Oral dosage forms with prolonged action

 

(57) Abstract:

The invention relates to the pharmaceutical industry. Oral dosage form partially prolonged action. The pharmaceutical active substance is tramadol. It is partially represented as formed in situ connection with the solubility of 100 mg/ml Tramadol and acid pharmaceutical active substance and/or auxiliary substance or their respective water-soluble salts, and optionally other excipients are mixed, several times moisturize and supply the necessary energy mix is processed in the target composition. The invention allows to reduce the cost of the process. 2 C. and 27 C.p. f-crystals, 7 PL.

The present invention relates to oral dosage forms at least part of the slow-release pharmaceutical active substance which tramadol is at least partially represented as formed in situ connection with the solubility of 100 mg/ml, as well as to methods for their preparation.

The use of pharmacological active substances, primarily analgesic active substances, in the form of compositions with prolonged action (retard) can improve their therapeutic aceska active substances with relatively short half-life in the body, allows you to obtain the appropriate composition of the prolonged action and due to a more uniform level in the blood to avoid, in addition, side effects, and increase the accuracy of adherence of patients to the instructions for dosage.

Retardation of pharmacological active substances can be provided, for example, due to their embedding in the corresponding ("retardiculous") matrix or coating of the respective film coating ("reagiruya shell").

The retardation highly water-soluble active substances, such as tramadol hydrochloride analgesic used for the treatment of severe and very severe pain, with film coverings is often associated with considerable costs, and in addition, such coatings in many cases are insufficient diffusion barrier for the active substances or their permeability during storage significantly worse (R. C. O'Donnell, J. W. McGinity, Mechanical Properties of Polymeric Films Prepared from Aqueous Polymeric Dispersions in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Drugs and the Pharmaceutical Science, volume 79, publishing house of J. W. McGinity, Marcel Decker, New York, Basel, Hong Kong (1997)).

To get dosage forms with reagiruyushchimi film coating (membrane) damage from Volochek, or methods of treatment associated with a significant investment of time; these methods are described, for example, in patents US 5645858, US 5580578, US 5681585. US 5472712 and K. Bauer in "Coated Pharmaceutical Dosage Forms", published by medpharm Scientific Publishers, Stuttgart (1998), C. Sutler, dissertation, University of düsseldorf (1987) or in F. N. Christensen in Proceed. Intern. Symp. Contr. Rel. Bioact. Mater. 17, page 124 (1990).

Retardation of pharmaceutical active substances can also be achieved by reducing their solubility, for example, by the formation of poorly soluble salts (N. Sucker, Pharmazeutische Technologie, published by Georg Thieme Verlag, Stuttgart, New York (1991)). However, the use of such soluble salts due to the partly very expensive methods of obtaining them.

Based on the foregoing, the present invention was based on the task to create a dosage form, which would not have the disadvantages inherent in such dosage forms of the prior art.

With the invention it has been unexpectedly found that this problem can be solved using oral dosage forms of tramadol at least partially prolonged action, retardirovannah fraction of active substances which are represented as formed in situ connection of tramadol and other active viewer in situ connection 50 mg/ml, particularly preferably 30 mg/ml and most preferably 10 mg/ml

To obtain a formed in situ connection active ingredient tramadol, preferably in the form of soluble salts, particularly preferably in the form of tramadol hydrochloride, is subjected to the interaction with water-soluble pharmaceutically acceptable salt of another acid pharmaceutical active substances or excipients, which forms with tramadol connection with the solubility of 100 mg/ml, preferably 50 mg/ml, particularly preferably 30 mg/ml and most preferably 10 mg/ml Such compounds belong to the group of compounds poorly soluble in water. Under the concept of "education" in situ", according to the invention mean that tramadol, accordingly, the water-soluble salt, preferably upon receipt of the proposed dosage forms, mixed with another acid pharmaceutical active substance or auxiliary substance or with their respective water-soluble salts, moisturize several times, if necessary ekstragiruyut or making use of any other energy.

As a water-soluble salt of another acid, pharmace what has been created in situ connections tramadol preferable to use the sodium salt of diclofenac, of naproxen, acetylsalicylic acid, salicylic acid, benzoic acid or saccharin, cyclamate or Acesulfame.

Proposed in the invention, the oral pharmaceutical form prolonged action can contain tramadolbuy component and other pharmaceutical active and/or auxiliary substance in any molar ratio.

In one of the preferred ways to obtain the dosage forms according to the invention tramadolbuy component is introduced in excess and may be released at least two different speeds. This means that along with slow release tramadol from formed in situ connection part of the active substance is rapidly released in the form of the initial dose.

