RU2483728C1 - Combined antihypertensive drug and method for preparing it - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combined antihypertensive drug containing an agent presented by Amlodipine besilate and Lisinopril dehydrate mixed with an excipient. As the excipient, the specified antihypertensive drug contains microcrystalline cellulose of an average particle size of 90-100 mcm and a bulk density of 0.28-0.33 g/ml; as additives, it contains colloidal silicon dioxide, magnesium stearate and sodium carboxymethyl starch. The invention also refers to a method for preparing the mentioned antihypertensive drug by direct compression.

EFFECT: providing a stable drug preparation, more storage-stable, having high producibility, active substance distribution uniformity and bioavailability.

8 cl, 2 tbl, 3 ex

Description

The invention relates to medicine, specifically to combination drugs and methods for their preparation, and can be used to treat arterial hypertension. The combination of amlodipine besilate and lisinopril dihydrate is selected as the active substance in the claimed preparation.

The results of large controlled clinical trials performed in different countries of the world, including Russia, indicate that a significant number of patients with arterial hypertension (AH) of the 1st degree and almost all patients with hypertension of the 2nd and 3rd degrees to achieve optimal control of arterial pressure (BP), you must simultaneously take at least two antihypertensive drugs. As indicated in national and international recommendations for the treatment of hypertension, the simultaneous administration of antihypertensive drugs with various mechanisms of action makes it possible to more quickly and persistently lower blood pressure to the target level, to suppress the counter-regulatory mechanisms of increasing blood pressure, provides more effective protection of target organs, and also reduces the frequency occurrence of side effects. One way to solve this problem is to create fixed combination drugs.

When administered orally, the drug passes through the mucous membrane of the stomach, liver, etc. and only part of it enters the systemic circulation. The effect of the drug largely depends on how large this part is. This indicator characterizes the bioavailability of the drug. At the same time, not only the route of administration of the drug, but also biopharmaceutical factors (dosage form, its composition, features of the production technology of the drug) affect the bioavailability of the drug.

As active substances in the inventive combination tool selected: 3-ethyl-5-methyl (4RS) -2 - [(2-aminoethoxy) methyl] -4- (2-chlorophenyl) -6-methyl-1,4-dihydropyridine- Benzenesulfonate-amlodipine 3,5-dicarboxylate besilate; and (S) -1-N ² -carboxy-3-phenylpropyl) -L-lysyl] -L-proline dihydrate-lisinopril dihydrate.

Lisinopril is an angiotensin converting enzyme (ACE) inhibitor, reducing the formation of angiotensin II, aldosterone, while increasing the formation of bradykinin (a vasodilating mediator). It reduces the pressure in the pulmonary capillaries, does not affect the heart rate. Improves blood supply to the ischemic myocardium. With prolonged use, it reduces hypertrophy of the myocardium and the walls of the arteries of the resistant type. Slows the progression of left ventricular dysfunction (LV) after myocardial infarction, not complicated by heart failure (HF). Effective for arterial hypertension with a low level of renin, reduces albuminuria (due to lower blood pressure, changes in the hemodynamics of the glomerular apparatus). Does not affect glucose levels in patients with diabetes mellitus. The antihypertensive effect develops 1 hour after administration, the maximum effect - after 6 hours, the duration of action - 24 hours. When treatment is discontinued, there is no “withdrawal" syndrome (a sharp increase in blood pressure).

Amlodipine - a blocker of "slow" calcium channels, has an antianginal and hypotensive effect. It reduces the intake of calcium gluconate in the myocardial cells and smooth muscle cells of the vascular wall (to a greater extent). Reduces overall peripheral vascular resistance. Antianginal action is due to the expansion of arteries and arterioles, reducing afterload. Increases oxygen supply to intact (especially with vasospastic angina pectoris) myocardium and ischemic myocardial sites. Does not cause reflex tachycardia, does not affect myocardial conduction and contractility. Reduces the frequency of angina attacks and the need for nitroglycerin. It has a long hypotensive effect. It does not adversely affect metabolic processes, does not change plasma lipids. It can be used in patients with concomitant bronchial asthma, diabetes mellitus, gout. The combination of lisinopril with amlodipine helps to prevent the development of undesirable effects caused by antiregulation of active substances. The slow calcium channel blocker (BMCC), expanding arterioles, can lead to a delay of Na ⁺ and water, therefore it can activate the renin-angiotensin-aldosterone system (RAAS). ACE inhibitor blocks this process. The drug is recommended in cases where taking individual components in the same doses is not effective. Prolonged circulation of both active substances makes it possible to take 1 time per day.

It is known that a combination of active pharmaceutical ingredients selected from amlodipine or its pharmaceutically acceptable salts and an angiotensin converting enzyme inhibitor (ACE inhibitor), for example lisinopril, is useful for the prevention (prevention) and / or treatment of cardiovascular diseases (see, for example, patent U.S. 6,245,787, 2001). Clinical studies confirming this are known from the prior art, but data regarding the composition of the pharmaceutical composition used are not known.

