about 90 wt.%, for example, less than about 70 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of testing high�obojdetsya from about 0 wt.% to about 5 wt.% total amount of the fumaric acid ester, contained in the composition, and

during the first 3 hours after start of the test is released from about 15 wt.% to about 35 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test is released from about 30 wt.% to about 50 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 4 hours after start of the test releases from about 50 wt.% to about 70 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% total amount of the fumaric acid ester contained in the composition, and

during the first 3 hours after start of the test is released from about 15 wt.% to about 35 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test visualaid�tsya from about 30 wt.% to about 50 wt.% total amount of the fumaric acid ester, contained in the composition; and

during the first 4 hours after start of the test releases from about 50 wt.% to about 70 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% total amount of the fumaric acid ester contained in the composition, and

during the first 3 hours after start of the test is released from about 30 wt.% to about 55 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test is released from about 60 wt.% up to about 80 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 4 hours after start of the test visvobodi�Xia from about 80 wt.% to about 95 wt.% total amount of the fumaric acid ester, contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% total amount of the fumaric acid ester contained in the composition, and

during the first 3 hours after start of the test is released from about 30 wt.% to about 55 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test is released from about 60 wt.% up to about 80 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 4 hours after start of the test is released from about 80 wt.% to about 95 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 5 hours after start of the test is released from about 80 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention �swobodnie ester of fumaric acid - when exposed to the test on solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% total amount of the fumaric acid ester contained in the composition, and

during the first 3 hours after start of the test is released from about 60 wt.% to about 85 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test is released from about 80 wt.% to about 95 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 4 hours after start of the test is released from about 85 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% total amount of the fumaric acid ester contained in the composition, and

during the first 3 hours after start of the test is released from about 60 wt.% to about 85 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test is released from about 80 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 4 hours after start of the test is released from about 85 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 15 wt.% to about 35 wt.% the fumaric acid ester contained in the composition, and

during the first 3 hours after start of the test is released from about 55 wt.% up to about 80 wt.% General�th amount of the fumaric acid ester, contained in the composition; and

during the first 3.5 hours after the start of the test is released from about 70 wt.% to about 90 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 4 hours after start of the test is released from about 80 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% total amount of the fumaric acid ester contained in the composition, and

during the first 3 hours after start of the test releases from about 10 wt.% up to about 30 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test is released from about 15 wt.% to about 40 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 4 hours after start of the test visualaid�tsya from about 30 wt.% to about 50 wt.% total amount of the fumaric acid ester, contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% total amount of the fumaric acid ester contained in the composition, and

during the first 3 hours after start of the test releases from about 10 wt.% up to about 30 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test is released from about 15 wt.% to about 40 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 4 hours after start of the test is released from about 30 wt.% to about 50 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 6 hours after start of the test is released from about 75 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention �swobodnie ester of fumaric acid - when exposed to the test on solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% total amount of the fumaric acid ester contained in the composition, and

during the first 3 hours after start of the test is released from about 5 wt.% to about 25 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test releases from about 10 wt.% up to about 30 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 4 hours after start of the test is released from about 20 wt.% to about 40 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% total amount of the fumaric acid ester contained in the composition, and

during the first 3 hours after start of the test is released from about 5 wt.% to about 25 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test releases from about 10 wt.% up to about 30 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 4 hours after start of the test is released from about 20 wt.% to about 40 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 5 hours after start of the test is released from about 30 wt.% to about 50 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to prima�but 5 wt.% total amount of the fumaric acid ester, contained in the composition, and

during the first 3 hours after start of the test is released from about 2 wt.% up to about 20 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test is released from about 5 wt.% up to about 20 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 4 hours after start of the test is released from about 5 wt.% to about 25 wt.% total amount of the fumaric acid ester contained in the composition.

In one variant of implementation of the present invention the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to about 5 wt.% total amount of the fumaric acid ester contained in the composition, and

during the first 3 hours after start of the test is released from about 2 wt.% up to about 20 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 3.5 hours after the start of the test releases�I from about 5 wt.% up to about 20 wt.% total amount of the fumaric acid ester, contained in the composition; and

during the first 4 hours after start of the test is released from about 5 wt.% to about 25 wt.% total amount of the fumaric acid ester contained in the composition; and

during the first 5 hours after start of the test releases from about 10 wt.% up to about 30 wt.% total amount of the fumaric acid ester contained in the composition.

In one embodiment, the implementation of the present invention, the release has kinetic characteristics of zero-order release, first order or with square root (Higuchi).

In another embodiment, the in vitro release has a combination of kinetic characteristics of zero-order release, first order and square-root (Higuchi), for example, a combination of the characteristics of the in vitro release of zero and first order.

Different kinetic models such as zero order (1), first order (2), square root (Higuchi equation) (3), can be used to explain the release kinetics of the drug.

1: Mt=M0+k0*t

2: lnMt=lnM+k1*t

3: Mt=M0+kH*t1/2

In these equations, Mtrepresents the total amount of drug released at any particular time, and M represents the dose of the active substance included in the pharmaceutical composition, k0, k1and kHrepresent the rate constants for the equation of zero order, first order and Higuchi equation, respectively.

One aspect of the present invention relates to the characteristics of the release of the zero-order dissolution. Another aspect relates to the characteristics of the release of the dissolution of the first order. Another aspect relates to the characteristics of the release of dissolution with the square root (Higuchi equation).

The active substance in the composition according to the present invention is a suitable ester of fumaric acid.

In one variant of implementation of the present invention the fumaric acid ester is preferably selected from the group consisting of dimethylfumarate, diethylfumarate, dipropylamine, dibutylphtalate, dimetilfumarato, methylethylamine, methylpropylamine, methylbutylamine, methylpentylamine, monomethylfumarate, monomethylfumarate, monopropionate, monomethylfumarate and monomethylfumarate, including pharmaceutically acceptable salts of the specified substances.

Pharmaceutically acceptable salts of these compounds include metal salts, such as salt selected from alkali metal salts and salts of alkaline earth metals, VK�uchumi sodium salt, potassium, calcium, magnesium, strontium or zinc, salts of amino acids, etc.

In another embodiment of the present invention the fumaric acid ester is present in the form of a monosaccharide ester, such as, for example, described in EP 06753340.6.

In another embodiment of the present invention the fumaric acid ester is present in salt form amino acids. The amino acid may be a naturally occurring amino acid such as glycine, alanine, valine, Norvaline, isovaline, leucine, norleucine, isoleucine, methionine, phenylalanine, tryptophan, serine, threonine, cysteine, penicillamine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, ornithine, lysine, arginine, histidine, Proline, 4-hydroxyproline and pipecolinate acid.

In a specific embodiment of the present invention the fumaric acid ester is a mono-(C1-C5-alkylether fumaric acid that is present in the form of pharmaceutically acceptable salts. Suitable salts are, for example, metal salts, such as salt selected from alkali metal salts and salts of alkaline earth metals, including sodium, potassium, calcium, magnesium, strontium or zinc.

The term (C1-C5)-alkyl refers to a branched or unbranched alkyl group containing from one to five ATO�s carbon inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-propyl and pentyl.

In another embodiment, the composition according to the present invention contains dimethyl fumarate as active substance.

In another embodiment, the composition according to the present invention contains monomethylfumarate as the active substance, possibly in the form of a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium, strontium and/or zinc salt.

In another embodiment, the composition according to the present invention contains monomethylfumarate as active substances, perhaps in the form of salts of amino acids.

In another embodiment, the composition according to the present invention essentially consists of dimethylfumarate as active substances.

In another embodiment, the composition according to the present invention consists of dimethylfumarate as active substances.

In another embodiment, the composition according to the present invention essentially consists of monomethylfumarate as the active substance, possibly in the form of a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium, strontium and/or zinc salt.

In another embodiment, the composition according to the present Fig�structure consists of monomethylfumarate as active substances, perhaps in the form of pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium, strontium and/or zinc salt.

In another embodiment, the composition according to the present invention contains dimethyl fumarate and monomethylfumarate (possibly in the form of a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium, strontium and/or zinc salt) as the active substances in a weight ratio from about 1:10 to about 10:1.

In another embodiment, the composition according to the present invention essentially consists of dimethylfumarate and monomethylfumarate (possibly in the form of a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium, strontium and/or zinc salt) as the active substances in a weight ratio from about 1:10 to about 10:1.

In another embodiment, the composition according to the present invention consists of dimethylfumarate and monomethylfumarate (possibly in the form of a pharmaceutically acceptable salt like e.g. its sodium, potassium, calcium, magnesium, strontium and/or zinc salt) as the active substances in a weight ratio from about 1:10 to about 10:1.

In one embodiment, the implementation of the composition according to the present invention is designed for insertion Odie�, two or three times a day.

In one embodiment, the implementation of the specified composition is suitable for administration once a day.

In one embodiment, the implementation of the specified composition is suitable for administration twice a day.

Daily dose of the pharmaceutical composition of controlled release according to the present invention that is administered to treat a patient depends on several factors, among which are included, without limitation, weight and age, and cure the root causes of a condition or disease and its determination is within the competence of the doctor.

In accordance with one aspect of the present invention, the daily dose may be, for example, from 200 to 400 mg of active agent administered in one to three doses, in accordance with another aspect 300 to 500 mg of active agent administered in one to three doses, in accordance with another aspect of 400 to 600 mg of active agent administered in one to three doses, in accordance with another aspect of from 500 to 700 mg of active agent administered in one to three doses, in accordance with another aspect of from 600 to 800 mg of active agent administered in one to three doses, in accordance with another aspect of from 700 to 900 mg of active agent administered in one to three doses, in accordance with another aspect of 800 to 1000 mg of active agent administered in one to three doses, in a suitable�accordance with another aspect of 900 to 1100 mg of active substance, administered in one to three doses, in accordance with another aspect of from 1000 to 1200 mg of active agent administered in one to three doses, in accordance with another aspect of 1100 to 1300 mg of active agent administered in one to three doses, in accordance with another aspect of 1200 to 1400 mg of active agent administered in one to three doses, and in accordance with another aspect of from 1300 to 2000 mg of active agent administered in one to three doses.

One of the variants of realization of the present invention is a pharmaceutical composition containing:

i) from 40 wt.% to 55 wt.% dimethylfumarate;

(ii) 4-6 wt.% the hydroxypropyl cellulose;

(iii) 35-55 wt.% of lactose.

