Peroral composition with prolonged molsidomine release for atherosclerosis treatment
SUBSTANCE: method is proposed for preventing or slowing down development of atherosclerosis. It involves administration of molsidomine or a pharmaceutically acceptable salt thereof in the form of solid peroral composition with prolonged release of the active substance, effective for 24 hours and containing 14 to 24 mg of molsidomine. The composition is to be administered for at least 6 months.
EFFECT: method significantly decreases level of circulating ICAM-1s (an anti-inflammatory marker of endothelium dysfunction and therapeutic target at atherosclerosis pathological conditions) which play an important role in emergence and development of atherosclerosis.
6 cl, 2 dwg, 2 tbl
The technical FIELD
The present invention relates to a new therapeutic application of molsidomine and its pharmaceutically acceptable salts, especially oral galenical form slow release of the active substance that is effective within 24 hours, intended for the prevention or treatment of atherosclerosis.
Atherosclerosis is a progressive disease of the arteries, which violates the provision of blood in the first place, those organs which are supplied to the peripheral blood. Accordingly, the appearance on the walls of the coronary artery atheromatous plaque restricts blood flow to the heart and cause ischemia, which, in turn, can lead to myocardial infarction is the main cause of death in industrialized countries.
Risk factors, such as hypercholesterinemia or hypertension, contribute to the formation of atherosclerotic lesions.
If hypercholesterinemia mechanism leading to the formation of these lesions may resemble the following:
The low-density lipoprotein (LDL, low density lipoproteins, LDL) are accumulated in the inner membrane (tunica's intima), i.e. in the innermost layer of the arterial wall, where they then undergo oxidation to ox-LDL.
Presence in NR the inner shell such oxidized molecules leads to the synthesis and expression on the surface of endothelial adhesion molecules, such as SAM-1 (intercellular adhesion molecule-1, intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1, vascular cell adhesion molecule-1).
These adhesion molecules have the property of binding (commit) monocytes originating from the bloodstream, which then pass through the walls of blood vessels and are transformed into macrophages.
Macrophages absorb ox-LDL (phagocytosis) and then slowly transformed into foam cells, rich in lipids. In addition, macrophages release cytokines, which cause a local inflammatory response that, in turn, further contributes to a significant increase of monocytes.
Smooth muscle cells proliferate and migrate into the inner membrane, where they secrete collagen, elastic fibers and proteoglycans, leading to compaction of atherosclerotic lesions.
Foamy cells synthesize tissue factor, which is also involved in the deposition of fibrino in atheromatous plaques and leads to increasingly large lesions of the endothelium.
As follows from the above, adhesion molecules, particularly SAM-1, participate in the formation of atherosclerotic lesions.
Indeed, SAM-1 sverkhekspressiya on the surface of the endothelium covering the atheromatous plaques in the coronary and carotid arteries man is ka.
Held earlier clinical studies have shown that the severity of such diseases as atherosclerosis, is correlated with the level of soluble SAM-1 (SAM-1s). In addition, in the study of atherosclerosis in mouse models, it was found that the decrease in the level SAM-1s prevents progressive course of atherosclerosis.
Therefore, the reduced levels of soluble SAM-1 is an effective means to restore the normal functions of the endothelium and the prevention and/or delay the development of atherosclerosis.
It is known that molsidomin successfully applied, in particular for prophylactic treatment of angina (angina pectoris) in all its varieties, its action causes relaxation of vascular smooth muscle fibers and inhibition of early stages of platelet activation.
Currently molsidomin is a commercial product and mainly presents
- in the form of divisible tablets with immediate release of the active substance dose of 2 mg and 4 mg, commonly assigned to three times daily in the treatment of angina voltage and four times per day for the treatment of pain at rest and strokes voltage (severe); and
- in the form of tablets slow release of the active substance dose 8 mg, intended for administration twice a day for profilactic the ski and long-term treatment of angina.
Previously a commercial preparation of molsidomine (especially under the trade name Coruno® in Belgium) was presented in the form of a solid composition with a slow release of the active substance and the dose of 16 mg effective within 24 hours, intended for oral administration for prophylactic and long-term treatment of stable States of angina. Efficiency and immunity to such a composition was shown when conducting short-term and long-term studies in large numbers of patients.
The authors of the present invention unexpectedly found that molsidomin, especially in the form of a solid composition with a slow release of active ingredient, which is effective within 24 hours and is intended for oral administration, causes the restoration of the functions of the endothelium and thus prevents the physiological processes that lead to atherosclerosis, and/or slows down their development.
