Composition for treatment of cardiovascular diseases

Abstract

FIELD: pharmaceutical industry.SUBSTANCE: pharmaceutical composition for the treatment of cardiovascular diseases, made in the form of a tablet, comprising a core coated with a shell, wherein the core contains 1.5 mg of indapamide, a cellulose polymer and core fillers, and the shell contains from 2 to 32 mg of candesartan cilexetil, a non-ionic surfactant and shell fillers, wherein the weight of the pharmaceutical composition is from 200 to 450 mg.EFFECT: creation of an effective combined composition of candesartan and indapamide, which is not inferior in bioavailability to mono-preparations, while indapamide is in a slow-release form, and candesartan in an immediate-release form, and such a composition is obtained by inexpensive methods and has high stability (i.e., does not form impurities, especially carcinogenic ones, during production / storage).9 cl, 2 dwg, 14 tbl, 7 ex

Description

[0001] Field of technology to which the invention relates

[0002] The invention pertains to the chemical and pharmaceutical industry and concerns a pharmaceutical composition containing indapamide and candesartan cilexetil as active ingredients. The pharmaceutical composition is formulated as a solid pharmaceutical dosage form for oral administration, comprising a core and a shell, wherein the core contains indapamide and excipients for the prolonged release of indapamide, and the shell contains candesartan cilexetil. This composition can be used to treat cardiovascular diseases and expands the arsenal of treatments for these conditions. The developed composition is also characterized by an effective treatment profile, ease of use, reduced side effects, a reduced amount of impurities, high stability, and cost-effective production.

[0003] Technology Level

[0004] Arterial hypertension (AH) is a chronic condition characterized by persistently elevated blood pressure (BP) above 140 / 90 mmHg. It is one of the most common and dangerous cardiovascular diseases, which can lead to serious complications, including stroke, myocardial infarction, heart failure, and chronic kidney disease.

[0005] The prevalence of arterial hypertension worldwide is very high. According to the World Health Organization (WHO), more than 1 billion people (1.28 billion as of 2023) worldwide suffer from hypertension, representing approximately 26% of the global adult population. In Russia, according to Rosstat, hypertension affects over 40% of the adult population.

[0006] Arterial hypertension is one of the leading causes of death worldwide. According to the WHO, hypertension causes the death of approximately 9.4 million people annually, accounting for approximately 17% of all deaths worldwide. In Russia, hypertension causes the death of approximately 700,000 people annually.

[0007] According to the latest studies (see the articles by Samorodskaya I.V. et al. “Mortality from arterial hypertension in the regions of the Russian Federation in the period from 2013 to 2019”, Cardiology 2021, 61(12):59-65, Dolgalev I.V. et al. “Arterial hypertension as a risk factor for death in men and women 20-59 years old: a 34-year cohort prospective study” Cardiovascular Therapy and Prevention 2023, 22(8):3602), in Russia, hypertension significantly increases the risk of death among men by 1.4 times, and among women - by 2.5 times.

[0008] The impact of hypertension on human mortality is due to its ability to cause serious complications, including:

[0009] • Stroke: Hypertension is the leading cause of stroke, which can lead to death or disability.

[0010] • Myocardial infarction: Hypertension can lead to myocardial infarction, which can be life-threatening.

[0011] • Heart failure: Hypertension can lead to heart failure, which can be chronic and progressive.

[0012] • Chronic kidney disease: Hypertension can lead to chronic kidney disease, which may require dialysis or kidney transplant.

[0013] Prevention and treatment of arterial hypertension involves lifestyle changes, including:

[0014] • Reducing salt intake

[0015] • Increase physical activity

[0016] • Weight loss

[0017] • Reducing alcohol consumption

[0018] • Quitting smoking.

[0019] In addition, medications may be prescribed to help control blood pressure and reduce the risk of complications.

[0020]

[0021] The above formula shows that blood pressure depends on cardiac output, vascular resistance, and vascular wall area. Treatment of hypertension is aimed at reducing these factors and controlling blood pressure.

[0022] Treatment of arterial hypertension involves the use of various classes of drugs, each with its own mechanisms of action and indications. Here are the main classes of drugs used to treat hypertension:

[0023] 1. Diuretics:

[0024] - These drugs help the body get rid of excess fluid and salt, which reduces blood volume and, consequently, blood pressure.

[0025] - Examples: hydrochlorothiazide, furosemide, indapamide.

[0026] 2. Beta-blockers:

[0027] - They reduce the heart rate and the force of heart contractions, which helps lower blood pressure.

[0028] - Examples: atenolol, metoprolol, bisoprolol.

[0029] 3. Angiotensin-converting enzyme (ACE) inhibitors:

[0030] - These drugs block the conversion of angiotensin I to angiotensin II, which leads to dilation of blood vessels and a decrease in pressure.

[0031] - Examples: enalapril, lisinopril, ramipril.

[0032] 4. Angiotensin II receptor blockers (ARBs):

[0033] - They act directly on angiotensin II receptors, promoting vasodilation.

[0034] - Examples: losartan, valsartan, candesartan.

[0035] 5. Calcium antagonists:

[0036] - These drugs relax the smooth muscles of blood vessels, which leads to a decrease in vascular resistance.

[0037] - Examples: amlodipine, nifedipine, diltiazem.

[0038] 6. Alpha blockers:

[0039] - They block alpha-adrenergic receptors, which leads to relaxation of blood vessels and a decrease in pressure.

[0040] - Examples: doxazosin, terazosin.

[0041] 7. Central agonists:

[0042] - These drugs act on the central nervous system, reducing sympathetic activity and lowering blood pressure.

[0043] - Examples: clonidine, methyldopa.

[0044] 8. Combination drugs:

[0045] Some medications contain combinations of different classes, which can improve blood pressure control and reduce the number of pills taken.

[0046] - Examples of effective combinations: combinations of beta-blockers with diuretics or ACE inhibitors, combinations of angiotensin II receptor blockers with diuretics.

[0047] Each patient is unique, and the choice of drug or combination depends on a number of factors, including comorbidities, age, gender, and individual tolerance. It is important that treatment is prescribed by a physician who can consider all these factors and monitor the effectiveness of therapy. Therefore, there is a constant need for new solutions for the treatment of cardiovascular diseases, particularly combination drugs that promote more effective blood pressure control and are characterized by improved adherence (once-daily dosing).

[0048] Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the primary pressor agent of the renin-angiotensin system. Its effects include vasoconstriction, stimulation of aldosterone synthesis and release, cardiac stimulation, and renal sodium reabsorption. Angiotensin II helps maintain constant blood pressure despite fluctuations in a person's hydration status, sodium intake, and other physiological variables. Angiotensin II also performs regulatory functions by inhibiting renal sodium excretion, inhibiting norephedrine reuptake, and stimulating aldosterone biosynthesis. For this reason, angiotensin II receptor antagonists have found widespread use among various categories of patients with cardiovascular diseases.

[0049] Candesartan is a potent, long-acting, selective angiotensin II receptor antagonist of the ATi subtype. Candesartan is a useful therapeutic agent for the treatment of circulatory diseases such as hypertension, cardiac diseases (e.g., hypercardia, heart failure, myocardial infarction, etc.), stroke, cerebral apoplexy, and nephritis, among others. Candesartan meets the requirement for high potency, but it is poorly absorbed after oral administration. Therefore, a prodrug of candesartan, cilexetil, was developed. Upon absorption from the gastrointestinal tract, candesartan cilexetil is rapidly and completely hydrolyzed to candesartan. The chemical name of candesartan is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid.The chemical name of candesartan cilexetil is (±)-l-[[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-l-[[2'-(lH-tetrazol-5-yl)[l,l-biphenyl]-4-yl]methyl]-lH-benzimidazole-7-carboxylate.

[0050] The structural formulas of these compounds are presented below.

