Galenic preparation with prolonged releasing molsidomine designated for oral administration

FIELD: medicine, pharmacy.

SUBSTANCE: invention concerns a new oral formulation of the galenic preparation molsidomine with prolonged releasing an active substance and designated in treatment of stenocardia attack in all its variations (stress stenocardia, spastic stenocardia, nonstable stenocardia). This novel formulation of galenic preparation comprises the therapeutically effective dose of molsidomine or one of its active metabolites and shows the following dissolving rate values in vitro [measured by spectrophotometry method at wavelength 286 or 311 nm according to a method reported in Pharmacopee Europeene, 3-d edition (or U. S. P. XXIV) at 50 rev./min in 500 ml of medium consisting of 0.1 N HCl at 37°C]: 15-25% of molsidomine released in 1 h; 20-35% of molsidomine released in 2 h; 50-65% of molsidomine released in 6 h; 75-95% of molsidomine released in 12 h; >85% of molsidomine released in 18 h, and >90% of molsidomine released in 24 h wherein the maximal blood plasma concentration of molsidomine in vivo appears in 2.5-5 h but preferably in 3-4 h after intake of abovementioned formulation and has value from 25 to 50 ng/ml of blood plasma. Invention provides reducing amount of doses of drug per a day that is more suitable for a patient.

EFFECT: improved and valuable pharmaceutical properties of preparation.

14 cl, 5 dwg, 2 tbl, 7 ex

 

The technical FIELD

The present invention relates to a new oral galenical form of molsidomine slow release of the active substance, intended for the treatment of angina pectoris in all its varieties (angina or angina at rest, unstable angina).

PRIOR art

It is known that molsidomine (N-(etoxycarbonyl)-3(4-morpholinyl)sydnonimine) is the first representative of a new family antiaging medicines sydnonimines, which was described in a special patent for the medicinal product No. 6734.

This connection is applicable, in particular, in the preventive treatment of angina in all its forms, because it causes relaxation of smooth muscle fibers and blood vessels and suppression of the early stages of the formation of atherosclerotic plaques.

The action of this compound is based on its ability in the course of its biological transformation directly to free radical NO.

More specifically, molsidomin is a prodrug is a precursor of the active substance.

After oral administration of molsidomine completely absorbed and undergoes liver enzyme changes (hydrolysis and decarboxylation). This produces SIN-1, which, in turn, is converted in the blood without the participation of the enzyme is in SIN-1A. SIN-1 and SIN-1A are active metabolites of molsidomine.

Then SIN-1A through oxidation decomposes to inactive SIN-1C with NO release.

After the SIN-1C, in turn, undergoes metabolism in the liver, as described in the work of Bernd Rosenkranz and al., Clinical Pharmacokinetics of Molsidomine, Clin. Pharmacokinet. 1996, May; 30 (5) 372-384.

Currently molsidomin is a commercial product and is mainly presented in the form of tablets in a 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 in severe form.

Was later proposed new Galanova form of molsidomine slow release dose of 8 mg, intended for injection twice a day for prevention and long-term treatment of angina pectoris is sold in Belgium drug called CORVATARD™ (see Compendium 2003, 21émeédition, Association Générale de I lndustrie du Médicament).

In this dosage form, the maximum concentration of molsidomine in the blood plasma between the first and third hours after injection.

Usually molsidomin lasts for 4-5 hours, being appointed in a dose of 4 mg, and within 10-12 hours, being appointed in a dose of 8 mg

In General, from the point of view of convenience for the patient, more preferred dosage forms with Bo is its long-term therapeutic effect, that allows to reduce the number of doses per day, and reducing the number of receptions is more convenient for the patient.

At the same time in the pharmaceutical industry it is known that the extension of therapeutic effect of causing a significant reduction in the maximum concentration in plasma and later enroll in a therapeutic area.

The INVENTION

It was found, and this forms the basis of the present invention that in respect of molsidomine and its active metabolites extension of therapeutic effect can be achieved without significant decrease of the maximum concentration in blood plasma, when therapeutic area, comparable to their receipt of the dosage forms dose of 4 mg and 8 mg

Thus, the form Galanova drug (Galanova form) in accordance with the present invention, having a prolonged action, releases sufficient and verified the amount of the active substance in the acidic environment, mainly in the stomach, which provides a quick intake (about 30 min on an empty stomach and 1 h 30 min at destination after eating) in therapeutic area (5-10 ng/ml), and the maximum content in the blood plasma (33-40 ng/ml), which corresponds to the maximum content of the drug in blood plasma, measured for forms of herbal preparations immediate-release.

The contribution of metabolism in the stomach, and the YMI words, in the acidic environment was able to show by measuring ratios of in vivo - in vitro. It is in the environment HCl 0.1 N. the greatest correlation between the percentage of release in vitro and fractional absorption in vivo, and for all forms of molsidomine.

