RU2618471C2 - Oral pharmaceutical composition of diuretics and ace inhibitor in micronized form, drug and its application - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention refers to medicine, namely to pharmacy. The pharmaceutical composition contains active ingredients - ramipril (angiotensin-converting enzyme (ACE) inhibitor) and indapamide (sulfonamide diuretic) or pharmaceutically acceptable salts thereof. The active ingredients are in micronized form with average particle size less than 50 microns. The pharmaceutical composition comprises lactose monohydrate, colloidal silicon dioxide and calcium stearate as auxiliary substances. The composition provides a dissolution nature such that at least 80% of the ramipril is released within 45 minutes and at least 80% of indapamide is released within 45 minutes. A hypotensive-effect drug which contains 0.5 - 2.5 mg of indapamide and 1-20 mg of ramipiril is also described. Application of a combined agent containing indapamide and ramipril as a means with cerebral and organ protection properties is also described.

EFFECT: invention allows expansion of the range of domestic drugs with hypotensive effect, with the required characteristics and a shelf life of 5 years.

4 cl, 12 dwg, 16 tbl

Description

The invention relates to medicine, in particular to pharmacy, and can be used in the manufacture of solid combined dosage forms of drugs that have a hypotensive effect on both systolic and diastolic blood pressure, increasing cardiac output and increasing exercise tolerance. The pharmaceutical compositions contain the active ingredients an ACE angiotensin converting enzyme inhibitor (e.g. ramipril) and a diuretic (e.g. indapamide) or their pharmaceutically acceptable salts, the active ingredients being contained in micronized solid form. A micronized mixture of an ACE inhibitor and an ACE diuretic has an average particle size of less than 50 microns. A micronized form is claimed having a specific surface area of at least 20 * 10 ³ cm ² / mg.

In the new recommendations for the treatment of arterial hypertension, RIOAG / GFCF, special attention is paid to the issues of combination therapy as an essential component of success in the prevention of cardiovascular complications. Along with controlling blood pressure, the protection of target organs (blood vessels, heart, brain and kidneys) is one of the most important goals of antihypertensive therapy. In this regard, combination therapy has an advantage compared to monotherapy, which is due to more effective control of blood pressure and organoprotective properties of each drug. One of the rational combinations is the combined use of ACE inhibitors and diuretics. To improve the prognosis of the life of a patient with arterial hypertension, it is important to use not any ACE inhibitors and diuretics, but drugs with a proven ability to prevent cardiovascular catastrophes. To date, the most effective in terms of preventing cardiovascular complications is the combination of an ACE inhibitor ramipril and an indapamide diuretic.

A large randomized study of HOPE and several other studies (PART-2, APRES, etc.) showed that ramipril has cerebro- and cardioprotective effects, which are independent of its antihypertensive effect, in different categories of patients with a high risk of developing cardiovascular complications . In particular, according to the HOPE study, in the group of patients receiving ramipril therapy, the reduction in the relative risk of stroke was 32%, which is an outstanding indicator. A SECURE sub-study showed that ramipril at a prophylactic dose of 10 mg slows the progression of atherosclerosis, and the antiatherosclerotic efficacy of ramipril is not associated with an antihypertensive effect. Based on the available extensive evidence base, it can be argued that this is the only ACE inhibitor that has proven the ability to prolong life in all high-risk patients.

The invention allows to obtain drugs with increased bioavailability and dissolution rate of the active substance.

Indapamide is a drug with hypotensive (diuretic, vasodilator) effects. By pharmacological properties, it is close to thiazide diuretics (violation of Na ⁺ reabsorption in the cortical segment of the Henle loop). Ramipril is an antihypertensive drug belonging to the group of ACE inhibitors. It is intended to maintain the target level of blood pressure in individuals with arterial hypertension.

