KR20120117986A - Capsules of active pharmaceutical ingredients and polyunsaturated fatty acid esters for the treatment of cardiovascular diseases - Google Patents

Abstract

Pharmaceutical compositions in capsule form for the treatment and / or prevention of cardiovascular diseases comprising polyunsaturated fatty acid (PUFA) alkyl esters and active pharmaceutical ingredients

Description

CAPSULES OF ACTIVE PHARMACEUTICAL INGREDIENTS AND POLYUNSATURATED FATTY ACID ESTERS FOR THE TREATMENT OF CARDIOVASCULAR DISEASES}

The present invention relates to a pharmaceutical composition of a capsule formulation comprising a suspension suspended in an oil comprising a polymer microcapsule comprising a polyunsaturated fatty acid (PUFA) alkyl ester, wherein the microcapsule comprises at least A pharmaceutical composition comprising one polymer and one active pharmaceutical ingredient and the use of the pharmaceutical composition for the treatment and / or prevention of cardiovascular diseases.

Among the active pharmaceutical ingredients most commonly used to treat cardiovascular diseases, especially hypertension, are angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers (ARBs) and angiotensin II. There are angiotensin II receptor antagonists: ACE inhibitors and ARBs act on the rennin-angiotensin system ACE inhibitors inhibit angiotensin converting enzymes to prevent angiotensin I from converting to angiotensin II ACE inhibitors are very effective antihypertensive agents used in the treatment of heart failure and myocardial infarction.Most ACE inhibitors are administered in the form of diethyl esters, although the carboxyl group in the alpha position relative to the secondary amino group is administered. Acid is a form with biological activity.

ARB blocks angiotensin II receptors in the arteries and inhibits their action. Thus, ARB is also the first line of defense for patients with high blood pressure, especially in patients who cough because of ACE inhibitors. ARB is also used to treat heart failure and diabetic kidney disease.

Polyunsaturated fatty acids also have a known beneficial effect in the prevention of cardiovascular disease and are often used in combination therapy in patients who have suffered from some types of cardiovascular disease. Numerous studies have been conducted on the effects of polyunsaturated fatty acids on antihypertension, serum cholesterol reduction, antihypertriglyceridemia, antiarrhythmia, antiplatelet and anti-inflammatory effects [Bucher HC et. al . Am . J. Med . 112: 298-304 (2002); Benatti P. et al . J. Am . Coll . Nutr . 23: 281-302 (2004); Lee JH et al . Mayo Clin . Proc . 83: 324-332 (2008); Heinz R. Adv . Ther . 26: 675-690 (2009).

Polyunsaturated fatty acids are essential fatty acids and must be obtained from food. Polyunsaturated fatty acids are divided into omega-3 ( n- 3) and omega-6 ( n- 6) fatty acids, depending on the location of the first unsaturation. Major omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are found in fish oils. Polyunsaturated fatty acids can be found in the form of triglycerides or alkyl esters. Commercial compositions of omega-3 fatty acid alkyl esters vary in purity and content of fatty acids and are usually indicated in terms of EPA and DHA content.

Polyunsaturated fatty acids are easily oxidized in any form and should be stored under inert gas and protected from light. Commercial compositions contain antioxidants to minimize degradation.

Very unstable properties of the aforementioned pharmaceutical antihypertensive active ingredients, in particular ACE inhibitors, are also known. ACE inhibitors can undergo three types of degradation: a) to form diketopiperazines through intramolecular cyclization reactions, or b) to produce diacids through hydrolysis of side chain ester groups, or and c) undergo oxidation that produces unwanted coloring products. Decomposition takes place in both liquid and solid states.

According to WO 2006/050533 A2 and EP 0317878 B1, US 5442008 A, US 5151433 A, WO 2004/064809 A1, EP 1429748 B1, the instability of known ramipril formulations is determined by mechanical stress, manufacturing process, excipients, storage conditions. It is influenced by several factors such as heat and moisture. As a result, ramipril needs very controlled formulation conditions to minimize this degradation and to prevent the generation of the above-mentioned degradation products (diketopiperazine and diacid). According to WO 2008/000040 A1 and WO 2008/001184 A2, the choice of different excipients influences the stability of ramipril and other ACE inhibitors such as quinapril, enalapril, or spirapril. In addition to accelerate their decomposition, as well as mechanical stresses associated with the manufacturing process are important causes of degradation.

According to US 2007281000 A1, in order to improve the stability of the water-sensitive active pharmaceutical ingredient, in the case of cilazapril, water scavenger compounds such as copovidone are contained in the formulation. Can be. Fosinopril is unstable because it is susceptible to hydrolysis in ester groups and phosphodiester groups, and trandolapril occurs in ester groups. In EP 1906931 B1 a composition consisting of these two active ingredients is stabilized with dimethicone, as a result of which cyclization, hydrolysis and / or oxidation are inhibited.

