Solid peroral dosed out forms of valsartan

FIELD: medicine.

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

EFFECT: valsartan bioavailability augmentation.

5 cl, 9 tbl, 12 ex

 

Angiotensinogen, i.e. α2-macroglycogen, is cleaved by the enzyme renin to form Decapeptide of angiotensin I, which itself has only a very weak biological activity. In the next stage of transformation hatshepsuts 2 more amino acids under the action of angiotensin-converting enzyme (ACE), which is primarily associated with the endothelium, with the formation of angiotensin II. The latter is believed to be one of the most powerful natural vasoconstrictors.

Angiotensin II interacts with specific receptors on the surface of target cells. Currently, progress has been made in the identification of subtypes of receptors, which, for example, is designated as the al1receptors and al2-receptors. The number of system studies of the renin-angiotensin, in particular in relation to hypertension, over the last ten years has increased almost exponentially. In the presently identified a number of receptors of angiotensin II, and some of them have been cloned and analyzed. Currently, significant efforts are being made to identify substances that are associated with al1receptor, and active compounds of this type are often referred to as antagonists of angiotensin II. As a result of inhibition at1-these receptor antagonists may, for example,be used as antihypertensive drugs, or for the treatment of congestive heart failure.

Al1and al2receptors are also explored in relation to their distribution (the relative content) and biological properties and it was found that despite a 30%homology, they are characterized by very different distribution and activity.

Al1-a receptor, which plays a major role in the regulation of blood pressure, was found in the cortical substance of adrenal glands, kidney, uterus, etc. At the cellular level, it is detected in fibroblasts, macrophages and smooth muscle cells (MMC).

In contrast, the al2-a receptor found mainly in embryonic tissues and in tissues of adult organisms, especially in susceptible to pathological changes of tissue, for example, in ischemic heart disease. In this tissue, it is localized in fibroblasts and endothelial cells.

The aim in this study was the investigation of the distribution AT1and al2receptors in the lung of a person with the use of immunohistochemical techniques and in situ hybridization.

Previously created specific antibodies to epitopes AT1-receptor, but such specific research tools are not available for the al2-receptor. As a result of its assessment apply histological studies based on the use of labeled using for the active isotope of receptor antagonists, in combination with autoradiography, which allows to obtain only a relatively coarse data on the localization in the tissue. However, in the last 2 years became available specific well-characterized antibodies to the human receptor, and it was used in the following studies.

Methods and materials

1. The specificity of the antibodies and probes for in situ hybridization (ISD and titration

To confirm the specificity of the immunocytochemical (ISA) research and research method ISF, from the Department of pathology, University hospital (Pathology Dept., University Hospital, Ghent, Belgium, had been embedded in paraffin blocks normal human adrenals (cortical substance and the brain substance) and used as material for testing. It is known that al1-receptors are mainly localized in the cortical substance of adrenal glands, and al2receptors in the medulla.

For the study of human light control material received after the autopsy, when patients died for reasons not related to lung disease, for example, in accidents. Some of these materials were received from the above organisations, Ghent, some from the archives of Department of pathology hospital of Pennsylvania (Pathology Dept. of The Pennsylvania Hospital, Philadelphia, USA. Selected fabrics, containing some m is high and the respiratory tract, because they are probably more prone to damage.

All samples were fixed in 10%buffered formalin as quickly as possible after death, obezvozhivani and embedded in paraffin wax. Did the slice thickness of 3-5 μm and placed on drugs are covered with the silane glass slides.

In order to minimize the various changes associated with processing on each glass slide was placed on two consecutive slice, one for processing the antibody to the al1and the other for processing the antibody to the al2. Concurrently processed up to 20 slide so that, with the exception of primary antibodies, all reagents, including the Chromogen were identical. Thus, the only variable factor was the thickness of the slices, which cannot fully control.

2. Antibodies

Tested two antibodies AT1-receptor, obtained from company Santa Cruz Inc., San Diego, California USA, (clones # 10 and 306), and found the same distribution of the receptor in the cortical substance of the adrenal glands.

The main part of the research conducted with antibody to the al2the receptor obtained from the firm Santa Cruz (clone C18), which for the experiments found that it gives the same pattern of staining in the medulla of the adrenal gland and lung, as the first antibody.

All antitaliban strictly analyzed by manufacturers and private providers in terms of their specificity and cross-reactivity.

3. IS-probes

The products of polymerase chain reaction (PCR products) were obtained and used as follows:

Designed oligonucleotides that are specific for the human receptor type I angiotensin II (GenBank registration number M) and receptor type II angiotensin II (GenBank registration number U15592), using the software Oligo 5.0 for homologous regions of the two sequences (table 1). cDNA from human bone were obtained using standard methods (Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: a Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989). For PCR used the following pairs of oligonucleotide primers: for receptor type I angiotensin II-5'-CTggCTgACTTATgCTTTTTACTgACT-3' and 5'-gATgCAggTgACTTTggCTACA-3'; (PCR product length 236 base pairs) and receptor type II angiotensin II-5'-ATTTACTCCTTTTggCTACTCTTCCTC-3' and 5'-ggTCACgggTTATCCTgTTCTTC-3' (PCR product length 489 base pairs). PCR amplification was performed using 10 ng of cDNA template, using thermoacetica type MJ Research PCR Cycle and the following cycles of PCR: 1) 94°C/2 min, 2) 94°C/10 s, 60°C/30 s, 72°C/15 C for 35 cycles, using polymerase High Fidelity Taq (firm Boehringer Mannheim) in combination with the components included in kits manufacturers. The products of PCR amplifiable identified by electrophoresis on 0.8% agarose/TBE-gel (Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: a Laboratory Manual, 2nd ed., Cold Spring Habor Laboratory Press, Cold Spring Harbor, NY, 1989). To confirm the identity of PCR products amplification DNA was suirable from the gel and cloned into the cloning vector And/T pMOSBlue (firm Amersham). For colonies containing DNA inserts of the correct size (table 1)was subjected to complete sequencing of both circuits to confirm their identity.

Each probe as sense and antisense for AT1and only antisense, as described above, were marked by fluorescent (fluorescently-cyanate; FITZ) and the presence of mRNA in the cells was determined after hybridization with the probe, applying for detection of mouse antibody to FITZ plus system alkaline phosphatase - antibody to alkaline phosphatase (ARAR). This method of introduction of the label increases the probability of detecting very small quantities of copies.

4. Immunocytokine

For all antibodies used the following procedure. Slices with a thickness of 5 μm was first processed using the methods return antigen in combination with treatment with microwaves nitrate buffer (pH 6.0).