Known pharmaceutical composition (patent EA No. 010288, published 29.08.2008), which is closest to the claimed tool and containing as active ingredients from 0.3 to 30 wt.% Amlodipine besilate and from 0.1 to 75 wt.% lisinopril dihydrate and optionally containing one or more of the excipients conventionally used in the pharmaceutical industry, with the condition that the excipient is not a calcium salt of phosphoric acid. The invention also provides a method for preparing the above pharmaceutical composition, which comprises preparing a mixture comprising lisinopril dihydrate, sodium carboxymethylamylopectin and microcrystalline cellulose; granulating the resulting mixture in water; drying the obtained wet granular mass in vacuum at a product temperature below 35-40 ° C; homogenization of the dry mixture obtained by mixing amlodipine besilate, sodium carboxymethylamylopectin and microcrystalline cellulose; the final mixing of the mixture with magnesium stearate and pressing the mixture to obtain tablets or filled capsules.

According to EA patent No. 010288, granulation of the mixture, homogenization are used to prepare the pharmaceutical composition, and only after that the mixture is pressed. The description of patent EA No. 010288 indicates that the need for wet granulation is due to the fact that lisinopril dihydrate is characterized by a very small particle size, 80% of the particles have a size of less than 40 microns, and a low bulk density from 0.05 to 0.3 g / ml . These symptoms can cause undesirable fluidity and compressibility of the mixture, even if lisinopril dihydrate is present in a minimal amount. The addition of substances traditionally used in the pharmaceutical industry does not solve this problem, which can lead to unsatisfactory homogeneity of the mixture and dosage form made from it. In addition, due to the low compressibility of the mixture, the tablets may have insufficient strength to carry out further technological operations with them.

It should be noted in connection with the above that the known decomposition product of lisinopril dihydrate is S, S, S-lisinopril-diketopiperazine, and the oxidized amlodipine besylate is the decomposition product of amlodipine besilate. Elevated temperature and humidity, which inevitably affect the mixture during wet granulation and subsequent drying, enhance the decomposition process. In addition, the implementation of the wet granulation process requires high-tech equipment and time-consuming.

The technical task of the proposed solution is to expand the arsenal of combined drugs with antihypertensive and antianginal effects and to obtain a stable drug with a long shelf life and low cost.

The technical result of the application of the new solution is to provide the possibility of manufacturing a domestic stable drug of low cost with a long shelf life obtained by direct compression, more stable during storage, with high adaptability, uniform distribution of active substances and bioavailability.

The specified technical result is achieved due to the fact that the inventive combined antihypertensive agent contains, as an active principle, a combination of amlodipine besilate and lisinopril dihydrate and, as a filler, a special type of microcrystalline cellulose with an average particle size of 90-100 microns and a bulk density of 0.28-0, 33 g / ml, and colloidal silicon dioxide, magnesium stearate and carboxymethyl starch as auxiliary substances.

The optimal ratio of ingredients is, wt.%:

Active start 5.0-10.0 Microcrystalline cellulose 83.5-93.3 Silicon Colloidal Dioxide 0.2-1.0 Magnesium stearate 0.5-1.5 Sodium carboxymethyl starch 1.0-4.0

The composition of the inventive combined antihypertensive drugs was selected taking into account the characteristics of the direct compression method. It was unexpectedly discovered that when using microcrystalline cellulose with a particle size of 90-100 microns and a density of 0.28-0.33 g / ml close to the bulk density of the active components as a filler, a high homogeneity of the mixture is achieved with sufficient fluidity for pressing significant strength (compression) obtained from this mixture of tablets.

The claimed ratio of ingredients is determined experimentally and allows you to get the specified technical result.

The active principle of the claimed drug is a combination of amlodipine besilate and lisinopril dihydrate. The preferred weight ratio of amlodipine besilate and lisinopril dihydrate is 1: 1.57.

Excipients used in the proposed composition are:

- microcrystalline cellulose is used as a filler;

- colloidal silicon dioxide and magnesium stearate are used as anti-friction substances;

- sodium carboxymethyl starch is used as a disintegrant.

The goal, namely the creation of a stable combined drug with a long shelf life and low cost, is achieved in the manufacture of tablets by direct compression with the stated percentage of active principle and auxiliary components.

The combined antihypertensive agent is made in a simple, economical way, which does not require granulation of the components — by direct compression, has a shelf life of more than 3 years, and has high bioavailability. It is carried out in the form of a solid dosage form, preferably in the form of tablets, which ensures maximum manufacturability of the subsequent packaging and accuracy of dosing of the active principle.

