UA112855C2 - BENZIMIDASOL COMPOSITIONS WITH MODIFIED RELEASE - Google Patents

Abstract

The invention relates to a pharmaceutical composition which comprises, in combination: a) particles containing omeprazole or a salt thereof and having a release release polymer coating containing a combination of at least one pH-independent polymer and at least one pH-dependent polymer, the coating being soluble at pH values from 5 to 7.5; and (b) particles containing omeprazole or its salt and having a polymer coating soluble at pH values of 5 to 6.

Description

Aspects of this application relate to pharmaceutical compositions that include a drug based on substituted benzimidazole, and methods of obtaining such compositions. Particular aspects relate to compositions comprising omeprazole. Aspects further relate to therapeutic uses and methods of treatment using compositions comprising omeprazole, including methods of treating disorders associated with gastric acid secretion.

Certain substituted benzimidazole derivatives, including rabeprazole, omeprazole, esomeprazole, lansoprazole, pantoprazole, and mixtures thereof, are known to be useful in inhibiting gastric acid secretion in mammals and humans by controlling gastric acid secretion at the final step of the acid secretory pathway. These active ingredients are acid-labile, creating some problems in formulating such acid-labile compounds into oral dosage forms, due to the acidic environment of the stomach. In particular, these drugs will quickly decompose and change color in wet conditions or in an aqueous solution from acidic to neutral.

When these compounds are formulated into pharmaceutical preparations for oral administration, special technical techniques are required to avoid contact of the medicinal product with the gastric acid of the stomach. One technique used involves coating an acid-labile compound or granules or pellets (solid spherical particles with a coating) containing such compound with an enteric coating that is water-insoluble under acidic conditions and water-soluble under neutral to alkaline conditions. . However, the substance used in enteric coatings is itself acidic, which can cause decomposition of the acid-labile compound. Such decomposition occurs even in the process of applying an enteric coating, which leads to discoloration of the surface of the nuclei that contain the drug. To avoid such problems, an inert coating in the form of a non-acidic sub-layer can be provided between the drug-containing core and the enteric coating.

For substances that are labile in an acidic environment, but have better stability in a neutral to alkaline environment, it may be beneficial to add alkaline inactive excipients to increase the stability of the active compound during manufacturing and storage.

In particular, substituted benzimidazole derivatives, such as omeprazole, esomeprazole, etc., are not only unstable in acidic conditions, but also unstable in a neutral solid state.

Therefore, in order to improve storage stability, an alkaline base such as sodium bicarbonate or magnesium carbonate can be added to the compositions, and/or substituted benzimidazole derivatives can be converted into their alkaline base salts, which are usually more stable than the free compounds. .

Among the active ingredients used in this invention, a substituted benzimidazole compound can be specified, which has the chemical name 5-methoxy-2-|(4-methoxy-3,5-dimethyl-2-pyridinyl)methylisulfinyl|-1H-benzimidazole , and represented by the structural formula I, hereinafter referred to in this application under its registered name "omeprazole". . M is! M

She", - u

Nz3o

Formula

Omeprazole is the active ingredient in products sold as REIGO5ES- prolonged-release capsules containing 10 mg, 20 mg or 40 mg of omeprazole in the form of enteric-coated granules, and is marketed by Abviga-7epesa. Long-acting RKIOBES capsules contain the following inactive ingredients: cellulose, disodium hydrogen phosphate, hydroxypropyl cellulose, hypromellose, lactose, mannitol, sodium lauryl sulfate and other ingredients. Capsule shells contain the following inactive ingredients: gelatin-ME, EOZZ blue

I, PrasC red 540, O5C red 228, titanium dioxide, synthetic black iron oxide pigment, isopropyl alcohol, butyl alcohol, ROS blue 22, 08. red 7 calcium varnish and, in addition, 10 mg and 40 mg capsule shells also contain OS yellow 210.

US Patent No. 7,790,755 discloses a controlled release formulation, in particular a capsule comprising a tablet, granule, or small particle where the release of the active ingredient is controlled and a gelling polymer that slows the rate of migration in the gastrointestinal tract. This provides a controlled release drug, where the release of the active ingredient of the drug is controlled, which releases the active ingredient over a long period of time with a stop or slow migration in the gastrointestinal tract.

US Patent No. 5,175,003 discloses a dual drug release mechanism using a polymer mixture consisting of pH-sensitive enteric substances and film-forming plasticizers capable of imparting permeability to the enteric substance for use in drug delivery systems; a matrix granule, which consists of a polymer mixture with a dual mechanism, which is impregnated with a drug and sometimes covers a pharmaceutically neutral core; a coated granule comprising a matrix granule coated with a polymer mixture with a double mechanism in the form of a shell having the same or a different composition; and a pharmaceutical dosage form containing matrix granules. The matrix granule releases acid-soluble drugs by diffusion under acidic pH conditions and by decomposition at pH levels nominally around 5.0 or higher.

US patent Mo 7635490 discloses a dosage form that includes at least one active ingredient and a first core and a second core that are surrounded and separated by a shell. Such a dosage form provides a delay of at least 1 hour between the initial release of the active ingredient contained in said first core and the initial release of the active ingredient contained in said second core after contacting the dosage form with a liquid medium.

US Patent Application Publication Mo 2009/0214599 discloses a pharmaceutical composition comprising at least one proton pump inhibitor structured and organized to provide an initial pH-dependent time-delayed release and a pH-dependent sustained release of the at least one proton pump inhibitor. These delivery systems are designed to provide unique PPI release rates, and especially for compositions designed to treat conditions associated with stomach acid, particularly to counteract nocturnal acid spikes. The compositions, in particular, contain compositions of the proton pump inhibitor, which include a pH-dependent protective layer, and demonstrate a pH-dependent prolonged effect.

US Patent Application Publication Mo 2009/0028941 discloses dosage forms for sustained and pulsed release of therapeutic agents in the stomach. There are such dosage forms

With dosage forms that are retained in the stomach, which achieve the release of the therapeutic agent in the stomach and upper gastrointestinal tract after the administration of the dosage form. These dosage forms find specific use for the administration of acid-labile active agents, such as proton pump inhibitors, and for the treatment of disorders of gastric acid secretion, such as gastroesophageal reflux (GERD) and nocturnal acid reflux (NAB).

US Patent No. 6,013,281, the entire content of which is incorporated by reference, discloses that the separation layer is formed by directly applying an acidic enteric soluble substance to an alkaline core containing benzimidazoles.

US Patent Application Publication No. 2007/0141137 describes a formulation in capsule form that includes a drug that is unstable to moisture, stable at low humidity, and has pH-independent decomposition properties.

There is a need to provide pharmaceutical compositions comprising omeprazole or its esomeprazole derivative or a pharmaceutically acceptable salt to provide effective plasma concentrations of the active substance over a long period of time.

Brief description of the invention

Aspects of the present disclosure relate to modified release drug compositions comprising at least one benzimidazole compound, such as omeprazole, for oral administration, together with one or more excipients.