According to another preferred variant of the receipt of the dosage forms according to the invention tramadolbuy component and another, acid pharmaceutical active substance or excipient presented in equimolar amounts as formed in situ, poorly soluble compounds. This provides prolonged release of both active substances, respectively, of active substances and auxiliary substances which x2">In a particularly preferred embodiment, receiving the proposed dosage forms tramadol hydrochloride and diclofenac sodium was converted at the exchange reaction in situ in connection with extremely low water-solubility of 0.3 mg/ml, Preferably proportion of tramadol and diclofenac in these dosage forms according to the invention is from 0.5:1 to 4:1, particularly preferably from 1:1 to 2:1. Tramadol interacting in situ with diclofenac should be used in excess, which results in the rapid release of the initial dose of tramadol, tramadol and diclofenac together released with a corresponding slowing down with the same speed. Thanks to this combination with immediately released active substance as a starting dose possible to relieve pain. The subsequent gradual release of the active substances from the retard helps to keep the blood over a long period of time.

Preferred pharmaceutical form prolonged action according to the invention contain formed in situ compound, which is obtained from equimolar amounts of active substances - tramadol and diclofenac, thanks cheaprelative the invention the oral dosage form of tramadol is at least partially prolonged action is made preferably in the form of multiple particles of the compositions, especially preferably in the form of granules, microparticles, microtablets or pellets (spherical granules), most preferably in the form of pellets, and under certain conditions, put them in capsules. The pellets are preferably formed by extrusion or spheroidizing preferably with a diameter from 0.1 to 3 mm.

Dosage forms according to the invention can be produced also in the form of pills or tablets, preferably in the form of a rapidly disintegrating tablets. Such tablets may consist of compacted pellets, which particularly preferably quickly disintegrate.

A special advantage of the proposed dosage forms is that the retardation tramadol guaranteed in the manufacture of corresponding pharmaceutical form due to the formation of in situ connection with the solubility of 100 mg/ml of tramadol and one active substance and/or auxiliary substances without using this reagiruya matrix and/or reagiruya shell.

Dosage forms according to the invention preferably have at least one resistant to gastric juice membrane, dissolving depending on pH. Thanks to this active shell(CNIC, where is their controlled release. Resistant to gastric juice membrane can be applied from an aqueous solution or dispersion and/or from the organic solution. Preferably such resistant to gastric juice, the shell dissolves at pH values from 5 to 7. The shell specified in the execute preferably from shellac, a copolymer of acrylate poly (methacrylic acid or a methacrylic acid/methyl acrylate/methyl methacrylate, copolymers of methacrylic acid and methyl methacrylate, acetolactate hydroxypropylmethylcellulose, acatitla cellulose, polivinilatsetatftalat, phthalate of hydroxypropylmethylcellulose and/or acetotartrate pulp.

In addition to the retardation provided in situ, and thus to the possibility of any modification regarding the release of the active substance tramadol and optionally used other active substances using various methods known to experts in this field.

The preferred approach is to create retardery shells. Suitable for this purpose retardery membranes are water-insoluble waxes and polymers, such e.g. icellulse. These materials are known from the prior art, in particular from the publication authors Bauer, Lehmann, Osterwald, Rothgang. Ueberzogene Arzneiformen published by Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, page 69 et seq (1988), which is incorporated into this description by reference.

To achieve the envisaged rate of release of active substances reagiruya shell along with water-insoluble polymers may contain, under certain conditions, also do not have similar properties, preferably water-soluble polymers in amounts up to 30 wt.%, such as polyvinylpyrrolidone or water-soluble cellulose, preferably the hypromellose or hydroxypropylcellulose, and/or hydrophilic pore, such as sucrose, sodium chloride and mannitol, and/or known plasticizers.

In another preferred embodiment, the retardation of the dosage form according to the invention may contain a partially soluble formed in situ tramadolbuy connection in the corresponding reagiruya matrix, preferably uniformly distributed in it. As materials for such a matrix can be used physiologically acceptable hydrophilic materials, a well-known expert who obanno preferably ethers and esters of cellulose and/or acrylic resin. Most preferred as these materials ethylcellulose, hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or its derivatives, such as salts, amides or esters.

Equally preferred to obtain the matrix and hydrophobic materials such as hydrophobic polymers, waxes, fats, fatty acids long chain fatty alcohols and the corresponding complex or ethers, or their mixtures. Particularly preferably used as the hydrophobic materials mono - or diglycerides WITH12-C30ozirny acids and/or C12-C30airnya alcohols and/or waxes or a mixture thereof.

