Composition inhibiting secretion of acid in stomach

FIELD: medicine; pharmacology.

SUBSTANCE: peroral pharmaceutical dosed out form for treatment of the conditions bound to secretion of acid in a stomach, includes an acid-sensible inhibitor of the proton pump and antagonist of H2-molecular switchers, with the delayed and-or prolonged liberation of the proton pump acid-sensible inhibitor, and fast liberation of antagonist of H2-molecular switchers.

EFFECT: maximum suppression of acid in a stomach after the first dose and throughout all course of treatment.

69 cl, 4 dwg, 7 ex

 

The technical field to which the invention relates.

The present invention relates to a composition, inhibiting the secretion of acid in the stomach, its preparation and its use in the treatment of diseases associated with the secretion of acid in the stomach.

The level of technology

Over the last decade a lot of progress in suppressing the secretion of acid, which is an integral part of the treatment of diarrheal diseases, such as gastro-esophageal reflux (GORD), gastric ulcer and duodenal ulcer and non-ulcer dyspepsia. Although the pathophysiology of these diseases varies, inhibition of acid secretion in the stomach plays a cardinal role in the treatment of organic damage, mitigation of symptoms of discomfort and improve quality of life. Moreover, the damaging effect of acid may underlie the transition in cancer and other late complications of these diseases. Inhibition of acid secretion is the key moment in treatment regimens aimed at the eradication of Helicobacter pylori infection.

Dyspepsia (acid indigestion) is a common disorder. Symptom of dyspepsia is heartburn. Estimated at 44% of Americans experiencing heartburn at least once a month, but only about 25% of them go to the doctor about dyspepsia. Symptoms associated the dyspepsia, are, for example, pain/discomfort in the upper abdomen and heartburn, indigestion, sour stomach and gastro-esophageal reflux.

Dyspepsia is a multi-factorial disease and may be associated with organic pathology such as duodenal ulcer, gastric ulcers, esophagitis, Barrett's syndrome or inflammation of the stomach and duodenum (e.g., Helicobacter pylori infection). Dyspepsia also covers the conditions under which organic pathology is not detected, such as non-ulcer dyspepsia (NUD) or functional dyspepsia.

Dyspepsia can be controlled by introduction of drugs that increase the pH in the stomach. For therapeutic means, effective in the treatment of dyspepsia, include funds that suppress the release of acid in the stomach, such as receptor antagonists of the histamine type 2 (hereinafter referred to as antagonists H2-receptor), kislotoustoytchive proton pump inhibitors, antacids/alginates, anticholinergic and prokinetics funds. They differ in their mechanism of action, safety profile and pharmacokinetics. The gastric pathogen Helicobacter pylori was associated with dyspepsia, gastric ulcer and duodenal ulcer and gastric cancer. Infection treatment N. pylori usually includes the use of a combination of suppressing the release of acid means and one or dhanibekov.

Therapeutic effect is associated with discomfort dyspepsia and organic damage by inhibiting the production of acid by the use of inhibiting the secretion of acid drugs depends on the degree of inhibition of acid and also from the beginning and duration of action of a particular drug. Most patients with symptoms of acid reflux a normal mucosa of the esophagus or only mild esophagitis. Treatment, consisting in the relief of symptoms as they arise, perhaps, is the best way to treat these patients, in which the rate of relief of symptoms is of the highest importance.

Antacids, i.e. neutralizing the acid funds, and alginates are the primary medicines for the treatment of mild heartburn. They have an extremely short duration of action, but are inexpensive and safe. Antacids have a local effect by neutralizing acid in the stomach. Alginates provide some mechanical protection from acid reflux from the stomach into the esophagus. The main advantage of antacids and alginates is that they provide a rapid reduction in symptoms. The main drawback of antacids and alginates is extremely short duration of action, therefore, their introduction has castroverde, so patients do not have symptoms, in addition, antacids are often not provide the withdrawal symptoms, that is, the complete attenuation of symptoms. Moreover, these tools are quite unsuitable for treatment caused by organic acid damage, GORD or Helicobacter pylori infection.

There are several classes of compounds that affect the secretion of acid in the stomach. Of these the most famous kislotoustoytchive proton pump inhibitors such as substituted benzimidazole - omeprazole, lanzoprazol, rabeprazole and pantoprazole, and receptor antagonists of the histamine type 2, such as cimetidine, ranitidine and famotidine. Inhibitors H2-receptor and kislotoustoytchive proton pump inhibitors are prescribed systematically on a large scale to reduce the secretion of acid in the stomach.

Development of therapy suppression of acidity requires a detailed understanding of the mechanisms underlying the secretion of hydrogen ions, namely the parietal cells and hydrogen-potassium adenosinetriphosphatase (N+To+-ATPase), so that these mechanisms become an effective target for pharmacological intervention. Identified three key factors for achieving effective pharmacological treatment associated with acid disorders (Dig Dis Sci 1995, vol. 40: 24S-49S. Optimizing acid suppression for treatment of acid-related diseases):

1) the start time, then e is th inhibition of acid secretion must occur as soon as possible;

2) the degree of inhibition of acid, i.e., the pH inside the stomach should be significantly higher than 4;

3) duration of action, i.e. inhibition of acid secretion should be almost complete within 24 hours at the first dose and stay full throughout the course of treatment.

All these factors need to be considered when choosing how to optimize this suppression therapy. However, some aspects of the physiology of parietal cells and pharmacology/biochemistry existing pharmaconnect not yet have the ability to achieve this goal.

A Central element of the mechanism of acid secretion are the parietal cells of the stomach. These cells secrete hydrogen ions into the lumen of the stomach under control Neurocrine, paracrine and endocrine pathways. One of the major paracrine factors is histamine, which is released enterochromaffin (ECL) cells. Secreted by cells ECL histamine stimulates parietal cell acid secretion through receptors of histamine type 2, located on the cell surface. Activation of these receptors leads to increased cyclic adenosine 3,5-monophosphate (camp) and the binding of camp to the regulatory subunit. Is the phosphorylation of a number of proteins related to the activation of secretion. Although supposedly the molecular analysis of this intracellular pathway is still far from complete, the action of camp includes translocation of N+To+-ATPase at the secretory tubules and activation vectors KCl, i.e. the translation of parietal cells in the secretory state.

The first attempts to reduce the secretion of acid were aimed at paracrine way, that is caused by the receptors of histamine type 2 stimulation of gastric secretion. Accordingly, the first class of inhibitors of acid amounted antagonists H2-receptor (H2 blockers), including compounds such as cimetidine, ranitidine, famotidine and nizatidine. Their mechanism of action is antagonism of histamine effects, i.e. the inhibition of the transition of the proton pump in the secretory tubules and reducing the activity of the transport KCl. While parietal cells become non-secretory state and thereby decreases the production of hydrogen ions (Dig Dis Sci 1995, vol 40: 3S-23S. Pharmacological aspects of acid secretion).

However, the phenomenon of return acidity and tolerance are the main obstacle to the use of these drugs in the treatment connected with acid diseases. With the reintroduction of the decrease of the ability to reduce acidity by about 50%, which greatly limits the application of this class of drugs in the treatment of, for example, GORD (aliment oil displayed pure Pharmacol Ther 1990, vol 4: 29-46. Tolerance during 29 days of conventional dosing with cimetidine, nizatidine, famotidine or ranitidine). Moreover, these environments is TBA quite unsuitable for the treatment of Helicobacter pylori infection, which is dependent on effective and long-lasting reduction of gastric secretion.

Modern treatment involving acid disorders focused on more direct target - N+To+-ATPase ("proton pump") active parietal cells. These cells form the ultimate sources of the acid - secretory tubules and the pump for acid. Therefore, drugs designed to inhibit the secretion of acid at this level, more efficiency and specificity. Because proton pump inhibitors (IDU) are at the stage after stimulation of parietal cells, applying these compounds have not developed a tolerance, in contrast to antagonists H2-receptor. Moreover, these drugs affect the final target, which converge all other ways, that is, N+To+-ATPase in acid compartment or tubule stimulated parietal cells.

Individual pit close in relation to the overall structure, which consists of substituted paradimethylaminobenzaldehyde. In these compounds the values of the PKandvary from 4.0 to 5.0. All IDU have the same pharmacological mechanism, which is essentially the same: the values of the PKandlimit the accumulation of these compounds with acidic compartments such as those that exist in the parietal cells. For the accumulation of the MO in the tubules of parietal cells should stage of acid activation when this pit into sulfenamide acid or sulfonamide. The formation of these reactive intermediates allows them to communicate with cysteine residues on facing the lumen of the surface of the N+To+-ATPase. The enzyme is subjected to functional inactivation through the formation of covalent disulfide bonds. Inhibition of N+To+-ATPase under the action of IIT leads to relatively stable inhibition of the enzyme, so as to reverse the inhibition of the necessary enzyme synthesis de novo. These mechanisms of action described in Dig Dis Sci 1995, vol 40: 3S-23S. Pharmacological aspects of acid secretion.

One of the fundamental properties of IIT is that they operate only in the active parietal cells, i.e. cells must be in secretory state. The reasons for this are three. First, the majority of parietal cells of the pH value in the acid compartment (tubule) is about 1.0. If the pH value PKandIIT allow them to accumulate in the parietal cells in the 1000-10000-fold degree. But at higher pH, for example 3, the accumulation is reduced by two orders of magnitude, that is 10-100-fold degree. Thus, the properties of IDU as weak bases allow them to accumulate only when the parietal cells to produce acid. This becomes important in the introduction of IIT in conditions when the and parietal cells become non-secretory state. Secondly, the transformation of IIT in Sultanova acid or sulfenamid is acid process. Thirdly, N.+To+-ATPase must be activated, i.e., the enzyme needs to be embedded in the membrane of secretory canaliculi, where cysteine residues will be available to sulfenamides (Pharmacotherapy 1997, vol. 17: 22-37. Proton pump inhibitors and acid-related diseases; Drugs 1998, vol. 56: 307-335. Proton pump inhibitors: pharmacology and rationale for use in gastrointestinal disorders; Ann NY Acad Sci 1997, vol. 834: 65-76. Structural aspects of the gastric H+,K+-ATPase; Annu Rev Pharmacol Toxicol 1995, vol. 35: 277-305. The pharmacology of the gastric acid pump).

These characteristics pharmacology/biochemistry IIT strongly affect the pharmacodynamics of this class of compounds. On the one hand, these drugs need active enzyme for inhibition, and some pumps are inactive at a time when the drug is present in the blood. On the other hand, IDU are relatively short half-life in plasma is about 60 minutes and the new pumps are synthesized at a rate of 25% for 24 hours.