The exposure time was 20 min, and slides were left to cool in the buffer. When antibody was a goat polyclonal antibodies, we used the method based on a mixture of peroxidase-antibody to peroxidase (PAP) diaminobenzidine (DAB) as a Chromogen, and the rabbit polyclonal antibodies used in the system ARAAR with new fuchsin. Sections were first treated with 1%bovine serum albumin (BSA) for 30 min to block non-specific receptors, and then incubated with primary antibody for 30 min at room temperature. Each antibody was titrated and received the following optimal cultivation:

Used antibodiesLung tissuesThe adrenal gland
Al1clone N 101:2001:500
clone N 3061:2001:500
Al2clone 181:1501:500

As a negative control for rabbit polyclonal antibodies were applied negative serum from Dako (firm Prosan, Ghent, Belgium), goat polyclonal antibody primary antibody is not used.

IS

Slices with a thickness of 5 μm was released from paraffin and then subjected to hybridization "in situ", according to well known methods. The slices are first treated with a solution for pre-hybridization for 20 min at 55°C. Then they were washed before being processed by probes during the course the e night at 55°C. After additional washing, they were treated murine antibody to FITZ and system for detecting ARAAR to locate the specific transcript. For al1-receptor semantic probe consisted of a negative control, for the al2-receptor probe is not used.

Image analysis

To quantify the intensity of staining slides were visually examined with the device type Leica MR500 and the amount of paint per unit area of the fabric was evaluated in units of image pixels), following the instructions in the Leica. This was performed to determine correlations AT1-receptor and al2-receptor in various fields. These areas include (a) the epithelium of the respiratory tract, (b) located under the epithelium of interstate,) MMC from the area around the blood vessels and g) mucous glands.

Results

Distribution in sections of the adrenal glands

The distribution of al1receptor: both antibodies obtained following the scheme of distribution in the cortical substance of adrenal glands, for which, as expected, characterized by different staining around the cells of the smooth muscles surrounding blood vessels, as well as network interstate on fibroblasts and around them. Staining of endothelial cells was not detected.

The distribution of al2receptor: From what ispolzovaniem antibodies was evaluated distribution in the medulla of the adrenal glands, in this area revealed a pronounced staining of cells pheochromocytoma.

IS: Both antisense probe gave the same picture.

Assessment of lung

The distribution of al1receptors: Found a very clear staining of cells interstate underlying the epithelium of the respiratory tract (subepithelial), as well as the edges of the smooth muscle cells (MMC)surrounding blood vessels. Positive staining was detected for macrophages.

The distribution of al2receptor: receptor revealed that he is largely associated with the epithelial cells of the respiratory tract, and the most heavily painted brush border. Positively stained cells are also found in some mucous glands, some endothelial cells of blood vessels and fibroblasts, chondrocytes and macrophages. Not detected staining MMC.

IS: In this analysis, the probes gave the same picture. In particular, using the al2probe a strong signal is received only on endothelial cells and some mucous glands.

Image analysis

The distribution of protein and, consequently, receptors, defined by the intensity of staining, i.e. in pixels/μm2tissue presented in the following table.

The epithelium of the respiratory tractThe subepithelial regionGlandMMC
AT10,0080,0010
Al250-150,00

The presence of angiotensin II receptors in the cortical substance, and the medulla of the adrenal glands was previously demonstrated by biochemical and histological methods. Data obtained using both commercially available and obtained from specialists antibodies confirm these results, but also allow to prove the possibility of applications immunocytochemical and IS methods that were used in the present invention.

Taking into account the results obtained in this study was the comparison of the distribution of al1and al2receptors in normal and diseased tissues of the lung in order to clarify the specificity of the distribution of al1and al2receptors and their relationships.

The presence AT1receptors in the lung was previously confirm redene biochemically and in this study demonstrated their precise cellular localization. This information is extremely important to identify the relative content of al1and al2receptors in various regions of the lung in normal and pathological conditions.

Information about the distribution, first of all, al2receptors are brand new, because so far no data on their presence or distribution. From the results of this study follows several important provisions.

First, the presence of al2-receptor on epithelial cells of the small bronchi of the respiratory tract. As it was already known that this receptor is considered to be antifibrosis, antiproliferative and proapoptotic. Therefore, increasing or decreasing regulation in epithelial cells has a significant impact on the replacement of epithelial cells, hyperplasia and even plays a role in the development of lung cancer.

Secondly, the presence of significant amounts of protein in the brush border of epithelial cells may well korrelirovat with the level of mucus secretion, as has been established, some of the epithelial cells of mucous glands also have this receptor. From the data obtained using IS, it follows that some glands contain a large number of copies of mRNA.

Finally, the presence of al2-receptor on endothelial the s cells of blood vessels in the present invention confirmed as using immunocytochemistry, and by in situ hybridization. Found that they are comparatively rare and not all the cells of each particular vessel.

These studies confirm and extend the data on the presence and distribution of angiotensin II receptor type al1and al2in light of the person. The presence of al2-receptor on epithelial cells of the small Airways is important for understanding the origin of diseases associated with changes in the function of these cells.

There is very little data on the localization of AT receptors in the lung of man and their distribution, increasing or decreasing regulation and the ratio in normal and diseased lung tissue. For this study received the samples of normal lung samples from patients suffering from chronic obstructive pulmonary disease (chronic obstruction of the respiratory tract) (HOLS) ± hypertension.

Samples of light

The lung samples were received from the following groups of patients, all of whom had clinically confirmed diagnosis.

NN (n=3)- non-Smoking, normal tissue
With (n=5)- smokers, but otherwise normal
OLZ (n=8) - HOL-positive, with normal blood pressure (KD)
HOLZ/N (n=3)- HOLES plus hypertension
N (n=4)- smokers with a high KD

The respiratory tract was carefully cut from the lungs immediately after removal of the light from the body of the patient during tumor resection or for other indications. Carefully selected a region that does not contain any cancerous tissue. Then small blocks were fixed in 4%paraformaldehyde for 2 h at room temperature to fill in paraffin wax. This ensures optimum structural integrity and preservation of antigenic activity.

Methods for determining the localization of the receptor

a) Immunocytokine (ICH). Tested 2 x antibodies against al1the firm Santa Cruz (clone N-10 and 306). Also tested one antibody to the al2the firm Santa Cruz (clone 18).

These digital images were shown:

The distribution of al2-receptor in the epithelial cells of the bronchioles, including brush fringe, and on the cells of the mucous glands.

For the neighboring slice, painted against AT1receptors found a strong difference in the distribution on the smooth muscle cells, fibroblasts/stroma and macrophages.

Analysis of human lung, in atogo patients

Out of all the received material was prepared slices and stained according ICH to identify localization as AT1and al2-receptor using appropriate negative controls. The image analysis began with obtaining data for a single slice, obtained from the lung of one patient (it is a slow process, since it must be strictly complied with baseline). Were evaluated epithelium and subepithelium and blood vessel. This analysis was performed "blind", so that couldn't be made any comments, except for the fact that some "patients" are pronounced levels, differ greatly from the average. Differences associated with different thickness sections and staining, were minimized as a result of simultaneous implementation AT1and al2-ICH using two consecutive slices. Thus, also could be used by one party Chromogen.