[0051] Candesartan formula Candesartan cilexetil formula

[0052] Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to ATi receptors in many tissues, such as vascular smooth muscle and the adrenal glands. By inhibiting the binding of angiotensin II to ATi receptors, candesartan disrupts ATi-mediated vasoconstriction. Blocking vasoconstriction by angiotensin II has been found to have a beneficial effect on patients with hypertension. Thus, the US Food and Drug Administration (FDA) has approved candesartan for the treatment of hypertension, both alone and in combination with other antihypertensive agents. Candesartan cilexetil (the active prodrug form of candesartan) is sold in the United States and many other countries around the world (including Russia) under the trade names Atacand, Candecor, Ordiss, Hyposart, and others.The original Atacanda tablets contain candesartan cilexetil and the following excipients: hydroxypropyl cellulose, polyethylene glycol, lactose, corn starch, calcium carboxymethylcellulose and magnesium stearate.

[0053] Candesartan, due to its long-acting nature, has proven to be particularly effective in various combination drugs that allow patients to successfully combat cardiovascular diseases, control blood pressure, and reduce the risk of complications of cardiovascular diseases and the occurrence of adverse reactions.

[0054] Among the combination drugs for the treatment of cardiovascular diseases, the combination of angiotensin II receptor blockers with diuretics is very common, especially the combination of candesartan with hydrochlorothiazide (see the articles Melian EB et. al., “Candesatan cilexetil plus hydrochlorothiazide combination: a review of its use in hypertension”, Drugs, 2002, 62(5):787-816; Karlson BW et. al., “A dose-response analysis of candesartan-hydrochlorothiazide combination therapy in patients with hypertension”, Blood Pressure, 2009, 18(3):149-156). On the Russian market, the combination of candesartan with hydrochlorothiazide is represented by the drugs Atacand Plus, Hyposart N, Ordiss N, Candecor N.

[0055] Despite the positive experience of using the combination of candesartan and hydrochlorothiazide, it has a number of disadvantages. Hydrochlorothiazide often causes pain in the upper gastrointestinal tract. In addition, among diuretics, hydrochlorothiazide is inferior to indapamide in terms of blood pressure lowering efficacy (see the article by Roush GC et. al., “Head-to-head comparisons of Hydrochlorothiazide with indapamide and chlorthalidone: antihypertensive and metabolic effects,” Hypertension, 2015, 65(5):1041-1046). In this regard, from a medical point of view, there is a need to create compositions of candesartan with indapamide, since their effectiveness in the treatment of cardiovascular diseases is expected to be higher than the compositions of candesartan and hydrochlorothiazide known on the market.

[0056] The combination of candesartan with indapamide was first proposed in Chinese patent application CN 1493284, published on 05.05.2004. However, the combination of candesartan with indapamide was not directly disclosed in the examples of the said application.

[0057] The first formulation combining candesartan and indapamide was developed by Krka and described in European Patent Application EP 4374855, published on May 29, 2024. This application discloses a solid pharmaceutical dosage form for oral administration comprising an intragranular phase containing candesartan cilexetil and an extragranular phase containing indapamide. The dosage form is an immediate-release formulation.

[0058] The disadvantage of the above-described dosage form is that it is an immediate-release form of drugs. In this form, indapamide is less effective in lowering blood pressure and also produces more side effects than if indapamide were in an extended-release form (see the article Robinson DM et. al., “Indapamide sustained release: a review of its use in the treatment of hypertension”, Drugs, 2006, 66(2):257-271). In this regard, there is a need to create a finished dosage form of candesartan and indapamide, in which candesartan is in an immediate-release form (due to its long action in an extended-release form, it will simply be ineffective), and indapamide in an extended-release form.

[0059] At the same time, the creation of combination dosage forms is always complicated by the formation of impurities, which are exacerbated by the combination of active compounds and excipients required for each of the active compounds in the combination dosage form. According to international patent application WO2017116150, published July 6, 2017, when candesartan is combined with other active compounds, the amount of the impurity desethyl candesartan very often increases. When indapamide is combined with other active compounds and during storage of such compositions, the formation of the carcinogenic nitroso impurity indapamide greatly increases (see Chinese patent application CN114594174, published June 7, 2022).

[0060] In European patent application EP4373474, published on 29 May 2024, Krka succeeded in creating a bilayer tablet containing an immediate-release layer of telmisartan (like candesartan, an angiotensin II receptor antagonist) and a sustained-release layer of indapamide. The disadvantage of this tablet is the complexity and high cost of the production technology. In fact, three tablets have to be produced: first, separate tablets of telmisartan and indapamide, and then combined into a single bilayer tablet. In addition, the tablet layers are formed using water (wet granulation), which enhances the formation of impurities, especially nitroso impurities (see Chinese patent application CN114594174, published on 07 June 2022).

[0061] Therefore, there is a need in the art for an effective combination formulation of candesartan and indapamide that is equal to (and preferably superior to) the bioavailability of the individual drugs, with indapamide in a sustained-release form and candesartan in an immediate-release form. Moreover, such a combination should be produced using inexpensive methods and be highly stable (i.e., not form impurities, especially carcinogenic ones, during production and storage). The present invention addresses this need.

[0062] Disclosure of invention

[0063] In the present invention, the inventors have unexpectedly discovered that by incorporating indapamide into a core composition along with cellulose polymers and suitable excipients, followed by coating the core with a shell comprising candesartan cilexetil, a non-ionic surfactant, and suitable excipients, a composition of immediate-release candesartan cilexetil and sustained-release indapamide candesartan cilexetil candesartan cilexetil, expanding the arsenal of agents and methods for the effective treatment of cardiovascular diseases. Moreover, such a composition is characterized by the bioavailability of candesartan cilexetil and indapamide no less than that of immediate-release candesartan cilexetil and sustained-release indapamide, which significantly contributes to treatment adherence.Moreover, such a composition is characterized by high stability and low content of specific impurities both after production and after long-term storage.

[0064] Thus, the present invention is directed to a pharmaceutical composition for the treatment of cardiovascular diseases, made in a solid pharmaceutical dosage form for oral use, comprising a core coated with a shell, wherein the core constitutes from 41.67 to 83.3% of the composition weight and contains 1.5 mg of indapamide, from 14 to 31% of the composition weight of a cellulose polymer and core fillers - the rest, the shell constitutes from 16.7 to 58.33% of the composition weight and contains from 2 to 32 mg of candesartan cilexetil, from 0.3 to 5.4% of the composition weight of a non-ionic surfactant, shell fillers - the rest, and the weight of the pharmaceutical composition is from 200 to 450 mg.

[0065] In one embodiment of the invention, the composition contains conventional pharmaceutically acceptable excipients adopted in the technology of preparing dosage forms (including cores and shells of dosage forms), such as binders, fillers, preservatives, flow regulators, softeners, wetting agents, dispersants, emulsifiers, solvents, antioxidants, plasticizers, action prolongators (Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991; “Handbook of Pharmaceutical Excipients”, Pharmaceutical Press, 6 th edition, 2009).

[0066] In another embodiment of the invention, the core of the composition as a cellulose polymer contains hydroxypropyl cellulose or hydroxypropyl methylcellulose and is made by a method without using water, selected from direct compression and dry granulation.

[0067] In a preferred embodiment of the invention, the shell of the composition as a non-ionic surfactant contains a surfactant selected from the group consisting of poloxamer 188, poloxamer 407, poloxamer 124, poloxamer 237, poloxamer 338, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauroyl polyoxyl-32 glyceride, hydrogenated triglycerides C 12 -WITH 18 and their mixtures.

[0068] In another preferred embodiment of the invention, the core composition contains, as core fillers, from 25.17 to 61.2% by weight of the filler composition selected from the group consisting of lactose, microcrystalline cellulose, starch, pregelatinized starch, sucrose, glucose, calcium hydrogen phosphate, microcrystalline cellulose, sorbitol, mannitol, pectin, dextrin, sodium starch glycolate and mixtures thereof, from 1.8 to 6% by weight of the binder composition selected from the group consisting of methylcellulose, sodium carboxymethylcellulose, povidone, natural gums, polyvinyl alcohol, sodium alginate, hydroxypropyl methylcellulose, carboxymethylcellulose and mixtures thereof, as well as from 0.2 to 2% by weight of the lubricant composition selected from the group consisting of starches, talc, silicon Colloidal dioxide, macrogol 4000, macrogol 6000, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium lauryl sulfate and mixtures thereof.

