Compositions applicable for oral administration and containing triazolo[4,5-d]pyrimidine derivative

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry and represents a pharmaceutical composition containing: {1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3;4-difluorophenyl)cyclopropyl]amino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol; an excipient representing mixed mannitol and dibasic calcium phosphate dihydrate; a binding agent representing hydroxypropyl cellulose; a disintegrant representing sodium starch glycolate; and one or more lubricating agents.

EFFECT: invention provides preparing the composition of the active compound possessing high stability and high bioavailability of the active agent.

12 cl, 1 ex

 

The present invention relates to pharmaceutical compositions and more specifically to pharmaceutical compositions containing the compound of formula (I)

The compound of formula (I) in a conventional manner is called {1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol, and here below, it will be referred to as 'the Agent'.

This Agent is disclosed as an antagonist of ADP-receptor in the international patent application number PCT/SE99/02256 (publication number WO 00/34283) and in international patent application number PCT/SE01/01239 (publication number WO 01/92262). It was found that adenosine-5'-diphosphate (ADP) acts as a key mediator of thrombosis. ADP-induced platelet aggregation mediates receptor subtype P2Tlocalized on the membrane of platelets. P2T-receptor (also known as P2YADPor P2TAC) is mainly involved in mediating aggregation/activation of platelets and is a receptor associated G-protein, which is not yet cloned. Pharmacological characteristics of this receptor are described, for example, in Humphries et al., Br. J. Pharmacology (1994),113, 1057-1063 and Fagura et al., Br. J. Pharmacology (1998)124, 157-164. It is shown that antagonists of this receptor provide a significant improvement in comparison with the other is mi antithrombotic agents (see J. Med. Chem. (1999)42, 213).

The pharmaceutical compositions of the present invention are suitable for oral administration. One of the qualities desirable in pharmaceutical compositions suitable for oral administration, is bioavailability. The bioavailability of drugs represents the relative amount of the administered dose that reaches the systemic circulation in the unchanged form. Therefore, bioavailability is important in determining therapeutically active concentrations at the site of action. As the release of drug from the composition and stability of the composition will affect its bioavailability. It is therefore important that the composition of the medicinal product released essentially the entire quantity of the medicinal product (see Aulton ME, Pharmaceutics - The Science of Dosage Form Design, 2ndEdition, 2002, Churchill Livingstone). Bioavailability can be measured using tests known in this field, for example using a standard apparatus for dissolution according to the US Pharmacopoeia (USP) and the standard 'bio-relevant' environment for dissolution, for example FaSSIF (Pharm. Res., 17:439-444, 2000).

There are pharmaceutical compositions containing an Agent that hold a certain amount of the Agent and, consequently, reduce its biological d is the access.

The inventors have proposed a new pharmaceutical composition of the Agent, which has favorable properties and solves one or more problems associated with obtaining drugs Agent. In the first aspect, the authors propose a pharmaceutical composition, which is suitable for oral administration and which releases essentially all of the Agent. In one aspect the pharmaceutical composition releases at least 90% of the Agent. In another aspect the pharmaceutical composition releases at least 95% of the Agent. In another aspect the pharmaceutical composition releases at least 97% of the Agent.

Accordingly, the invention relates to pharmaceutical compositions containing:

Agent;

one or more fillers selected from mannitol, sorbitol, dihydrate dibasic calcium phosphate, anhydrous dibasic calcium phosphate and trehosnovnogo calcium phosphate or mixtures thereof;

one or more binding agents selected from hydroxypropylcellulose, alginic acid, sodium

carboxymethylcellulose, copovidone and methylcellulose or mixtures thereof;

one or more loosening agents selected from sodium glycolate, croscarmellose sodium and crosspovidone, or a mixture thereof;

and one or more lubricating agents.

The filler may, not only is th a 'soluble' filler or 'insoluble' filler. 'Soluble' filler is a filler which is essentially soluble in water at ambient temperature. 'Insoluble' filler is a filler which has a low or slow solubility in water at ambient temperature.

