RU2543637C2 - Prolonged antihypertension pharmaceutical composition and method for preparing it - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents a composition in the form of a gelatine capsule possessing the antihypertensive action, containing lisinopril dihydrate granules and verapamil hydrochloride tablets in a ratio of 1:5 to 1:20.

EFFECT: invention refers to a method for preparing this composition, consisting in encasing the lisinopril granules and verapamil tablets into the gelatine capsule that provides the ease of preparing the dosage form, and an acceptable profile of the therapeutic substance release.

2 cl, 2 ex, 4 tbl, 2 dwg

Description

The invention relates to the field of pharmaceutical industry, in particular to pharmaceutical compositions for the manufacture of sustained release solid dosage forms and methods for their preparation.

A study of the drug therapy of arterial hypertension (AH) showed that for the treatment of the disease requires constant use of drugs that must be effective and safe. In this regard, the demand and demand for extended-release drugs (PM) are increasing. Effective drug therapy also involves the appointment of a combination of two antihypertensive drugs - primarily fixed combinations, bypassing the monotherapy stage.

Thus, the priority in the choice of drugs for the treatment of hypertension is given to combined antihypertensive drugs of prolonged action.

Among all kinds of combinations of antihypertensive drugs belonging to various pharmacological groups, not all are suitable for long-term treatment of hypertension. It is believed that one of the rational combinations with a synergistic antihypertensive effect and at the same time good tolerance is a combination of drugs from the groups of angiotensin converting enzyme inhibitors (i-ACE) and calcium antagonists (AK) (Advantages of the combination therapy of arterial hypertension: a new fixed combination angiotensin converting enzyme inhibitor and calcium antagonist / DV Preobrazhensky [et al.] // Cardiology. - 2007. - T.9, No. 11. - S.11-14).

To date, the proportion of foreign-made drugs in the list of combined antihypertensive drugs is 90.5%.

Patents RU 2344816, CZ 286168, CZ 286187, US 5098910, US 5500434, US 5721244, CN 102423482 describe possible combinations of i-ACE with AK.

Currently, only 3 compositions of the studied combination of patents CN 102423482, JP 10182456, WO 9421285 are presented on the pharmaceutical market of Russia.

The authors of the claimed invention proposes the technological development of a new pharmaceutical composition of i-ACE lisinopril and AK verapamil.

As a prototype of the selected dosage form (Pat. HU 211747), consisting of two components: i-ACE - trandolapril and AK - verapamil. The composition is a gelatin capsule in which the granules of i-ACE - trandolapril (2 mg) and tablets AK - verapamil (180 mg) are placed. As auxiliary substances for the manufacture of lisinopril granules the following were used: corn starch (37.15 mg), lactose monohydrate (54.50), povidone (5.35), sodium stearyl fumarate (1 mg). The verapamil tablet contains microcrystalline cellulose (59.10), sodium alginate (240 mg), povidone (36 mg), magnesium stearate (2.40), and purified water (22.50).

The verapamil tablet is coated with a film coating containing the following components: hypromellose (6 mPa - 9.576 mg; 15 mPa - 0.950 mg), hyprolose (7 mPa - 0.944 mg), macrogol 400 (1.485 mg), macrogol 6000 (0.266 mg), talc ( 0.677 mg), colloidal silicon dioxide (0.031 mg), sodium docusate (0.025 mg), titanium dioxide E-171 (2.546 mg).

The disadvantages of the described composition include the fact that the prolonged effect in it is ensured by one tablet of verapamil, which leads to an uneven release and jumps in drug concentrations. The dissolution of one tablet does not allow to maintain a fairly constant concentration of the drug at a therapeutic level without pronounced extremes.

The task of the invention is the development of a domestic combined pharmaceutical composition of i-ACE with AK prolonged action and a method of obtaining a dosage form that allows you to maintain therapeutic concentrations of active substances at a given level for a long time.

The essence of the invention lies in the fact that granules of lisinopril dihydrate and extended-release tablets of verapamil hydrochloride are placed in a gelatin capsule, while the ratio of lisinopril and verapamil in dosage form should be from 1: 5 to 1:20.

The advantages of the proposed combination over imported drugs containing the same therapeutic groups of drugs are less impact on the functional state of the liver and kidneys of patients, as well as the possibility of prescribing it for the treatment of hypertension in patients with obesity.

