High drug load mesalazine sachet

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to oral pharmaceutical composition in the form of a granulate produced without spheronisation. The composition contains 92-98 wt % of mesalazine or its pharmaceutically acceptable salt, 2-8 wt % of polyvinylpyrrolidone and an ethylcellulose coating, wherein the above coating weight relates to the above mesalazine weight as 0.3-1.5% and the ethylcellulose coating weight makes 0.11-0.15 mg/cm2. The granulate is packed in a sachet, a capsule or a blister. What is also described is a method for preparing a pharmaceutical composition.

EFFECT: ethylcellulose-coated mesalazine granulate combines a high drug load and a desired mesalazine release profile, namely, 5-25% of released mesalazine 15 min later, 30-70% of released mesalazine 90 min later and 75-100% of released mesalazine 240 min later.

10 cl, 1 ex

 

Field of the invention

The present invention relates to a pharmaceutical preparation containing a high load of active drug.

In particular, it relates to a pharmaceutical preparation in the form of particles containing a high load (i.e. high mass % of the active drug is 5-aminosalicylic acid (5-ASA, mesalamine, mesalazine) for oral administration and its method of production and to Sasha for this drug.

Claimed the priority of an application for a patent Denmark RA 2003 00612, European patent application EP 03388023 and provisional patent application U.S. 60/464649.

Prior art

Well-known oral pharmaceutical preparations containing mesalazine, which are either tablets or granules. The granules may be Packed in sachets. For the purposes of the present invention, the term "sachet" refers to the envelope or package for granular, whereas the term "granulate" refers to a particle, pellet or spheronisation particles.

Currently known tablets containing 250 or 500 mg of mesalazine. Tablets containing 250 mg usually weigh about 540 mg, that is, they have the burden of medications (250/540) mass % =46% by weight. Pills containing up to 84% by weight of mesalazine described in the patent application WO 00/44353 called "Pharmazeutische Zusammensetzungen"

As for Sasha, Dr. Falk Pharma has launched a product that contains allegedly 500 mg of mesalazine in sachet weight 930 mg, which corresponds to the load of drugs constituting 54% by mass.

At the present time for the daily treatment of diseases of the gastrointestinal tract, such as Crohn's disease or ulcerative colitis, often prescribed for up to 4 g mesalazine.

If you enter 4 g mesalazine tablets containing 250 mg, the patient needs to swallow 16 pills a day. On the other hand, you can enter the tablets containing 500 mg, but with a load of drugs, about 50% of each tablet will weigh about 1 g, and for many patients, they would be too large to swallow.

There is a need to create a product which will provide the possibility of introducing a large daily doses of medication without any negative impact on patient compliance with treatment regimens.

Known methods of manufacture of oral pharmaceutical products containing mesalazine, on an industrial scale. However, in the known methods of manufacture to produce a product having the desirable characteristics of the release, requires a large number of manufacturing steps, which makes the production of bulky and expensive (e.g., as in W097/23199, which is the closest analogue of the invention.

Description of the invention

Aspects of this invention relate to the above problems and other problems mentioned below.

According to one aspect of the present invention relates to oral pharmaceutical preparation, preferably for sachets containing the number of mesalazine selected from the group consisting of 55; 60; 65; 70; 75; 80; 85; 90; 92; 94 and 96% by weight. According to a preferred aspect, the drug contains 92-98, preferably 94 to 96% by weight of mesalazine.

These aspects offer a pharmaceutical composition with a high load.

For the purposes of the present invention, the term "mesalazine" also includes its pharmaceutically acceptable salts and esters, such as salts and esters mentioned in WO 97/23199, page 15, line 17 - page 6, line 12, and also as a prodrug, such as balsalazide.

The drug is preferably in the form of material in the form of particles, such as granules, spheres, pellets, particles, preferably granules.

According to one aspect of the present invention relates to pharmaceutical drug, optionally containing pharmaceutically acceptable binder, preferably povidone, in an amount selected from the group consisting of 1; 2; 3; 4; 5; 6; 7; 8; 9; 10 and 12% by weight. According to a preferred aspect, the drug contains 1-10, preferably 2-8; more preferably 37; preferably 4-6, most preferably 5% by weight of povidone.

Pharmaceutically acceptable binding agent can include any acceptable binding agent, such as acacia gum, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, polyethylene glycol (PEG), povidone, sucrose, starch or a mixture of any of these. Povidone (polyvinylpyrrolidone, PVP) is preferred.

According to one aspect of the present invention relates to a pharmaceutical preparation further comprising a shell.

The shell should preferably contain an agent that modifies the release, such as ethylcellulose, Carnauba wax, shellac, or a mixture of any of these. Ethylcellulose is preferred.

Selected shell depends among others from the desired character of the release. It can be selected from limiting the rate of barrier materials, such as enteric material or shell material of deferred action, such as polymethacrylate, commercially available in the form of Eudragit, such as Eudragit NE 40 D or Eudragit L 100. In the case of semi-permeable polymer the preferred shell is ethylcellulose.

According to one aspect of the drug is�tsya drug with modified release, preferably the drug slow release.

