Tablet with high drug content

FIELD: medicine.

SUBSTANCE: present invention relates to pharmaceutics and a tablet with high drug content, which contains an active component in form of a formula (I) compound or its pharmaceutically acceptable salt in amount of approximately 30-80 wt % of active component, in total mass of the tablet and at least one binding substance, which contains microcrystalline cellulose or hydroxypropylmethicellulose.

EFFECT: design of a tablet with high drug content.

16 cl, 1 dwg, 3 ex

 

The invention relates to pharmaceutical tablets containing 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2-ylamino)phenyl]benzamide, or its pharmaceutically acceptable salt, which is further referred to as compound I.

Compound I has the formula (I)

Compound I in the form of a free base and its acceptable salts are disclosed in European Patent application 0564409. Mesilate compounds I and alpha - and beta-crystalline form of nelfinavir compounds I are disclosed in international patent application WO 99/03854.

Appointed in the treatment of leukemia daily dosing of nelfinavir compounds I are generally high, for example, 400-800 mg for adults. Thus, there is a need for oral dosage form that is convenient for the introduction and provides the amount of compound I, is equal to the daily dosage.

Accordingly, the present invention provides tablets with high content drug, which include pharmacologically effective amount of compound I or its pharmaceutically acceptable salt, present in the amount from about 30% to 80%, for example at least about 35, 40, 45, 50 or 55% to 60, 65, 70, 75 or 80%, preferably more than 55%. In particular, the number of connections I can vary from 45 is about 80%, for example, from 50 to 70 wt.% calculated on the total weight of the tablet.

Compound I may be in the form of a free base or its pharmaceutically acceptable salts, for example, in the form of monomethylated. Active component corresponds to the compound I in free base form. For example, 119,5 mg mesilate salt of compound I is equivalent to 100 mg of the active component - free base of compound I.

In addition, the present invention provides a tablet comprising

(a) a pharmacologically effective amount of compound I and

(b) at least one pharmaceutically acceptable excipient suitable for receiving tablets, in which the amount of compound I or its pharmaceutically acceptable salts, expressed as a percentage (by weight) of the active component in the calculation of the whole tablet is from about 30% to 80%, for example at least about 35, 40, 45, 50 or 55% to 60, 65, 70, 75 or 80%, preferably more than 55%. In particular, the number of connections I can vary from 45 to 80%, for example, from 50 to 70 wt.% the active component in the calculation of the total mass of the tablet.

In another design of the invention provides a tablet, in which compound I is in crystalline form.

Additional purpose of the invention is applied monomethylamine Sol is connected to the I I.

In a preferred embodiment of the invention monomethylamine salt of compound I is in crystalline form, for example, alpha - or beta-crystalline form, the most preferred is monomethylamine salt of compound I in the beta crystalline form.

Tablets may contain one or more pharmaceutically acceptable excipients, such as those traditionally used, for example, (1.1) at least one binder material, for example, microcrystalline cellulose, hypromellose, (1.2) at least one agent that causes disintegration, for example, crosslinked polyvinylpyrrolidone, for example Crospovidone®, (1.3) at least one agent for slide, for example, colloidal silicon dioxide, (1.4) at least one lubricant, e.g. magnesium stearate and/or (1.5) basic the coating. In the tablet according to the present invention, the microcrystalline cellulose is used as a binder material.

In the literature there are many references relating to these and other fillers to such methods, see, for example, Handbook of Pharmaceutical Excipients Handbook of pharmaceutical excipients, 3rd edition), Third Edition, p/edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende Gebiete edited by H.P. Fiedler, 4t Edition, Edito Cantor, Aulendorf and earlier editions, which are included in this invention as references.

Binder materials (1.1) include, but are not limited to, starches, such as potato, wheat or corn starch; microcrystalline cellulose, for example, products such as Avicel®, Filtrak®, Heweten® or Pharmacel®; hydroxypropylcellulose; hydroxyethyl cellulose; hypromellose, for example, hypromellose Type 2910 USP, hypromellose, and polyvinylpyrrolidone (PVP), for example, Povidone® K30 from BASF. Preferably, applied hypromellose Type 2910 USP.

Suitable agents that cause the disintegration of (1.2), according to the invention include, but are not limited to, corn starch; Ca carboxymethylcellulose (CMC)-; Na-CMC; microcrystalline cellulose; crosslinked PVP, for example, are known and commercially available under the trade names Crospovidone®, Polyplasdone®, marketed by the company ISP, or Kollidon® XL; alginic resin; sodium alginate and guar gum. Preferably, applied crosslinked PVP, for example, Crospovidone®.

As agent for slide (1.3) can be used one or more of the following substances: silica; colloidal silicon dioxide, for example, anhydrous colloidal silicon dioxide, for example, Aerosil® 200, magnesium trisilicate, powdered cellulose, starch and talc. Pre is respectfully, use anhydrous colloidal silica and/or colloidal silicon dioxide.

As a lubricant (1.4) can be used one or more of the following substances: stearate Mg, Al or Ca, PEG 4000-8000 and/or talc. Preferably, apply magnesium stearate.

One or more of these fillers may be selected and used with specific desirable properties of tablets the usual experimental method.

According to the present invention, the amount of binder (1.1) can vary in the range from approximately 1 to 40%, preferably from 1 to 30%, especially from 1 to 25 wt.% calculated on the total weight of the tablet.