The authors of the claimed invention developed the composition of the granules of lisinopril. It was taken into account that excipients should provide the necessary flowability, bulk volume, fractional composition of lisinopril granules, and not be related to lactose and its derivatives (Eyjolfsson Reynir. Lisinopril - lactose incompatibility / Eyjolfsson Reynir // Drug Dev. And Ind. Pharm. - 1998. - V.24, No. 8. - P.797-798).

The authors developed the composition of lisinopril granules containing calcium phosphate dihydrate as a filler, and Plasdone K-30 as a binder in the form of a 20% aqueous solution, wt.%:

Lisinopril dihydrate (2.5-10)

Calcium Hydrogen Phosphate Dihydrate (80-85)

Plasdone K-30 (3-6)

Granules are prepared by wet granulation. The sieved calcium hydrogen phosphate dihydrate, lisinopril dihydrate are mixed and a 20% aqueous Plasdone K-30 solution is added, mixed again. The wet mass is granulated and dried at a temperature of 40-50 °. The dried granules are cooled to room temperature and dry granulation is carried out.

The developed lisinopril granules provide the initial antihypertensive effect of the combination, which was confirmed during the Dissolution test.

To create the effect of prolonging the hypotensive effect of the dosage form, the authors of the claimed invention used verapamil hydrochloride tablets, created at different pressing pressure, which were placed in a capsule (table 1).

Compositions 5, 6 have rather high values of flowability, compressibility and bulk density, do not show the likelihood of undesirable effects such as sticking of the substance to the matrix walls, a decrease in its degree of filling, and are most suitable for tableting (Table 2).

Obtained in accordance with the examples and the results of the test for the release of the amount of substance in solution, the pharmaceutical composition for creating verapamil tablets has the following composition, wt.%:

Verapamil Hydrochloride (10-35)

Sodium Alginate (30-70)

MCC Avicel RN-103 (7-20)

Plasdone K-90 (3-10)

Magnesium Stearate (0.2-1)

Tablets meet all the necessary quality indicators included in the regulatory documentation.

The essence of the invention lies in the fact that the use of such a composition of excipients does not lead to the disintegration of the tablets into their constituents, but to their gradual dissolution, and, accordingly, the uniform release of the active substance.

Moistened masses were granulated through a stainless steel mesh with a hole diameter of 2 mm, dried at a temperature of not more than 60 ° C. The dried granules were cooled to room temperature and dry granulation was carried out using a mesh with a hole diameter of 1 mm. Dry granulate was dusted with magnesium powder with stearate. The mixture was mixed to a homogeneous mass and pressed on a manual hydraulic press with a double-concave oblong press tool with a diameter of 4-6 mm using successively increasing pressing pressure.

The essence of the invention lies in the fact that verapamil tablets are obtained in a capsule, obtained with a successively increasing pressing pressure: 25, 50, 75 and 100 MN / m ² . This allows for a uniform release rate of the active substance. In addition, the tablets do not need additional coating.

The “Dissolution” test of prolonged-acting verapamil tablets was performed using a “rotating basket” type instrument. Methodology Wednesday: Stage I - gastric (acidic) medium pH 1.1; Stage II - intestinal environment (phosphate buffer) pH 6.8. The volume of the medium is 800 ml ± 5 ml, the rotation speed is 50 rpm. Analysis technique: spectrophotometric analysis.

The study allowed us to conclude that the tablets provide the necessary delayed release of verapamil into the dissolution medium. Dissolving sequentially, according to the compression pressure used, the tablets maintain the concentration of the active substance at a relatively constant level for a long time.

The release profile of verapamil from the prototype (Fig. 1) is characterized by a significant (about 40%) transition of the substance from the tablet dosage form to the solution within the first two hours of dissolution in an acidic environment, after 6 hours of dissolution in a phosphate buffer medium, almost 100% of the drug substance was dissolved .

A comparative analysis of the dynamics of the release of verapamil into the dissolution medium showed that the total release of verapamil from tablets occurs more slowly than from tablets of the prototype (Fig. 2). This is due to the sequential dissolution of each of the four tablets of the substance that makes up the capsule. The resulting tablets release about 28% of the substance into the acidic medium during the first two hours of dissolution and 87% after 6 hours of dissolution in phosphate buffered saline. Thus, we can conclude that tablets obtained with different compression pressures will provide a more pronounced than the prototype, prolonged release of verapamil.

A comparative analysis of the hypotensive effect of the composition relative to the prototype.

Example 1. Patient Prilutsky G.V. with symptoms of high blood pressure, with concomitant mild obesity, supraventricular tachyarrhythmia, he took the proposed composition 1 capsule 1 time per day in the morning for 30 days.