One of the variants of realization of the present invention is a pharmaceutical composition containing:

(i) from 30 wt.% to 60 wt.% dimethylfumarate;

ii) 3-6 wt.% the hydroxypropyl cellulose;

(iii) 35-65 wt.% of lactose.

One of the variants of realization of the present invention is a pharmaceutical composition in form of tablet with the biodegradable matrix containing:

A) a tablet core containing:

(i) 40-60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substances,

(iii)35-55 wt.% binders;

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable matrix leads to the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer pH 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to less than about 10 wt.% the fumaric acid ester contained in the composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% the fumaric acid ester contained in the composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% the fumaric acid ester contained in the composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

One of the variants of realization of the present invention is a pharmaceutical composition in the form of Tadla�key with the biodegradable matrix containing:

A) a tablet core containing:

(i) 30-60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substances,

ii) 3-6 wt.% controlling the speed of the agent;

(iii) 35-65 wt.% binders;

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable matrix leads to the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to less than about 10 wt.% the fumaric acid ester contained in the composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% the fumaric acid ester contained in the composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% ester fumaric keys�located the whereabouts, contained in the specified composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

One of the variants of realization of the present invention is a pharmaceutical composition in the form of a monolithic tablet with the biodegradable matrix containing:

A) a tablet core containing:

(i) 40-60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substances,

(ii) 4-6 wt.% controlling the speed of the agent;

(iii) 35-55 wt.% binders;

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable matrix leads to the release of the fumaric acid ester - when subjected to the test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to m�it about 10 wt.% ester of fumaric acid, contained in the specified composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% the fumaric acid ester contained in the composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% the fumaric acid ester contained in the composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

One of the variants of realization of the present invention is a pharmaceutical composition in the form of a monolithic tablet with the biodegradable matrix containing:

A) a tablet core containing:

(i) 30-60 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation fumaric acid and mono-(C1-C5)alkylation fumaric acid, or their pharmaceutically acceptable salts as active substances,

ii) 3-6 wt.% controlling the speed of the agent;

(iii) 35-65 wt.% binders;

B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable matrix leads to the release of the ester of fumaric acid�you when exposed to the test on solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to less than about 10 wt.% the fumaric acid ester contained in the composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% the fumaric acid ester contained in the composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% the fumaric acid ester contained in the composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% total amount of the fumaric acid ester contained in the composition.

One of the variants of realization of the present invention is a pharmaceutical composition in form of tablet with the biodegradable matrix containing:

A) a tablet core containing:

(i) 40-55 wt.% dimethylfumarate,

(ii) 4-6 wt.% the hydroxypropyl cellulose;

(iii) 35-55 wt.% lactose;

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% �t specified mass nuclei;

the specified decomposition of degradable matrix leads to the release of dimethylfumarate - exposure test on solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to less than about 10 wt.% dimethylfumarate contained in the specified composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% dimethylfumarate contained in the specified composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% the fumaric acid ester contained in the composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% the total number of dimethylfumarate contained in the specified composition.

One of the variants of realization of the present invention is a pharmaceutical composition in the form of a monolithic tablet with the biodegradable matrix containing:

A) a tablet Core containing:

(i) 40-55 wt.% dimethylfumarate,

(ii) 4-6 wt.% the hydroxypropyl cellulose;

(iii) 35-55 wt.% La�cozy;

(B) the enteric coating in the amount of approximately 1.5 to 3.5 wt.% by weight of the specified kernel;

the specified decomposition of degradable matrix leads to the release of dimethylfumarate - exposure test on solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

during the first 2 hours after start of the test is released from about 0 wt.% to less than about 10 wt.% dimethylfumarate contained in the specified composition, and/or

during the first 3 hours after start of the test is released from about 20 wt.% to about 75 wt.% dimethylfumarate contained in the specified composition, and/or

during the first 4 hours after start of the test releases from about 50 wt.% to about 98 wt.% the fumaric acid ester contained in the composition, and/or

during the first 5 hours after start of the test is released from about 70 wt.% to about 100 wt.% the total number of dimethylfumarate contained in the specified composition.

Obtaining tablets with the biodegradable matrix according to the present invention may be accomplished by granulation with subsequent tableting and possibly applying planon�and/or enteric coating on the obtained core tablets. The core can be obtained, for example, by conventional wet granulation or continuous granulation, such as extrusion with subsequent compaction of the granules into tablets. Then the core may be coated with the use of appropriate technology, preferably air-suspension method.

One aspect of the present invention is a method of obtaining a composition according to the present invention, comprising the following steps:

(a) Dissolving (or suspending) either one of or both of the ester of fumaric acid, and possibly controlling the speed of the agent in the form of a polymer matrix substance in water to obtain an aqueous suspension of said substances;

(b) Applying a specified water slurry spray into pellets ester of fumaric acid and/or binder during the period of time that is sufficient for obtaining uniform coatings;

c) drying the obtained granules;

d) Possibly, sieving or grinding of these granules;

e) preparation of the mixture with any pharmaceutically acceptable excipients and additives essentially known method of obtaining the composition in the form of pills;

f) it is Possible to apply film and/or enteric coating on said composition is in tablet form essentially known manner;

while any �do all of the above steps is carried out at this temperature, so that the product temperature does not exceed 45 º C. In one variant of implementation of the present invention any or all of the above steps is carried out at this temperature to product temperature did not exceed 40 ° C, for example, did not exceed 35 ° C, for example, does not exceed 30ºC. Thus, it has surprisingly been shown that obtaining the composition according to the present invention can be carried out by using only water as solvent, thus eliminating the need for any organic solvents. In addition, all steps of the method can be carried out at a low temperature. Thus, minimise or reduce any sublimation of the active pharmaceutical component and get the power saving method of reducing the loss of AFI, which thus reduces the cost and improves environmental safety and worker safety.

In this context, the particle size measured by means of traditional analysis using sieves, are known to those skilled in the art.

In one variant of implementation of the present invention the fumaric acid ester finely ground to obtain a particle size in which at least 90% of the particles have a size less than 50 microns, e.g., not more than 30 μm, e.g. 10 μm, before step (a) above.

In another embodiment the average particle size of active pharmaceutical component (ether esters) fumaric acid) reduce, for example, by sieving or grinding so that at least 50% of the particles have a size of less than 800 microns, e.g., less than 600 microns, e.g., less than 500 microns, e.g., less than 400 μm, for example less than 200 μm before step (a) above.

In another embodiment the average particle size of active pharmaceutical component (ether esters) fumaric acid) reduce, for example, by sieving or grinding so that at least 80% of the particles have a size of less than 800 microns, e.g., less than 600 microns, e.g., less than 500 microns, e.g., less than 400 μm, for example less than 200 μm before step (a) above.

In another embodiment the average particle size of active pharmaceutical component (ether esters) fumaric acid) reduce, for example, by sieving or grinding so that at least 90% of the particles have a size of less than 800 microns, e.g., less than 600 microns, e.g., less than 500 microns, e.g., less than 400 μm, for example less than 200 μm before step (a) above.

In another embodiment, the crystals of the ester of fumaric acid was sieved or milled so that 90% of the particles have a size in the range of 5-1000 μm, such as in the range of 10-900 μm, such as in the range of 20-800 μm, such as in the range of 30-750 μm, such as in �the range of 40-600 μm, such as in the range of 50-500 μm, such as in the range of 100-400 μm, such as in the range of 200-300 μm, such as in the range of 300-600 μm, such as in the range of 300-400 μm, such as in the range of 400-600 μm, or such as in the range of 500-600 µm in front of the stage (a) above.

In another embodiment the average particle size of active pharmaceutical component (ether esters) of fumaric acid is in the range of 5-1000 μm, such as in the range of 10-900 μm, such as in the range of 20-800 μm, such as in the range of 30-750 μm, such as in the range of 40-600 μm, such as in the range of 50-500 μm, such as in the range of 100-400 μm, such as in the range of 200-300 μm, such as in the range of 300-600 μm, such as in the range of 300-400 μm, such as in the range of 400-600 μm or such as in the range of 500-600 µm in front of the stage (a) above.

In another embodiment, the distribution of particles of active pharmaceutical component (ether esters) fumaric acid) in size is such that 0-5% of the particles have a size of >500 μm and 45-53% of the particles have a size of >250 microns, prior to step a) above. In one of its variants 7-15% of the particles have a size of <100 μm in front of the stage (a) above.

In another embodiment, the distribution of particles of active pharmaceutical component (ether esters) fumaric acid) in size is that the 0-7% of the particles have a size of >500 μm and 42-59% of the particles have a size of >250 microns, �before step (a) above. In one of its variants 3-12% of the particles have a size of <100 μm in front of the stage (a) above.

In another embodiment, the distribution of particles of active pharmaceutical component (ether esters) fumaric acid) in size is such that 0-10% of the particles have a size of >500 μm and 40-65% of the particles have a size of >250 microns, prior to step a) above. In one of its variants 2-10% of the particles have a size of <100 μm in front of the stage (a) above.

In one variant of implementation of the present invention the average particle size of active pharmaceutical component (ether esters) fumaric acid) reduce, for example, by sieving or grinding, with the specified sieving or grinding is carried out with the formation of a minimum amount of heat. Thus, minimise or reduce any sublimation of the active pharmaceutical component and get the power saving method of reducing the loss of the API, thus, reduces the cost and improves environmental safety and worker safety. Screening or grinding may occur in one stage sieving or grinding or may be repeated several times to obtain the necessary distribution of the particles. In one embodiment, the implementation of the present invention, the sieving or grinding occurs in two stages. In one embodiment, carrying out� of the present invention, in which the sieving or grinding is carried out in several stages, an agent to reduce agglomeration is added between these stages.

Without being bound by any specific theory, the authors present invention believe that the active pharmaceutical ingredient (ether esters) fumaric acid), which has a distribution of particle sizes in the above ranges results in slower dissolution in vitro and, thus, allows the use of lower amounts of controlling the speed of the agent compared with the composition having a distribution of particles with a large particle size such that more than 10% of the particles have a size of >500 μm and/or more than 65% of the particles have a size of >250 microns.

In accordance with one aspect of a lower number of controlling the speed of the agent allows to produce a tablet with high drug loading, such as at least 40%, 45%, 50%, 55% or 60% of the active pharmaceutical component based on the total weight of the tablet.

In one variant of implementation of the present invention step b) is carried out in the granulator fluidized bed.