In more detail, it was found that daily administration of such galenical forms of molsidomine significantly reduces the number of circulating soluble SAM-1, which is considered a biomarker of atherosclerosis. It was also found that in addition to known antianginal properties of molsidomin causes inhibition of the fixation of monocytes to the endothelium and, therefore, which allows recovery of the functions of the endothelium and prevents and/or retards the development of atherosclerosis.
In accordance with the first aspect of the present invention relates to the use of molsidomine or one of its pharmaceutically acceptable salts, especially in the form of a solid composition with a slow release of active ingredient, which is effective within 24 hours and is intended for oral administration, for the manufacture of drugs to prevent or slow the development of atherosclerosis.
In the framework of the present invention, molsidomin can be used both in free form and in the form of pharmaceutically acceptable salts such as hydrochloride.
The term "molsidomin"as it is used in the present description, refers to a free form and a salt form of the molecule.
When treating atherosclerosis according to the present invention molsidomin can be administered orally, in particular it relates to slow release tablets active ingredient, effective within 24 hours.
The term "effective within 24 hours," as it is used in the present description, means that the number of molsidomine released from used pharmaceutical forms, is sufficient to maintain a therapeutic blood plasma concentration equal to at least 5 ng/ml, preferably at least 10 ng/ml of technopride time approximately 24 hours.
The influence of molsidomine for treatment of atherosclerosis is especially important in long-term treatment (for at least six months). This effect is especially significant in patients with stable angina.
In the treatment of atherosclerosis the most valuable results have been obtained in accordance with the present invention with the introduction of tablets slow release of the active substance containing a dose of 16 mg, and tablets corresponded to proprietary medicinal product Coruno®, sold in Belgium.
This Galanova form and method of its manufacture have been described in published international application WO 01/62256, which is incorporated into this description by reference.
In General, glenavy form of molsidomine, described in the publication of the international application, characterized essentially by the fact that in vitro they have the following dissolution rate (measured according to the method described in the European Pharmacopoeia, 3rd ed. (or U.S. P.XXIV) spectrophotometrically at 286 or 311 nm, 50 rpm in 500 ml of 0.1 G. of HCl at 37°C):
- from 15% to 25% of molsidomine released after 1 hour,
- from 20% to 35% of molsidomine released after 2 hours,
- from 50% to 65% of molsidomine released after 6 hours,
from 75% to 95% of molsidomine released after 12 hours,
- Bo is it 85% of molsidomine, released after 18 hours,
more than 90% of molsidomine released after 24 hours,
moreover, the peak concentration of molsidomine in plasma is achieved in vivo through 2.5-5 hours, preferably 3-4 hours after injection of the specified form, and has a value of from 25 to 40 ng/ml of plasma.
The term "peak concentration of molsidomine in plasma achieved in vivo", as used in the present description corresponds to the maximum concentration of molsidomine detected in the plasma at least 10 healthy volunteers.
Any Galanova form described in international publication WO 01/62256, can also be applied according to the present invention.
Typically, such glenavy forms allow you to enter molsidomin in daily doses, preferably in the range from 14 to 24 mg, more preferably in the range of from 16 to 20 mg.
Such glenavy form of molsidomine with 24-hour release profile and characterized by the absence of sharp peaks and distinct areas at least, are most suitable for the treatment of atherosclerosis, ensuring a constant and stable release of molsidomine in areas affected by atherosclerosis.
Therefore, a relatively slow and constant release of molsidomine in plasma, carried out without the areas minim is mA and sharp peaks, is important to obtain the desired impact on the treatment of atherosclerosis.
The use of molsidomine in galenical forms of slow release is particularly significant, because this connection is not addictive and security (safety) its use has been proven by the large number of patients.
INFORMATION CONFIRMING the POSSIBILITY of carrying out the INVENTION
Demonstration of the influence of molsidomine in the treatment of atherosclerosis
1. Characteristics of the target population and the organization of the experiment
The favorable influence of molsidomine in the treatment of atherosclerosis has been demonstrated according to the results of long-term clinical studies conducted in 172 patients who are currently stable angina.
The study consisted of three consecutive phases:
- 7-day preliminary study with the introduction of placebo;
- 4-week randomized, double-blind, placebo-controlled cross-sectional study, during which patients received serially (2×2 weeks) the pharmaceutical composition on the basis of molsidomine dose of 8 mg (this song is currently for sale in Belgium under the trade name Corvatard® (2 daily dosage units)and the pharmaceutical composition on the basis of molsidomine what osoi 16 mg, effective within 24 hours (this song is currently for sale in Belgium under the trade name Coruno® (1-day dosage unit)); and
- A 12-month open study, during which 172 patients received the pharmaceutical composition on the basis of molsidomine dose of 16 mg, and this song is currently for sale in Belgium under the trade name Coruno®.