Data on the localization in the epithelium of the lung, al2-receptor important for several reasons. Because we found that this receptor is antiproliferative, antifibrosis and proapoptotic, you can expect it to increase regulation can lead to various lung diseases; for example, that only one Smoking has an effect. This receptor games the et role in areas related to fibrosis conditions, as respiratory distress syndrome in adults (ARDS), or even in reducing the proliferative capacity of epithelial lung cancer.

Results

Localization of receptor

All antibodies and ribonucleotidic probes were tested against normal cortical substance of the brain substance of adrenal glands, where, as you know, both types of receptors are present in relatively large amounts.

The process was repeated using normal lung tissue, in which the applicants were able to detect and AT1and al2receptors and their mRNA. Localization was the following:

AT1- on the smooth muscle cells, fibroblasts/stroma, macrophages. This result was very predictable, except that the intensity of staining and the number of receptors in normal lung tissue was very high.

Al2- on the epithelial cells of the bronchi (especially on the brush border), on the mucous glands (some). In addition, the epithelial cells of blood vessels, fibroblasts, macrophages and cartilage cells. These data are completely unexpected and new and need additional study. Localization in epithelial cells and mucous glands confirmed in content as protein and mRNA localization in the brush border associated with secretion of mucus.

Distribution AT1and al2the angiotensin receptor in the lungs of patients with chronic bronchitis compared with the control
GroupThe epitheliumSubapicallyRatio
Al1Al2AT1Al2AT1(subepithelial)/al2(apital s)
control (1)0,027,154,070,010,56
smokers N=4
control (2)0,029,496,451,30,67
Smoking
N=5
control (3)0,17,9711,020,041,38
smokers suffering from hypertension
HOLZ0,106,8419,640,112,87
smokers, without hypertension (N=7
HOLZ0,306,016,120,051,01
smokers suffering from hypertension N=3

The device Leica (analyzer image type MR 500) translates the intensity of color in the gray scale (0-250), each unit corresponds to one pixel. It enables us to quantify the data.

These data are based on the analysis of the image of the body of the patient. Data are expressed in pixels per unit area of positively stained tissue and the average value for the five areas on a glass slide.

As can be seen from the above results, the ratio of the content AT1in subepithelial and al2in the epithelium in normal lung tissue significantly below 1, while this ratio is close to 1 or above 1 in diseased lung tissue. The epithelium forms the inner lining of the trachea and the majority of the bronchi. The increase in the ratio of the concentrations of the receptors at1/Al2in the bronchial subepithelial region of the lung of patients with chronic bronchitis compared with the control is primarily a result of increase in number AT1receptors found on fibroblasts and macrophages surrounding the epithelium of the respiratory tract, which results in elevated levels of inflammation and fibrosis characteristic of HOLZ.

The above results clearly indicate that al1receptors, which modulate angiotensin II localized in the subepithelial tissue of the lung and, above all, that their relative content in the corresponding tissue of the lung increases. Thus, inhibition of angiotensin II antagonists AT1-receptor leads to a decrease of airway obstruction.

In addition, the experiments showed that the relative content

Al2in epithelial tissue of the lung, primarily in the corresponding diseased tissue, for example, mainly in the epithelial cells of the bronchi, as well as in the structural cells of the alveoli, for example, on the mucous glands of the alveoli increases. Since al2receptors are antiproliferative, antifibrosis and proapoptotic, their modulation can be used to treat certain forms of conditions and diseases of the lungs, primarily for the treatment of respiratory distress syndrome in adults (ARDS), and to reduce the proliferative capacity of epithelial lung cancer and breast cancer, in addition, for the treatment of septic syndrome, forms of lung lesions, such as pneumonia, aspiration of gastric contents, chest trauma, shock, burns, fat embolism, extracorporeal circulation, poisoning About2, hemorrhagic pancreatitis, interstitial and bronchoalveolar inflammation, cast new erace epithelial and interstitial cells, the accumulation of collagen, fibrosis.

The distribution of receptors in normal breast tissue and in breast tissue of patients suffering from breast cancer

Samples of breast tissue analyzed in this study, randomly selected from the files of the Department of pathology, University hospital (Pathology Dept., University Hospital, Ghent. They were fixed in formalin, placed in paraffin wax and using pathologists from the Department of pathology was determined by their pathological status. Was studied 16: 14 invasive related to the channel (flow) carcinomas, 1 invasive colloid carcinoma and 1 invasive relating to the slice (lobular) carcinoma.

Immunocytochemical analysis was performed using soaked in paraffin wax sections of tissue using polyclonal antibodies to the al1and al2that were used in the study of light, in combination with the above-mentioned method based on the use of a complex of streptavidin-Biotin-peroxidase.

To create a suitable model for evaluation of antagonists cell line derived from breast tissue of a person, also assessed in relation to the content of the receptors. This may be a suitable working model for further biochemical and cytological studies in vitro.

Results

the Obtained data clearly indicate the presence of receptors type 1 and 2 of angiotensin II in normal breast tissue of a person, and al2found on the cuboid cells of the epithelial lining of the ducts, and al1mainly present on myoepithelial duct cells. All staining was stopped with the removal of the primary antibody from the mixture to incubate.

In all cases, the connective tissue found positive staining AT1-a receptor, but staining of the cancer cells were absent (11/16) or weak (5/16). In contrast to the al2-receptor detected positive staining of all carcinomas and almost complete absence of reactivity in the stroma (1/16).

The results obtained using the studied cell lines, was very interesting from the point of view of various schemes staining detected for each of them. Korotkova cultures of normal epithelial breast cells gave very strong positive reaction to AT1-a receptor, but only a weak staining in respect of al2-receptor.

Breast carcinoma
PatientAT1Al2
Carcinoma of breastKa is cinema StromaCarcinomaStroma
1invasive sredneperesechennoy running carcinoma - 2nd degree according to the classification of the bloom-Richardson (Bloom-Richardson)++++-
2invasive sredneperesechennoy running adenocarcinoma+++++ point-
3invasive subdifferentiable running carcinoma - flowing carcinoma in situ+++-
4invasive sredneperesechennoy running carcinoma is a vast flow carcinoma in situ-+++-
5invasive colloid carcinoma- ++++-
6invasive sredneperesechennoy running carcinoma-flowing carcinoma in situ+++++-
7invasive, well-differentiated flow carcinoma - large flowing carcinoma in situ-++++-
8invasive subdifferentiable running carcinoma - flowing carcinoma in situ++++++-
9invasive, well-differentiated flow carcinoma-+++ point-
10invasive subdifferentiable running carcinoma - flowing carcinoma in situ-+ +-
11invasive subdifferentiable running carcinoma is multifocal carcinoma in situ-++++-
12invasive subdifferentiable running carcinoma-++++++
13invasive subdifferentiable invasive+++++-
14invasive subdifferentiable running carcinoma - a few running carcinoma in situ-++ point++-
15invasive subdifferentiable running carcinoma - a few running carcinoma in situ+++++-
16invasive lobular carcinoma - resectively vnutridolkovom carcinoma+++-

Conclusion

As can be seen from the above results, the presence of AT1-receptor in normal epithelial cells, probably varies very lightweight. However, the type of epithelial cells can be attributed to myoepithelial, since al2-the receptor in both tissues found on the cuboid epithelial cells. At the same time, positive staining of stroma in relation to AT1receptors are also detected in both tissues. It is obvious that the latter fact is due to the presence of fibroblasts in the extracellular matrix.

