Pharmaceutical composition of imatinib or its pharmaceutically acceptable salt, method for preparing it and method(s) of treating

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmaceutics, namely to a pharmaceutical composition (a solid oral dosage form (a tablet or a capsule)) of tyrosine kinase Bcr-Abl inhibitor - imatinib(4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)-pyrimidin-2-ylamino)phenyl]benzamide). The pharmaceutical composition contains 25-45 wt % of imatinib, preferentially imatinib mesylate, more preferentially an α-crystalline form of imatinib mesylate, a binding agent representing povidone, and at least two desintegrant representing low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.

EFFECT: invention provides the min 80% imatinib release from the tablet for 15 minutes after oral administration and enables extending the range of drugs used for leukaemia.

14 cl, 4 dwg, 3 tbl, 2 ex

 

The invention relates to new pharmaceutical compositions (solid oral dosage form, preferably a tablet or capsule) of the compound (I)

or its pharmaceutically acceptable acid additive salts (such as mesilate (methanesulfonate), and also to a method for producing such pharmaceutical compositions and to methods of treatment.

The compound (I) (international nonproprietary name: imatinib, chemical name: (4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)-pyrimidine-2-ylamino)phenyl]benzamide), STI571), open a base in the patent [1] (and also in corresponding Russian patent [2]) and in the publication [3], is an inhibitor of receptor proteincontaining, which inhibits tyrosine kinase Bcr-Abl, C-Abl at the cellular level both in vitro and in vivo.

The basis of action of imatinib is blocking areas tyrosine kinase responsible for the binding of ATP, which leads to disruption of signal transmission and stop proliferation or induction of apoptosis in cells expressing tyrosinekinase Bcr-Abl.

Imatinib selectively inhibits proliferation and induces apoptosis in cell lines positive for Bcr-Abl, as well as young leukemia cells in patients with chronic myeloid leukemia with Philadelphia positive chromium is wash with acute lymphoblastic leukemia. In the analysis of the transformation of the colonies, carried out ex vivo on samples of peripheral blood and bone marrow was observed selective inhibition by imatinib Bcr-Abl-positive colonies in patients with chronic myeloid leukemia.

The activity of imatinib and its pharmaceutically acceptable salts shown for chronic myeloid leukemia [4]; leukemia, positive for the Philadelphia chromosome (leukemia Ph+) [5]; system mastocytosis (in patients with mutation of c-Kit D816V) [6], [7]; CD117-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors gastrointestinal tract (GIST) [8], [9].

Imatinib is an inhibitor of the tyrosine kinase receptor for platelet growth factor (PDGF) and stem cell factor (SCF), C-Kit (C-kit) and suppresses cell responses mediated by these factors.

In the prior art imatinib is known not only as the Foundation of [1], [2], but also in the form of pharmaceutically acceptable salts, in particular, D(-) and L(+)-tartrate, succinate, malonate [10].

International PCT publication [11] and the patent of the Russian Federation [12] reveal mesilate ((mono)methanesulfonate) of imatinib, as well as a number of crystalline forms of imatinib nelfinavir (in particular, β-crystalline form);

while the β-form is characterized by physical-chemical properties, providing a special advantage when receiving the AI is solid oral dosage forms of imatinib; in particular, the β-form of imatinib or its pharmaceutically acceptable salt) is less hygroscopic, has a better flow characteristics and thermodynamically stable at temperatures less than 140°C. the solubility of nelfinavir of imatinib in water at pH less than 5.5 is >1300 mg/ml

As companies Novartis AG belong to 2018 exclusive rights to β-crystalline form of imatinib nelfinavir, and pharmaceutical compositions containing the β-crystalline form of imatinib nelfinavir [12] (on the basis of this crystalline form of imatinib nelfinavir is made, in particular, the drug Gleevec®), there is a need to develop reproduced oral dosage forms of imatinib or its pharmaceutically acceptable acid additive salts) on the basis of other crystalline and amorphous forms of a given substance; the number of such crystalline and amorphous form of imatinib and its pharmaceutically acceptable salts disclosed in patent documents[13]-[22].

The prior art known [23] the pharmaceutical composition with delayed release of imatinib or its pharmaceutically acceptable salts (in particular, nelfinavir), intended for oral administration that includes obtained from melt granules of imatinib or any of its salts of the retarder release in which the specified retarder release is a polymer with a glass transition temperature below the melting temperature of the nelfinavir of imatinib and/or polimerny retarder release, which melts at a lower temperature compared to the melting temperature of imatinib or used salt of imatinib;

as moderator of the specified release pharmaceutical composition contains gidrirovannoe castor oil (polimerny retarder release) or polymer selected from insoluble but capable of swelling in water of the polymers based on cellulose (hydroxypropylcellulose, hydroxypropylmethylcellulose, ethyl cellulose), acrylic (methacrylate) polymers, polysaccharides (karraginanom, galactomannans, xanthan gum, or mixtures thereof) and polyols.

The composition of imatinib in accordance with the patent [23] provides a release of not more than 80% of the active substance within 1 hour and not less than 80% within 10 hours after admission (in another embodiment no more than 80% of the active substance within 2 hours and not less than 80% within 8 hours after administration),

and also provides a medium level of imatinib in plasma of healthy people no more than 3.5 μg/ml (in 2 hours after ingestion on an empty stomach or after a light Breakfast).

In some cases, however, there is a need in the pharmaceutical composition is Yah immediate release able in a short period of time after intake (15-20 minutes) to release high doses of imatinib.

The prior art pharmaceutical composition (pill) [24], proposed as the closest analogue of the present invention and containing a pharmacologically effective amount of imatinib or its pharmaceutically acceptable salt, in the amount of from about 30 to 80 wt.% (preferably from 50 to 600 mg of imatinib or its salts, more preferably from 100 to 400 mg, most preferably, 100 or 400 mg of imatinib or its salts); this tablet contains at least one binder comprising microcrystalline cellulose, or hypromellose, or mixtures thereof.

In the patent [24] described also is a method of obtaining tablets of imatinib or its pharmaceutically acceptable salt according to which mix of imatinib or its pharmaceutically acceptable salt with a pharmaceutically acceptable fillers, damp granulation, mixing the granulate with pharmaceutically acceptable excipients with the formation of the mixture and press the mixture with obtaining tablets; in addition, the tablet may be coated.