According to one aspect, the drug comprises a shell, wherein the ratio of the mass of the specified shell to the mass of the specified mesalazine or the specified pharmaceutically acceptable salt is selected from 0,1-10%; 0,3-7%; 0,5-5%; 0,7-3%; 0,8-2% and 0.9 to 1.5%. The number of membranes can be adjusted to achieve the desired release profile. A very large number of shells may prevent release of the active ingredient.

According to another aspect of the present invention relates to a pharmaceutical product, essentially consisting of mesalazine, a pharmaceutically acceptable binding agent and a shell.

According to one aspect of the present invention relates to a pharmaceutical preparation having release characteristics of mesalazine in vitro comprising at least 40, 50, 60, 70, 80 or 90% released after 240 minutes of mesalazine from the total amount of mesalazine in the product, measured in a model system using a USP Paddle System 2, operating at 37°C with agitation at 100 rpm is Usually to ensure the effective release in the intestine is preferable to a more rapid release.

According to one aspect of the present invention relates to a pharmaceutical preparation having the following�following features release mesalazine in vitro:

(a) 5-25% released mesalazine in 15 min;

b) 30-70%, preferably 40-60%, of the release of mesalazine after 90 min and

b) 75-100% released mesalazine after 240 min;

of the total number of mesalazine in the product, measured in a model system using a USP Paddle System 2, operating at 37°C with agitation at 100 rpm.

The dissolution parameters for this model system were as follows:

the dissolution medium: 1000 ml of deaerated 0.1 M sodium phosphate buffer pH 7,5;

Device: USP 23 Paddle (Apparatus 2)

Shaft speed: 100 Rev/min For experiments used a sachet weighing 1 g.

According to the first preferred aspect of the present invention relates to a pharmaceutical preparation with a similarity factor of f2higher the number selected from 25, 30, 35, 40, 45, 50, 55, 60, 65 and 70, when compared with the standard, with the following release characteristics of mesalazine in vitro:

a) 12% of the released mesalazine in 15 min;

b) 50% of the release of mesalazine after 90 min and

b) 85% of the release of mesalazine after 240 min; measured in the conditions specified above.

The similarity factor f2defined as

f2=50log{[1+(1/n) t=1n(Rt-Tt)2]-0.5100}

where n represents the number of time points, R(t) represents the average percentage of dissolved active ingredient from the standard, a T(t) represents the average percentage of dissolved active ingredient from the formulation according to the invention. The factor of similarity is generally considered satisfactory if it is in the range from 50 to 100, but for the purposes of the present invention, it may even be less.

According to a second preferred aspect of the present invention relates to a pharmaceutical preparation with a similarity factor of f2higher the number selected from 25, 30, 35, 40, 45, 50, 55, 60, 65 and 70, when compared with the standard, with the following release characteristics of mesalazine in vitro:

g) 21% released mesalazine in 15 min;

e) 68% released mesalazine after 90 min and

(e) 94% released mesalazine after 240 min,

measured in the conditions specified above.

According to another aspect of the present invention relates to pharmaceutical drug packaging�n in sachet.

According to one aspect of the present invention relates to a method of manufacturing a granulate, which includes stages:

a) mixing of mesalazine with a granulating liquid;

b) obtaining a granulate by granulating, compacting or extruding;

b) drying the granulate;

g) bringing the size of the granules to the desired size and

e) sieving of the granulate as necessary; characterized by the additional step:

(e) coating of the granulate membrane;

and maybe additionally:

g) sieving the granules, coated;

h) purging granules, coated the air.

According to another aspect of the present invention relates to a method in which granules, coated, Packed in sachets.

Other suitable forms of packing containers are usually used for oral medication.

This method is a simple method of manufacturing pharmaceuticals.

According to one aspect of the invention proposed pharmaceutical composition produced without a spheronization. Thus, the composition can be obtained without a spheronization. Through this eliminates the need for auxiliary means for the spheronization that enables the preparation of pharmaceutical compositions with a high load of drugs�.

Spheronization used to obtain on an industrial scale reproducible product, visually attractive and convenient for the introduction, which leads to a high degree of compliance by the patient.

Before the creation of the present invention mesalazine medications considered it necessary to serenitybase in order to obtain a visually attractive and easily implement the product in the form of a sachet. Spheronization involves the use of auxiliary means or amplifier of spheronization, such as microcrystalline cellulose. The presence of an auxiliary means for the spheronization is the result of a load of drugs, lower compared with the loads obtained according to the present invention.

There is a need for pharmaceutical compositions with a high load, free from dust. A pharmaceutical product that meets these criteria, receive according to the aspect of the present invention without a spheronization. Such a composition can be created by obtaining a granulate. To produce a product that is visually appealing for the subject, which types the pharmaceutical preparation of the granulate can be obtained by granulation, extrusion or extrusion. Pressing can be done, for example, by means of rollers. Granular p�edocfile is produced by extrusion.