As a material for reagiruya matrix can also be used mixtures of the above-mentioned hydrophilic and hydrophobic materials. The rate of release of active substances should be calculated based on a maximum of two, particularly preferably a single dose of dosage forms according to the invention in the day. Working with analgesics experts know, what dosage should be prescribed these drugs to achieve the desired effect.

An additional opportunity modifizierten forms according to the invention consists in a corresponding variation of the surface of the latter and/or the use of hydrophilic excipients. Thus, in particular, the increase in surface area of, for example, through the use of spherical granules (pellets) smaller size allows you to accelerate the release of active substances. The increase in the number of hydrophilic excipients in the core of such granules, for example lactose, can also improve the rate of release of the active (s) substance (s).

Proposed in the invention the dosage form suitable, preferably as a means of dealing with the pain or for the treatment of urinary incontinence, cough, inflammatory and/or allergic reactions, depression, drug and/or alcohol abuse, gastritis, diarrhoea, cardiovascular diseases, respiratory diseases, mental disorders or epilepsy.

Another object of the invention is in accordance with these methods of obtaining the proposed oral dosage forms at least part of the prolonged action where (how) tramadol, respectively, the salt is mixed with another, acid pharmaceutical active substance or auxiliary substance, according to their water-soluble salts and optionally other auxiliary vases case moisturize preferably using aqueous media, especially preferably water or aqueous solutions of binders. The necessary energy fail due to a pressure and/or due to the heat.

According to one of preferred embodiments of the proposed method the mixture several times moisturize and granularit and at least once passed through the extruder, conducting, if necessary, the final processing.

After each operation by moisturizing and granulation, it is preferable to carry out the extrusion and/or drying of the mixture.

Preferably the mixture after repeated wetting, granulation, extrusion and/or drying to palletirovanie (i.e. make it spherical granules) and after an optional mixing with other excipients to tablet. Before the process of pelletierine mixture it is advisable to ekstradiroval.

According to one particularly preferred embodiments of the method according to the invention moistened mixture of salts granularit, ekstragiruyut, re-hydrate and granularit, ekstragiruyut and at the end give the granules a rounded shape. In another particularly preferred variant of the method the wetted mixture granularit, dried, re-wvla is advisable to cover the shell, resistant to gastric juice.

According to one of preferred embodiments of the proposed method to obtain a formed in situ connections use tramadol hydrochloride and diclofenac sodium.

If provided the final processing of the dosage forms according to the invention with the aim to get them ready for release, then the processing can be performed using various methods known to experts in this field.

Proposed in the invention the dosage form depending on their implementation can contain, in addition, as other ingredients conventional, well-known specialists auxiliary substances and additives. Because of the dosage form according to the invention should have a corresponding envelope, put the envelope can be normal for such purposes by methods such as drazhirovanie, plating solutions, dispersions or suspensions, application in the form of a melt or powder coatings deposition.

The proposed dosage form, as unexpectedly, it was found, differ in that the variation of the conditions of release of active substances, due about the drug buffers of different types and/or different mechanical loads, does not have to release tramadol and optionally used other active substances of the dosage forms according to the invention no effect. Even after a long period of storage at elevated temperature up to 40°With the rate of release of the active (s) of substances (substances) of the dosage forms according to the invention is not changed. Thus, the resulting dosage forms show the high stability during storage.

This release of the active substances of the proposed oral dosage forms at least part of the prolonged action occurs in accordance with the corresponding kinetics, which can be achieved in principle through the use of expensive matrix systems. Unexpected as it was found, is the fact that the retardation of the pharmaceutical active substances is possible without the use of conventional retardery systems. The release mechanism can be modeled in this variation of the size of the dosage form and soluble auxiliary substances while maintaining the total for both active substances speed of release. This release of both active substances of the jointly produced in situ small the front 5 μm, unexpectedly occurs with exactly the same slowdown as the release obtained separately salts of tramadol and diclofenac of the identical dosage forms, however, having substantially greater particle size of about 20-100 microns.

Since the retardation of the active substance tramadol and optionally used other active substances in dosage forms according to the invention can be provided without the use of any other retardery systems, it becomes possible to obtain medicines with high reproducibility by more efficient technologies, i.e., with less expenditure of time and money.