The presence of al1-receptor carcinoma cells, as well as them so wide and reproducible distribution is unexpected. Describes the types of cells bearing specific receptors, represent an ideal model to study in vitro.

These experiments clearly demonstrate the unexpected phenomenon, consisting in the fact that when used in accordance with the present invention as model cells, breast carcinoma, al1-receptors are mainly distributed in the stroma, while the al2receptors mainly in the manifest in the carcinoma cells.

All these unexpected results clearly indicate that any antagonist al1-receptor or modulator al2the receptor can be used to treat conditions or diseases associated with increased content AT1receptors in the subepithelial area or increasing the content of al2receptors in the epithelium, primarily for the treatment of obstructive respiratory diseases. According to the classification to the obstructive respiratory diseases are respiratory infections, which are characterized by increased size of the Airways and increased secretion in the respiratory tract, resulting in reduced ventilation of the alveoli. Obstructive diseases of the respiratory tract include reversible and irreversible condition and these include, for example, chronic obstructive pulmonary disease, such as bronchitis, for example, chronic bronchitis and emphysema, and asthma, cystic fibrosis, interstitial lung disease, invasive lung cancer and increased resistance of the Airways during forced expiration. Any of these treatment options also may not necessarily be associated with the treatment of hypertension as non-smokers and in smokers.

These unexpected results clearly indicate that any modulator al2-prescriptions the ora can be used to treat conditions or diseases, associated with the increase in the content of al2receptors in epithelial lung tissue, primarily for the treatment of certain forms of conditions and diseases of the lungs, in particular, for the treatment of respiratory distress syndrome in adults (ARDS), and to reduce the proliferative capacity of the epithelium in invasive lung cancer, in addition, for the treatment of septic syndrome, forms of lung lesions, such as pneumonia, aspiration of gastric contents, chest trauma, shock, burns, fat embolism, extracorporeal circulation, poisoning O2, hemorrhagic pancreatitis, interstitial and bronchoalveolar inflammation, proliferation of epithelial and interstitial cells, accumulation of collagen, fibrosis.

Antagonists AT1-receptor or modulator al2receptors are agents that modify the biological response of the host to tumor cells, which ensures their therapeutic value. An increased level of expression of al1-receptor in myoepithelial breast duct and al2-receptor in the cuboid epithelium of the mammary gland suggests that any antagonist AT1-receptor or modulator al2the receptor can be used for the treatment of invasive breast carcinoma. These carcinomas include compacted infilterate of pupil the Yarnykh, running, medullary and lobular malignant mammary gland tumors and metastases in the lung, pleura, bones and liver. Treatment can be considered as an additional therapeutic measures in combination with surgery, radiotherapy, or as palliative therapy in combination with hormonal therapy or with other biological response modifiers such as interferons, interleukins, tumor necrosis, monoclinal antibodies, etc.

While clinical examination or mammography suggest the presence of breast cancer, but only to establish the diagnosis allows assessment of tissue biopsy. Distribution scheme at1and al2receptors can be used as a marker hyperplasia (localization of al1receptors) and invasive cancer (localization of al2receptors) and, consequently, for the diagnosis of malignant tumor development.

Antagonists AT1receptors include compounds having different structural features. For example, it should be noted compounds listed in the application for the European patent published under the number 443983 (EP 443983), in particular, the claimed compounds and final products of examples of the preparation, the content of this publication invention included in the present description by reference.

Prepact the tion is (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]Amin[valsartan]formula

and its pharmaceutically acceptable salts.

In addition, the compounds listed in the application for the European patent published under the number 253310 (EP 253310), in particular, the claimed compounds and final products of examples of getting included in the present description by reference.

Preferred is the compound [losartan] the following formula

and its pharmaceutically acceptable salts.

In addition, it should be noted the connection specified in the application for the European patent published under the number 403159 (EP 403159), in particular, the claimed compounds and final products of examples of getting included in the present description by reference.

Preferred is the compound [eprosartan] the following formula

and its pharmaceutically acceptable salts.

It should also be noted the connections defined in the patent application PCT published under the number WO 91/14679, in particular, the claimed compounds and final products of examples of getting included in the present description by reference.

Preferred is the compound [irbesartan] the following formula

and its pharmaceutically acceptable salts.

In addition, it should be noted the connections defined in the Declaration the EC to the European patent published under the number 420237 (EP 420237), in particular, the claimed compounds and final products of examples of getting included in the present description by reference.

Preferred is the compound [E-1477] the following formula

and its pharmaceutically acceptable salts.

Also of note is the connection specified in the application for the European patent published under the number 502314 (EP 502314), in particular, the claimed compounds and final products of examples of getting included in the present description by reference.

Preferred is the compound [telmisartan] the following formula

and its pharmaceutically acceptable salts.

In addition, it should be noted the connection specified in the application for the European patent published under the number 459136 (EP 459136), in particular, the claimed compounds and final products of examples of getting included in the present description by reference.

Preferred is the compound [candesartan] the following formula

and its pharmaceutically acceptable salts.

Also of note is the connection specified in the application for the European patent published under the number 504888 (EP 504888), in particular the claimed compounds and final products of examples obtained the I, included in this description by reference.

Preferred is the compound [SC-52458] the following formula

and its pharmaceutically acceptable salts.

In addition, it should be noted the connection specified in the application for the European patent published under the number 514198 (EP 514198), in particular the claimed compounds and final products of examples of getting included in the present description by reference.

Preferred is the compound [capricornian] the following formula

and its pharmaceutically acceptable salts.

In addition, it should be noted the connection specified in the application for the European patent published under the number 475206 (EP 475206), in particular the claimed compounds and final products of examples of getting included in the present description by reference.

Preferred is a compound of the following formula

and its pharmaceutically acceptable salts.

It should also be noted the connections defined in the patent application PCT published under the number WO 93/20816, in particular, the claimed compounds and final products of examples of getting included in the present description by reference.

Preferred is the compound [ZD-8731] the following formula

and its pharmaceutically acceptable salts.