In one aspect, the pharmaceutical composition contains at least one 'soluble' filler selected from mannitol, sorbitol, maltodextrin, maltose and dextrin.

In another aspect, the pharmaceutical composition contains one or more 'insoluble' fillers selected from the dihydrate dibasic calcium phosphate, anhydrous dibasic calcium phosphate, partially pregelatinized starch and trehosnovnogo calcium phosphate.

In one aspect, the pharmaceutical composition contains one or more 'instant' fillers. In another aspect, the pharmaceutical composition contains one 'soluble' filler.

In one aspect, the pharmaceutical composition contains one or more 'insoluble' fillers. In another aspect, the pharmaceutical composition contains one 'insoluble' filler.

In one aspect the pharmaceutical composition comprises one or more binding agents. In another aspect the pharmaceutical composition comprises one binding agent.

In one aspect the pharmaceutical composition comprises one or more lubricating agent. In another aspect the pharmaceutical composition comprises one lubricating agent.

In another aspect, the filler is a mixture of mannitol and dihydrate dibasic calcium phosphate.

In one aspect of 'soluble' filler selected from mannitol and sorbitol. In another aspect of 'soluble' filler selected from mannitol.

In one aspect of the 'insoluble' filler selected from the dihydrate dibasic calcium phosphate, anhydrous dibasic calcium phosphate and trehosnovnogo calcium phosphate. In another aspect of the 'insoluble' filler selected from the dihydrate dibasic calcium phosphate.

In another aspect, the binding agent is selected from hydroxypropylcellulose.

In one aspect baking powder selected from sodium glycolate and croscarmellose sodium. In one aspect baking powder selected from sodium glycolate.

Additional conventional excipients that may be added include preservatives, stabilizers, antioxidants, modifiers yield on the basis of silicon dioxide, agents against sticking or sliding agents.

Other suitable lubricating agents and additional excipients that can be used disclosed in the Handbook of Pharmaceutical Excipients, 2ndEdition, American Pharmaceutical Association; theory and Practice of Industrial Pharmacy, 2nd Edition, Lachman, Leon, 1976; Pharmaceutical Dosage Forms: Tablets Volume 1, 2ndEdition, Lieberman, A. Hebert, et al. 1989; Modern Pharmaceutics, Banker, Gilbert and Rhodes, Christopher T, 1979; Remington's Pharmaceutical Sciences, 15thEdition, 1975.

Suitable lubricating agents include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, Carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycols and sodium fumarate.

In one aspect, the lubricating agent is selected from magnesium stearate and sodium fumarate. In another aspect, the lubricating agent is a stearate.

In one aspect the pharmaceutical composition comprises from 1% to 50% by weight of the Agent. In particular, it contains from 20% to 45% by weight of the Agent.

In another aspect the pharmaceutical composition comprises from 1% to 90% by weight of filler. In particular, it contains from 20% to 70% by weight filler.

In another aspect the pharmaceutical composition comprises 1-70% by weight of 'soluble' filler. In particular, it contains from 20% to 45% by weight of 'soluble' filler.

In another aspect the pharmaceutical composition comprises from 1% to 30% by weight of 'insoluble' filler. In particular, it contains from 10% to 30% by weight of 'insoluble' filler.

In the other aspect, the pharmaceutical composition comprises from 2% to 8% by weight of a binding agent. In particular, it contains from 3% to 6% by weight of a binding agent.

In another aspect the pharmaceutical composition comprises from 2% to 6% by weight of loosening agent.

You have to understand that one particular excipient may also act as a binding agent, and as a filler or as a binding agent, a filler, and baking powder. In typical cases, the total amount of filler, a binding agent and loosening agent is, for example, from 50% to 90% by weight of the composition.

In typical cases, one or more lubricating agent is present in an amount of from 0.5% to 3% and in particular from 0.5% to 1% by mass.

In another aspect this invention relates to pharmaceutical compositions containing the Agent, mannitol, dibasic dihydrate calcium phosphate, hydroxypropylcellulose, sodium starch glycolate, and one or more lubricating agent.