In some embodiments, the present invention provides dosage forms that include a first part of the drug that has a delayed release from the dosage form after oral administration and a second part of the drug that has a sustained release from the dosage form after oral administration.

In some embodiments, the present invention provides modified release omeprazole compositions that are in the form of solid multiparticulates or solid multiparticulates that are encapsulated.

Brief description of the drawings

Fig. 1 represents the dissolution profile of the composition obtained in example 3.

Fig. 2 represents the dissolution profile of the composition obtained in example 13, using 0.1 N HCl for the first 2 hours, then pH 6.5 Break buffer, with 900 ml of medium and stirring using a paddle mixer at 75 rpm. 60 Detailed description of the invention

Aspects of the present disclosure relate to modified release drug compositions comprising at least one benzimidazole drug, such as omeprazole, together with one or more excipients, for oral administration.

In some embodiments, the present invention provides dosage forms comprising a first drug portion that has a delayed release from the dosage form after oral administration and a second drug portion that has a sustained release from the dosage form after oral administration.

In some embodiments, the present invention provides modified release omeprazole compositions that are in the form of solid multiparticulates or solid multiparticulates that are encapsulated.

In some embodiments, the present invention provides modified release compositions where the benzimidazole drug is a proton pump inhibitor such as omeprazole, esomeprazole, lansoprazole, or dexlansoprazole.

In some embodiments, the present invention provides stabilized modified-release omeprazole compositions comprising at least two fractions of solid multiparticulates, wherein at least one fraction is in the form of immediate release, delayed release, sustained release, sustained release over an extended period of time, pulsed release or sustained release.

In some embodiments, the present invention provides modified-release omeprazole compositions comprising at least two fractions, wherein the mass ratios of the first and second solid multiparticulate fractions vary from about 1:9 to about 9:1.

In some embodiments of the invention, the delivery carrier includes a component that protects at least part of the dose from inactivation due to exposure to the acidic environment of the stomach.

In some embodiments of the invention, this disclosure relates to compositions of omeprazole with a dual type of release, including, in combination: (a) omeprazole; and (B) polymeric excipient; where the polymeric excipient acts to provide an initial pH-dependent release with a time delay and a pH-dependent sustained release of the drug.

In some embodiments of the invention, the first part of the drug is released from the dosage form less than about 60 minutes after taking the dosage form. In some embodiments of the invention, the second part of the drug is released from the dosage form within about 2 hours to about b hours after taking the dosage form.

In some embodiments, the present invention provides modified release compositions comprising omeprazole, esomeprazole, lansoprazole or dexlansoprazole.

Omeprazole is used in the following discussion as a representative representative of the entire class of substituted benzimidazole drugs, but this application is not limited to the use of this particular drug.

In some embodiments, this application includes methods of obtaining dosage forms of omeprazole, which include: a) applying a layer of suspension, dispersion or solution of omeprazole and at least one water-soluble excipient on particles of a pharmacologically inert substance; r) optional, applying an intermediate coating; c) applying an enteric coating that surrounds the core a) or intermediate layer B); a) optionally, applying a release-controlling coating layer on top of c), where the release-controlling coating layer is a diffusion-controlling layer, a gel-forming polymer layer, a pH-dependent soluble layer, a sustained-release coating layer, or any combination thereof; and f) combining the composition with at least one pharmaceutically acceptable excipient.

In some embodiments of the invention, the drug stabilizer may be present in the sublayer of the coating.

In some embodiments, this application relates to stabilized modified release compositions that contain omeprazole and a water-soluble excipient such as polyvinylpyrrolidone.

In some embodiments, the present invention provides methods of obtaining an omeprazole composition, which include: a) layering a suspension, dispersion or solution of omeprazole, a water-soluble excipient and a dissolution-enhancing agent, together with one or more other pharmaceutically acceptable excipients on particles of a pharmacologically inert substance;

p) optional, applying an intermediate coating and drying; c) applying an enteric coating that surrounds the core a) or the intermediate layer b); a) optional, applying a release-controlling coating layer on top of c), where the release-controlling coating layer is a diffusion-controlling layer, a gel-forming polymer layer, a pH-dependent soluble layer that provides a long-term release coating layer or any combination thereof; and f) combining the obtained composition with at least one pharmaceutically acceptable excipient.

The modified release compositions disclosed in this application are intended to provide effective plasma concentrations of the active agent contained therein for a long period of time after administration.

In some embodiments of the invention, the omeprazole used to obtain the compositions or contained in the compositions is present in an amorphous form or in one or more crystalline forms or in the form of a mixture of such forms. In some embodiments of the invention, omeprazole, which is used as an active agent, is present in an essentially amorphous form, while this form is essentially preserved in the process of obtaining the composition, as well as in the process of storing the composition for acceptable, from a commercial point of view, periods of time. In some embodiments of the invention, the omeprazole used as an active agent is present in an essentially crystalline form, while such form is essentially preserved in the process of obtaining the composition, as well as in the process of storing the composition for acceptable, from a commercial point of view, periods of time.

In some embodiments, the present invention provides compositions of modified release of omeprazole that are in the form of solid multiparticulates or solid multiparticulates placed in capsules.

In some embodiments of the invention, the omeprazole compositions disclosed in this application are in the form of pellets or mini-tablets placed in capsules.

In some embodiments of the invention, the omeprazole compositions disclosed in this application include only one fraction of solid multiparticulates, such as pellets or mini-tablets, placed in capsules, where the fraction of solid multiparticulates includes cores that contain a medicinal

Sustained-release agents having a coating layer applied to them that contains an immediate-release drug. They can be additionally coated with an enteric polymer, where such solid multiparticles are optionally coated to form a sublayer before the enteric coating is applied.

In some embodiments of the invention, the omeprazole compositions disclosed in this application include at least two fractions of solid multiparticulates, such as mini-tablets or pellets, placed in capsules, where one fraction of solid multiparticulates is coated with an enteric polymer that dissolves at a pH within from about C to 7 with the release of the active substance, and where the other fraction of the solid multiparticulates is coated with an enteric polymer that dissolves at a pH in the range of from about 4 to 8 with the release of the active substance, and where the solid multiparticulates in each of these two fractions are necessarily have a coating applied to form a sublayer before applying an enteric coating.

In some embodiments of the invention, the compositions disclosed in this application are obtained using omeprazole or a pharmaceutically acceptable form of omeprazole having the following particle size distribution: 100 from about 1 μm to about 1000 μm, or from about 1 μm to about 500 μm, or from about 10 μm to about 250 μm; and Ozo from about 1 μm to about 500 μm, or from about 1 μm to about 250 μm, or from about 1 μm to 100 μm. The value Ox represents the maximum particle size, where "x" represents the percentage of particles in the sample.