These facts indicate a therapeutic dilemma pit at the present time. Since these compounds accumulate and undergo transformation in the acidic compartment of the parietal cells, it will be inhibited only those pumps that secrete acid. Because cells have the stock inactive pumps and constantly synthesize new pumps, many of the pumps that I is active within the next 24 hours, will not be inhibited by the first dose. However, the next day, when following the introduction of the pit, will be replenished with new pumps, which can be inhibited, and pumps, zingiberone 24 hours earlier, will not yet be completely filled. Therefore, the response to IDU is cumulative, for the first time reaching a stationary state and therapeutic inhibition of acid at least three consecutive days of treatment.

Thus, the current concept for the mechanism of action of IIT is that their effect must have an active pumps. In the rest of parietal cells do not produce acid, and the pump remains inactive. Inhibition of production of the acid pit occurs when these pumps are in the active state, when the accumulation in the parietal cells so that subsequent activation of the drug leads to inhibition of the pump (Eur J of Gastroenterol Hepatol 2001, vol. 13: S35-S41. Improving on PPI-based therapy of GORD).

So, none of the class of antisecretory means available at the present time, does not achieve the goal of controlling the acidity of the above, then there is a quick start action, a strong inhibition of acid secretion and prolonged duration of treatment. This goal is of the highest importance for the clinical outcome of treatment, as Ter the non-therapeutic effect depends on the beginning, the degree and duration of action, i.e. how fast, how much and for a long time will be increased pH in the stomach.

Have been described by various combinations of antacid and/or protecting the mucous membrane means with means which reduce the secretion of acid, useful in the treatment of dyspepsia.

In WO 95/017080 described composition for use in the treatment of, for example, heartburn, including the antagonist of H2-receptor type famotidine and alginate, as well as optional simethicone (activated polysiloxan).

In EP 338861 AS described solid pharmaceutical preparation consisting of antacid and fillers to be used in conjunction with islamochristiana a proton pump inhibitor or any other substance, inhibiting the secretion of acid in the stomach. Thus it is not proposed to combine these substances in a fixed dosage form.

In the US 5244670 As described pharmaceutical composition for oral administration comprising a substance selected from the group consisting of antacids, means for preventing the secretion of acid, bismuth funds and mixtures thereof, and 3-(1-menthoxy)-propane-1,2-diol, which should provide a cool feeling in the throat.

In WO 97/25066 described pharmaceutical composition, comprising a combination of kislotoustoichivoje of proton pump inhibitor or H2 antagonist-re is aptara and one or more antacids or alginates.

No kislotoustoytchive proton pump inhibitors or antagonists H2-receptor, alone or in combination with antacids and/or alginates, do not provide a satisfactory manner quick and lasting relief for patients, for which the rate of relief of symptoms is paramount, but who also wish to remain free from symptoms for a longer time. Thus, none of the solid pharmaceutical preparations for oral administration, known to the present time, does not satisfy the basic requirements: quick start inhibiting the secretion of acids, strong reducing acid secretion and long-lasting inhibition of gastric secretion.

In addition, the use of proton pump inhibitors has a serious drawback in terms of chemical stability.

These substances are extremely unstable to acid, which caused the need for special structures. Usually these substances protect in vivo by applying stable to acid in the stomach coating (intersolubility shell) on the active substance. Because such membranes are themselves acidic (release hydrogen ions), it was found that it is necessary to provide some protection also in vitro, i.e. when the product is stored.

This protection in vitro can be arranged as described in the US 6183776 B1 (Depui et al.), when the proton pump inhibitor type giving an alkaline reaction substance and cause additional protective coating (subblock) directly under stable to acid in the stomach membrane.

Another approach is described in WO 00/78284 (US 5225202), when stable to acid in the stomach membrane is neutralized so that it does not show acidic reaction during storage. After swallowing hydrogen ions in the stomach will acidify the shell and thus to recreate kislotozawisimah properties of the membrane in situ.

Now it was discovered that the problem fast and long-lasting withdrawal symptoms, and the problem of chemical instability kislotoustoytchivi of proton pump inhibitors can be solved by the present invention.

The purpose of the invention

The aim of the invention is to obtain medications that provide quick and lasting relief to patients suffering from diseases associated with the secretion of acid in the stomach.

Another objective of the invention is the provision of a method of treating patients suffering from diseases associated with the secretion of acid in the stomach, which provides quick and lasting relief.

The following objectives of the invention will become apparent from the subsequent brief description of the invention, its preferred embodiments and the accompanying formula is subramania.

Disclosure of inventions

The present invention relates to solid pharmaceutical dosage forms for oral administration, which differs in that it includes the antagonist of H2-receptors intended for quick release, and the IIT designed for extended release. In this dosage form quickly released antagonist of H2-receptors will be quickly absorbed and to inhibit the secretion of acid by the above mechanisms. Designed for delayed and/or prolonged release IIT will provide maximum suppression of acid immediately after the first dose and will provide maximum suppression of acid throughout the course of treatment.

Kislotoustoytchive proton pump inhibitors are acid-activated prodrugs that are covalently inhibit N+To+-ATPase in gastric enzyme, transporting protons and participating in the formation of hydrochloric acid in the stomach. The action of H+To+-ATPase stomach is the final stage in the chain of events leading to the hydrochloric acid secretion of parietal cells. Therefore, inhibition of this enzyme is the most effective and specific means of controlling acid secretion irrespective of the nature of the stimulus for secretion. As traces of the lo to expect with this mechanism of action, it was found that the proton pump inhibitors type omeprazole inhibit both basal and stimulated secretion of acid. Omeprazole is a weak base that accumulates in acidic environment of the secretory membrane of parietal cells, where he was in the presence of acid converted into the active form of sulfenamide, which then reacts with sulfhydryl groups of the acid pump.

In gastric mucosal kislotoustojchivy proton pump is located in the apical membrane and tubular vesicles, bordering the secretory tubules of parietal cells. So, after a single dose of omeprazole rapidly accumulates in the acidic compartment of the secretory membrane, where its active form - sulfenamid - irreversibly binds to the N+To+-ATPase. However, N+To+-ATPase, located in tubular vesicles, will not be available activated omeprazole. A large part of the synthesized N+To+-ATPase, thus, will not be blocked after a single dose of omeprazole. Apparently, this explains the fact that the maximum effect of inhibition of acid is achieved only after five days of treatment.

Antagonists H2-receptor competitive way inhibit the action of histamine on all H2-receptors, mainly on the surface of the parietal layer of the cells. In therapeutic doses, these substances are not only able to reduce basal and nocturnal secretion of acid, but the secretion stimulated by food, histamine, insulin, and pentagastrinom. A single dose of the antagonist of H2-receptors leads to the maximum effect of inhibition of acid in 2 hours after administration. Moreover, the effect of inhibition of acid produced when high doses of the antagonist of H2-receptors, is growing rapidly, but has a tendency to a significant decline over the next 2-7 days, whereas the effect of inhibition of acid omeprazole increases gradually over the same period of time.

The present invention is based on the unexpected discovery that an almost complete inhibition of acid secretion is achieved with the first dose kislotoustoichivoje of proton pump inhibitor in the form of a composition for sustained release. In addition, as should be expected that inhibition are only activated proton pumps, secreting acid, at a time when pit is present in plasma, it was unexpectedly found that prolonged inhibition of acid secretion can be achieved at a time when the parietal cells become non-secretory state under the action quickly released antagonist of H2-receptors.

Thus, in accordance with and the acquisition provides oral pharmaceutical dosage form, comprising a pharmacologically effective amount kislotoustoichivoje of proton pump inhibitor or salt and antagonist H2-receptor or its salts, and pharmaceutically acceptable excipients, which leads to delayed and/or sustained release of the proton pump inhibitor. The term "proton pump inhibitor" and "antagonist of H2-receptors" cover their isomers, for example enantiomers of proton pump inhibitors, and pharmaceutically acceptable salts of such isomers.

The invention is particularly suitable for the treatment of "emergency" conditions, complaints of gastro-esophageal reflux type of heartburn when you need a strong reduction of acidity in a short time and most importantly fast onset of action and preferably the maximum reduction in acidity. The maximum effect of inhibition of acid can be maintained for 7 days at elimination of the phenomenon of "fading", which was observed after the introduction of only one H2-blocker. This becomes important in order to reduce the time to treat stomach ulcers caused by acid damage to the esophagus and eradication of Helicobacter pylori.

To overcome the previously mentioned problems associated with proton pump inhibitors, the invention consists of three parts:

1) when turning on the proton pump inhibitor in the composition comp the positions, releasing the active substance with delayed effect (delayed release) and/or prolonged effect (prolonged release), it turns out the song, which is completely opposite of what until recently was considered as a rapid onset of effect. However, a new type of protection for these unstable to acid pharmaceutical substances.

This type of composition with controlled release of well-known experts in this field and has several different designations.

In the present description the expression "extended release" is used as a synonym for "extended release" and "extended release". Regardless of what expression is used, the overall effect is that the release of the active substance slows down and stretches for a longer time. This is usually accomplished either by applying to the core of the active substance coating or membrane of suitable auxiliary means, control release, or the inclusion of the active substance in the matrix of the appropriate tools.

The expression "delayed release" in the present description is used to describe compositions, not releasing the active substance immediately. Beginning wisweb the Denia displaces in the small intestine or colon. This type of composition is usually obtained by applying to the core of the active substance coating or membrane subject to change during the passage through the gastrointestinal tract when exposed to changes of pH on the composition or by changing the shell depending on the time during which the composition is in contact with the liquid environment of the body. This type of composition should not be confused with compositions that are resistant to acid in the stomach ("enterocoele release"), which serve to protect the composition from hydrogen ions or, alternatively, to protect the patient from harmful effects of medical compounds in the stomach.

The expression "controlled release" and "modified release" can also be used to describe this part of the invention, but they are more collective designations which do not specifically describe this type of release mechanisms.

All of these types of signs, the basis of preparation of the formulation and suitable auxiliary means well known to specialists in this field and you can reference manual "Pharmaceutics. The Science of Dosage Form Design", 1st edition; Ed. M.E.Aulton, Churchill Livingstone, Edinburgh 1988, which is incorporated into this invention by reference. Especially noteworthy p.289-305.