The amount of agent that causes the disintegration of (1.2)may vary in the range from 5 to 40%, for example from 10 to 35 wt.% calculated on the total weight of the tablet.

The number of agent for slide (1.3) can vary in the range from 0.1 to 10%, especially from 0.1 to 5%, for example from 0.5 to 3 wt.% calculated on the total weight of the tablet or from 2 to 4 wt.%calculated on the total weight of the tablet.

The amount of lubricant (1.4) can vary in the range from 0.1 to 5%, for example from 0.5 to 2 wt.%calculated on the total weight of the tablet.

The number of primary coating (1.5) can vary from 1 to 10%, preferably from 1.5 to 5 wt.%calculated on the total weight of the tablet.

You acknowledge that any libraryinformation can perform several functions, for example, the agent that causes disintegration, binder agent for slide, and/or a lubricant.

In a preferred design of the invention, the tablet includes the following fillers, one or more binders in a total amount from about 1% to 25 wt.% calculated on the total weight of the tablet, one or more agents that cause disintegration in the total number of from about 10% to 35 wt.%calculated on the total weight of the tablet, one or more agents to slip in a total amount from about 0.5% to 3 wt.% calculated on the total weight of the tablet, and/or one or more lubricants in a total amount from about 0.5% to 2 wt.%calculated on the total weight of the tablet.

The absolute amount of each filler and quantity in relation to other fillers similarly depends on the desired properties of the tablet and can also be selected conventional experimental method. For example, tablets can be chosen in such a way that they showed accelerated and/or delayed release of the compound I with the quantitative control the selection of the active substance, or without control. Preferably, the tablet is chosen so that it provides instant selection of compound I, for example, in the form of monomethylamine salt of beta-crystalline Faure is s connection I.

The authors present invention has faced challenges in obtaining tablets of compound I, due to the high brittleness and low strength, wear. In addition, flexibility on the number of fillers, such as agents that cause disintegration is limited due to the high content of drug in the product. Thus, there is still a need in the industrial acceptable dosage forms of compound I for oral destination the patient with sufficient ease of administration.

According to the present invention it has been unexpectedly discovered that we have a stable and pharmaceutically acceptable tablets containing compound I. the Authors of the present invention found that pharmaceutically acceptable solid oral dosage forms as tablets, which are particularly easy to receive and are stable, can be obtained using the methods of tablet pressing. More specifically, the tablets of the invention can be obtained by granulation, preferably wet granulation, followed by means of pressing. Particles of the compounds I, particularly his mesilate salt, have large dimensions, for example, 60% of the particles of source material connection I have a size greater or equal to 100 μm, for example, 90% of the particles less than or equal to 420 microns. Usually the method of wet granulation is carried out, using particles of the source material smaller than 100 microns.

A distinctive property of the tablets according to the invention is that it has a high content of compound I at a given relatively small amount of filler. It provides tablets are small in size. The total number of fillers in a uniform dosage may be about 70 wt.% or less based on the total weight of the tablet, more specifically, about 50% or less. Preferably, the content of the filler is in the range from approximately 30 to 55%, more particularly from 35 to 50 wt.% calculated on the total weight of the tablet.

Unexpectedly according to the invention is provided by the introduction given a uniform dose of compound I for smaller tablets than it was possible for the tablets of the prior art. Despite the high content drug, tablets according to the invention are small and therefore they are comfortable with the introduction. This leads to improved treatment regimen of the patient.

In another embodiment, this invention provides a tablet containing from 50 mg to 600 mg of compound I, for example, from about 100 mg to 400 mg Most preferably, the tablets according to the invention are tablets containing 100 mg and/or 400 mg of compound I.

Accordingly, the present invention provides a tablet containing mesilate of compound I, for example, alpha-crystalline form nelfinavir compounds I and/or beta-crystalline form nelfinavir compound I in an amount equal to 100 mg and/or 400 mg of free base of compound I. the Most preferred form nelfinavir connection I used for tablets according to the invention, is a beta-crystalline form.

According to the invention, a method of producing tablets consists in forming the internal phase, mixing this phase together with the external phase, pressing the mixture and, optionally, the coating of the tablets.

The internal phase comprises a compound I. Preferably, the internal phase contains a compound I and one or more fillers, more preferably one or more binders, and most preferably the amount of one or more binders in the internal phase is in the range from about 1 to 30%, preferably from 1 to 20% and more preferably from 1 to 15%. Preferably, the binder materials of the internal phase according to the invention are microcrystalline cellulose and hypromellose. The amount of microcrystalline cellulose in the internal phase may vary priblizitelen is from 10 to 29%, in particular from 12 to 14 wt.%calculated on the total weight of the tablet. The number of hydroxypropylmethylcellulose in the internal phase can vary from 1 to 5%, preferably, from 1 to 2 wt.% calculated on the total weight of the tablet. Compound I and pharmaceutically acceptable excipients internal phase are mixed together with water, and the mixture process for granulating, for example, using a wet granulator with a high degree of shear and getting wet granules. Then wet the granules can be dried, for example, in the drying device with a fluid layer of granules.