According to one preferred aspect of the present invention a pharmaceutical composition is prepared according to which the joint consideration of the patent application PCT/D01/00677 with the title "Method of obtaining pharmaceutical compositions containing 5-aminosalicylic acid for use in the treatment of ulcerative colitis and Crohn's disease", with several modifications. These modifications are that the shell needs to be adapted according to the present invention, and in that after the coating sheath, sifting and purging with nitrogen obtained granules are Packed in sachets without the need for additional excipient (Ref. Example 3 and Fig.4 of this application). Especially preferred is that the granulating liquid comprises at least 50%, more preferably 60%, preferably 70%, more preferably 80%, preferably 85%, more preferably 90% wt/wt. water.

According to one aspect of the present invention relates to a method, where a granulating fluid consists of povidone dissolved in water.

According to another aspect of the present invention relates to a method in which the specified stage of drying (b) is carried out in a fluidized bed dryer.

According to another aspect of the present invention relates to a method, in Kotor�m specified stage of bringing the size (d) is carried out by milling.

According to another aspect of the present invention relates to the method wherein the sifting stage (d) is carried out by selection of the granules passing through a sieve with hole size 1.8 mm but not passing through a sieve with a mesh width of 0.5 mm.

For the selection of the desired granules is possible to use other suitable sieves, for example having dimensions selected from the group consisting of 4,0; 3,15; 2,5; 2,0; 1,8; 1,6; 1,4; 1,25; 1,18; 1,0; 0,9; 0,8; 0,71; 0,6; 0,5 and 0.4 mm. you Can select sieves to determine the upper and/or lower limits of particle size.

According to another aspect, the resulting granules after milling, have a particle size distribution, measured using sieve analysis, where the main fraction is from 850 μm to 1000 μm. To obtain the desired particle size can be varied openings in the extruder. According to one aspect, more than 75%, more preferably 85% and most preferably more than 90% of the granules have a particle size of 850 μm to 1000 μm.

According to one aspect, the present invention relates to a method, wherein the step of coating the shell (e) is carried out using ethyl cellulose.

According to another aspect, the present invention relates to a method, wherein the step of coating the shell (e) is effected by applying the amount of shell material, far from settled�tion according to the specific surface area, so it was in the range of 0.09-0.17 mg/cm2preferably of 0.11-0.15 mg/cm2, most preferably from 0.12 to 0.14 mg/cm2, followed by drying. It was found that these quantities are suitable for the coating of ethyl cellulose.

It was found that the desired release profile can be obtained by controlling the amount of shell material used according to the specific surface. The specific surface can be measured using permenetly according to "Evaluation of a permeametry technique for surface area measurement of coarse particulate materials, International Journal of Pharmaceutics, Eriksson et al., 1990, 63, p.189-199".

The granules obtained according on the joint consideration of the patent application PCT/DK01/00677, preferably with modifications according to the present invention, is particularly preferred because it has a smooth surface that facilitates the measurement of the specific surface and the subsequent application of the shell.

In order to make it possible to determine the number of the shell, which should be applied to the granules, measured surface area. Based on the measured correlation between the number of membranes on the surface area and the velocity profile of dissolution, it is possible to predict the required number of shells on the basis of the measured surface area of the granules. This number is reguliruetsya trial and error, because it depends on the exact conditions used, for example from setting and excipients.

According to one aspect of the present invention relates to a method, wherein the step of sieving (g) is carried out on rotary sieve, preferably with a hole size of 2.5 mm, to obtain coated granules with size smaller or equal to 2.5 mm.

For selection of desirable size of the coated granules can be used other suitable sieves, for example having a mesh size selected from the group consisting of 4,0, 3,15, 2,5, 2,0, 1,8, 1,6, 1,4, 1,25, 1,18, 1,0, 0,9, 0,8, 0,71, 0,6, 0,5 and 0.4 mm.

According to one aspect of the present invention relates to a pharmaceutical preparation, preferably according to any one of the above mentioned aspects, obtained according to this method.

According to one aspect of the invention relates to pharmaceutical preparations for use in medicine.

According to another aspect of the present invention relates to the use of mesalazine for the manufacture of a pharmaceutical preparation according to the invention, containing the total amount of mesalazine selected from the group consisting of 0.5 g, 1.0 g, 1.5 g, 2 g, 3 g, 4 g, 5 g, 6 g, 8 g and 10 g.

According to another aspect of the present invention relates to the use where the medicine is intended to treat ill�of the gastrointestinal tract (SECT), preferably, Crohn's disease or ulcerative colitis.

The preparations according to the invention are suitable for treatment SECT.

According to one aspect of the invention relates to a method of treatment SECT, comprising administering to the patient the drug according to the invention, preferably 1, 2, 3 or 4 times daily.

The preparations according to the invention can be Packed in different containers, which provide the possibility of their administration to patients, such as capsules, blister packs, dispensers, glass or plastic containers and sachets.

According to one aspect of the present invention relates to a sachet for a pharmaceutical product, preferably according to the invention.

Currently sachet can be used for any pharmaceutical drug, but it is particularly suited for storage of pharmaceutical preparations containing sensitive substances, such as mesalazine.