The solubility of the compounds tramadol and other appropriate acid pharmaceutical active substances or excipients was determined as follows:

From the obtained in each case by the method according to the invention and having reagiruya shell granules (pellets) containing the compound of tramadol, (1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and the corresponding acid pharmaceutical active substances or excipients, selected a certain number, which was added at 25° what atom, so when this temperature has formed a saturated solution, saturation, which persisted after 24 hours of shaking (vibrator type Vibrax, the mode of vibration baths: 1200 at 25°C).

The range of the corresponding solubility to achieve saturation was determined in preliminary experiments using the obtained in each case separately salt of tramadol and the corresponding acid pharmaceutical active substances or excipients.

After settling transparent solution transparent supernatant was removed with a pipette and centrifuged for 5 min at 3500 rpm part of the thus obtained clear supernatant was placed in a test tube for GHUR and the concentration of tramadol and the corresponding acid pharmaceutical substances or excipients was determined in comparison with tramadol hydrochloride as standard.

The mechanism of release obtained in the examples of drugs were identified as follows.

Compositions investigated or apparatus with a rotating drum pancake type (examples 1-6) or device with a blade stirrer (example 7) according to UP>-1accordingly 50 min-1. In example 1, the composition was tested for 10 h in example 6 for 5 h in example 5 for 4 h in 900 ml of artificial intestinal juice without enzymes (pH of 7.2). In examples 2-4 and 7, the composition was tested during the first 2 h in 600 ml of artificial gastric juice without enzymes (pH of 1.2), and then in the next 8 hours in 900 ml of artificial intestinal juice without enzymes (pH of 7.2). Released at the appropriate time, the number of active substances was determined by GHWR. The obtained values and the curves represent averages of three selected in each case the samples.

Below the invention is explained in more detail by way of examples, which in no way limit its scope.

Examples

Example 1

125 g of tramadol hydrochloride, 125 g of diclofenac sodium and 250 g of microcrystalline cellulose (Avicel PH 101, FMC) was mixed for 10 minutes prior to the formation of a homogeneous mixture in the type mixer Kenwood Chef Mixer, after which was grained with usage sufficient to hydrate the amount of water. Then this sticky, lumpy granular mass was extrudible in Nica extruder Extruder (type El 40) with extrusion jirawala in very dry extrudate insufficient for further spheroidizing plasticity. Therefore, the extrudate was re-moistened and re-granulated. The obtained granulate is again passed through the extruder Nica Extruder, after which the wet extrudate was processed using spheroidization Nica Spheroniser (type S450) with the formation of round granules (pellets) of the same size. Then the granules were dried in a dryer at a temperature of about 50°C and divided according to the size of the fraction, to deliver 90% of the granules within the desired size class 800-1250 mm.

The composition of the granules, mg:

Tramadol-HCl 50

Diclofenac-Na 50

Microcrystalline cellulose

(Avicel PH 101, FMC) 100-200

The solubility of the active substance tramadol from formed in situ connection, which was determined for the received described by granules according to the above method, was 0.36 mg/ml

Investigation of the mechanism of release of active substances, which was performed using the above method gave the following results:

Example 2

200 g of tramadol hydrochloride, 100 g of diclofenac sodium, 22 g of powdered succinic acid and 332 g of microcrystalline cellulose (Avicel PH 101, FMC) was mixed for 10 minutes in the type mixer Kenwood Chef Mixer to obrazovanii (pellets).

The composition of the granules mg

Tramadol hydrochloride 100

Diclofenac sodium 50

Succinic acid, powder 11

Microcrystalline cellulose

(Avicel PH 101, FMC) 166

327

Then 500 g are sorted according to the size of the granules in the fluidized bed at a temperature of supply air 40°C with an aqueous solution of shellac was applied when the weight of the applied layer of shellac 5 wt.%, in terms of the mass of granules, membrane, resistant to gastric juice.

Composition, g:

Film coating (sheath) for 500 g of the granules

An aqueous solution of shellac ASL 125

(solid content

matter 20%, the firm Marchand & Cie) 125

Triethylcitrate 1,25

Water 136,25

The results of the study of the mechanism of release of active substances, carried out by the above method, are presented in the table below.