The present invention relates to a method for producing tablets containing the external phase. The external phase is a mixture of internal phase with one or more fillers. The internal phase and one or more fillers external phase are mixed together, for example, by using a diffusion mixer. It is preferable to add one or more binder materials. It is most preferable type microcrystalline cellulose. Even more preferably microcrystalline cellulose is added in an amount of from 1% to 10 wt.%calculated on the total weight of the tablet. In a preferred embodiment of the invention, the amount of microcrystalline cellulose in the external phase comprises about 5 wt.% calculated on the total weight of the tablet. Also, external phase according to the invention may contain one or more agents that cause disintegration, most preferably Crospovidone®. In a preferred embodiment, the amount of agent that causes disintegration, in the external phase varies from about 10 to 30%, preferably from 12 to 25%, most preferably about 15%.

In particular concept of the invention in the external phase is entered one or more agents to slip.

According to the invention in the external phase is entered, one or more lubricants.

Additional purpose of the invention, tablets are obtained by pressing a mixture of internal and external phases, using, for example, press for tableting.

The tablets may be optionally coated, preferably as described in the following.

In one embodiment of the invention, a method of obtaining the pill, which is that:

(a) is the inner phase, which includes

(i) mixing the compound I together with pharmaceutically acceptable excipients,

(ii) wet granulation,

(b) is formed in the external phase, which includes:

(iii) adding additional pharmaceutically acceptable excipients in the internal phase, and mixing;

(C) is formed tablet by

(iv) press the mixture Finance, obtained in stage (iii), and, optionally,

(g) coating.

More specifically, in one aspect of the present invention developed a method lies in the fact that:

(i) mixing the compound I and pharmaceutically acceptable excipients, for example, one or more binders, such as microcrystalline cellulose, intensive mixer shift;

(ii) add water, put the mixture of wetting/mixing, for example, in the intensive mixer shift, sift using a mechanical sieve and a rotating impeller and dried, for example, in the drying device with the fluid layer;

(iii) add pharmaceutically acceptable excipients, for example, sieved fillers, such as one or more agents that cause disruption, for example, Crospovidone®, one or more binders, for example, microcrystalline cellulose, one or more agents for slide, for example, colloidal silicon dioxide, and mixed, for example, in a diffusion mixer;

(iv) add pharmaceutically acceptable excipients, such as one or more lubricants, for example magnesium stearate, sift, for example, manually using sieves, for example, a size of 900 μm, and mixed, for example, in a diffusion mixer;

(v) tabletirujut mixture obtained in the study is (iv), by pressing, for example, in a conventional tablet press, for example, in the device tableting with a Cam EC-0 Korsch or in a rotary device tabletting, preferably in a rotary device, and

(vi) cover, for example, in lubricating the form of, for example, type Glatt, Accela.

The term "core" means the phase of the granular phase (i) and (ii)), including the active drug compound I and an external phase consisting of fillers.

The term "total weight of the tablet" means the mass of the tablet, and with the internal and external phases and coating (if any).

According to the invention a method of coating can be carried out at a low temperature, for example, between 30 and 40°C, preferably between 32 and 39°C, most preferably at a temperature in the range from approximately 35 to 38°C. the Method of coating can be carried out with the degree of dispersion is preferably in the range from 30 to 105 g covering dispersion per 1 kg of cores per hour, preferably from 35 to 105 g/(KGC). Unexpectedly it was found that the swelling agent, causing the disintegration of, for example, Crospovidone®, also does not cause sticking of the core during sputtering to cover the mixture held at a low temperature, as could be expected on the basis of the experience of the expert in this field of technology.

Moreover, tablets are high coloring strength is ü resistance. Physical and chemical stability can be tested in a traditional way, for example, you can test the actual tablets by measuring solubility, fragility, time of destruction, analyzing the decomposition products of the compound I, the appearance and/or microscopy data, for example, after storage at room temperature i.e. 25°C, and/or storage at 40°C.

The core tablet may have various shapes, such as round, oval, rectangular, cylindrical or any other suitable shape. A distinctive property of the tablets according to the invention is their small size with regard to the content of compound I or a salt of compound I in these pills.

In a preferred embodiment of the invention described above, the tablets obtained by the compaction method, are round or oval. The edges of the tablets may have a beveled or rounded edge. Most preferably, the tablets are oval and/or round. Tablets according to the invention may have a groove on the surface. Oval tablet may be small in length, for example, from 10 to 20 mm, preferably, from 15 to 20 mm, most preferably from 17 to 19 mm; 5 to 10 mm, preferably from 6.5 to 8 mm, the thickness of the tablet is from 4 to 8 mm, preferably, from 6 to 8 mm. To obtain the molded tablets with estudia compression force of between 10 and 20 kN, preferably from 12 to 18 kN. Preferably, oval tablet contains 400 mg of compound I. Round tablet may have the following dimensions, for example, from 5 to 15 mm in diameter, preferably from 7 to 10 mm, most preferably about 9 mm, the thickness of the tablets can be from 2 to 5 mm, preferably from 2.5 to 4 mm, To obtain a molded tablets are applied compression force of between 6 and 8 kN, preferably from 8 to 14 kN. Preferably, round tablet contains 100 mg of compound I. Preferably, the tablet weight of 100 mg is a tablet with a notch, most preferably, the tablet has on one side a notch with a gap.