[0069] In the most preferred embodiment of the invention, the shell of the composition contains from 15.3 to 42.1% by weight of the composition a finished film coating selected from Opadry white 03F280065, Opadry II white 85F18422, Opadry II white 85G568918, or as shell fillers, the shell contains from 11.5 to 28.5% by weight of the composition of a film-forming agent selected from the group consisting of hypromellose, polyvinyl alcohol, polyvinyl acetate, ethylcellulose, from 2 to 5.5% by weight of the composition of a lubricant selected from the group consisting of talc, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate and mixtures thereof, from 1 to 5.1% by weight of the composition of a plasticizer selected from the group consisting of glycerol, triacetin, polyethylene glycols (macrogols), triethyl phthalate and mixtures thereof, from 0.8 to 3% by weight of the composition of a dye selected from titanium dioxide, colored aluminum lakes, yellow iron oxide (III), red iron oxide (III) and mixtures thereof.

[0070] Brief description of figures and drawings

[0071] Figure 1 shows the average bioavailability profiles (area under the graph of the drug concentration (ng / ml) in blood plasma versus time) of indapamide when taking the combination drug according to Example 1 of the present invention and the monodrugs Atacand® and Arifon® retard after meals.

[0072] Figure 2 shows the average bioavailability profiles (area under the graph of the drug concentration (ng / ml) in blood plasma versus time) of candesartan cilexetil when taking the combination drug according to Example 1 of the present invention and the monodrugs Atacand® and Arifon® retard after meals.

[0073] Implementation of the invention

[0074] The claimed invention relates to a composition of indapamide and candesartan cilexetil, characterized by a bioavailability of candesartan cilexetil and indapamide no less than that of immediate-release candesartan cilexetil and sustained-release indapamide. The use of such a combination composition for the treatment of cardiovascular diseases significantly improves treatment adherence compared to the use of the individual drugs. Furthermore, such a composition is characterized by high stability and low levels of specific impurities both after production and after long-term storage.

[0075] The implementation of the present invention consists in placing indapamide in the core of the composition together with cellulose polymers and suitable fillers, followed by coating this core with a shell in which candesartan cilexetil, a non-ionic surfactant and suitable fillers are included, which makes it possible to obtain a composition of candesartan cilexetil with immediate release, and indapamide with delayed release, expanding the arsenal of means and methods for the effective treatment of cardiovascular diseases.

[0076] This invention relates to a composition for treating cardiovascular diseases, made in a solid pharmaceutical dosage form for oral use, comprising a core coated with a shell, wherein the core constitutes from 41.67 to 83.3% of the composition weight and contains 1.5 mg of indapamide, from 14 to 31% of the composition weight of a cellulose polymer and core fillers - the rest, the shell constitutes from 16.7 to 58.33% of the composition weight and contains from 2 to 32 mg of candesartan cilexetil, from 0.3 to 5.4% of the composition weight of a non-ionic surfactant, shell fillers - the rest, and the weight of the pharmaceutical composition is from 200 to 450 mg.

[0077] According to WHO statistics, arterial hypertension is the most common cardiovascular disease, which over time contributes to the development of other cardiovascular diseases, including coronary heart disease, heart failure, cerebrovascular disease, acquired heart defects, and others. Therefore, the composition of the present invention is primarily aimed at the treatment of arterial hypertension.

[0078] According to OFS 1.4.1.0001.15 "Dosage Forms," ​​solid pharmaceutical dosage forms for oral use include tablets, granules, dragees, lozenges, candies, minitablets, and pellets. Preferably, the composition of the present invention is in the form of tablets, granules, dragees, minitablets, and pellets. Most preferably, the composition of the present invention is in the form of tablets.

[0079] The composition of the present invention in the form of a solid pharmaceutical dosage form for oral use can be prepared using conventional technologies for the manufacture of dosage forms (see V.A. Grossman, "Technology of Manufacturing Dosage Forms," ​​textbook, Moscow: GEOTAR-Media, 2018, 336 p.). The inventors of the present invention unexpectedly discovered that the exclusion of water when working with indapamide significantly reduces the formation of indapamide-related impurities. In this regard, it is preferable that the composition of the present invention, especially the core of the composition, be prepared without the use of water. Preferably, the core of the composition of the present invention is obtained by dry granulation or direct compression.

[0080] According to recent studies published in the article by Hummler H. et al., “Impact of Tablet Size and Shape on the Swallowability in Older Adults,” Pharmaceuticals 2023, 15(4), 1042, the weight of an oral composition for chronic use by elderly patients should be less than 500 mg. Compositions less than 500 mg are easily swallowed by elderly patients without causing discomfort or disruption to daily treatment adherence. Compositions of about 250 mg are more preferable for long-term use by elderly patients. Taking into account the above studies, as well as the fact that the main patients with cardiovascular diseases are elderly people, the weight of the composition of the present invention ranges from 200 to 450 mg. This range of composition weights will contribute to higher adherence to daily treatment among patients.

[0081] The inventors have found that the composition of the present invention, consisting of a core and a shell, can be obtained and has suitable physicochemical properties of a solid pharmaceutical dosage form for oral use (hardness, disintegration, solubility) with a core weight of 41.67 to 83.3% of the composition weight and a shell weight of 16.7 to 58.33% of the composition weight. When the core weight is less than 41.67% of the composition weight, the composition itself has unsatisfactory hardness for a solid pharmaceutical dosage form for oral use. When the core weight is more than 83.3%, the bioavailability of the active substances deteriorates, which does not allow obtaining a composition with the bioavailability of candesartan cilexetil and indapamide equivalent to the bioavailability of immediate-release candesartan cilexetil monopreparations and the bioavailability of sustained-release indapamide monopreparations.

[0082] Indapamide in the composition of the present invention is used in the only approved dosage of 1.5 mg for the prolonged form (see the article Robinson DM et. al., “Indapamide sustained release: a review of its use in the treatment of hypertension”, Drugs, 2006, 66(2):257-271).

[0083] According to the instructions for use of candesartan cilexetil, this medication can be administered to adults and children one to two times daily. For adults, the starting dose is 4 mg once daily and cannot exceed 32 mg daily. For children, the starting dose is 2 to 8 mg once daily, depending on the child's age and weight.

[0084] The core of the composition of the present invention contains, in addition to 1.5 mg of indapamide, also from 14 to 31% by weight of the composition of a cellulose polymer, which acts as a prolonged matrix for indapamide. Hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl methylcellulose of various grades and viscosities can be used as the cellulose polymer. It is preferable to use cellulose polymers of medium and high viscosity (for example, as defined in European patent application EP1669062 of 14.06.2006). More preferably, hydroxypropyl cellulose or hydroxypropyl methylcellulose are used as cellulose polymers.

[0085] The present inventors have discovered that using a cellulose polymer in an amount less than 14% by weight of the composition is insufficient to create a sustained-release matrix for indapamide. Furthermore, using a cellulose polymer in an amount greater than 31% by weight of the composition results in poorer disintegration of the composition. As a result, the bioavailability of indapamide in the combination product differs by 20% or more from that of the monotherapy.

[0086] Also, the core of the composition of the present invention may contain core excipients, which are pharmaceutically acceptable excipients adopted in the technology of preparing cores of dosage forms, such as fillers, binders, lubricants (Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgard, 1991; “Handbook of Pharmaceutical Excipients”, Pharmaceutical Press, 6 th edition, 2009).

[0087] The core of the composition of the present invention may contain from 25.17 to 61.2% by weight of the composition of a filler selected from the group consisting of lactose, microcrystalline cellulose, starch, pregelatinized starch, sucrose, glucose, calcium hydrogen phosphate, microcrystalline cellulose, sorbitol, mannitol, pectin, dextrin, sodium starch glycolate and mixtures thereof.

[0088] The core of the composition of the present invention may contain from 1.8 to 6% by weight of the composition of a binder selected from the group consisting of methylcellulose, sodium carboxymethylcellulose, povidone, natural gums, polyvinyl alcohol, sodium alginate, hydroxypropyl methylcellulose, carboxymethylcellulose and mixtures thereof.

[0089] The core of the composition of the present invention may contain from 0.2 to 2% by weight of the composition of a lubricant selected from the group consisting of starches, talc, colloidal silicon dioxide, macrogol 4000, macrogol 6000, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium lauryl sulfate and mixtures thereof.