According to another aspect of the present invention relates to a sachet containing the following layers:

1) paper;

2) binding layer, preferably the binding agent, such as polyethylene;

3) the barrier layer, preferably aluminum foil; and

4) insulating layer, preferably low density polyethylene.

Mesalazine sensitive to moisture, air and/or light. �Ashe for the product containing mesalazine, therefore, should preferably provide a barrier to moisture, air and light. Sasha also has to be convenient for opening the patient, preferably without the use of additional tools such as scissors. There was a problem creating the sachet with the necessary barrier properties without compromising the ability of opening the sachet by breaking the fingers of a person. In addition, the existing Sasha have a tendency to accumulate static electricity. Preferably, the sachet should be easy to manufacture, easy to fill and to empty, and it should have the appearance, attractive for the patient to improve compliance with treatment regimens.

In this aspect of the proposed sachet, ensuring long-term stability when stored therein a pharmaceutical composition, for example, when the active pharmaceutical ingredient is mesalazine. In addition, it is convenient to tear and static electricity in it is eliminated, which provides the possibility of its complete emptying. The combination of Sasha and oral preparation according to the present invention ensures a low accumulation of static electricity.

According to one aspect of the present invention relates to a sachet, where the binding layer (2) preferably has�t quantity of mass per unit area, component of 6-20 g/m2preferably 9-15 g/m2, more preferably 12 g/m2; the barrier layer (3) preferably has a thickness of 6-30 μm, more preferably 7 to 25 μm, preferably 9-25 μm, more preferably 8-20 μm, preferably 9 to 15 μm, more preferably 12 μm; and/or insulating layer (4) preferably has a mass per unit area, which is 10-100 g/m2more preferably 15-75 g/m2, preferably 20-50 g/m2more preferably 30-40 g/m2, most preferably 35 g/m2.

The outer paper (1) in the preferred embodiment has a mass per unit area, which is 10-100 g/m2preferably 30-70 g/m2, most preferably 50 g/m2.

According to another aspect of the present invention relates to the use sachets for pharmaceutical compositions according to the invention.

Sasha demonstrated the suitability for storage of pharmaceutical compositions according to the invention.

According to another aspect of the present invention relates to the use sachets for medical purposes.

According to the aspect of the present invention it is not limited to the use of mesalazine as the active ingredient, and also relates to other active ingredients such as the ingredients mentioned in WO 00/44353, pp. 12-16. D�I of the present invention are suitable for other less effective active ingredients. As a substitute of mesalazine is the most promising ibuprofen.

According to one aspect of the present invention in the composition of the invention may include additional excipients, such as fillers, disintegrants, pH regulators or surfactants. Such excipienti well known from the literature, such as the number of suitable excipients see WO 00/44353, pp. 16-20.

Examples

Unless otherwise indicated, all percentages are quoted as % by weight.

Example 1

The party for the manufacture 180000 sachets with granules prolonged release had the following composition.

ComponentsNumberSpecification
Mesalazine180 kgFerring
Povidone9 kgPh. Eur.
Purified water33,3 kg∗∗Ph. Eur.
Ethylcellulose1.9 kg∗∗∗Ph. Eur.
Acetone188 kg∗∗ Ph. Eur.

∗∗ Evaporated during the production process.

∗∗∗ The amount of ethyl cellulose was regulated in such a way as to provide the desired dissolution profile of the final product.

Ph. Eur. (European Pharmacopoeia) refers to the current edition at the date of filing the present application.

The manufacturing method is very similar to the method of manufacture, are described in the joint consideration of the patent application PCT/DK01/00677, with some exceptions. Regulate the amount and type of ingredients, and in particular, the amount of ethyl cellulose reduced so as to obtain a desirable dissolution profile. In this example, tablets are produced, so necessary for the purpose of excipients not included. Also not carried out by dry mixing after air blowing and not spend tableting. Therefore, the granulated product obtained in this way differs from the tablet in the specified application.

A method of manufacturing a drug can be divided into 9 stages:

1. Preparation of granulating fluid

2. Granulation of mesalazine with water and PVP

3. Extrusion

4. Drying in a fluidized bed

5. The grind

6. Screening

7. The application wrapper

8. Screening

9. A blast of air

The equipment for manufacture
Function
NICA extruder E220Extrusion
Rotostat tMixing
The fluidized bed dryerDrying
NIRO
Quadra Comil U10Grinding
Sieve MogensenSieving
Huttlin Kugelcoater HKC 400Drawing of the shell
Rotary sieve ProdimaSieving
Installation for purgingA blast of air

Stage 1:

To prepare one batch of a granulating liquid filled water drum Muller (Muller). Set the mixer to its working position and begin the process. The water slowly sprayed polyvinylpyrrolidone (PVP) and leave the mixer to operate for a fixed time until complete dissolution of all PVP.

Stage 2 and 3:

IU�Alain placed in a vibrating hopper Prodima and by means of the conveyor are transported in a weight tape dispenser, dosing mesalazine in-line continuous Niro. In the first part of the line Niro mesalazine and an aqueous solution of PVP to mix wet mass before transporting the extruder. After pushing wet mass of mesalazine and PVP/water through a sieve with meshes of 0.9 mm, the granules fall directly into the fluidized bed dryer.