The study can be schematically represented as follows:
In the diagram above and in the following description, the abbreviation "DRD" (short for "twice a day") is used to characterize how the introduction of molsidomine, namely 8 mg of molsidomine was administered in two daily dosage units, and the abbreviation "org" (short for "once a day") is used to characterize how the introduction of molsidomine, namely 16 mg of molsidomine was administered as a single daily dosage units.
You need to specify that during the second phase of the study, concomitant use of other antianginal drugs was prohibited except isosorbide dinitrate (ISDN) 5 mg in the form of sublingual tablets, which can ease the pain of angina.
In addition, during the third phase was allowed concomitant use of beta-blockers and/or ant is honesto calcium, while oral administration of nitro compounds and sildenafil has always been prohibited.
Molsidomine 16 mg and needed to be taken orally every morning for one year.
This study was conducted in accordance with protocols used for clinical studies of antianginal drugs established by the Committee for proprietary medicinal products (CPMP) and in accordance with Good clinical practice (phase 4), as adopted in the European Union.
In the course of the study were noted: flash frequency of angina during the week and the reception frequency sublingual tablets ISDN 5 mg for weeks.
Also of particular importance are the concentrations of ICAM-1s, which were measured after each of the three research stages, with the first dimension represents the baseline (control).
In more detail, the concentration of ICAM-1s measured as follows:
Blood samples (5 ml) is placed in najprimitivniji tubes. Samples incubated at room temperature and then centrifuged. The serum was separated and immediately frozen at -20°C until and unless it is needed for analysis.
Levels of circulating ICAM-1s measured using a commercially available system for enzyme-linked immunosorbent assay (ELISA)supplied by the company R&D Sytems Europe.
2. Statistical analysis
In order to characterize the demographic and other parameters specific to the study of human populations, we used the method of descriptive statistics (standard deviations (SD) and %).
When conducting research to assess changes in the frequency of outbreaks of angina during the week, the reception frequency sublingual ISDN tablets during the week, and levels of circulating ICAM-1s for preventive treatment (second phase) and long-term treatment (third phase), following methods were used: analysis of differences in results of repeated measurements, at which time it was used as the classification criterion, and the subsequent method Bonferonni (Bonferonni post-hoc test), the results of which were significant.
In order to assess the influence of gender, alcohol consumption, nicotine, and concomitant use of drugs on the levels of ICAM-1s measured after each phase of the study (control - a preliminary study with the introduction of placebo after 4 weeks of treatment and after treatment for one year), were used such statistical methods of analysis: T-test t-test (student T-test or analysis of variance (ANOVA) with one classification criterion.
To assess the impact of the above risk factors on the change in the levels of ICAM-1s were used in the analyses of differences in results of repeated measurements.
To determine possible dependencies between the levels of ICAM-1s and continuous demographic variables or risk factors for each patient were calculated correlation coefficients. A similar method was applied to evaluate dependencies between differences in the level of ICAM-1s and changes in risk factors.
In addition, after treatment for one year were found four quartiles of changes in the levels of ICAM-1s. Therefore, to determine the impact on changes in the level of ICAM-1s were used analysis of variance with one classification criterion consistent with the subsequent method Bonferonni, the results of which were significant. The study was conducted in four categories (4th quartile) and observed changes (in the range: from control to end of treatment in one year) in the flash frequency of angina during the week and the frequency of reception of tablets ISDN.
Demographic characteristics of the population examined relative to control (preliminary research with the introduction of placebo) are listed in Table 1.
|Demographic characteristics and the value of control for patients participating in the study|
|is the||Control (N)||A value of ± WITH or %|
|The duration of the disease is angina (years)||172||4,4±4,5|
|Weight (kg)||172||to 77.7±12,0|
|Flash frequency of angina per week||107||3,7±3,8|
|Reception frequency sublingual tablets ISDN in a week||107||2,5±3,2|
|Arterial blood pressure (mm Hg)||172||82,0±8,0|
|Arterial top pressure (mm Hg)||172||131,2±15,1|
|Heart rate (beats per minute)||172||76,6±11,0|
|The level of ICAM-1s (ng/ml)||172||272±92|
|No other antiangiogenic medication||116||67,4|
|Beta-blockers and calcium antagonists||4||2,3|
|<1 Cup a day||161||93,6|
|≥1 glass per day||11||6,4|
|WITH standard deviation|
As follows from Table 1, the patients participating in the study were in the age of 56.2±8.3 years (value ± standard deviation), predominantly male (68%), and suffered from angina during the period of time equal to 4.4±4.5 years.