Despite the fame of the prior art, the pharmaceutical compositions of imatinib [24], there is still the task of expanding the range of drugs (solid dosage forms, in particular, tablets) of imatinib or its pharmaceutically acceptable salts (such as imatinib mesilate)containing high doses of the active substance and is capable of releasing imatinib in a short period of time after administration of solid dosage forms (at least 80% of the active substance within 15 minutes after administration), not inferior in characteristics of the original drug (Gleevec®).

These solid dosage forms should be patent-clean (do not disturb owned by the company-developer of imatinib exclusive rights to pharmaceutical compositions of imatinib or its pharmaceutically acceptable salts) and have low production costs.

This problem was solved by the applicant in the context of the present invention through the development of the original composition of the pharmaceutical composition (tablets or capsules) of imatinib or its pharmaceutically acceptable salt containing a binder other than microcrystalline cellulose, or hydroxypropylmethylcellulose, or mixtures thereof, and a combination of the two openers, where these leavening agents include hyprolose (hydroxypropylcellulose nitrosamino) and carboximetilkrahmal sodium.

It should be emphasized that hydroxypropylcellulose specified in Patan is e [23] the number of possible moderators of the release of the active substance from the oral pharmaceutical composition of imatinib (see [23], page 3 (last paragraph), page 6, page 12 (lines 20-25)).

Brief description of drawings

Figure 1. The dissolution profile of the original drug imatinib nelfinavir (β-crystalline form) (Gleevec®, coated tablets, NOVARTIS AG), dosage of 100 mg.

Figure 2. The dissolution profile of the original drug imatinib nelfinavir (β-crystalline form) (Gleevec®, coated tablets, NOVARTIS AG), dosage 400 mg

Figure 3. The dissolution profile of the drug imatinib nelfinavir (α-crystalline form) in accordance with the invention (tablets, coated tablets, CJSC Biocad), dosage of 100 mg.

Figure 4. The dissolution profile of the drug imatinib nelfinavir (α-crystalline form) in accordance with the invention (tablets, coated tablets, CJSC Biocad), dosage 400 mg

The invention

In the framework of the present invention it has been unexpectedly discovered that the use in the solid dosage forms (tablets or capsules) of imatinib hyprolose (hydroxypropylcellulose nitrosamino) and sodium carboxymethyl amylum, on the one hand, and a binder other than microcrystalline cellulose, hydroxypropylmethylcellulose or their mixtures, on the other, allows you to create a dosage form that provides rapid release of the active agent from the tablet (which is 80% of the active substance within 15 minutes after taking the drug).

The preferred pharmaceutically acceptable salt of imatinib, in accordance with the present invention, is of imatinib mesilate (nanomeasurement); the most preferred crystalline form of imatinib nelfinavir, in accordance with the invention is α-crystal form of imatinib nelfinavir.

Thus, one of the objects declared in accordance with the present invention is a film-coated tablet, containing as active substance imatinib

or its pharmaceutically acceptable acid additive salt in an amount of from 25 to 45 wt.% (calculated on the basis of imatinib, calculated on the total weight of the solid dosage forms),

and excipients,

where the excipients include at least one binder that is different from hydroxypropylmethylcellulose, microcrystalline cellulose or mixtures thereof, and at least two of baking powder (disintegrant), non-cross-linked polyvinylpyrrolidone.

It was found experimentally that the most preferred (but not limiting the amount of claims in accordance with the present invention) composition of solid dosage forms (tablets or capsules) of imatinib (or pharmaceutically acceptable salt of imatinib, such as imatinib mesilate,α-crystalline form) includes:

- 25-45 mass % (wt%) of imatinib or its pharmaceutically acceptable salt, such as imatinib mesilate (calculated on the basis of the compound (I), based on the total weight of the pharmaceutical composition);

- 35-50 wt.% (based on the total weight of the pharmaceutical composition) hydroxypropylcellulose (hyprolose) nitrosamines (baking powder 1);

- 10-20 wt.% (based on the total weight of the pharmaceutical composition) Na-carboxymethyloxime (baking powder 2);

- 0.1 to 1.0 wt.% (based on the total weight of the pharmaceutical composition) povidone (binder);

- 0.5 to 5.0 wt.% (based on the total weight of the pharmaceutical composition) of colloidal silicon dioxide (glidant, disintegrant);

- 0.5 to 1.0 wt.% (based on the total weight of the pharmaceutical composition) magnesium stearate (lubricant).

A tablet in accordance with the invention can be (optionally) a coating (film sheath) on the basis of hypromellose, such as Opadry®.

The most preferred embodiments of the present invention are:

- tablet, containing imatinib mesilate (α-crystalline form), including the core and covering his shell, containing:

Kernel:

- imatinib mesylate, 45-65 mg (in the most preferred embodiment is 59,75 mg of imatinib nelfinavir, which corresponds to 50 mg of the imatinib);

- is prolazu nitrosamino - 60-70 mg;

- povidone - 0.15 to 0.4 mg;

- carboximetilkrahmal sodium - 17-25 mg;

- colloidal silicon dioxide is 1.0-3.0 mg;

- magnesium stearate and 0.5-2.0 mg;

Shell:

commercially available mixture for coating based on hypromellose (e.g., Opadry®) - 5-9 mg;

- tablet, containing imatinib mesilate (α-crystalline form), including the core and covering his shell, containing:

Kernel:

of imatinib mesylate, 105-125 mg (in the most preferred embodiment - 119,5 mg of imatinib nelfinavir, which corresponds to 100 mg of the imatinib);

- hyprolose nitrosamino - 120-140 mg;

- povidone - 0.4-0.8 mg;

- carboximetilkrahmal sodium - 40-45 mg;

- colloidal silicon dioxide - 3,0-5,0 mg;

- magnesium stearate and 1.5 - 2.5 mg

Shell:

commercially available mixture for coating based on hypromellose (e.g., Opadry®) - 11-17 mg;

- tablet, containing imatinib mesilate (α-crystalline form), including the core and covering his shell, containing:

Kernel:

- imatinib mesylate, 450-500 mg (in the most preferred embodiment, 478 mg, which corresponds to 400 mg of the imatinib);

- hyprolose nitrosamino - 480-560 mg;

- povidone - 1.0 to 4.0 mg;

- carboximetilkrahmal sodium - 150-185 mg;