In medical practice, several different antihypertensive rational combinations are used. The most commonly prescribed of all non-fixed and fixed drug combinations is a combination of a diuretic and an ACE inhibitor. The high efficacy and safety of the combination of an ACE inhibitor and diuretic in the treatment of hypertension was noted in the recommendations of WHO, GFCF, EOG-EOC and JNS-7 (1999, WHO; 2003 ESH; Chobanian AV, Bakris GL, Blorck HR et al., 2003. Recommendations for prevention, diagnosis and treatment of arterial hypertension. Russian recommendations, 2004).

The pharmaceutical composition of ramipril and indapamide (application WO 2008124611), which has a hypotensive effect, was taken as the closest analogue. This dosage form is a capsule containing granules or powder of ramipril, a stabilizer, a hydrolysis-minimizing agent, and an indapamide tablet, which determines the controlled release of the latter. The manufacturing process of the described dosage form is technologically laborious and requires significant economic costs. In addition, a large number of stages of this method leads to mechanical losses.

As another analogue, the drug described in RU 2280450 can be considered. This analogue is a combined preparation (Noliprel) containing an ACE inhibitor perindopril erbumin (representative of the pharmacological group of ramipril) and diuretic indapamide (chlorosulfamoyl derivative). 1 tablet of the drug contains perindopril erbumin 0.6-6.6 mg and indapamide 0.1-2.1 mg as active substances. Excipients: microcrystalline cellulose, magnesium stearate, aerosil, croscarmellose sodium, milk sugar. The pharmacological effect is due to a combination of the individual properties of each component, as well as their synergism. The pronounced antihypertensive effect is associated with the synergism between perindopril and indapamide. Thus, it seems advisable to search for a new combination drug containing an ACE inhibitor and a diuretic that are superior in magnitude to the induced antihypertensive effect.

There is also a method for producing a drug having a hypotensive effect and containing indapamide as the active substance by mixing the active substance with milk sugar, microcrystalline cellulose, starch glycolate, granulation, drying, dry granulation, dusting with magnesium stearate and tabletting (application RU 2003103482). The disadvantages of the described method for manufacturing a dosage form include the fact that it leads to mechanical losses and a change in the properties of the active substance in the process of technological operations following mixing.

Oral administration is the most preferred route for administering pharmaceuticals, as this method is particularly convenient and acceptable for patients. However, obtaining a solid oral dosage form having all the necessary characteristics sometimes poses a serious problem for a person skilled in the art of preparing pharmaceutical compositions. In order for the substance to be effective, it must reach appropriate concentrations in the bloodstream of the patient within an acceptable time after administration. In other words, the substance must have acceptable bioavailability. A very important factor affecting the bioavailability of a substance after oral administration is dissolution, i.e. the dissolution rate of the substance, in particular in the gastric fluid. It is believed that the dissolution of the solid dosage form of this invention should be at least 75% in 45 minutes in 0.1 N HCl at 37 ° C. The specified test methodology is similar to the test methods mentioned in the official pharmacopoeia, for example, U.S. Pharmacopaeia XXII.

The person skilled in the art of developing pharmaceutical compositions is faced with the problem of preparing a solid dosage form suitable for oral administration, so that the active substances have an acceptable dissolution. In addition, the developed pharmaceutical composition must be obtained on an industrial scale and must meet the requirements for internal and external quality control.

The objective of the invention is the creation of a combined drug in solid dosage form (tablets, capsules, pellets) based on a combination of a diuretic and an ACE inhibitor, where these active substances are in micronized form. The specified drug has an acceptable dissolution and provides a high bioavailability of the active substances, as well as the creation of a technologically affordable method of manufacturing a combined preparation that reduces the mechanical loss of the active substance and allows you to save its properties unchanged.