In addition, the tablets of the invention, containing approximately 100 mg of compound I, may have a hardness from about 30 to 140 N, for example, from 40 to 140 N, from 30 to 100 N, from 40 to 100 H, preferably from 50 to 80 N. Tablet of the invention contains approximately 400 mg of compound I, may have a hardness of from about 100 to 270 N, for example, from 100 to 250 N, from 160 to 270 N, from 160 to 250 N, preferably from 195 to 235 N.

The time of the destruction of the tablets may be approximately 20 minutes or less. Preferably, for tablets with 100 mg of compound I, the time of destruction is in the range from approximately 2 to 10 minutes, preferably from 4 to 10 minutes, for example, from 4 to 8 minutes. Prefer the Ino, for tablets with 400 mg of compound I, the time of destruction is in the range from approximately 7 to 15 minutes, preferably from 8 to 15 minutes, for example, from 8 to 14 minutes.

Friability of the tablets was measured according to the method of U.S. Pharmacopeia (USP). The fragility of the tablets according to the invention, investigated the application of recommendations of the United States Pharmacopeia, is 0% (see drawing).

In addition, the tablets of the invention can be dyed, and/or tablets, or the coating can be marked so that they had a different appearance and to make them easily recognizable. The use of dyes can improve the appearance and identification of tablets. Dyes suitable for use in medicinal preparations usually include carotenoids, iron oxides or chlorophyll. Tablets of the invention can be labeled using the printed code.

Methods that can be used can be conventional or known from the prior art, or based on such methods, such as that described in the book by L. Lachman, etc. theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, H. Sucker et al., Pharmazeutische Technologie, Thieme, 1991, Hagers Handbuch der pharmazeutischen Praxis, 4th Ed. (Springer Verlag, 1971) and Remington''s Pharmaceutical Sciences, 13th Ed., (Mack Publ., Co., 1970) or in the later editions.

Tablets of the invention are used for patients who are prescribed connection I, for example, for l the treatment of tumors as shown in the standard tests. Activity and other indicators of the tablets of the invention can be characterized in a standard clinical trials and/or in animal tests.

In particular, the tablets of the invention are used, for example, for the treatment of non-malignant and malignant proliferative disorders, such as leukemia, gliomas, sarcomas, prostate tumors, breast, lung, ovarian, and gastrointestinal system.

Tablets of the invention containing a pharmacologically effective amount of compound I or a salt of compound I, can be assigned as the only active drug or may provide for the appointment together with another active drug, for example, with simultaneous or separate introduction of other medicines.

Moreover, the obtained tablets of the invention are stable in the process of obtaining and storing, for example, within 2 years or even 3 years in a traditional package, for example, in a sealed blister pack of aluminum. During this time, can decompose approximately less than 5%, for example, 2 or 3% or less of compound I or a salt of compound I as defined in traditional tests.

Tablets of the invention, for example, tablets of 100 and 400 mg, biologically equivalent to that available in selling the e hard gelatin capsules with 100 mg of compound I. Patients can easily tolerate the introduction of 400 mg of compound I in hard gelatin capsules (4×100 mg) in the form of one of the tablets covered with a film.

Depending on age, individual condition, mode of appointment and considered the clinical picture of the disease, for patients weighing approximately 70 kg is entered effective doses, for example daily dose of the tablets of the invention, containing, for example, 100-1000 mg, for example from 100 to 800 mg, preferably from 100 to 600 mg, especially 400 mg of compound I.

In addition, this invention relates to a method of introducing patient-a person in need of such treatment, the compounds I or its pharmaceutically acceptable salt in tablet form, once a day for a period of more than 3 months. This invention particularly relates to such a method in which an adult is entered daily dose of from 100 to 1000 mg, preferably from 100 to 800 mg, especially from 200 to 600 mg, preferably 400 mg of compound I. it Should be recognized that the specific dose level for any particular patient will depend on many factors, including age, weight, General health, a combination drug with one or more active drugs, the type and severity of the disease.

Accordingly, in an additional aspect of the present invention provided yet a method of treatment of a subject, which is to receive the tablets according to the invention, which comprises a pharmacologically effective amount of the salt of compound I to a subject in need of such treatment, optionally with the simultaneous, sequential or separate introduction of another drug, for example, cyclosporine, rapamycin, ascomycin, corticosteroids, cyclophosphamide, azathioprine, methotrexate, brequinar, Leflunomide, mizoribine, mycophenolic acid and/or mycophenolate mofetil.

When the tablets of the invention taken in joint therapy, nelfinavir dosage of compound I can be reduced, for example, from one-half to one-third of their dosage used for individual reception.

Packaging of a medicinal product includes tablets according to the invention and printed instructions instructing that one or more tablets of compound I can be administered orally.

The following, non-limiting examples illustrate the invention.

Example 1. Formulation of tablets (100 mg tablet)

The composition of the standardized form of the dosage and quantity at loading

ComponentComposition one dose (mg)The amount of loading (kg
Mesilate connection I12119,500167,300
Microcrystalline cellulose1(1.1)25,00035,000
Hypromellose/ hypromellose1(1.1)2,5003,500
Microcrystalline cellulose3(1.1)9,85013,790
Crospovidone(1.2)28,00039,200
Colloidal anhydrous silica/colloidal silicon dioxide(1.3)1,2501,750
Magnesium stearate(1.4)1,4001,960
Yellow premix basic coverage(1.5)7,1258,55049,97514,3644
Red premix basic coverage(1.5)0,3750,45040,5250,7564
The total mass195,00196,500273,000~275,000

ComponentComposition one dose (mg)The amount of loading (kg)
Loading unit1'400'000
1Components of the granules2119,5 mg nelfinavir connection I correspond to 100 mg of compound I in free base form,3Microcrystalline cellulose added to the external phase in the form of a dry binding material,4including a 20%excess production covering the dispersion to cover losses is asplenia during the primary stages of coverage.