During the first phase of the study (with placebo)prior to the actual treatment, the frequency of outbreaks of angina during the week and the reception frequency sublingual tablets ISDN were respectively 3.7±3.8 outbreaks per week and 2.5±3.2 tablets per week.
Although during this phase of the study was permitted concomitant use antiangiogenic drugs, 67,4% of patients were not taking any medications except molsidomine, and 29.1% of patients took only beta-blockers.
Figure 1 illustrates the change in frequency of outbreaks of angina during the week and receive frequencies sublingual tablets ISDN during the second and third phases of the study.
The results are presented in the following form: value ± average standard error (SEM)analysis of variance (ANOVA) to repeat the relating to measuring R< 0,0001; method Bonferonni: ** compared with control, p<0,0001; £ - comparison between treatment within 4 weeks of treatment and at one year, p=0.002; NS - comparison between treatment within 4 weeks of treatment and at one year, p=0,105.
As shown in figure 1, during the study was observed (analysis of variance, p<0,0001), a significant overall reduction in the frequency of outbreaks of angina during the week and receive frequencies sublingual tablets ISDN.
As for the flashing frequency of angina, obtained during the study of the differences between the values of control and treatment within four weeks (p<0,0001; method Bonferonni) and between the values of control and treatment for one year (p<0,0001; method Bonferonni) were significant. Differences between values related to treatment within four weeks of treatment and at one year (p<0,002; method Bonferonni) were also significant.
With regard to the frequency of taking the sublingual tablets ISDN, obtained during the study of the differences between the values of control and treatment within four weeks (p<0,0001; method Bonferonni) and between the values of control and treatment for one year (p<0,0001; method Bonferonni)were significant.
Table 2 below lists the concentrations of ICAM-1 (ng/ml)measured in the course of preventive treatment (second phase) the long-term treatment (third phase) in the course of the study, in particular, the influence of gender, alcohol consumption, nicotine addiction and concomitant medication on changing levels of circulating ICAM-1s.
As can be seen from the data presented in Table 2, the 4-week treatment molsidomine (16 mg ord or 8 mg DRD) does not affect the levels of circulating ICAM-1s.
However, after taking molsidomine within 12 months (16 ord) levels of ICAM-1s became significantly (p<0,0001) lower (approximately 10%) compared with the value of control to cross-examination.
The levels of circulating ICAM-1s tend to increase, expressed to a greater extent in women than in men. However, according to analysis of variance based on gender was not significant (p=0,914) and reduced levels of ICAM-1s during the 12-month treatment molsidomine occurred simultaneously in patients of both sexes.
Alcohol consumption leads to reduced levels of ICAM-1s patients compared with patients not taking alcohol. However, these differences were not significant and the change in the levels of ICAM-1s during the 12-month treatment molsidomine occurred simultaneously in patients of both groups (p=0,149).
Smokers typically have higher levels of ICAM-1s compared to non-smokers or former smokers, however, the change in the levels of CAM-1s was also the same as for patients with nicotine dependence, and for patients without nicotine dependence (p=0,192).
Concomitant use of drugs such as statins, beta-blockers, or a combination, had no effect on the level of ICAM-1s. Differences were not significant and the change in the levels of ICAM-1s occurred regardless of the type of concomitant medications, absorbed within a 12-month treatment period (p=0,598).
The study found no relationship (relative to control) between the concentrations of ICAM-1s and demographic factors or risk factors such as age (r=-0,068), weight (r=-0,079), disease duration (r=0,042), the frequency of outbreaks of angina during the week (r=0,137), frequency of use sublingual tablets ISDN during the week (r=0,124), lower blood pressure (r=0,051), arterial top pressure (r=0,097) or heart rate (r=0,176).
Similar conclusions can also be done regarding the relationship between the differences in the level of ICAM-1s and changes in demographic factors or risk factors for 12-month period of treatment with molsidomine (data not shown).
Figure 2 illustrates the decrease in the frequency of taking the sublingual tablets ISDN as a function of differences in the levels of circulating ICAM-1s after the 12-month period of treatment with molsidomine 16 mg ord; 4 categories of changes in the levels of ICAM-1s correspond to the 4 quartiles of the distribution.