There are numerous examples in the literature confirming that various ACE inhibitors degrade during the formulation of the active pharmaceutical ingredient, even during the manufacture of tablets. Adding acid stabilizers to solve this problem (EP 0264888 B1; EP 0468929 B1; US 4830853 A), enalapril salt formation (WO 01/32689), using meglumine (WO 2005/041940 A1), mixing a dispersion of a metal dispersed in an alcohol with an ACE inhibitor (WO 04/071526 A1), inhibiting the cyclization or color change using alkali carbonates or alkaline earth metals and inhibiting hydrolysis using sugars (US 4743450 A), Or use of magnesium oxide (EP 1083931 B1; WO 2008/000040 A1) as a stabilizer for cyclization and as a means for controlling moisture.

The method of stabilizing pharmaceutical compositions containing ACE inhibitors without the addition of stabilizing excipients can be achieved by polymerizing ramipril as agglomerates (US 5151433 A) or as individual particles (WO 2006/050533 A2) in the final solid formulation, There are methods of coating the inert nucleus with the active ingredient itself (US 2005202081 A1) to prevent degradation induced by both mechanical stress of compression and contact of the incompatible excipient with the active ingredient.

Some ARBs also present problems when formulating, and the situation with water should be avoided, as deduced from the formulations described in the literature on valsartan (EP 1674080 A1).

For example, non-acidic powders, ilbesartan and valsartan, and adherent candesartan cilexetil, are very difficult to formulate into tablets or capsules due to their physical properties. Difficult (EP 0747050 B1, EP 1774967 A1, WO 2008/012372 A1).

Formulations such as losartan potassium salt suspensions, when light, break down and destroy the imidazole ring (Seburg RA et al.). al . J. Pharm . Biomed . Anal . 42: 411-422 (2006). Furthermore, losartan potassium salt is not stable in amorphous form, and tends to change to crystalline form with lower solubility and lower biological activity. This amorphous can then be stabilized using polymers for formulation into tablets (WO 2004/064834 A1, US 2006160871 A1). The same is true of Valsartan (US 2007166372 A1, US 2008152717 A1).

Candesartan cilexetil is stable against temperature, moisture and light in its isolated state, but degrades over time in the form of tablets with excipients. The main product of degradation is O- desethyl derivatives. These decompositions, caused by pressure, abrasion, and heat applied during granulation or high pressure forming processes, before compaction, are low-melting oil-containing substances (EP 0546358 B1), lipids or phospholipids (WO 2005/079751 A2). Other cosolvents (WO 2005/070398 A2), carbohydrates for adsorbate formation of the active ingredient (EP 1952806 A1), water soluble polymers (WO 2005/084648 A1), or methacrylate polymers with the amorphous active ingredient Can be reduced by inclusion in the formulation (EP 1997479 A1).

Compressive forces that promote degradation are inevitable in the manufacture of solid oral formulations in tablet form. An alternative to this solid oral dosage form is gelatin capsules.

Gelatin capsules, whether hard or soft, allow the active pharmaceutical ingredient to be incorporated into the capsule, but the protection of the active ingredient is not satisfactory if the substance is degradable or unstable with water or oxidizing agents.

Conventional gelatin capsules have an outer layer whose base component is gelatin, and in general, these capsules can be hard or soft, and soft capsules contain plasticizers. The coating layer of a conventional gelatin capsule consists of a single outer layer of uniform thickness and composition, the single outer layer covering the interior, which contains the active pharmaceutical ingredient mixed with a suitable excipient. The contents of the soft gelatin capsules are usually liquid or semi-liquid, oils, polar liquids, microemulsions, suspensions, waxes or colloids. The water content inside the liquid cannot exceed 20% so as not to dissolve the gelatin layer.

The outer layer of the capsule contains a certain amount of water as a component. However, the presence of water in the coating layer of conventional gelatin capsules is a serious problem if the active pharmaceutical ingredient or salt thereof formulated is water soluble, degradable in the presence of water or unstable when in contact with water. In fact, when producing soft gelatin capsules using common ingredients and techniques, either the production of the finished capsule or the storage of the finished capsule, either because the water in the coating layer partially diffuses towards the inside of the capsule or because some of the active ingredient contacts the capsule wall. In any case, it is impossible to prevent the active pharmaceutical ingredient contained in the capsule from contacting the water present in the gelatinous mass of the outer layer. The outer coating layer of the capsule contains not only water, but also conventional additives such as plasticizers, colorants, opacifiers, preservatives in a remarkable amount, so as to sufficiently prevent the incompatibility between these additives and the active ingredient or Control is also very difficult. These additives may accelerate the oxidation, degradation or hydrolysis process, resulting in the loss of activity of the formulated active ingredient (EP 0769938 B1). Another factor to consider is the possible chemical interaction between the contents of the capsule and the gelatin, which can easily cross-link and inhibit the solubility of the capsule in aqueous media ( Slow down the rate of capsule breakdown).