Thus, first of all, the object of the present invention is a solid oral form Galanova drug slow release of molsidomine, characterized in that it contains a therapeutically effective amount of molsidomine or one of its active metabolites and the fact that it has the following dissolution rate of the active substance in vitro (measured according to the method described in Pharmacopée Européenne, 3 ed. (or USP XXIV) at 50 rpm in 500 ml of 0.1 G. of HCl at 37°C):

15-25% of molsidomine released after 1 hour,

20-35% of molsidomine released after 2 hours,

50-65% of molsidomine released after 6 hours,

75-95% of molsidomine released after 12 hours,

>85% of molsidomine released after 18 hours,

>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.

In the present description "the maximum concentration of molsidomine in plasma... in vitro" line is there is a mean maximum concentration of molsidomine, detectable in plasma at least 10 healthy volunteers.

The expression "therapeutically effective amount"used in the present invention means the number of molsidomine sufficient to ensure its concentration in the blood plasma of at least 5 ng/ml, preferably not less than 10 ng/ml, over a period of about 24 hours.

As a rule, form Galanova of the preparation according to the present invention may contain 14-34 mg, preferably 16-20 mg of molsidomine per unit dose, and presently preferred form, containing 16 mg of molsidomine.

The expression "active metabolites of molsidomine aims to bring together, in particular, the compounds of SIN-1 and SIN-1A, formed as a result of biological transformation, which is exposed to molsidomin after its introduction.

A new form Galanova of the preparation according to the present invention has many advantages compared with existing commercial galenovye forms of molsidomine.

First of all, it is very convenient for the patient as to achieve the desired therapeutic action, only one drug per day. Compliance with the requests of the patient increases.

In addition, maintaining high maximum concentration in plasma provides optimal the real efficiency during the first hours after dosing when a very fast (on an empty stomach 30 min and 1 hour 30 minutes after eating) enroll in a therapeutic area (5-10 ng/ml).

For this reason, the proposed new Galanova form allows you to avoid

on the one hand, any periods of time during which the patient would not be protected (characterized by a concentration of 5-10 ng/ml) and

on the other hand, the side effects caused by over multiple peak concentrations in plasma in the day associated with multiple daily doses of the drug.

In addition, preliminary clinical trials unexpectedly showed that patients whose condition has stabilized as a result of treatment by molsidomine (slow release tablets dose 8 mg)is given 2 times a day in combination with sublingual intake of organic nitro-derivatives in the time of the attack, after subsequent treatment galenical form according to the present invention (at a dose of, for example, 16 mg) experienced a significant decrease in the number of attacks of angina pectoris, resulting in decreased consumption of organic nitro-derivatives.

A new form Galanova of the drug in accordance with the invention can take the form of, for example, tablets, powder or spheroids (balls), and the form of tablets is preferred.

To achieve the objectives of molsidomin embedded in a system of release that allows you to reach those speeds the dissolution of the activities of the respective substances in vitro, what is defined above.

This system of release of the active substance can, in particular, consist in the use of media ("matrix") with slow release or use of molsidomine in the traditional form, covered with a protective sheath, ensure its prolonged release.

In accordance with one example implementation of the present invention, such a system of release of the active substance consists of an active medium containing mixed with molsidomine or one of its active metabolites polymeric material, highly swellable upon contact with water or aqueous solutions, or gel-forming polymer material, and the above-mentioned polymeric materials can constitute one and the same polymeric material, at the same time having the properties of swelling and gelation; however, the above-mentioned storage media may further comprise a variety of conventional auxiliary substances (adjuvants), in particular with the aim to make it suitable for tabletting characteristics.

Such excipients can be, in particular, soluble substances such as lactose, lubricants such as magnesium stearate, granulating agents, such as polyvinylpyrrolidone, agents that improve the fluidity, is such as, for example, colloidal silica and pigments such as iron oxide.

These excipients may be included in the specified media in the amount of 25-60 wt.% with respect to the total weight of the carrier.

Polymeric materials, which have increased the property of swelling and which can be used within the present invention are, for example, carboxymethylcellulose mesh structure in the sodium form, hydroxypropylcellulose mesh structure, hydroxyethylmethylcellulose high molecular weight poly (methyl methacrylate), polyvinylpyrrolidone mesh structure or a high molecular weight polyvinyl alcohol.

Suitable for use within the present invention the gel-forming polymers are, for example, methylcellulose, carboxymethylcellulose, and low molecular weight hypromellose, low molecular weight polyvinyl alcohol, polyoxyethyleneglycol or polyvinylpyrrolidone nesecito structure.

In the framework of the present invention preferably uses a single polymeric material having both swelling properties and gelation. This substance is a high molecular hypromellose, such as the product known under the trade name METHOCEL® KM, and this connection will complement the correctly reported by a finite mixture of excellent viscosity.

In the General case, the polymer material having an increased ability to swell and gel-forming polymer material amount from 40% to 60%, preferably 49,0 wt.% from the total mass of the specified media.

The mass ratio between the polymer material with enhanced ability to swell and gel-forming polymeric material may vary within wide limits.

In some cases, to achieve the desired speed of dissolution in vitro, it may be necessary to include in the carrier of lipophilic designed to control the speed of release of molsidomine.

Such lipophilic substance can be hydrophobic lipid compound such as hydrogenated castor oil (Cutina®), stearyl, cetosteatil, cetyl alcohols, mono-, di-, triglycerides, such as glycerylmonostearate, glycerylmonostearate, solid paraffin.