Another aspect of the present invention is a method of obtaining a composition according to the present invention, comprising the following steps:

a) a Solution of�tion (or suspending) controlling the speed of the agent in the form of a polymer matrix substance in water to obtain an aqueous suspension of a specified substance;

(b) Applying a specified water slurry spray into pellets ester of fumaric acid during the period of time that is sufficient for obtaining uniform coatings;

c) drying the obtained granules;

d) Possibly, sieving or grinding of these granules;

e) preparation of the mixture with any pharmaceutically acceptable excipients and additives essentially known method of obtaining the composition in the form of pills;

(f) Possibly, coating film and/or enteric coating on said composition is in tablet form essentially known manner;

while any or all of the above steps is carried out at this temperature to product temperature did not exceed 45 º C. In one variant of implementation of the present invention any or all of the above steps is carried out at this temperature to product temperature did not exceed 40 ° C, for example, did not exceed 35 ° C, for example, does not exceed 30ºC. Thus, minimise or reduce any sublimation of the active pharmaceutical component and get the power saving method of reducing the loss of AFI, which thus reduces the cost and improves environmental safety and worker safety.

In one embodiment, the implementation of the present invention, the ester of fumaric acid with finely ground by�doctrine of particle size, wherein at least 90% of the particles have a size less than 50 microns, such as not more than 30 microns, such as not more than 10 μm, before step (b) above.

In another embodiment the average particle size of active pharmaceutical component (ether esters) fumaric acid) reduce, for example, by sieving or grinding, wherein at least 90% of the particles have a size of not more than 800 μm, such as not more than 600 μm, such as not more than 500 μm, such as not more than 400 μm, such as not more than 200 μm before step (b) above.

In one variant of implementation of the present invention step B) is carried out in the granulator fluidized bed.

Another variant implementation of the present invention is a method of obtaining a composition according to the present invention, comprising the following steps:

a) Possibly, sieving or grinding of crystals of the ester of fumaric acid;

(b) Mixing the above crystals of fumaric acid ester may control the speed of the agent in the form of a polymer matrix substance and any pharmaceutically acceptable excipients and additives by direct compression with obtaining a composition in the form of pills;

c) Perhaps drawing film and/or enteric coating on said composition is in tablet form essentially known manner;

while any or useis the above steps is carried out at this temperature, so that the product temperature does not exceed 45 º C. In one variant of implementation of the present invention any or all of the above steps is carried out at this temperature to product temperature did not exceed 40 ° C, for example, did not exceed 35 ° C, for example, does not exceed 30ºC. Thus, minimise or reduce any sublimation of the active pharmaceutical component and get the power saving method of reducing the loss of AFI, which thus reduces the cost and improves environmental safety and worker safety.

Another variant implementation of the present invention is a method of obtaining a composition according to the present invention, comprising the following steps:

Perhaps the sieving or grinding of crystals of the ester of fumaric acid;

(b) Mixing the above crystals of the ester of fumaric acid with any pharmaceutically acceptable excipients and may control the speed of the agent in the form of a polymer matrix substance essentially known method of obtaining the composition in the form of pills;

c) Milling the mixture, and sieving/milling to obtain granules;

(d) preparation of a mixture of any additional pharmaceutically acceptable excipients with said granules to obtain a final mixture ready for preformed�I;

(e) Pressing with obtaining tablets;

(f) Possibly, coating film and/or enteric coating on the tablets.

In one embodiment, the implementation of the present invention, the ester of fumaric acid is premixed with one or more pharmaceutically acceptable excipients prior to step (a) above.

The stability of the compositions according to the present invention can be determined by measuring baseline characteristics of dissolution of the tablets and in vitro dissolution characteristics in vitro after different periods of storage and by comparing the obtained characteristics of dissolution in vitro. In one variant of implementation of the present invention the tablets are stable for at least 6 months, for example at least 9 months, for example at least 12 months, e.g., at least 18 months, for example, at least 24 months Stability of compositions according to the present invention can also be determined by standardized methods of measurement of any changes, for example, in the content, colour or decay products.

In one embodiment, the implementation of the present invention, the stability of the composition can be determined using objective criteria, such as, for example, a maximum change amount of API released in advance opredelennymi time during a standardized test, the in vitro solubility when comparing the start time of the test with the test at a later time. In one embodiment, the implementation of the present invention, the amount of API released from the composition stored in ICH conditions (e.g., 25 degrees C/60% OB, for example, 30 degrees C/65% OB, for example, 40 degrees C/75% OB) within a certain period of time (such as at least 1 month, such as at least 3 months, such as at least 6 months, such as at least 9 months, such as at least 12 months) in comparison with the initial moment of time (time =0, set for stability testing) - when exposed to the test on solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the specified test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution is as follows:

1 hour after start of testing see the difference constituting less than 10 percentage points, for example, less than 9 percentage points, for example, less than 8 percentage points, for example, less than 6 percentage points, for example, less than 4 percentage points, for example, less than 2 percentage points, for example, less than 1 percentage point in the amount of active pharmaceutical component is released and� composition, and/or

2 hours after start of the test see the difference constituting less than 10 percentage points, for example, less than 9 percentage points, for example, less than 8 percentage points, for example, less than 6 percentage points, for example, less than 4 percentage points, for example, less than 2 percentage points, for example, less than 1 percentage point in the amount of active pharmaceutical component is released from the composition, and/or

3 hours after start of the test see the difference constituting less than 10 percentage points, for example, less than 9 percentage points, for example, less than 8 percentage points, for example, less than 6 percentage points, for example, less than 4 percentage points, for example, less than 2 percentage points, for example, less than 1 percentage point in the amount of active pharmaceutical component is released from the composition, and/or

4 hours after start of the test see the difference constituting less than 10 percentage points, for example, less than 9 percentage points, for example, less than 8 percentage points, for example, less than 6 percentage points, for example, less than 4 percentage points, for example, less than 2 percentage points, for example, less than 1 percentage point in the amount of active pharmaceutical component is released from the composition, and/or

5 hours after start of the test see the difference constituting less than 10 percentage points, for example, less than 9 percentage points for example, less than 8 percentage points, for example, less than 6 percentage points, for example, less than 4 percentage points, for example, less than 2 percentage points, for example, less than 1 percentage point in the amount of active pharmaceutical component is released from the composition.

In one embodiment, the implementation of the pharmaceutical composition according to the present invention is intended for use for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (PC), juvenile diabetes, Hashimoto's thyroiditis, grave's disease, SLE (systemic lupus erythematosus), sjögren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, of optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/isiana pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or anulyarnaya granuloma.

One of the variants of the implementation is the use of pharmaceutical composition according to the present invention for Paul�obtain drugs for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (PC), juvenile diabetes, Hashimoto's thyroiditis, grave's disease, SLE (systemic lupus erythematosus), sjögren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/isiana pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or anulyarnaya granuloma.

Another variant implementation of the present invention is a method of treating psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (PC), juvenile diabetes, Hashimoto's thyroiditis, grave's disease, SLE (systemic lupus erythematosus), sjögren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, mastani� gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/isiana pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or anulyarnaya granuloma, wherein said method comprises the oral administration to a patient in need this, the effective dose of the pharmaceutical composition according to the present invention.

In one embodiment, the implementation of the present invention, the composition according to the present invention is intended for use in the treatment of psoriasis.

In one embodiment, the implementation of the present invention, the composition according to the present invention is intended for use in the treatment of psoriatic arthritis.

In one embodiment, the implementation of the present invention, the composition according to the present invention is intended for use in the treatment of multiple sclerosis or relapsing-remitting multiple sclerosis.

In one embodiment, the implementation of the present invention, the composition according to the present invention is intended for use in the treatment of rheumatoid arthritis.

It should be understood that the present invention is not limited to the specific described variants�AMI implementation because these options can certainly vary. It should also be understood that the terminology used in this description to describe only specific variants of implementation, and is not limiting because the scope of the present invention is limited only by the appended claims of the invention. If the range of values, it is clear that each intermediate value of up to a tenth of the unit of the lower limit unless the context explicitly States otherwise, between the upper and lower limit of this range, and any other specified or intermediate value in the given specified range included in the present invention. The upper and lower bounds of data smaller ranges can be independently included in the smaller ranges, and are included in the present invention, subject to any specifically excluded the border in the specified range. In the case where the stated range includes one or both borders, ranges excluding either one or both boundary data are included, also included in the present invention. If not defined otherwise, all technical and scientific terms used in this description have the same meaning commonly understood by a person skilled in the art to which the present invention relates. Although any methods and substances similar�s or equivalent to those described herein, can also be used in the implementation or testing of the present invention described preferred modes and substances. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or substances for which the publication data given. It should be noted that, in the present description and the attached claims, the singular form include the plural, unless the context explicitly States otherwise. Patents and publications mentioned in this document are solely for their descriptions to the filing date of the present application. No part of this document may be considered as an admission that the present invention should not be carried to an earlier date specified patent or publication on the basis of prior invention. In addition, given the publication date may differ from the actual publication dates which may need to be independently confirmed. As is obvious to a person skilled in the art after reading this description, each of the individual variants of implementation described and illustrated herein has discrete components and features which can be easily separated or combined with �rinakama any of several other variants of implementation within the scope or the substance of the present invention. The figures given in the present description, are not necessarily shown to scale, with some components and features have been exaggerated for clarity.

Although the foregoing invention is described in detail with illustrations and examples for his clear and full understanding, for the specialist in the art it is obvious in the light of the ideas of the present invention that there may be some changes and modifications within the substance or scope of the attached claims.

EXAMPLES

During the implementation of all the following stages in examples 1 to 24 and 26-42 take the necessary precautions (protective clothing with external air source, double gloves, armlets, respiratory mask, etc.).

Example 1

Obtaining cores tablets

540,5 g of finely chopped dimethylfumarate (average particle size 10 μm) and 31.5 g of hydroxypropyl cellulose HPC-SL suspended in 1716 g of purified water. The suspension was sprayed for about 2 hours on 405,5 g of lactose, Granular® 140 placed in the basket granulator fluidized bed. The pellets were dried for 5 minutes.A protective coating was applied by spraying a solution of 22.5 g of HPC-SL in 2265,5 g of purified water for about 2 hours. The product temperature never exceeded 35 ° C. Mixed various parties, and sieved through a 1.1 mm sieve.