- colloidal silicon dioxide - 12-20 mg;

- magnesium stearate - 6-10 mg

Shell:

commercial on the vent mixture for coating based on hypromellose (for example, Opadry®) - 25-45 mg

Another alternative preferred embodiment of the present invention are gelatin capsules containing:

- imatinib mesylate, 45-65 mg (in the most preferred embodiment is 59,75 mg of imatinib nelfinavir, which corresponds to 50 mg of the imatinib);

- hyprolose nitrosamino 60-70 mg;

- povidone - 0.15 to 0.4 mg;

- carboximetilkrahmal sodium - 17-25 mg;

- colloidal silicon dioxide is 1.0-3.0 mg;

- magnesium stearate and 0.5-2.0 mg;

or

- imatinib mesylate, 105-125 mg (in the most preferred embodiment - 119,5 mg of imatinib nelfinavir, which corresponds to 100 mg of the imatinib);

- hyprolose nitrosamino - 120-140 mg;

- povidone - 0.4-0.8 mg;

- carboximetilkrahmal sodium - 40-45 mg;

- colloidal silicon dioxide - 3,0-5,0 mg;

- magnesium stearate and 1.5 - 2.5 mg;

or

- imatinib mesylate, 450-500 mg (in the most preferred embodiment, 478 mg, which corresponds to 400 mg of the imatinib);

- hyprolose nitrosamino - 480-560 mg;

- povidone - 1.0 to 4.0 mg;

- carboximetilkrahmal sodium - 150-185 mg;

- colloidal silicon dioxide - 12-20 mg;

- magnesium stearate - 6-10 mg

In the framework of the present invention also sought protection for a method of obtaining tablets of imatinib or its pharmaceutically acceptable salt according to which:

(i) crushed on escu of imatinib or its pharmaceutically acceptable salt (preferably, of imatinib nelfinavir, α-crystalline form);

(ii) sieved sample hydroxypropylcellulose nitrosamines and colloidal silicon dioxide through a sieve;

(iii) preparing an aqueous solution of the binder (povidone);

(iv) mixing the sieved sample of imatinib (or pharmaceutically acceptable salt of imatinib), hydroxypropylcellulose nitrosamines and colloidal silicon dioxide (disintegrant) in the fluidized bed granulator;

(v) moisten the mixture with an aqueous solution of the binder (povidone), obtained in step (iii);

(vi) dry the wet granules in the fluidized bed;

(vii) mixed dried in step (vi) of the granulate with hypromellose and carboximetilkrahmala sodium;

(viii) optivault the mixture of colloidal silicon dioxide and magnesium stearate;

(ix) pressed granules on teletrauma machine, obtaining tablets-cores;

(x) cause the coating on the tablet core.

States in the framework of the present invention is a method of obtaining capsules imatinib or its pharmaceutically acceptable salt according to which:

(i) crushed a portion of imatinib or its pharmaceutically acceptable salt (preferably, imatinib nelfinavir, α-crystalline form);

(ii) sieved sample hydroxypropylcellulose nitrosamines and colloidal silicon dioxide through a sieve;

(iii) preparing an aqueous solution of the binder (povidone);

(iv) mixing the sieved sample of imatinib (or pharmaceutically acceptable salt of imatinib), hydroxypropylcellulose nitrosamines and colloidal silicon dioxide (disintegrant) in the fluidized bed granulator;

(v) moisten the mixture with an aqueous solution of the binder (povidone), obtained in step (iii);

(vi) dry the wet granules in the fluidized bed;

(vii) mixed dried in step (vi) of the granulate with hypromellose and carboximetilkrahmala sodium;

(viii) optivault the mixture of colloidal silicon dioxide and magnesium stearate;

(ix) fill the mixture gelatin capsules.

Another object of the present invention is a method of treating a patient suffering from a disease selected from the first detected positive for the Philadelphia chromosome (Ph+) chronic myeloid leukemia (children and adults),

Ph+chronic myeloid leukemia in chronic phase (after failure of previous therapy with interferon α), or in the acceleration phase, in phase or in blast crisis (children and adults),

newly diagnosed positive for the Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) in adults,

recurrent or refractory (Ph+) acute lymphoblastic LEU is oz in adult patients,

myelodysplastic/myeloproliferative diseases,

associated with genetic rearrangements of the receptor of the platelet growth factor (adult patients),

hypereosinophilic syndrome and/or chronic eosinophilic leukemia in adults with positive or negative abnormal FIP1L1-PDGRF α-receptor,

unresectable, recurrent and/or metastatic wybuchowa dermatofibrosarcoma (in adult patients),

where the specified method of treatment includes the introduction in need of such treatment to the patient a therapeutically effective amount of the pharmaceutical composition in accordance with the invention.

The inventive object-level "method of treatment", in our opinion, is determined, first of all, the possibility of creating a high concentration of active substances in biological environments of the patient in a short period of time after administration of the pharmaceutical compositions in accordance with the invention;

indications for use of the pharmaceutical compositions according to the invention correspond to the indications of the drug Gleevec®Novartis AG (CH)) [25].

Below are examples of the preparation of tablets of imatinib in accordance with the invention, and the results of research their dissolution profile in an environment that simulates gastric juice of man,1 N. HCl).

These examples are provided merely to illustrate the present invention and not to limit the scope of the claims.

Example 1. The reception of tablets imatinib nelfinavir in accordance with the invention.

Formulation of tablets of the present invention (for doses of imatinib 50 mg, 100 mg and 400 mg) are presented in Table 1. All compounds as the active agent used imatinib mesilate (α-crystalline form).