In the framework of the present invention preferably will be applied glycerinated, in particular the drug, known under the trade name COMPRITOL® 888 ATO, because this connection allows you to perfectly adjust the permeability of the matrix medium.

Mentioned lipophilic substance may be present in the matrix composition of the medium in a quantity of about 12-20 wt.% in relation to the total weight of the matrix but is of Italia.

The system of release of molsidomine used in the framework of the present invention can be prepared by conventional methods known to the professionals, which includes stages of mixing, screening, granulation, drying and tabletting.

To achieve the desired release profile may be appropriate to give the matrix carrier geometric shape that prolong the release of the active substance up to 24 hours.

Thus, the system of release of the active substance, applicable in the framework of the present invention may be a multilayer matrix carrier comprising at least one active layer containing molsidomin, in combination with at least one inactive layer, preferably consisting mainly of the same substances as the active layer, but not containing molsidomine.

In accordance with a preferred embodiment of the invention, the shape Galanova of the preparation according to the present invention is made in the form of tablets in which the active layer is located between the two inactive layers.

In more detail, explain the present invention the following examples are only explanatory purposes.

INFORMATION CONFIRMING the POSSIBILITY

For carrying out the INVENTION

The USE of the 1

Preparation of form Galanova of the preparation according to the present invention in the form of multilayer tablets dosage of 16 mg

Form Galanova of the preparation according to the present invention is made in the form of tablets containing the active layer located in the gap between two inactive layers with the following dimensions:

is the tablet diameter: 8.0 mm

- the thickness of the intermediate active layer: about 2.1 mm

- the thickness of the inactive layer: about 1.55 and 1.95 mm

Each of these layers was prepared from substances, mainly identical, taken in amounts shown in Table I, per pill.

TABLE I
COMPONENTSThe ACTIVE LAYERINACTIVE LAYERS
mgmgmg
MOLSIDOMINE16,00--
- METHOCEL K100M Premium60,0039,8831.90 beef
- COMPRITOL 888 ATO20,0013,5010,80
- MANNITOL 605,00--
- PLASDONE K29-323,705,004,00
- MAGNESIUM STEARATE 1,061,000,80
- AEROSIL 2000,440,500,40
SIKAVICA YELLOW 10-0,250,20
POWDER LACTOSE·H2O-39,8731.90 beef
The TOTAL MASS106,20100,0080,00

The active layer was prepared as follows.

Were mixed to homogeneity, molsidomin, polymeric material (METHOCEL® K100 M), lipophilic (COMPRITOL® 888 ATO), hydrophilic excipient (MANNITOL® 60) and a granulating agent (PLASDONE® K29-32) in a suitable mixer.

In addition, preparing a 95%solution of ethanol used for wetting the above pulverized mixture.

Thus obtained homogeneous mass was subjected to granulation and drying over liquefied air to obtain, after calibration, granulate.

Thus obtained homogeneous granulate was mixed with protivoprotosanam (a substance that improves the fluidity - AEROSIL® 200) and the lubricant (magnesium stearate), then alloy preformed.

Inactive layers was obtained according to the same recipe as above for the active layer, while the force of compression at all stages of the tabletting chose to get the exac the NGOs homogeneous tablet (pressure of about 1000 kg/cm 2).

EXAMPLE 2

Determination of dissolution profiles in vitro galenical form according to the present invention

The share of dissolution in vitro galenical form according to the present invention, in particular galenical form, prepared in Example 1 was measured using the techniques described in the Pharmacopée Européenne, 3 ed. (or USP XXIV).

The measurements were carried out under the following experimental conditions:

The device Sotax AT7 with speakers

Rotation speed: 50 rpm

Environment temperature: 37°

Filtering: filter Wathman GF-D

Dosing: UV spectrophotometry at a wavelength of about 286 or 311 nm

Spectroscopy: Hitachi U-3000 with a quartz cuvette with 1 cm thickness

Environment for dissolution: 500 ml HCl 0.1 N. (acidic pH).

Thus were obtained the following results:

18% of the released molsidomine in 1 hour

27% of the released molsidomine 2 hours

57% of the released molsidomine after 6 hours

88% of the released molsidomine 12 hours

96% of the released molsidomine after 18 hours

100% of the released molsidomine 24 hours

EXAMPLE 3

A comparative study of the main pharmacokinetic characteristics of dosage forms on the basis of molsidomine

To prove the advantages of the galenical form according to the present invention as compared with previously known galenovye forms mol is Domina were measured main pharmacokinetic characteristics of the three following dosage forms.

Dosage form based molsidomine dosage 4 mg, corresponding to Belgian commercial drug CORVATON® 4 mg.

Dosage form based molsidomine dosage of 8 mg, corresponding to Belgian commercial drug CORVATARD®.

Dosage form in accordance with the present invention a dosage of 16 mg (obtained in accordance with Example 1).

When using experimental procedures that are familiar to specialists for each of these dosage forms were measured the following parameters:

Cmax: the maximum concentration in plasma.

Tmax: the time during which the observed value of the Cmax.

AUC 0-t: area under the curve between times 0 and t.

T1/2: half-life of the drug.

MRT: mean time presence of substances in the body.