Stage 4:

The fluidized bed dryer is divided into two main sections. In the first section of the dried pellets from the surface to prevent them from sticking. In this section of the dryer fluidized bed occurs indiscriminate mixing of granules. After treatment for a certain period of time, the granules move to the second part of the dryer where there is a real drying. In this second part of the dryer granules treated by passing drying air through the dryer (a special kind of holes in the Gill plate). When the granules are dry, give them to fall into the drum, located below the fluidized bed dryer. The fluidized bed dryer is designed so that the total residence time in the dryer was approximately 2.5 hours.

Stage 5:

Drums containing dry pellets, placed upside down in the top of the mill and gently grind the pellets, using a sieve, which breaks only too long pellets. After the passer�moving through the mill the granules fall into the drum.

Stage 6:

Due to the fact that the milling process leads to the formation of a small amount of the insufficient size of the granules, the granules are sieved using a vibrating sieve Mogensen (Mogensen). The pellets that pass a 0.8 mm sieve, discard, or they can be collected for recycling if stored in an airtight, labeled containers.

Stage 7:

200 kg sieved granules covered with a shell in the installation of Kugele (Kugel) for coating system (fluidized bed) using a film-forming liquid consisting of ethyl cellulose dissolved in acetone.

In order to make it possible to determine the exact amount of ethyl cellulose required for application to the granules to obtain a desired velocity profile of dissolution, before the operation of coating measured the surface area of the granules. The method of predicting the number of membranes that must be applied to the granules was developed on the basis of the fact that there is a correlation between the number of membranes on the surface area and dissolution rate of the granules.

When the stage of the coating was performed in an installation for applying the sheath 400 AUC Huttlin Kugel with subsequent sieving to size, characteristics of the release according to the invention, measured as released % of total� mesalazine, or according to the first preferred aspect, defined by the factor of similarity, obtained when the amount of ethyl cellulose was increased to 0.13 mg/cm2.

After the process of coating the granules, coated, charged into the drum for further processing.

Stage 8:

After drawing on them shell granules, coated, screened in a rotary sieve Prodima. Large lumps of cast.

Step 9:

After sifting batch of granules, coated, they are distributed in two reels for compressed air or nitrogen. The pellets are purged for 6-14 hours. This process of purging required to reduce the amount of residual solvent (acetone) in granules, coated.

This party gave the granulate with the following approximate composition:

Mesalazine94,3%
Povidone4,7%
Ethylcellulose1,0%

Further, this granulate is filled sachet.

The sachet material had the following composition:

Paper, claycoated50 g/m2
Polyethylene (PE) low density12 g/m2
Aluminum foil12 µm
Low-density polyethylene35 g/m2

For this example, 12 g/m2PE corresponds to 13 microns, and 35 g/m2PE corresponds to 38 μm. The material has a mass of 1 m2equal to 129 g/m2. The permeability to water vapor was less than 0.05 g/m2, 24 h, 25°C, RH (relative humidity) 75%, and O2- less than 0.05 ml/m2, 24 h, ATM (101325 PA), 23°C, RH 75%.

Sasha folded around the feed tube filling/packing installation so that the paper was on the outside of the sachet, and then glued in the longitudinal direction of the low density polyethylene as an insulating layer. After the formation of the transverse seam in the lower part of the sachet it was filled with pellets and then re-glued at the top and finally cut off.

All cited documents are incorporated in their entirety by reference.

1. Oral pharmaceutical composition in the form of granules obtained without a spheronization containing
- 92-98% by weight of mesalazine or its pharmaceutically acceptable salt and
- 2-8% by weight of polyvinylpyrrolidone,
the given com�azizia additionally includes a shell, containing ethylcellulose, where the ratio of the mass of the specified shell to the mass of mesalazine (or its salts) is 0.3-1.5% and the weight of the shell of ethyl cellulose 0.11-0.15 mg/cm2
and has the following release characteristics of mesalazine in vitro:
(a) 5-25% released mesalazine after 15 min,
b) 30-70% released mesalazine after 90 min and
b) 75-100% released mesalazine after 240 min;
of the total amount of mesalazine in the composition, measured in the model system using a USP Paddle System 2, operating at 37°C with agitation at 100 rpm,
where said composition is packaged in a sachet, capsule or blister packing.

2. Pharmaceutical composition according to claim 1 having the similarity factor f2calculated by the formula

where n represents the number of time points, R(t) represents the average percentage of dissolved active ingredient from the standard, a T(t) represents the average percentage of dissolved active ingredient of the composition,
above 30 when compared to the standard having the following release characteristics of mesalazine in vitro:
a) 12% of the release of mesalazine after 15 min,
b) 50% of the release of mesalazine after 90 min and
b) 85% of the release of mesalazine after 240 min,
measured in the conditions specified in paragraph 1.

3. Phar�maceutical composition according to claim 1 or 2, essentially consisting of mesalazine, polyvinylpyrrolidone and shell.