Thus, although soft gelatin capsules are widely used in the pharmaceutical industry, the use of soft gelatin capsules is not recommended for active ingredients that are unstable when an adequate amount of water is present.

In order to overcome the difficulty of formulating active ingredients that are susceptible to hydrolysis into soft gelatin capsules, EP 0769938 B1 describes not only one or more hydrophobic polymer layers underneath the gelatin layer, but also the silicone resin inside the capsule. The active ingredient, especially the active ingredient which may be an anti-cholesterol agent such as ACE inhibitor or omega-3 fatty acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), may be mixed, dissolved, Found in suspension or combined state. However, the process and manufacturing equipment require significant modification of the general method and equipment.

It is also known that formulations based on lipids increase the bioavailability of certain active pharmaceutical ingredients. Examples of formulations which utilize polyunsaturated fatty acids to increase the bioavailability of the active ingredient are described in the literature and are generally by emulsion formation. Thus, US 5447729 A consists of emulsions or dispersions of active ingredient particles, which may be active ingredients, inter alia ACE inhibitors, and a release system is proposed in which different hydrophobic and hydrophilic layers are alternately formed. Emulsions may be included in capsules or tablets, and long chain fatty acids such as linolenic acid, linoleic acid, or arachidonic acid are used in the formulation. WO 2006/135415 A2 describes microemulsion formulations formed by nanoparticles of acids such as eicosapentaenoic acid (EPA), among others comprising an active pharmaceutical ingredient such as an ACE inhibitor or ARB. In all these cases, contact with water or excipients of the formulations that cause degradation of many active ingredients is inevitable.

In particular, formulations for minimizing degradation of ACE inhibitors and ARBs, as well as other examples in the literature regarding formulations that may contain polyunsaturated fatty acids for the same purpose, are mentioned.

As already mentioned, in WO 2005/079751 A2 candesartan cilexetil was stabilized in tablets by adding lipids or phospholipids to the composition. The lipid may be a fatty acid such as linoleic acid and / or arachidonic acid or a glyceryl ester thereof.

WO 2007/103557 A2 is a solution to the problem of chemical incompatibility in compositions with two or more active pharmaceutical ingredients, comprising one or more capsule coating layers comprising a first active ingredient such as omega-3 fatty acids, said capsule coating layers At least one of them consists of a polymer combined with another active ingredient, such as enalapril, wherein the coating layer comprising the active ingredient is contained in the capsule and optionally in the hard or soft gelatin capsule separated from the outside by additional coating layers. Suggested physical separation of components. However, due to the fragility and water-soluble nature of the gelatin coating layer, the manufacturing process is complicated, and strict control of temperature and deposition rate is required during coating.

In WO 2006/081518 A2, complexes of these active ingredients and ion exchange resins have been prepared to achieve controlled release of several active pharmaceutical ingredients such as antihypertensive agents. The complex is a polymer coating layer suspended in alcohol, polyols, oils, triglycerides or waxes, among which non-ionic and non-aqueous vehicles ("NINA" media), such as omega-3. Or there is no such polymer coating layer. The active pharmaceutical ingredient must contain an acid or base functional group to form such a complex. Furthermore, in the examples of this document, these formulations are administered only by topical route. The use of resinates for oral administration is controversial because administration of large amounts of ion exchange resins or their long-term use in chronic treatment can alter the inter-ion binding capacity of gastrointestinal fluids, leading to electrolyte imbalance.

While most of the references described address attempts to address instability problems associated with pharmaceutical compositions comprising ACE inhibitors and / or ARBs, the problems arising from the above techniques may improve the stability of these pharmaceutical compositions, particularly in the presence of moisture. There is a need. The solution proposed by the present invention is a pharmaceutical capsule comprising an alkyl ester of polyunsaturated fatty acid and microcapsules of the desired active ingredient separated into polymers.

Subject of the present invention is a pharmaceutical composition in the form of a capsule that can better protect the active pharmaceutical ingredient from possible chemical interactions with moisture, oxidants and / or additives of the outer coating layer. Pharmaceutical capsules of the present invention can conveniently formulate active pharmaceutical ingredients known for their instability, such as angiotensin converting enzyme inhibitors (ACE inhibitors) and / or angiotensin II receptor blockers (ARBs), thus providing a polymeric coating of active pharmaceutical ingredients And by separation of the suspension suspended in a polyunsaturated fatty acid alkyl ester thereof, it is possible to prevent degradation of the active pharmaceutical ingredient.

Accordingly, the present invention provides new pharmaceuticals that can prevent the problem of active pharmaceutical ingredients such as angiotensin converting enzyme inhibitors (ACE inhibitors) and / or angiotensin II receptor blockers (ARBs) being degraded when formulated into pharmaceutical capsules for oral administration. To a red composition.