Obviously, the obtained base composition can be combined with routines that bypass other AIDS. For example, proton pump inhibitors can be mixed with a substance which gives an alkaline reaction to neutralizirati a small amount of hydrogen ions that can penetrate the structure of the membrane or matrix when passing through the stomach. Such measures are not mandatory, but they lead to a more perfect song. Similarly you can apply resistant to the acid in the stomach coating on the outer side of the membrane or matrix in the composition. In the following embodiment, these two measures of preparation of the formulation can be applied at the same time;

2) the problem of slow start increasing pH, obviously, does not dare to further slow or lengthening the duration of the release. But now it turned out that you can enter the antagonist of H2-receptors, with rapid onset of effect (which is achieved by means of a quick release), without compromising the onset of action released later kislotoustoichivoje of proton pump inhibitor. This was unexpected, as an important feature of the pit lies in the fact that their actions are necessary to actively pump. Under the influence of the antagonist of H2-receptors of parietal cells become dormant. In the rest of parietal cells do not produce acid and the pump is inactive. Inhibition of production is acid under the action of IIT occurs only when the pump is in the active state when the accumulation in the parietal cells so that subsequent activation of the drug leads to inhibition of the pump. Thus, the present invention provides a novel pharmaceutical composition, using a rapid inhibition of the secretion of acid receptor antagonist of the histamine type 2 without reducing the validity of the entered simultaneously IIT;

3) based on current data on the mechanism of action IIT and biochemistry of N+To+-ATPase unclear how to achieve maximum inhibition of the secretion of acid in one dose IIT (see above). But now it turned out that lengthening the time during which there is a release of pit, leads to an unexpectedly effective inhibition of acid secretion from the first dose. When lengthening the time spent pit in the blood of newly synthesized pumps will continuously undergo inactivation. This was unexpected, because after the initial inhibition of the pump pH in the secretory compartment will increase, and the drug will undergo deprotonation and will diffuse out of the tubules. In addition, you will not have the second, is clearly a necessary stage action IIT, i.e. acid catalysis becoming active sulfenamid.

Described by the authors of the present invention combination may bitopology in two ways. First, the individual dose delayed/slow release of the proton pump inhibitor can be introduced together with a single dose of the antagonist of H2-receptors. On the other hand, these two substances with different release profiles can be combined in one preparation. A few examples should clarify how it is possible to arrange.

Thus, the present invention provides long-lasting suppression of acid after the first dose. This is achieved by means of products offered on the prior art.

H2 blockers are only active during the first 6-8 hours.

H2 blockers + antacids provide quick effect, but they are active only 6-8 hours.

IIT not give effect after the first dose.

IIT + antacids active for approximately 1 hour due to the effect of antacid.

Enantiomer IIT does not reach its full potential after the first dose.

Slow release IIT itself gives effect only after 5-6 hours.

Thus, the present invention provides a significant improvement compared with the formulations of the prior art. It is believed that this improvement effect due to unexpected clinical/physiological effect, achieved through a unique compound according to the invention, i.e. delayed/prolongedopen the first steps IDU in combination with quick release H2-blocker.

Known to some patent publication, in which is disclosed a combination of proton pump inhibitor and compositions for delayed release, and you can rely on US 6132768, US 6274173 B1 and DE 19925710 A1. These links are aimed at improving the stability of proton pump inhibitors on the degradation and decolorization caused by hydrogen ions. However, they say nothing about any combination of the proton pump inhibitor and an antagonist of H2-receptors and unexpected advantages gained by this.

In addition, the composition, inhibiting the secretion of acid in the stomach, known from international patent application PCT/SE02/00757. This composition includes a combination of kislotoustoichivoje of proton pump inhibitor and an antagonist of H2-receptors, but does not mention system of the fillers of the present invention and its unexpected advantages.

In accordance with the invention provides an oral dosage form comprising an antagonist of H2-receptors in amounts effective to reduce the acidity in the stomach after administration, and kislotoustojchivy the proton pump inhibitor in an amount effective to maintain the low pH-induced antagonist of H2-receptors for a long time. Preferably these pharmacologically effective amount is capable of being in order to raise the pH in the stomach above 3 within 2 hours after administration and to keep it above 3, at least 4 hours, preferably at least 8 hours. More preferably these pharmacologically effective amount capable of increasing the pH in the stomach 4 or above within 2 hours after administration and support it above 4, at least 8 hours, more preferably at least 16 hours.

In accordance with the first preferred aspect of the invention, the antagonist of H2-receptors located in the quantity which is capable of providing at least 80% of the maximum reduction, more preferably at least 95% of the maximum reduction of acidity in the stomach for about 2 hours. "Maximum reduction" there is a decrease in acidity, which can be obtained by the maximum with the introduction of only one antagonist of H2-receptors in a therapeutically acceptable amount, that is, in the quantities in which these drugs are used in this area. The term "antagonist(s) H2-receptors" in the present invention covers all the tools that significantly inhibit or block the secretion of acid in the stomach by binding to receptors of histamine type 2 in the stomach. In therapeutic doses such antagonists H2-receptor is not only able to reduce basal and nocturnal secretion of acid, but the secretion stimulated by food, histamine, insulin, and pentagastrinom. Examples of the Academy of Sciences of the agonists H2-receptor according to the invention is represented by cimetidine, ranitidine and nizatidine and famotidine, which are usually used in the form of their pharmacologically acceptable salts, in particular hydrochloride. Dosage form according to the invention preferably contains from 1 mg to 800 mg of antagonist H2-receptor or its salt, more preferably from 5 mg to 400 mg

In accordance with a second preferred aspect of the invention kislotoustojchivy the proton pump inhibitor is in an amount which is capable of maintaining low acidity, caused by the antagonist of H2-receptors, for at least 6 hours. Kislotoustoytchive proton pump inhibitors quickly take place on the market antagonists H2-receptor. The term "kislotoustojchivy proton pump inhibitor" in the present invention includes derivatives of benzimidazole, which has significant activity inhibition of N+To+-ATPase, in particular omeprazole, pantoprazole, lanzoprazol, rabeprazole, alprazol, leminoprazole and their pharmaceutically acceptable salts, enantiomers and salts of enantiomers, but also covers and other compounds described on p.7-11 WO 97/25066, which is incorporated into this invention by reference, as well as compounds disclosed in EP 005129 A1, EP 174726 A1, EP 166287 A1, GB 2163747, WO 90/06925, WO 91/19711, WO 91/19712, WO 94/27988, WO 95/01977.

Thus, the dosage form according to the invention with the holding preferably from 1 mg to 100 mg, more preferably from 5 mg to 50 mg, per dose kislotoustoichivoje of proton pump inhibitor or salt. Kislotoustojchivy a proton pump inhibitor or salt is separated from the H2 antagonist-receptor according to the principle of making the recipe, in which only the proton pump inhibitor is covered by a membrane or embedded in the matrix with the aim of delayed and/or sustained release.

In accordance with a third preferred aspect of the invention, the antagonist of H2-receptors in the dosage form for quick release and kislotoustojchivy the proton pump inhibitor in a dosage form for the delayed and/or prolonged release should not be in the same pharmaceutical compositions, but can be entered individually for a short period of time, for example one hour, preferably within 30 minutes, most preferably within 10 minutes So it looks appropriate dosage regimen for separate, but collaborative introduction kislotoustoichivoje of proton pump inhibitor and an antagonist of H2-receptors for the treatment of diseases associated with the secretion of acid in the stomach.

Thus, the oral dosage form according to the invention contains kislotoustojchivy the proton pump inhibitor in a dosage form for the delayed and/or the prolonged release antagonist of H2-receptors in the dosage form for quick release and optional tool to suppress acid in the stomach and/or alginate. Preferably the dosage form according to the invention contains from 100 mg to 1000 mg antacid and/or alginate. Antacids tool according to the invention includes one or more from among aluminum hydroxide, calcium carbonate, magnesium carbonate, basic magnesium carbonate, magnesium hydroxide, magnesium oxide and sodium bicarbonate.

Due to the fact that kislotoustoytchive proton pump inhibitors in General sensitive to acid (kislotoustoytchive proton pump inhibitors), they need to enter in a way that protects them from degradation in the stomach and allows it to pass into the small intestine where they are absorbed. In this invention this is mostly solved by using fillers for delayed and/or prolonged release, which provide protection, and without a known disadvantage intersolubility membranes (release hydrogen ions, which increases the rate of degradation of the proton pump inhibitors). On the other hand, antagonists H2-receptor can be entered without such protection. In accordance with the following preferred aspect of the invention compositions can be adapted so that they corresponded to t the NML of the present invention, what are disclosed in WO 97/25066.

Oral dosage forms according to WO 97/25066 include kislotoustojchivy the proton pump inhibitor in a quantity close or identical to that used in the compositions of the present invention, and one or more antacid funds and/or alginates. Adaptation of the compositions of WO 97/25066 basically consists, first, in addition to the membrane system or system matrix to the portion of the composition, which contains a proton pump inhibitor, and, secondly, the replacement pharmacologically effective amount of an antagonist of H2-receptors of part or all of the amount of antacid and/or alginate.

In accordance with the invention provides oral mnogoagentnye tableted dosage form containing kislotoustojchivy proton pump inhibitor individually covered units for delayed/prolonged release optional covered intersolubility shell, together with an antagonist of H2-receptors in the form of powder or granules, pressed into a pill. Intersolubility shell surrounding an individual unit with islamochristiana a proton pump inhibitor, has properties such that pressing them into the tablet does not have a significant influence on the resistance to acid individually aircraft is s units. Moreover, mnogoagentnye tableted dosage form provides a good stability of the active substances with long-term storage.

In accordance with the invention also provides mnogoagentnye tableted dosage form, which can be divided and easy to handle. This mnogoagentnye tableted dosage form contains granules coated for delayed/sustained release with islamochristiana a proton pump inhibitor, optionally covered intersolubility sheath, pressed powder antagonist of H2-receptors. Such a dosage form may also contain effervescent components that promote rapid disintegration when released into the water. The pH value of the aqueous phase should be slightly acidic to prevent the dissolution of any intersolubility shell. Such dosage form can be given to patients with swallowing disorders and Pediatrics. Such a suspension of dispersed units/granules of appropriate size can be used for oral administration, as well as for insertion through nosolution tube.

In accordance with the invention also contemplates the preparation of tablets containing kislotoustojchivy the proton pump inhibitor in combination with fillers, forming the core of tablets is, which covered fillers for delayed and/or prolonged release, and a separate layer surrounding the core tablet. Surrounding layer contains antagonist of H2-receptors in a mixture with a pharmaceutical excipient. Optional separating layer is applied to the core tablets before coating on the core. An additional option is to apply intersolubility shell on top of other coatings. On the other hand, finished tablet may consist of separate layers, each of which contains a different active substances. One of the layers, preferably the inner (core)contains kislotoustojchivy the proton pump inhibitor in the form of coated granules mixed with pharmaceutical excipients, and the other layer (s) contains the antagonist(s) - receptor histamine type 2 respectively mixed with pharmaceutical excipients. Not necessarily these two layers are separated by a dividing layer to prevent adhesion between the two layers. Covered kernel containing kislotoustojchivy a proton pump inhibitor, can also be covered intersolubility shell, for example, according to the procedures disclosed in WO 00/78284, which is incorporated into this invention by reference.

According to the invention kislotoustojchivy the proton pump inhibitor in the form of a coated the granules can be mixed with the antagonist(s) H2-receptors and optional pharmaceutical(s) filler(s) for use in sachets for oral administration after dispersion in weakly acidic aqueous solution.