If the dosage form according to the present invention these pharmacokinetic characteristics were determined in healthy young volunteers on an empty stomach, and then after a meal.

Thus obtained results are summarized in Table II

TABLE II
MOLSIDOMIN 4 mg (n=12)MOLSIDOMIN 8 mg (n=12)MOLSIDOMINE 16 mg on an empty stomach (n=10)MOLSIDOMINE 16 mg after the water (n=10)
Cmax(ng/ml)40,13±of 19.0333,80±15,4434,19±25,3734,76±15,03
Tmax(h)0,75±0,341,67±0,943,00±1,414,60±2,10
AUC 0-t (ng·h/ml)103,6±79,40195,5±124,5372,5±278,1RUR 327.7±166,9
AUC O-∞ (ng·h/ml)114,8±89,40229,8±154,4527,2±466,6409,3±194,1
T1/2 (hour)1,55±0,503,35±0,7811.87 per±10,3511,54±of 10.21
MRT (h)2,64±0,745,81±1,4718,99±11,8417,58±11,33

In addition, figure 1 presents the graphs of the variation of the concentration of each of the tested drugs in plasma, depending on the time.

The results show that the dosage form dosage of 4 mg ensures the presence of the active substance in the blood plasma for about 4-5 hours, dosage form dosage of 8 mg for about 10-12 hours, and the dosage form according to the present invention a dosage of 16 mg to about 24 hours.

It can be argued that the maximum is oncentrate in plasma is relatively equivalent for all three dosage forms and ranges from 33 to 40 ng/ml.

The result obtained for the dosage form according to the present invention, was completely unexpected, because the extension of therapeutic action does not lead here to a significant decrease of Cmax. There are no statistically significant differences in this characteristic between the galenical form according to the present invention and traditional forms (analysis of variance with subsequent study of post-hoc on Bonferonni).

In addition, the results show that the medicinal product in accordance with the present invention provides an efficiency that is comparable to the efficacy of known drugs, even in the first hours after admission, with the rapid flow in therapeutic area (within about 30 minutes on an empty stomach and 90 minutes after a meal).

EXAMPLE 4

A comparative study of the correlation between the kinetics of release in vitro in a different environment and kinetics of absorption in vivo

The ratio of in vivo - in vitroMolsidomin 4 mgMolsidomin 8 mgMolsidomine 16 mg on an empty stomachMolsidomine 16 mg, after a meal
at pH 6.80,9580,8350,7120,761
at acidic pH
(in HCl 0.1 N.)0,8770,8550,7480,812
the dependence on pH *not applicable0,8170,7190,755
* Note: the term "dependence on dh " means that the study of the in vitro dissolution test subjects tablet was maintained: at pH 1.3 in 1 hour

at pH 5.0 in the continuation of 30 minutes

at pH 6.3 in further 3 hours at pH 7.0 in the continuation time remaining

All correlation coefficients are significant (p<0,01; test Pearson). The best correlation (0,958) obtained for the form of immediate action (molsidomin 4 mg), which seems quite logical. In fact it is known that the more complicated Galanova form, the more difficult it is to find the relationship between the release in vitro and absorption in vivo. For molsidomine 8 mg the correlation coefficient is very high (0,855). For molsidomine 16 mg best correlation (0,812) occurs when you take into account the kinetics after eating and dissolution in the acidic environment. In General, to form slow release of the active substance, the correlation is always better when the release is carried out in an acidic environment. This is due to the fact that a large part of the kinetics of malsi the omina depends on the absorption in the stomach.

EXAMPLE 5

A study of drug concentration in blood plasma in a prescription form of molsidomine according to the present invention, depending on the time in elderly patients suffering from angina.

Thirty-three coronary patients with stable angina received a single dose of molsidomine 16 mg (dosage form according to Example 1), adopted on 8 o'clock in the morning with Breakfast. The sample was represented by 22 men and 11 women with an average age 62,6±1.3 years (extreme values of 49 and 73). Divided into 7 groups of patients had a blood test on the content of molsidomine respectively through 3, 6, 10, 14, 18, 22 and 24 hours after taking the drug.

Figure 2 presents the average concentration of molsidomine in plasma and standard error of the mean for each of the 7 groups of subjects patients.

As shown in figure 2, the kinetics defined in elderly patients, is highly correlated with the kinetics determined in healthy young volunteers and presented in figure 1. In addition, the value of Cmax, Tmaxand the half-life comparable in the two groups of subjects.

Also received the following information:

the average maximum concentration is 36,0±to 10.8 ng/ml;

the highest average concentration determined in group 2, i.e. after 6 hours after administration of molsidomine;

- Konzentrat what I decreases slowly, 50% within 8 hours;

the concentration of molsidomine in plasma is maintained approximately at the same level within 8 hours, between 14th and 22nd hours after administration and varies between 16,5 and 18.1 ng/ml;

residual concentration of 8.5±4.3 ng/ml was observed even after 24 hours after the appointment of a single dose of molsidomine 16 mg.

EXAMPLE 6

To study the correlation between clinical efficacy and concentration in blood plasma dosage forms of molsidomine according to the present invention.