Example 3

1.25 kg of tramadol hydrochloride, 1.25 kg of diclofenac sodium, 1.0 kg of lactose monohydrate, 0.75 kg of microcrystalline cellulose (Avicel PH 101, FMC) and 0.75 kg of colloidal microcrystalline cellulose (Avicel RC 591, FMC) was mixed in a Diosna mixer (type P25) and the mixture granuloma is s, namely, sticky, wet granulate after granulation was not extrudible and directly spread on the foil lattice pallets and within 20 minutes was heated in a dryer at 50 to 70°C, avoiding loss of moisture; after that, the granulate was re-moistened and granulated. The extrusion was carried out in the extruder type Nica Tour (E Extruder with a diameter of extrusion heads of 0.8 mm, Spheroidization extrudate was carried out in spheroidization Nica Spheroniser (type S450). After drying, the granules in the dryer they were divided according to the size, to deliver 90% of the granules within the desired size class 0,63-1,0 mm

The composition of the granules, mg:

Tramadol hydrochloride 75

Diclofenac sodium 75

Lactose monohydrate 60

Microcrystalline cellulose

(Avicel PH 101, FMC) 45

Colloidal microcrystalline

cellulose (Avicel RC 591, FMC) 45

300

Then 5 kg of pellets of an aqueous dispersion of the following composition using a device for coating type Kugelcoater when the supply air temperature 40°With the weight of the applied coating 21 wt.% Eudragit L-55, calculated on the total weight of the pellets were covered with a shell.

Composition, g:

Captivity is S="ptx2">ethyl acrylate and poly (methacrylic

acid 1:1 copolymer) 3500

Eudragit NE30D (firm

(30% aqueous dispersion

politicalit and methyl methacrylate,

copolymer) 315

Triethylcitrate 175

Talc micronized 262,5

Water 3657,5

The capsules

Portion 400 mg of pellets in the shell together with 46 mg of granules released with the initial dose of tramadol (corresponding to 25 mg of tramadol hydrochloride, 10.5 mg Avicel PH 105 and 10.5 mg isopropylidenediphenol LH31) using machines for assembling split capsules type Zanasi E6 with two dosing units were Packed up in capsules with terrorisation coating of size 0.

The results of the study of the mechanism of release of active substances, carried out by the above method, are presented in the table below.

Example 4

1.5 kg of tramadol hydrochloride, 1.0 kg of diclofenac sodium, 1.0 kg of lactose monohydrate, 0.75 kg of microcrystalline cellulose (Avicel PH 101, FMC) and 0.75 kg of colloidal microcrystalline cellulose (Avicel RC 591, FMC) was mixed in a Diosna mixer (type P25) and the mixture was granulated. The process of formation of granules (pellets) were mainly aglorithm carried out directly after the first granulation in the mixer by heating the double-shirts for 30 min until a temperature of 70°C activating this several times, the blades of the mixer in a short period of time; upon completion the reaction mixture directly, without unloading was granulated for the second time.

The composition of the granules, mg:

Tramadol hydrochloride 75

Diclofenac sodium 50

Lactose monohydrate 50

Microcrystalline cellulose

(Avicel PH 101, FMC) to 37.5

Colloidal microcrystalline

cellulose (Avicel RC 591, FMC) 37.5

250

Then 5 kg of pellets of an aqueous dispersion of the following composition using a device for coating type Kugelcoater when the supply air temperature 40°With the weight of the applied coating 22 wt.% Eudragit L-55, calculated on the total weight of the pellets were covered with a shell. Film coating (sheath) for 5 kg of pellets

Eudragit L30D-55 (firm

a 30% aqueous dispersion

polymethacrylic acid and

ethyl acrylate 1:1 copolymer) 3667

Triethylcitrate 220

Talc micronized 550

Water 4913,5

The capsules

Portions of 348 mg of pellets in the shell together with 46 mg of granules released with the initial dose of tramadol (corresponding to 25 mg of tramadol hydrochloride, Zanasi E6 with two dosing units were Packed up in capsules with terrorisation coating of size 0.

The results of the study of the mechanism of release of active substances, carried out by the above method, are presented in the table below.

Example 5

100 g of tramadol hydrochloride, 69 g of saccharin sodium and 169 g of microcrystalline cellulose (Avicel PH 101, FMC) was mixed for 10 minutes in the type mixer Kenwood Chef Mixer prior to the formation of a homogeneous mixture, which was then processed as in example 1, resulting in the required granules (pellets).

The composition of the granules, mg:

Tramadol hydrochloride 100

Saccharin sodium 69

Microcrystalline cellulose

(Avicel PH 101, FMC) 169

338 mg

The results of the study of the mechanism of release of the active substance, held on the above method, are presented in the table below.

Example 6

100 g of tramadol hydrochloride, 84 g of naproxen sodium and 184 g of microcrystalline cellulose (Avicel PH 101, FMC) was mixed for 10 minutes in the type mixer Kenwood Chef Mixer prior to the formation of a homogeneous mixture, which was then processed as in example 1, resulting in the required granules (pellets).