Preferably the dosage form according to the invention contains kislotoustojchivy a proton pump inhibitor or salt, is protected by a coating layer for delayed and/or prolonged release and optional intersolubility shell. Preferably the dosage form according to the invention comprises two concentric layers, optionally separated by one or more separating layers, with one layer contains the specified kislotoustojchivy a proton pump inhibitor or its salt, and the other layer contains the specified antagonist H2-receptor or its salt.

The inner layer contains kislotoustojchivy a proton pump inhibitor or its salt, and the outer layer contains the antagonist of H2-receptor or its salt. In accordance with a preferred aspect of the outer layer includes dezintegriruetsja substance. Oral dosage form according to the invention may take various forms, such as tablets, capsules, divided compositions of powder/granules, etc.

In addition, as described above, containing kislotoustojchivy proton pump inhibitor part of the composition has the effect of delayed and/or prolonged release in the coating on the core material with a proton pump inhibitor. However, another approach is to replace Obolo the key, that is, the membrane system, the system matrix. Then choose fillers, forming a lipid or water-insoluble matrix. Function matrix is the implementation of the prolonged release of the proton pump inhibitor.

In accordance with the invention is also disclosed a method of manufacturing an oral tablet dosage forms containing kislotoustojchivy a proton pump inhibitor or salt and antagonist H2-receptor or its salt in the amount of pharmacologically effective in the treatment of diseases associated with dyspepsia, and this method includes forming a first layer containing a specified kislotoustojchivy a proton pump inhibitor or salt, coatings, fillers for delayed and/or prolonged release and optional intersolubility shell surrounding said first layer and second layer containing a specified antagonist H2-receptor or its salt and surrounding said first layer and the coating. Also disclosed a method of manufacturing an oral dosage form containing specified kislotoustojchivy a proton pump inhibitor or salt and antagonist H2-receptor or its salt in the amount of pharmacologically effective in the treatment of diseases associated with dyspepsia, and this with the persons involves the formation of granules, containing the specified kislotoustojchivy a proton pump inhibitor or salt, drawing on the above granules of the above coatings and mixing of these granules with medium containing the indicated antagonist H2-receptor or its salt, and a carrier optionally includes dezintegriruetsja substance. The above mentioned methods according to the invention additionally include a final stage tabletting, optionally followed by a stage of deposition of the film.

Another method of manufacture of oral dosage forms according to the invention includes filling capsules, able to disintegrate in the gastrointestinal fluid, releasing its contents, a mixture comprising coated granules with a proton pump inhibitor and an antagonist of H2-receptors in the form of powder or granules.

Regarding the manufacturing methods as described above, containing a proton pump inhibitor part of the composition has the effect of delayed and/or prolonged release in the coating on the core material with a proton pump inhibitor. However, another approach is to replace the membrane, i.e. the membrane system, the system matrix. Then choose fillers, forming a lipid or water-insoluble matrix. Function matrix is the implementation prolongirovanne what about the release of the proton pump inhibitor.

The use of the pharmaceutical dosage forms according to the invention, however, is not limited to providing fast and lasting relief of patients suffering from diseases associated with the secretion of acid in the stomach. You should expect rapid onset of inhibition of acid secretion in the stomach, combined with the maintenance of inhibition as far as necessary (by re-introducing a composition containing kislotoustojchivy a proton pump inhibitor, preferably by re-introducing the composition according to the invention), will have a positive effect on the healing of gastric ulcers and duodenal ulcers and esophagitis, which shows the maintenance of the pH inside the stomach above 4 on the maximum time (Huang, J.Q. and R.H. Hunt, rn, healing rate and option relief in patients with GERD, Yale J Biol Med 1999, 72: 181-94). Thus, the composition according to the invention is also preferred to maintain the pH in the stomach above 4 for a long time, for example for 4 hours and more.

Dosage form according to the invention can also be used together with one or more antibiotics to eradicate Helicobacter pylori.

In accordance with the invention is also disclosed a method of treating diseases associated with the secretion of acid in the stomach, which includes the introduction of dosage forms according to the invention or the simultaneous introduction of two separate peror the selected dosage forms, one contains a pharmacologically effective amount kislotoustoichivoje of proton pump inhibitor or salt in the dosage form for the delayed and/or prolonged release, and the other contains a pharmacologically effective amount of the antagonist of H2-receptor or its salt in the dosage form for quick release.

In addition, in accordance with the invention, disclosed is a method of treatment of Helicobacter pylori infection involving the introduction of a dosage form according to the invention or the simultaneous introduction of two separate oral dosage forms, one contains a pharmacologically effective amount kislotoustoichivoje of proton pump inhibitor or its salt, and the other contains a pharmacologically effective amount of the antagonist of H2-receptor or its salts, in combination with the introduction of one or more antibiotics that are effective against N. pylori.

The above methods of treatment according to the invention preferably include the dosage, capable of maintaining the pH in the stomach above 4 for at least 95% of the time, starting 2 hours after the first dose and continued until 6 hours after the last dose, in particular such a regime in which the time period is one week or more, predpochtitelnei weeks and more even more preferably four weeks and more. In this regard, preferred dosage regimen is capable of maintaining the pH in the stomach above 3 for at least 95% of the time, starting 2 hours after the first dose and continued until 6 hours after the last dose, in particular four weeks and more.

Hereinafter the invention will be described in more detail with the involvement of some preferred, but non-limiting embodiments presented in the drawings.

Brief description of figures

Figure 1-4 represent schematic cross section representing the following.

Figure 1 - mnogoagentnye tableted dosage form containing kislotoustojchivy the proton pump inhibitor in the form of coated granules for delayed and/or prolonged release in a mixture with an antagonist of H2-receptors, dispersed in a pharmaceutical carrier.

Figure 2 - tableted dosage form of two halves, one of which contains coated for delayed and/or prolonged release granules with islamochristiana a proton pump inhibitor in combination with fillers, while the other contains the antagonist of H2-receptors in combination with fillers.

Figure 3 - multi-layer tablet dosage form, tereasa kislotoustojchivy the proton pump inhibitor in the nucleus, surrounded by a shell for delayed and/or prolonged release, and surrounding the core layer containing antagonist of H2-receptors, dispersed in a pharmaceutical carrier.

4 is a capsule dosage form containing kislotoustojchivy the proton pump inhibitor in coated for delayed and/or prolonged release granules, mixed with H2 antagonist receptors and pharmaceutical excipients.

The implementation of the invention

Mnogoagentnye tableted dosage form. Mnogoagentnye tableted dosage form according to the invention, represented in figure 1, consists of the main mass of 1, optionally covered with a layer of film 3, and a small granules 2, distributed randomly in the bulk 1. Granules contain 2 kislotoustojchivy the proton pump inhibitor in the form of a racemate, an alkaline salt or one of the enantiomers. Individual unit 2 (small beads, granules, or beads)containing kislotoustojchivy proton pump inhibitor and optionally containing an alkaline substance, the cover layer(s)having(I) properties of delayed release and/or sustained release, and optional additional intersolubility shell. Then covered in unit 2 is mixed with antagonist is 2-receptors and standard excipients for tablets, forming in the end, the bulk of the tablet 1. Antagonist of H2-receptors and excipients for tablets can be mixed dry or wet granules. The mixture of coated units, antagonist of H2-receptors and fillers are compressed in mnogodenek tableted dosage forms. The expression "individual unit" means small beads, pellets or beads, which are hereinafter referred to as granules with a proton pump inhibitor. In the following embodiment of the invention on "individual unit" also put antagonist of H2-receptors. Then the antagonist of H2-receptors should be located in a peripheral position in relation to the shells for delayed and/or prolonged release and intersolubility shell so that he was quickly released in the gastrointestinal tract. When pelletizing the mixture must be careful to not much change the acid resistance of coated granules. With respect to the material for coating core granules containing kislotoustojchivy a proton pump inhibitor that is sent to the application WO 97/25066, s, from the second to the last paragraph - p.15, the end of the second paragraph, which is incorporated into this invention by reference. In relation to shell carrying out delayed and/or prolonged release sent to US 6274173 to the categories included in the present invention by reference. You can also refer to "Pharmaceutics. The Science of Dosage Form Design", 1st edition; Ed. M.E.Aulton, Churchill Livingstone, Edinburgh 1988. It should especially be noted p.289-305. In relation intersolubility shell(shells) are sent to the application WO 97/25066, p.15, from the second to the last paragraph - p.18, the end of the second paragraph, which is incorporated into this invention by reference. Granules with islamochristiana a proton pump inhibitor coated for delayed and/or prolonged release and optional intersolubility shell, can be optionally covered with one or more outer (protective) layers. In respect of such outer (protective) layers refer to the application WO 97/25066, p.18, last paragraph - p.19, the end of the first paragraph, which is incorporated into this invention by reference.

Antagonist of H2-receptors are mixed dry with inactive excipients, such as fillers, binders, dezintegriruetsja agents, and other pharmaceutically acceptable excipients. From this mixture to form a wet mass using a granulation liquid. The wet mass is dried, preferably to a loss of less than 3% by weight. Then the dry mass is crushed to an appropriate size for pellets, preferably less than 1 mm Suitable inert fillers are, for example, mannitol, corn starch, potato Brahma is, slabosolenaja hydroxypropylcellulose, microcrystalline cellulose, and crosslinked polyvinylpyrrolidone. A dry mixture containing antagonist of H2-receptors, can be mixed with a suitable granulation liquid containing, for example, hydroxypropylcellulose or polyvinylpyrrolidone dissolved in water or alcohol, or mixtures thereof. Alternatively, the antagonist of H2-receptors are mixed dry with pharmaceutically acceptable excipients (see above). As indicated above, in another embodiment of the invention, the antagonist of H2-receptors can be applied to small units 2 and not mixed with fillers for forming the main mass of the tablet 1. Regardless of how the inclusion of the antagonist of H2-receptors, it must have the property of fast release.

Action of a multiunit tablets. Coated granules containing kislotoustojchivy a proton pump inhibitor, is mixed with granules antagonist of H2-receptors or ready dry mixture containing antagonist of H2-receptors. This mixture is mixed with the lubricant and are compressed in mnogodenek tableted dosage form. Suitable lubricating agents for tabletting process are, for example, sodium fumarate, magnesium stearate and talc. Pressed tablet NeoMaster is but cover film-forming agent to obtain a smooth surface. This shell may optionally include additives such as funds from sticking, dyes and pigments, or other additives.