In one aspect, the invention is a pharmaceutical capsule comprising a suspension of polymer microcapsules comprising at least one polymer and an active pharmaceutical ingredient selected from the group consisting of ACE inhibitors and ARB, wherein the microcapsules are polyunsaturated fatty acid alkyls. A pharmaceutical capsule is suspended in an oil containing an ester. The polymer of the microcapsules constitutes the outer portion and provides a complete coating for the active pharmaceutical ingredient in the capsule.

In the pharmaceutical capsule of the present invention, the active pharmaceutical ingredient is found inside the polymer microcapsules suspended in an oil containing an alkyl ester of polyunsaturated fatty acid. The active pharmaceutical ingredient is separated from both the external medium and the polyunsaturated fatty acid alkyl ester via the polymer, and the polymer is readily degraded in the gastrointestinal tract medium. The pharmaceutical capsules of the present invention not only allow the combined administration of the active pharmaceutical ingredient in combination therapy, but also allow the active pharmaceutical ingredient to be separated from external moisture and oxygen as well as moisture and capsule coating additives. The polymer coating layer provides stability to the active pharmaceutical ingredient, and prevents decomposition, production by moisture, compression, and high temperature during preparation of the final composition in the form of a pharmaceutical capsule.

Preferably, the fatty acid of the polyunsaturated fatty acid alkyl ester belongs to the omega-3 family. Preferably, the polyunsaturated fatty acid is EPA (Eicosapentaenoic acid, ( all - cis ) -5,8,11,14,17-eicosapentaenoic acid, eicosapentaenoic acid, timnodonic acid, icosapent (C20: 5 n -3)), DHA (docosahexaenoic acid, ( all - cis ) -4,7,10,13,16,19-docosahexaenoic acid, docosahexaenoic acid, cervonic acid, doconexent (C22: 6 n -3)) It is selected from, and / or ohmako (Omacor®), Rover chair (Lovaza®), or the group consisting of a mixture of EPA and DHA, such as jodin (Zodin®). In a preferred embodiment the EPA: DHA relationship may vary from 100: 0 to 0: 100, preferably from 4: 1 to 1: 4, more preferably from 1: 2 to 2: 1. The polyunsaturated fatty acid may comprise only EPA or only DHA.

Preferably, the alkyl radical of the polyunsaturated fatty acid alkyl ester is selected from the group consisting of short chain alkyl radicals having 1 to 8 carbon atoms. Preferably, the alkyl radical is selected from the group consisting of ethyl, methyl, propyl, butyl and / or mixtures thereof. More preferably, the alkyl radical is an ethyl group.

Preferably, the oil comprising the polyunsaturated fatty acid alkyl ester is an oil enriched in polyunsaturated fatty acid alkyl ester, wherein the oil contains more than 50% polyunsaturated fatty acid alkyl ester, more preferably more than 60% Polyunsaturated fatty acid alkyl esters, more preferably greater than 85% polyunsaturated fatty acid alkyl esters.

In a preferred embodiment, the content of the polyunsaturated fatty acid alkyl esters contained in the pharmaceutical capsules of the present invention is comprised between 0.01 and 4 g, preferably between 0.1 and 2 g.

In one embodiment, the active pharmaceutical ingredient is captopril, enalapril, enalaprilat, ramipril, quinapril, quinapril, perindopril, Lisinopril, benazepril, fosinopril, spirapril, trandolapril, moexipril, morazipril, cilazapril, imida Imidapril, rentapril, temoapril, alacepril, delapril, moveltipril, zofenopril, pentopril ), Libenzapril, pivopril, ceronapril, indolapril, teprotide, pharmaceutically acceptable salts thereof and acids thereof Angiotensin converting enzyme inhibitors selected from the group without limitation.

In another embodiment, the active pharmaceutical ingredient candesartan, eprosartan, ilbesartan, losarartan, olmesartan, olmesartan, telmisartan (telmisartan), valsartan, tasosartan, pratosartan, azilsartan, saralasin, ripisartan, elisartan ), Milfasartan, embusartan, fonsartan, fonsartan, saprisartan, zolasartan, forasartan, pomisartan ), AVI Te Sar Tan (abitesartan), castor oil Sar Tan (fimasartan), N-benzyl-losartan (N -benzyl-losartan), enol Tasso Sar Tan (enoltasosartan), glycidyl shot chamber Sar (glycyl-losartan), Va'a-o Opomisartan, trityl-losartan, sarmesin, isoteolin, and pharmaceutically acceptable salts thereof An angiotensin II receptor blocker is selected from the group consisting of, without limitation.