Re ulitity presented in the following form: value ± average standard error (SEM); analysis of variance for repeated measurements, p<0,031; * method of Bonferroni, p=0,038.
Figure 2, shows the distribution into four quartiles of changes in the levels of ICAM-1s during the third phase of the study, illustrates that the impact of changes in the level of ICAM-1s to change the frequency of taking the sublingual tablets ISDN is significant (p=0,031).
The values obtained using the method of Bonferroni, show that the reduction in consumption ISDN between the beginning and the end of the third phase of the study (after 12 months) was most evident in the group showing a greater reduction in the level of ICAM-1s (4th quartile of the distribution) (p=0,038).
A similar trend was observed for changes in the frequency of outbreaks of angina during the week with the exception that the differences between the 4 quartiles of changes in the level of ICAM-1s were not significant (p=0,072) (data not shown).
The present study provides an opportunity to evaluate the effect of maintenance period (4 weeks) and treatment period (1 year) molsidomine 16 mg ord on patients suffering from angina.
Unexpectedly, the results showed that after the introduction of this galenical form within one year of significant antianginalnye impacts previously identified after treatment for 4 weeks, continue to exist, and the levels of circulating ICAM-1s(proinflammatory marker of endothelial dysfunction and a potential therapeutic target in pathological States of atherosclerosis) are significantly reduced.
In the beginning of the study, after a 7-day preliminary research with the introduction of placebo, the levels of ICAM-1s were comparable with values obtained according to other studies, patients suffering from ischemic heart disease and angina. Women and long-time smokers have higher levels than men and non-smokers or former smokers, which is confirmed by the observations made in the earlier stages.
Prophylactic treatment (4 weeks) molsidomine not affect the levels of circulating ICAM-1s. However, for patients with stable angina, the effectiveness of the 4-week antianginalnogo treatment was sufficient, because the total number of outbreaks and consumption ISDN declined.
After 12-month treatment molsidomine 16 mg and levels of ICAM-1s reduced significantly. This reduction did not depend on other parameters, such as gender, alcohol consumption, nicotine addiction and concomitant use of medications. After one year antianginalnoe the influence of molsidomine was maintained or even increased in patients with a maximum reduction of the levels of ICAM-1s (4th quartile) and an overall reduction in the consumption of sublingual tablets ISDN.
In conclusion, we can say that the decrease in the number of marker ICAM-1s after treatment with molsidomine 6 mg ord in one year indicates that along with antianginalnami functions this connection contributes to less activation of the endothelium and therefore has a preventive effect and/or slows the development of atherosclerosis in patients suffering from angina.
1. A method of preventing or slowing the development of atherosclerosis, including the introduction for at least 6 months, molsidomine or one of its pharmaceutically acceptable salts in the form of a solid oral composition with a slow release of the active substance that is effective for 24 h and containing from 14 to 24 mg of molsidomine.
2. The method according to claim 1, characterized in that this composition has the following dissolution rate in vitro, measured spectrophotometrically at 286 or 311 nm, 50 rpm in 500 ml of 0.1 N. Hcl at 37°C, according to the method described in the European Pharmacopoeia, 3rd ed. (or U.S.P. XXIV):
from 15 to 25% of molsidomine released after 1 h,
from 20 to 35% of molsidomine released after 2 h,
from 50 to 65% of molsidomine released after 6 h,
from 75 to 95% of molsidomine released after 12 h,
more than 85% of molsidomine released after 18 h,
more than 90% of molsidomine released after 24 h, and the peak concentration of molsidomine in plasma is achieved in vivo through 2.5-5 h, preferably 3-4 h after injection of the specified form,and has a value of from 25 to 40 ng/ml of plasma.
3. The method according to claim 1 or 2, characterized in that the composition contains 16 mg of molsidomine in dosage unit intended for daily administration.
4. The method according to claim 1 or 2, characterized in that the solid oral composition is administered to patients suffering from angina.
5. The method according to claim 3, characterized in that the solid oral composition is administered to patients suffering from angina.
6. The method according to claim 1 or 2, characterized in that the solid oral composition is administered to patients for approximately one year.
SUBSTANCE: treatment of the patients with chronic heart disease and obliterating atherosclerosis of lower limb is ensured by a course of plasmapheresis consisting of 5-6 sessions every 3-5 days. Each session starts with introduction of 50-60 ml of physiologic saline and removal of 300 ml to 900-1200 ml of plasma prepared by centrifugation in a cold centrifuge at rotary speed 1500-1800 rpm and temperature +4 ° - + 6°C within 15-20 minutes. Plasma is compensated with physiologic saline at the ratio 1:1. The course involves gradual increase of the volume of removed plasma starting with the minimal amount in the first session to the maximal amount to the middle and following decrease of this volume to minimum by the end. Total amount of removed plasma is 1-1.5 volumes of circulating plasma.