Ten coronary patients suffering from stable angina, received complex treatment of angina pectoris (nitro-derivatives of prolonged action, molsidomin, calcium antagonists and/or beta-blockers) at least three days, in the case of beta-blocker treatment was longer; some were written during this period, the reception isosorbide-trinitrate 5 mg tablets under the tongue or use of nitroglycerin in the aerosol.

Then the subjects patients received once molsidomine 16 mg (dosage form according to Example 1) or placebo, in accordance with appliances, double-blind, randomized, placebo-controlled experiment, including the observation period at least during two days.

The sample consisted of 8 men and 2 women with cf is ne age 61,3± 3.1 years (extreme values for 49 years and 73 years).

Being divided into 7 groups, patients after exercise on the Bicycle Ergometer was donating blood for the maintenance of molsidomine later respectively 3, 6, 10, 14, 18, 22 and 24 hours after taking the medicine or a placebo.

The test apparatus consisted of an initial load of 30 W with an increase by 30 W every 3 minutes until you stop the test when symptoms of angina pectoris, the maximum theoretical heart rate, muscle fatigue or for security reasons (rhythm disturbance or intracardiac conduction, the pressure jump by more than 20 mm Hg, the suppression of the site ST≥3 mm). Both alone and in all tests the load was shot ECG and blood pressure readings.

The clinical efficacy of the dosage form according to the present invention was determined quantitatively according to the following criteria:

a) the difference in the total duration of the exercise, in the second expression, under the action of placebo and under the action of molsidomine;

b) the difference in the volume of work performed expressed as the sum of the watt·min produced at each stage of the load, under the action of placebo and under the action of molsidomine.

Figure 3 presents data on the concentrations of molsidomine in plasma, detected in each of the 10 patsie the tov, and the corresponding differences in the total duration of the exercise.

The equation of the linear regression between the variable X (the difference between the total duration of the exercise under the action of placebo and under the action of molsidomine) and variable (concentration of molsidomine in plasma) is: Y=0,18X+5,35.

The Pearson correlation coefficient g is equal to 0.88 (P<0,001), which corresponds to the coefficient of determination r2=0,77, that is, 77% of the variation range of evidence about clinical effectiveness can be explained due to the presence of molsidomine in the blood plasma of the patients.

Neither quadratic nor cubic model does not improve the correlation coefficient.

If considered clinically significant difference in 30 seconds between tests under load under the action of placebo and molsidomine, it turns out that it is necessary for this level of efficiency, the concentration of molsidomine in plasma is 10,75 ng/ml value practically achievable even after 24 hours after a single dose of molsidomine 16 mg according to the present invention (see Figure 2).

Figure 4 presents data on the concentrations of molsidomine in plasma from each of 10 patients, and the difference produced in total.

The equation of the linear regression between the variable X (the difference between the total produced by the operation under the effect of placebo and under the action of molsidomine) and eromenoi (concentration of molsidomine in plasma) is: Y=0,11X+5,90.

The Pearson correlation coefficient r accounts for 0.86 (P=0.002), which corresponds to the coefficient of determination r2=0,74, i.e. 74% of the variation series of indicators of clinical efficacy may be explained by the presence of molsidomine in the blood plasma of the patients.

Neither quadratic nor cubic model does not improve the correlation coefficient.

If considered clinically significant difference in 50 W·min between tests under load under the action of placebo and molsidomine, it turns out that it is necessary for this level of efficiency, the concentration of molsidomine in plasma is 11,40 ng/ml value practically achievable even after 24 hours after a single dose of molsidomine 16 mg according to the present invention (see Figure 2).

EXAMPLE 7

The study of clinical effectiveness of dosage forms of molsidomine according to the present invention

Two hundred twenty-two patients with stable angina participated in an international multicenter randomized double-blind placebo-controlled study.

After single purpose a single dose of molsidomine 16 mg (dosage form according to Example 1) or a placebo patients passed the load test on the Ergometer, delayed by the time period from 2 to 24 hours after administration of the doctors who NTA. The amount of load (the total produced work, expressed in W·min) under the action of molsidomine turned out to be significantly greater than under the placebo effect as statistically (p<0,001)and clinically (mean improvement is 53 W·min).

The introduction of the same single daily dose of 16 mg of molsidomine (in the dosage form according to Example 1) within 2 weeks causes an improvement in physical condition comparable to the improvement achieved after a single dose, as statistically significant (p<0,001)and clinically (mean improvement is 58 W·min).

These results indicate the absence of habituation to molsidomine 16 mg after long-term treatment (Figure 5). They also indicate that therapeutic effect lasts for 24 hours.

Note that the clinical improvement observed in this study is in good agreement with the clinically effective concentrations of molsidomine in plasma, derived from the correlation of total jobs / molsidomin in the plasma, are presented in figure 4.

The results obtained in the foregoing Examples 5, 6 and 7 prove the originality of the new galenical forms of molsidomine according to the invention.

The main advantages of this form in comparison with existing forms can be summarised as follows.