The polymer of the microcapsules of the pharmaceutical capsule of the present invention is without limitation in the group consisting of proteins, polysaccharides, polyesters, polyacrylates, polycyanoacrylates, polyethylene glycols and / or mixtures thereof Is selected. Preferably, the polymer of the microcapsules is gelatin, albumin, alginates, carrageenans, pectin, gum arabic, chitosan, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose, HPMC) Nitrocellulose, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate succinate), polyvinyl acetate phthalate (polyvinyl acetate phthalate), poly (ε- caprolactone) (poly (ε-caprolactone) ), poly (p - dioxanone) (poly (p -dioxanone)) , poly (δ- Valerolactone) (poly (δ-valerolactone)), poly (β-hydroxy Poly (β-hydroxybutyrate), poly (β-hydroxybutyrate) copolymer, β-hydroxyvalerate, and poly (β-hydroxypropyrate) Cypionate) (poly (β-hydroxypropionate)), methacrylic acid copolymers (Eudragit® L and S), dimethylaminoethyl methacrylate copolymer (eudragit E), trimethylammonium ethyl methacrylate Latex copolymers (eudragit RL and RS), polymers and copolymers of lactic acid and glycolic acid and polyethylene glycol, and / or mixtures thereof.

Optionally, the polymer of the microcapsules of the pharmaceutical capsule of the present invention may comprise a plasticizer additive. The plasticizer additives include triethyl citric acid, tributyl citric acid, acetyl tributyl citric acid, citric acid alkyl esters such as acetyl triethyl citric acid, phthalates such as butyl phthalate and diethyl phthalate, glycerin, sorbitol, maltitol, propylene glycol, polyethylene glycol, glucose, Metal salts of fatty acids such as sucrose, lanolin, palmitic acid, oleic acid, stearic acid, stearic acid or palmitic acid, sodium stearate, potassium stearate, propylene glycol monostearate Acetylated monoglycerides or triacetin, glyceryl lecithin, glyceryl monostearate, such as monoacetylated glycerin and glyceryl triacetate. alkyl sebacates, alkyl fumarates, alkyl succinates, medium chains such as yl monostearate, dibutyl sebacate or diethyl sebacate Triglycerides (medium chain triglycerides, MCT), lysine oil (ricin oil), hydrogenated vegetable oils (hydrogenated vegetable oils), waxes and / or mixtures selected from the group consisting of.

Optionally, other technical additives of the polymer that enhance or promote the encapsulation process, such as fluidifying agents such as talc, colloidal silicon dioxide, glycerin, polyethylene glycol, glycerin monostearate and / or metal stearate salts, May be included.

Optionally, the pharmaceutical capsule of the present invention is butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tertiary butylhydroquinone (tert-butylhydroquinone (TBHQ), propyl gallate (propyl) gallic acid esters such as gallate, tocopherols such as vitamin E acetate, ascorbic acid esters such as ascorbyl plamitate and ascorbyl acetate, carnitine and / or mixtures thereof, But not limited to, at least one antioxidant. Preferably, the antioxidant is vitamin E acetate.

In one embodiment, the microcapsules comprise 0.001% to 80%, preferably 0.01% to 60%, more preferably 0.1% to the total weight of the pharmaceutical capsule of the present invention. 50%.

The amount of active pharmaceutical ingredient contained in these microcapsules comprises 1% to 80% by weight, preferably 1% to 60% by weight relative to the total weight of the microcapsules. The total amount of active pharmaceutical ingredient contained in the pharmaceutical capsule of the present invention depends on the daily dose.

The pharmaceutical capsule of the present invention is not particularly limited as long as it is a gelatine or a polymer generally used for preparing capsules in the pharmaceutical industry. For example, hydroxypropyl methylcellulose (HPMC), pullulan, and denaturation. Hard or soft capsules of starch, carrageenan and / or mixtures thereof. Preferably, the pharmaceutical capsule is a gelatin capsule. More preferably, this capsule is made of soft gelatin. Optionally, the capsule has an enteric coating layer. The capsule coating layer may include other additives such as plasticizers, colorants, pigments, opacifiers, preservatives, humectants, surfactants, sweeteners and / or flavors. The preparation of the capsules is done through conventional procedures in the pharmaceutical industry, and may be of any shape and size known to those skilled in the art.

The preparation of the microcapsules can be done according to any of the methods described in the literature. For the sake of explanation, various methods for obtaining microcapsules may be divided as follows, but are not limited thereto.

A) simple coacervation procedure

A solution consisting of the polymer and its potential additives is prepared in a suitable solvent. The active pharmaceutical ingredient to be encapsulated is suspended in the polymer solution, and a solvent in which the polymer is not dissolved is added to deposit the polymer on the crystal of the active ingredient. Examples of such methods can be found in literature such as ES 2009346 A6, EP 0052510 A2, and EP 0346879 A1.