Table 1.
Formulation of tablets of imatinib nelfinavir in accordance with the invention

The sample is pre-crushed and sifted a-crystalline form of imatinib nelfinavir (59,75 g, 119,5 g or 478,00 g, which corresponds 50,00 g 100,00 g or, respectively, 400,00 g base imatinib), pre -

Componentdata I (50 mg)Dose II (100 mg)Dose III (400 mg)Kernel:Active substance - imatinib mesilate (in terms of the basis), mg,75 mg (50 mg)119,5 mg (100 mg)478,00 mg (400 mg)Hyprolose (hydroxypropyl cellulose) nizkozameshhennoj, mg (Eur. Pharm.1, USP2)65,19 mg,38 mg,52 showicon (Eur. Pharm., USP)0,285 mg,57 mg,28 carboxymethyl sodium (Eur. Pharm., USP)21,055 mg,11 mg,44 mgcini the dioxide colloidal (Eur. Pharm., USP)1,99 mg,98 mg,92 mgagne stearate (Eur. Pharm.,1,035 mg,07 mg,28 USP)Shell:a Mixture for coating of tablets based on hypromellose,2 mg,4 mg, 64 mg1European Pharmacopoeia
2Pharmacopoeia of the United States of America, United States Pharmacopeia

sifted nitrosamines hydroxypropylcellulose (respectively, 52,45 g, 104,91 g or 419,64 g), and colloidal silicon dioxide (Aerosil®, 0,99 g, 2.0 g or 8.0 g, respectively) are mixed in a fluidized bed granulator;

a portion of Plasdone povidone®K (respectively, 0,285 g, 0,57 g or 2.28 g) is dissolved in water, getting a 0.5% aqueous binder solution;

the mixture in the fluidized bed granulator hydrate binder;

then the obtained wet granules are dried in the installation of fluidized bed up until the residual moisture in the granules will not exceed 3%;

another part nitrosamines hydroxypropylcellulose (respectively, 12,74 g, 25,47 g or 101,88 g), together with carboximetilkrahmala sodium (respectively, the number of 1,035 g 2,07 g or of 8.28 g), sieved through a sieve, mix for 10 minutes with the obtained dry granulate, optivault of magnesium stearate and part II of silicon dioxide colloidal (respectively, the number 0,99 g, 1.98 g or a 7.92 g) for 3 mine is;

the resulting mixture using a press tool on tabletirujut press get tablets kernel.

From each sample mixture for tabletting get 1000 tablets-cores, weight 149,305 mg, 298,61 mg or 1194,44 mg, containing, respectively, 59,75 mg, 119,5 mg or 478,00 mg of imatinib nelfinavir (α-crystalline form), which corresponds to 50 mg, 100 mg and 400 mg of the imatinib.

The obtained tablet cover film cover installation for coating drum - couture; private embodiment of the invention, the shell can be made of commercially available coating mixtures on the basis of hypromellose (Opadry®and others).

Example 2. The dissolution profile of the tablets of imatinib nelfinavir in accordance with the invention.

Using described in Example 1 way, got the compositions of the tablets in accordance with the invention, containing 119,5 mg and 478 mg of imatinib nelfinavir (α-crystalline form).

The dissolution profile of these tablets was investigated in accordance with the General pharmacopoeial article (CFC) 42-0003-04 Dissolve, using apparatus Paddle stirrer, at room temperature dissolution +37,0±0.5°C and at a speed of rotation of the blades of the stirrer at 50 rpm

As the environment dissolution used 1000 ml of 0.1 G. of hydrochloric acid (environment, simulating gastric juice h the inhabitants); as the comparison drug used drug Gleevec®company "NOVARTIS AG", film-coated tablets (doses of 100 and 400 mg, respectively).

For each dosage of imatinib nelfinavir (100 mg and 400 mg, calculated on the basis of imatinib) investigated 3 tablets (No. 1-No. 3) from different batches of product.

In the beginning of the experiment (0 min)and after 5, 10, 15, 20, 30, and 45 minutes after the start of the process of dissolution of a tablet, a sample was taken of the solution was filtered through a membrane filter, discard the first portion of the filtrate was determined (HPLC) percent released into the environment Foundation of imatinib.

The results of the study are presented in Tables 2-3 and Figures 1-4 (in coordinates: % freed of imatinib - time (min))

Table 2
Release (%) of imatinib from drug Gleevec®(film-coated tablets, NOVARTIS AG (CH))
The time from the beginning of the dissolution of tablets, minGleevec 100 mg, No. 1Gleevec 100 mg, No. 2Gleevec 100 mg, No. 3Gleevec 400 mg, No. 1Gleevec 400 mg, No. 2 Gleevec 400 mg, No. 3
0000000
557,4240,4755,8270,1571,2277,40
1090,7989,9490,03to 90.1194,5194,52
1589,5388,4587,8691,8696,5793,84
2090,6291,2692,3493,9895,0796,42
30of 91.4492,77repossessed a 93.4496,47than 94.699,58
4592,9193,2092,5095,7093,68for 98.00

Table 3
Release (%) of imatinib from a solid dosage form in accordance with the invention (tablets imatinib nelfinavir, coated, CJSC Biocad)
The time from the beginning of the dissolution of tablets, minImatinib (Biocad) 100 mg, No. 1Imatinib (Biocad) 100 mg, No. 2Imatinib (Biocad) 100 mg, No. 3Imatinib (Biocad) 400 mg, No. 1Imatinib (Biocad) 400 mg, No. 2Imatinib (Biocad) 400 mg, No. 3
0000000
562,2066,8071,8056,9157,78 61,91
1076,4078,9082,2174,6779,3382,12
1584,1085,3085,7081,7785,2182,06
2088,7087,5086,8089,8791,5087,01
3090,8089,2193,6995,3992,5890,25
4591,6093,9090,2897,4596,8195,43

The experimental data clearly show that in the framework of the present invention has managed to create a solid dosage form of imatinib or its pharmaceutically acceptable salt (preferably, is of imatinib nelfinavir, more preferably, the α-crystalline form of imatinib nelfinavir)having a dissolution profile that is close to the original drug imatinib (Gleevec®), and is capable ingested quickly (within 15 minutes) to release at least 80% of the active substances, ensuring the creation of high concentrations of imatinib in biological environments of the patient's body.

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Sergeev Gleb Borisovich (RU), published 27.08.2009.

14. International PCT publication WO 2004/106326 A1 "NOVEL POLYMORPHS OF I MATIN IB MESYLATE)), the applicant HETERO DRUGS LIMITED [IN]the inventors PARTHASARADHI REDDY BANDI [IN]; RATHNAKAR REDDY KURA [IN]; RAJI REDDY RAPOLU [IN]; MURALIDHARA REDDY DASARI [IN]; SUB ASH CHANDER REDDY KESIREDDY [IN], op is blikovano 09.12.2004.