183,3 g of the dried sieved granules were mixed with of 58.7 g of spray dried lactose (Flolan® 100) using a drum mixer at 30 rpm for 15 minutes. Finally, there was added 2.4 g of magnesium stearate and mixed for a further 10 minutes at 30 rpm. the Final mixture was pressed into biconvex tablets with a diameter of 10 mm and a weight of 375 mg.

Example 2

Obtaining cores tablets

540,5 g unground dimethylfumarate and 405,5 g of Granulate® 140 was placed in a basket granulator fluidized bed. 62.1 g of hydroxypropyl cellulose HPC-SL was dissolved by stirring in 3043 g of purified water and sprayed on the DMF for 2.5 hours. The pellets were dried for 4 minutes at 29 º C, and sieved through a 1.1 mm sieve. The product temperature never exceeded 30 ° C.

135 g of the dried granules were mixed with 30.4 g of spray dried lactose (Flolan® 100), 24.4 g HPC-SL, and 0.3 g of Aerosil with a drum mixer at 30 rpm for 15 minutes. Finally, there was added 1.8 g of magnesium stearate and mixed for a further 10 minutes at 30 rpm. the Final mixture was pressed into biconvex tablets with a diameter of 10 mm and a weight of 315,5 mg.

Example 3

Obtaining cores tablets

621,5 g of finely chopped dimethylfumarate (average particle size 500 μm) was suspended in 1793,5 g of purified water and stirred using an Ultra-turrax for 5 hours until reduced size h�STIC. Was then added to 36.2 g of hydroxypropyl cellulose HPC-SL. The suspension was sprayed for about 2 hours on 405,5 g of Granulate® 140 placed in the basket granulator fluidized bed. The pellets were dried for 5 minutes. Then applied a protective coating obtained from at 26.3 g of HPC-SL in 2605 g of purified water, by spraying the solution for about 2 hours on these pellets. The product temperature never exceeded 30 ° C.

183,3 g of the dried granules were mixed with of 58.7 g of spray dried lactose (Flolan® 100) and 0.5 g of Aerosil with a drum mixer at 30 rpm for 15 minutes. Finally, there was added 2.2 g of magnesium stearate and mixed for a further 10 minutes at 30 rpm. the Final mixture was pressed into biconvex tablets with a diameter of 10 mm and a weight 375,4 mg.

Example 4

Obtaining cores tablets

1200 g of unground dimethylfumarate was placed in a basket granulator fluidized bed. 75 g of hydroxypropyl cellulose HPC-SL was dissolved by stirring in 2925 g of purified water and sprayed on the DMF for about 2.5 hours before spraying 70 g of the GOC. The pellets were dried for 4 minutes at 29 º C, and sieved through a 1.1 mm sieve. The product temperature never exceeded 30 ° C.

378,2 g of the dried granules were mixed with 400,6 g spray-dried lactose (Flolan® 100), 14,6 g of HPC-SL, and 0.9 g of Aerosil with pomodorino mixer at 30 rpm for 15 minutes. Finally, was added 5.8 g of magnesium stearate and mixed for a further 10 minutes at 30 rpm. the Final mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 275 mg.

Example 5

Applying a film coating of core tablets according to example 4

Applying a film coating

For film coating 800 g of kernels of tablets received a 15% suspension of Opadry (é) by adding 36 g of Opadry to 204 g of purified water. Approximately 66% of this suspension was sprayed onto the core tablets in a period of 35 minutes in the chamber of a fluidized bed. The product temperature never exceeded 40 degrees Celsius. For the coating process was followed by a period of drying for 16 minutes at 30ºC.

Example 6

Drawing film and enteric coating on the cores of the tablets according to example 4

Applying a film coating

Film coating was applied onto 800 g of kernels of tablets. Receive 15% suspension of Opadry by adding 18 g of Opadry to 102 g of purified water. Approximately 66% of this suspension was sprayed onto the core tablets in a period of 20 minutes in the chamber of a fluidized bed. The product temperature never exceeded 40 degrees Celsius. For the coating process was followed by a period of drying for 9 minutes at 30ºC.

The application of enteric coating

1 kg of liquid coating resistant to gastric acid�about juice obtained by heating 350 ml of purified water to 70-80 ° C, add 20 g of triethylcitrate, 3 g of glyceryl monostearate (Cutina GMS V), 1 g of Tween 80 (Tween 80) and mixing using UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 427,8 g of purified water and the mixture was stirred using a propeller stirrer until the emulsion at room temperature. Then this emulsion was slowly added to 210 g of a dispersion of Eudragit L30 D 55. Approximately 66% of the fluid coating, which is resistant to gastric acid, sprayed on 780 g covered with a film coating of tablets in the chamber of a fluidized bed at a temperature of 30 º C for about 2.5 hours. There was then a period of drying at 30 ° C for 30 minutes and the period of aging at 35 º C for another 30 minutes.

Example 7

The application of enteric coating on the cores of the tablets according to example 4

The application of enteric coating

Got 1 kg of liquid coating, which is resistant to gastric acid, and sprayed onto the core tablets as described in example 6.

Example 8

Granules were prepared as described in example 4.

416 g of the dried granules were mixed with 360,8 g spray-dried lactose (Flolan® 100), 16 g of HPC-SL, and 1 g of Aerosil with a drum mixer at 30 rpm for 15 minutes.Finally, was added 6.4 g walls�ATA magnesium and mixed for a further 10 minutes at 30 rpm. The final mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 250 mg.

Example 9

Applying a film coating of core tablets according to example 8

Applying a film coating

The application of film coating was performed as described in example 5.

Example 10

Drawing film and enteric coating on the cores of the tablets according to example 8

Applying a film coating

Film coating was applied onto 800 g of kernels of tablets as described in example 6.

The application of enteric coating

Got 1 kg of liquid coating, which is resistant to gastric acid, and was applied as described in example 6.

Example 11

Granules were prepared as described in example 4.

404,5 g of the dried granules were mixed with 272,9 g spray-dried lactose (Flolan® 100), 15.5 g of HPC-SL, and 0.9 g of Aerosil with a drum mixer at 30 rpm for 15 minutes. Finally, there was added 6.2 g of magnesium stearate and mixed for a further 10 minutes at 30 rpm. the Final mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 225 mg.

Example 12

Applying a film coating of core tablets was carried out according to example 11.

Applying a film coating

For film coating 800 g of the cores of the tablets were coated as described in example 5. To obtain 80 g of tablets available for the coating of active pills mixed with painted placebo.

Example 13

Drawing film and enteric coating on the cores of the tablets according to example 11.

Applying a film coating

Film coating was applied onto 800 g of kernels of tablets as described in example 5. To obtain 800 g of pills available for the coating of active pills mixed with painted placebo.

The application of enteric coating

Got 1 kg of fluid for applying PKLITE, resistant to gastric acid, and was applied as described in example 6.

Example 14

Granules were prepared as in example 4.

130 g of the dried granules were mixed with 52.7 g spray-dried lactose (Flolan® 100), 40 g of HPC-SL, and 0.3 g of Aerosil with a drum mixer at 30 rpm for 15 minutes. Finally, there was added 2.0 g of magnesium stearate and mixed for a further 10 minutes at 30 rpm. the Final mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 225 mg.

Example 15

Applying a film coating of core tablets according to example 14

Applying a film coating

For film coating 800 g of tablets were coated as described in example 5. To obtain 800 g of pills available for the coating of active pills mixed with painted placebo.

Approx�R 16

Drawing film and enteric coating on the cores of the tablets according to example 14

Applying a film coating

Film coating was applied onto 800 g of kernels of tablets. Therefore, containing the active pharmaceutical ingredients of the pill was mixed with painted placebo with obtaining the required number. Receive 15% suspension of Opadry and applied as described in example 6.

The application of enteric coating

Got 1 kg of liquid coating, which is resistant to gastric acid, and was applied as described in example 6.

Characteristics of dissolution film coated and enteric coated tablets according to this example were obtained in accordance with the test in vitro in United States Pharmacopoeia (USP). The test was performed with 37º with the use of the device with the blade for dissolution at 100 rpm using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution for the remaining period of the test. The result follows from Fig.1.

Example 17

1.2 kg of dimethylfumarate sieved through a 700 μm sieve and placed in a basket granulator fluidized bed. 70,6 g of the polymer of hydroxypropyl cellulose HPC-SL was dissolved by stirring at 2753 g of purified water and sprayed on the DMF for 2.5 to 3 hours. Granulysin for 3 minutes at 29 º C. Mixed a few batches, and sieved through an 800 μm sieve.

1730,7 g of the dried and optionally sieved through a 500 µm sieve pellets were mixed with 781,3 g of granulated lactose (Tablettose 100), with 66.7 g of HPC-SL and pre-mixture of Aerosil® and Tablettose® drum mixer at 20 rpm for 15 minutes. Specified in advance the obtained mixture was prepared in a polyethylene package of 4 g of colloidal silicic acid (Aerosil) and 390,6 g of Tablettose®, and sieved through a 500 μm sieve. Finally, added to 26.7 g of magnesium stearate. The final mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 225 mg.

Example 18

Drawing film and enteric coating on the cores of the tablets according to example 17

Applying a film coating

For film coating 800 g of kernels of tablets received a 15% suspension of Opadry by adding 18 g of Opadry to 102 g of purified water. Approximately 66% of this suspension was sprayed onto the core tablets in a period of 20 minutes in the chamber of a fluidized bed. The product temperature never exceeded 40 degrees Celsius. For the coating process was followed by a period of drying for 9 minutes at 30ºC.

The application of enteric coating

1 kg of the liquid coating, which is resistant to gastric acid, obtained by heating 350 ml of purified water to 70-80ºC, DOB�population of 9.5 g of triethylcitrate, 1.9 g of glyceryl monostearate (Cutina GMS V), 0.7 g of Tween 80 and mixing with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 427,8 g of purified water and the mixture was stirred using a propeller stirrer until the emulsion at room temperature. Then this emulsion was slowly added to 210 g of a dispersion of Eudragit L30 D 55. Approximately 66% of the fluid coating, which is resistant to gastric acid, sprayed on 780 g covered with a film coating of tablets in the chamber of a fluidized bed.

Characteristics of dissolution film coated and enteric coated tablets according to this example were obtained in accordance with the test for solubility in vitro as described in example 16, using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution. The result follows from Fig.1.