B) complex coacervation procedure

This method, based on the interaction between two colloids with opposite charges, creates an insoluble complex that is deposited on the particles of the active pharmaceutical ingredient to be encapsulated to form a membrane that separates the active ingredients. Examples of such methods can be found in literature such as GB 1393805 A.

C) double emulsion procedure

The active pharmaceutical ingredient to be encapsulated is dissolved in water or other auxiliaries solution and emulsified in a solution in which the polymer and additives are dissolved in a suitable solvent such as dichloromethane. The resulting emulsion is emulsified again in an aqueous solution of an emulsifier such as water or polyvinyl alcohol. When this second emulsification is carried out, the solvent in which the polymer and the plasticizer are dissolved is removed by evaporation or extraction. The resulting microcapsules are obtained directly by filtration or evaporation. Examples of such a method can be found in literature such as US 4652441 A.

D) simple emulsion procedure

The active pharmaceutical ingredient, the polymer, and the additive to be encapsulated are dissolved together in a suitable organic solvent. This solution is emulsified in an aqueous solution of an emulsifier such as water or polyvinyl alcohol, and the organic solvent is removed by evaporation or extraction. The resulting microcapsules are recovered by filtration or drying. Examples of such methods can be found in literature such as US 5445832 A.

E) solvent evaporation procedure

The active pharmaceutical ingredient, the polymer, and the additive to be encapsulated are dissolved together in a suitable organic solvent. The solution is evaporated and the resulting residue is micronized to a suitable size or dried by spray-drying. Examples of such methods can be found in literature such as GB 2209937 A.

Another aspect of the invention relates to the pharmaceutical capsule of the invention for the treatment and / or prevention of cardiovascular disease. Preferably, the cardiovascular disease is selected from the group consisting of hypertension, heart failure, and myocardial infarction.

Another aspect of the present invention relates to a method of treating and / or preventing cardiovascular disease comprising administering the pharmaceutical capsule of the present invention. Preferably, the cardiovascular disease is selected from the group consisting of hypertension, heart failure, and myocardial infarction.

The following specific examples provided herein illustrate the nature of the invention. These examples are included for illustrative purposes and should not be construed as limiting the invention claimed below.

< Example >

Example  Simple Coacervation method  Having through gelatin Ramipril  Preparation of Pharmaceutical Capsules Containing Microcapsules

A 1% gelatin aqueous solution was prepared.

100 mL of this solution was taken and 1 g of ramipril powder was dispersed in the solution. Then 30 mL of saturated aqueous sodium sulfate solution was added. After stirring the mixture for 1 hour, 0.5 mL of 50% aqueous glutaraldehyde solution was added.

The microcapsules formed by filtration were collected, washed with water and dried in a vacuum drying oven. The ramipril content of this microcapsules was 35%.

The obtained microcapsule powder was directly dispersed in an oil containing at least 90% of polyunsaturated fatty acid ethyl ester containing at least 85% of EPA / DHA in a 1.2: 1 ratio (a 719 mg microcapsule suspension per 100 g of oil was obtained). Next, 1.00 g of the microcapsule dispersion dispersed in the oil was included in the soft gelatin capsule to obtain 2.5 mg of ramipril per capsule.

Example  2. Trandoraphril  Microcapsules and Poly ( Lactic -nose- Glycolic acid ) ( poly ( lactic - co - glycolic acid )) ( PLGA ) And the preparation of pharmaceutical capsules containing vitamin E. Preparation of the microcapsules by a simple emulsification method (in oil-in-water).

A solution: A dichloromethane (DCM) A solution of 10% PLGA having an intrinsic viscosity (I.V.) of 0.17 and a lactic acid / glycolic acid ratio of 1: 1 was prepared.

B solution: 5 g of transdorapril and 1 g of vitamin E acetate were dissolved in 100 mL of A solution.

C solution: A 1% polyvinyl alcohol (PVA) aqueous solution was prepared.

100 mL of B solution to 1000 mL of C solution was stirred vigorously with slow addition until a milky or rare emulsion was obtained. In the stirring process, nitrogen was flowed into the emulsion for two hours to remove most of dichloromethane. Thereafter, the obtained suspension was lyophilized. To remove excess polyvinyl alcohol with a large amount of water and dried under reduced pressure to obtain a powder.

The resulting microcapsule powder contained 31% of transdorapril and was directly dispersed in an oil containing at least 60% of polyunsaturated fatty acid ethyl esters containing at least 40% of DHA. Next, the microcapsule dispersion in the oil thus obtained was included in the soft gelatin capsule. The amounts used to prepare capsules with different sizes and amounts of transdorapril are shown in Table 1.

Example  3. Triple emulsification triple emulsion method )On by Lisinopril  Microcapsules and Poly ( Lactic-co-glycolic acid) (PLGA Preparation of a pharmaceutical capsule comprising).