The present invention also provides a method for producing the inventive combined antihypertensive agent, which is carried out mainly in accordance with known simple technological processes - mixing and calibration. Suspended lisinopril dihydrate, amlodipine besilate, colloidal silicon dioxide and sodium carboxymethyl starch are mixed in a centrifugal paddle mixer. The resulting concentrate is mixed in a powder mixer with microcrystalline cellulose with an average particle size of 90-100 microns and a bulk density of 0.28-0.33 g / ml, then magnesium stearate is powdered. The resulting mixture is calibrated on a vertical granulator. The quantity standardized mixture is tabletted on rotary presses. Get tablets of white or white with a beige shade of the color of a cylindrical shape with a chamfer on both sides and a risk on one side, which are Packed in blisters or plastic containers.

Table 1 shows the options for the claimed composition.

Table 1 Ingredients Content, wt.% Examples one 2 3 Active principle, incl. 8.91 5,0 10.0 Amlodipine Besilate 3.47 1.95 3.89 Lisinopril dihydrate 5.44 3.05 6.11 MCC-102 86.50 93.3 83.5 Silicon Colloidal Dioxide 0.50 0.2 1,0 Magnesium stearate 1.00 0.5 1,5 Sodium carboxymethyl starch 3.09 1,0 4.0

The direct compression method used in the claimed invention is currently the most important and urgent task of pharmaceutical science and production, since the method belongs to one of the most economical technologies for tabletting drugs because of the exclusion of certain technological operations that entail additional costly funds. Due to the reduction in the number of technological operations by 3-4 times, the advantage of direct pressing is obvious. The elimination of wet granulation saves about 80% of the production area, 60% of the costs of granulation, 95% of energy and 75% of the workforce. It should be noted that in the case of direct compression, there are better indicators of the results for the release of active substances. This is due to the fact that tablets made by wet granulation first disintegrate into granules, while direct compression immediately produces smaller particles that are more efficiently absorbed by the body. Also, in the manufacture of tablets by direct compression, the disintegration time of the tablets and the dissolution of the active substance are significantly reduced. Table 2 summarizes the experimental tablet stability test data.

Further, the present invention will be illustrated by means of non-limiting examples.

Example 1

Lisinopril dihydrate (54.4 g), amlodipine besilate (34.7 g), colloidal silicon dioxide (5 g), sodium carboxymethyl starch (30.9 g) are mixed in a paddle mixer for 30 seconds, microcrystalline cellulose (865 g) is added to the resulting concentrate ) and magnesium stearate (10 g) and mixed in a capacitive mixer for 2 minutes, then the mixture is calibrated by sifting through a sieve with a mesh size of 0.5 mm. The mixture is pressed in a laboratory rotary press into tablets weighing 200 mg, round, flat, 8 mm in diameter. The composition of the pharmaceutical composition is presented below:

- lisinopril dihydrate 10.88 mg - amlodipine besilate 6.94 mg microcrystalline cellulose 173.0 mg - colloidal silicon dioxide 1.0 mg - magnesium stearate 2.0 mg - sodium carboxymethyl starch 6.18 mg Total: 200 mg

Dissolution of active substances from tablets is more than 97% (norm is not less than 80%), disintegration is less than 1 minute (norm is not more than 15 minutes), dosage uniformity is 97% -104% (norm 85-115%), tablet compressive strength - 90 kN.

Example 2

Lisinopril dihydrate (0.61 kg), amlodipine besilate (0.39 kg), colloidal silicon dioxide (0.04 kg), sodium carboxymethyl starch (0.20 kg) are mixed in a centrifugal paddle mixer for 30 seconds, microcrystalline cellulose is added to the resulting concentrate (18.86 kg) and magnesium stearate (0.1 kg) and mixed in a drum-type mixer for 5 minutes, then the mixture is calibrated on a vertical granulator through a mesh with a mesh diameter of 1.0 mm. The mixture is pressed in a laboratory rotary press into tablets weighing 100 mg, round, flat, 6 mm in diameter. The composition of the pharmaceutical composition is presented below:

- lisinopril dihydrate 3.05 mg - amlodipine besilate 1.95 mg microcrystalline cellulose 93.3 mg - colloidal silicon dioxide 0.2 mg - magnesium stearate 0.5 mg - sodium carboxymethyl starch 1.0 mg Total: 100 mg

The dissolution of active substances from tablets is more than 98%, disintegration is less than 30 seconds, dosage uniformity is 98% -105%, tablet compressive strength is 50 kN.