Example 19

1.2 kg of dimethylfumarate sieved through a 700 μm sieve and placed in a basket granulator fluidized bed. 70,6 g of hydroxypropyl cellulose HPC-SL was dissolved by stirring at 2753 g of purified water and sprayed on the DMF for 2.5 to 3 hours. The pellets were dried for 3 minutes at 29 º C, and sieved through a 500 μm sieve.

964 g of the dried sieved granules were mixed with 565,5 g gra�lirovannomu lactose (Tablettose® 100), 37,4 g HPC-SL and pre-mixture of Aerosil® and Tablettose® drum mixer at 20 rpm for 15 minutes. Specified in advance the obtained mixture was prepared in a plastic bag from 2.3 g of colloidal silicic acid (Aerosil) and 282,7 g of Tabletz, and also sieved through a 500 μm sieve. Finally, was added to 14.9 g of magnesium stearate. The final mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 250 mg.

Example 20

Drawing film and enteric coating on the cores of the tablets according to example 19

Applying a film coating

For film coating 800 g of kernels of tablets received a 15% suspension of Opadry and applied as described in Example 18.

The application of enteric coating

1 kg of the liquid coating, which is resistant to gastric acid, obtained by heating 350 ml of purified water to 70-80ºC, adding 9.5 g of triethylcitrate, 1.9 g of glyceryl monostearate (Cutina GMS V), 0.7 g of Tween 80 and mixing with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 427,8 g of purified water and the mixture was stirred using a propeller stirrer until the emulsion at room temperature. Then this emulsion was slowly added to 210 g of a dispersion of Eudragit L30 D 55. Approximately 66% of the fluid coating, resistant to Ki�lot of gastro - juice sprayed on 780 g covered with a film coating of tablets in the chamber of a fluidized bed at a temperature of 30 º C for about 2.5 hours. There was then a period of drying at 30 ° C for 30 minutes and the period of aging at 35 º C for another 30 minutes.

Characteristics of dissolution film coated and enteric coated tablets according to this example were obtained in accordance with the test for solubility in vitro as described in example 16, using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution. The result follows from Fig.1.

Example 21

1.2 kg of dimethylfumarate sieved through a 700 μm sieve and placed in a basket granulator fluidized bed. 70,6 g of hydroxypropyl cellulose HPC-SL was dissolved by stirring at 2753 g of purified water and sprayed on the DMF for 2.5 to 3 hours. The pellets were dried for 3 minutes at 29°C. was Mixed with several parties, and sieved through an 800 μm sieve.

1416 g of the dried and optionally sieved through a 500 µm sieve pellets were mixed with 1002,9 g of granulated lactose (Tablettose® 100), and 54.6 g of HPC-SL and pre-mixture of Aerosil® and Tabletsi using a drum mixer at 20 rpm for 15 minutes. Specified in advance the obtained mixture was prepared in carton s�Renova package of 3.3 g of colloidal silicic acid (Aerosil®) and 501,4 g of Tablettose®, and sieved through a 500 μm sieve. Finally, I added 21.8 g of magnesium stearate. The final mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 275 mg.

Example 22

Drawing film and enteric coating on the cores of the tablets according to example 21

Applying a film coating

For film coating 800 g of kernels of tablets received a 15% suspension of Opadry and applied as described in Example 18.

The application of enteric coating

1 kg of the liquid coating, which is resistant to gastric acid, obtained by heating 350 ml of purified water to 70-800C, adding 9.5 g of triethylcitrate, 1.9 g of glyceryl monostearate (Cutina GMS V), 0.7 g of Tween 80 and mixing with UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 427,8 g of purified water and the mixture was stirred using a propeller stirrer until the emulsion at room temperature. Then this emulsion was slowly added to 210 g of a dispersion of Eudragit L30 D 55. Approximately 66% of the fluid coating, which is resistant to gastric acid, sprayed on 780 g covered with a film coating of tablets in the chamber of a fluidized bed at a temperature of 30 º C for about 2.5 hours. There was then a period of drying at 30 ° C for 30 minutes and the period of aging at 35 º C for another 30 mi�ut.

Characteristics of dissolution film coated and enteric coated tablets according to this example were obtained in accordance with the test for solubility in vitro as described in example 16, using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution. The result follows from Fig.1.

Example 23

Applying a film coating of core tablets according to example 18

Applying a film coating

For film coating 800 g of kernels of tablets received a 15% suspension of Opadry by adding 36 g of Opadry to 204 g of purified water. Approximately 66% of this suspension was sprayed onto the core tablets in a period of 35 minutes in the chamber of a fluidized bed. The product temperature never exceeded 40 degrees Celsius. For the coating process was followed by a period of drying for 16 minutes at 30ºC.

Characteristics of dissolution covered with a film coating of tablets according to this example, subjected to test for solubility in vitro using 0.1 N hydrochloric acid as the medium for dissolution within the first 2 hours of the test and then 0.05 M phosphate buffer with a pH of 6.8 as medium for dissolution, followed by Figs.2.

Example 24

18 g of pure DMF (particle size of 250-500 μm) was mixed with 6.3 g of HPC-SL, 9.1 g you�uchennai spray lactose (Flolan® 100) and 0.045 g of Aerosil. Finally, there was added 0.3 g of magnesium stearate and mixed. The final mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 225 mg.

Example 25

The study was a single-centre study after open, randomized, "inverted" design for the study of plasma concentrations, pharmacokinetics, safety and tolerability of the pharmaceutical compositions according to the present invention in comparison with the market composition of Fumaderm® as a reference. Tablets were administered as a single oral dose of 240 mg (2 tablets, each containing 120 mg) in each period of treatment according to randomization 20 healthy men of the European race. The study was divided into four periods of treatment (treatment Period 1, 2, 3 and 4), which was separated by a "washout" period, amounting to at least 7 days.

Subjects were selected for suitability at least 21-2 days before the first injection, including: verification of the criteria of inclusion/exclusion; demographic data (including age, height, body weight, body mass index (BMI) and ethnicity); medical examination; complete medical history; a 12-lead electrocardiogram (ECG); basic signs (blood pressure (BP), pulse rate (PR) and body temperature (TT)); clinical laboratory parameters (Hematology�I, serum biochemistry and urinalysis); documentation of concomitant disease and drug therapy.

In each of the four periods of treatment, the subjects came to the center of the study on the evening of 1 Day and remained there until the 24 hour blood sample for FC analysis and carrying out all the dimensions of security (=morning 2 days).

Subjects refrained from eating the night before. A single oral dose (two tablets) of one of the compounds according to the present invention (Examples 18, 20 or 22) or two covered with enteric-coated tablets reference medicinal product of Fumaderm®, each containing 120 mg of dimethylfumarate (total dose 240 mg dimethylfumarate), was administered on Day 1 (according to randomization). The introduction was carried out by the subjects on an empty stomach together with 240 ml of tap water. Between each introduction withstand a wash-out interval of at least 7 days.

Conducted the following evaluations/measurements:

Blood sampling was performed to determine plasma concentrations and FC-parameters before and at pre-scheduled time after administration of the doses.

Adverse events documented in detail throughout the study.

Urine was collected before and at pre-scheduled time after administration of the doses.

Repeated examinations were performed after at least 7 last� the last injection (treatment 4), including: medical examination; basic signs (BP, SP and TT); body weight; 12-lead ECG; clinical laboratory parameters (Hematology, serum biochemistry and urinalysis); documentation of concomitant drug therapy and adverse events.

Example 26

Obtaining cores tablets

Dimethyl fumarate was sieved through a 500 µm manual sieve.

29,3 g sifted dimethylfumarate, 2,93 g HPC-SL, 22,17 g of granulated lactose (Tablettose® 100), 0.07 g of Aerosil®, and 0.49 g of magnesium stearate were mixed for 10 minutes. The mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 225 mg.

Example 27A

Obtaining cores tablets

Dimethyl fumarate was sieved through a 500 µm manual sieve.

500 g sifted dimethylfumarate, 48 g of HPC-SL, 447 g of spray dried lactose (Flolan® 100) and 1.2 g of Aerosil® was mixed using a drum mixer for 15 minutes at 20 rpm. Finally, there was added 4 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, and the Mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 250 mg.

The application of enteric coating

The liquid coating, which is resistant to gastric acid, obtained by heating 247 g of purified water to 70-80 ° C, then was added 9 g of triethylcitrate, 1.8 g of glyceryl monostearate (Cutina GMS V)and 0.72 g of Tween 80, and stirred using UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added to 495 g of purified water and the mixture was stirred using a propeller stirrer until the emulsion at room temperature. Then this emulsion was slowly added to 200 g of the dispersion of Eudragit L30 D 55. The resulting liquid coating, which is resistant to gastric acid, is sprayed onto the core tablets directly in a perforated drum coater. The amount of solution sprayed on the tablets, was 1.5 wt.% solids, leading to weight gain is covered by a coating of tablets compared to the cores of the tablets by 1%.

Example 27b

Obtaining cores of the tablets was performed as described in Example 27A.

The application of enteric coating

The liquid coating, which is resistant to gastric acid, obtained by heating 247 g of purified water to 70-80 ° C, then was added 9 g of triethylcitrate, 1.8 g of glyceryl monostearate (Cutina GMS V) and 0.72 g of Tween 80, and stirred using UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added to 495 g of purified water and the mixture was stirred using a propeller stirrer until the emulsion at room temperature. Then this emulsion was slowly added to 200 g of the dispersion of Eudragit L30 D 55. The resulting liquid coating, �Stoycheva to acid gastric juice, sprayed onto the core tablets directly in a perforated drum coater. The amount of solution sprayed on the tablets, was 2.5 wt.% solids, leading to weight gain is covered by a coating of tablets compared to the cores of the tablets by 1.8%.

Example 28

Obtaining cores tablets

Dimethyl fumarate was sieved through a 500 µm manual sieve.

500 g sifted dimethylfumarate, 48 g of HPC-SL, 447 g of granulated lactose (Tablettose® 100) and 1.2 g of Aerosil® was mixed using a drum mixer for 15 minutes at 20 rpm. Finally, there was added 4 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, and the Mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 250 mg.

The application of enteric coating

The liquid coating, which is resistant to gastric acid, obtained by heating 99 g purified water up to 70-80 ° C, was then added to 10.1 g of triethylcitrate, 2.0 g of glyceryl monostearate (Cutina GMS V) and 0.8 g of Tween 80, and stirred using UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 198 g of purified water and the mixture was stirred using a propeller stirrer until the emulsion at room temperature. Then this emulsion was slowly added to 224 g of a dispersion of Eudragit L30 D 55. The resulting liquid coating, mouth�compressed to acid gastric juice, sprayed onto the core tablets directly in a perforated drum coater. The solution was sprayed with an increase in the mass of nuclei tablets 3%.