The composition of the granules, mg:

cel PH 101, FMC) 184

368

Investigation of the mechanism of release of active substances, which was performed according to the above method gave the following results.

Example 7

1.5 kg of tramadol hydrochloride, 1.0 kg of diclofenac sodium, 1.0 kg of lactose monohydrate, 0.75 kg of microcrystalline cellulose (Avicel PH 101, FMC) and 0.75 kg of colloidal microcrystalline cellulose (Avicel RC 591, FMC) was mixed in a Diosna mixer (type P25) before formation of a homogeneous mixture, which was then processed as in example 3 with the results in the required granules (pellets)

The composition of the granules, mg:

Tramadol hydrochloride 75

Diclofenac sodium 50

Lactose monohydrate 50

Microcrystalline cellulose

(Avicel PH 101, FMC) to 37.5

Colloidal microcrystalline

cellulose (Avicel RC 591, FMC) to 37.5

250

Then 5 kg of pellets of an aqueous dispersion of the following composition using a device for coating type Kugelcoater when the supply air temperature 40°With the weight of the applied coating 21 wt.% Eudragit L-55, calculated on the total weight of the pellets were covered with a shell.

Composition, g:

Film coating (holocrystalline

acid 1:1 copolymer) 3500

Eudragit FS 30D (firm

a 30% aqueous dispersion

poly (methacrylic acid),

of methyl acrylate and methyl methacrylate,

copolymer) 350

Triethylcitrate 210

Glycerol monostearate

(firm Cutina GMS, Henkel) 92,4

Water 3134,6

Then portions of the granules on 322,5 mg each, which corresponds to the dose of tramadol hydrochloride 75 mg and diclofenac sodium 50 mg, was mixed first with 22,5 mg cross-linked polyvinylpyrrolidone (Kollidon CL, BASF), and then 205,6 mg cellular lactose (company Meggle), 25 mg of tramadol hydrochloride and 1.4 mg of magnesium stearate and the resulting mixture is extruded oblong pill size 7×14 mm with a notch and a lot 577 mg In the aquatic environment these pills again break up into separate granules.

Investigation of the mechanism of release of active substances, which was performed using the above method gave the following results.

1. Oral dosage form of tramadol, in which at least a portion tramadol provides a prolonged effect, characterized in that tramadol, providing a prolonged effect, represents a formed in situ cm with a solubility of 100 mg/ml

2. Dosage form under item 1, characterized in that the solubility of 50 mg/ml, preferably 30 mg/ml and particularly preferably 10 mg/ml

3. Dosage form under item 1 or 2, characterized in that tramadol for formed in situ compounds are used in the form of soluble salts, preferably in the form of tramadol hydrochloride.

4. Dosage form under item 1 or 2, characterized in that to obtain a formed in situ connections use a water-soluble pharmaceutically acceptable salt of another acid, pharmaceutical active substances or excipients.

5. Dosage form under item 4, characterized in that a water-soluble pharmaceutically acceptable salt using sodium salt of diclofenac, naproxen, acetylsalicylic acid, salicylic acid, benzoic acid, saccharin, cyclamate or Acesulfame.

6. Dosage form according to any one of paragraphs.1-3 and 5, characterized in that tramadolbuy component presents in excess.

7. Dosage form under item 6, characterized in that tramadol is released at least two different speeds.

8. Dosage form by lubaina substance presented in equimolar amounts as formed in situ connection.

9. Dosage form under item 8, wherein tramadol and acid pharmaceutical active substance or auxiliary substance are released with the same speed.

10. Dosage form according to any one of paragraphs.5-7 and 9, characterized in that the tramadol hydrochloride and diclofenac sodium are used as active substances for the formation of compounds in situ.

11. Dosage form under item 10, characterized in that the molar ratio between tramadol and diclofenac is from 0.5:1 to 4:1, preferably 1:1-2:1.

12. Dosage form under item 11, wherein tramadol and diclofenac at least partially released with the same speed.

13. Dosage form under item 10, wherein tramadol and diclofenac presented in equimolar amounts as formed in situ connection and accordingly the total number of each of these active substances is released with the same speed.

14. Dosage form according to any one of paragraphs.1-3, 5, 7, 9, 11-13, characterized in that they are a composition of many particles, preferably in the form of granules, microparticles, microtablets or pellets (spherical grain is according to any one of paragraphs.1-3, 5, 7, 9, 11-13, characterized in that they are presented in the form of pills or tablets, preferably in the form of a rapidly disintegrating tablets.