4. A method of manufacturing a pharmaceutical composition according to claim 1, which includes stages:
a) mixing of mesalazine with a granulating liquid containing polyvinylpyrrolidone;
b) obtaining a granulate by granulating, compacting or extruding without a spheronization;
b) drying the granulate;
g) bringing the size of the granules to the desired size and
e) sieving of the granulate as necessary;
(e) coating the granulate with a shell of ethyl cellulose, where the ratio of the mass of the specified shell to the mass of mesalazine (or its salts) is 0.3-1.5% and the weight of the shell of ethyl cellulose 0.11-0.15 mg/cm2; and
g) packing of these coated granules in sachet, a capsule or blister packing.

5. A method according to claim 4, comprising the additional steps of:
g) sieving the granules, coated;
h) purging granules, coated the air.

6. A method according to claim 4 or 5, where the specified granulating fluid consists of polyvinylpyrrolidone dissolved in water.

7. A method according to claim 4 or 5, where the specified stage of drying (b) is carried out in a fluidized bed dryer.

8. A method according to claim 4 or 5, where the specified stage of bringing the size (d) is carried out by milling.

9. A method according to claim 4 or 5, where the specified stage of screening (e) carry out PU�eat selection of the granulate, passing through the sieve with hole size 1.8 mm but not passing through a sieve with a mesh width of 0.5 mm.

10. A method according to claim 5, where the specified stage sieving (g) is carried out on rotary sieve.



 

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2 cl, 2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to therapy and gastroenterology, and can be used to assess the effectiveness of prokinetics at a various degree of bradientery in patients with aggravated chronic obstructive pulmonary disease (COPD) receiving standard therapy, and a prokinetic or a combination of prokinetics. That is ensured by calculating an average bradientery index (index) before the beginning of the therapy and on the 11th day from the beginning of the therapy with scoring a circadian rhythm regularity of the intestinal evacuation function. If the patient has a stool 7 days a week, zero points are assigned; if he/she has a stool 5-6 days - one point is assigned; 3-4 days - two points, 1-2 days - three points. The formula index=(P0+P1+P2+P3) /Pcom, wherein P0 is the number of patients in the group having zero points, P1 - having one point, P2 - having two points, P3 - having three points; Pcom is the number of patients in the group. That is followed by calculating a bradientery manifestation coefficient Cbm by formula Cbm=(index 11 day /index 1 day)×100%, wherein index 1 day is the bradientery index before the beginning of the treatment; index 11 day is the bradientery index on the 11th day of the treatment. If Cbm makes more than 70%, then the clinical effect of the prokinetic is considered to be unpronounced. If Cbm makes 40% to 70%, the moderate manifestation of the clinical effect of the prokinetic is considered. If Cbm is less than 40%, the clinical effect of the prokinetic is considered to be adequate for the correction of the motor evacuation dysfunction of the gastrointestinal tract.

EFFECT: providing the clinical assessment of the clinical effectiveness of the prokinetics of various groups, as well as enabling the selection of the most optimal preparation for the correction of the gastrointestinal motility disorders in the patients with COPD.

2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to new oxyindole derivatives of formula (I) or their pharmaceutically acceptable salts, based pharmaceutical compositions and using them for treating various disorders, which are mediated through the motilin receptor (GPR38). In general formula I, R1 means hydrogen, C1-C4alkyl or C3-C7cycloalkyl; R2 means C1-C4alkyl or C3-C7cycloalkyl; or R1 and R2 together with atoms which they are bound to, form a 3-6-merous ring, which can contain oxygen; R3 and R4 mean hydrogen or C1-C4alkyl; R5 means hydrogen or C1-C4alkyl; R6 and R7 mean hydrogen, C1-C4alkyl or C1-C4alkoxy C1-C4alkyl; or R6 and R7 together with a nitrogen atom which they are bound to, form a 4-6-merous ring, which can contain nitrogen or oxygen; the 4-6-merous ring is optionally substituted by 1-4 substitutes specified in a group consisting of C1-C4alkyl, amino, C1-C4alkylamino and di(C1-C4alkyl)amino; A means or , wherein p, q and r independently have the values of 0, 1 or 2; R8 and R9 mean hydrogen or C1-C6alkyl; wherein alkyl is optionally substituted by hydroxy, C1-C4alkyl, amino, C1-C4alkylamino and di(C1-C4alkyl)amino; or R8 and R9 can be combined to form a C3-C7-merous ring; or R8 and R9 can be independently combined with one or both R8 and R9 groups to form alkylene bridges between terminal nitrogen and an alkyl part of R8 or R9 groups; the bridge contains 1 to 5 carbon atoms; the above bridge is optionally substituted by 1-4 C1-C4 alkyl groups; W means N-R10, the above R10 means hydrogen or C1-C4alkyl; X means C0-C4alkylene or C0-C4alkylene-K-C0-C4alkylene, wherein K means -O- and wherein alkylene is optionally substituted by C1-C4alkyl; Y means hydrogen or a 5-10-merous ring; the above ring is optionally substituted by hydroxyl, halogen, halogen C1-C4alkyl, C1-C4alkyl or C1-C4alkoxy; provided X means C0, Y means other than hydrogen; Z means halogen or C1-C4alkyl; m has the value of 0, 1, 2, 3 or 4; n has the value of 0, 1 or 2.