EFFECT: method allows administering out-patient continuous treatment of said group of the patients, including in case of resistance to drug therapy.
4 tbl, 2 ex
SUBSTANCE: treatment of depression in the patients suffering from coronary heart disease is ensured by introduction of essential fatty acids or a related drug containing eicosanpentanoic acid ether or docosahexaenoic acid ether, either separately, or mixed in the developed effective doses.
EFFECT: improved cardioprotective and antidepressive action in the given group of patients.
SUBSTANCE: invention relates to a novel compound or its salt of formula 1: , where A, E, D, R0, R1-R4 and a assume values given in the formula of invention. The invention also relates to an antioxidant medicinal agent.
EFFECT: effectiveness during treatment of ischemic diseases of organs, during treatment of diseases caused by oxidation cell disorders and when inhibiting disorders of the retina.
4 cl, 1 tbl, 6 ex
SUBSTANCE: treating of lipidosis and body-weight reduction in the patients with cardiovascular diseases is ensured by diet therapy based on the lacto-vegetarian diet. It involves introduction of proteins in daily amount of 67-79 g, including animal 48-57%, fats in daily amount of 32-49 g, including animal 40-52%, carbohydrates in daily amount of 240-257 g, cholesterol in daily amount of 40-268 mg, cellulose in daily amount of 18-20 g, dietary fibers in daily amount of 150 mg, potassium (K) in daily amount of 4567-6433 mg, magnesium (Mg) in daily amount of 535-693 mg, vitamin E in daily amount of 44-53 mg, arginine in daily amount of 3.9-5.2 g, dehydrated powdered maral meat in daily amount of 1200 mg, microcrystalline cellulose in daily amount of 900 mg. Duration of the diet therapy course is 33 days.
EFFECT: method provides suppression of cholesterol biosynthesis and intensification of excretion thereof that reduces the atherogenic index, reduces manifestations of oxidative stress, with reduced risk of realisation of the modified factors of a cardiovascular pathology.
SUBSTANCE: as additional components, a new medicinal form contains stearic acid or its pharmaceutically acceptable salt, succinic acid or its pharmaceutically acceptable salt, microcrystalline cellulose, magnesium carbonate, starch and hydroxypropyl cellulose.
EFFECT: extended range of storage-stable preparations of 3-oxy-6-methyl-2-ethylpyridine as solid oral dosage forms without by-effects of existing preparations.
14 cl, 2 tbl
SUBSTANCE: invention concerns a solid oral dosage form composition containing therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in amount exceeding 46 wt %. The oral dosage form represents a tablet or a film-coated tablet. Aliskiren tablet is made by wet granulation with using mixed organic solvents or organic binding solutions.
EFFECT: elimination of aqueous granulation provides high stability of the dosage form of aliskiren and prolonged shelf-life.
18 cl, 2 ex
SUBSTANCE: there is offered to apply 4-(2-hydroxyethyl)phenol(n-thyrozol) as a medicinal agent with anti-ischemic properties.
EFFECT: intravenous introduction of n-thyrozol improves the survival rate of animals with old myocardial ischemia and reperfusion, reduces a region of myocardial ischemia, and enables higher integrity of myocardial tissue.
3 tbl, 3 ex
SUBSTANCE: described are novel triazole derivatives with general formula where values of radicals are given in the formula of invention, a pharmaceutical composition containing said derivatives, and a method of treating autoimmune diseases. Compounds with general formula (1) and their pharmaceutically acceptable salts have inhibition effect on S1P and its Edg-1 receptor (S1P1).
EFFECT: possibility of use as a pharmaceutical product.
43 cl, 10 ex, 1 tbl
SUBSTANCE: for treatment of left ventricle hypertrophy (HLV) in patients with coronary disease in combination with hypertension during 6 months standard drug therapy, consisting of IATA, beta-blocker, aspirin and stanin is realised. Additionally ivabradin in day dose 5 - 15 mg is introduced in two intakes daily.
EFFECT: method ensures transformation of HLV in concentric remodeling of left ventricle and in such way reduces degree of cardiovascular complications risk.