[0090] The coating of the composition of the present invention, in addition to candesartan cilexetil, contains from 0.3% to 5.4% of the composition weight of a non-ionic surfactant. Candesartan cilexetil belongs to class II of the Biopharmaceutical Classification System (BCS), i.e., it has high permeability but low solubility. Therefore, the content of non-ionic surfactant directly affects the bioavailability of candesartan cilexetil.

[0091] The inventors of the present invention unexpectedly discovered that a non-ionic surfactant content of less than 0.3% by weight of the composition leads to insufficient solubilization of candesartan cilexetil, due to which the bioavailability of candesartan cilexetil in the combination preparation becomes lower than in the commercially available candesartan cilexetil monopreparation. At the same time, a non-ionic surfactant content of more than 5.4% by weight of the composition in a comparative dissolution kinetics test led to the formation of a stable emulsion and a decrease in the solubility of candesartan cilexetil in the combination preparation. That is, a non-ionic surfactant content of more than 5.4% by weight of the composition reduced the bioavailability of candesartan cilexetil in the combination preparation, compared with the commercially available candesartan cilexetil monopreparation.

[0092] Nonionic surfactants (also known as nonionic surfactants) are chemical compounds with surface-active properties that do not dissociate into ions in aqueous solutions. Nonionic surfactants include polysorbates (also known as Tweens), poloxamers (also known as Pluronics), synthanols, neonol, nonoxynol, tyloxapol, and various hydrogenated triglycerides. 12 -WITH 18 , polyoxylglycerides.

[0093] Polysorbates are oxyethylated sorbitans. The most common are polysorbate-20 (based on coconut oil), polysorbate-80 (based on olive oil), and polysorbate-40 and polysorbate-60 (based on palm oil).

[0094] Poloxamers are block copolymers of polyoxyethylene and polyoxypropylene, the most common ones are poloxamer 188, poloxamer 407, poloxamer 124, poloxamer 237 and poloxamer 338.

[0095] Polyoxylglycerides refer to a mixture of monoesters, diesters, and triesters of glycerol and monoesters and diesters of polyethyleneglycols. Examples of polyoxylglycerides are caprylocaproyl polyoxylglyceride (polyethylene glycol glycerides of caprylic and caproic acids), lauroyl polyoxylglyceride (polyethylene glycol glycerides of lauric acid), linoleoyl polyoxylglyceride (polyethylene glycol glycerides of linoleic acid), oleoyl polyoxylglyceride (polyethylene glycol glycerides of oleic acid), or stearoyl polyoxylglyceride (polyethylene glycol glycerides of stearic acid). A more specific example of polyoxylglycerides is lauroyl macrogol-32 glyceride, also known as lauroyl polyoxyl-32 glyceride, lauroyl macrogolglyceride, lauroyl polyoxylglyceride, polyoxyl glyceryl laurate, PEG glyceryl laurate, PEG-32 esters of hydrogenated coconut oil, or Gelucire 44 / 14.

[0096] The most preferred non-ionic surfactants of the present invention are surfactants selected from the group consisting of poloxamer 188, poloxamer 407, poloxamer 124, poloxamer 237, poloxamer 338, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauroyl polyoxyl-32 glyceride, hydrogenated triglycerides C 12 -WITH 18 and their mixtures.

[0097] The coating of the composition of the present invention, along with candesartan cilexetil and a non-ionic surfactant, contains coating fillers generally accepted in tablet production technology. Thus, the coating fillers can be a ready-made film coating from various manufacturers, for example, Opadry from Colorcon, AquaPolish, VivaCoat, Sheffcoat, more preferred are Opadry white 03F280065 (hypromellose, titanium dioxide, talc and macrogol), Opadry II white 85F18422 (partially hydrolyzed polyvinyl alcohol, titanium dioxide, macrogol 4000 and talc), Opadry II white 85G568918 (polyvinyl alcohol, lecithin, titanium dioxide, macrogol and talc). Preferably, the finished film coating is contained in an amount of 15.3 to 42.1% of the composition weight.

[0098] Instead of the finished film coating, substances necessary for the formation of the film coating, namely film formers, sliding agents, plasticizers and dyes, can be used as shell fillers, and the total content of the above substances is from 15.3 to 42.1% of the weight of the composition.

[0099] The film-forming agent used is a polymer selected from the group of polymers including hypromellose, polyvinyl alcohol, polyvinyl acetate, and ethylcellulose. Preferably, the film-forming agent is used in the coating in an amount of 11.5 to 28.5% of the composition's weight.

[0100] The lubricant used is a substance selected from the group consisting of talc, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate, and mixtures thereof. Preferably, the lubricants in the coating are used in an amount of 2 to 5.5% of the composition's weight.

[0101] The plasticizer may be a substance selected from the group consisting of glycerin, triacetin, polyethylene glycols (macrogols), triethyl phthalate, and mixtures thereof. Preferably, the plasticizer in the shell is used in an amount of 1 to 5.1% by weight of the composition.

[0102] The dye can be a substance selected from the group consisting of titanium dioxide, yellow iron (III) oxide, red iron (III) oxide, colored aluminum lakes, and mixtures thereof. Preferably, the dye is used in the coating at a rate of 0.8 to 3% by weight of the composition.

[0103] The qualitative and quantitative composition of the claimed pharmaceutical composition has been determined experimentally and is optimal. The composition of the present invention, compared to prior art solutions, is characterized by at least an improved treatment profile, ease of use, reduced side effects, reduced impurities, high stability, and cost-effective production.

[0104] The pharmaceutical composition can be prepared by any suitable known manufacturing methods. The core composition can be obtained using compression (direct compression) or granulation (dry or wet). It is most preferable to prepare the core composition by a water-free method selected from direct compression and dry granulation, as this avoids degradation of indapamide from exposure to water and reduces the formation of impurities.

[0105] The pharmaceutical composition obtained according to the invention is intended for the treatment of cardiovascular diseases, particularly arterial hypertension, which over time contributes to the development of other cardiovascular diseases, including coronary heart disease, heart failure, cerebrovascular diseases, acquired heart defects, and others. The composition of the present invention can be used to treat heart failure, including chronic heart failure, and can also be used to treat left ventricular systolic dysfunction.

[0106] EXAMPLES

[0107] The examples presented below illustrate (without limiting the scope of claims) the most preferred embodiments of the invention, and also confirm the possibility of obtaining the claimed pharmaceutical composition of indapamide and candesartan, as well as achieving the specified technical results for it.

[0108] Example 1. Technology for producing a composition with a core obtained by direct compression

[0109] The technology for producing the composition of the present invention is illustrated by a composition with the following composition.

[0110] Table 1. Composition of the composition of indapamide and candesartan cilexetil No. 01GI

[0111] Component Weight, mg Content, % Purpose Core Indapamide 1,5 0,50 Active ingredient Hypromellose 2208 64,0 21,33 Prolongator (cellulose polymer) Povidone 90 8,6 2,87 Binding agent Lactose monohydrate 124,5 41,50 Filler Silicon dioxide colloidal anhydrous 0,4 0,13 Sliding substance Magnesium stearate 1,0 0,33 Sliding substance shell Candesartan cilexetil 16,0 5,33 Active ingredient Polysorbate 80 1,74 0,58 Solubilizer (non-ionic surfactant) Hypromellose 2910 51,89 17,30 Film former Talc 14,09 4,70 Sliding substance Macrogol 3350 9,69 3,23 Plasticizer Titanium dioxide 6,59 2,20 Dye

[0112] To prepare the tablet mass, add the indapamide, colloidal silicon dioxide, and lactose monohydrate (1 part) mixture to the suspended lactose monohydrate (2 parts), hypromellose 2208, and povidone and mix. Then add the sifted magnesium stearate and mix.

[0113] Perform tableting on a rotary tablet press to obtain cores of the composition.

[0114] To prepare the film-forming mixture, add purified water to a mixing vessel. Hypromellose 2910, talc, macrogol 3350, and titanium dioxide are added while stirring. Allow to stand with constant stirring until a homogeneous mixture is obtained.