In some embodiments, the present application includes modified release compositions comprising omeprazole or pharmaceutically acceptable salts thereof that release less than about 10 95 of the active ingredient contained therein within about 120 minutes after immersion in 750 or 1000 mL of a dissolution medium of 0.1 N hydrochloric acid (pH 1.2), using test method 711 "Solutions" in the United States Pharmacopoeia 29, Opiiea ziage5z RPpaptasoreia! Sopmepiip, Ips., KosKmiPe, Maguiapa, 2005 ("О5Р") and devices of type 2.

Further release of the drug occurs upon further immersion in an aqueous medium of neutral or alkaline pH, with from about 10 95 to about 4595 of the drug dissolved within about 90 minutes, and from about 50 95 to about 100 95 of the drug dissolved within about 300 minutes.

The environment with which the dosage form is likely to come into contact when administered to humans (i.p.) can be compared to i.p. dissolution studies performed using different dissolution media, such as simulated gastric fluid medium (5OBE) with or without pepsin, simulated intestinal fluid medium (5IR) with or without pancreatin, 0.01 N solution of hydrochloric acid (HC), pH 1.2, 4.5, 5.5, 6.0, 6.8, 7.0, 7.2 and 7, 4 buffers, pH 2/1

ZON, pH 5.0 and 4.5 acetate buffers, pH 4.5 ammonium acetate buffer, pH 5.0 imitation of the intestinal liquid environment after a meal (Bezzinet), pH 6.5 imitation of the intestinal liquid environment on an empty stomach (Razvbie), pH 6, 8 phosphate buffer with or without sodium lauryl sulfate (51 5), pH 1.5 HCI buffer and the like. Many useful dissolving media are described in O5R.

In some embodiments, this application relates to a composition of modified release of omeprazole, which includes, in combination: (a) omeprazole or a pharmaceutically acceptable salt thereof; and (b) a water-soluble excipient.

In some embodiments, this application relates to a composition of modified release of omeprazole, which includes, in combination: (a) omeprazole or a pharmaceutically acceptable salt thereof; and (B) a water-soluble excipient; where the water-soluble excipient acts as a stabilizer for the drug.

In some embodiments, this application relates to a modified release composition of omeprazole having a concentration of a dissolution enhancing agent ranging from about 0.1 95 to 5 95 based on the total weight of the composition.

Various alkaline inorganic salts that are useful in the compositions include, but are not limited to, alkaline inorganic salts of sodium, potassium, magnesium, and calcium. Examples of alkaline inorganic sodium salts include sodium carbonate, sodium bicarbonate, sodium hydroxide, and the like.

Examples of alkaline inorganic potassium salts include potassium carbonate, potassium bicarbonate, potassium hydroxide, and the like. Examples of alkaline inorganic magnesium salts include magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium metasilicate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite (MaovAg(OH):in:SbOz:4H2O|, aluminum-magnesium hydroxide

I2.5М90:А2Оз:хН2О| and the like. Examples of alkaline inorganic calcium salts include precipitated calcium carbonate, calcium hydroxide, and the like.

Organic bases that can be used in this application include pharmaceutically acceptable organic bases, including, for example, meglumine, lysine, M, M'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and mixtures of two or more of these substances.

In some embodiments, the present invention relates to a composition of modified release of omeprazole, where the concentrations of alkaline compounds are in the range of about 0.1 95 to 10 95 based on the total weight of the composition.

In some embodiments, the present invention relates to a modified release composition of omeprazole, wherein the mass ratios of omeprazole to alkaline compound are in the range of about 1:0.01 to 1:5.

In some embodiments, the present invention relates to a modified release composition containing about 20-60 mg of omeprazole in a capsule.

In some embodiments, the present invention includes compositions and/or compositions where omeprazole remains in its original physical form in the composition when exposed to storage conditions in the stability test, such as, but not limited to, 409 and 75 to 95 relative humidity (RH) for about three months.

The compositions of the present invention, after their preparation, can be further processed into various pharmaceutical dosage forms or can be combined with one or more pharmaceutically acceptable excipients. Various pharmaceutical dosage forms that include the pharmaceutical compositions disclosed in this application include solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules.

Modified release compositions may include hydrophilic, lipophilic, or hydrophobic substances that control the release rate, or combinations of such substances to form a matrix or reservoir or combinations of matrix and reservoir systems.

The compositions can be obtained using any methods, such as direct mixing, dry granulation, wet granulation (aqueous or non-aqueous, or partially aqueous and partially non-aqueous or aqueous-alcoholic) or by extrusion and spheronization. Compositions can be presented as compositions without coating, compositions with a film coating; sugar-coated, pressed, powder-coated, and enteric-coated, or in modified-release forms that have a coating.

In some embodiments, this application includes oral pharmaceutical compositions in a solid dosage form comprising: (a) a core containing omeprazole, a water-insoluble excipient and, optionally, an alkaline compound; (B) coating in the form of a sublayer applied to the core; and

(c) enteric coating applied to the substrate. In some embodiments, the underlayer coating is chemically inert.

In some embodiments, the present invention includes oral pharmaceutical compositions in a solid dosage form comprising: (a) a core containing omeprazole, a water-insoluble excipient, a dissolution enhancing agent, and, optionally, an alkaline compound; (B) optionally, a coating in the form of a sublayer applied to the core; and (c) enteric coating. In some embodiments of the invention, the enteric coating is applied directly to the core. In some embodiments of the invention, oral pharmaceutical compositions additionally include a coating in the form of a sublayer applied to the core, while the enteric coating is applied to the sublayer.

The cores may include pharmaceutically acceptable excipients, such as any one or more diluents or fillers, surfactants, disintegrants, stabilizers, pH-dependent or pH-independent polymers, binders and other substances. The cores according to this application can be obtained by homogeneously mixing omeprazole and one or more pharmaceutically acceptable excipients, such as any of the substances indicated above. In some embodiments of the invention, the cores according to this application include inert substances in the form of particles, such as a diluent or sugar spherical particles, on which a solution containing omeprazole is sprayed or layered. The mixture can then be formulated as small spherical particles, pellets, granules, fine particles or mini-tablets and placed in hard gelatin capsules or soft gelatin capsules using conventional procedures.

The inert sublayer can separate the core from the enteric coating of the polymer, which contains free carboxyl groups that can cause decomposition and/or discoloration of the drug. The inert sublayer can also serve as a pH buffer zone in which hydrogen ions diffusing outward toward the alkaline core can interact with hydroxyl ions diffusing from the alkaline core to the surface of the coated products. The coating that forms the sublayer may include one or more layers.

The inert coating in the form of a sublayer can be applied to the pellet or mini-tablet core components using any method, including traditional application procedures

From the coating in a suitable coating tank or in a fluidized bed device, using water and/or organic solvents for solutions or dispersions that are applied as a coating. Water-soluble or water-insoluble polymers that can be used for the inert sublayer include, for example, sugars, zein, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, polyvinyl alcohols, polyethylene glycols, poloxamers (e.g., Rygopis products), ethyl celluloses, gelatin, polyarginines, polyglycines , polyvinylpyrrolidones, vinyl acetate copolymers and any mixtures of such substances.