15. International PCT publication WO 2005/077933 Al "NOVEL POLYMORPHIC FORM OF I MATIN I, MESYLATE AND A PROCESS FOR ITS PREPARATION)), the applicant NATCO PHARMA LTD [IN]the inventors AMALA KOMPELLA [IN]; SRINIVASA RAO THUNGATHURTHI [IN]; ADIBHATLA KALI SATYA BHUJANGA [IN]; RACHAKONDA SREENIVAS [IN]; VENKAIAH CHOWDARY NANNAPANENI [IN]; PODILI KHADGAPATHI [IN]published 25.08.2005.

16. Published patent application US US 2005/0234069 Al "Novel polymorphs of imatinib mesylate)), the applicant HETERO DRUGS LIMITED [IN]the inventors PARTHASARADHI REDDY [IN]; RATHNAKAR REDDY [IN]; RAJI REDDY R [IN]; MURALIDHARA REDDY D [IN]; SUB ASH CHANDER REDDY [IN]published 20.10.2005.

17. International PCT publication WO 2006/048890 A1 "IMTINIB MESYLATE CRYSTAL FORM AND PROCESS FOR PREPARATION THEREOF*the applicant SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN]the inventors PATEL HETALKUMAR VIRENDRABHAI [IN]; RAJA JANI JYOTIR [IN]; THENNATI RAJAMANNAR [IN]published 11.05.2006.

18. Published patent application US US 2006/0223816 A1 "Imatinib mesylate alpha form and production process therefore)), the applicant CHEMAGIS LTD [IL], the authors of the invention ADIN ITAI [EL]; IUSTAIN CARMEN [IL]; GUY DAVIDI [IL]; WEISMAN ALEX [IL]; BENTOLILA MOSHE [IL]; MEYER ELAZAR [IL]; KASPI, JOSEPH [IL], published 05.10.2006.

19. International PCT publication WO 2006/054314 A1 ((POLYMORPHIC FORMS OF I MATIN I, MESYLATE)), the applicant NATCO PHARMA LIMITED [IN]the inventors KOMPELLA AMALA KISHAN [IN]; ADIBHATLA KALI SATYA BHUJANGA [IN]; PODILI KHADGAPATHI [IN]; VENKAIAH CHOWDARY NANNAPANENI [IN]published 26.05.2006.

20. International PCT publication WO 2007/023182 A1 ((DELTA AND EPSILON CRYSTAL FORMS OF I MAT IN I, MESYLATE)), applicants NOVARTIS AG [CH]; NOVARTIS PHARMA GMBH [AT]inventor MICHAEL MUTZ [DE], published 01.03.2007.

21. International PCT publication WO 2007/05996 A1 ((F, G, H, I AND TO CRYSTAL FORMS OF I MATIN I, MESYLATE)), applicants NOVARTIS AG [CH]; NOVARTIS PHARMA GMBH [AT]inventor MICHAEL MUTZ [DE], published 31.05.2007.

22. Published patent application US US 2007/0197545 A1 ((Crystalline Polymorphs Of Methanesulfonic Acid Addition Salts Of Imatinib, the applicant INSTYTUT FARMACEUTYCZNY [PL], the authors of the invention SZCZEPEK WOJCIECH [PL]; SAMSON-LAZINSKA DOROTA [PL]; ZAGRODZKI BOGDAN [PL]; GLICE MAGDALENA [PL]; MARUSZAK WIOLETA [PL]; KORCZAK KATARYZNA [PL]; MODZELEWSKI RYSZARD [PL]; LAWECKA MARTA [PL]; LUKASZ KACZMAREK [PL]; SZELEJEWSKI WIESLAW [PL]; FRACZEK URSZULA [PL]; CMOCH PIOTR [PL], published 23.08.2007.

23. Patent RU 2404775 C2 PHARMACEUTICAL COMPOSITIONS CONTAINING IMATINIB AND RETARDER RELEASE", the patentee NOVARTIS AG (CH), the inventors ASANTEWAA Madhav (US), LAXMAN Jay Parthiban (US), TONE Waiting (US), SERAJUDDIN Abu T.M. (US), published 27.11.2010.

24. Patent RU 2363450 C2 "TABLET WITH a HIGH CONTENT of the DRUG, the patent holder NOVARTIS AG (CH), the inventors of RUTTENSTEIN Christian-Peter (DE), BIANCHI Jean-Claude (FR), EGORKA ierg (DE), KALB Oscar (DE), published 10.08.2009.

25. Instruction for medical use of the drug GLEEVEC®(GLIVEC®) (imatinib: film-coated tablets; capsules), NOVARTIS (AG): (available on the Internet on 21.08.2012).

1. Pharmaceutical composition containing as an active substance of imatinib mesilate in the amount of 25-45 wt.% (calculated as base) and an excipient, contains Asia in povidone as a binder in an amount of 0.1 to 1.0 wt.%, and as leavening agents 35-50 wt.% nitrosamines hydroxypropylcellulose (hyprolose) and 10-20 wt.% PA-carboxymethyl amylum.

2. The pharmaceutical composition according to claim 1, characterized in that of imatinib mesilate is in the α-crystalline form.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that it further comprises a slip agent (glidant), which is a colloidal silica in the amount of 0.5-5.0 wt.%.

4. The pharmaceutical composition according to claim 1 or 2, characterized in that it further comprises a lubricating agent (lubricant)selected from the group comprising stearic acid, magnesium stearate or calcium stearate, in amounts of 0.5-1.0 wt.%.

5. The pharmaceutical composition according to claim 1, characterized in that it is made in tablet form.

6. The pharmaceutical composition according to claim 5, characterized in that it further coated.

7. The pharmaceutical composition according to claim 6, characterized in that the shell is a film coating on the basis of hypromellose.

8. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of a capsule.

9. The pharmaceutical composition according to claim 1, characterized in that it releases at least 80% of the active substance within 15 minutes on the results of the analysis methodology (CFC) 42-0003-04 Dissolve using the apparatus of the Lobed mixer" (when the rotation speed of paddle stirrer at 50 rpm in 1000 ml of 0.1 N. hydrochloric acid and at a temperature of dissolution +37,0±0.5°C).

10. Pharmaceutical composition containing imatinib mesilate, characterized in that it is made in the form of a tablet comprising a core and a cover shell, where this tablet contains:
25-45 wt.% of imatinib nelfinavir (calculated as base),
35-50 wt.% nitrosamines hydroxypropylcellulose (hyprolose),
10-20 wt.% Na-carboxymethyl amylum,
0.5 to 5.0 wt.% colloidal silicon dioxide,
0.5 to 1.0 wt.% magnesium stearate, calcium stearate or stearic acid.