Ligands (modulators) al2receptors include compounds having different structural features. For example, it should be noted compounds listed in WO 94/13651, in particular, the claimed compounds and final products of examples of the preparation, the content of this publication invention included in the present description by reference.

It should also be noted compounds mentioned in WO 94/13642 in particular, the claimed compounds and final products of examples of getting included in the present description by reference.

Antagonists AT1receptors or ligands at2receptors, respectively, which, for example, have at least one basic centre can form an acid additive salt. They can be obtained, for example, with strong inorganic acids such as mineral acids, for example sulfuric acid, phosphoric acid or a halogen acid, with strong organic carboxylic acids, such as1-C4alcancarao acid, which can be unsubstituted or substituted, for example halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as is hydroxycarbonate acid, for example, ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or such as benzoic acid, or with organic sulfonic acids, such as C1-C4alkanesulphonic acid or arylsulfonic acid, which can be unsubstituted or substituted, for example halogen, for example methanesulfonate acid or para-toluensulfonate acid. Examples of acceptable salts with bases are metal salts, for example alkali metal salts or salts of alkaline-earth metals, for example, salts of sodium, potassium or magnesium salts, or salts with ammonia or organic amines, such as morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di -, or three (ness.) alkylamine, for example ethyl-, tert-butyl-, diethyl-, aminobutiramida-, triethyl-, tributyl or dimethylpropylene, or mono-, di - or trihydroxy (ness.) alkylamine, for example mono-, di - or triethanolamine. In addition, there can be obtained the corresponding internal salts.

The invention also relates to pharmaceutical compositions comprising an antagonist AT1-receptor or modulator al2-receptor, respectively, or its pharmaceutically acceptable salt, designed to treat conditions or diseases associated with the increase in content is AT 1receptors in the subepithelial region or increasing the content of al2receptors in the epithelium.

The invention also relates to the application of the antagonist AT1-receptor or modulator al2-receptor, respectively, or its pharmaceutically acceptable salts for the preparation of pharmaceutical compositions intended for the treatment of conditions or diseases associated with elevated levels AT1receptors in the subepithelial region or increasing the content of al2receptors in the epithelium.

The invention also relates to a method for treating conditions or diseases associated with elevated levels AT1receptors in the subepithelial region or increasing the content of al2receptors in the epithelium, introducing a therapeutically effective amount of the antagonist AT1-receptor or modulator al2-receptor, respectively, or its pharmaceutically acceptable salt.

The invention also relates to the application of the antagonist AT1-receptor or modulator al2-receptor, respectively, or its pharmaceutically acceptable salts for the treatment of conditions or diseases associated with elevated levels AT1receptors in the subepithelial region or increasing the content of al2receptors in the epithelium.

These pharmaceutical preparations is practical composition can be intended for enteral, for example, oral, and also rectal or parenteral administration warm-blooded animals, and compositions containing pharmacologically active compound, either individually or in combination with conventional pharmaceutical excipients. For example, the pharmaceutical compositions contain from about 0.1% to 100%, preferably from about 1% to about 80% active ingredient. Pharmaceutical compositions for enteral or parenteral administration and for injection into the eye, are, for example, the standard dose, such as filmtablette, tablets, capsules or suppositories, and also ampoules. They are produced well-known methods, for example using conventional mixing, granulation, coating, solubilization, or lyophilization. Thus, pharmaceutical compositions for oral administration can be prepared by combining the active substance with solid excipients, if you want granulation of the mixture and, if appropriate or required, by processing the mixture or granules, after adding acceptable excipients to obtain tablets or cores filmtabletten.

The dose of active ingredient may depend on numerous factors such as route of administration, the species of warm-blooded animal, the age and/or ind the individual state. As a rule, in the case of oral administration the approximate daily dose is from about 10 mg to about 360 mg, for example in the case of valsartan, for example, about 40 mg, 80 mg, 160 mg or 320 mg, for a patient weighing approximately 75 kg

Another object of the present invention is a solid oral dosage forms of valsartan, which can be used to treat diseases and conditions such as those listed above in the present description.

In WO 97/49394 (the contents of which are incorporated into this description by reference, as a particular (but without limitation) the claimed object) described extruded solid oral dosage forms, for example, received the seal of valsartan (optionally in salt form), optionally in combination with hydrochlorthiazide (HCTZ). In WO 97/49394 concentration of cellulose preferably range from 10 to 30%, for example, 21%, for the compositions of valsartan/HCTZ, and 5% in the case of a single valsartan. The preferred range of concentration of cross-linked polyvinylpyrrolidone (crosspovidone) is 10-20%, for example, 13%.

After exhaustive research it has been unexpectedly found that it is possible to improve the characteristics of the biological availability of known solid compositions of valsartan by increasing the relative content of microcrystalline cellulose. Also neojidan is installed, what could be improved, for example, to achieve greater uniformity in terms of weight or to improve the ability of the tablets to the pressing, known solid compositions of valsartan by reducing the relative content of crosslinked polyvinylpyrrolidone (PVP) crosspovidone.

Thus, another object of the present invention is a solid oral dosage form, including valsartan as active substance and more than 30% of microcrystalline cellulose, calculated on the total weight of the core components of solid oral dosage forms, for example, 31-65%, for example, 50%.

And another object of the present invention is a solid oral dosage form, including valsartan as active ingredient and microcrystalline cellulose, in which the mass ratio of valsartan and microcrystalline cellulose is from 2.5:1 to 0.3:1, e.g. from 2:1 to 1:1, for example, 1,4:1.

According to another variant implementation of the solid oral dosage form according to the invention contains less than 13% of crosspovidone, for example, from 2 to 10% based on the total weight of the core components of solid oral dosage forms.

Preferably the mass ratio of valsartan and crosspovidone is from 7:1 to 3:1, for example, from 6:1 to 4:1, for example, 5,3:1.

Preferably the mass ratio of the group of microcrystalline cellulose and crosspovidone is from 7:1 to 1:1, for example, from 4:1 to 2:1, for example, 3,6:1.

Solid oral dosage form according to the invention may contain from 20 to 360 mg valsartan 40, 80, 160, 320 mg When using a range of doses may be increased flexibility and effectiveness of the treatment, for example, in lowering blood pressure.

Another object of the invention is a solid oral dosage form, including

20-65% of valsartan

31-65% microcrystalline cellulose

2-13% crosspovidone.

A typical composition may include

20-65% of valsartan

31-50% microcrystalline cellulose

2-10% crosspovidone

1-10% of magnesium stearate

0.5 to 5% colloidal anhydrous silica.

If necessary, may be added from 1 to 10% based on the weight of the engine components, for example, 5-10% of cutin, or from 1 to 10% based on the weight of the engine components, for example, 5-10% of stearic acid.

Preferably a solid oral dosage form according to the invention have the form of compressed tablets.

And another object of the invention is a solid oral dosage form, for example, compressed tablet, which includes more than 250 mg and less than 360 mg, for example, 320 mg of valsartan as the active substance.