In the case of mini tablets, the coating can also be applied using the dry coating method. The inert coating in the form of a sublayer may also include pharmaceutically acceptable water-soluble excipients for tablets that rapidly disintegrate in water. Traditional plasticizers, pigments, titanium dioxide, talc and other additives can also be included in the inert sublayer. In the case of gelatin capsules, the gelatin capsule itself serves as a substrate.

The amount of inert sublayer according to this application can vary from about 0.1 95 to 10 95 or from about 0.5 to 4 95, based on the total weight of the core.

Useful water-soluble excipients include any pharmaceutically acceptable water-soluble polymers such as, but not limited to, polyvinylpyrrolidones or povidones (such as the K25, K29, KZ0, and KU0O classes), hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, sodium carboxymethyl cellulose, and any what mixtures of such substances. Other water-soluble excipients according to this application include sugars and sugar alcohols, preferably with low hygroscopicity, and include, for example, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, and mixtures of two or more such substances.

In some embodiments, this application relates to a modified release composition of omeprazole, wherein the concentration of the water-soluble excipient is in the range of about 0.001 95 to about 10 95 based on the total weight of the composition.

Substances in the form of solid multiparticulates may optionally include an agent that increases dissolution. Dissolution enhancing agents increase the rate of dissolution of the drug from the carrier. Generally, solubilizing agents are amphiphilic compounds and are generally more hydrophilic than the carrier. Examples of dissolution enhancing agents include: salts such as sodium chloride, potassium chloride, lithium chloride,

calcium chloride, magnesium chloride, sodium sulfate, potassium sulfate, sodium carbonate, magnesium sulfate, and potassium phosphate; alcohols such as stearyl alcohol, cetyl alcohol and polyethylene glycol; surfactants such as poloxamers (such as poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407), docusate salts, polyoxyethylene alkyl ethers, polyoxyethylene-modified castor oil derivatives, polysorbates, polyoxyethylene alkyl esters, sodium lauryl sulfate, and sorbitan monoethers ; sugars such as glucose, sucrose, xylitol, sorbitol and mannitol; amino acids such as alanine and glycine; and any mixtures of such substances. For example, a dissolution enhancing agent may be a salt such as sodium chloride.

In some embodiments, this application relates to compositions of modified release of omeprazole, where the concentration of the agent that increases dissolution is in the range of about 0.1 95 to 5 95 based on the total weight of the composition.

The enteric coating is applied either directly to the cores or to the coated cores as a sublayer, often using traditional coating techniques such as, for example, using a tank or fluidized bed for coating, using solutions of pH-dependent polymers in water, and /or appropriate organic solvents or the use of polymer suspensions, providing a modified release of the active substance. Enteric coating polymers that can be used include, for example, cellulose acetophthalates (CAPs), hydroxypropylmethylcellulose phthalates (HPMCP), polyvinyl acetophthalates (PMAP), hydroxypropylmethylcellulose acetosuccinates (HPMCAb), acetylcellulose trimethylates, hydroxypropylmethylcellulose succinates, cellulose acetosuccinates, cellulose acetylcellulose hexahydrophthalates, propionate , copolymers of methyl methacrylic acid and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (for example, the Sapige7"M E5 series), copolymers of ethyl methacrylate-methyl methacrylate-ethyl acrylate chlorotrimethylammonium, natural resins such as zein, shellac and gum soPorpogisht .

From commercially available enteric dispersion systems (for example, Eshtsagadiy? 130055,

Eshpagadchiiye E5300, Etsagadiy? 1100-55, Eyagadia? 5100 (all from Emopik Ipaivigiev), Koiissoai? MAEZO0 and

ZOOR (from VAB5BE), Eviasgu!? 300 (from Easitus Speptisai), Adiaiegis? and Adoiasoai? SROZO (from EMO), and any mixtures of such substances.

The enteric coating layer may optionally contain a pharmaceutically acceptable plasticizer, such as, for example, cetanol, triacetin, citric acid ester, such as, for example, those known under the trademark SygoPyekh? (Riigeg, Memzh/ Mogk), phthalic acid ether, dibutyl succinate or similar plasticizers. The amount of plasticizer is usually optimized for each enteric coating polymer, and an amount in the range of about 1-40 95 enteric coating polymer is used. Dispersants such as talc, dyes and pigments can also be included in the enteric coating layer.

The weight of the enteric coating applied is about 0.5-20 95 or about 2-10 95 of the weight of the core substance or the core substance with the coating that forms the sublayer.

In some embodiments of the invention, the coating is applied either directly to the cores, or to the cores having the coating as a sublayer, using coating techniques such as, for example, using a reservoir or fluidized bed for coating, using pH-independent polymers, dissolved or dispersed in water and Mabo organic solvents, or the use of polymer suspensions, providing a modified release of the active substance.

In some variants of the embodiment of the invention, the cores contain one or more modifying release polymers in a mixture with omeprazole, with the formation of a matrix. In some embodiments of the invention, the matrix of the modified release, in addition, has a coating of pH-dependent polymer or pH-independent polymer or their combinations.

One or more polymers that can be used in the controlled release coating layer according to the present invention for modified release include hydrophilic, hydrophobic and lipophilic substances and combinations thereof. Examples of polymers include, but are not limited to, cellulose ethers, such as hydroxypropylmethylcellulose (hypromellose or HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidones, including uncrosslinked polyvinylpyrrolidones, carboxymethyl starches, polyethylene glycols, polyoxyethylenes, poloxamers (polyethylene copolymers or polyoxy polyoxypropylene), polyvinyl alcohols, glucans (glucans), carrageenans,

scleroglucans (scleroglucans), mannans, galactomannans, gellans, alginic acid and its derivatives (eg, sodium or calcium alginate, propylene glycol alginate), polyamino acids (eg, gelatin), methyl vinyl ether/maleic anhydride copolymers, polysaccharides (eg, carrageenan, guar gum , xanthan gum, tragacanth, and locust bean gum), alpha-, beta-, or gamma-cyclodextrins, dextrin derivatives (eg, dextrin), hydroxypropylmethylcellulose phthalates, cellulose acetophthalates, carboxymethylethylcellulose, methyl methacrylate-methacrylic acid copolymers, methacrylic acid-ethylacrylate copolymers, ethyl acrylate-methyl methacrylate-ethyl methacrylate of trimethylammonium chloride, methyl methacrylate-ethyl acrylate copolymers, methacrylic acid-methyl acrylate-methyl methacrylate copolymers, hydroxypropyl cellulose acetosuccinates, polyvinyl acetate phthalates, polymethacrylates (for example, acrylic and methacrylic acid ether copolymers containing quaternary ammonium group), acrylic acid polymers (for example, carbomers), shellac and its derivatives, cellulose acetates, cellulose butyrates, cellulose diacetates, cellulose triacetates, cellulose propionates, cellulose acetobutyrates, other acetylated cellulose derivatives and the like, including any mixtures of such substances .