Oral use of an ACE inhibitor (ramipril, enalapril, perindopril, lisinopril, fosinopril) and a diuretic (from the group indapamide, chlortiazide, methiclotiazide, bendroflumethiazide, chlortalidone, metolazone and hydrochlorothiazide) interferes with its poor crystalline form, when it is in its normal form that leads to a decrease in the bioavailability of active substances. The addition of additional auxiliary substances (surfactants, disintegrant, etc.) that improve the dissolution process, upon receipt of the required solid dosage form did not lead to the required dissolution character. In the course of studies aimed at improving the bioavailability of an ACE inhibitor and diuretic, the products were subjected to fine grinding (micronization) to obtain particles with an average size of less than 50 microns. Micronization of the active substances made it possible to achieve the required dissolution with a minimum amount of auxiliary components (see a comparison of the compositions with micronized and non-micronized forms of substances in tables 1-14 and figures 1-12).

Table 1 Composition 1 Component Name Amount mg Note Ramipril 5.00 nemikroniz. substance Indapamide 1.25 nemikroniz. substance Lactose Monohydrate 139.50 Polysorbate-80 1,50

Silicon Colloidal Dioxide 1,50 Calcium stearate 1,50 The mass of the contents of the capsule: 150.00

table 2 Kinetics of dissolution of the composition 1 Dissolution time, min 5 10 fifteen twenty 25 thirty 35 40 45 The amount of released indapamide,% 28.1 40.6 47.4 53.0 56.2 59.3 60.5 61.8 62,4 The amount of ramipril released,% 32.1 46.3 54,2 60.6 64,2 67.7 69.2 70.6 71.3

Table 3 Composition 2 Component Name Amount mg Note Ramipril 5.00 nemikroniz. substance Indapamide 1.25 nemikroniz. substance Lactose Monohydrate 139.50 Sodium Lauryl Sulfate 1,50 Silicon Colloidal Dioxide 1,50 Calcium stearate 1,50 The mass of the contents of the capsule: 150.00

Table 4 Kinetics of dissolution of the composition 2 Dissolution time, min 5 10 fifteen twenty 25 thirty 35 40 45 The amount of released indapamide,% 34.8 50,2 58.7 65.7 69.6 73,4 75.1 76.5 77.3 The amount of ramipril released,% 32,4 46.7 54.6 61.1 64.7 68.3 69.7 71.2 71.9

Table 5 Composition 3 Component Name Amount mg Note Ramipril 5.00 nemikroniz. substance Indapamide 1.25 nemikroniz. substance Lactose Monohydrate 139.50 Croscarmellose sodium 1,50 Silicon Colloidal Dioxide 1,50 Calcium stearate 1,50 The mass of the contents of the capsule: 150.00

Table 6 Kinetics of dissolution of the composition 3 Dissolution time, min 5 10 fifteen twenty 25 thirty 35 40 45 The amount of released indapamide,% 25.8 37,2 43.5 48.7 51.6 54,4 55.6 56.7 57.3 The amount of ramipril released,% 28.3 40.8 47.7 53,4 56.5 59.7 60.9 62,2 62.8

Table 7 Composition 4 Component Name Amount mg Note Ramipril 5.00 nemikroniz. substance Indapamide 1.25 nemikroniz. substance Lactose Monohydrate 131.75 Sodium Starch Glycolate 9.00 Silicon Colloidal Dioxide 1,50 Calcium stearate 1,50 The mass of the contents of the capsule: 150.00

Table 8 Kinetics of dissolution of the composition 4 Dissolution time, min 5 10 fifteen twenty 25 thirty 35 40 45 The amount of released indapamide,% 30.6 44.3 51.8 57.9 61.3 64.7 66.1 67.4 68.1 The amount of ramipril released,% 33.8 48.8 57.1 63.8 67.6 71.3 72.8 74.3 75.1

Table 9 Composition 5 Component Name Amount mg Note Ramipril 5.00 nemikroniz. substance Indapamide 1.25 nemikroniz. substance Lactose Monohydrate 83.75 Povidone 5.00 Crospovidone 3.00 Silicon Colloidal Dioxide 1.00 Calcium stearate 1.00 Tablet weight: 100.0