Example 2. Patient Isaev M.S. also with symptoms of high blood pressure, left ventricular hypertrophy and with high cholesterol in the blood, took 1 capsule of the prototype 1 time a day in the morning for 30 days.

Table 3, 4 presents data on the effect of monthly therapy of the proposed composition and the prototype drug on clinical and laboratory parameters.

As can be seen from the data presented, the antihypertensive effect of the combination exceeds the hypotensive effect of the prototype drug. The content of verapamil in the composition (100 mg) is less than in the prototype (120 mg), 5 mg of lisinopril versus 2 mg of trandolapril. The decrease in blood pressure when taking the composition was accompanied by a decrease in heart rate by 13.9% and 10.5% when taking the prototype drug.

Thus, the proposed composition is superior to the prototype in terms of the effectiveness of the main action.

Table 1 Model controlled-release granulate formulations of verapamil hydrochloride tablets Components Composition number (g / tab.) one 2 3 four 5 6 Drug substance Verapamil 0.1 0.1 0.1 0.1 0.1 0.1 Matrix Sodium Alginate 0.2 0.2 0.2 0.2 MCC Avicel PH-103 0.06 0.06 Hypromellose 15000 0.2 Hypromellose 4000 0.2 Lactose 0.06 0.06 0.06 0.06 Sliding and lubricating agents Magnesium stearate 0.0024 0.0024 Stearic acid 0.002 0.002 0.003 0.003 Binders Plasdone K-30 0,03 Plasdone K-90 0,03 Plasdone S-630 0.004 0.02 Kollidon VA-64 0.004 0.02 Weight 1 tablet 0.366 0.366 0.383 0.386 0.392 0.392

table 2 The results of determining the technological parameters of verapamil granules No. p / p Name of indicator, dimension No. of model granulate one 2 3 four 5 6 one Flowability (g / s) 3.8 4.2 4.8 5,4 7.85 7.12 2 Bulk volume (cm ³ / g) 0.36 0.44 0.53 0.55 0.63 0.62 3 Slope angle (deg. °) 46 42 38 36 35 34 four Compressibility (MN) 32 34 54 61 93 108 5 Ejection pressure from the matrix (MPa) 9.3 8.1 7.2 8.3 5.2 4.7

Table 3 Clinical characteristics of the patient receiving the proposed composition Indicator The initial state Monthly therapy GARDEN, mmHg 154.3 129.4 DBP, mmHg 93.6 78.1 Heart rate, beats / min 76.3 65.7 LDL, mmol / l 3,7 3.2 HDL, mmol / l 0.9 1,2

Table 4 Clinical characteristics of the patient receiving the prototype drug Indicator The initial state Monthly therapy GARDEN, mmHg 156.1 135.5 DBP, mmHg 93.8 80.3 Heart rate, beats / min 74,4 66.7 LDL, mmol / l 3.8 3.3 HDL, mmol / l 0.9 1,1

Claims (2)

1. The composition in the form of a gelatin capsule with antihypertensive effect, characterized in that it contains verapamil hydrochloride tablets of the following composition, wt.%:
verapamil hydrochloride 10-35 sodium alginate 30-70 MCC Avicel PH-103 7-20 Plasdone K-90 3-10 magnesium stearate 0.2-1
and additionally contains granules of lisinopril dihydrate of the following composition, wt.%:
lisinopril dihydrate 2,5-10 calcium hydrogen phosphate dihydrate 80-85 Plasdone K-30 3-6
with a ratio of granules of lisinopril dihydrate and verapamil hydrochloride tablets from 1: 5 to 1:20. 2. The method of obtaining the composition according to claim 1, characterized in that sieved calcium hydrophosphate dihydrate, lisinopril dihydrate are mixed to obtain granules of lisinopril hydrochloride and a 20% aqueous solution of Plasdone K-30 is added, mixed again, then the wet mass is granulated and dried at 40 -50 ° C, the dried granules are cooled to room temperature and dry granulation is carried out, and for the manufacture of verapamil hydrochloride tablets, the moistened components are granulated, dried at a temperature of not more than 60 ° C, the dried granules are azhdayut to room temperature and allowed to dry granulation, then the dry granulate is dusted with a powder of magnesium stearate, the mixture was stirred until a homogeneous mass and pressed on the manual hydraulic press using a receiving sequentially increasing the compacting pressure: 25, 50, 75 and 100 MN / m ^2, then the resultant granules and the tablets are placed in a gelatin capsule.

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