Examples of lipophilic or hydrophobic substances that can be used in this application include, without limitation, waxes (eg, carnauba wax, microcrystalline wax, beeswax, and polyethoxylated beeswax), natural fats (coconut, soy, and cocoa), including modified forms , such as fully or partially hydrogenated, hydrogenated castor oil, hydrogenated vegetable oil, fatty acid derivatives such as mono-, bi- and tri-substituted glycerides, phospholipids, glycerophospholipids, glyceryl palmitostearate, glyceryl behenate, glyceryl monostearate, diethylene glycol palmitostearate, polyethylene glycol stearate, polyethylene glycol palmitostearate, polyoxyethylene glycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, fatty alcohols associated with polyethoxylated fatty alcohols, cetyl alcohol, stearic acid, saturated or unsaturated fatty acids and their hydrogenated derivatives, lecithin, cephalins, chitosan and their derivatives, sphingolipids, sterols such as cholesterol and its replaced by commuting, etc.

In some variants of the embodiment of the invention, a regulatory agent is applied to the solid multiparticles

A release layer of a gel-forming polymer coating, where the release-regulating layer of the gel-forming polymer coating is a layer containing one or more types of substances, such as polyethylene oxides (PEOs), for example, Polyethylene oxides? M/ZA 303, molecular weight: 7000000, Royuoch? MUZK Coagulant, molecular weight: 5000000, Royuoch? M/5A 301, molecular weight: 4,000,000, Roiuoh? MUZA M-60OK, molecular weight: 2000000 and Roiuoh? MUZA 205, molecular weight: 600000, from the manufacturing company Yuom/ SPpetis! Co., C.O., hydroxypropylmethylcellulose (HPMC), such as Meiose? 90510000, Meiose? 905Н5БОО000 and

Meiosis? 90530000, from the manufacturing company ЗПпип-ЕБЙ Спетиса!и, Со, Це,., carboxymethylcellulose (СМСО-Ма), such as Zapiose E-1000MS, hydroxypropyl cellulose (HRC), for example, HPO-Н, from the manufacturing company Mirrop Zoda So., Tsa., hydroxyethyl cellulose (NES), carboxyvinyl polymer NIMIZUMAKO 103, 104 and 105 from the manufacturing company Uuako

Riga Spetis! Ipdyziyieeh CYA. carbomers such as SAVVOROI? 943 from the company I ibgi2o!

Sogrogayop, chitosan, sodium alginate, pectin and the like. These substances can be used individually or in the form of any mixture of at least two such substances by mixing in appropriate proportions.

In some embodiments of the invention, a coating layer for controlling the diffusion of release is applied to the solid multiparticles, where the coating layer for controlling the diffusion of release is a layer containing one or more types of substances, such as a copolymer of ethyl acrylate-methyl methacrylate-trimethylammonium methyl methacrylate chloride (Ecydgadi? B) (aminoalkyl methacrylate copolymer K5) or Ecydgadi? And (aminoalkyl methacrylate copolymer KU), methyl methacrylate-ethyl acrylate copolymer (Enagadiya? MEZOI), egyl cellulose and the like. In addition, these substances can be mixed in the desired ratio and can be used by mixing with hydrophilic pore-forming substances, such as hydroxypropyl methylcellulose / (HPMO), hydroxypropyl dicellulose / (HPS), carboxyvinyl polymers, polyethylene glycols (for example, PES 6000), lactose, mannitol and organic acid

Etsagadi? polymers are products from the company Emopik Ipdivigie5 As, Evzep,

Segtapu Commercially available products include, but are not limited to, EOOKASIT KI,

ESHOVASIT 5, EOSHOVASIT VI RO, EOOVASIT AB RO, EOOVASIT VO, EEOOVASIT I, EOOVASIT

Z, EESHOVASIT I 100-5, EOOKASIT ME 300 and EOOKASIT E 100. because Polymers commercially available as EOOKASIT "M" contain a common repeating link:

SnNze NSNU b--sn.- 0-s penninnnnia a2-S-6-

So Kk

and oh

AND

Alkyl where K is COOH for ESOKASIT I products, KE is COOSNoM(CH3)" for EOOKASIT E products, EE is COOSN" for EOOKASIT ME 30 0 products, and K is COOSNSNaM'(CH3)zCI for EOOKASIT E products and for EOOKASIT KZ5 products.

Alkyl groups vary in different products and contain 1-4 carbon atoms.

Tpe Opiyea 5iage5 Ripaptasorovia apa Maiyopa! Eoptshiiagu describes a "methacrylic acid copolymer" as a fully polymerized copolymer of methacrylic acid and an acrylic or methacrylic acid ester. In this monograph, three types of copolymers are defined, namely type A, type B and type C. They differ in the content of methacrylic acid in them and in the viscosity of the solution. Type C may contain appropriate surfactants. Polymers, type A (e.g., EOOMKASIT HER) and type B (e.g., EOOKASIT 5), may be specified as "ammonium methacrylate copolymers" consisting of fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.

Similar polymers are available from other sources. Some of the products have multiple uses, for example, for enteric coatings and/or intermediate coatings, for the purposes of this application.

In some embodiments, this application includes modified release pharmaceutical compositions comprising omeprazole, optionally together with one or more pharmaceutically acceptable excipients, where said compositions are in the form of solid multiparticulates.

In some embodiments, the present application includes modified release pharmaceutical compositions comprising cores comprising omeprazole, optionally together with one or more pharmaceutically acceptable excipients, and having a coating comprising one or more polymers, wherein the compositions are in in the form of solid multiparticles.

In some embodiments of the invention, the modified-release omeprazole solid multiparticulates include nonpareil cores such as sugar or similar substances onto which the omeprazole is applied, optionally together with one or more pharmaceutically acceptable excipients, using any technique such as

From powder layering, solution spraying, suspension spraying and any other techniques known to specialists in this field.

In some embodiments of the invention, the modified release compositions of this application include omeprazole-loaded nonpareil cores that have a coating that includes one or more pH-independent polymers, pH-dependent polymers, or combinations thereof.

In some embodiments, the present invention includes pharmaceutical compositions that include modified release solid multiparticulates that include omeprazole-containing cores and a coating that includes one or more polymers, and that optionally have one or more additional coatings.

In some embodiments of the invention, solid multiparticles including omeprazole additionally contain one or more non-functional or functional coatings to provide a modified release of the active substance.

Compositions in the form of solid multiparticles according to this application can be obtained using the techniques described in this application, as well as other methods known to specialists in this field.

In some embodiments of the invention, fractions of solid multiparticulates comprising omeprazole are coated with different concentrations of polymers, resulting in fractions having different release profiles, and can be combined to form a pharmaceutical composition or dosage form to achieve desired modified release profiles.

In some embodiments of the invention, fractions of solid multiparticulates, including omeprazole, are coated with different types of polymers, either enteric-soluble polymers (pH-dependent polymers) or polymers for modified release (pH-independent polymers), obtaining different release profiles, and they can combine to form a pharmaceutical composition or dosage form to achieve desired modified release profiles.