Table 10 Kinetics of dissolution of the composition 5 Dissolution time, min 5 10 fifteen twenty 25 thirty 35 40 45 The amount of released indapamide,% 32,4 46.9 54.8 61.3 64.9 68.5 69.9 71,4 72.1 The amount of ramipril released,% 29.4 42.5 49.7 55.6 58.9 62.1 63,4 64.7 65,4

Table 11 Composition 6 Component Name Amount mg Note Ramipril 5.00 nemikroniz. substance Indapamide 1.25 nemikroniz. substance Lactose Monohydrate 68.75 Pregelatinized Starch 20.00 Hydroxypropyl cellulose 3.00 Silicon Colloidal Dioxide 1.00 Calcium stearate 1.00 Tablet weight: 100.0

Table 12 Kinetics of dissolution of the composition 6 Dissolution time, min 5 10 fifteen twenty 25 thirty 35 40 45 The amount of released indapamide,% 31,2 45.0 52.7 58.9 62,4 65.8 67.2 68.6 69.3 The amount of ramipril released,% 32.3 46.7 54.6 61.0 64.6 68,2 69.6 71.1 71.8

Table 13 Composition 7 Component Name Amount mg Note Ramipril 5.00 micronysis. substance Indapamide 1.25 micronysis. substance Lactose Monohydrate 139.50 Silicon Colloidal Dioxide 1,50 Calcium stearate 1,50 The mass of the contents of the capsule: 150.00

Table 14 Kinetics of dissolution of the composition 7 Dissolution time, min 5 10 fifteen twenty 25 thirty 35 40 45 The amount of released indapamide,% 43.8 63,2 73.9 82.7 87.6 92.4 94.4 96.3 97.4 The amount of ramipril released,% 44.6 64,4 75.3 84.2 89.2 94.4 96.1 98.2 99.1

The invention consists in the following. The proposed drug is a composition containing an ACE inhibitor and a diuretic in micronized form. The ACE inhibitor is selected from the group of ramipril, enalapril, perindopril, lisinopril, fosinopril. The diuretic is selected from the group indapamide, chlortiazide, methiclotiazide, bendroflumethiazide, chlortalidone, metolazone and hydrochlorothiazide. A preferred embodiment of the invention is a medicament comprising an ACE inhibitor and a diuretic in micronized form, where ramipril is used as an ACE inhibitor and indapamide is used as a diuretic. When comparing the results of the PROGRESS, PATS and HYVET studies, it becomes obvious that the diuretic indapamide has a cerebroprotective effect in patients who have suffered a cerebrovascular accident. In particular, in the PROGRESS study, in patients with controlled blood pressure levels who had a stroke or transient ischemic attack, combination therapy with perindopril and indapamide reduced the likelihood of recurrent stroke by 30-40%, and according to the PATS study, a decrease in blood pressure under the influence of indapamide was accompanied by a decrease in risk recurrence of stroke by 29%. The final results of the HYVET study showed a significant reduction in the risk of fatal strokes by 39% during treatment with indapamide in elderly patients. Thus, the combination of ramipril and indapamide in micronized form, each of which has a proven ability to maximally prevent cardiovascular disasters in high-risk patients, increases the bioavailability of each component and, thus, further enhances their cerebro and organ protective properties.

The technical result of the invention is to provide the introduction of the second active substance - an ACE inhibitor (for example, ramipril) - with insignificant losses in the manufacture of the product and maintaining its properties unchanged while ensuring high bioavailability of the active substances due to their micronization.

Micronized forms of an ACE inhibitor and a diuretic can be obtained using the fine grinding methods known in the art, for example, by grinding in appropriate mills and sieving through appropriate sieves.