Solution A: 5 g PLGA having an intrinsic viscosity (I.V.) of 0.4 dL / g and a lactic acid / glycolic acid ratio of 1: 1 was dissolved in 50 mL of dichloromethane (DCM).

Solution B: 1.08 g of lisinopril dihydrate was dissolved in 10 mL of water.

C solution: A polyvinyl alcohol (PVA) aqueous solution was prepared at a concentration of 0.5% p / v.

The aqueous phase (B solution) was emulsified in a PLGA solution (A solution) using an Ultra Turrax homogenizer (water-in-oil emulsion).

The prepared water-in-oil emulsion was added to 1 L of aqueous polyvinyl alcohol solution (C solution) with vigorous stirring. While stirring the newly formed emulsion, dichloromethane was evaporated by flowing nitrogen into the reactor at a rate of 50 L or more per minute. The microcapsules were recovered by filtration through a membrane with a pore diameter of 5 μm. It was then washed with sufficient water to remove excess polyvinyl alcohol and lyophilized.

The resulting microcapsule powder contained 16% lisinopril and was directly dispersed in an oil containing at least 90% polyunsaturated fatty acid ethyl ester containing at least 85% EPA / DHA at a ratio of 1.2: 1 (100 g of oil). 1.59 g of sugar microcapsule suspension were obtained). Next, 1.00 g of the microcapsule dispersion dispersed in the oil was included in the soft gelatin capsule to obtain 2.5 mg of ricinopril per capsule.

Example  4. Composite In coacervation law  by Candesartan Cilexetil  With microcapsules and gelatin Carboxymethyl Cellulose  Preparation of a pharmaceutical capsule comprising.

A solution: A 1% gelatin aqueous solution was prepared to adjust the pH to be equal to or higher than 7.

B solution: A 1% sodium carboxymethylcellulose aqueous solution was prepared to adjust pH to equal or higher than 7.

250 mL of A solution and 250 mL of B solution were mixed and heated to 40 ° C. 4 g of powdered candesartan cilexetil were dispersed in the mixture. When all powders were dispersed and free of lumps, the pH was adjusted to 4 to 4.5 by adding acetic acid. After the mixture was stirred at 40 ° C. for 1 hour, the mixed solution was cooled to 10 ° C. and maintained at this temperature for 1 hour. 2 mL of 50% glutaraldehyde aqueous solution was added.

The resulting suspension was dried by spray drying to obtain a microcapsule powder containing 40% of candesartan cilexetil.

This microcapsule powder was directly dispersed in an oil containing at least 90% polyunsaturated fatty acid ethyl ester containing at least 85% EPA / DHA at a ratio of 1.2: 1. Next, the microcapsule dispersion dispersed in oil was included in the soft gelatin capsule. The amounts used to prepare capsules of different sizes and candesartan cilexetil fractions are shown in Table 2.

Example  5. Valsartan  Preparation of pharmaceutical capsules comprising microcapsules and methacrylic acid copolymers.

10 g of valsartan is placed in 100 mL of Eudragit FS 30D® (suspension with 30% methacrylic acid, methylmethacrylate and methyl acrylate copolymer in water) suspension until fine suspension is obtained. I was. Triethyl citrate was added to this suspension (polymer plasticizer) to a 5% concentration.

The resulting suspension was dried by spray drying to obtain a microcapsule powder containing 22% of valsartan.

The obtained microcapsule powder was directly dispersed in an oil containing at least 65% of polyunsaturated fatty acid ethyl ester containing at least 45% EPA / DHA in a ratio of 1.2: 1 (25.0 g of microcapsule suspension was obtained per 100 g of oil). Next, 1.00 g of the microcapsule dispersion dispersed in the oil was included in the soft gelatin capsule to obtain 40 mg of valsartan per capsule.

Example  6. Polyunsaturated Fatty Acids Alkyl  In oils containing esters Suspended Ramipril , Trandoraphril, Lisinopril , Candesartan Cilexetil , And Valsartan  Stability Study of Soft Gelatin Capsules Containing Microcapsule Suspensions.

A soft gelatin capsule comprising a suspension in which the active pharmaceutical ingredient is suspended in an oil containing a polyunsaturated fatty acid alkyl ester.

a) the active pharmaceutical ingredient comprises a soft gelatin capsule (control composition) without a polymer coating layer,

b) The active pharmaceutical ingredient is accelerated stability (accelerated stability, 40 ± 2 ° C, 75 ± 5% RH) in the soft gelatin capsule (composition of the present invention) contained in the microcapsules prepared according to the embodiments The test was performed.

After 1 month, 2 months, 3 months and 4 months of storage in a amber glass bottle, the percentage of the active pharmaceutical ingredient in the capsule was confirmed by HPLC. Percentages of the active pharmaceutical ingredients are shown in Table 3.

The stability of polyunsaturated fatty acids (alkyl ester concentrations of EPA and DHA and EPA / DHA ratio) was also investigated by gas chromatography, but no changes were observed in the composition.