16. Dosage form under item 15, characterized in that the tablets are composed of compacted pellets (spherical granules).

17. Dosage form according to any one of paragraphs.1-3, 5, 7, 9, 11-13 and 16, characterized in that they have at least resistant to gastric juice shell.

18. Dosage form according to any one of paragraphs.1-3, 5, 7, 9, 11-13 and 16 to fight the pain.

19. Dosage form according to any one of paragraphs.1-3, 5, 7, 9, 11-13 and 16 for the treatment of urinary incontinence.

20. The method of obtaining oral dosage forms with prolonged action according to any one of paragraphs.1-19, characterized in that the tramadol and acid pharmaceutical active substance and/or auxiliary substance or their respective water-soluble salts, and optionally other excipients are mixed, several times moisturize and supply the necessary energy mix is processed in the target dosage form.

21. The method according to p. 20, characterized in that the mixture is moistened aqueous media, preferably water or aqueous solutions of binder.

22. The method according to p. 20 ="ptx2">23. The method according to p. 20 or 21, characterized in that the mixture is subjected several times to the hydration and pelleting and at least a single extrusion and then optional post-processing.

24. The method according to p. 20 or 21, characterized in that the mixture, after repeated wetting, granulation, extrusion and/or drying, optionally after mixing with other excipients pellitero.

25. The method according to p. 20 or 21, characterized in that the hydrated mixture granularit, ekstragiruyut, re-hydrate and granularit, ekstragiruyut and at the end pellitero.

26. The method according to p. 20 or 21, characterized in that the hydrated mixture granularit, dried, re-hydrate and granularit, ekstragiruyut and at the end pellitero.

27. The method according to p. 20 or 21, characterized in that the pellets tabletirujut.

28. The method according to p. 27, characterized in that the pellets prior to pelletizing cover at least resistant to the action of gastric juice by the shell.

29. The method according to any of paragraphs.20, 21 and 28, characterized in that as the salt of tramadol use tramadol hydrochloride, as well as other active substances are used diclofenac sodium.



 

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The invention relates to the field of pharmaceutical industry and relates to a pharmaceutical composition for improving cerebral circulation and method of its production

The invention relates to medicine, namely to create MiniPack emergency self - help and mutual aid

The invention relates to pharmaceutical industry and relates to pharmaceutical compositions containing 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate, to prevent, treatment or inhibition of the development of a simple retinopathy or preproliferative retinopathy; the method of preventing, treating or inhibiting the development of a simple retinopathy or preproliferative retinopathy; and applying the 2-ethoxy-1-[[2'-(1 N-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]the benzimidazole-7-carboxylate

The invention relates to medicine and relates to inhibitors for use in hemostasis and immune response

The invention relates to medicine and can be used in the manufacture of solid dosage forms of drugs, which have found application in the prevention and treatment of hypertension, myocardial ischemia, caused by organic obstruction and spasm/vasoconstriction of the coronary arteries

The invention relates to medicine, in particular to pharmaceutical compositions containing the blocker of calcium and pharmacologically acceptable alkaline material, which is added in an amount such that the aqueous solution or dispersion solution of a specified pharmaceutical compositions containing a blocker of calcium, would have a pH of at least 8

The invention relates to the field of pharmaceutical industry and relates to the production of solid dosage forms of drugs to reduce the resistance of the coronary arteries and increase coronary blood flow, ischemia of heart contractions, reducing the need of oxygen, increase energy reserves attacks
The invention relates to medicine, in particular to Pediatrics, Allergology and pulmonology

The invention relates to the field of medicine and relates to a spontaneously dispersible pharmaceutical composition for oral administration comprising (2R,4S)-N-(1 -(3,5-bis(trifluoromethyl)benzoyl)-2-(4-Chlorobenzyl)-4-piperidinyl)quinoline-4-carboxamide as an antagonist of substance P and the carrier medium containing a hydrophilic component and a surfactant, and methods of treatment using the composition of CNS disorders, including depression and fear of society, and respiratory diseases, such as asthma and chronic bronchitis

The invention relates to new compounds of General formula

which have the properties of receptor antagonists neirokinina-1(NK-1)

The invention relates to medicine, in particular the creation of far metologicheskikh drugs with anti-allergic effect