The specific surface area of these finely divided substances should be at least about 20 * 10 ³ cm ² / g (2.0 * 10 ³ m ² / kg), preferably the specific surface should be more than 25 * 10 ³ cm ² / g (2 5 * 10 ³ m ² / kg), more preferably more than 28 * 103 cm ² / g (2.8 * 103 m ² / kg), and most preferably more than 31 * 10 ³ cm ² / g (3, 1 * 103 m ² / kg).

According to this invention, the characteristics of the finely divided ACE inhibitor and diuretic are as follows: the micronized form of the active components has an average particle size of less than 50 microns. In the best case, the particles can have a size of 30 microns.

The composition of the invention may include pharmaceutically acceptable carriers and diluents, such as excipients, for example, lactose, sucrose, mannitol, maize starch, microcrystalline cellulose or calcium acid phosphate; lubricants, for example stearic acid, polyethylene glycol, magnesium stearate, talc or silica; disintegrants, e.g. rice, potato or maize starch, sodium starch glycolate or croscarmellose sodium (i.e. sodium carboxymethyl cellulose); binding agents, for example, pregelatinized rice starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose; and wetting agents, for example sodium dioctyl sulfosuccinate and polysorbates.

Also, excipients of interest are lactose, sucrose or microcrystalline cellulose; lactose and microcrystalline cellulose are preferred. Lubricants of interest are stearic acid, polyethylene glycol, hydrogenated vegetable oil, sodium stearyl fumarate or magnesium stearate, preferably magnesium stearate. Disintegrators of interest are rice, potato or maize starch, croscarmellose sodium is preferred. A preferred binder is hydroxypropyl methylcellulose.

The composition according to the invention exhibits solubility characteristics such that at least 80% of the diuretic is released within 45 minutes and at least 80% of the ACE inhibitor is released within 45 minutes. With such data on the dissolution kinetics of the composition, the time to reach the maximum concentration of active components in the plasma is from 0.5 to 4 hours. The composition according to this invention detects the maximum concentration of indapamide in the plasma C _max from 0.01 μg / ml to 10 μg / ml, and ramipril - C _max from 0.01 μg / ml to 10 μg / ml.

The technical result is also achieved by a method of manufacturing a drug having a hypotensive effect, according to which the active components are preliminarily finely ground (micronized), sieved, then an ACE inhibitor and a diuretic, lactose, silicon dioxide colloidal (aerosil) are mixed, wet granulation, drying are carried out , the granulate is dusted with a mixture of silicon dioxide colloidal (aerosil) and calcium stearate and the resulting pharmaceutical composition is packaged in hard gelatin to capsules. Examples of compositions are presented in tables 15, 16.

The combined introduction of micronized forms of indapamide and ramipril as part of one drug contributes to:

- a significant increase in the time to reach the maximum concentration of indapamide by 1.2 times;

- a significant increase in the level of maximum ramipril concentration by 1.3 times;

- a significant increase in the area under the ramipril curve by 1.2 times;

- a significant decrease in clearance of ramipril 1.3 times;

- a significant decrease in the distribution volume of ramipril by 1.3 times.

Claims (6)

1. An oral pharmaceutical composition containing a combination of ramipril and indapamide and pharmaceutically acceptable excipients, characterized in that ramipril and indapamide are in micronized form with a particle size of less than 50 microns, and as pharmaceutically acceptable excipients it contains lactose monohydrate, colloidal silicon dioxide, calcium stearate and exhibits a dissolution pattern such that at least 80% of ramipril is released within 45 minutes and at least 80% of indapamide releases for 45 minutes 2. The oral pharmaceutical composition according to claim 1, characterized in that the micronized form of ramipril and indapamide has a specific surface area of at least 20 * 10 ³ cm ² / mg. 3. Antihypertensive drug containing an oral pharmaceutical composition according to any one of paragraphs. 1 and 2, characterized in that it contains ramipril and indapamide in an amount, mg:                 Indapamide 0.5 - 2.5                 Ramipril 1 - 20. 4. The use of a medicinal product according to any one of paragraphs. 1-3 as a means of cerebro-and organoprotective properties.

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