2 ex, 1 tbl
SUBSTANCE: pharmaceutical compositions include divalent, namely calcium, magnesium or zinc salt, of pravastatin or fluvastatin and omega-3 fat, for prevention, reduction or treatment of increased cholesterol levels, atherosclerosis, hyperlipidemia, cardio-vascular disorders and diseases, coronary heart disease and/or cerebrovascular disease.
EFFECT: improved bioavailability of compositions, easily obtained and introduced.
40 cl, 33 dwg, 2 tbl, 8 ex
SUBSTANCE: invention refers to a carrier for drugs, biologically active substances, biological objects used in medicine for diagnostics and treatment in pharmaceutical industry. The carrier represents a material sensitive to external magnetic or electric fields and consisting of magnetic or ferroelectric material filmed with biocompatible thermosensitive, biodegradable polymer and/or dispersed in thermosensitive medium properties of which change with varying temperature relative to that of human body within 15.9 to 42°C. The magnetic or ferroelectric materials are made of substance with great magnetocaloric or electrocaloric component effect 1 to 13 K, have temperature of magnetic or ferroelectric phase transition within temperature range 33 to 37°C, and are chosen from the group including rare-earth, transition and precious metals, their alloys and compounds.
EFFECT: invention also concerns methods of controlled drug delivery by means of such carrier with enabling release thereof (regulated desorption) in the preset point.
32 cl, 9 ex
SUBSTANCE: invention refers to chemical-pharmaceutical industry and medicine, namely to an oral gindarine tranquiliser. There is offered composition for capsule containing as an active substance, gindarine in the form of gindarine hydrochloride, and an adjuvant chemically inert to the active substance and physiologically acceptable or number of adjuvants enabling prolonged release of gindarine hydrochloride. The composition represents granules, or mixed powders, or mixed granules and powder, or liquid, or soft form. As adjuvants, the composition contains an excipient, alone or combined with a disintegrant, or an antifriction substance, or a binding substance, or mixture thereof. The composition representing the liquid form - suspension, or the soft form - gel, as adjuvant contains a liquid base, alone or mixed with a thickener or a preservative, or mixture thereof.
EFFECT: according to the invention the composition is characterised by prolonged release of gindarine from oral dosage capsular form.
10 cl, 18 ex
SUBSTANCE: composition contains a pharmacological agent, water-soluble polymer and a fatty base. The pharmacological agent is chosen from a group, containing diclofenac, acetylsalicylic acid, paracetamol, ibuprofen, ketorolac, pentoxifeylline and ciprofloxacin. The water-soluble polymer is chosen from a group, containing hydroxypropylmethicellulose, polyvinylpyrrolidone, egg white, sodium caseinate, milk protein, guar gum, sodium alginate, pectin, chitosan acetate, polygalactomannan, dextran or their mixture. The fatty base relates to oils consumed by human beings, which melt at temperature between 30 and 36°C and chosen from a group containing: cocoa bean oil, coconut oil, milk fat, pork fat, hydrofat or their mixture. The said pharmacological agent and water-soluble polymer are contained in the composition in form of a non-covalent complex.
EFFECT: obtaining a dosage form with intense prolonged effect.
3 cl, 3 dwg, 1 tbl, 1 ex
FIELD: medicine; pharmaceutics.
SUBSTANCE: capsule for medicinal and-or vitamin preparations contains covers encapsulated one in another with walls soluble in a human body, medicinal and-or vitamin preparations located between walls, differs that the covers which walls have different time fastness to dissolution, are located in the following sequence: a gelatin cover; a cover from the gelatin processed in pairs of formic aldehyde; a cover from acetyl phthalyl cellulose; a cover from ethyl cellulose with microporous structure.
EFFECT: optimum time conditions of entering of medicinal and vitamin preparations in an organism of the patient.
1 dwg, 1 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention concerns medicine area, namely to peroral medicinal forms on a basis of biphosphonates, containing safe and effective quantity of the pharmaceutical composition containing biphosphonate, chelated agent and an agent for effective delivery of a pharmaceutical composition in the bottom gastroenteric tract of a mammal, and also pharmaceutically active biphosphonate absorption together with nutrition or drinks or without them. The present invention essentially reduces interaction between biphosphonates and nutrition or a drink, which (interaction) leads to that active biphosphonate component is not accessible to absorption. The final peroral medicinal form can be accepted both with food, and without it. Further, the present invention influences delivery biphosphonate and chelated agent in a bottom of GI tract, essentially reducing irritation of top of the GI tract, bound with biphosphonate therapy.
EFFECT: maintenance of fuller observance with the patient of a regimen biphosphonate therapy.