EFFECT: preparing the new oxyindole derivatives.

10 cl, 15 tbl, 99 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to substituted imidazo[1,2-a]pyridines of formula I

,

where R is -CH2COOH or -COOH. The invention also relates to a method of producing a compound of formula I and use of the compound of formula I.

EFFECT: obtaining novel substituted imidazo[1,2-a]pyridines, which inhibit exogenically or endogenically stimulated secretion of gastric acid and which can be used in preventing or treating diseases associated with gastric acid, and inflammatory gastrointestinal diseases.

6 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and chemical-pharmaceutical industry, namely to drug preparations used in various spastic intestinal and pancreatic-biliary conditions, especially in irritable bowel syndrome, and to methods for making them. The drug preparation in the form of an orally dispersible tablet characterised by the fact that it contains a combination of hyoscine butyl bromide and diclofenac or its sodium salt in complex with polacrilin potassium in ratio of diclofenac or its sodium salt and polacrilin potassium of 1:2, and pharmaceutically acceptable additives containing mannitol, aspartame and crospovidone. Polyvinyl pyrrolidone K30, a flavouring agent and anhydrous colloidal silicon dioxide.

EFFECT: tablets have the improved bioavailability of the agent.

2 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and represents a therapeutic composition in the form of an orally dispersed tablet for treating a pain syndrome in smooth muscle spasm characterised by the fact that it contains a combination of hyoscine butylbromide and a non-steroidal anti-inflammatory drug (NSAID) in the therapeutically effective amounts as active ingredients and pharmaceutically acceptable additives.

EFFECT: invention provides the higher efficacy and improved bioavailability of the active ingredient.

5 cl, 6 ex, 1 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to use of the Lactobacillus paracasei CNCM I-2116 strain to treat irritable bowel syndrome. A probiotic includes dead Lactobacillus paracasei CNCM I-2116 bacteria, a fermentation substrate and/or material made from Lactobacillus paracasei CNCM I-2116.

EFFECT: invention provides the capacity to normalise post-infection hyper-contractible state of intestinal muscles.

2 cl, 4 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to therapeutic preparations of mumiyo. The therapeutic preparation which contains purified mumiyo, grapefruit citrosept, edible glycerol, ethanol and water at specific proportions.

EFFECT: preparation has a prolonged shelf life.

8 tbl

FIELD: medicine.

SUBSTANCE: invention refers to a method for Helicobacter pylori eradication of a gastroduodenal zone by a silver nitrate monotherapy consisting in administering an electrolyte solution of silver ions in the concentration of 300 mcg/l in a daily volume of 960 ml, for the first three days - in an amount of 120 ml every 3 h, 160 ml - every 4 hours and for the following three days - every 6 hours in an amount of 240 ml.

EFFECT: achieving the stable eradication of the vegetative and coccal forms of Helicobacter pylori, reducing the length of treatment by the early recovery of the involved gastric and duodenal mucosa.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine and concerns a pharmaceutical composition for treating gastrointestinal disorders and conditions containing: (a) peptide of 14 amino acids, which activates a guanylate cyclase C (GC-C) receptor, (b) an agent specified in: a proton-pump inhibitor, an H2 receptor agonist, an opioid receptor antagonist, an opioid receptor agonist, and (c) a pharmaceutically acceptable carrier.

EFFECT: invention provides reducing inflammation, pain, and improves the patient's gastrointestinal motility.

3 cl, 6 ex, 10 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to gene engineering, more specifically to producing the peptide GLP-1, modified by an oligosaccharide chain, and can be used in medicine for treating or preventing diseases associated with GLP-1. In the peptide GLP-1 with SEQ ID NO: 2 or SEQ ID NO: 3 two amino acid peptides are substituted by an amino acid modified by a complex bi-antennal oligosaccharide chain, and wherein each of the centres is specified in a group consisting of positions 18, 22, 26, 30, 34 and 36 in the peptide GLP-1 with SEQ ID NO: 2 or SEQ ID NO: 3. The above modified peptide GLP-1 can involve the deletion, substitution or attachment of 1-5 amino acids, except for the amino acids modified by the oligosaccharide chain.

EFFECT: invention enables producing the peptide GLP-1 modified by the oligosaccharide chain, which shows the stronger activity of blood glucose suppression and twice increased half lifetime as compared to GLP-1 with SEQ ID NO: 3.

24 cl, 5 dwg, 6 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention involves a granule of epidermal growth factor and a sulphur antioxidant specified in a group consisting of methionine and K2S2O7. The granules possess a target solution profile.

EFFECT: there are presented a method for preparing the above granules, a capsule, and using the above granule in treating ulcerative colitis.