[0115] Preparation of candesartan cilexetil suspension with polysorbate 80: Disperse candesartan cilexetil in polysorbate 80 solution.

[0116] Add the candesartan cilexetil suspension to the mixing vessel containing the film-forming mixture and mix. Filter the film-forming mixture.

[0117] Applying a film-forming mixture with candesartan onto the cores of the composition in a coating apparatus to obtain cores coated with the shell of the present invention.

[0118] Example 2. Technology for producing a composition with a core obtained by wet granulation

[0119] The technology for producing the composition of the present invention is illustrated by a composition with the following composition.

[0120] Table 2. Composition of the composition of indapamide and candesartan cilexetil No. 02GI

[0121] Component Weight, mg Content,% Purpose Core Indapamide 1,5 0,75 Active ingredient Hydroxypropyl cellulose 28 14 Prolongator (cellulose polymer) Sodium carboxymethylcellulose 3,6 1,8 Binding agent Mannitol 55,1 27,55 Filler Talc 0,4 0,2 Sliding substance Magnesium stearate 0,4 0,2 Sliding substance shell Candesartan cilexetil 16,0 8,0 Active ingredient Polysorbate 20 10,8 5,4 Solubilizer (non-ionic surfactant) Opadry white 03F280065 (hypromellose 57.78%, titanium dioxide 22.22%, talc 4.44%, macrogol 15.56%) 84,2 42,1 Ready-made film casing

[0122] Micronize indapamide in a 1:1 aqueous-alcoholic solution of sodium carboxymethylcellulose and hydroxypropylcellulose. Mix the resulting suspension with mannitol. Dry the resulting granulate at 45°C in a hot-air dryer to a residual moisture content of no more than 1.0%. Grade the dried granulate through a vibrating sieve, e.g., 30 mesh, mix, and dust with talc and magnesium stearate in a cone mixer until smooth. The powdered granulate is used to obtain the composition cores.

[0123] Preparation of candesartan cilexetil suspension with polysorbate 20: Disperse candesartan cilexetil in polysorbate 20 solution.

[0124] To prepare the film-forming mixture, add purified water to the mixing vessel and stir the prepared film coating. A suspension of candesartan cilexetil with polysorbate 20 was added to the mixing vessel containing the prepared film coating. The resulting film-forming mixture was filtered.

[0125] Applying a film-forming mixture with candesartan to the cores of the composition in a coating apparatus to obtain cores coated with the shell of the present invention.

[0126] Example 3. Compositions of indapamide and candesartan cilexetil prepared by obtaining a core by direct compression

[0127] Table 3. Compositions of indapamide and candesartan cilexetil formulations No. 03GI, No. 04GI and No. 05GI

[0128] Compositions No. 03GI No. 04GI No. 05GI Component Weight, mg (Content, %) Core Indapamide 1,5 (0,33) 1,5 (0,6) 1,5 (0,47) Hypromellose 2208 139,5 (31) 40 (16) 73,6 (23) Methylcellulose 27 (6,0) 10 (4,0) 5,76 (1,8) Starch 165,65 (36,81) 107,5 (43) 139,94 (43,73) Talc 2,25 (0,5) 0,5 (0,2) - Sodium stearyl fumarate 2,25 (0,5) 0,5 (0,2) 3,2 (1,0) shell Candesartan cilexetil 16 (3,56) 4 (1,6) 8 (2,5) Polysorbate 80 1,35 (0,3) 8,5 (3,4) 8 (2,5) Finished film coating (hypromellose 3.09%, titanium dioxide 8.01%, talc 17.12%, macrogol 11.78%) 94,5 (21) 77,5 (31) 80 (25)

[0129] Table 4. Compositions of indapamide and candesartan cilexetil formulations No. 06GI, No. 07GI and No. 08GI

[0130] Compositions No. 06GI No. 07GI No. 08GI Component Weight, mg (Content, %) Core Indapamide 1,5 (0,75) 1,5 (0,54) 1,5 (0,38) Hydroxypropyl cellulose 28 (14) 64,1 (22,89) 62,5 (15,62) Microcrystalline cellulose 53,9 (26,95) 71,4 (25,5) 160 (40) Calcium hydrogen phosphate - 78,4 (28,0) - Polyvinyl alcohol 3,6 (1,8) 8,4 (3,0) 14 (3,5) Calcium stearate 2 (1) 2 (0,71) 2 (0,5) shell Candesartan cilexetil 16 (8,0) 4 (1,43) 8 (2,0) Poloxamer 188 10,8 (5,4) 7,3 (2,61) 16 (4,0) Opadry 85F18422 Ready-to-Use Film Casing 84,2 (42,1) 42,9 (15,32) 136 (34,0)

[0131] Table 5. Compositions of indapamide and candesartan cilexetil formulations No. 09GI, No. 10GI and No. 11GI

[0132] Compositions No. 09GI No. 10GI No. 11GI Component Weight, mg (Content, %) Core Indapamide 1,5 (0,5) 1,5 (0,43) 1,5 (0,5) Hypromellose 75 (25,0) 98 (28,0) 42 (14) Povidone 6 (2,0) 15,75 (4,5) 9,0 (3,0) Guar gum 6 (2,0) - - Lactose 129,1 (43,03) 114,75 (32,78) 127,9 (42,63) Macrogol 4000 1,5 (0,5) - - Magnesium stearate 1,5 (0,5) 2,8 (0,8) 1,5 (0,5) shell Candesartan cilexetil 8 (2,67) 8 (2,29) 8 (2,67) Polysorbate 80 15 (5,0) - 7,5 (2,5) Poloxamer 407 - 7,0 (2,0) - Hypromellose 34,5 (11,5) - - Polyvinyl alcohol - 66,85 (19,1) - Polyvinyl acetate - - 85,5 (28,5) Talc 16,5 (5,5) 7,0 (2,0) - Sodium stearyl fumarate - - 6,0 (2,0) Triacetin 3 (1,0) - - Macrogol 3350 - 17,85 (5,1) - Macrogol 6000 - - 7,5 (2,5) Green aluminum varnish - 10,5 (3,0) - Yellow iron(III) oxide 2,4 (0,8) - - Red iron(III) oxide - - 3,6 (1,2)

[0133] Table 6. Compositions of indapamide and candesartan cilexetil formulations No. 12GI, No. 13GI and No. 14GI

[0134] Compositions No. 12GI No. 13GI No. 14GI Component Weight, mg (Content, %) Core Indapamide 1,5 (0,38) 1,5 (0,5) 1,5 (0,5) Hydroxypropyl cellulose 70,9 (17,72) 42 (14) 63 (21) Lactose 244,8 (61,2) 84 (28) 107,5 (35,83) Sodium starch glycolate - 75,5 (25,17) - Sodium carboxymethylcellulose 14,4 (3,6) 18 (6,0) 12 (4,0) Sodium lauryl sulfate 1,6 (0,4) 0,6 (0,2) - Stearic acid - - 6,0 (2,0) shell Candesartan cilexetil 2 (0,5) 8 (2,67) 32 (10,67) Polysorbate 80 3,6 (0,9) - - Lauroyl polyoxyl-32 glyceride - 8,7 (2,9) - Poloxamer 338 - - 9,0 (3,0) Opadry II 85G568918 Ready-to-Use Film Casing 61,2 (15,3) - 69 (23) Finished film coating (hypromellose 63.09%, titanium dioxide 8.01%, talc 17.12%, macrogol 11.78%) - 61,7 (20,56) -

[0135] Example 4. Release of indapamide from the compositions of the present invention in a comparative dissolution kinetics test

[0136] The determination is carried out in accordance with the requirements of FEAEC 2.1.9.3. Dissolution test for solid dosage forms.

[0137] The amount of indapamide transferred into solution is determined by HPLC (FEAES 2.1.2.28. High performance liquid chromatography).

[0138] Norm: From 17 to 27% should pass into the solution after 4 hours; from 35 to 55% after 8 hours; and at least 75% of the declared amount of indapamide after 16 hours.

[0139] Dissolution conditions

[0140] Device for determining the dissolution of solid dosage forms "ERWEKA DT 820" from ERWEKA, Germany or alternative equipment.