Tablets according to the invention with 100 mg of compound I in free base form and the above tablets produced by wet granulation of a mixture of salts of compound I with (1.1), mix with3(1.1), (1.2), (1.3) and (1.4), pressing and coating the obtained tablets water dispersion covering a mixture of (1.5).

The coating process can be carried out at a low temperature, for example, in the range from approximately 35 to 38°C. the coating Process can be carried out when the degree of dispersion is preferably in the range from 30 to 105 g covering dispersion per 1 kg of cores per hour ("core" corresponds to the compressed internal and external phase), for example, from 35 to 105 g per kg of cores per hour.

Example 2. Formulation of tablets (tablet 400 mg)

Tablets according to the invention with 400 mg of compound I, and the following tablets produced by wet granulation of a mixture of salts of compound I with (1.1), mixing3(1.1), (1.2), (1.3) and (1.4), pressing and coating the obtained tablets water dispersion covering a mixture of (1.5).

The composition of the standardized form of the dosage and quantity at loading
ComponentComposition one dose (mg) The amount of loading (kg)
Mesilate connection I12478,000167,300
Microcrystalline cellulose1(1,1)100,00035,000
Hypromellose/ hypromellose1(1,1)10,0003,500
Microcrystalline cellulose3(1,1)39,40013,790
Crospovidone(1,2)112,00039,200
Colloidal anhydrous silica/colloidal silicon dioxide(1,3)5,000 1,750
Magnesium stearate(1,4)5,6001,960
Yellow premix basic coverage(1,5)17,10020,42545,9858,5884
Red premix basic coverage(1,5)to 0.9001,07540,3150,4524
The total mass768,000771,50268,80~270,000
Loading unit350'000
1Components of the granules2478 mg nelfinavir compounds I according to testout 400 mg of compound I in free base form. 3Microcrystalline cellulose added to the external phase in the form of a dry binding material,4including 20%th production surplus covering the dispersion to cover losses during the spraying process stage cover.

The coating process can be carried out at a low temperature, for example, in the range from approximately 35 to 38°C. the coating Process can be carried out when the degree of dispersion is preferably in the range from 30 to 105 g covering dispersion per 1 kg of cores per hour ("core" corresponds to the compressed internal and external phase), for example, from 35 to 105 g per kg of cores per hour.

Example 3. Size tablets

Free base of compound I per tabletThe shape and size
100 mgRound, the diameter of 9.1-9.3 mm, curved, beveled edges, thickness: 2.8-3.4 mm; with one side of the notch with a gap
400 mgOval, 18,1-18,3×7,2-7,4 mm, curved, beveled edges, and the thickness of 6.6-7.2 mm
100 mgRound, diameter 9.1 to 9.4 mm, curved, SC is high edges, thickness: 2.8-3.4 mm; with one side of the notch with a gap
400 mgOval, 18,1-18,4×7,2-7,5 mm, curved, beveled edges, and the thickness of 6.6-7.2 mm

For tablets with a dosage equal to or less than 650 mg sample was collected from the total number of tablets with a total weight corresponding to close to 6.5 g (see drawing). For tablets with a dosage of more than 650 mg sample was collected from 10 of all tablets. Tablets should be thoroughly cleaned from dust prior to testing. Carefully determined weight of sample tablets and these tablets were placed in the drum. The drum was rotated 100 times and took the pill. Remove any traces of dust with these tablets, as before spinning in the drum, and carefully weighed.

As a result of experience gained tablets almost unchanged with a high resistance to attrition and friability 0,0%.

1. Tablet containing a pharmacologically effective amount of the compounds of formula (I)

or its pharmaceutically acceptable salt in an amount of from about 30 to 80 wt.% the active component in the calculation of the total mass of the tablet, and where this tablet contains at least one binder, which contains microcrystalline cellulose or hypromellose, or mixtures thereof.

2. T is bleda, contains
(a) a pharmacologically effective amount of compound I and
(b) one or more pharmaceutically acceptable excipients suitable for the preparation of tablets, in which the compound of formula I or its pharmaceutically acceptable salt is present in amount of from about 30 to 80 wt.% the active component in the calculation of the total mass of the tablet, and where this tablet contains at least one binder, which contains microcrystalline cellulose or hypromellose, or mixtures thereof.

3. The tablet according to claim 1, in which the compound of formula (I) or its pharmaceutically acceptable salt is present in amount of from about 50 to 80 wt.% the active component in the calculation of the total mass of the tablet.