Can be used with other excipients, such as oil or improving the slip substance,usually used as solid compositions for oral administration, such compounds are widely described in the literature, see, for example, in Fiedler''s "Lexicon der Hilfstoffe", 4th ed., ECV Aulendorf 1996 and "Handbook of Pharmaceutical Excipients" Ed. by Wade and Weller (1994), the contents of which are incorporated into this description by reference.

Solid oral dosage forms of the present invention can be a bean, in this case, the solid oral dosage form coated, usually with sugar, shellac or other film coatings, are well known in this field. Mention should be made of numerous known methods of coating applied in this area, such as a coating by spraying in a fluidized bed, for example, known methods using devices supplied by firms Aeromatic, Glatt, Wurster or Hüttlin, perforated VAT according to the method Accela Cota, or according to the method of coating with the use of the method of loaded sheet. In such methods using additives commonly used in the production. For example, coatings that you can use, described in WO 97/49394, Opadry etc.

The pharmaceutical compositions of the present invention can be applied for known indications for the use of concrete included in each of the active substance.

The exact dose of the active substance and the specific composition of the subject with an introd the tion, depend on numerous factors, such as the condition to be treated, the desired duration of treatment, and the speed of release of the active substance. For example, the number of the desired active substance and its rate of release can be determined using known methods in vitro or in vivo, to determine how long a certain concentration of the active substance remains in the blood plasma at a level sufficient for therapeutic effect.

For example, the composition according to the invention in clinical trials was comparable biological availability marketed form of Diovan®.

Preferably, the dissolution rate of the solid forms of the present invention is approximately 90% in 30 minutes

For example, for treatment of a mammal, such as man, weighing 75,5 kg, and standard models with animals can be used from 10 mg to 360 mg of valsartan in the day. Very high tolerability of valsartan in his inclusion in the composition can be found in standard animal experiments and in clinical trials.

The next object of the invention is a method for preparing the above-described solid oral dosage forms. Such solid oral dosage form can be prepared by processing the components and specified in WO 97/49394 (incorporated in the present description by reference), taken in quantities sufficient to prepare a standard dosage forms, for example using the following process.

For example, below is the method of preparation of the above-mentioned solid oral dosage forms providing for stage

I) grinding the active substance and pharmaceutically acceptable additives,

(II) compacting a mixture of powdered active substance and additives to seal with obtaining karimata (compacted earth)

III) the conversion of karimata in granular and

IV) compressing the granules with the preparation of solid oral dosage forms.

This process is carried out in the absence of water, i.e. it is a method of dry pressing. The process can be carried out at a temperature and humidity environment; does not require that the process was carried out in an anhydrous atmosphere.

The initial stage of grinding I) can be carried out using conventional methods of grinding or fine grinding.

The active substance and additives can be ground either individually or in conjunction with obtaining particles whose size ranges from about 0.1 micrometer (μm) to about 1500 microns, for example, from 1.0 μm to 900 μm, for example, from 60 μm to 600 μm. At least 90% Chris who allow as the active substance, and additives have a particle size in the specified ranges. Particles of this size get accepted methods of grinding, for example by grinding in vostokstrojj mill, hammer crusher and mill with sieve mill, fine grinding, ball mill or vibrating mill.

Fine grinding is preferably carried out with known methods, for example, using an ultrasonic disintegrator, for example, the type of BRANSON Sonifier, or by stirring the suspension using a high-speed mixer, such as mixer type HOMOREX.

At this stage, the ground particles may not necessarily be sifted and mixed using known methods.

Seal with obtaining karimata provides for the pressing of dry powdered components. The seal may be effected using methods clumping or preferably by roller compaction. Device for roller compaction is a common and mostly based on the use of two rollers which rotate towards each other. Hydraulic piston presses one of the rolls to the other, which causes a compressive force acting on the ground particles are loaded in a roller compactor with worm conveyor system.

Can be applied compressive force from 25 to 65 kN, for example, from 2 to 45 kN. In the claimed invention unexpectedly found that within a specified range of compressive strength for each particular composition should be used a minimum compressive strength in order to get a solid oral dosage form, in which the granulate is divided into separate primary particles with a desired speed, for example the destruction occurs 6 times faster for solid oral dosage forms, compacted with the use of force in excess of the minimum compressive strength. This high rate of destruction is unusual for tablets and matches the speed of the destruction of the composition in the form of capsules. Concrete minimum compressive strength depends on the content of active substance in a specific composition and, therefore, also depends on the number and nature of the present additives.

With this information, the person skilled in the art can easily determine the minimum compressive strength for other songs with the usual experiments and without excessive effort.

The speed of the rolls may be set at from 1 to 20 rpm, and preferably 9-15 rpm After passing through the rolls densified mass (copymat) is a thin segmented tape.

Copymat can be sieved or milled to obtain granules. Screening in its most ol the stand form includes the transmission of karimata, removed from the rolls, through a sieve with a mechanical pressure. More preferably copymat sieved by vibrating mill, for example, type MGI 624 Frewitt (firm Key International Inc.).

Compressing the granules with obtaining cores of tablets can be carried out using generally teletrauma machine, for example, using eccentric teletrauma machine type EC-0 Korsch, or rotary teletrauma machine, for example, when compressive force of more than 2 kN. Core tablets may vary in shape and may have, for example, round, oval, oblong, cylindrical or any other suitable shape and can vary in size depending on the concentration of therapeutic agents. A distinctive feature of the tablets according to the invention is their relatively small size included in their composition amount of the active substance.

According to a preferred variant implementation of the tablets obtained by the method described above pressing, are slightly oval. The edges of the tablets can be beveled or rounded.

According to a particularly preferred variant implementation of the solid oral dosage form is pressed to obtain tablets having an elongated shape in which the ratio length:width:height is, for example, 2,5-5,0:0,9-2,0:1,0, and in which preferably the upper and lower surface tablets independently from each other are flat or convex relative to the longitudinal axis; the sides are flat, the end faces can be of any shape, and the edges are optional beveled or rounded.

According to a preferred variant implementation of the solid oral dosage form is pressed from the granulate to obtain tablets are oblong in shape, the length of which is approximately 10,0-15,0 mm, width approximately 5,0-6,0 mm and a height of about 3,0-4,0 mm

According to another preferred variant implementation of the solid oral dosage form is pressed from the granulate to obtain tablets are oblong in shape, the length of which is approximately 15,0-18,0 mm, width approximately 6,0-9,0 mm and a height of about 3.5 to 5.0 mm

And another preferred embodiment is a tablet with almost discoid shape, the upper and lower sides of which are slightly convex surface. Preferably, the tablet has a diameter of about 8-8 .5 mm and a height of about 3-3,5 mm or a diameter of about 16 mm and a height of about 6 mm, the Pill can have a volume from about 0.1 cm3to about 1 cm3for example, from 0.1 cm3to about 0.45 cm3for example, from 0.2 to 0.3 cm3for example, about 0,125 cm3or 0.25 cm3.