Example 29A

Obtaining cores tablets

Dimethyl fumarate were crushed by 1143 μm and 610 μm sieves.

500 g sifted dimethylfumarate, 48 g of HPC-SL, 447 g of granulated lactose (Tablettose® 100) and 1.2 g of Aerosil® was mixed using a drum mixer for 15 minutes at 20 rpm. Finally, there was added 4 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, and the Mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 250 mg.

The application of enteric coating

The liquid coating, which is resistant to gastric acid, obtained by heating 247 g of purified water to 70-80 ° C, then was added 9 g of triethylcitrate, 1.8 g of glyceryl monostearate (Cutina GMS V) and 0.72 g of Tween 80, and stirred using UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added to 495 g of purified water and the mixture was stirred using a propeller stirrer until the emulsion at room temperature. Then this emulsion was slowly added to 200 g of the dispersion of Eudragit L30 D 55. The resulting liquid coating, which is resistant to gastric acid, is sprayed onto the core tablets directly in a perforated drum for applying pokr�Tiya. The number of Eudragit sprayed on the tablets, was 2.5 wt.% solids, leading to weight gain is covered by a coating of tablets compared to the cores of the tablets is 1.5%.

Example 29b

Obtaining cores of the tablets was performed as described in Example 28a.

The application of enteric coating

The liquid coating, which is resistant to gastric acid, obtained by heating 247 g of purified water to 70-80 ° C, then was added 9 g of triethylcitrate, 1.8 g of glyceryl monostearate (Cutina GMS V) and 0.72 g of Tween 80, and stirred using UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added to 495 g of purified water and the mixture was stirred using a propeller stirrer until the emulsion at room temperature. Then this emulsion was slowly added to 200 g of the dispersion of Eudragit L30 D 55. The resulting liquid coating, which is resistant to gastric acid, is sprayed onto the core tablets directly in a perforated drum coater. The number of Eudragit sprayed on the tablets, was 3.5 wt.% solids, leading to weight gain is covered by a coating of tablets compared to the cores of the tablets by 2%.

Example 30

Obtaining cores tablets

2500 g of dimethylfumarate crushed by 1575 μm and 813 µm sieves. Prior to making this second�and grinding was added 6 g of Aerosil. The resulting distribution of particle size was approximately 11% >500 µm, approximately 70% >250 microns and approximately 7% <100 μm. The average particle size was 358 mm.

The crushed substance is additionally mixed with 240 g of HPC-SL and 2714 g of granulated lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, there was added 20 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, and the Mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 275 mg core tablets may have caused the enteric coating as described in example 33.

Example 31

Obtaining cores tablets

2500 g of dimethylfumarate crushed by 1575 μm and 813 µm sieves. Before the implementation of the second stage grinding was added 6 g of Aerosil®. The resulting distribution of particle size was approximately 3% >500 µm, approximately 65% >250 microns and approximately 6% <100 μm. The average particle size was 290 μm.

The crushed substance is additionally mixed with 240 g of HPC-SL and 2714 g of granulated lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, there was added 20 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, and the Mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 275 mg. On nuclei� tablets can be coated with the enteric coating, as described in example 33a or b.

Example 32

Obtaining cores tablets

2500 g of dimethylfumarate crushed by 1575 μm and 813 µm sieves. Before the implementation of the second stage grinding was added 6 g of Aerosil®. The resulting distribution of particle size was approximately 3% >500 μm, approximately 50% >250 microns and approximately 10% <100 μm. The average particle size was 250 μm.

The crushed substance is additionally mixed with 240 g of HPC-SL and 2714 g of granulated lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, there was added 20 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, and the Mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 275 mg core tablets may have caused the enteric coating as described in example 33b.

Example 33a

The application of enteric coating

The liquid coating, which is resistant to gastric acid, obtained by heating 1193 g purified water up to 70-80 ° C, was then added 45 g of triethylcitrate, 13.5 g of glyceryl monostearate (Cutina GMS V) and 5.4 g of Tween 80, and stirred using UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 2385 g of purified water and the mixture was stirred using a propeller stirrer until the emulsion at room temperature. Then �annoy emulsion was slowly added to 1500 g of a dispersion of Eudragit L30 D 55. The resulting liquid coating, which is resistant to gastric acid, is sprayed onto the core tablets directly in a perforated drum coater. The number of Eudragit sprayed on the tablets, was 3.0 mass%, what led to the increase of mass is covered with a coating of tablets compared to the cores of the tablets of 2.5%.

Example 33b

The application of enteric coating

The liquid coating, which is resistant to gastric acid, obtained by heating 1193 g purified water up to 70-80 ° C, was then added 45 g of triethylcitrate, 13.5 g of glyceryl monostearate (Cutina GMS V) and 5.4 g of Tween 80, and stirred using UltraTurrax for 10 minutes to obtain a homogeneous mixture. Added 2385 g of purified water and the mixture was stirred using a propeller stirrer until the emulsion at room temperature. Then this emulsion was slowly added to 1500 g of a dispersion of Eudragit L30 D 55. The resulting liquid coating, which is resistant to gastric acid, is sprayed onto the core tablets directly in a perforated drum coater. The number of Eudragit sprayed on the tablets, was 3.5%, leading to weight gain is covered by a coating of tablets compared to the cores of the tablets is 3%.

Example 34

Obtaining cores tablets

2500 g of dimethylfumarate ismalic�whether through 1575 μm and 813 µm sieves. Before the implementation of the second stage grinding was added 6 g of Aerosil®. The resulting distribution of particle size was 8% >500 µm, 80% >250 microns and 0% <100 μm. The average particle size was 360 μm.

The crushed substance is additionally mixed with 240 g of HPC-SL and 2234 g of granulated lactose (Tablettose 100) using a drum mixer for 15 minutes at 20 rpm. Finally, there was added 20 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, and the Mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 250 mg core tablets can be coated with the enteric coating, as described in example 33 a or B.

Example 35

Obtaining cores tablets

2500 g of dimethylfumarate crushed by 1575 μm and 813 µm sieves. Before the implementation of the second stage grinding was added 6 g of Aerosil®. The resulting distribution of particle size was 6% >500 μm, 65% >250 microns and 6% <100 μm. The average particle size was 305 μm.

The crushed substance is additionally mixed with 240 g of HPC-SL and 2234 g of granulated lactose (Tablettose 100) using a drum mixer for 15 minutes at 20 rpm. Finally, there was added 20 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, and the Mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 250 mg core tablets can b�you applied the enteric coating, as described in example 33a or b.

Example 36

Obtaining cores tablets

2500 g of dimethylfumarate crushed by 1575 μm and 813 µm sieves. Before the implementation of the second stage grinding was added 6 g of Aerosil®. The resulting distribution of particle size was 3% >500 µm, 63% >250 microns and 6% <100 μm. The average particle size was 290 μm.

The crushed substance is additionally mixed with 240 g of HPC-SL and 2234 g of granulated lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, there was added 20 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, and the Mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 250 mg core tablets can be coated with the enteric coating, as described in example 33a or b.

Example 37

Obtaining cores tablets

2500 g of dimethylfumarate crushed by 1575 μm and 813 µm sieves. Before the implementation of the second stage grinding was added 6 g of Aerosil®.

The crushed substance is additionally mixed with 240 g of HPC-SL and 1714 g of granulated lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, there was added 20 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, and the Mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 225 mg. For kernel table�current can be applied to the enteric coating, as described in example 33a or b.

Example 38

2500 g of dimethylfumarate crushed by 1575 μm and 813 µm sieves. Added 240 g of HPC-SL, 2,734 g of Tablettose 100 and 6 g of Aerosil®, and was mixed with DMF. The mixture was valavala and passed through a 1 mm sieve to obtain granules. Mixing 20 g of magnesium stearate to obtain a final mixture ready for tableting. This mixture was pressed into tablets having a weight of 275 mg core tablets can be coated with the enteric coating, as described in example 33a or b.

Example 39

2500 g of DMF were mixed with 6 g of Aerosil®, and then were crushed by 1575 μm and 813 µm sieves. Added 240 g of HPC-SL, 2,734 g of Tablettose 100 and and was mixed with DMF and Aerosil. The mixture was valavala and passed through a 1 mm sieve to obtain granules. Mixing 20 g of magnesium stearate to obtain a final mixture ready for tableting. This mixture was pressed into tablets having a weight of 275 mg core tablets can be coated with the enteric coating, as described in example 33a or b.

Example 40

2000 g of dimethylfumarate crushed by 1575 μm and 813 µm sieves. Before the implementation of the second stage grinding was added 4.8 g of Aerosil®.

To 475.3 g of crushed substance optionally mixed with 519,8 g of granulated lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. NAC�finally, added 3.8 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, and the Mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 263 mg core tablets can be coated with the enteric coating, as described in example 33a or b.

Example 41

2000 g of dimethylfumarate crushed by 1575 μm and 813 µm sieves. Before the implementation of the second stage grinding was added 4.8 g of Aerosil.

468,2 g of crushed substance was further mixed with 15 g of HPC-SL and 512 g of granulated lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, was added 3.7 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, and the Mixture was pressed into biconvex tablets with a diameter of 8 mm and a weight of 267 mg core tablets can be coated with the enteric coating, as described in example 33a or b.

Example 42

2000 g of dimethylfumarate crushed by 1575 μm and 813 µm sieves. Before the implementation of the second stage grinding was added 4.8 g of Aerosil.

500 g of crushed substance optionally mixed with 32 g of HPC-SL and 562,8 g of granulated lactose (Tablettose® 100) using a drum mixer for 15 minutes at 20 rpm. Finally, there was added 4 g of magnesium stearate and the mixture is again mixed for 10 minutes at 20 rpm, the Mixture is extruded in the lenticular�the tap hole with a diameter of 8 mm and a weight of 250 mg. At the core tablets can be coated with the enteric coating, as described in example 33a or b.

Example 43

Study, such as described in example 25 was carried out with the use of tablets described in examples 18 and 22, and compared with the corresponding data for the composition of Fumaderm® the prior art. The results of this study are shown in Table I and Table II below.