The share of coated granules is preferably less than 60% of the total weight of the tablet. In this preferred formula mnogoagentnykh tablets consists of coated for delayed and/or prolonged release granules, optional covered intersolubility shell and containing kislotoustojchivy a proton pump inhibitor, optionally in a mixture with the giver alkaline substances, pressed into tablets with a prepared mixture antagonist of H2-receptors/filler(s). Optional intersolubility shell(and) makes the granules of this dosage form is insoluble in acidic media, but dezintegriruetsja/dissolving in an almost neutral and alkaline environments, such as gastric juice in the proximal part of the small intestine, where it is desirable dissolution and absorption kislotoustoichivoje of proton pump inhibitor. Then the wrapper for the delayed release will begin to release kislotoustojchivy a proton pump inhibitor after a certain period of time in the gastrointestinal tract or when a certain pH values in some place of the intestine or the colon. Shell for prolonged in which osvobojdenie will prolong the release of the proton pump inhibitor, that will lead to the absorption of the drug over several hours. Granules of proton pump inhibitor coated for delayed and/or prolonged release can also be covered with an outer protective layer prior to pelletizing, and they may also contain one or more separation layers between the core material and the other layers.

The method of obtaining mnogoagentnykh tablets. The way to obtain this dosage form is another aspect of the invention. After the formation of granules by mixing dry (an ordered mixture, spraying or applying kislotoustoichivoje of proton pump inhibitor in the seed or by extrusion/spheronization or granulation granules first optional deal separator(s) layer(s), then the layer(s) for delayed and/or prolonged release, and then not necessarily cause intersolubility(s) cover(s). The coating is carried out as described above and in the accompanying examples. Preparation of a mixture with an antagonist of H2-receptors are also described in the examples. Optional antagonist of H2-receptors can be applied to already existing layers constituting the coating for delayed and/or prolonged release and intersolubility shell.

Coated granules, together with external (protect Tim) layer or without it, mix with the prepared granules or dry powder antagonist of H2-receptors, fillers for tablets and other pharmaceutically acceptable additives and tabletirujut. Alternatively, the coated granules of the proton pump inhibitor may be applied a second layer containing antagonist of H2-receptors, as described in subsequent examples. In addition, as shown in figure 2, covered with granules 4 can be uniformly mixed with fillers 5 and subjected to a preliminary pressing, then add the drug antagonist of H2-receptors and the whole weight of the tablets are subjected to final pelletizing, optionally together with film-forming(they are) the substance(s) 6 to obtain a smooth surface. As a further alternative, are presented in figure 3, kislotoustojchivy the proton pump inhibitor in the form of a powder may be mixed with excipients for tablets and subjected to pressing into tablets 8, which does not necessarily cover the separating layer, and then apply the coating 9 for delayed and/or sustained release. Optional put intersolubility shell. On the resulting core tablets then zapressovyvajut drug antagonist H2-receptor 10. Finally, the tablets can be coated outer shell 11 to obtain a smooth surface.

You can also requesting kislotoustojchivy the proton pump inhibitor in the form of coated granules in sachet together with an antagonist of H2-receptors and do not necessarily mix with fillers.

Figure 4 presents hard gelatin capsules 16, filled not subjected to pressing the core material 14, 15 of the embodiment presented in figure 1.

In the above examples (1, 2, 3, and 4) apply the terms of coverage, shell or layer. These terms are interchangeable and also identical to the term membrane. Regardless of the items they have in common is that they correspond more or less continuous phase materials, fillers, caused, for example, by sputtering on the core material. Due to the nature of their processing these membranes are relatively thin in relation to the thickness.

Suitable materials fillers to form a coating (or membranes) for delayed and/or prolonged release are polimernye or polymeric materials, such as calcium phosphate, ethylcellulose, a copolymer of methacrylate, polyamide, polyethylene, polyvinyl alcohol or polyvinyl acetate.

In addition, as described above, containing a proton pump inhibitor part of the song (2 on 1, 4 on 2, 8 on figure 3 and 15 in figure 4) has the effect of delayed and/or prolonged release when NAS is saving coating on the core material with a proton pump inhibitor. However, another approach is to replace the membrane, i.e. the membrane system, the system matrix. Then choose fillers, forming a lipid or water-insoluble matrix. Function matrix is the implementation of the prolonged release of the proton pump inhibitor. Suitable fillers for the formation of the matrix are such polimernye or polymeric materials, such as calcium phosphate, ethylcellulose, a copolymer of methacrylate, polyamide, polyethylene, or polyvinyl acetate, Carnauba wax, cetyl alcohol, hydrogenated vegetable oil, microcrystalline wax, mono - and triglycerides, polyethylene glycol or polietilenglikolmonostearat and most preferred are Carnauba wax, cetyl alcohol, hydrogenated vegetable oil, microcrystalline wax, mono - and triglycerides, polyethylene glycol or polietilenglikolmonostearat. For optimum speed of release, you don't need to add hydrophilic pore-forming fillers. Suitable hydrophilic pore-forming fillers are alginates, carbopol, gelatin, hydroxypropylcellulose, hypromellose or methylcellulose.

In General, methods WO 97/25066 to receive oral pharmaceutical dosage forms, provided kislotoustojchivy proton pump inhibitor and antacid agent or alginate, can be adapted to the purposes of the present invention, firstly, by adding a membrane system or system matrix to the portion of the composition, which contains a proton pump inhibitor, and, secondly, the replacement of part or all of the amount of antacid or alginate on pharmacologically effective amount of the antagonist of H2-receptors, and the rest of the antacid agent or alginate (if replacement is not equal to 1:1 by weight) is skipped or replaced with such fillers as microcrystalline cellulose, silica, lactose, mannitol, etc.

The use of dosage forms according to the invention

Dosage forms according to the invention is especially preferred in the treatment of dyspepsia and other gastrointestinal disorders associated with the production of acid in the stomach, to provide quick and lasting relief of symptoms. These dosage forms are applied one or more times a day. A typical daily dose kislotoustoichivoje of proton pump inhibitor and an antagonist of H2-receptors depend on various factors such as the individual needs of patients, the method of application and the particular disease to be treated. In General, each dosage form must contain from 1 mg to 100 mg kislotoustoichivoje of proton pump inhibitor and from 1 mg to 800 mg of antagonist H2 p the receptors. Preferably each dosage form should contain from 5 mg to 50 mg kislotoustoichivoje of proton pump inhibitor and from 5 mg to 200 mg of the antagonist of H2-receptors. Medication in the form action of a multiunit tablets are also suitable for dispersion in water, slightly acidified by adding citric acid.

EXAMPLE 1

Mnogoagentnye tableted dosage form containing a magnesium salt of omeprazole and cimetidine hydrochloride, lot size: 400 tablets. About producing granules Mg-salt of omeprazole (the core material, a separating layer, intersolubility shell and the outer protective layer, see application WO 97/25066, s-23 under the relevant headings) see application WO 97/25066, the first two paragraphs, which is all included in the present invention by reference. Layer for prolonged release is applied in the form of a coating between the separation layer and intersolubility sheath in accordance with those described in patent US 6274173, examples 1-4, using ethylcellulose or polyvinyl acetate as fillers for prolonged release, and information from it is included in the present invention by reference.

Tablets

300,0 g
The finished granules containing Mg-salt of omeprazole31,3 g
Microcrystalline cellulose
Cimetidine hydrochloride40,0 g
Potato starch50.0 g
Water200,0 g
PVP cross stitched38.0 g
The sodium fumarate4.6 g

Dissolve a small amount of potato starch in purified hot water for formation of granulation liquid. Mix dry hydrochloride, cimetidine, the rest of the potato starch and microcrystalline cellulose. To the dry mixture granulation liquid and mix the wet mass. The wet mass is dried in an oven at 50°C. the Obtained granulation mass is crushed through a sieve of 1 mm on the vibration setting. Mixing the coated granules with a protective layer, the finished granules antagonist of H2-receptors, cross crosslinked polyvinylpyrrolidone and sodium fumarate and pressed tablets using a tablet press machine, equipped with an oval stamps. The amount of omeprazole in each tablet is about 10 mg, and the number of cimetidine hydrochloride about 100 mg.

With a little modification this mnogoagentnye tablet form may contain antacid agent (instead of 300 mg microcrystalline cellulose: 100 mg microcrystalline cellulose, 100 mg of calcium carbonate, 100 mg OK the IDA magnesium, all other components, except water, in the above amounts).

EXAMPLE 2

Three-layer tablet dosage form. Tablets contain kislotoustojchivy the proton pump inhibitor omeprazole, a separating layer and a core containing cimetidine hydrochloride. Lot size: 1000 tablets.

The first layer tablets

Cimetidine hydrochloride200,0 g
Microcrystalline cellulose250,0 g
PVP cross stitched13,0 g
The sodium fumarate3.8 g

The separating layer

Microcrystalline cellulose80,0 g

The second layer tablets

Coated granules containing

Mg-salt of omeprazole (as in example 1)to 78.3 g
Microcrystalline cellulose174,0 g
PVP cross stitched26,0 g
The sodium fumarate1.4 g

An integral part of the first layer of the tablet dry mix and subjected to preliminary pressing as the first layer using a tablet press machine, SN is Biennal oval stamps. On top of the first layer is applied microcrystalline cellulose, forming a separating layer for the next layer. An integral part of the second layer of the tablet dry mix and put on the separating layer. These three layers are compressed in a three-layer tablet, which can be covered by an outer protective layer. The amount of omeprazole is about 10 mg, and the number of cimetidine hydrochloride 200 mg per pill.

EXAMPLE 3

Capsule dosage form. Hard gelatin capsules No. 1 (16) (figure 4, the volume of 0.48 ml) was filled with pellets of omeprazole coated for prolonged release (15)containing 20 mg of omeprazole (obtained in example 1), and the dry mixture 14 from commercially available famotidine 20 mg and closed.

EXAMPLE 4

Separated the composition of the powder/granules. Pellets for sustained release, containing 15 mg of lansoprazole (obtained analogously to example 1) and the drug famotidine, mixed dry with citric acid. Portions corresponding to one dose and containing 10 mg of lansoprazole and famotidine hydrochloride and 200 mg of powdered citric acid, Packed dry in a plastic laminate. The composition should pour 20 ml of water, little mix and drink.

EXAMPLE 5

Mnogoagentnye capsule dosage form. The capsules contain a magnesium salt of omeprazole famotidine hydrochloride. About coating for sustained release see US 6274173, examples 1-4, the information of which is included in the present invention by reference. About intersolubility shell and the outer protective layer, see WO 97/25066, s-23 under the appropriate headings, information from which is included in the present invention by reference.

Mix the magnesium salt of omeprazole with microcrystalline cellulose microspheres to obtain an ordered mixture. This mixture is covered with a layer for prolonged release consisting of polyvinyl acetate, powdered lactose, propylene glycol and ammonia (25%), installation of fluidized bed. Then, these pellets for sustained release cover intersolubility shell consisting of methacrylic acid copolymer, mono - and diglycerides, triethylcitrate and Polysorbate, installation fluidized bed. Then on these ordered units for prolonged release with intersolubility shell cause the outer layer by using a water suspension containing famotidine hydrochloride, hypromellose and magnesium stearate, in the installation of fluidized bed. This mixture for prolonged release with intersolubility shell and the outer protective layer of fill hard gelatin capsules. The number of the of eprazole is about 10 mg, and the number of famotidine hydrochloride 200 mg per capsule.