4. The tablet according to claim 1 or 2, in which the compound of formula (I) represents monomethylamine salt form.

5. The tablet according to claim 4, in which monomethyl the compounds of formula (I) is in the beta crystalline form.

6. The tablet according to claim 1, which additionally contains baking powder.

7. The tablet according to claim 6, in which the baking powder contains cross-linked polyvinylpyrrolidone.

8. The tablet according to claim 1, which further comprises a slip agent.

9. The tablet of claim 8, in which the sliding agent contains colloidal silica and/or colloidal anhydrous silica.

1. The tablet according to claim 1, which further comprises a binder.

11. Tablet of claim 10, in which the binder contains magnesium stearate.

12. The tablet according to claim 1, in which the filler includes:
at least one binding agent in a total amount of from about 1 to 25 wt.% calculated on the total weight of the tablet,
at least one baking powder in a total amount of from about 10 to 35 wt.% calculated on the total weight of the tablet,
at least one slip agent in a total amount of from about 0.5 to 3 wt.% calculated on the total weight of the tablet, and/or
at least one lubricating agent in a total amount of from about 0.5 to 2 wt.% calculated on the total weight of the tablet.

13. A method of producing a tablet according to one of the preceding paragraphs, which is that:
(i) mixing the compound of formula (I) or its pharmaceutically acceptable salts with pharmaceutically acceptable excipients, (ii) conduct wet granulation, (iii) is mixed with pharmaceutically acceptable excipients with the formation of the mixture; and
(iv) pressing the mixture obtained in stage (iii), with taking tablets.

14. The method according to item 13, in which the tablet cover.

15. The tablet according to any claims 1 to 12, obtained by the wet granulation.

16. The method of treatment of a subject, which consists in the introduction tablets is according to any claims 1 to 12 or 15, which includes a pharmacologically effective amount of the salt of the compounds of formula (I) to a subject in need of such treatment.



 

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34 cl, 15 dwg, 6 ex, 11 tbl

FIELD: medicine; oncology.

SUBSTANCE: invention can be used for treatment of an acute myelogenetic leukemia or myelodysplastic syndrome. For this purpose use a combination of preparations hemetuzumab ozohamicin, daunorubicin and cytarabinum in certain doses and regimens.

EFFECT: invention promotes effective treatment of the specified diseases due to synergistic effect at influence of these preparations on an organism.

2 cl, 2 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns application of N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9N-diindolo [1,2,3-gh:3', 2', 1'-lm] pyrrolo[3,4-j][1,7]benzodiasonine-11-yl]-N-methylbenzamide of formula or its salts for production of pharmaceutical composition intended for treatment of diseases associated with uncontrolled activity of receptor tyrosine kinase FLT3, pharmaceutical preparation and product, containing connection of formula (II).

EFFECT: high efficiency of treatment.

6 cl, 1 tbl, 2 ex

FIELD: medicine, oncology, hematology.

SUBSTANCE: method involves the complex using symptomatic, antibacterial, general tonic agents and nonspecific immunomodulating therapy. For this aim, lysozyme hydrochloride powder is given orally in the daily dose 500-1800 mg, 2 times per a day, every day for 20-30 days in combination with dosing sodium nucleinate in the daily dose 100-1500 mg, 2 times per a day, for 20-30 days by oral or sublingual route, and lactulose given orally in the dose 2.5-5 ml, 1-2 times per a day, every day for 10-30 days. Lysozyme hydrochloride is given 0.5-1 h before eating, sodium nucleinate is given after intake of lysozyme hydrochloride directly and lactulose is given 20-30 min before eating, or before eating immediately, or in 3-4 h after intake of lysozyme hydrochloride and sodium nucleinate. Method provides the complex correction of nonspecific resistance of body in patients suffering from leukosis and involving maintenance of immune homeostasis, plasma proteolysis, intestine microecology and reparative processes and improved tolerance of scheduled polychemotherapy.

EFFECT: improved method of treatment.

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for chemotherapy of acute leucosis. Method involves isolation of blast cells and interphase cells from marrow puncture sample leukocyte fraction of blood of a patient subjected for chemotherapy. Then cells are deposited by centrifugation in medium 199 and their concentration is brought about to the level (2-3) x 106 cells/ml. Then isolated cells are incubated with each chemotherapeutic drug chosen from the following group: dexamethasone, cyclophosphanum, vincristine, teniposide, etoposide, citarabinum that are diluted preliminary with isotonic solution to the concentration 1:1000. Then cells treated with chemotherapeutic drugs are centrifuged repeatedly in medium 199 followed by carrying out the annexin test. In the schedule treatment drugs that showed the maximal percent of cells apoptosis are used. Method provides maximal decreasing adverse and toxic effects of chemotherapeutic drugs and to enhance apoptosis of tumor cells based on individual selection of chemotherapeutic drugs for a patient, to prolong remission period and to exclude using additional curative effects.

EFFECT: improved and enhanced method of chemotherapy.

2 ex

FIELD: organic chemistry, medicine, oncology, pharmacy, biochemistry.