23 cl, 20 ex
SUBSTANCE: invention refers to medicine. There is disclosed capsule containing various reactant pellets differing with reactant release profile in gastrointestinal tract and containing at least two various reactants specified from vitamin complexes, mineral matters, microelements, unsaturated fatty acids, amino acids and/or vegetative extracts and substances. Differing reactant release profiles are related to fast, average and/or slow dissolution of reactant pellets. Such controlled reactant release provides stable absorption in various and optimum gastrointestinal parts.
EFFECT: dosage form offered in the invention allows improving essentially reactant bioavailability even in increased amounts.
14 cl, 5 dwg, 1 ex
SUBSTANCE: invention concerns the solid medicinal composition, including flupirtin or its physiologically comprehensible salts as biologically active substance. At least, one part of flupirtin exists as preparative ready form with the slowed down liberation of the active component. The preparative ready form contains the pressed forms flupirtin, which are preferably in regular intervals covered by a prolonging component. Form pressing of flupirtin is characterised by the size of particles of 160-800 mcm, in bulk volume less than 5 ml/g and preferably are spherical or close to spherical. The prolonging component provides diffused-controllable flupirtin release and preferably includes polymer or a copolymer from acrylic acid, derivatives of acrylic acid, methyl-acrylic acid and-or derivatives of the methyl-acrylic acid, or their admixtures.
EFFECT: new flupirtin composition provides uniform and long release of active substance during long time, frequency of reception to two times day, more rare implication of side effects and a risk exception of a "dose dumping".
16 cl, 3 dwg, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to medicine, particularly to electro-spinning, i. e. polymer nano-fibres obtaining process from solution or melt due to the electric force action, applying to production of stable solid dispersions of amorphous drug substances in polymer nano-fibres.
EFFECT: production of stable solid dispersions of amorphous drug substances.
48 cl, 4 dwg, 3 tbl, 14 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: method consists in as follows: initial organic drug substance and auxiliary low-molecular organic ingredient, serving as a matrix to prolongate the release of the former substance into aqueous solution, are simultaneously and separately vaporised in rarefied neutral gas medium. The simultaneously obtained vapours of the mentioned substance and the matrix ingredient are then co-condensed on deposition surface. The angle between deposition velocity vectors of the mentioned drug substance and the matrix-forming ingredient, and inclination of the angle bisector to deposition surface are 5-170° and 10-90° respectively. Microcapsulation is effected or at positive temperatures of deposition surface during co-condensation process, or at negative temperatures of deposition surface during the co-condensate obtained warming to positive temperatures.
EFFECT: production of micronised powder of encapsulated organic drug substance with prolonged dissolution in aqueous medium during single-stage process.
5 cl, 4 dwg, 5 ex
SUBSTANCE: invention involves compositions of lamotrigine and its pharmaceutically acceptable derivative of prolonged release. Composition includes: 1) nucleus with lamotrigine or its pharmaceutically acceptable derivative; 2) outer coating of nucleus thickness of which is selected so that it is actually resistant for ambient liquids and actually resistant for release of lamotrigine or its pharmaceutically acceptable derivative, and 3) mentioned outer coating has one or more pores from outer face of coating through essentially all the coating without penetration to mentioned nucleus enabling release of lamotrigine or its pharmaceutically acceptable derivative from nucleus into ambient liquid. Mentioned pores have area or integrated area from approximately 10 to approximately 60% of front-face area of mention composition. And release of lamotrigine or its pharmaceutically acceptable derivative is performed essentially trough mentioned pores. Outer surface at that dissolves in the event ambient pH exceeds 5. Composition provides prolonged release of lamotrigine by two procedures: slower release due to initial release of lamotrigine through the pore, and faster release in further step due to dissolving of outer coating.
EFFECT: elimination of side effects accompanying lamotrigine-based or its pharmaceutically acceptable derivatives therapy.
5 cl, 7 dwg, 9 tbl, 6 ex
SUBSTANCE: prolonged release pharmaceutical preparative form contains approximately 35-80% of ranolasine, a pH-independent binding agent and one or more pharmaceutically acceptable excipient. The pharmaceutical preparative form of ranolasine contains hydroxypropylmethyl cellulose as said pH-independent binding agent. The pharmaceutically acceptable excipients represent magnesium stearate and microcrystalline cellulose. The preparative form of ranolasine is used for treatment of cardiovascular diseases.
EFFECT: preparative form of ranolasine under the invention provides effective levels of ranolasine in blood plasma within 12 hours.
15 cl, 5 ex