EXAMPLE 6

Mnogoagentnye tableted dosage form. Tablets contain magnesium salt of omeprazole and cimetidine hydrochloride. Magnesium salt of omeprazole is mixed with mannitol granules to obtain an ordered mixture, which cover shell for extended release and intersolubility shell, as described in example 5. Cimetidine hydrochloride is subjected to granulation, as described in example 1. Covered with an ordered mixture comprising a magnesium salt of omeprazole, cimetidine granules and fillers, are mixed dry and pressed into tablets. The amount of omeprazole in each tablet is about 10 mg and about cimetidine 100 mg

EXAMPLE 7

Mnogoagentnye tableted dosage form for quick release of the antagonist of H2-receptors and prolonged release in the colon of a proton pump inhibitor. Tablets contain magnesium salt of omeprazole and cimetidine hydrochloride.

The core material

Magnesium salt of omeprazole120 g
Sugar granular150 g
The hypromellose18 g
Polysorbate 802.4 g
Purified water562 g

The coating suspensions were performed in the installation of the fluidized bed. Magnesium salt of omeprazole was sprayed on the granular sugar from water suspension containing the dissolved binder and Polysorbate 80. The size of grains of sugar were in the range from 0.25 mm to 0.35 mm

Layer for extended release

The core material (see above)200 g
Eudragit®RTM100 g
Hydroxypropylcellulose10 g

Layer delayed release

Granules coated with a layer
prolonged release (see above)250 g
Eudragit®FS 30 D100 g

The prepared core material covered with a layer for prolonged release layer and for delayed release in the installation of fluidized bed using a commercially available aqueous suspension Eudragit®RTM and Eudragit®FS 30 D, respectively.

Intersolubility shell

Granules coated with a layer
prelungirea the aqueous release
and a layer for delayed release (see above)250 g
Methacrylic acid copolymer (30% suspension)333,7 g
Triethylcitrate30 g
Mono - and diglycerides (NF)5 g
Polysorbate 800.5 g
Purified water196 g

Intersolubility shell composed of a copolymer of methacrylic acid, mono - and diglycerides, triethylcitrate and Polysorbate, was applied by spray granules, coated with layers for extended/delayed release, installing the fluidized bed. Granules with intersolubility shell were separated by size by sieving.

Tablets

The finished granules containing Mg-salt of omeprazoleof 63.7 g
Cimetidine hydrochloride65.0 g
Calcium carbonate123,9 g
Magnesium hydroxide123,9 g
Potato starch52,2 g
Purified water435
Microcrystalline cellulose175 g
Polyvidone cross stitched50.0 g
The sodium fumarate6.0 g

Dissolved a small amount of potato starch in hot purified water for formation of granulation liquid. Mixed dry cimetidine hydrochloride, calcium carbonate, magnesium hydroxide and potato starch. To the dry mix was added to the granulation liquid and mixed wet mass.

The wet mass was dried in an oven at 40°C. the Obtained granulation mass was ground through a 1 mm sieve vibration installation.

Mixed granules with a multilayer coating, the finished granules, cross stitched polyvidone, microcrystalline cellulose and sodium fumarate and extruded tablets in tablet press machine is equipped with 9 oval stamps by 20 mm, the Amount of omeprazole in every pill about 20 mg and the same number of cimetidine hydrochloride.

The hardness of the tablets was 30N.

Optional obtained tablets were covered with an external protective coating.

1. Oral pharmaceutical dosage form for the treatment of conditions associated with the secretion of acid in the stomach, comprising a pharmacologically effective amount kislotoustoichivoje of proton pump inhibitor or salt and antagonist H2-receptor or its salt, and at least one pharmaceutically acceptable excipient that PR is leads to the delayed release and/or extended release kislotoustoichivoje of proton pump inhibitor or its salts, as specified antagonist H2-receptor or its salt is included so that it is rapidly released from the specified dosage forms.

2. Dosage form according to claim 1, in which kislotoustojchivy a proton pump inhibitor selected from lansoprazole, omeprazole, pantoprazole, rabeprazole, ariprazole, leminoprazole, their pharmaceutically acceptable salts, enantiomers and salts of enantiomers.

3. Dosage form 2 containing from 1 to 100 mg kislotoustoichivoje of proton pump inhibitor or its salts in a single dose.

4. Dosage form according to claim 1, in which the antagonist of H2-receptors selected from cimetidine, ranitidine, nizatidine and famotidine, their pharmaceutically acceptable salts, isomers and salts of isomers.

5. Dosage form according to claim 4, containing from 1 to 800 mg of antagonist H2-receptor or its salts.

6. Dosage form according to claim 1, in which the filler carries out controlling the release function in the form of a membrane deposited on the core, containing kislotoustojchivy a proton pump inhibitor or salt, or in form of the system matrix, in which kislotoustojchivy a proton pump inhibitor or salt included in the filler.

7. Dosage form according to claim 1, in which the antagonist of H2-receptor or its salt to form an outer layer deposited on the core, containing kislotozavisimyh the local proton pump inhibitor or salt and fillers, and forms the core of the system matrix or membrane system capable of delayed and/or prolonged release kislotoustoichivoje of proton pump inhibitor or salt.

8. Dosage form according to claim 6 or 7, in which the fillers used for the formation of a membrane or matrix, are inert or lipid.

9. Dosage form of claim 8, in which the inert fillers are polimernye or polymeric materials, such as calcium phosphate, ethylcellulose, a copolymer of methacrylate, polyamide, polyethylene, polyvinyl alcohol or polyvinyl acetate.

10. Dosage form of claim 8, in which the lipid fillers are polimernye or polymeric materials such as Carnauba wax, cetyl alcohol, hydrogenated vegetable oil, microcrystalline wax, mono - and triglycerides, polyethylene glycol or polietilenglikolmonostearat.

11. Dosage form according to claim 9 or 10, in which are more hydrophilic fillers such as alginates, carbopol, gelatin, hydroxypropylcellulose, hypromellose or methylcellulose.

12. Dosage form according to claim 6 or 7, in which the membrane system or the system matrix applied intersolubility shell and, optionally, the layer separating intersolubility about what olocco from the membrane system matrix.

13. Dosage form according to claim 6 or 7, which includes giving an alkaline reaction of the substance with islamochristiana a proton pump inhibitor or salt.

14. Dosage form according to claim 1, in which the mentioned pharmacologically effective amount capable of increasing the pH in the stomach above 4 within 2 h after injection, and keep it above 4 for at least 4 hours

15. Dosage form 14 in which the specified quantity is capable of maintaining the pH in the stomach above 4 for at least 8 hours

16. Dosage form 14 or 15, in which the mentioned pharmacologically effective amount capable of increasing the pH in the stomach above 3 within 2 h after injection, and keep it above 3, at least 4 hours

17. Dosage form according to item 16, in which the specified quantity is capable of maintaining the pH in the stomach above 3 at least 8 hours

18. Dosage form according to claim 1, containing from 100 to 1000 mg antacid and/or alginate.

19. Dosage form p in which antacids means includes one or more from among aluminum hydroxide, calcium carbonate, magnesium carbonate, basic magnesium carbonate, magnesium hydroxide, magnesium oxide and sodium bicarbonate.

20. Dosage form according to claim 1, in which kislotoustojchivy a proton pump inhibitor or salt and fillers, which jointly about who will formed membrane system or the system matrix, are in the form of the action of a multiunit system, consisting of many small units consisting of beads, granules, or beads.

21. Dosage form according to claim 20, in which small units in mnogodetnoi system also contain outer layer antagonist H2-receptor or its salts.

22. Dosage form according to claim 20, in which small units dispersed in the antagonist of H2-receptor or its salt, optionally in a mixture with pharmaceutically acceptable excipients such as dezintegriruetsja substances.

23. Dosage form according to claim 1, comprising two halves, one of which contains kislotoustojchivy a proton pump inhibitor or its salt in a mixture with fillers, are capable of forming the system matrix or membrane system, and the other half contains the antagonist of H2-receptor or its salt, optionally in a mixture with pharmaceutically acceptable excipients such as dezintegriruetsja substances.

24. Dosage form according to claim 1 in the form of capsules.

25. Dosage form according to claim 1 in the form of a separated structure from powder/granules.

26. Dosage form according to claim 1 in the form of tablets.

27. Dosage form p, which may be divided.

28. Dosage form p, which can be dispersed in water.

29. Dosage form p, including dezintegriruetsja substance.

30. Ways is receiving oral pharmaceutical dosage form according to claim 1, comprising a pharmacologically effective amount kislotoustoichivoje of proton pump inhibitor or salt and antagonist H2-receptor or its salt, and at least one pharmaceutically acceptable excipient, resulting in delayed release and/or extended release kislotoustoichivoje of proton pump inhibitor or its salt, and the antagonist of H2-receptor or its salt is included so that it is rapidly released from the specified dosage forms, the method includes forming a first layer containing a specified kislotoustojchivy a proton pump inhibitor or salt, forming thereon a coating of at least one specified filler and forming a second layer containing a specified antagonist H2-receptor or its salt and surrounding said first layer and coating, and then the manufacture of the combined product from the specified first layer, coating and the second layer in the form of oral pharmaceutical dosage forms.

31. The method according to item 30, wherein said kislotoustojchivy the proton pump inhibitor is enclosed in at least one specified filler, forming a lipid or water-insoluble matrix.

32. The method according to item 30 or 31, in which the specified first layer of formation what are balls, subsequently cover the at least one specified filler, and then mixed with the carrier containing the specified antagonist H2-receptor or its salt.

33. The method according to p, wherein said carrier includes pharmacological dezintegriruetsja substance.

34. The method according to item 30, wherein said combined product prepared in tablet form.

35. The method according to item 30, wherein said combined product prepared in the form of capsules that can disintegrants in gastrointestinal fluids.

36. The method according to item 30, in which the specified oral pharmaceutical dosage form is supplied intersolubility shell.

37. The method according to item 30, wherein said kislotoustojchivy a proton pump inhibitor selected from the group consisting of lansoprazole, omeprazole, pantoprazole, rabeprazole, ariprazole, leprosula and their pharmaceutically acceptable salts, enantiomers and salts of enantiomers.

38. The method according to item 30, in which the antagonist of H2-receptor selected from the group consisting of cimetidine, ranitidine, nizatidine, famotidine and their pharmaceutically acceptable salts, isomers and salts of isomers.

39. The use of oral pharmaceutical dosage form according to any one of claims 1 to 29 for the manufacture of a medicinal product for the treatment of diseases associated with the secretion of acids in the stomach, including gastroesophageal reflux disease.