SUBSTANCE: invention relates to amide derivative represented by the following formula [1]:

in any of the following cases (A) or (B), or its salt. In the case (A) R1 represents 5-7-membered saturated cyclic group comprising 1-2 nitrogen atoms as atom forming cycle (saturated cyclic amino-group can be substituted with 1-3 similar or different substitutes chosen from group consisting of (C1-C10)-alkyl, (C1-C10)-alkoxycarbonyl), mono-(C1-C10)-alkylamino- or di-(C1-C10)-alkylamino-group; R2 represents (C1-C10)-alkyl, halogen atom, halogen-(C1-C10)-alkyl, (C1-C10)-alkoxy-group, (C1-C10)-alkoxycarbonyl, nitro-group, mono-(C1-C10)-alkylcarbamoyl, di-(C1-C10)-alkylcarbamoyl or cyano-group; R3 represents hydrogen atom, halogen atom or (C1-C10)-alkoxy-group; Het1 represents any of the following formulae: [2] , [3] , [4] , [5] , [6] , [7] and [8] ; Het2 represents pyridyl, pyrimidinyl, pyrazinyl or 1,2-dihydropyridazinyl (wherein Het2 can be substituted with 1-3 similar or different substitutes chosen from halogen atom) but except for compound wherein R1 means (i) pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl and each of them can be substituted with 1-3 similar or different substitutes chosen from group consisting of alkyl, alkoxycarbonyl, halogen atom, halogenalkyl, hydroxyalkyl, amino-, monoalkylamino-, dialkylamino-group, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl; (ii) monoalkylamino-group, or (iii) dialkylamino-group; Het1 means group of the formula [6], and Het2 means pyrazinyl or pyridyl and each of them can mean a substituted alkyl. In case the (B) R1 represents 4-methylpiperazin-1-yl, 1-pyrrolidinyl, piperidino-group, 4-ethylpiperazin-1-yl, 4-n-propylpiperazin-1-yl, cis-3,5-dimethylpiperazin-1-yl, morpholino-, dimethylamino- or diethylamino-group; R2 represents methyl, halogen atom, trifluoromethyl, methoxy-group, methoxycarbonyl, nitro-group, dimethylcarbamoyl or cyano-group; R3 represents hydrogen atom, bromine atom or methoxy-group; Het1 represents compound of the formula [6]; Het2 represents 3-pyridyl. Invention relates to a pharmaceutical composition possessing inhibitory activity with respect to BCR-ABL tyrosine kinase comprising amide derivative of the formula (I) or its salt as active component and a pharmaceutically acceptable nontoxic and inert carrier. Also, invention relates to BCR-ABL tyrosine kinase inhibitor, therapeutic agents comprising amide derivative of the formula (I) or its salt and, optionally, a pharmaceutically acceptable nontoxic and inert carrier used in treatment of chronic myelogenous leukemia, acute lymphoblast cell leukemia, acute myelogenous leukemia. Invention provides and proposes amide derivative inhibiting activity of BCR-ABL tyrosine kinase.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 2 tbl, 83 ex

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical composition that contains compounds of chlorogenic acid isolated from Piper betel leaves extract or from any other part of plant Piper betel and a pharmaceutically acceptable excipient. Invention provides enhanced effectiveness of treatment of such diseases as acute and chronic myeloid leucosis and lymphoid leucosis and absence of its effect on normal cells. Invention can be used in treatment of patients suffering from acute and chronic myeloid and lymphoid leucosis.

EFFECT: enhanced and valuable medicinal properties of pharmaceutical composition.

32 cl, 4 tbl, 4 dwg, 11 ex

FIELD: medicine.

SUBSTANCE: medicinal preparation for diabetes treatment contains active pharmaceutical ingredients, obtained from root of rehmania (Radix Rehmanniae), root of astragalus (Radix Astragali), rhizomes of yam (Rhizoma Dioscoreae), root of kudzu hemp (Radix Puerariae Lobatae), root of snake gourd (Radix Trichosanthis), baculums with stigmas of corn (Stylus Zeae Maydis), fruits of schizandra (Fructus Schisandrae Sphenantherae) and Glibenclamidum (Glibenclamide), taken in a certain parity. Way of preparation of a medicinal preparation in the form of drop-pills. A way of preparation of a medicinal preparation in the form of pills. A way of preparation of a medicinal preparation in the form of capsules. A way of preparation of a medicinal preparation in the form of tablets. A way of preparation of a medicinal preparation in the form of granules. A way of preparation of a medicinal preparation in the form of soft capsules. A way of preparation of a medicinal preparation in the form of a powder.

EFFECT: efficiency for diabetes treatment.

14 cl, 3 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention reveals a composition for reception of the pressed solid dosed out form which represents a free-fluid pressed simethicon admixture, an adsorbent and the unessential active agent where the weight parity of simethicon and an adsorbent makes at least 1:2.22. The invention also opens the solid dosed out forms received from a free-fluid pressed simethicon admixture, an adsorbent and the unessential active agent where the weight parity of simethicon and an adsorbent makes at least 1:2.22.

EFFECT: solid dosed out form contains larger simethicon percentage by weight, having same size as before, or contains the same simethicon percentage by weight in smaller volume.

27 cl, 11 ex

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention concerns a way of reception of the pharmaceutical composition containing fenophibrate as active substance or one of its derivatives, if needed in association with the second active substance, in the form of tablets, differing that it includes a stage of compaction of active substance and excipients using dry granulation.

EFFECT: simplification of a way of reception of a tablet, with conservation of high bioavailability of active substance.

23 cl, 4 ex, 20 tbl

FIELD: medicine.

SUBSTANCE: invention concerns a tablet containing fluvastatin with sodium carboxymethylcellulose of calcium in the form of raising agent. The fluvastatin tablet is characterised by time of disintegration from 10 to 30 minutes and good bioavailability equivalent to bioavailability of serially produced capsules, containing fluvastatin. Manufacturing of tablets does peroral application of fluvastatin economically more favourable and more convenient for patients.