11. The pharmaceutical composition of claim 10, wherein the imatinib mesilate is in the α-crystalline form.

12. The pharmaceutical composition of claim 10 or 11, characterized in that it is obtained by the method, according to which:
(i) crushed a portion of imatinib nelfinavir,
(ii) sieved sample hydroxypropylcellulose nitrosamines and colloidal silicon dioxide through a sieve,
(iii) preparing an aqueous solution of povidone,
(iv) mixing the sieved sample of imatinib nelfinavir, hydroxypropylcellulose nitrosamines and colloidal silicon dioxide in a fluidized bed granulator,
(v) moisten the mixture with an aqueous solution of povidone obtained in step (iii),
(vi) dry the wet granules in the fluidized bed,
(vii) mixed dried in step (vi) of the edge of the Yat with hypromellose and carboximetilkrahmala sodium
(viii) optivault the mixture of colloidal silicon dioxide and magnesium stearate,
(ix) pressed granules on teletrauma machine, obtaining tablets-cores
(x) cause the coating on the tablet core.

13. Pharmaceutical composition containing imatinib mesilate, characterized in that it is made in the form of a capsule, where the specified capsule contains:
25-45 wt.% of imatinib nelfinavir (calculated as base),
35-50 wt.% nitrosamines hydroxypropylcellulose (hyprolose),
10-20 wt.% Na-carboxymethyl amylum,
0.5 to 5.0 wt.% colloidal silicon dioxide,
0.5 to 1.0 wt.% magnesium stearate, calcium stearate or stearic acid.

14. The pharmaceutical composition according to item 13, characterized in that it is obtained by the method, according to which:
(i) crushed a portion of imatinib nelfinavir,
(ii) sieved sample hydroxypropylcellulose nitrosamines and colloidal silicon dioxide through a sieve,
(iii) preparing an aqueous solution of povidone,
(iv) mixing the sieved sample of imatinib nelfinavir, hydroxypropylcellulose nitrosamines and colloidal silicon dioxide in a fluidized bed granulator,
(v) moisten the mixture with an aqueous solution of povidone obtained in step (iii),
(vi) dry the wet granules in the fluidized bed,
(vii) mixed dried in step (vi) of the granulate with hypromellose and carboxy what milkroom sodium
(viii) optivault the mixture of colloidal silicon dioxide and magnesium stearate,
(ix) fill the mixture gelatin capsules.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described are novel pyrazine triazinone derivatives of general formula wherein Ra represents C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkinyl; Rb represents phenyl, substituted with acyl, alkoxy, hydroxyl, nitro, NH2, thioalkyl group or -C(=O)Re, where Re is C1-C6 alkyl, or group -C(=O)Re, where Re represents C1-C6 alkyl or cyclopropyl and Rp represents -H, -PO3H2, -HPO3-Na+, -PO32-Na2+, pharmaceutical composition, containing thereof, and method of treating acute myeloleukosis.

EFFECT: novel compounds represent reverse turn mimetics and can be applied in medicine.

9 cl, 1 dwg, 3 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to using a purine derivatives for preparing drug preparations for treating chronic lymphocytic leukaemia and polycystic kidneys.

EFFECT: invention provides preparing the compounds possessing higher activity on lymphocytic leukaemia and polycystic kidneys.

8 cl, 3 dwg, 1 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new alkylthiopyrimidines of formula III or pharmaceutically acceptable salts thereof: In the compound III X represents a direct bond; R2 means hydrogen, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, -NR8aR8b or the group -SR3; each R3 independently represents (C1-C6)alkyl, optionally mono-, di- or trisubstituted by halogen; or (C3-C7)cycloalkyl; R4a and R4b represent hydrogen; R6 represents aryl; or heteroaryl; wherein aryl and heteroaryl are optionally substituted in a substituted position by one or more substitutes specified in a group consisting of (a) halogen; (b) cyano; (c) nitro; (a) hydroxy; (e) guanidino; (f) heteroaryl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy (k) -NR8aR8b; (1) -C(O)R9; (m)-C(O)NR8aR8b, (n) - OC(O)NR8aR8b; (o) -C(O)OR9; (p) -NR7C(O)0R9; (q) -NR7C(O)R9; (r) sulphamoyl; (s) (C1-C6) alkylsulphonyl; (t) (C1-C6)alkylaminosulphonyl; (i) di(C1-C6)alkylaminosulphonyl; (v) (C1-C6)alkyl, optionally mono-, di- or trisubstituted by halogen; (w) (C1-C6) alkoxy, optionally mono-, di- or trisubstituted by halogen; and (x)(C1-C6)alkylthio, optionally mono-, di- or trisubstituted by halogen R7 represents hydrogen. The other radical values are specified in the patent claim.

EFFECT: compounds possess CRTH2 (G-protein related chemoattractant receptor expressed on Th2 cells) antagonist activity and are applicable for treating and preventing the diseases related to CRTH2, including treating allergic diseases, eosinophil and basophile related diseases.

14 cl, 6 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is disclosed is a pharmaceutical formulation containing an active agent stabilising an amorphous form of imatinib mesylate, and amorphous imatinib mesylate. The active agent is selected from solid dispersions, and dry co-milling products with excipients. The solid dispersion contains an additional excipient selected from cellulose derivatives, polyvinylpyrrolidone, polyethylene glycols of various molecular weight, polyethylene/polypropylene/polyethylene oxide block copolymers, and polymethacrylates. The excipients for dry co-milling selected from polyvinylpyrrolidone, cellulose derivatives, alkaline earth silicates, and silicon dioxide.

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3 cl, 4 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology and hematology, and may be used in treating the patients with refractory and recurrent clinical course of Hodgkin's lymphoma. For this purpose, 24 hours before the leucopheresis procedure, a granulocyte colony-stimulating factor is administered to the patient. That is followed by the leucopheresis procedure with using MCS "Haemonetics" blood separator, and the prepared leukapack is divided on 4 portions. The leukapack portions are collected in sterile containers and incubated for 180 minutes at temperature 37°C: portions 1 and 3 with recombinant interleukin-2 5 thousand IU/ml, portions 2 and 4 with interferon-α-2b 10 thousand IU/ml. That is followed by the intravenous, drop-by-drop reinfusions of the leukapack before a course of the polychemotherapy: portions 1 and 2 on the day of the leucopheresis procedure, portions 3 and 4 of the laukapack are kept in a fridge at temperature 0 to 8°C for 24 hours and then incubated with immune preparations in the specified mode and administered to the patient. After the course of the polychemotherapy has been completed, the leucopheresis procedure is conducted again. The above therapy is prescribed for cycles 4 and 6 of the polychemotherapy used for refractory Hodgkin lymphoma and for cycles 2 and 4 cycles of the polychemotherapy used for recurrent Hodgkin's lymphoma, regardless of a response to therapy.