Maintaining otnositelno constant level of increased concentration of molsidomine in plasma (16,5 at 18.1 ng/ml) for 8 hours (from 14 to 22 hours after taking the drug). A relatively constant level of concentration in the blood plasma, providing significant clinical efficacy in coronary patients with stable angina, as evidenced by the close correlation between the increase in load and concentration of molsidomine in the blood, and this improvement is maintained in the following 24 hours after drug administration.

The absence of habituation to molsidomine, with significant clinical efficacy persists after two weeks of treatment in coronary patients with stable angina.

1. Solid oral form Galanova preparation of molsidomine slow release of the active substance, characterized in that it contains from 14 to 24 mg per unit dose of molsidomine or one of its active metabolites, and its rate of dissolution in vitro [measured spectrophotometrically at a wavelength of 286 or 311 nm according to the method described in Pharmacopee Europeenne, 3rd ed. (or U.S.P. XXIV) at 50 rpm in 500 ml of medium consisting of 0.1 G. of HCl at 37°] is:

15-25% of molsidomine released after 1 h,

20-35% of molsidomine released after 2 h,

50-65% of molsidomine released after 6 h,

75-95% of molsidomine released after 12 h,

>85% of molsidomine released after 18 h,

>90% of molsidomine, biswalo is established after 24 h,

furthermore, the peak content of molsidomine in plasma in vivo appears in 2.5-5 hours, preferably within 3-4 hours after taking the above form and has a value of from 25 to 40 ng/ml plasma, while it includes the release of molsidomine, consisting of a matrix sustained release or conventional dosage forms with a protective shell, providing a prolonged release of molsidomine.

2. Form Galanova preparation according to claim 1, characterized in that it contains from 16 to 20 mg of molsidomine per unit dose.

3. Form Galanova preparation according to claim 1 or 2, characterized in that it presents in the form of tablets, in the form of a dispersion or in the form of pills.

4. Form Galanova preparation according to claim 1, characterized in that said system of release of the active substance consists of an active matrix comprising mixed with molsidomine or any of its active metabolites: a polymeric material having high ability to swell upon contact with water or aqueous solutions; gel-forming polymer material, moreover, these polymeric materials can be represented by one and the same material, at the same time having the properties of swelling and gelation; however, this matrix may additionally include various auxiliary substances is a, in particular, normally intended to make it suitable for tabletting properties.

5. Form Galanova preparation according to claim 4, characterized in that the said excipients are selected among soluble substances, such as lactose; lubricants such as magnesium stearate; granulating agents such as polyvinylpyrrolidone; agents for improving the fluidity, in particular, such as colloidal silicon oxide, and pigments, such as iron oxide.

6. Form Galanova preparation according to claim 4 or 5, characterized in that the active matrix consists of high-molecular hydroxypropylmethylcellulose that has both properties of swelling and gelation, in particular, such as the product known under the trade name METHOCEL ® K100M.

7. Form Galanova preparation according to claim 4 or 5, characterized in that the active matrix includes the additional lipophilic substance that is involved in the regulation of the speed of release of molsidomine.

8. Form Galanova preparation according to claim 6, characterized in that the active matrix includes the additional lipophilic substance that is involved in the regulation of the speed of release of molsidomine.

9. Form Galanova preparation of claim 8, characterized in that the lipophilic substance is selected from hydrophobic lipiany the compounds such as hydrogenated castor oil, stearyl, cetosteatil, cetyl alcohols; mono-, di-, triglycerides, such as glycerylmonostearate, glycerylmonostearate, solid paraffin.

10. Form Galanova preparation according to claim 9, characterized in that said lipophilic substance is glycerinated, in particular, the product known under the trade name COMPRITOL ® 888 ATO.

11. Form Galanova preparation according to claim 1 or 2, characterized in that it is made in the form of multilayer tablets, preferably includes one active layer containing molsidomin, in combination with at least one inactive layer, preferably consisting mainly of the same substances as the active layer, but not containing molsidomine.

12. Form Galanova drug claim 11, characterized in that it includes one active layer positioned between two inactive layers.

13. Form Galanova preparation of claim 10, characterized in that it is made in the form of multilayer tablets, preferably includes one active layer containing molsidomin, in combination with at least one inactive layer, preferably consisting mainly of the same substances as the active layer, but not containing molsidomine.

14. Form Galanova drug in 13 different t is m, it includes one active layer positioned between two inactive layers.



 

Same patents:

FIELD: medicine, phytotherapy, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to using Belamcanda chinensis extract for preparing organ-selective medicinal preparation without uterotropic effect or with minimal such effect that is used as estrogen-like preparation. This preparation is used in selective treatment and/or prophylaxis of cardiovascular diseases, in particular, atherosclerosis and osteoporosis, climacteric disturbances, especially for prophylaxis or softening congestions of blood. Extract is used in manufacturing a medicinal preparation in ready formulation for selective treatment and/or prophylaxis of cardiovascular diseases, in particular atherosclerosis, and for selective treatment and/or prophylaxis of osteoporosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood. Extract promotes to effective prophylaxis and/or treatment of cardiovascular diseases, in particular, atherosclerosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood.

EFFECT: valuable medicinal properties of extract.

4 cl, 4 ex

FIELD: medicine, neurology.