Table I
The coefficients of variation in % (CV).
Example 18Example 22Fumaderm®
ACC22%18%38%
Cmax34%26%49%

Table II
Summary table: Percentage of subjects with adverse effects/side effects after administration of the composition according to examples 18 and 22, respectively, in comparison with the introduction of Fumaderm®.
Unwanted effect/side effectAfter the introduction of the composition according to example 18 in comparison with the introduction of FumadermAfter the introduction of the composition according to example 22 in comparison with the introduction of Fumaderm
Redness35%65%
Associated with gastrointestinal adverse effects50%73%
Any undesirable effect50%77%

The above results from clinical studies (table II) show that the tested materials have a significantly reduced frequency of adverse effects in combination with lower variability (see Table 1) compared with Fumaderm®. Thus, this example shows that the compositions according to the present invention show unexpectedly strong reduction of variability in the ACC and Cmaxcompared with the composition of Fumaderm, known in the art.

1. Pharmaceutical composition in form of tablet with erodium matrix that contains:
1) a core containing:
i) from 10 wt.% to 80 wt.% one or more fumaric acid esters selected from di-(C1-C5)alkylation �Umarova acid and mono-(C 1-C5)alkylation fumaric acid selected from dimethylfumarate and monomethylfumarate or their pharmaceutically acceptable salts as active substance;
ii) 3-6 wt.% from the mass of the nucleus controlling the speed of the agent representing hydroxypropyl cellulose;
(iii) 35-60 wt.% from the mass of the nucleus of the binder constituting the lactose; and
2) the enteric coating, wherein the specified enteric coated at a level of 1.5 to 3.5 wt.% from the mass of the nucleus.

2. The pharmaceutical composition according to claim 1, characterized in that said uroderma matrix is a monolithic erodium matrix.

3. The composition according to claim 1, further comprising one or more pharmaceutically acceptable excipients and additives selected from the group comprising lubricants, substances promoting sliding, leavening agents, agents, controlling the fluidity, soljubilizatory, agents that regulate pH, surfactants and emulsifiers.

4. The composition according to claim 1, wherein the hydroxypropyl cellulose has a viscosity of 3.0 to 5.9 MP, measured in an aqueous solution containing 2 wt.% the hydroxypropyl cellulose in the calculation of the dry residue, at 20°S.

5. Pharmaceutical composition according to any one of claims. 1-4 for use for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory diseases�evania bowel such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (PC), juvenile diabetes, Hashimoto's thyroiditis, grave's disease, SLE (systemic lupus erythematosus), sjögren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/isiana pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or anulyarnaya granuloma.

6. A method of obtaining a composition according to any one of claims.1-4, comprising the following stages:
(a) dissolving or suspending the fumaric acid ester selected from dimethylfumarate and monomethylfumarate and controlling the speed of the agent representing hydroxypropyl cellulose, in the form of a polymer matrix substance in water to obtain an aqueous suspension of said substances;
(b) applying a specified water slurry spray into pellets in a binder, which is a lactose, during the period of time that is sufficient for obtaining uniform coverage;
c) drying the obtained granules
d) possibly, sieving or grinding of these granules;
e) mixing the binder constituting the lactose, with any pharmaceutically acceptable excipients and additives essentially known method of obtaining the composition in the form of the core tablet;
(f) applying the enteric coating to the specified composition in the form of the tablet core is essentially known manner;
while the above steps is carried out at this temperature to product temperature did not exceed 45°C.

7. A method of obtaining a composition according to any one of claims.1-4, comprising the following stages:
(a) dissolving or suspending controlling the speed of the agent representing hydroxypropyl cellulose, in the form of a polymer matrix substance in water to obtain an aqueous suspension of a specified substance;
(b) applying a specified water slurry spray into pellets of the fumaric acid ester selected from dimethylfumarate and monomethylfumarate, during the period of time that is sufficient for obtaining uniform coverage;
c) drying the obtained granules;
d) possibly, sieving or grinding of these granules;
e) mixing the binder constituting the lactose, with any pharmaceutically acceptable excipients and additives essentially known method of obtaining the composition in the form of the core tablet;
f the application of enteric coating on said composition is in the form of the tablet core is essentially in a known manner;
while the above steps is carried out at this temperature to product temperature did not exceed 45°C.

8. A method of obtaining a composition according to any one of claims.1-4, comprising the following stages:
a) possibly, sieving or grinding of crystals of fumaric acid ester selected from dimethylfumarate and monomethylfumarate;
(b) mixing the above crystals of fumaric acid ester, which controls the speed of the agent representing hydroxypropyl cellulose, in the form of a polymer matrix substance, the binder constituting lactose, and any pharmaceutically acceptable excipients and additives by direct compression with obtaining a composition in the form of the core tablet;
c) applying enteric coating on said composition is in the form of the tablet core is essentially known manner;
while the above steps is carried out at this temperature to product temperature did not exceed 45°C.

9. A method according to claim 8, in which the crystals of the ester of fumaric acid was sieved or milled so that 90% of the particles have a size in the range of 5-1000 μm, such as in the range of 10-900 μm, such as in the range of 20-800 μm, such as in the range of 30-750 μm, such as in the range of 40-600 μm or such as in the range of 50-500 microns.

10. Use of pharmaceutical composition according to any one of claims. 1-4 to obtain medicinal deterge�VA for the treatment of psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (PC), juvenile diabetes, Hashimoto's thyroiditis, grave's disease, SLE (systemic lupus erythematosus), sjögren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/isiana pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or anulyarnaya granuloma.

11. The use according to claim 10 for the treatment of psoriasis.

12. The use according to claim 10 for the treatment of psoriatic arthritis.

13. The use according to claim 10 for the treatment of multiple sclerosis.

14. The use according to claim 10 for the treatment of rheumatoid arthritis.

15. A method of treating psoriasis, psoriatic arthritis, neurodermatitis, inflammatory bowel disease, such as Crohn's disease and ulcerative colitis, polyarthritis, multiple sclerosis (PC), juvenile diabetes, Hashimoto's thyroiditis, grave's disease, SLE (systemic red�th erythematosus), sjögren's syndrome, pernicious anemia, chronic active (lupus) hepatitis, rheumatoid arthritis (RA), lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, scleroderma, optic neuritis, pain such as radicular pain, pain associated with radiculopathy, neuropathic pain or sciatica/isiana pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica or anulyarnaya granuloma, wherein said method comprises the oral administration to a patient in need this, the effective dose of the pharmaceutical composition according to any one of claims. 1-4.

16. A method according to claim 15 for the treatment of psoriasis.

17. A method according to claim 15 for the treatment of psoriatic arthritis.

18. A method according to claim 15 for the treatment of multiple sclerosis.

19. A method according to claim 15 for the treatment of rheumatoid arthritis.



 

Same patents:

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.

SUBSTANCE: invention relates to medicine, in particular to application of medication "Osteomed" for treating arthritis and arthrosis.

EFFECT: said application makes it possible to accelerate treatment of arthritis and arthrosis, increased efficiency of such treatment with simultaneous elimination of risk of hypercalcemic condition development.

2 dwg

FIELD: medicine.

SUBSTANCE: 10-day conventional drug therapy comprising a daily vascular therapy by intravenous drop-by-drop administration of Trental 5 ml dissolved in 0.9% normal saline 200 ml is followed by a local therapeutic exposure on the involved shoulder joint. That is ensured by intramuscular administration of a therapeutic mixture containing Depot-Medrol 1 ml - 40 mg, 2% lidocaine hydrochloride 6 ml - 120 mg and cyanocobalamine 3 ml - 1.5 ml into trigger areas of supraspinous, infraspinous, deltoid and subscapular muscles. Administering the therapeutic mixture follow the schedule: on the first therapeutic day, the therapeutic mixture is injected into the trigger areas of supraspinous and infraspinous muscles in an amount of 5 ml into each muscle once a day; on the second therapeutic day, the therapeutic mixture is injected into the trigger areas of deltoid and subscapular muscles in an amount of 5 ml into each muscle once a day; from the third to ninth therapeutic day, the therapeutic mixture is introduced in a dose of 10 ml every second day into the trigger areas of the subscapular muscle.

EFFECT: method enables increasing the clinical effectiveness in the patients with scapulohumeral periarthrosis by recovering the shoulder joint function with reducing the recurrent pain syndrome considerably.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to immunology. Presented are anti-Dickkopf 1 (anti-Dkk-1) antibodies and their functional fragments specified among the antibodies: 1) containing CDR1 VH containing the amino acid sequence SSYAIS, SYAIS or GFTFSSY; CDR2 VH containing the amino acid sequence SVSGTGLGFGTYYPDSVKG or SVSGTGLGFGTY; and CDR3 VH, containing the amino acid sequence TSLENYAFDY or SLENYAFDY; and CDR1 VL containing the amino acid sequence RASESVDDFGISFIN; CDR2 VL containing the amino acid sequence AGSKQGS; and CDR3 VL containing the amino acid sequence QQLKEVPPT; and 2) the antibodies disclosed in Table 4 presented in the application materials. Described are: nucleic acids coding the above antibodies or their functional fragments; expression vectors containing the above nucleic acids; and cells used for expression of the above antibodies or their functional fragments and containing the above expression vectors. Presented is a method for producing the antibody or its functional fragment involving the stage of culturing the above expression cell. Disclosed is a composition possessing Dkk-1 binding activity, containing the antibody or its functional fragment in a therapeutically effective amount and a pharmaceutically acceptable excipient, thinner or carrier.

EFFECT: invention enables extending the range of products for treating the diseases associated with Dkk-1 and LRP5/6 excessive reaction, which cause Wnt activation.

14 cl, 14 dwg, 14 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of N-[-2[[(2,3-difluorophenyl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl]oxy}-4-pyrimidinyl]-1-azatidine-sulphonamide, which has an X-ray powder diffractogram, measured with the application of a wavelength of X-rays of 1.5418 E and containing, at least, one crystalline peak with a value 2-theta (in degrees) 21.0, 28.8 and/or 29.1; or containing, at least, 2 crystalline peaks with a value 2-theta (in degrees) 21.0, 28.8 and/or 29.1; or containing, at least, 3 crystalline peaks with a value 2-theta (in degrees) 21.0, 28.8 and/or 29.1. The said crystalline form can contain additional crystalline peaks with a value 2-theta (in degrees), selected from 12.9 and 18.0, obtained under the said conditions.