EFFECT: method enables the effective therapy of the given pathology ensured by activation of the proper anti-tumour response.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and may be used for treating Philadelphia chromosome positive leukaemia (Ph+ leukaemia). A method of treating chronic myeloid leukaemia (CML) or Philadelphia chromosome positive acute lymphoblast leukaemia (Ph+ALL) in a group of human patients involves the stages as follows: (a) introducing the pre-determined fixed amount of imanitib or a pharmaceutically acceptable salt thereof in human patients in need thereof, (b) selecting at least one blood sample in the specified patients for at least first three months of the therapy, (c) determining minimal plasma imanitib (Cmin), and (d) specifying a dose of imanitib or the pharmaceutically acceptable salt thereof so that Cmin falling within the range of 1000 ng/ml and 3000 ng/ml is achieved in each patient wherein threshold Cmin 1000 ng/ml has not been achieved before specifying the dose. The group of inventions also involves the use of imanitib or the pharmaceutically acceptable salt thereof for preparing a medicine for treating Ph+ leukaemia.

EFFECT: group of inventions enables minimising or avoiding the formation of resistance, loss of effectiveness and a risk of recurrence in human patients suffering CML or Ph+ALL and treated with imanitib or the pharmaceutically acceptable salt thereof.

14 cl, 8 dwg, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: pharmaceutical combination for treating proliferative disease, including a) pyrimidylaminobenzamide of formula A compound and b) kinase Thr315lle inhibitor, representing (3-trifluoromethyl-phenyl)amide 6-(2-aminopyrimidin-4yloxy)naphthalene-1-carboxylic acid, or [6-[[1-[[4-[(4-methyl-1-piperasinyl)methyl]-3-(trifluoromethyl)phenyl-amino]carbonyl]-1H-indol-5-yl]oxy]-4-pyrimidyl]acetamide, N-[3-[[1-[6-(cyclopropylamino)-4-pyrimidinyl]-1H-imidasol-2-yl]amino]-4-methylphenyl]-3-(4-methyl-1H-imidazole-1yl)-5-(trifluoromethyl)benzamide, AP24534 or their combinations in sinergetically effective quantity, method of treatment or prevention of proliferative disease with application of such combination and methods of treating leucosis (versions).

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7 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to novel pyridyloxy derivatives or its pharmaceutically acceptable ester or a pharmaceutically acceptable salt of the mentioned derivatice or ester of general formula (I), wherein R represents a pyridyl group substituted by 1-3 groups independently specified in a group of substitutes A; the group of substitutes A represents a group comprising halogen atom, C1-C6 alkyl group and C1-C6 alkoxy group, and Me represents a methyl group. Also, the invention refers to specific compounds of formula (I), to a pharmaceutical composition and a receptor-γ activator/modulator on the basis of a compound of formula (I), to a method of treating and/or preventing a disease.

EFFECT: there are prepared novel pyridyloxy derivatives effective in treating the disease mediated by peroxisome proliferator activated receptor-γ (PPAR) γ.

37 cl, 2 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel imidazopyridin-2-one derivatives of general formula or pharmacologically acceptable salts thereof, where (R1)n-A is a 1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, 3-fluoro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group or 3-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl group, B is a 3-6-member saturated or partially saturated monocyclic hydrocarbon group and can contain 1 or 2 oxygen atoms, a nitrogen atom and/or sulphonyl groups as ring components, B can have as substitutes identical or different R2 in amount of m, R2 is a substitute represented at a carbon atom or a nitrogen atom forming B, R2 is a substitute selected from a group consisting of a hydroxy group, a halogen atom, a cyano group, an oxo group, a C1-4alkyl group (where the C1-4 alkyl group can be substituted with 1 C1-4 alkoxy group) and a C1-4 alkoxy group, when R2 is a substitute represented at a carbon atom forming B, and R2 is a substitute selected from a group consisting of a C1-4 alkyl group and a C1-4 alkylcarbonyl group, when R2 is a substitute represented at a nitrogen atom forming B, m is any integer from 0 to 2, Q is a bond or a C1-4 alkylene group, R3 and R4 are identical or different and each denotes a hydrogen atom or a halogen atom, and R5 and R6 are identical or different and each denotes a hydrogen atom, a halogen atom or a C1-4 alkyl group. The invention also relates to specific compounds of formula (I), pharmacologically acceptable salts of compounds of formula (I), a pharmaceutical composition based on the compound of formula (I) and use of the compound of formula (I).

EFFECT: novel imidazopyridin-2-one derivatives, having mTOR inhibiting action, are obtained.

21 cl, 161 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to production of sterol derivatives, and can be used in producing 4-hydroxy-17R-methylincisterol from ergosterol by photoisomeration. When carrying out the method, a weighed portion of ergosterol is dissolved in a weakly polar solvent while illuminating the solution with optical radiation in the near UV range. The obtained solution is chromatographically separated. The fraction which is cytotoxic for HeLa line of cancer cells and human myeloid leukaemia cells is sorbed. The pH is raised to neutral value and the solution is evaporated until a milky appearance is achieved. The weakly polar solvent is added and extracted, and the organic layer is separated on separating funnel. The organic layer is evaporated and dissolved. The obtained solution is separated by analytical HPLC with subsequent purification and separation of incisterol.

EFFECT: invention enables to obtain a 4-hydroxy-17R-methylincisterol preparation by chemical synthesis.

10 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to microcapsulation of cephalosporins related to β-lactam antibiotics. A method for preparing cephalosporin microcapsules is implemented by physicochemical non-solvent addition. That involves using two non-solvents that are carbinol and isopropyl alcohol taken in ratio 1:4. The microcapsule yield makes more than 90%.