In some embodiments of the invention, solid multiparticulates comprising omeprazole can be combined with pharmaceutically acceptable excipients and compounded to obtain a pharmaceutical composition that can be pressed into tablets or placed into appropriate shells in the form of capsules, using techniques known to those skilled in the art In some embodiments of the invention, the compositions disclosed in this application are filled into hard gelatin capsules, where the shells of the empty hard gelatin capsules include one or more substances, such as hydroxymethyl cellulose, carrageenan, potassium chloride, vinyl polymers such as polyvinyl acetate and polyvinyl alcohol, and the like.

Pharmaceutically acceptable excipients in accordance with the present application include, for example, any one or more of the diluents, binders, stabilizers, lubricants, glidants, disintegrants, antioxidants, surfactants, and other additives commonly used to prepare solid pharmaceutical formulations. medicinal forms.

Various useful excipients or diluents according to this application include, but are not limited to, starch, lactose, mannitol (eg, Reagio!m 50200), cellulose derivatives, confectioners' sugar, and the like. Various types of lactose include, but are not limited to, lactose monohydrate, lactose OT (for direct tableting), anhydrous lactose, RioulLasm (available from Meddie Rgodisi5), PPagtase"mMm (available from OMUM), etc. Various starches include, but not limited to, corn starch, potato starch, rice starch, wheat starch, pregelatinized starch (for example, ROS RS10 from 5idpei Spetis! Sogrogayop), starch 1500, starch 1500 GM grade (low moisture grade) from Soyogsop, fully pregelatinized starch (eg

Mayiope! 78-1551 from the company E5zeh Ogaip Rgodysiv), etc. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include, but are not limited to, SeoiYi5 mM KG801, Amise| tm

RNIOI, RNIO2, RNZOI, RNZO2 its RN-B20, RN-112 microcrystalline cellulose 114 and microcrystalline cellulose 112. Other useful diluents include, but are not limited to,

From carmellose, sugar alcohols such as mannitol (for example, Reagiyoi "m 50200), sorbitol and xylitol, calcium carbonate, magnesium carbonate, calcium hydroorthophosphate and tricalcium phosphate.

Various useful binders for use in this application include, but are not limited to, hydroxypropyl celluloses, also referred to as LDCs (eg, Kiyse! "m | Er, Kiyse!/ M

ЕХРЕ) and useful in various grades, hydroxypropyl methylcellulose, also called hypromellose or NRMS (such as MeiShose!M products) and useful in various grades, polyvinylpyrrolidone (RUR or povidone, such as grades K25, K29, KZO and KOO ), copevidones (eg

Riazdopetm 5 630), powdered gum arabic, gelatin, guar gum, carbomers (such as SAEVORO!? products), methyl cellulose, polymethacrylates and starch.

Various useful leavening agents include, but are not limited to, carmellose calcium (soy

Uakiyip So., Tsa.), sodium carboxymethyl starch (Maizshapi KadaKy So., Tsa., Kitiga Zapduo

So., M., etc.), croscarmellose sodium (As-aii-5017M4 from the company EMC-Azaii Spetisai! Ipdivigu So.,

Tsa.), cross-povidones, examples of commercially available cross-povidone products include, but are not limited to, cross-linked povidone, Coiidope'mMm SI (VA5BE, Septapu), Roiuriazdope "m

XII, XI-10 and IME-10 (IBR Ips., OA) and low-substituted hydroxypropyl cellulose. Examples of low-substituted hydroxypropyldelulose include, but are not limited to, low-substituted hydroxypropyldelulose I NIT1, GN21, I NZ1, GN22, I NZ2, GN20, I NZO, I NZ2, and I NZZ (all from Zpip-Eiba Spetis! So. , 4.). Other useful leavening agents include sodium starch glycolate, colloidal silicon dioxide, and starch.

Useful surfactants according to this application include nonionic, cationic, anionic and zwitterionic surfactants. Useful nonionic surfactants include ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitol esters (eg, Zrap'"m products) and polyhydroxyethylene-treated sorbitol esters (eg, Tu'eep "M products), ethers of aliphatic alcohols and poly(ethylene glycol), and ethers of phenol and REb. Useful cationic surfactants include quaternary ammonium salts (eg, cetyltrimethylammonium bromide) and amine salts (eg, octadecylamine hydrochloride). Useful anionic surfactants include sodium stearate, potassium stearate, ammonium stearate and calcium stearate, triethanolamine stearate, sodium lauryl sulfate, sodium dioctylsulfosuccinate, and sodium dodecylbenzenesulfonate. It is also possible to use natural surfactants, such as, for example, phospholipids, for example, diadylphosphatidylglycerols,

diacetylphosphatidylcholines and diadetylphosphatidic acids, precursors and their derivatives, such as, for example, soy lecithin and egg yolk.

In some embodiments of the invention, the stabilized compositions disclosed in this application contain at least one antioxidant. The antioxidant may be present either as part of the composition or as a component of the package. Thus, in one specific embodiment of the method according to this application, the antioxidant is introduced into the composition at the stage of loading the medicinal product onto inert nuclei. Antioxidants are present in an amount effective to delay the breakdown of omeprazole, as it is prone to oxidation.

In some embodiments of the invention, the antioxidant content in the composition ranges from about 0.001 to 10 percent of the amount of the active substance.

Of the antioxidants, non-limiting examples that can be used include ascorbic acid and its salts, tocopherols, sulfite salts such as sodium metabisulfite or sodium sulfite, sodium sulfide, aI-alpha-tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, and propyl gallate. Other suitable antioxidants can be readily determined by those skilled in the art.

Useful lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, sodium calcium stearate, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid and any combination of such substances.

One or more slip agents can be used, which improve the fluidity of powder mixtures, pellets, mini-tablets, etc. and minimize variations in the mass of dosage forms. Useful slip agents include, but are not limited to, silicon dioxide, talc, and combinations thereof.

Dyes can be used for color labeling of the compositions, for example, to indicate the type and dose of the therapeutic agent in the compositions. Dyes can also be used to differentiate different fractions of solid multiparticulates comprising a standard dosage form such as a capsule. Acceptable colorants include, without limitation, natural and/or artificial compounds such as ROS colorants, natural sap concentrates, pigments such as titanium oxide, silicon dioxide, iron oxides and zinc oxide, combinations of such substances, and the like.

In the methods of obtaining pharmaceutical compositions according to this application, various solvents can be used, including, but not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monetyl ether, diethylene glycol monobutyl ether, diethylene glycol monetyl ether, dimethyl sulfoxide, M, /M-dimethylformamide, tetrahydrofuran and any mixtures of such substances. As a rule, liquids that are used as solvents and carriers for various technological operations are not present in the finished composition, as they are evaporated when they are no longer needed. For example, the liquid phase of the liquid composition of the coating must be evaporated during the drying process, when the coating has already been applied.