EFFECT: crystalline form has the X-ray powder diffractogram, measured with the application of a wavelength of X-rays of 1,5418 E, with the crystalline peaks with a value 2-theta (in degrees) 12,9, 13,1, 18,0, 21,0, 22,5, 25,1, 25,3, 28,8, 29,1 and 30,4, and has melting point (beginning) 152,7°C.

6 cl, 3 dwg, 2 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: intra-articular injections of medications are performed in two stages. The first stage of treatment includes the introduction of 4.4 ml of Zeel T medication with lidocaine solution, the manipulation is repeated with a 2-3 day interval in the number of 10 injections. The second stage is started 2-3 days after finishing the first stage with the application of adgelon medication for intra-articular injections in a single dose of 2.0 ml, the manipulation is repeated after 2-3 days in the number of 10 injections.

EFFECT: method makes it possible to reduce the expression of pain syndrome, crepitus, volume of analgesics, with the simultaneous increase of motor activity and roentgenologic value of the joint space.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutics, in particular a pharmaceutical composition in the form of a peroral drug form is described. The composition includes rebamipide as an active ingredient and a pharmaceutically acceptable carrier. Rebamipide is contained in an amount from 0.5 to 50 mg/kg, preferably from 0.6 to 6 mg/kg.

EFFECT: application of the rebamipide-based pharmaceutical composition for the prevention and treatment of arthrosoarthritis.

5 cl, 3 dwg, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine. What is described is a method for preparing a high-purity drug preparation for treating degenerative-dystrophic diseases of peripheral synovial joints and spinal column. The method provides introducing L-proline, an amino acid in an amount of 10-70 g/l into aqueous chondroitin sulphate solution containing no more than 11.5% of an active ingredient, and filtering the solution at temperature 20-50°C through ZetaCarbon (Cuno) R54SLP, R51SLP, R53SLP or AKS (Pall) - AKS 1, 2, 6, 7 filters.

EFFECT: method provides preparing the high-grade 99% pure liquid or lyophilised chondroprotective preparation stabilised with L-proline with the residual content of organic purities: protein - no more than 0,2%, lipids (per 1mg of chondroitin sulphate) - no more than 0,05 mcg, bacterial endotoxins (per 1mg of chondroitin sulphate) - no more than 0,05 EU.

6 cl, 3 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: mixture of 0.5% Novocaine or 0.25% Lidocaine 19.0ml and venous autoblood 1.0 ml is administered into the acupuncture points fu-tu and zu-san-li once every day or every second day in total number of blocks 8-16, in an amount of 5 ml into each point at a penetration depth of 1.5-2.0 cm.

EFFECT: reducing pain syndrome and oedema of paraarticular tissues, improving support ability of the lower extremities and knee joint functions by improving microcirculation in the lower extremities.

4 ex

FIELD: medicine.

SUBSTANCE: treating acute knee arthritis is ensured by measuring a pre-therapeutic blood lymphocyte percentage in the patient. That requires performing 5 sessions of finger point massage of the points IV.9, XI.34, VII.60, III.36. If the lymphocyte percentage is less than 25%, Myelopidum 6 mg a day is administered additionally every second day, in number of 5 injections.

EFFECT: reducing the clinical manifestations of acute knee arthritis taking into account the immune state.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the beauty industry, representing a gel-like composition for topical application, containing salicylic acid with the concentration of ca. 17 wt %, elastic collodion in the amount of 5 to 10 wt % and ethyl lactate in the amount of 20 to 25 wt %, where the elastic collodion contains 65.8 wt % diethyl ether, 24.3 wt % ethanol, 2 wt % camphor, 3 wt % castor oil and 4.9 wt % nitro-cellulose.

EFFECT: invention provides excellent stability, even drying and the formation of a uniform film.

5 cl, 1 tbl, 4 dwg

FIELD: medicine.

SUBSTANCE: melanin having water-solubility of at least 80% and an paramagnetic centre concentration of at least 8·1017 spin/g is administered orally into the animals having been exposed to the radiation in a dose high enough to cause a spinal radiation injury; melanin is administered after dissolved in distilled water in the effective concentration. Melanin water is used as drinking water for the mice having been exposed to single and fractionated acute radiation, which is able to cause acute radiation disease. Melanin water is taken from the 1st to 30th day following the single radiation, or from the 1st day of the fractionated radiation to the 30th day on completion of the radiation.

EFFECT: higher survival rate, faster recovered haemopoiesis, body weight and orientation and motion activity.

7 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, more specifically to clinical dentistry. The invention represents a composition for treating erosive ulcerative and exudative hyperaemic forms of oral lichen planus.

EFFECT: implementing the invention provides high oral adhesion of the preparation, increases the therapeutic concentration of the preparation in the area of involvement (inflammation), accelerates the length of treatment (reduces the size of erosion, the length of epithelisation of erosions).

2 dwg

FIELD: medicine.

SUBSTANCE: pharmaceutical composition possessing a therapeutic action on various skin pathologies contains triptantrin, chitosan and distilled water, a lanoline and Vaseline mixture and protein-nucleic hydrolyzate of the salmonid fishes milt in a certain mixture ratio.

EFFECT: composition enables increasing the clinical effectiveness in the skin pathologies of various origins and extending the range of pharmaceutical compositions having the therapeutic effect on the various skin pathologies.

3 tbl, 4 dwg, 7 ex

Elastase inhibitor // 2548794

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical and cosmetic industries, namely to an elastase inhibitor. The elastase inhibitor containing active ingredients presented by raspberry (Rubus idaeus L.) extract and hydroxyproline in the dry state in a certain amount, wherein the raspberry extract is prepared by using an extraction solvent specified in a group consisting as follows: water, methanol, ethanol, hydroethanol, 1,3-butylene glycol, acetone and/or ethyl acetate. The composition for external skin application containing the elastase inhibitor.

EFFECT: agent is the effective elastase inhibitor.

6 cl, 2 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, namely to production of medications for treating dermatosis. Medication according to invention, made in form of cream, contains mometasone furoate, preservative, hydrophilic no-aqueous solvent, emulsifying agent of 1st kind, emulsifying agent of 2nd kind, emollient, disodium edetate (trilon B), pH-regulating agent, and purified water in quantities, given in invention formula.

EFFECT: invention can be applied for treating inflammatory diseases and itching in case of dermatosis, yielding to glycocorticosteroid therapy.

9 cl, 3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to novel derivatives of pyrazole pyridine of formula , as well as to its tautomers, geometrical isomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, where G1 represents H; G2 represents -CHR1R2; R1 and R2 independently on each other are selected from H; C1C6-alkoxy-C1C6-alkyl; C1-C6-alkyl; optionally substituted phenyl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted morpholine-C1-C6-alkyl; or -CHR1R2 together form a ring, selected from an optionally substituted C3-C8-cycloalkyl and substituted piperidine; G3 is selected from an optionally substituted C1C6-alkoxy -C1-C6-alkyl; C1-C6-alkyl; substituted phenyl; substituted phenyl-C1C6-alkyl; G4 is selected from a substituted acyl-C1C6-alkyl, where acyl represents a group -CO-R and R stands for H or morpholine; optionally substituted C1-C6-alkyl; optionally substituted phenyl or indene; substituted phenyl-C1-C6-alkyl; optionally substituted pyridine- or furanyl-C1C6-alkyl; morpholine- or piperidine-C1-C6-alkyl; G5 represents H; where the term "substituted" stands for the groups, substituted with 1 to 5 substituents, selected from the group, which includes a "C1-C6-alkyl," "morpholine", "C1-C6-alkylphenyl", "di-C1-C6-alkylamino", "acylamino", which stands for the group NRCOR", where R represents H and R" represents a C1-C6-alkyl, "phenyl", "fluorine-substituted phenyl", "C1-C6-alkoxy", "C1-C6-alkoxycarbonyl", "halogen". The invention also relates to a pharmaceutical composition based on the formula (I) compound and particular compounds.

EFFECT: obtained are the novel derivatives of pyrasole pyridine, useful for the treatment and/or prevention of disorders or states, associated with NADPH-oxidase.

12 cl, 3 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: from the 2nd-3rd day and 10 days on after admission to hospital, Derinat is administered intramuscularly as an immunomodulatory preparation for 1-2 minutes in a dose of 1.5% (75 mg) of the solution every 45 hours (as directed in the instructions). On the 3rd-4th postoperative day, at the stage of granulation formation, the wound is coated by uniform layers of an aquacomplex of glycerosolvate titanium 0.3 g per 1 square dm of the wound as local daily applications for 10-20 days.

EFFECT: higher clinical effectiveness and reduced length of treatment and side reactions accompanying the administration of immunomodulatory agents, enabled reduction of complications of the erysipelas, considerably reduced length of intoxication manifestations, accelerated regression of local manifestations, and stimulated wound regeneration.

2 ex

FIELD: medicine.

SUBSTANCE: skin care compound possessing the antifungal properties, alcoholic extract of birch leaves, pine paste, tea tree, fir, lemon and eucalyptus essences, an emulsion base in certain proportions.

EFFECT: compound possesses the pronounced antifungal properties.

4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to novel pyridine derivatives of the general formula

and to their pharmaceutically acceptable salts, where R1 stands for (C1-6) alkyloxy, CN or halogen, R2 stands for a hydrogen atom, R3 stands for a hydrogen atom or (C1-6) alkyl, R4, R5, R6, R7 are similar or different and stand for a hydrogen atom or halogen. The invention also relates to the cosmetic application of the formula (I) compound.

EFFECT: novel pyridine derivatives, useful in the treatment of diseases associated with a receptor of androgens, are obtained.

9 cl, 1 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: this invention aims at pharmaceutical compositions and methods for making these compositions containing a number of controlled-release particles. At least one assembly of said particles comprises a nucleus containing weakly basic drug substance, an alkaline buffer layer above the nucleus, and a controlled-release coating. The weakly basic drug substance contains at least one nitrogen-containing fragment with pKa from approximately 5 to approximately 14, with a solubility from at least 200 mg/ml at room temperature in an aqueous solution at pH approximately pH 1.2-6.8 and solubility of no more than approximately 10 mg/ml at pH 8 and more. The controlled-release coating contains a water-insoluble polymer. The pharmaceutical composition also contains rapidly degrading microgranules. This invention also aims at pharmaceutical dosage forms containing orally degrading tablets, classical tablets and capsules, as well as methods for making them.

EFFECT: invention provides the sustained release of the weakly basic drug substance in the small intestine.

65 cl, 1 dwg, 1 tbl, 7 ex

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