In another aspect this invention relates to pharmaceutical compositions containing:

Agent in an amount of from 20% to 45% by weight;

mannitol in an amount of from 20% to 45% by weight;

the dihydrate dibasic calcium phosphate in an amount of from 10% to 30% by weight;

hydroxypropylcellulose in an amount of from 3% to 6% by weight;

the sodium glycolate in an amount of from 2% to 6% by weight and

one or more lubricating agents in amounts of from 0.5% to 3% by mass.

Preferably, th is would the physical properties of these compositions were stable during storage, because of the changes, for example, in terms of time raspadaemosti, the dissolution rate or hardness of tablets among other things, can affect the performance of the product. It is possible that the decrease in the dissolution rate when stored in conditions of stability testing in accordance with the requirements of the International Council on harmonization of technical requirements for registration of pharmaceutical products for human use (ICH), is used to determine the shelf life of the product, may reduce the bioavailability of the Agent. Stability of physical properties can be measured by methods according to the US Pharmacopoeia (USP) for testing time raspadaemosti and dissolution.

Preferably, the compositions were chemically stable, because the decomposition through oxidation, hydrolysis, isomerization, photolysis, polymerization, or any other way of decomposition, or by mixing with excipients or any other way may result in reduced bioavailability. Chemical stability can be measured appropriate showing the stability of the chromatographic method for determination of decomposition products (see Aulton ME, Pharmaceutics - The Science of Dosage Form Design, 2ndEdition, 2002, Churchill Livingstone).

In another aspect of the proposed pharmaceutical composition, the cat heaven suitable for oral administration, which releases essentially all of the Agent and has the desired profile stability.

In one aspect the invention relates to pharmaceutical compositions, obtained by wet granulation.

Granulation is a process in which the original particles (powder) stick together, forming large, consisting of many particles of education, called granules. Granulation in norm begins after the initial dry mixing the powdered ingredients to achieve an almost uniform distribution of ingredients throughout the volume of the mixture. Methods of granulation can be divided into two types, namely methods of wet granulation using a liquid for the formation of granules, and dry methods in which the liquid is not used.

In the methods of the dry granulation of the original powder particles aggregate under pressure (or pressing). There are two basic ways: a large pill (also known as briquettes) are obtained by using a powerful desktop tablet press, or the powder particles are pressed between the two rollers with the receiving plate element or 'tape' substances (method, known as roller compaction). In both cases, the pressed material is milled using a suitable grinding equipment to produce granulated material. Gr is noly can then be pressed in a standard tablet press to obtain tablets.

Wet granulation involves gaining mass of the primary particles of the powder by using a granulating fluid. The liquid contains a solvent, which can be removed by drying, and which is non-toxic. Granulating liquid can be used by itself or, what is more typical, with linking agent (binding agent) to promote adhesion of the particles in the dry state. Binding agents may be added to the system in the form of binding solution (as part of the granulating liquid) or dry matter, mixed with particles of the initial powder. There are three main types of wet granulator: shear granulators (such as planetary mixers, granulators with high shearing force such as a Fielder or Diosna) and granulators fluidized bed (such as Aeromatic or Glatt).

In another aspect of the proposed pharmaceutical composition obtained by the wet granulation, which is suitable for oral administration and releases essentially all of the Agent and has the desired profile stability.

In another aspect this invention relates to a pharmaceutical composition obtained by the wet granulation containing the Agent, mannitol, dibasic dihydrate calcium phosphate, hydroxypropylcellulose, sodium starch glycolate, and one or more lubricating agents.

In other the second aspect of this invention relates to pharmaceutical compositions, obtained by wet granulation in high shear.

Wet granulation in high shear is a method that includes intensive dry mixing of the primary powders and subsequent addition of granulating liquid, which leads to the formation of granules. Granulating liquid contains a volatile solvent (usually water) and may also include a binding agent that provides adhesion of the particles (linking agents can also be added to dry in the form of powders by weight of the drug, subject to granulation). Compared with powders, of which they are composed, granules has great benefits in terms of improved flow characteristics, reduced risk of segregation, high homogeneity (information taken from Aulton ME, Pharmaceutics - The Science of Dosage Form Design, 2ndEdition, 2002, Churchill Livingstone).