20 cl, 7 ex, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and concerns a pharmaceutical composition for treating gastroduodenal ulcer in the form of tablets, capsules or gel, containing therapeutic agents and a consistency base applicable for each dosage, wherein the therapeutic agents are as follows: recombinant interferon specified in a group: recombinant interferon alpha, recombinant interferon beta, recombinant interferon gamma; antiseptics; amino acids specified in a group: arginine, histidine, lysine, cysteine, methionine, glutamic acid; and antioxidants specified in a group: beta-carotene, vitamin C, vitamin E.

EFFECT: invention has the integrated body effect promoting faster healing of the mucosal defect accompanying the aggravated gastroduodenal ulcer and preventing recurrences, including by the eradication effect.

6 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a tabletted multiunit dosage form containing an active substance specified in a compound of N+K+ATPhase inhibitor, one its individual enantiomer and its alkaline salt, wherein individually enteric-coated units of a nuclear material containing the active substance optionally mixed with alkaline compounds, is mixed with tablet excipients and tabletted. The enteric coating is at least 10 mcm thick and has such mechanical properties that tabletting the individual units mixed with the excipients in the multiunit tabletted dosage form does not reduce the acid stability of the enteric coated units by more than 10%. The invention also refers to a method for preparing the multiunit dosage form, according to which the material units containing the active substance are mixed whenever necessary with the alkaline compounds; then these can be coated with separate layers; the enteric coating is applied, mixed with the excipients and tabletted.

EFFECT: what is declared is a method for inhibiting gastric acid secretion or treating gastrointestinal diseases in mammals and humans by administering a therapeutically effective dose of the multiunit tabletted dosage form.

17 cl, 2 tbl, 19 ex

FIELD: medicine.

SUBSTANCE: method involves prescribing proton pump inhibitor with one antibiotic in a dual therapy and with two antibiotics with a triple therapy twice a day within the course of 7-10 days. Helicobacter is eradicated by the separate administration of drugs. The proton pump inhibitor (omeprazole or pantoprazole) is administered two hours before the antibiotic in the dual therapy and four hours before the second antibiotic in the triple therapy. The drugs are taken for the second time 12 hours after the first one. The antibiotics (clarithromycin, amoxicillin or fromilid) are taken with water 250ml.

EFFECT: invention enables providing the more effective eradication of Helicobacter by the exposure of total therapeutic bioavailability of each preparation with underlying permanent gastric alkaline environment.

2 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel amides of Lambert acids (13-E-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) eudesmanolides) of formula (Ia-c), having antiulcer activity. In formula (Ia-c)

where R1=R2=Me, X=H (Ia) or R1=R2=Me,

R1=R2=C7H15, R2=H, X=H (Ic). The compounds relate to class 3 moderately hazardous substances.

EFFECT: compounds exhibit marked antiulcer activity on an indomethacin ulcer model.

1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, represented by formula 1, where m stands for an integer number from 1 to 5; and Q represents a heteroaromatic ring or phenyl, where the heteroaromatic ring is selected from the group, consisting of triazole, tetrazole, indole, imidazole, pyridine and pyrrole, and is independently substituted with 0, 1, 2 or 3 substituents, selected from C1-C4alkyl, C1-C4alkoxy, hydroxy and halogen, and where phenyl is independently substituted with 1, 2 or 3 substituents, selected from hydroxy and fluorine; a method of obtaining them and a 5-HT4 receptor agonist, which contains them as an active ingredient.

EFFECT: obtaining the novel compounds.

17 cl, 4 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics, namely to application of water-soluble polyelectrolyte complex kappa-carrageenan:chotosan with component ratio 1:10 i/v with molecular weight of kappa-carrageenan 311 kDa and with molecular weight of chitosan 115 kDa and degree of N-acetylation 6% as medication, possessing gastroprotective activity.

EFFECT: invention provides extension of arsenal of natural medications, possessing gastroprotective action, and prevention of ulcerogenic impact on stomach mucosa by creation of protective layer on its surface, as well as demonstrates larger efficiency of ulcer formation reduction in comparison with kappa-carrageenan and chitosan, taken separately.

2 cl, 4 ex, 4 tbl, 1 dwg

FIELD: medicine.

SUBSTANCE: establishing the diagnosis of myocardial infarction is immediately followed by prescribing trimetazidine MB, a modified-release cardiocytoprotector trimetazidine in a dose of 35 mg 2 times a day accompanied by enhancing motion activity gradually: degree Ia activity - turning to the sides; degree Ib activity - sitting for 5-10 minutes 2-3 times a day; degree IIa activity - sitting for 20 minutes, sitting meals, changing on a chair; degree IIb activity - walking along the chamber; degree IIIa activity - coming out into the corridor, unlimited sitting; degree IIIb activity - walking along the corridor, going up the stairs one level higher; degree IVa activity - going for a walk; degree IVb activity - taking 1.0-1.5km walk. The next degree is started in accordance with the patient's chronotropic response to physical exercises providing a heart rate gain to age-specific submaximal values.

EFFECT: method enables providing the more effective rehabilitation of the patients by the combined use of physical exercises and drug treatment accompanied by controlling an age-specific chronotropic criterion.

3 ex, 4 tbl, 1 dwg

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