Example 3

Lisinopril dihydrate (1.53 kg), amlodipine besilate (0.97 kg), colloidal silicon dioxide (0.25 kg), sodium carboxymethyl starch (1.0 kg) are mixed in a centrifugal paddle mixer for 30 seconds, microcrystalline cellulose is added to the resulting concentrate (20.88 kg) and magnesium stearate (0.37 kg) and mixed in a drum-type mixer for 5 minutes, then the mixture is calibrated on a vertical granulator through a mesh with a mesh diameter of 1.0 mm. The mixture is pressed on a laboratory rotary press into tablets weighing 400 mg, round, flat, 10 mm in diameter. The composition of the pharmaceutical composition is presented below:

- lisinopril dihydrate 24.44 mg - amlodipine besilate 15.56 mg microcrystalline cellulose 334.0 mg - colloidal silicon dioxide 4.0 mg - magnesium stearate 6.0 mg - sodium carboxymethyl starch 16.0 mg Total: 400 mg

The dissolution of active substances from tablets is more than 95%, disintegration is less than 30 seconds, dosage uniformity is 97% -102%, tablet compressive strength is 140 kN.

It should be noted that in the manufacture of tablets with compositions similar to the above examples, where part of the microcrystalline cellulose was replaced with povidone binder in an amount of 2.5% by weight of the mixture and wet granulation was performed, the disintegration time of the tablets increased and ranged from 3 to 6 minutes depending on tablet weight and compression force.

With direct pressing, due to the reduction of operations, the centers of contamination of the finished product are also excluded. It can also be noted that microbial contamination of tablets obtained by direct compression is lower than tablets made from granulate. Table 2 shows the data on the stability of the composition under the conditions of the method of “Tests of stability and determination of the shelf life of drugs”.

table 2 Indicators The rate of impurities,% A tablet containing 10.88 mg of lisinapril dihydrate and 6.94 mg of amlodipine bisilate according to patent EA 010288,% The tablet according to the claimed invention described in Example 1 containing 10.88 mg of lisinapril dihydrate and 6.94 mg of amlodipine bisilate,% Immediately after manufacturing Lisinopril diketopiperazine <1.5 0.12 0.14 Amlodipine Impurity D <0.3 0,07 0.08 Amlodipine total impurities <1.5 0.21 0.15 After 3 months of storage at t = 40 ° C and 75% air humidity Lisinopril diketopiperazine <1.5 0.12 0.12 Amlodipine Impurity D <0.3 0.09 0.08 Amlodipine total impurities <1.5 0.27 0.17 After 6 months of storage at t = 40 ° C and 75% humidity Lisinopril diketopiperazine <1.5 0.18 0.16 Amlodipine Impurity D <0.3 0.17 0.12 Amlodipine total impurities <1.5 0.43 0.16

Comparing stability data, it should be noted that the composition according to the claimed invention contains impurities in an amount close to the known composition according to patent EA 010288, and after a time even less.

The dissolution, disintegration and uniformity of dosage of the inventive combined antihypertensive agent meets the requirements of the European Pharmacopoeia and the State Pharmacopoeia of the Russian Federation.

Claims (8)

1. The combined antihypertensive agent containing, as an active principle, a combination of amlodipine besilate and lisinopril dihydrate mixed with an excipient, characterized in that the antihypertensive agent contains microcrystalline cellulose with an average particle size of 90-100 microns and a bulk density of 0.28-0 , 33 g / ml, and as auxiliary substances - silicon colloidal dioxide, magnesium stearate, sodium carboxymethyl starch in the following ratio of ingredients, wt.%:
Active start 5.0-10.0 Microcrystalline cellulose 83.5-93.3 Silicon Colloidal Dioxide 0.2-1.0 Magnesium stearate 0.5-1.5 Sodium carboxymethyl starch 1.0-4.0 2. The combined antihypertensive agent according to claim 1, characterized in that it contains amlodipine besilate and lisinopril dihydrate, preferably in a ratio of 1: 1.57. 3. The combined antihypertensive agent according to claim 1, characterized in that it contains colloidal silicon dioxide as an antifriction substance. 4. The combined antihypertensive agent according to claim 1, characterized in that it contains magnesium stearate as an antifriction substance. 5. The combined antihypertensive agent according to claim 1, characterized in that it contains sodium carboxymethyl starch as a disintegrant. 6. The tool according to any one of claims 1 to 5, characterized in that it is made in the form of a solid dosage form. 7. The tool according to claim 6, characterized in that it is made in the form of tablets. 8. A method of obtaining a combined antihypertensive agent, as defined in claims 1-7, comprising mixing in a centrifugal paddle mixer suspended suspended lisinopril dihydrate, amlodipine besilate, colloidal silicon dioxide and sodium carboxymethyl starch; mixing in the mixer-dusting agent of the obtained concentrate with microcrystalline cellulose with an average particle size of 90-100 μm and a bulk density of 0.28-0.33 g / ml; dusting the resulting mixture of magnesium with stearate; calibrating the mixture on a vertical granulator, compressing the resulting mixture to obtain tablets and packing the tablets into blisters or plastic containers.