SUBSTANCE: the present innovation deals with treating cerebral vascular diseases accompanied with psychic disorders. For this purpose one should introduce homeopathic preparations named Cerebrum compositum and Hepar compositum per 2.2 ml every other day for 20 d intramuscularly, and beginning since the 11th d one should additionally prescribe Vertigohel preparation per 10 drops thrice daily for 10 d. The innovation suggested provides decreased different psychotic and unpsychotic depressive syndromes that considerably improves quality of life in this category of patients.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, cardiology, pharmacy.

SUBSTANCE: invention proposes applying moxonidine as an active component in preparing pharmaceutical compositions designated for treatment of injuries of heart muscle caused by infarction. Indicated compositions promote to prophylaxis in the infarction progression and to treatment of its complications also.

EFFECT: valuable medicinal properties of composition.

3 cl, 1 tbl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

21 cl, 70 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a medicinal formulation consisting of a core and the stomach-dissolving envelope. The core comprises trimetazidine dihydrochloride as an active component, and starch, mannitol, povidone, magnesium stearate, croscarmelose and microcrystalline cellulose as accessory substances. The envelope comprises hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide, magnesium stearate and acid red as a dye. Also, invention describes a method for making the trimetazidine medicinal formulation. Trimetazidine tablets show high mechanical strength in the low pressing strength (3.5-5 kH). The composition of the medicinal formulation provides releasing 80% of trimetazidine for 30 min.

EFFECT: improved and valuable properties of formulation.

3 cl, 1 tbl, 1 ex

FIELD: organic chemistry, chemical technology, biochemistry.

SUBSTANCE: invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives of the general formula (1):

eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):

wherein R1, R2 and R3 have above given values; R5 represents hydroxyl or chlorine atom, and to their applying for preparing compounds of the general formula (1.2):

and (1.3):

wherein R1, R2 and R4 have above given values.

EFFECT: valuable medicinal and biochemical properties of compounds.

6 cl, 4 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: pharmaceutics.

SUBSTANCE: the suggested pharmaceutical composition at delayed release contains fluvastatin or its pharmaceutically acceptable salt hydroxypropylmethylcellulose and nonionic hydrophilic polymer. The latter is being hydroxyethylcellulose at average molecular weight ranged 90000-1300000 or hydroxypropylcellulose at average molecular weight ranged 370000-1500000 or polyethylenoxide at average molecular weight ranged 100000-500000. The suggested pharmaceutical composition is necessary to obtain peroral medicinal remedy for decreasing cholesterol level in plasma, it, also, provides the supply of fluvastatin into the body during prolonged period of time, for example, for more than 6 h and enables to minimize the possibility for premature release or "discharge" of considerable fluvastatin quantities.

EFFECT: higher efficiency.

21 cl, 6 dwg, 5 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: means has lipid fraction obtained from Berryteuthis Magister Comandor squid liver containing 10% of polyunsaturated fatty acids and 50% of alkyl-diacylglycerides showing marked lipid-correcting and immunomodulating properties.

EFFECT: enhanced effectiveness in treating lipid metabolism disorders and immunity system disorders.

4 tbl

FIELD: medicine, therapy, gastroenterology, pharmacy.

SUBSTANCE: method involves oral intake of solid medicinal formulation at vertical position of patient and change of medicinal formulation position into stomach is carried out in each 5 min, not rare. Change of medicinal formulation position is carried out by pressing on epigastrium region by hand or by cyclic change of position of patient body from its vertical position to horizontal position and back. Method provides enhancing safety in enteral using a solid medicinal formulation due to diminishing its ulcerogenic effect. Invention can be used in enteral using solid medicinal formulations.

EFFECT: improved method for diminishing ulcerogenic effect.

2 ex

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for pressing in preparing a medicinal formulation of phenytoin sodium, method for pressing in rollers and preparing a pharmaceutical composition involves stages of addition of phenytoin sodium into a mixer receiver and addition of at least one excipient into indicated mixer. Mixture is stirred and transferred into roller thickener wherein pressure is applied on the mixture of phenytoin sodium and excipient. The prepared compact-(briquette) is ground and prepared granulate is mixed repeatedly that is suitable from further processing to a medicinal formulation. Excipients involve magnesium stearate, sugar, lactose monohydrate and talc, or talc is added directly before the second mixing the granulate.

EFFECT: improved pressing method.

15 cl, 10 tbl, 2 dwg, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to agents stimulating the central nervous system, i. e. psychomotor stimulators. Invention proposes combination of sydnocarbum with ladastenum taken in the ratio = 1:(0.4-2) as an agent. Invention provides enhancing physical working ability, prevents the development of acute physical fatigue and exceeds effect of sydnocarbum and ladastenum by 2.7 and 1.6 times, respectively.

EFFECT: enhanced effectiveness and valuable medicinal properties of agent.