Claims (17)

A suspension of polymer microcapsules comprising at least one polymer and an active pharmaceutical ingredient selected from the group consisting of angiotensin converting enzyme inhibitors and angiotensin receptor blockers, the microcapsules suspended in oils containing polyunsaturated fatty acid alkyl esters. Pharmaceutical capsules. The method of claim 1,
The polyunsaturated fatty acid of the polyunsaturated fatty acid alkyl ester is a pharmaceutical capsule belonging to the omega-3 series. The method of claim 2,
Wherein said polyunsaturated fatty acid of said polyunsaturated fatty acid alkyl ester is selected from the group consisting of eicosapentaenoic acid, docosahexaenoic acid, and / or mixtures thereof. The method of claim 1,
The alkyl radical of the polyunsaturated fatty acid alkyl ester is a pharmaceutical capsule selected from the group consisting of short chain alkyl radicals having 1 to 8 carbon atoms. The method of claim 4, wherein
Wherein said alkyl radical of said polyunsaturated fatty acid alkyl ester is selected from the group consisting of ethyl, methyl, prokill, butyl and / or mixtures thereof. The method of claim 1,
The oil is a pharmaceutical capsule containing more than 50% polyunsaturated fatty acid alkyl ester. The method of claim 1,
The angiotensin converting enzyme inhibitor is captopril, enalapril, enalapril, enalaprilat, ramipril, quinapril, perindopril, lisinopril, lisinopril. ), Benazepril, fosinopril, spirapril, trandolapril, trandolapril, moexipril, silazapril, cilazapril, imidapril, Rentiaapril, temocapril, alacepril, delapril, moveltipril, zofenopril, pentopril, ribenzapril (libenzapril), pivopril, ceronapril, indolapril, teprotide, pharmaceutically acceptable salts thereof and acids thereof. Ever capsule. The method of claim 1,
The angiotensin II receptor blocker candesartan (candesartan), eprosartan (eprosartan), ilbesartan (irbesartan), losarartan (olmesartan), telmisartan, telmisartan, valsartan ( valsartan, tasosartan, pratosartan, azilsartan, azalasarin, saralasin, ripisartan, elisartan, milpasartan ( milfasartan, embusartan, fonsartan, saprisartan, zolasarartan, forasartan, pomisartan, abitesartan (abitesartan), castor oil Sar Tan (fimasartan), N-benzyl-losartan (N -benzyl-losartan), enol Tasso Sar Tan (enoltasosartan), glycidyl shot chamber Sar (glycyl-losartan), US Va'a-o-Sar Tan (opomisartan) , Trityl-losartan, sarmesin, isoteolin and their pharmaceutically acceptable salts. The pharmaceutical capsule is selected from the group true. The method of claim 1,
Wherein the polymer of the microcapsules is selected from the group consisting of proteins, polyesters, polyacrylates, polycyanoacrylates, polysaccharides, polyethylene glycols, and / or mixtures thereof. 10. The method of claim 9,
The polymer of the microcapsules is gelatin, albumin, alginates, carrageenans, pectin, gum arabic, chitosan, carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose (HPMC), nitrocellulose ( nitrocellulose, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate-succinate, poly polyvinyl acetate phthalate (polyvinyl acetate phthalate), poly (ε- caprolactone) (poly (ε-caprolactone)), poly (p - dioxanone) (poly (p -dioxanone)), poly (lactone δ- ballet) (poly (δ-valerolactone)), poly (β-hydroxybutyrate) (poly (β-hydroxybutyrate), poly (β-hydroxybutyrate) and β-hydroxyvalerate copolymer, poly (β-hydroxypropionate) (poly (β-hydroxypropionate)), methacrylic acid copolymer, dimethylaminoethyl methacrylate copolymer, trimethylammonium ethyl methacrylate copolymer, polymers and copolymers of lactic acid and glycolic acid and polyethylene glycol and / or mixtures thereof Pharmaceutical capsules selected from the group. The method of claim 1,
The microcapsules are 0.001% to 80% of the total weight of the capsule. The method of claim 1,
The amount of the active pharmaceutical ingredient contained in the microcapsules is 1 to 80% by weight pharmaceutical capsules. The method of claim 1,
Wherein said polymer of said microcapsules comprises at least one plasticizer, a fluidizing agent and / or an antioxidant. The method of claim 1,
The composition of the coating layer of the capsule is gelatin, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), pullulan (pullulan), modified starch, carrageenan and / or a mixture thereof. 15. The method of claim 14,
The coating layer is a pharmaceutical capsule made of soft gelatin. The method of claim 1,
Capsule is a pharmaceutical capsule comprising an enteric coating layer. The method of claim 1,
Pharmaceutical capsules for the treatment and / or prevention of cardiovascular diseases.