Useful pH-independent polymers according to this application include, but are not limited to, carbomers, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl ethers, polyvinyl halides, polyvinyl pyrrolidones, polyvinyl acetates, polyvinyl alcohols, polyglycolides, polysiloxanes, polyurethanes and their copolymers, alkylcelluloses, hydroxyalkyldocelluloses, cellulose ethers, cellulose esters, nitrocellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, natural polymers such as alginates and other polysaccharides, which include but are not limited to , arabinans, fructans, fucans, galactans, galacturonans, glucans, »mannans, xylans (such as inulin), levan, fucoidan, carrageenan, galactocarolose, pectic acid, pectin, amylose, pullulan, glycogen, amylopectin, dextran, pustulan , chitin, agarose, keratan, x ondroitan, dermatan, hyaluronic acid, alginic acid, xanthan gum, starch and various other natural homopolymers or heteropolymers, such as those containing one or more of aldoses, ketoses, acids or amines, erythrose, threose, ribose, arabinose ) , serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine and neuraminic acid, and their natural derivatives, and 60 including dextran and cellulose, collagen, their chemical derivatives (for example, due to substitutions and additions of chemical groups, for example, alkyl, alkylene, hydroxylation, oxidation and other modes fications routinely performed by specialists in this field), albumin and other hydrophilic proteins, zein and other prolamins and hydrophobic proteins, synthetic polymers such as lactic acid and glycolic acid polymers, polyanhydrides, poly(orthoethers), polyurethanes, poly(butyric acid) , poly(valeric acid), poly(caprolactone), poly(hydroxybutyrate), copolymers of poly(lactide-co-glycolide), poly(lactide-co-caprolactone) and any mixtures of such substances.

Various pH-dependent polymers for use in this application include, but are not limited to, Etsagadie 100 and Etsgadie MO 40, polymers and copolymers of acrylic and methacrylic acids, cellulose acetobutyrates, cellulose acetophthalates, hydroxypropylmethylcellulose phthalates, poly(methyl methacrylate) polymers, poly( ethyl methacrylate) polymers, poly(butyl methacrylate) polymers, poly(isobutyl methacrylate) polymers, poly(hexyl methacrylate) polymers, poly(isodecyl methacrylate) polymers, poly(lauryl methacrylate) polymers, poly(phenyl methacrylate) polymers, poly(methyl acrylate) )no polymers, poly(isopropyl acrylate) polymers, poly(isobutyl acrylate) polymers, poly(octadecyl acrylate) polymers and any mixtures of such substances.

In some embodiments of the invention, one or more pH-independent or pH-dependent polymers are used to cover the compositions according to this application, including, but not limited to, Echagadia? 5 RO and BI RO.

Useful coating additives include, but are not limited to, plasticizers, anti-stick agents, opacifiers, solvents, and optionally dyes, lubricants, pigments, antifoams, and polishing agents.

Various useful plasticizers include, but are not limited to, substances such as castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Mixtures of plasticizers can also be used. The type of plasticizer depends on the type of coating substance. A substance that makes the composition opaque, such as titanium dioxide, may also be present in amounts ranging from about 0.595 to about 2095, based on the total weight of the coating.

Anti-adhesives are often used in film coating methods to

To avoid sticking effects during film formation and drying. An example of a useful anti-adhesive for these purposes is talc. The anti-adhesive is often present in the film coating in an amount from about 0.5 95 (w/w) to 15 95 (w/w) based on the total weight of the coating.

The above descriptions of excipients should not be considered exhaustive. Other substances useful in the practice of this invention should be known to those skilled in the art, and the use of such substances is specifically included in this application.

In one aspect, the present disclosure includes methods of preparing pharmaceutical compositions according to the present application.

In some embodiments, the present invention includes pharmaceutical compositions of omeprazole that can be obtained by spray drying a suspension or solution that includes omeprazole and a water-soluble sugar derivative, with or without an organic base, and optionally together with one or more pharmaceutically acceptable excipients. Alternatively, omeprazole compositions can be obtained using fluidized bed granulation methods, where a solution or suspension of omeprazole, with or without a stabilizer and optionally together with one or more pharmaceutically acceptable excipients, is sprayed onto pharmacologically inert solid particles or layered onto inert solid particles.

In some embodiments, compositions according to this invention can be obtained by methods that include: (a) dissolving omeprazole or its pharmaceutically acceptable salt in an organic solvent; (B) adding a water-soluble excipient that acts as a stabilizer; (c) optionally, adding one or more pharmaceutically acceptable excipients, such as an alkaline compound, binder, polymer and/or disintegrant, to the solution; (4) spraying the solution on the substrate, including at least one diluent, optionally together with a disintegrant, to obtain a granular mass; (e) mass drying; (and optionally, grinding the mass; (e) mixing one or more excipients, such as a diluent, disintegrant, lubricant and/or slip agent, with the dried mass (e) or ground mass (); (n) pressing the substance ( 9) with obtaining mini-tablets; (I) optional coating on mini-tablets in the form of a sub-layer; (I) coating of mini-tablets (n) or (i) with a pH-dependent polymer or a pH-independent polymer; and ( K) encapsulating the coated minitablets In some embodiments, the capsule includes at least two fractions of coated minitablets, where one fraction is coated with one or more RNA-independent polymers and the other fraction is coated with one or by several pH-dependent polymers In other embodiments, the capsule includes at least two different fractions of minitablets that have a coating, where the fractions are independently coated with one or more pH-independent polymers or one or more pH-dependent polymers.

In variants of the embodiment of the composition according to this invention can be obtained by methods that include: (a) dissolving omeprazole or its pharmaceutically acceptable salt in an organic solvent; (b) adding a water-soluble excipient that acts as a stabilizer; (c) adding a solubilizing agent; (a) optionally, adding one or more pharmaceutically acceptable excipients, such as an alkaline compound, a binder, a polymer and/or a disintegrant, to the solution; (e) spraying the solution on the substrate, including at least one diluent, optionally together with a disintegrant, to obtain a granular mass; (i) mass drying; (9) optionally, mass grinding; (p) mixing one or more excipients, such as a diluent, disintegrant, lubricant and/or slip agent, with the dried mass (Her) or the crushed mass (4); () pressing of substance (n) to obtain mini-tablets; () optional coating on mini-tablets in the form of a sublayer; (K) coating mini-tablets (i) or (Yi) with a pH-dependent polymer or a pH-independent polymer; and (I) placing the coated mini-pills into a capsule. In some embodiments, the capsule includes at least two fractions of minitablets that have a coating, where one fraction is coated with one or more pH-independent polymers and the other fraction is coated with one or more pH-dependent polymers. In some embodiments, the capsule includes at least two different fractions of minitablets that have a coating, with the fractions independently coated with one or more pH-independent polymers or one or more pH-dependent polymers.