EFFECT: method for cephalosporin microcapsules provides accelerating the process for preparing and simplifying the method.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to microcapsulation of drug preparations, vitamins, herbicides, flavouring agents and polysaccharides. The microcapsules are prepared by physical-chemical nonsolvent addition with using benzol as a precipitator.

EFFECT: invention provides simplifying and accelerating the process of preparing the microcapsules, reducing losses in preparing the microcapsules (higher weight yield).

48 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to microcapsulation of drug preparations of cephalosporins referred to β-lactam antibiotics in konjac gum by physical-chemical precipitation in a non-solvent. Konjac gum is used as a microcapsule membrane. The microcapsules are prepared by physical-chemical precipitation in the non-solvent with using two precipitation agents - carbinol and chloroform. The process of microcapsules is carried out at 25°C with no special equipment required.

EFFECT: method according to the invention provides simplifying and accelerating the process of microcapsules of drug preparations of cephalosporins, and reducing losses (higher weight yield).

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to microencapsulation of drugs through the example of rivanol which can be used as an antimicrobial, antifungal topical preparation. A method for preparing microcaplues of rivanol in a water-soluble polymer representing polyvinyl alcohol or polyvinyl pyrrolidone is implemented by physical-chemical precipitation with a solvent wherein a precipitant is acetone. The process is carried out at 25°C with no special equipment required.

EFFECT: method for preparing the microcapsules of rivanol provides simplifying the process of microencapsulation.

13 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical microcapsulation of cephalosporins related to β-lactam antibiotics. As a microcapsule shell, the method of pharmaceutical microcapsulation of cephalosporins uses konjac gum; the microcapsules are prepared by physical-chemical technology implying the precipitation in a non-solvent using two precipitants - carbinol and diethyl ester in ratio 1:3; the method is conducted at 25°C with no special equipment.

EFFECT: invention provides simplified and accelerated preparation of the water-soluble pharmaceutical microcapsules of cephalosporins in konjac gum, loss reduction in preparing the microcapsules (higher yield-mass).

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared group of inventions refers to a pharmacological composition for intranasal introduction for cerebral delivery, and a method for preparing said composition. The declared composition comprises a container base formed by porous particles of calcium carbonate and titanium dioxide of particle size 100-5000 nm and a pharmacologically active component - loperamide. The container surface is modified by surfactants specified in polysorbates, or by polymers specified in a group containing glycosaminoglycanes and polypeptides, or their combination. A method for preparing the pharmacological composition consists in preparing the container base by porous particle synthesis, sorption of loperamide in its pore spaces and modification of the container surface by polymers and surfactants by container incubation in their solutions.

EFFECT: invention provides preparing the pharmacological composition which is applicable for cerebral loperamide delivery after the intranasal introduction.

5 cl, 5 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to composition for peroral introduction, which possesses properties of modified release. According to invention composition includes pharmaceutically acceptable excipients and complex medication-ion-exchanging resin with coating with modified release, which contains pharmaceutically active medication, combined with pharmaceutically acceptable ion-exchanging resin. Complex has solidified barrier coating with high rupture strength, water-permeable, water-insoluble, which contains polyvinyl acetate polymer, stabiliser and efficient amount of plastifier. Said coating is in fact non-sticky, when applied onto complex in absence of anti-adhesive preparation, if composition presents tablet, complex medication-ion-exchanging resin with coating additionally contains release-retarding substance in matrix together with complex medication-ion-exchanging resin. Invention also relates to product with modified release, including package which contains composition described above.

EFFECT: invention ensures regulated prolonged active agent release without breaking coating integrity, without application of water-soluble impregnating substances and without agglomeration of complex particles during application of coating.

27 cl, 22 ex

FIELD: medicine.

SUBSTANCE: there are described oral dosage forms of risedronate containing safe and effective amount of a pharmaceutical composition containing risedronate, a chelating agent and an agent for effective delayed release of risedronate and the chelating agent in small intestine. The pharmaceutical composition is directly released in a small intestine of a mammal with ensuring pharmaceutically effective absorption of bisphosphonate together with or without food or drinks. Present invention essentially reduces interaction between risedronate and food or drinks which leads to that the active component of bisphosphonate becomes inaccessible to absorption. Thus, the final oral dosage form can be taken with and without food. Further, present invention covers delivery of risedronate and the chelating agent in a small intestine, essentially reducing irritation of upper gastrointestinal tract associated with bisphosphonate therapy. These advantages simplify previous, complicated regimens and can lead to more complete observance of the bisphosphonate therapy regimen.

EFFECT: present invention essentially reduces interaction between risedronate and food or drinks which leads to that the active component of bisphosphonate becomes inaccessible to absorption.

23 cl, 12 ex

FIELD: medicine.

SUBSTANCE: invention refers to a carrier for drugs, biologically active substances, biological objects used in medicine for diagnostics and treatment in pharmaceutical industry. The carrier represents a material sensitive to external magnetic or electric fields and consisting of magnetic or ferroelectric material filmed with biocompatible thermosensitive, biodegradable polymer and/or dispersed in thermosensitive medium properties of which change with varying temperature relative to that of human body within 15.9 to 42°C. The magnetic or ferroelectric materials are made of substance with great magnetocaloric or electrocaloric component effect 1 to 13 K, have temperature of magnetic or ferroelectric phase transition within temperature range 33 to 37°C, and are chosen from the group including rare-earth, transition and precious metals, their alloys and compounds.

EFFECT: invention also concerns methods of controlled drug delivery by means of such carrier with enabling release thereof (regulated desorption) in the preset point.

32 cl, 9 ex

FIELD: medicine; pharmacology.

SUBSTANCE: minitablets have a kernel and an external cover which makes 2-15% of gross weight of minitablets, the kernel of the specified minitablets, includes a venlafaxine hydrochloride, microcrystallic cellulose and a polyvinylpyrolidone, and the specified cover includes polymer, insoluble in water, and a polymer, soluble in water.

EFFECT: provision of levels of concentration in a blood plasma above the minimum therapeutic concentration during the long period of time.

10 cl, 1 dwg, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and describes a solid pharmaceutical composition applicable for oral administration and containing: S1P receptor modulator which represents 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol in the free form or in the form of a pharmaceutically acceptable salt or a phosphate thereof and monocrystalline cellulose in the absence of a sugar alcohol.

EFFECT: invention provides higher storage stability of the composition.

9 cl, 40 ex, 11 tbl

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