[0141] • To evaluate dissolution, apparatus II is used - “Bladder stirrer”;

[0142] • paddle stirrer rotation speed - 50 rpm;

[0143] • dissolution medium - 0.01 M hydrochloric acid solution;

[0144] • volume of dissolution medium - 500 ml;

[0145] • temperature - (37 ± 0.5)°С;

[0146] • sampling time - 4, 8 and 16 hours;

[0147] • dissolution time - 16 hours;

[0148] • Dark glass dissolving vessels.

[0149] Samples for dissolution:

[0150] In the comparative dissolution kinetics test, compositions No. 01-14GI according to the present invention, as well as the monodrug indapamide 1.5 mg Arifon® retard (Servier Laboratories, France) were studied.

[0151] Preparation of the test solution. Place one tablet in a sinker (18 x 6 mm, Sotax, Cat. No. PSCAPWST-18 or equivalent). Place the sinker with the tablet in the dissolution vessel and conduct the test. After 4 h, 8 h, and 16 h, take 10 ml samples of the solution each and filter through a Millipore Millex-GV membrane filter with a pore size of 0.22 μm (or equivalent), discarding the first 2 ml of the filtrate. Immediately after each sample collection, add 10 ml of the dissolution medium, heated to a temperature of (37 ± 0.5) °C, to the vessel.

[0152] Chromatographic conditions:

[0153] • Alliance chromatographic system or equivalent;

[0154] • Waters in-line degasser or similar;

[0155] • chromatographic column made of stainless steel, 25.00 × 0.46 cm, packed with phenylsilane sorbent with a particle size of 5 μm, “Xterra®Phenyl 5 μm, 4.6 × 250 mm HPLC Column” by Waters, cat. No. 186001147 or equivalent;

[0156] • mobile phase (MP): mixture of acetonitrile for chromatography P - water for chromatography P - trifluoroacetic acid P (2: 3: 0.005);

[0157] • column temperature - 40°C;

[0158] • autosampler temperature - 20°C;

[0159] • spectrophotometric detector "Waters 2489" or similar with an operating wavelength of 215 nm;

[0160] • volume of injected sample - 50 µl of each solution;

[0161] • PF flow rate - 1 ml / min;

[0162] • estimated peak retention time of indapamide - from 5 to 7 min;

[0163] • chromatography time - 10 min;

[0164] • chromatogram registration time - 10 min;

[0165] • after every 20 injections of the test solutions, wash the column with a mixture of acetonitrile for chromatography P - water for chromatography P - trifluoroacetic acid P (7: 3: 0.01) for 30 min at a flow rate of 1 ml / min and a column temperature of 40°C, after which equilibrate the column with the mobile phase for 10 min and continue the analysis;

[0166] • After the analysis, wash the column counter-flow with a mixture of acetonitrile for chromatography P - water for chromatography P (7:3) for 2 hours at a flow rate of 1 ml / min and a column temperature of 30°C.

[0167] Chromatographic control - standard sample of Indapamide:

[0168] Indapamide USP RS, or EP CRS, or BP CRS, or LGC Mikromol (cat. no. MM0477.00) or Indapamide FSO.1.1.00102.

[0169] The table below presents data on the release of indapamide in a comparative dissolution kinetics test after 4, 8 and 16 hours from compositions No. 01-14GI according to the present invention, as well as the monodrug indapamide 1.5 mg Arifon® retard.

[0170] Table 7. Release of indapamide from the compositions of the present invention in a comparative dissolution kinetics test

[0171] The composition under study Amount of indapamide released over time: 4 hours 8 hours 16 hours Arifon® retard 21,1 % 43,0 % 80,4 % No. 01GI 23,9 % 50,3 % 86,1 % No. 02GI 23,6 % 50,2 % 80,9 % No. 03GI 23,1 % 47,1 % 81,0 % No. 04GI 23,7 % 48,4 % 91,0 % No. 05GI 23,8 % 47,8 % 82,1 % No. 06GI 26,3 % 53,0 % 91,2 % No. 07GI 23,0 % 48,2 % 87,1 % No. 08GI 24,1 % 49,0 % 86,1 % No. 09GI 22,3 % 46,8 % 82,7 % No. 10GI 20,9 % 42,7 % 80,6 % No. 11GI 23,1 % 50,9 % 84,8 % No. 12GI 21,3 % 47,5 % 82,7 % No. 13GI 24,6 % 51,1 % 85,3 % No. 14GI 20,2 % 45,4 % 81,4 %

[0172] As can be seen from Table 7, compositions Nos. 01-14GI of the present invention, like Arifon® retard, comply with the regulatory documentation for prolonged-release indapamide in terms of indapamide release in a comparative dissolution kinetics test. Moreover, the release profile of indapamide from Arifon® retard is similar to the release profiles of indapamide from compositions Nos. 01-14GI of the present invention (deviation less than 20%).

[0173] Example 5. Release of candesartan cilexetil from the compositions of the present invention in a comparative dissolution kinetics test

[0174] The determination is carried out in accordance with the requirements of FEAEC 2.1.9.3. Dissolution test for solid dosage forms.

[0175] The amount of candesartan cilexetil transferred into solution is determined by HPLC (FEAES 2.1.2.28. High performance liquid chromatography).

[0176] Norm: At least 70% (Q) of the stated amount of candesartan cilexetil should pass into solution after 45 minutes.

[0177] Dissolution conditions

[0178] Device for determining the dissolution of solid dosage forms "ERWEKA DT 820" from ERWEKA, Germany or alternative equipment.

[0179] • To evaluate dissolution, apparatus II is used - “Blade stirrer”;

[0180] • dissolution medium - 0.05 M phosphate buffer solution pH 6.5, containing 0.35% (w / v) polysorbate 20;

[0181] • paddle stirrer rotation speed - 100 rpm;

[0182] • volume of dissolution medium - 900 ml;

[0183] • dissolution time - 45 min;

[0184] • Dark glass dissolving vessels.

[0185] Samples for dissolution:

[0186] Compositions No. 01-14GI according to the present invention, as well as the monodrug candesartan cilexetil 16 mg Atacand® (AstraZeneca, Sweden) were studied in a comparative dissolution kinetics test.

[0187] Preparing the test solution. Place one tablet in a sinker (18 x 6 mm, Sotax, Cat. No. PSCAPWST-18 or equivalent). Place the sinker with the tablet in the dissolution vessel and perform the test. After 45 minutes, remove approximately 10 ml of the solution and filter it through a Millipore Millex-GV membrane filter with a pore size of 0.22 µm (or equivalent), discarding the first 2 ml of the filtrate.

[0188] Chromatographic conditions:

[0189] • Alliance chromatographic system or equivalent;

[0190] • Waters in-line degasser or similar;

[0191] • 25.00 × 0.46 cm stainless steel chromatography column packed with phenylsilane sorbent with a particle size of 5 μm, “Xterra®Phenyl 5 μm, 4.6 × 250 mm HPLC Column” by Waters, cat. No. 186001147 or equivalent;

[0192] • mobile phase (MP): mixture of acetonitrile for chromatography P - water for chromatography P - trifluoroacetic acid P (13: 7: 0.02);

[0193] • column temperature - 40°C;

[0194] • autosampler temperature - 20°C;

[0195] • Spectrophotometric detector "Waters 2489" or similar with an operating wavelength of 254 nm;

[0196] • volume of injected sample - 20 µl of each solution;

[0197] • PF flow rate - 1 ml / min;

[0198] • Estimated peak retention time of candesartan cilexetil is 5 to 7 min;

[0199] • chromatography time - 10 min;

[0200] • chromatogram recording time - 10 min;

[0201] • After the analysis, the column is washed counter-flow with a mixture of acetonitrile for chromatography P - water for chromatography P (7:3) for 2 hours at a flow rate of 1 ml / min and a column temperature of 30°C.

[0202] Chromatographic control - standard sample of Candesartan cilexetil:

[0203] Candesartan cilexetil USP RS, or BP CRS, or LGC company cat. No. MM0776.00-0250, or Candesartan cilexetil FSO.1.1.00105.