40. The application of 39, in which the specified oral pharmaceutical dosage form is introduced simultaneously in two separate oral dosage forms, one contains a pharmacologically effective amount specified kislotoustoichivoje of proton pump inhibitor or its salt, and the other contains a pharmacologically effective amount specified antagonist H2-receptor or its salts.

41. The use of oral pharmaceutical dosage form according to any one of claims 1 to 29 in combination with one or more antibiotics to eradicate Helicobacter pylori.

42. A method of treating diseases associated with the secretion of acid in the stomach, including gastroesophageal reflux disease, in which the oral pharmaceutical dosage form according to any one of claims 1 to 29 is inserted in a therapeutically effective amount of an individual person or an animal affected with this disease.

43. The method according to 42, in which the specified oral pharmaceutical dosage form is introduced simultaneously in two separate oral dosage forms, one contains a pharmacologically effective amount specified kislotoustoichivoje of proton pump inhibitor or its salt, and the other contains pharmacologic the ski effective amount specified antagonist H2-receptor or its salts.

44. The method of treatment of emergency conditions associated with the secretion of acid in the stomach, including gastroesophageal reflux disease, in which the oral pharmaceutical dosage form according to any one of claims 1 to 29 is administered in a therapeutically effective amount of an individual human or animal subject to specified conditions.

45. The method according to item 44, in which the specified oral pharmaceutical dosage form is introduced simultaneously in two separate oral dosage forms, one contains a pharmacologically effective amount specified kislotoustoichivoje of proton pump inhibitor or its salt, and the other contains a pharmacologically effective amount specified antagonist H2-receptor or its salts.

46. The method according to any of paragraphs 44 and 45, including the dosage, capable of maintaining the pH in the stomach above 4 for at least 95% of the time, starting 2 h after the first dose and continued until 6 h after the last dose.

47. The method according to item 46, wherein said period of time is at least one week.

48. The method according to item 46, wherein said period of time is at least two weeks.

49. The method according to item 46, wherein said period of time is, the lower is her least four weeks.

50. The method according to item 44 or 45, including the dosage, capable of maintaining the pH in the stomach above 3 for at least 95% of the time, starting 2 h after the first dose and continued until 6 h after the last dose, in particular, for four weeks.

51. A method of treating diseases associated with the secretion of acid in the stomach, including gastroesophageal reflux disease, in which two separate oral dosage forms administered at the same time, one dosage form containing a pharmacologically effective amount kislotoustoichivoje of proton pump inhibitor or its salt and at least one pharmaceutically acceptable excipient, which leads to delayed and/or prolonged release kislotoustoichivoje of proton pump inhibitor or its salt, and the other containing a pharmacologically effective amount of an H2-receptor antagonist or salt, and specified an H2-receptor antagonist or salt included in such a way that he quickly released from specified dosage forms.

52. The method according to 51, including the dosage, capable of maintaining the pH in the stomach above 4 for at least 95% of the time, starting 2 h after the first dose and continuing the gosia up to 6 h after the last dose.

53. The method of paragraph 52, wherein said period of time is at least one week.

54. The method of paragraph 52, wherein said period of time is at least two weeks.

55. The method of paragraph 52, wherein said period of time is at least four weeks.

56. The method according to 51, including the dosage, capable of maintaining the pH in the stomach above 3 for at least 95% of the time, starting 2 h after the first dose and continued until 6 h after the last dose, in particular, for four weeks.

57. The method of treatment of Helicobacter pylori infection, in which two separate oral dosage forms administered simultaneously in combination with one or more antibiotics that are effective against N. Pylori, one dosage form containing a pharmacologically effective amount kislotoustoichivoje of proton pump inhibitor or its salt and at least one pharmaceutically acceptable excipient, which leads to delayed and/or prolonged release kislotoustoichivoje of proton pump inhibitor or its salt, and the other containing a pharmacologically effective amount of an H2-receptor antagonist or salt, and specified an H2-receptor antagonist or salt included so about the time, he quickly released from the specified dosage forms.

58. The method according to 57, including the dosage, capable of maintaining the pH in the stomach above 4 for at least 95% of the time, starting 2 h after the first dose and continued until 6 h after the last dose.

59. The method according to 58, wherein said period of time is at least one week.

60. The method according to 58, wherein said period of time is at least two weeks.

61. The method according to 58, wherein said period of time is at least four weeks.

62. The method according to 57 or 58, including the dosage, capable of maintaining the pH in the stomach above 3 for at least 95% of the time, starting 2 h after the first dose and continued until 6 h after the last dose, in particular, for four weeks.

63. The method of treatment of Helicobacter pylori infection in which oral pharmaceutical dosage form according to any one of claims 1 to 29 in combination with one or more antibiotics that are effective against N. pylori, is introduced in a therapeutically effective amount to an individual or person affected by this infection.

64. The method according to p in which the specified oral pharmaceutical dosage form in titsa simultaneously in two separate oral dosage forms, one contains a pharmacologically effective amount specified kislotoustoichivoje of proton pump inhibitor or its salt, and the other contains a pharmacologically effective amount specified antagonist H2-receptor or its salts.

65. The method according to p or 64, including the dosage, capable of maintaining the pH in the stomach above 4 for at least 95% of the time, starting 2 h after the first dose and continued until 6 h after the last dose.

66. The method according to p, wherein said period of time is at least one week.

67. The method according to p, wherein said period of time is at least two weeks.

68. The method according to p, wherein said period of time is at least four weeks.

69. The method according to p or 64, including the dosage, capable of maintaining the pH in the stomach above 3 for at least 95% of the time, starting 2 h after the first dose and continued until 6 h after the last dose, in particular, for four weeks.



 

Same patents:

FIELD: medicine; veterinary science.

SUBSTANCE: vaccine includes inactivated adhesive antigens E.coli K88, E.coli K99, E.coli F-41, E.coli 987P and an adjuvant - aluminum hydrate. As the inactivated adhesive antigens E.coli use inactivated filamentous adhesive antigens E.coli K88 ab, E.coli K88 ad, E.coli K88 ad, E.coli K99, E.coli F-41, E.coli Att-25, E.coli 987P with activity level in reaction of the passive hemagglutination peer as 1:2048-4096; 1:1024-2048; 1:256-512; 1:1024-2056; 1:1024-2056; 1:32-64; 1:256-512, accordingly, at a following parity of components, wt. %: inactivated filamentous adhesive antigens E.coli K88 ab, E.coli K88 ad, E.coli K88 ad, E.coli K99, E.coli F-41, E.coli Att-25, E.coli 987P, taken in mass parities 1:(0.8-1.2:(0.8-1.2:(0.8-1.2:(0.8-1.2:(0.8-1.2:(0.8-1.2, accordingly - 55-65, 5.8-6.2%-s' aluminium hydrate the rest.

EFFECT: rising of safety of livestock of agricultural animals.

2 cl, 1 tbl, 8 ex

FIELD: medicine; pharmacology.

SUBSTANCE: perform processing of an elevated part and roots of the primrose plant (Primula macrocalyx Bge.) with an organic dissolvent - ligroin or hexane with the subsequent extraction with acetone and allocation of a target product using chromatography.

EFFECT: increase of output of the product.

4 ex, 2 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: system of delivery of medicinal substance includes one department consisting from (i) of a kernel from thermoplastic polymer, filled with medicinal substance, (ii) an intermediate layer from the thermoplastic polymer filled with medicinal substance, and (iii) covers from the thermoplastic polymer, covering an intermediate layer and not containing medicinal substance, where the specified intermediate layer is filled (a) with crystals of the first pharmacologically active substance, and (b) the second pharmacologically active substance in the dissolved form and where the kernel is filled specified to the second pharmacologically active substance in the dissolved form. The delivery system is intended for vaginal introduction of the medicinal substance.

EFFECT: possibility of adjustment of rate of liberation of two or more active ingredients irrespective of others, at maintenance of long physical stability of system at room temperature.

51 cl, 21 dwg, 10 tbl, 4 ex

FIELD: chemistry, immonology.

SUBSTANCE: hybrid protein includes 936 protein sequence from Neisseria meningitides or protein with sequence identical to the mentioned protein sequence by 90% or more, and 741 protein sequence from Neisseria meningitides or protein with sequence identical to the mentioned protein sequence by 90% or more. The sequences can be linked by N- and/or C-end to histidine labels, with or without a linker. Linker is selected out of group of polyglycine linker, histidine labels and GSGGGG linker. A nucleic acid encoding this protein is displayed. Invention also claims composition for treatment and/or prevention of disease caused by Neisseria meningitides bacterium, based on hybrid protein and one or more proteins of the following group: 287, 741, ORF46.1, 961, NH2-A-[X-L-]n-B-COOH, where n=2, X1=287, and X2 is selected out group of: 953, 919, 961, 741. Invention claims application of composition in production of medicine for treatment of disease caused by Neisseria.

EFFECT: efficient treatment and prevention of disease.

13 cl, 5 dwg, 28 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of formula (I) and their pharmaceutically acceptable salts as β-lactamase inhibitors, method of their production, pharmaceutical composition based on them, and methods of treatment involving the claimed compounds. In the general formula (I) one of A and B is hydrogen, while the other is optionally substituted condensed bicyclic heteroaryl group; if aromatic ring part of bicyclic heteroaryl group is imidazole, non-aromatic ring part does not include S atom adjacent to head carbon atom of bridge group; X is S; R5 is H, C1-C6-alkyl or C5-C6-cycloalkyl; or its pharmaceutically acceptable salt where bicyclic heteroaryl group is (1-A) , where one of Z1, Z2 and Z3 is independently S, while the others are CR2 or S, if one of Z1-Z3 is carbon and is linked to the rest of molecule; W1, W2 and W3 are independently CR4R4, S, O or N-R1, if it does not form S-S, O-O, or S-O link with saturated ring system; t=1-4; R1 is H, C1-C6-alkyl, C5-C7-cycloalkyl, -C=O-aryl, -C=O(C1-C6)-alkyl, -C=O(C5-C6)-cycloalkyl, aryl-C1-C6-alkyl, optionally substituted C1-C6-alkoxy; heteroalkyl- C1-C6-alkyl or C=O(heteroaryl), where heteroaryl is 6-member ring containing 1 nitrogen atom, R2 is hydrogen, C1-C6-alkyl, R4 ir H, C1-C6-alkyl.

EFFECT: efficient application in bacterial infection treatment.

29 cl, 3 tbl, 58 ex

FIELD: medicine.

SUBSTANCE: invention relates to veterinary and medicine, particularly substances with cytostatic and bactericidal properties; it can be applied in pharmaceutical industry. The water-soluble composition includes, in wt %: 0.007 to 0.7 metronidazole, 0.0085 to 0.85 silver hexamethylenetetramine nitrate, 0.0284 to 2.84 sodium thiosulphate, water or physiological solution to 100.