In addition, they can be transparent, colorless or colored and can also be applied to a label that gives adamopoulou distinctive appearance and makes it quickly recognizable. The use of dyes can improve the appearance and recognizability compositions. Suitable for use in pharmacy colorants normally include carotenoids, iron oxides or chlorophyll.

The following examples illustrate the invention described above; however, they are in no way intended to limit its scope.

The example 1 composition:

Filmtablette:

ComponentsComposition per dose (mg)Standards
Granulation
valsartan [= active ingredient]80,00
ComponentsComposition per dose (mg)Standards
microcrystalline cellulose/vicel PH 10254,00NF (national formula), Ph. Eur (European Pharmacopoeia
crosspovidone20,00NF, Ph.Eur
colloidal anhydrous silica/colloidal, dioxi the silicon/Aerosil 200 0,75Ph. Eur/NF
magnesium stearate2,5NF, Ph. Eur
Offset
colloidal anhydrous silica/colloidal silicon dioxide/Aerosil 2000,75Ph. Eur/NF
magnesium stearate2,00NF, Ph. Eur
Coating
purified water*)-
dye red light DIOLACK pale red OOF348997,00
Total weight pills167,00
*)Removed during processing

Filmtablette is made, for example, as follows:

The mixture containing valsartan, microcrystalline cellulose, crosspovidone, part of the colloidal anhydrous silica/call odnogo silicon dioxide/Aerosil 200, silicon dioxide and magnesium stearate, are pre-mixed in a diffusion mixer and then sift through the mill with a sieve. The resulting mixture is again mixed in a diffusion mixer, condense in the roller compactor and then sift through the mill with a sieve. To the resulting mixture add the remaining colloidal anhydrous silica/colloidal silicon dioxide/Aerosil 200 and prepare the final mixture in a diffusion mixer. The entire mixture is pressed at a rotary teletrauma car and on the pill cause a film coating in the perforated Chan, using light red dye Diolack.

Example 2 composition:

Filmtablette:

ComponentsComposition per dose (mg)Standards
Granulation
valsartan [= active ingredient]160,00
microcrystalline cellulose/Avicel PH 102108,00NF, Ph. Eur
crosspovidone40,00 NF, Ph. Eur
colloidal anhydrous silica/colloidal silicon dioxide/Aerosil 2001,50Ph. Eur/NF
magnesium stearate5,00NF, Ph. Eur
Mixing
colloidal anhydrous silica/colloidal silicon dioxide/Aerosil 2001,50Ph. Eur/NF
magnesium stearate4,00NF, Ph. Eur
Coating
dye light brown (Opadry Light Brown OOF33172)10,00
Total weight pills330,00

Filmtablette is made, for example, according to the process described in example 1 composition.

Example 3 composition:

Filmtablette:

ComponentsComposition per dose (mg Standards
Core: the Inner phase
valsartan [= active ingredient]40,00
silica, colloidal anhydrous (colloidal silicon dioxide) [= a substance that improves slide]1,00Ph. Eur, USP (USP CUIAVNF
magnesium stearate [= size]2,00USP/NF
crosspovidone [baking powder]20,00Ph. Eur
microcrystalline cellulose [= binder]124,00USP/NF
Internal phase
silica, colloidal anhydrous (colloidal silicon dioxide) [= a substance that improves slide]1,00Ph. Eur, USP/NF
magnesium stearate [= size]2,00 USP/NF
Film coating
dye brown Opadry®brown OOF 16711*)9,40
purified water**)-
Total weight pills199,44
*)The composition of the dye Opadry®brown OOF16711 below.
**)Removed during processing

The composition of Opadry®:

4,00
IngredientApproximate content (%) in the composition
iron oxide, black (C.1. No.77499, E 172)0,50
iron oxide, brown (C.1 No.77499, E 172)0,50
iron oxide, red (C.1. No.77491, E 172)0,50
iron oxide, yellow (C.1. No.77492, E 172)0,50
macropomum (Ph. Eur)
titanium dioxide (C.1. No.77891, E 171)14,00
hypromellose (Ph. Eur)80,00

Filmtablette is made, for example, according to the process described in example 1 composition.

Example 4 composition:

Capsules:

ComponentsComposition per dose (mg)
valsartan [= active ingredient]80,00
microcrystalline cellulose25,10
crosspovidone13,00
povidone12,50
magnesium stearate1,30
sodium lauryl sulfate0,60
The shell
iron oxide, red (C.1. No.77491, EU No. E 172)0,123
iron oxide, yellow (C.1. No.77492, EU No. E 172)0,123
iron oxide, black (C.1. No.77499, EU No. E 72) 0,245
titanium dioxide1,540
gelatin74,969
Total weight pills209,50

The tablet is made as follows:

Granulation/drying

Valsartan and microcrystalline cellulose granularit spray in the granulator, fluidized bed using the solution for granulation, which contains povidone and sodium lauryl sulfate dissolved in purified water. The obtained granulate is dried in a fluidized bed dryer.

Grinding/mixing

The dried granulate is milled together with crosspovidone and magnesium stearate. Then the mass is stirred in a conical mixer, a screw type for about 10 minutes

Encapsulation

Empty gelatin capsules are paved fill peremeshennoi portion of the pellets at a controlled temperature and humidity. Filled capsules dedust, visually inspect, examine mass and certify the quality assurance Department.

Example 5 composition:

Capsules:

ComponentsComposition per dose (mg)
valsartan [= active ingredient]160,00
microcrystalline cellulose50, 20mm
crosspovidone26,00
povidone25,00
magnesium stearate2,60
sodium lauryl sulfate1,20
The shell
iron oxide, red (C.1. No.77491, EU No. E 172)0,123
iron oxide, yellow (C.1. No.77492, EU No. E172)0,123
iron oxide, black (C.1. No.77499, EU No. E 172)0,245
titanium dioxide1,540
gelatin74,969
Total weight pills342,00

The composition is made, for example, according to the process described in example 4 composition.