[0204] The table below presents the data on the release of candesartan cilexetil in the comparative dissolution kinetics test after 45 minutes from compositions No. 01-14GI according to the present invention, as well as the monodrug of candesartan cilexetil 16 mg Atacand®.

[0205] Table 8. Release of candesartan cilexetil from the compositions of the present invention in a comparative dissolution kinetics test

[0206] The composition under study Amount of candesartan cilexetil released after 45 minutes Atacand® 88,3 % No. 01GI 91,2 % No. 02GI 97,1 % No. 03GI 84,9 % No. 04GI 94,5 % No. 05GI 90,8 % No. 06GI 97,7 % No. 07GI 89,6 % No. 08GI 94,8 % No. 09GI 93,7 % No. 10GI 90,4 % No. 11GI 89,1 % No. 12GI 88,9 % No. 13GI 92,3 % No. 14GI 91,1 %

[0207] As can be seen from Table 8, compositions Nos. 01-14GI of the present invention, like Atacand®, comply with regulatory documentation for the immediate release of candesartan cilexetil in the comparative dissolution kinetics test. Moreover, the release rate of candesartan cilexetil from compositions Nos. 01-14GI of the present invention in the comparative dissolution kinetics test is similar to the release rate of candesartan cilexetil from Atacand® monotherapy (deviation no more than 10%).

[0208] Example 6. Comparative study of the stability of the compositions of the present invention

[0209] The stability of candesartan cilexetil and indapamide formulations under accelerated aging conditions was evaluated at 40°C / 75% relative humidity, and the impurity content was determined over periods of 0, 1, 3, and 6 months. Formulations Nos. 01-14GI of the present invention were studied. Candesartan cilexetil Atacand® (16 mg) and indapamide Arifon® retard were used as reference formulations.

[0210] The tables below present the controlled impurities of candesartan cilexetil and indapamide.

[0211] Table 9. Structural formulas and impurity levels of candesartan cilexetil

[0212] impurity Structural formula Maximum content standard Impurity B No more than 1.5% Impurity D No more than 0.5% Impurity F No more than 1.5% Impurity G No more than 1.0% Single unidentifiable impurity - No more than 0.2% Sum of impurities - No more than 4.0%

[0213] Table 10. Structural formulas and impurity content standards of indapamide

[0214] impurity Structural formula Maximum content standard Impurity A No more than 20 ppm Impurity B No more than 1.0% 3-Sulfamoyl-4-chlorobenzoic acid No more than 0.5% Single unidentifiable impurity - No more than 0.5% Total impurities (excluding impurity B) - No more than 1.5%

[0215] Before the start of the accelerated aging experiment (0 months), compositions No. 01-14GI according to the present invention and the monodrug Atacand® (16 mg) were characterized by the following level of impurities for candesartan cilexetil: impurities B, D, G were not detected, impurity F no more than 0.10%, a single unidentifiable impurity no more than 0.05%, the sum of impurities no more than 0.15%.

[0216] After completion of the accelerated aging experiment (6 months), compositions No. 01-14GI of the present invention and the monodrug Atacand® (16 mg) are characterized by the following impurity level for candesartan cilexetil: impurity B is not more than 0.22%, impurity D is not more than 0.08%, impurity G is not more than 0.17%, impurity F is not more than 0.43%, a single unidentifiable impurity is not more than 0.14%, the sum of impurities is not more than 1.01%.

[0217] Thus, the compositions of the present invention in terms of candesartan cilexetil have high stability and are characterized by a reduced amount of impurities related to candesartan cilexetil.

[0218] Before the start of the accelerated aging experiment (0 months), compositions No. 01-14GI according to the present invention and the monodrug Arifon® retard were characterized by the following level of impurities for indapamide: impurity A less than 1 ppm, impurity B no more than 0.11%, 3-sulfamoyl-4-chlorobenzoic acid was not detected, a single unidentifiable impurity no more than 0.01%, the sum of impurities (excluding impurity B) no more than 0.19%.

[0219] After completing the accelerated aging experiment (6 months) of the composition Nos. 01-14GI according to the present invention and are characterized by the following level of impurities for indapamide: impurity A no more than 3 ppm, impurity B no more than 0.27%, 3-sulfamoyl-4-chlorobenzoic acid no more than 0.07%, a single unidentifiable impurity no more than 0.04%, the sum of impurities (excluding impurity B) no more than 0.41%.

[0220] Based on the above information, the compositions of the present invention in terms of indapamide have high stability and are characterized by a reduced amount of impurities related to indapamide (especially nitroso impurity, also known as impurity A).

[0221] Example 7. Comparative study of the bioavailability of the indapamide + candesartan cilexetil composition of the present invention in healthy volunteers

[0222] Study Title: "An open-label, randomized, crossover, comparative study of the pharmacokinetics and bioequivalence of Candesartan cilexetil + indapamide after repeated administration in healthy volunteers"

[0223] Investigational drug: Indapamide + Candesartan cilexetil, 1.5 mg+16 mg, film-coated modified-release tablets (composition No. 01GI from Example 1).

[0224] Research objective:

[0225] To study the pharmacokinetic parameters and relative bioavailability of the drug Candesartan+Indapamide, 16 mg+1.5 mg, extended-release film-coated tablets (composition No. 01GI from Example 1) in comparison with the drugs Atacand® (INN: candesartan), tablets, 16 mg (AstraZeneca AB, Sweden) and Arifon® retard (INN: indapamide), extended-release film-coated tablets, 1.5 mg (Servier Laboratories, France), when they are taken simultaneously on an empty stomach and after meals, followed by an assessment of the bioequivalence of the study drugs.

[0226] Research objectives:

[0227] • To study the pharmacokinetics of Candesartan+Indapamide, 16 mg+1.5 mg, extended-release film-coated tablets (composition No. 01GI from Example 1) when taken on an empty stomach and after meals.

[0228] • To evaluate the bioavailability of the study drug Candesartan + Indapamide, 16 mg + 1.5 mg, extended-release film-coated tablets (composition No. 01GI from Example 1) relative to the comparison drugs Atacand® (INN: candesartan), tablets, 16 mg (AstraZeneca AB, Sweden) and Arifon® retard (INN: indapamide), extended-release film-coated tablets, 1.5 mg (Servier Laboratories, France), when they are taken simultaneously on an empty stomach and after meals, based on the analysis of pharmacokinetic data, followed by an assessment of the bioequivalence of the study drugs.

[0229] • To evaluate the safety of Candesartan+Indapamide, 16 mg+1.5 mg, extended-release film-coated tablets (composition No. 01GI from Example 1) in comparison with Atacand® (INN: candesartan), tablets, 16 mg (AstraZeneca AB, Sweden) and Arifon® retard (INN: indapamide), extended-release film-coated tablets, 1.5 mg (Servier Laboratories, France), when taken simultaneously on an empty stomach and after meals.

[0230] Methodology: Open-label, randomized, crossover comparative study of pharmacokinetics and bioequivalence between fasted and fed subjects in healthy volunteers.

[0231] Number of patients: Screened - 76; Randomized - 72 (4 - backups who were not needed); Excluded - 0; Dropped out - 1 (due to taking other drugs); Completed - 71; Included in pharmacological analysis - 71; Included in statistical analysis - 71.

[0232] Investigational drug:

[0233] The composition of the drug candesartan cilexetil + indapamide corresponds to composition No. 01GI from Example 1.

[0234] The volunteer took a single dose of candesartan cilexetil + indapamide, 16 mg + 1.5 mg (1 film-coated extended-release tablet) in the morning on an empty stomach or after a meal, with 200 ml of drinking water (still).

[0235] Comparison drugs:

[0236] Atacand® tablets containing 16 mg of candesartan cilexetil as the active ingredient. Excipients: calcium carmellose (carmellose calcium salt) 5.6 mg, hyprolose (hydroxypropyl cellulose) 4.0 mg, iron oxide red E 172 0.26 mg, lactose monohydrate 81.4 mg, magnesium stearate 0.4 mg, corn starch 20.0 mg, macrogol 2.6 mg.

[0237] Arifon® retard extended-release tablets containing 1.5 mg of indapamide as the active ingredient. Excipients: hypromellose, lactose monohydrate, magnesium stearate, povidone 30, colloidal silicon dioxide anhydrous, glycerol, hypromellose, macrogol 6000, magnesium stearate, titanium dioxide.