In one aspect the pharmaceutical composition is a solid dosage form such as a tablet or capsule. In another aspect the pharmaceutical composition is in tablet form.

In another aspect this invention relates to a pharmaceutical composition obtained by the wet granulation high shear containing Agent, mannitol, dibasic dihydrate calcium phosphate, hydroxypropylcellulose, sodium starch glycolate, and one or more lubricating agents.

The agent exists in amorphous form and in four significantly different crystalline forms (see international patent application number PCT/SE01/01239 (publication number WO 01/92262)). In another aspect this invention relates to pharmaceutical compositions, as defined here above, where the Agent is in crystalline form.

In another aspect this invention relates to pharmaceutical compositions containing the Agent is essentially in the form of polymorph II.

In another aspect this invention relates to pharmaceutical compositions containing the Agent is essentially in the form of polymorph III.

The compositions of this invention of particular interest include, for example, the specific embodiment disclosed here below in the attached Example.

We must understand that in accordance with principles well known in this field, you can modify how wet granulation, including the order of addition of components and their sifting and mixing before pressing into tablets.

An additional aspect of the present invention is a method of obtaining a pharmaceutical composition, which comprises mixing the Agent with:

one or more fillers selected from mannitol, sorbitol, maltodextrin, maltose and dextrin, dihydrate dibasic calcium phosphate, anhydrous DV is osnovnogo calcium phosphate, partially pregelatinization starch and trehosnovnogo calcium phosphate or mixtures thereof;

one or more binding agents selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, alginic acid, sodium carboxymethyl cellulose, copovidone and methylcellulose or mixtures thereof;

one or more loosening agents selected from sodium glycolate, croscarmellose sodium and crosspovidone, or a mixture thereof;

and one or more lubricating agents.

The following pharmaceutical composition is intended to illustrate this invention.

Example 1
IngredientThe number on the standard doseNumber
The standard dose (mg)(wt.% or Mac./about.)
Agent90,0030,00
Mannitol126,0042,00
The dihydrate dibasic calcium phosphate63,0021,00
Guide oxypropylation 9,003,00
The glycolate sodium9,003,00
Magnesium stearate3,001,00
The mass of the nucleus tablets300,000100,00

Wet granulator, high shear (Fielder GP1 with a bowl capacity 10 l) was used for 4 minutes for dry mixing Agent, mannitol, dibasic dihydrate calcium phosphate, hydroxypropylcellulose and glycolate sodium in amounts necessary to obtain 2.5 kg of total product. Water was added through the discharge tank at about 50 g/min to about 25% by weight. The total mixing time was approximately 10 minutes.

Drying in the fluidized bed was carried out using a Glatt GPCG1 at 60°C until a product temperature of 42°C. the Obtained pellets were grinded in Quadra Comil 197, milled granules were mixed with magnesium stearate and the mixture extruded tablets.

1. Pharmaceutical composition containing: {1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol;
filler, PR is dstanley a mixture of mannitol and dihydrate dibasic calcium phosphate;
binding agent, which is hydroxypropylcellulose;
loosening agent representing the sodium glycolate;
and one or more lubricating agents.

2. The pharmaceutical composition according to claim 1, where the lubricating agent is selected from magnesium stearate and sodium fumarate.

3. The pharmaceutical composition according to claim 1, where {1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol is present in an amount of from 20% to 45% by mass.

4. The pharmaceutical composition according to claim 1, where the filler is present in an amount of from 20% to 70% by mass.

5. The pharmaceutical composition according to claim 1 where the binding agent is present in an amount of from 3% to 6% by mass.

6. The pharmaceutical composition according to claim 1, where loosening agent is present in an amount of from 2% to 6% by mass.

7. The pharmaceutical composition according to claim 1, where the lubricating agent is present in an amount of from 0.5% to 1% by mass.