Example 6 composition:

Gelatin capsule with a hard coating:

ComponentsComposition per dose (mg)
valsartan [= active ingredient]80,00
sodium lauryl sulfate0,60
magnesium stearate1,30
povidone12,50
crosspovidone13,00
microcrystalline cellulose21,10
Total weight pills130,00

Examples 7-11:

Example7891011
ComponentsComposition per dose (mg)Composition per dose (mg)Composition per dose (mg)Composition per dose (mg)Composition per dose (mg)
pharmaceutical substance of valsartan80,000160,00040,000320,000320,000
microcrystalline cellulose (NF, Ph.Eur.VAvicel PH 10254,000108,00027,000216,000216,000
crosspovidone (NF, Ph.Eur.)15,00030,0007,50080,00060,000
ComponentsComposition per dose (mg)Composition per dose (mg)Composition per dose (mg)Composition per dose (mg)Composition per dose (mg)
colloidal anhydrous silica (Ph. Eur.) /colloidal silicon dioxide (NFVAerosil 2001,5003,0000,7503,0006,000
magnesium stearate (NF, Ph.Eur.)3,0006,0001,50010,00012,000
Mixing
colloidal anhydrous silica (Ph. Eur.) /colloidal silicon dioxide (NFVAerosil 200---3,000-
magnesium stearate, NF, Ph.Eur.1,5003,0000,7508,0006,000
Weight kernel/mg155,000310,00077,500640,000620,000
Floor--3,80015,00016,000

Example 12: the solubility of the film-coated tablets (ETF) (Phi is pill)

Acceptable criteria of solubility are Q=75% within 30 min (paddle stirrer at 50 rpm, phosphate buffer, pH 6.8)

40 mgStrength320 mgStrength
Solubility PPT
level+ levellevel+ level
the mean value [%]98979389
standard deviation [%]1,062,482,122,34
minimum [%]96949086
maximum [%]999995 92

1. Compressed tablet, including valsartan as active substance and from 50 to 65% microcrystalline cellulose, calculated on the total weight of the core components of this compressed tablets.

2. Compressed tablet according to claim 1, comprising 50% of microcrystalline cellulose in terms of the total mass.

3. Compressed tablet according to claim 1 or 2, comprising less than 13 wt.% of crosspovidone.

4. Compressed tablet according to any one of claims 1 to 3, in which the mass ratio of valsartan to microcrystalline cellulose is from 2:1 to 1:1.

5. Compressed tablet according to any one of claims 1 to 3, which comprises more than 250 mg and up to 360 mg of valsartan as the active substance.



 

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SUBSTANCE: invention concerns medicine, particularly medical drugs with organic active components, medicines with sedative, vasodilating and antispasmodic effect, and methods of medicine obtainment, an can be applied in treatment of neuroses with high irritability, increased agitation, insomnia, neurocirculation dystonia, early stage of hypertension, non-acute cardiovascular spasm, digestive organ spasms related to neurovegetative disorders. Medicine of sedative and antispasmodic effect includes ethyl ether of α-bromisovaleric acid, Phenobarbital, peppermint oil, microcrystalline cellulose auxiliary substances for solid formulation obtainment in pellet form at the following component ratio, wt %: ethyl ether of α-bromisovaleric acid 1.37-8.2; Phenobarbital 1.25-7.5; peppermint oil 0.16-0.58; microcrystalline cellulose 2-15; the rest is auxiliary substances; pellets are covered with shell composed of β-cyclodextrin in amount of 10% of dry coating weight. First version of method of obtaining medicine with sedative and antispasmodic effect involves initial mixing of ethyl ether of α-bromisovaleric acid with peppermint oil, so that the mix comprises over 4.5% of total pellet, core pellet or capsule content weight, adding the mix to humid β-cyclodextrin taken in amount of up to 70% of total pellet core weight, stirring for 1-2 minutes, drying and pelletising of obtained mix, mixing granulate with Phenobarbital and microcrystalline cellulose powders and auxiliary filler, fluffer and slider substances, pellet compression and coating with shell containing β-cyclodextrin in amount of up to 10% of dry coating weight. Second version of method involves initial mixing Phenobarbital with auxiliary filler substance, separate preparation of mix of ethyl ether of α-bromisovaleric acid with peppermint oil, so that the ether oil mix comprises less than 4.5% of total pellet, core pellet or capsule content weight, adding microcrystalline cellulose powder, powders with extensive crystal surface area, auxiliary fluffer and slider substances, adding obtained mix to Phenobarbital and filler mix, pellet compression and coating with shell containing β-cyclodextrin in amount of up to 10% of dry coating weight.

EFFECT: medicine of sedative and antispasmodic effect in solid pellet form, with sedative and antispasmodic action matching that of drops with similar effect, ensuring stability of volatile components.

20 cl, 8 ex, 11 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: composition contains, essentially anhydrous ordered (adhesive) mixture of, at least, one pharmaceutically active agent in the form of microparticles linked to surface of carrier particles which are essentially greater than those of the active agent or agents, and, essentially are water insoluble or poor soluble, in a combination with the agent enabling bioadhesion and/mucoadhesion, linked to surface of specified carrier particles. The composition, mainly, is used for sublingual or intranasal introduction. Besides, the invention refers to method of composition preparation.

EFFECT: improved bioadhesive properties, fast release of active substance.

31 cl, 1 dwg, 1 tbl, 1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention is used for treatment of bacteriemic infections, it is prepared as composition in the form of dry powder, adapted for delution by water with reception of the suspension important pH in a range from approximately 5.0 to approximately 5.5 at initial delution and which in addition contains the stabilizer pH which represents sodium-carboxymethyl cellulose. Besides, the invention concerns application sodium-carboxymethyl cellulose for reduction of degree of degradation clavunalate and for stabilisation pH the received suspension.

EFFECT: stability improvement in preparation.

7 cl, 1 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is capable to be attached to wet surfaces of tissues of the body, including the first water-soluble adhesive layer and the second water blasted not adhesive protective layer regulating time of stay of the water blasted device; and the first layer includes water-soluble film-forming polymer in a combination with mucoadhesive polymer, and the second water-soluble non-adhesive protective layer includes membrane consisting of one component from number hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrolidone, polyvinyl alcohol, polyethyleneglycol, polyethylene oxide or copolymers of ethylene oxide and propylene oxide, and covered with hydrophobic polymer and water-soluble polymer at a parity hydrophobic polymer(s) to water-soluble polymer (frames) 1:1-9:1 (on weight).

EFFECT: good stickiness of product, comfort, desirable duration of influence.

18 cl, 1 tbl, 18 ex

FIELD: chemistry; medicine.

SUBSTANCE: in general formula I R1 stands for haloid, lower alkyl; R2 stands for lower alkyl or C3-C6-cycloalkyl; R3 stands for lower alkyl, C3-C6-cycloalkyl, -(CH2)n-C3-C6-cycloalkyl, (CH2)n-CN or -(CH2)n-O-(lower)alkyl, (lower)alkoxyaryl, Fn-R5, where R5 is lower alkyl or lower alkenyl; n takes values 1, 2 or 3; R4 is hydrogen or CH2R5, where R5 is hydrogen, C1-C6-alkyl, C3-C12-cycloalkyl; as well as its pharmaceutically acceptable salts. Invention also relates to methods of obtaining formula I compounds, medication based on formula I compound and its application.

EFFECT: obtained are novel imidazole derivatives, useful in treatment or prevention of disorders mediated by activity of glutamate receptor mGluR5.

18 cl, 31 ex

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