[0238] The volunteer took a single dose of Atacand® (16 mg - 1 tablet) and Arifon® retard (1.5 mg - 1 film-coated extended-release tablet) in the morning on an empty stomach or after a meal, with 200 ml of drinking water (still)

[0239] Study design:

[0240] A total of 72 volunteers who met the inclusion criteria and had no exclusion criteria were randomized into one of the following groups:

[0241] Group 1 (n=36) - volunteers took the drug on an empty stomach:

[0242] Group 1A - 18 volunteers received the study drug (T) in the first period of the study and comparison drugs (R) in the second period (TR sequence).

[0243] Group 1B - 18 volunteers received comparison drugs (R) in the first period of the study and the study drug (T) in the second period (RT sequence).

[0244] Group 2 (n=36) - volunteers took the drug after meals:

[0245] Group 2A - 18 volunteers received the study drug (T) in the first period of the study and comparison drugs (R) in the second period (TR sequence).

[0246] Group 2B - 18 volunteers received comparison drugs (R) in the first period of the study and the study drug (T) in the second period (RT sequence).

[0247] The duration of periods I and II was no more than 3.5 days, and between them there was a “washout” stage from the drugs lasting 7 days.

[0248] Quantity and time of blood sampling:

[0249] Blood sampling time for pharmacokinetic study for each volunteer: before taking the drug (0 h) and 1 h, 2 h, 2 h 30 min, 3 h, 3 h 30 min, 4 h, 4 h 30 min, 5 h, 6 h, 8 h, 9 h, 10 h, 11 h, 12 h, 12 h 30 min, 13 h, 14 h, 24 h, 36 h, 48 h, 72 h after taking the study drug / comparator drugs.

[0250] Points at which blood was collected to determine candesartan (16 points): before taking the drug (0 h) and 1; 2; 2.5; 3; 3.5; 4; 4.5; 5; 6; 8; 9; 10; 12; 24; 36 hours after taking the study drug / comparator drugs.

[0251] Points at which blood was collected to determine indapamide (14 points): 0; 2; 4; 6; 8; 10; 11; 12; 12.5; 13; 14; 24; 48; 72 hours after taking the study drug / comparator drugs.

[0252] The concentrations of candesartan and indapamide in the samples were determined by HPLC. Figures 1 and 2 show the time-dependent concentrations of candesartan and indapamide following administration of the formulation according to Example 1 and Atacand® (16 mg) + Arifon® retard (1.5 mg) after meals. Based on the obtained concentrations of candesartan and indapamide, their key pharmacokinetic parameters were determined.

[0253] Bioavailability assessment:

[0254] The mean values ​​of the main pharmacokinetic parameters of candesartan for the study drug and comparator drugs under fasting conditions were:

[0255] Parameter Candesartan cilexetil + Indapamide (composition No. 01GI) Atacand® (16 mg) and Arifon® retard (1.5 mg) Cmax (ng / ml) 187,19±66,78 176,65±81,05 AUC0-t (ng*h / ml) 1753,68±504,68 1650,23±628,58 tmax (h) 3,46 3,16

[0256] The mean values ​​of the main pharmacokinetic parameters of candesartan for the study drug and comparator drugs after taking food were:

[0257] Parameter Candesartan cilexetil + Indapamide (composition No. 01GI) Atacand® (16 mg) and Arifon® retard (1.5 mg) Cmax (ng / ml) 257,61±63,18 223,86±62,31 AUC0-t (ng*h / ml) 2139,96±603,14 1944,69±619,44 tmax (h) 3,64 3,68

[0258] The mean values ​​of the main pharmacokinetic parameters of indapamide for the study drug and comparator drugs under fasting conditions were:

[0259] Parameter Candesartan cilexetil + Indapamide (composition No. 01GI) Atacand® (16 mg) and Arifon® retard (1.5 mg) Cmax (ng / ml) 38,41±9,27 37,41±9,37 AUC0-t (ng*h / ml) 1230,25±348,31 1127,38±197,62 tmax (h) 10,96 11,01

[0260] The mean values ​​of the main pharmacokinetic parameters of indapamide for the study drug and comparator drugs after meals were:

[0261] Parameter Candesartan cilexetil + Indapamide (composition No. 01GI) Atacand® (16 mg) and Arifon® retard (1.5 mg) Cmax (ng / ml) 57,99±14,22 58,84±23,59 AUC0-t (ng*h / ml) 1285,18±387,82 1270,37±404,11 tmax (h) 7,24 8,08

[0262] As can be seen from the tables above, the combination drug of candesartan cilexetil and indapamide is bioequivalent (bioavailability parameters are within the range of 80-125%) to the two monodrugs Atacand® (16 mg) and Arifon® retard (1.5 mg). However, the combination drug exhibits slightly higher bioavailability parameters, particularly for candesartan cilexetil.

Claims

1. A pharmaceutical composition for the treatment of cardiovascular diseases, made in the form of a tablet, comprising a core coated with a shell, wherein the core contains 1.5 mg of indapamide, a cellulose polymer and core fillers, and the shell contains from 2 to 32 mg of candesartan cilexetil, a non-ionic surfactant and shell fillers, wherein the weight of the pharmaceutical composition is from 200 to 450 mg.

2. The composition according to claim 1, wherein the core constitutes from 41.67 to 83.3% by weight of the composition and contains from 14 to 31% by weight of the composition of a cellulose polymer selected from hydroxypropyl cellulose or hydroxypropyl methylcellulose, and the core is made by a method without the use of water, selected from direct compression and dry granulation.

3. The composition according to claim 1, wherein the core fillers comprise: filler in an amount from 25.17 to 61.2% of the composition weight; a binder in an amount of 1.8 to 6% of the composition weight; a sliding substance in an amount of 0.2 to 2% of the composition weight.

4. The composition according to claim 3, wherein the filler is selected from the group consisting of lactose, microcrystalline cellulose, starch, pregelatinized starch, sucrose, glucose, calcium hydrogen phosphate, sorbitol, mannitol, pectin, dextrin, sodium starch glycolate and a mixture thereof.

5. The composition according to claim 3, wherein the binder is selected from the group consisting of methylcellulose, sodium carboxymethylcellulose, povidone, natural gums, polyvinyl alcohol, sodium alginate, hydroxypropyl methylcellulose, carboxymethylcellulose and mixtures thereof.

6. The composition of claim 3, wherein the lubricant is selected from the group consisting of starches, talc, colloidal silicon dioxide, macrogol 4000, macrogol 6000, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium lauryl sulfate and mixtures thereof.

7. The composition according to claim 1, wherein the cellulose polymer is selected from hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose and hydroxypropyl methyl cellulose.

8. The composition according to claim 1, wherein the shell is in an amount of 16.7 to 58.33% by weight of the composition, and which contains a non-ionic surfactant in an amount of 0.3 to 5.4% by weight of the composition, selected from the group consisting of poloxamer 188, poloxamer 407, poloxamer 124, poloxamer 237, poloxamer 338, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauroyl polyoxyl-32 glyceride, hydrogenated triglycerides C12-C18 and mixtures thereof.

9. The composition according to claim 1, in which the shell fillers contain either a finished film coating in an amount of 15.3 to 42.1% of the composition weight, selected from Opadry white 03F280065, Opadry II white 85F18422, Opadry II white 85G568918, or contain: a film-forming agent in an amount of 11.5 to 28.5% of the composition weight, selected from the group consisting of hypromellose, polyvinyl alcohol, polyvinyl acetate, ethyl cellulose, a lubricant in an amount of 2 to 5.5% of the composition weight, selected from the group consisting of talc, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate and mixtures thereof, a plasticizer in an amount of 1 to 5.1% of the composition weight, selected from the group consisting of glycerin, triacetin, polyethylene glycols (macrogols), triethyl phthalates and mixtures thereof, a dye in an amount of 0.8 to 3% of the composition weight, selected from titanium dioxide, colored aluminum varnishes, yellow iron (III) oxide, red iron (III) oxide and mixtures thereof.

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