4 cl, 13 tbl

FIELD: medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to the orally decomposition composition comprising mirtazapine. A single dosed medicinal formulation decomposing rapidly after its oral administration is bioequivalent to usual tablet but shows advantages with respect to adverse effects, effectiveness, anxiolytic effects, dream-improving effects, and acceleration of onset effect of an antidepressant agent. Invention can be used in treatment of depression.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

5 cl, 1 tbl, 2 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to manufacturing solid medicinal formulations of preparations. Invention proposes a medicinal formulation consisting of a core comprising the following components: indometacin, lactose, calcium phosphate, hydroxypropylcellulose, magnesium stearate, sodium croscarmellose and envelope comprising collicute MAE 100P, propylene glycol, pigment titanium dioxide, talc, collidon-30, brown sycovite-70. Also, invention discloses a method for preparing the formulation. Invention provides enhancing stability of envelope to effect of stomach juice, rapid and complete release of active substance, simultaneous simplifying the process of applying the envelope for a single step.

EFFECT: improved and valuable pharmaceutical properties of formulation.

3 cl, 1 tbl

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a solid medicinal formulation eliciting an antihypertensive, anti-anginal, vasodilating, antioxidant and antiproliferative effect. The solid medicinal formulation comprises the following components: carvedilol, disaccharide, magnesium stearate, starch, calcium phosphate, hydroxypropylmethylcellulose, aerosil and carboxymethylcellulose sodium salt. Also, invention discloses a method for preparing this formulation. Invention provides preparing the formulation eliciting high rate and fullness in releasing an active substance in the human body, stability of quality indices for all fitness period and allowing the effective usage in manufacturing the medicinal agent. Invention can be used in treatment hypertension, stenocardia, myocardium ischemia and chronic cardiac insufficiency.

EFFECT: improved preparing method, valuable medicinal properties of formulation.

5 cl, 1 tbl, 4 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a new pharmaceutical composition comprising benzamide derivative and one or some additives taken among the following substances: 1) mixture of polyethylene glycol and surface-active substance; 2) amino acid or inorganic acid salt, and 3) propylene carbonate. The composition comprises benzamide derivative taken in the amount from 0.001 to 1000 mg per a single dosing formulation. The composition shows the enhanced solubility and absorption capacity in oral route of administration.

EFFECT: improved medicinal and pharmaceutical properties of composition.

9 cl, 4 tbl, 1 dwg, 5 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a solid pharmaceutical composition. The composition comprises tegaserod or its salts as an active component that is sensitive to acid effect and/or difficultly soluble in water, and a loosening agent taken in the amount at least 15 wt.-% as measured for the total mass of the composition. The composition is stable and can be prepared easily, it shows good rate release after its administration patients and good biological availability. The composition is designated for prophylaxis, modulation or treatment of visceral pain or discomfort, for modulation of visceral sensitivity or perception, improvement of sensory perception of rectum intestine tension and for treatment of anal dysfunction regulation.

EFFECT: improved and valuable medicinal properties of composition.

14 cl, 7 ex

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to a method for making compositions as carbonated tablets. Method involves granulation, drying, calibration, powdering and tableting. Method involves using anhydrous components and powder of each component is dried preliminary for 1 h, not less, at temperature below the decomposition point. Then powder components of active agent, basic and acid components providing the carbonated property are mixed being involving, if necessary, components of neutral substances, sweetening agents and special additives. Prepared mixture is granulated with 7-20% solution of a binding agent in isopropyl alcohol or ethanol and then the prepared granulate is dried at temperature not resulting to deterioration of granulate properties, to residual moisture 0.1-0.3%. Then method involves calibration of granules up to the size 1000-1200 mcm, powdering the prepared tablet mass and its tableting in moisture value of environment medium 5-25%. Invention provides reducing duration and labor intensity of the method due to exclusion the necessity carrying out the separate granulation of components and the development of technology providing the possibility for carrying out a single-step combined granulation of all components of the composition. Simplifying and acceleration of the method are attained in retention of high quality of ready tablets.

EFFECT: improved preparing method.

14 cl, 7 ex

FIELD: chemical-pharmaceutical industry and technology, pharmacy.

SUBSTANCE: omeprazole is a strong anti-ulcer agent that is absorbed in intestine preferably but it unstable in acid medium. Some methods for preparing stable pharmaceutical compositions and solution of two main problems of effect on their stability, pH and moisture, have been studied. Invention describes a method for preparing pharmaceutical composition as tablet formulation comprising omeprazole, sodium alginate and basic amino acid and involving following steps: (a) preliminary modification of external morphology of basic amino acid by wetting and the following drying up to the water content in the total amount less 0.75 wt.-% of amino acid mass; (b) incorporation of basic amino acid to preliminary prepared granulate comprising omeprazole and sodium alginate with the low moisture content; (c) incorporation of other excipients up to preparing granulate; (d) grinding granulate from step (c) up to preparing uniform granulometric composite; (e) incorporation of lubricating agent, carrying out the tableting process and applying enterosoluble coating on tablets made. Such method is simpler as compared with known ones and provides preparing compositions with improved indices of extrusion. The content of sodium alginate can up to 15 wt.-% of tablet mass, preferably, from 8 to 12 wt.-%. Basic amino acid can represent L-arginine, L-lysine or L-histidine. Pharmaceutical compositions prepared by this method comprise omeprazole in concentrations 10-40 mg per a tablet.

EFFECT: improved preparing method.

6 cl, 4 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacology.

SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.

EFFECT: valuable medicinal properties of gyrase.

54 cl, 5 tbl, 13 ex

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