EFFECT: obtaining of composition with cytostatic and bactericidal activity, lowered toxicity, and expanded storage time; it is inexpensive, can be prepared in the field, and moreover effective in therapy for leucosis in cattle

4 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly to abdominal surgery, and applied to treatment for extensive peritonitis. To do it during operative intervention the peritonitis source is eliminated, and abdominal cavity sanation is performed. Then 3% methylcellulose gel, preliminary saturated with 1200 mg/l sodium hypochlorite solution in proportion 3:1, is introduced.

EFFECT: preventing of parietal and visceral peritoneum mesothelium injury by microbial exo- and endotoxins, anti-microbial effect prolongation of sodium hypochlorite, and preventing inactivation of sodium hypochlorite by peritoneal toxic effluent.

1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: essence of the invention includes selection of the damaged organs from the dead nutrias from the local epidemical centre from which prepare suspension, perform bacterial inoculation in differenrial diagnostic mediums, separate pure cultures of originators of colibacillosis, salmonellosis and enterococcus infections, separately grow up cultures Escherichia coli. Salmonella typhimurium and Streptococcus, fecalis in a meat infusion agar with addition of 0.2% of a glucose with titer 4-5 billion microbic cells in 1 cm3, inactivate by entering of formalin to 0.4-0.6 % final concentration, condition at temperature 37°C within 72-96 hours, admix cultures in equal parities, then bring a solution of a aluminium hydroxide in amount of 20% to the volume, carefully admix, pack up and cork.

EFFECT: increase of an adjuvanticity of a vaccine.

1 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: agent possessing wound-healthing, antiinflammatory, antibacterial, immunomodulating, anaesthetising and antitumoral activity on a basis of terpenoids, contains a capsule extract of plants of Pinaceae bloodline exposed to short-term stressful influence, enriched with monoterpenes, obtained from a capsule extract. The pharmaceutical composition possessing wound-healthing, antiinflammatory, antibacterial, immunomodulating, anaesthetising and antitumoral activity, contains the above described agent in effective quantity and the target additive. Application of the above described agent for preparation of a medicinal preparation for treatment of pyoinflammatory diseases.

EFFECT: increased wound-healthing; antiinflammatory; antibacterial; immunomodulating; anaesthetising and antitumoral activities.

8 cl, 1 dwg, 6 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: agent contains Rifabutin sorbated in polymeric nanoparticles matrix, potassium cholesterylphosphate, or sodium glycocholate, or hexadecyl dihydrogen phosphate, or a-tocopheryl succinate, water-soluble polymeric stabiliser and bulking agents. Polymeric nanoparticles sized 100-800 nm include lactic acid polymer/polymers and/or lactic and glycolic acid copolymer/copolymers at glycolic acid content in specified copolymers up to 50 mole %. Molecular weight of specified polymers and copolymers is 5 to 300 kDa. Molecular weight of water-soluble polymeric stabiliser is no more than 70 kDa and is selected from the group including polyvinyl alcohol, polyvinylpyrrolidone, polysorbate and seralbumin.

EFFECT: new agent provides durable action of Rifabutin; higher bioavailability of Rifabutin and efficiency of bacterial infection treatment.

3 dwg, 1 tbl, 7 ex

FIELD: medicine; pharmacology.

SUBSTANCE: pharmaceutical composition of controlled release, specifically composition of pulse release, includes nucleus containing physiologically active substance, unstable in acidic medium, leavening agent and alkaline additive. Nucleus has release control coating containing water-insoluble polymer, entero-soluble polymer and hydrophobic wax. Amount of hydrophobic wax in coating is 20-35 wt % of release control coating weight. Physiologically active substance, unstable in acidic medium represents compound based on benzimidazole or its pharmaceutically acceptable salt.

EFFECT: invention provides slight delay difference in composition dissolution and dissolution percent with the course of time providing high reliability of dissolution properties.

28 cl, 16 dwg, 23 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and pharmacology and concerns application of [6-(4-(chlorfenil)-2,2-dimethyl-7-fenil-2,3-digidro-1H-pyrrolivin-5-il] of acetic acid for preparation of pharmaceutical composition for inhibition of gastral protonic pump, combination for treatment of inflammatory states and pharmaceutic composition for inflammatory states treatment.

EFFECT: provision of high efficiency of gastral protonic pump inhibition.

15 cl, 20 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: invention discovers improved composition for profile control of active compound release through the digestive tract, including particles, especially granules, containing the active compounds. They are covered with coating material, solution of which depends on pH value, or polymethacrylate material, solution of which, for preference, depends on pH value, the definite thickness, desirable place and speed of the active compound release. In preferable compositions two or more particles, in which particles of each multitude are covered with the coating material, the solution which depends on pH value, or polymethacrylate material, of different thickness in comparison with the particles of each other multitude, are contained in capsules with enterosoluble coating and provide the active substance release in different desirable places of the digestive tract.

EFFECT: provision of active substance release in desirable places of digestive tract.

28 cl, 7 dwg, 9 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. The compounds claimed by the invention have inhibition effect on VR1 receptor activation and can be applied in pain prevention or treatment. In the general formula (I) , or , L is a low alkylene, E cycle is benzene or 5-membered heteroaromatic ring containing sulfur atom as a heteroatom, D cycle is a monocyclic or bicyclic hydrocarbon cycle optionally condensed with C5-7 cycloalkyl, 6-membered monocyclic heteroaromatic cycle containing nitrogen atom as heteroatom or 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O, G cycle is a 5-7-membered monocyclic saturated or partially saturated heterocycle or 10-membered bicyclic heterocycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O. The invention also concerns pharmaceutical composition based on the said compounds, and application thereof in obtaining pain prevention or treatment medication, and a method of pain prevention or treatment.

EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: herbal mix comprising of cottonweed grass, chamomile flowers, knotweed grass, elecampane rhizome and root, licorice root, plantain leaves, rowan fruits, motherwort grass, nettle leaves, and fennel fruits, with ingredient proportion 2:2:2:2:2:2:1:1:1:1. Applying of the mix provides establishing of equilibrium between "aggression" and "protection" factors and activation of protective mechanisms.

EFFECT: widening of medicinal preparation assortment for stomach ulcer prevention and complex treatment.

1 dwg, 1 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention can be used for prevention of erosive and ulcer lesions of stomach caused by nonsteroid anti-inflammatory agents. Invention represents calcium pectate introduced orally in daily dose 0.025-0.5 g/kg of body weight within not less than 8 days prior to nonsteroid anti-inflammatory agents.

EFFECT: improved efficiency of ulcer prevention.

3 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, gastroenterology and concerns methods of stomach ulcer treatment. For this purpose, patient with suffering from mediagastral localisation of ulcer defect which is not cicatrising within six weeks, or from piloroduodenal ulcers which are not cicatrising within four weeks, in addition to traditional pharmacotherapy is prescribed with fluconasol. Single dose of fluconasol is 150 mg. Preparation is introduced once a week, within three weeks. Method provides effective utilisation of antithymicotic agents within stomach ulcer therapy based on first formulated specific indications for introduction, without preliminary examination of stated categories of patients.

EFFECT: development of effective method of stomach ulcer treatment due to antithymicotic agents.

7 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: description is given of a derivative of carboxylic acid with general formula , where R1 represents a hydrogen atom, C1-4alkyl, benzyl, E represents C(=O)-, -SO2- or -CH2-;R2 represents a halogen atom, C1-6 alkyl, C1-6 alkoxy, hydroxyl, C1-4 alkyl, substituted -OR8 , R3 represents a halogen atom, C1-6 alkyl, C1-6 alkoxy; R4 represents a hydrogen atom, C1-6alkyl; R5 represents C1-6 alkyl, C1-10 alkoxy, R8 represents C1-4 alkyl, phenyl; represents a benzol ring; G represents (1) C1-6 alkylene; represents dihydrobenzoxazine; m and n represent 0 or an integer from 1 to 4; I represents 0 or an integer from 1 to 8, where, when m is more or equal to 2, R2 is the same or different; when n is more or equal to 2, R3 is the same of different; when i is more or equal to 2, R5 is the same of different, or its pharmaceutical salt. Since the compound with formula (I), is linked to the DP receptor and has antagonistic effect to the DP receptor.

EFFECT: it is useful for preventing and/or curing such diseases as allergic rhinitis, allergic conjunctivitis, bronchial asthma, malt cell disease, migraine, contact dermatitis, stroke, ulcerative colitis, thrombocyte aggregration or sleep disorder.

FIELD: chemistry.

SUBSTANCE: invention relates to the compound with the formula (1): where R1 is C1-C12 alkyl group, which can have the substitute, or C2-C12 alkenyl group, which can have the substitute represented with the C6-C14 aryl group, which can be substituted with the halogen atoms; each of R2 and R3 represent the hydrogen atom, alkyl group, hydroxyalkyl group, dihydroxyalkyl group, or R2 and R3 form with the adjacent nitrogen atoms the 5-membered, 6-membered, or 7-membered nitrogen-containing saturated heterocyclic group, which can be substituted with the alkyl group; (the dotted line means the possible double bind), or its salt, as well as to the pharmaceutical composition containing the said compound, and to its application as a pharmaceuticals and to the treatment method.

EFFECT: invented compound demonstrates inhibiting activity against the tumor necrosis factor production (TNF-α) and improved absorbability after oral administration.

16 cl, 1 tbl, 18 dwg, 1 ex

FIELD: medicine; gastroenterology.

SUBSTANCE: therapy course includes medicinal agents aimed at eradication of Helicobacter pylori. Additionally oral intake of medium-mineralised sulphide water is prescribed. Intake is carried out every day 3 times a day 40-60 minutes before meals in dosage 3-5 ml/kg. Water therapy course includes 21-30 days. Invention enables to improve eradication effect regarding Helicobacter pylori, expedite recovery, increase disease remission owing to straight bactericidal action of mineral water to Helicobacter pylori, increase redox enzyme activity under the influence of mineral water, optimize energy metabolism.

EFFECT: increased treatment efficiency.

3 tbl, 2 ex, 2 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to solid dosed composition for pain treatment, containing: nucleus including active pharmaceutical ingredient and matrix, an coating including physical compound of polyvinyl acetate, polyvinyl pyrrolidone and active pharmaceutical ingredient, where active pharmaceutical ingredient and matrix are interconnected in such a way that release of pharmaceutical ingredient placed within nucleus from matrix is controlled, and release of composed active ingredient placed within nucleus occurs more slowly than release of active pharmaceutical ingredient placed in coating matrix. Yet nucleus and coating active pharmaceutical ingredient is the same and considered to tramadole or its stereoisomer or pharmaceutically acceptable salt. Invention also refers to tablet containing specified composition. Composition under invention provides pain relief not later than 2 hour after primary introduction in one dosage; pain relief lasts within at least 24 hours after introduction.

EFFECT: agent is characterised by high efficiency.

14 cl, 7 dwg, 9 tbl, 6 ex

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