EFFECT: rising of profitability and convenience of peroral fluvastatin application to patients.

12 cl, 7 dwg, 6 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: present invention concerns area of medical products, in particular, to the pressed tablet including valsartan as active substance and from 50% to 65% of microcrystallic cellulose in recalculation on a process weight of components of a kernel of this pressed tablet.

EFFECT: valsartan bioavailability augmentation.

5 cl, 9 tbl, 12 ex

FIELD: medicine.

SUBSTANCE: invention relates to a chemico-pharmaceutical industry, and concerns the solid pharmaceutical composition containing water-soluble salts of levothyroxine and-or liothyroninum as an active substance where water activity is set equal to less than 0.4 at measurement at a room temperature. The composition with 0.4 water activity or less possesses high stability at storage.

EFFECT: development of a composition which possesses high stability at storage.

18 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention concerns area of medical products, in particular to a tablet for preventive maintenance or treatment of bacteriemic diseases at the animals, containing from 20 to 45 wt % of enrofloxacin, from 18 to 35 wt % of lactose, from 5 to 10 wt % of microcrystallic cellulose and from 5 to 20 wt % of meat aromatisers. Besides the invention concerns a way of reception of the specified tablet.

EFFECT: maintenance of optimum mechanical properties of tablets.

2 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns area of a chemicopharmaceutical industry and concerns the solid medicinal form possessing antianginal and hypotensive activity, containing amlodipine besylate and target additives in quality of active substance at a following parity of ingredients, wt %: amlodipine besylate - 6-10, lactose - 65-90, starch potato - 0.3-0.6, sodium croscarmellose - 1.5-3, stearin acid and-or its salts - 0.5-1, pre-gelled starch - the rest.

EFFECT: reception of tablets with the lowered total weight.

8 cl, 1 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medical products and concerns the method of obtaining of a Solifenacin composition or its salts for use in a solid preparation which includes at least one stage chosen of the group consisting of (i) stage of wet granulation with use of a dissolvent for Solifenacin or its salts, thereat quantity of Solifenacin or its salts which should be dissolved in 1 ml of a dissolvent makes less than 0.1 mg, (ii) stage of dicrease of quantity or rate of addition of a dissolvent if the dissolvent moves Solifenacin or its salt in an amorphous condition, and quantity of Solifenacin or its salts which should be dissolved in 1 ml of a dissolvent 10 mg or more and (iii) stage of activisation of process of crystallisation of a composition of the wet granulation received by means of a usual way. Also the pharmaceutical composition for use in the solid preparation, showing selective opposing action against muscarinic M3 receptors is revealed.

EFFECT: rising of stability of the compositions containing Solifenacin or its salt.

12 cl, 3 tbl, 10 ex

Organic compounds // 2358716

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutics and concerns a solid pharmaceutical composition applicable for oral introduction and containing: (a) S1P receptor agonist; and (b) sugar alcohol.

EFFECT: invention provides homogeneous distribution of an active component in the solid composition with its high stability.

18 cl, 2 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents 3-10-member non-aromatic heterocyclic group, where group is limited by group containing nitrogen as ring-constituting atom, and nitrogen, having additional bond, or group represented by formula -NR11aR11b, where R11a and R11b can be similar or differ from each other, and each represents hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10-member heteroaryl or 4-10-member non-aromatic heterocyclic group, and R11a and R11b can be substituted with substituent selected from group of substituents A or group of substituents B, and R1 can be substituted with substituent selected from group of substituents A or group of substituents B; R2 and R3 represent hydrogen; R4, R5, R6 and R7 can be similar or differ from each other, and each represents hydrogen, halogen, C1-6 alkyl; R8 represents hydrogen or C1-6 alkyl; R9 represents 3-10-member non-aromatic heterocyclic group, where group is limited by group containing nitrogen as ring-constituting atom, and nitrogen, having additional bond, or group represented by formula -NR11aR11b, where R11a and R11b have the same values as described above; n represents integer 1 or 2; and X represents group, represented by formula -C(R10)=, or nitrogen, where R10 represents hydrogen; where group of substituents A consists of halogen, hydroxyl and oxogroup; where group of constituents B consists of C1-6 alkyl, C3-10 cycloalkyl, C6-10 aryl, 5-10-member heteroaryl, 3-10-member non-aromatic heterocyclic group, C1-6 alkoxy, 5-10-member heteroaryloxy, 4-10-member non-aromatic heterocyclic oxygroup and group represented by formula -T1-T2-T3, and each group in group of substitutes B can be substituted with substituent selected from group of substituents C, where T1 represents direct bond or C1-6 alkylene, T2 represents group represented by formula -NRT1-, T3 represents hydrogen or C1-6 alkyl, and RT1 represents hydrogen or C1-6 alkyl; and where group of substutuents C consists of hydroxyl, C1-6 alkyl, 3-10-member non-aromatic heterocyclic group and di-C1-6 alkylaminogroup, to pharmaceutical composition possessing anti-tumor activity, to inhibitors of: hepatocyte growth factor receptor, angiogenesis and cancer dissemination, as well as to anti-tumor medication.

EFFECT: obtaining novel compounds which demonstrate anti-tumor activity.

31 cl, 111 ex, 18 tbl

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