8. The pharmaceutical composition according to claim 1, where {1S-[1α,2α,3β(1S*,2R*),5β}-3-(7-{[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol, essentially present in the form of polymorph II.

9. The pharmaceutical composition according to claim 1, where {1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-differenl)cyclopropyl]amino}-5-(propylthio)-3H-12,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol, essentially present in the form of polymorph III.

10. The pharmaceutical composition according to claim 1, containing:
{1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3,4-differenl)cyclopropyl]-amino}-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol in an amount of from 20% to 45% by weight;
mannitol in an amount of from 20% to 45% by weight;
the dihydrate dibasic calcium phosphate in an amount of from 10% to 30% by weight;
hydroxypropylcellulose in an amount of from 3% to 6% by weight;
the sodium glycolate in an amount of from 2% to 6% by weight and
one or more lubricating agents in amounts of from 0.5% to 3% by mass.

11. The pharmaceutical composition according to any one of claims 1 to 10, which is obtained by the wet granulation.

12. The pharmaceutical composition according to claim 11, which is obtained by the wet granulation high shear.



 

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3 cl, 14 tbl, 7 ex

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24 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: composition of a solid quick-disintegrating tablet of low frangibility contains 1 to 20 wt % of ethyl cellulose as a binding agent and 2 to 15 wt % of a disintegrating agent. The ethoxy group content in ethyl cellulose is found within the range of 44 % to 54.9%. Viscosity of 5% ethyl cellulose makes a value within the range of 3 sP to 200 sP as mixed with solvents toluene/ethanol, 80:20. The disintegrating agent is specified in a group consisting of crossed-linked povidone, croscarmellose sodium salt (crossed-linked carboxymethyl cellulose sodium salt), starch glycolate sodium salt, low-substituted hydroxypropyl cellulose and guar gum. The composition may additionally contain an active pharmaceutical ingredient. What is also described is a method for preparing the quick-disintegrating tablet of low frangibility by direct compression.

EFFECT: invention provides creating the quick-disintegrating mechanically solid tablet of low frangibility for fast and effective delivery of the active ingredient into the nasal cavity.

27 cl, 8 tbl, 6 ex

Pressed tablets // 2472491

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pressed tablet containing a pressed non-chewable base and a volatile active agent, preferentially menthol or eucalyptol included in a spray-dried granule additionally containing a starch carrier and a polyol granulating agent. The pressed tablet may be a two-layer tablet containing a sparkling layer and a non-sparkling layer with the spray-dried granule included in the sparkling layer. The tablets in the present application are effective to provide decongestant effects in a nasal cavity.

EFFECT: invention additionally refers to the use of starch for increasing release rate of the volatile active agent from the pressed tablet and improving its disintegration smoothness.

12 cl, 3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents an oral tableted pharmaceutical composition used for oral administration and containing dexamethasone as an active ingredient, and the excipients: lactose, povidone, magnesium stearate, and differing by the fact that additionally contains the excipients: croscarmellose sodium, microcrystalline cellulose; lactose is lactose monohydrate with the ingredients taken in certain proportions, mg per one tablet.

EFFECT: invention provides high transportation durability and storage stability, and also enables reducing a number of tablets taken and side effects caused by prolonged treatment.

2 cl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to a therapy of the patients suffering rheumatoid arthritis accompanied by secondary osteoarthrosis. The presented method for integrated treatment involves: Methotrexate 7-15 mg per os 1 time a week, non-steroid anti-inflammatory preparations, diacerein 50 mg - 2 times a day in a combination with the exposure to low-intensity laser light, including the exposure of knee joints to skin infrared pulse laser light along a projection of a joint space, and the exposure of blood to supravenous red laser light.

EFFECT: implementing the method ensures an evident analgesic, anti-inflammatory effect, a reduced length of morning stiffness, improved functional capacity and expanded range of motion in the injured joints, as well as lower consumption of non-steroid anti-inflammatory preparations thereby reducing a rate of related side effects.

3 cl, 3 tbl, 2 ex

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