The invention relates to N-substituted indole-3-glycinamide General formula I, possess Antiasthmatic, antiallergic and immunosuppressive/immunomodulatory action

where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl; R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II

where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6)alkyl or halogen, or R1presents arylamination-2-methylprop-1-ilen group, or R and R1together with the nitrogen atom to which IGN="ABSMIDDLE">

where R7denotes phenyl or pyridinyl; R2means (C1-C6)alkyl, which optionally contains a phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium residue; R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)alkyl, or R3is cyclopentanecarbonitrile; Z denotes Oh, and alkyl, alkoxy or alkylamino mean as an unbranched group, such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and branched alkyl groups such as isopropyl or tert-butylene group; halogen means fluorine, chlorine, bromine or iodine and alkoxygroup means methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan, and their pharmaceutically acceptable salts with acids

The invention relates to the field of pharmaceutical industry and relates to nasal ointment for the prevention of inhalant allergic reactions

The invention relates to medicine, namely to Allergology, and can be used for the treatment of atopic dermatitis

The invention relates to the field of medicine, can be used in the treatment of allergic diseases and autoimmune diseases and relates to pharmaceutical compositions intended for use as an inhibitor of Th2-differentiation, comprising the compound of formula (I)

The invention relates to means for inhibiting the adhesion or migration of cells, or inhibition of VLA-4 receptor, representing the heterocycles of General formula (I), where W means R1-A-C (R13), Y represents carbonyl, Z denotes N(R0), And means a divalent residue of phenylene, divalent (C1-C6)-alkalinity balance, means the divalent (C1-C6)-alkalinity residue which may be substituted (C1-C8)-alkyl, D is C(R2) (R3), E mean R10CO., R and R0independently of one another denote hydrogen, if necessary substituted (C6-C14)-aryl, if necessary substituted heteroaryl, if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl or, if necessary, substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, R1means hydrogen, Gets the remainder R28N (R21)-C(O)-, R2means hydrogen, R3means CONHR4, R11NH, R4means (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from the range hydroxy (C6-C14)-aryl, R10means hydroxyl or (C1-C6)-alkoxy, R11means R12CO., R12means R15-O-, R13means (C1-C6)-alkyl, R15means R16-(C1-C6)-alkyl, R16means 7-12-membered bicyclic or tricyclic residue, a saturated or partially unsaturated and which may be substituted by one or more identical or different (C1-C4)-alkyl residues, R21means hydrogen, R28means R21, Het denotes a mono - or polycyclic, 4-14-membered, aromatic or non-aromatic cycle, which may contain 1, 2, 3 or 4 nitrogen atom, b, C, d and f independently of one another denote 0 or 1, but at the same time may not mean zero, e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts
The invention relates to medicine and pharmacology, specifically to the preparation of tools for the treatment of allergic rhinitis and allergic conjunctivitis

The invention relates to a new five-membered heterocyclic compounds of General formula I:

in which W denotes R1-A-C(R13); Y represents a carbonyl group; Z represents N(Rabout); And denotes phenylene; E denotes R10CO; means (C1-C6-alkylene, which may be unsubstituted or substituted (C1-C6)-alkyl; R0indicates if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; Rrepresents H or (C1-C6)-alkyl; R1denotes X-NH-C(=NH)-(CH2)p; p = 0; X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or, if necessary, substituted in the aryl residue phenoxycarbonyl or benzyloxycarbonyl; R2, R2a, R2bdenote hydrogen; R3means R11NH - or-CO-R5-R6-R7; R4denotes a divalent(C1-C4)-alkalinity residue; R5denotes a bivalent residue of a natural or unnatural amino acid with a lipophilic side chain, selected from grupy residues, if necessary, replaced byin the aryl residue, and, if necessary, substituted (C6-C12)-aryl residues; R6represents a simple bond; R7denotes Het; R10denotes hydroxyl or (C1-C6)-alkoxygroup; R11means R12-NH-C(O) R12-NH-C(S) or R14a-O-C(O) R12means (C6-C14)-aryl-(C1-C6)-alkyl, if necessary substituted in the aryl residue; R13means (C1-C6)-alkyl; R14aindicates if necessary substituted heteroaryl, heteroaryl-(C1-C6)-alkyl, if necessary substituted in the heteroaryl residue, or R15; R15means R16or R16-(C1-C6)-alkyl; R16mean residue 3-12-membered monocyclic or 6 to 24-membered bicyclic, or 6-24-membered tricyclic ring; Het means a 5-7 membered monocyclic residue of a heterocycle bound over the nitrogen atom in the ring, containing, if necessary, another heteroatom from the group consisting of N, O or S; g and h denote 0 or 1, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, the

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