In variants of the embodiment of the composition according to this invention can be obtained by methods that include: (a) dissolving omeprazole or its pharmaceutically acceptable salt in an organic solvent; (b) adding a water-soluble excipient that acts as a stabilizer; (c) adding a solubilizing agent; (a) optionally, adding one or more pharmaceutically acceptable excipients, such as an alkaline compound, a binder, a polymer and/or a disintegrant, to the solution; (e) coating of spherical sugar particles with a medicinal solution; (Y) drying of particles; (94) optional coating on particles covered with a layer of medicinal product in the form of a sublayer; () coating of particles (Her) or (9) pH-dependent polymer

Zo or pH-independent polymer; and (n) encapsulating the coated particles. In some embodiments, the capsule contains at least two fractions of particles that have a coating, where one fraction is coated with one or more pH-independent polymers and the other fraction is coated with one or more pH-dependent polymers. In some embodiments, the capsule includes at least two different fractions of particles that have a coating, where the fractions are independently coated with one or more pH-independent polymers or one or more pH-dependent polymers.

In embodiments of the invention, the composition of omeprazole can be obtained using a powder layering technique, where a powder including omeprazole, a stabilizer and a dissolution enhancing agent, optionally together with one or more other pharmaceutically acceptable excipients, is layered on pharmacologically inert particles, with spraying at the same time, a binder solution is applied to them. In certain embodiments, the compositions disclosed in this application can be obtained by methods including: (a) obtaining a powder for layering the drug by mixing the drug with a water-soluble excipient, a dissolution-enhancing agent, and a diluent, optionally together with one or more pharmaceutically acceptable excipients, such as an alkaline compound and/or disintegrant; (B) obtaining a binder solution; (c) coating the sugar spherical particles with a drug layering powder, while spraying a binder solution to obtain pellets with a layering of the drug; (a) pellet drying; (e) optional, coating the pellets in the form of a sub-layer; (Her) covering pellets (a) or (e) with a pH-dependent polymer or a pH-independent polymer; and (e) placing the coated pellets into capsules. In some embodiments, the capsule includes at least two pellet fractions having a coating, where one fraction is coated with one or more pH-independent polymers and the other fraction is coated with one or more pH-dependent polymers. In some embodiments, the capsule includes at least two different pellet fractions having a coating, where the fractions are independently coated with one or more pH-independent polymers or one or more pH-dependent polymers.

Equipment suitable for processing pharmaceutical compositions according to this application includes any one or more devices such as high-speed mixing granulators, planetary mixers, bulk mixers, belt-screw mixers, fluidized bed processors, mechanical screeners, blenders , roller seals,

extrusion spheronizing devices, pressing machines, capsule filling machines, centrifuge bowls or coating tanks, drying trays, fluidized bed dryers, rotary conical vacuum dryers, multi-shredders, hydromixers, ball mills, colloid mills, roller mills, hammer mills and similar

In embodiments, this disclosure includes forms of packaging for omeprazole compositions to ensure stability during storage and transportation. Stabilization of the omeprazole compositions of the present invention can be improved by using forms of packaging, such as packaging, preferential penetration of oxygen and moisture, packaging with an atmosphere of inert gas (where the air is replaced by gases that do not include oxygen), vacuum packaging and packaging containing placed therein deoxidant Stabilization is improved by reducing the amount of oxygen with which the solids come into direct contact using these forms of packaging. When the deoxidant is present in the package, the pharmaceutical solid preparation is packaged with an oxygen-impermeable substance, and it can be contained in another package. Oxygen scavengers such as eabioch? products, are useful for minimizing the decomposition of the active substance as a result of oxidation.

In the variants of the embodiment of the composition according to this invention, include a moisture absorber and Mabo oxygen absorbent as a component of the package. A moisture absorber is a hygroscopic substance that induces or maintains a state of dryness (dehydration) in an area close to it in a hermetically sealed container. Conventional prepackaged desiccants are solids in small pouches, and they work by absorbing or adsorbing water, or a combination of both. Special purpose desiccants may be in forms other than solid form and may operate on other principles, such as chemical bonding of water molecules. Pre-packaged desiccants are most often used to remove excess moisture that would normally degrade or even destroy moisture-sensitive products. Non-limiting examples of various desiccants include anhydrous calcium sulfate (eg, Ogier?), silica gels, calcium chloride, montmorillonite clays, and molecular sieves.

In one aspect, the present application provides methods of treating gastrointestinal inflammatory and gastric acid-related diseases in mammals and humans, including

From esophageal reflux, gastritis, duodenitis, gastric ulcer and duodenal ulcer, by administering the drugs and pharmaceutical compositions disclosed in this application. Compounds and compositions according to this application can be administered to a subject in a therapeutically effective amount.

Pharmaceutical dosage forms according to this application are intended for oral, buccal or sublingual administration to a patient in need thereof.

Definition

The following definitions are used in connection with this application, unless the context indicates otherwise. As used in this application, the term "omeprazole" includes compounds of omeprazole, its pharmaceutically acceptable salts, esters, prodrugs, active metabolites of omeprazole and their prodrugs and their polymorphs, solvates and hydrates.

The term "pharmaceutically acceptable salt", as used in this application, refers to salts that are known to be non-toxic and are commonly used in pharmaceutical practice. Such pharmaceutically acceptable salts include metal salts, salts with organic bases, salts with basic amino acids, etc. Metal salts include, for example, alkali metal salts, such as sodium and potassium salts, and alkaline earth metal salts, such as calcium, magnesium salts and barium. Salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, M,M-dibenzylethylenediamine, etc. Salts with basic amino acids include, for example, salts with arginine, lysine and etc. Also included are acid addition salts, such as hydrochloride salts and

Because they are similar.

In this application, omeprazole and its salts can be used in any crystalline form, amorphous form or in a combination of such forms.

The term "modified release" (MC) in accordance with the present invention means that the release of the drug can be time-delayed release (OK), sustained release (EC), sustained release over a long period of time (5K), pulsed release (ROC) ) or sustained release (SR), or a combination of immediate release and one or more of time-delayed release, sustained release, continuous release over a long period of time, pulsed release, and sustained release.

The term "delayed release" in accordance with the present invention means that the drug is essentially not released in the stomach region of the gastrointestinal tract (GI); instead, drug release occurs essentially in the upper intestine or further down the intestinal tract.

The term "sustained release over a long period of time" according to this invention means that the drug is released in different amounts essentially throughout the gastrointestinal tract (GI) in a controlled manner.

The term "pulse release" according to the present invention means that the drug is released in the form of one or more pulses in any part of the SIT, immediately or in a delayed manner.

The term "sustained release" in accordance with the present invention means that the drug is essentially not released in the gastric region of the IT; instead, drug release occurs essentially in the upper intestine over a long period of time.

The term "sustained release" according to the present invention means that a small portion of the drug is released directly at once, that is, the initial release of the drug begins after a certain delay in time, followed by an immediate release of the drug either in a certain part of the SIT, or different amounts of the drug are released in OT later.

The term "release-controlling coating layer" according to the present invention means a coating layer having the function of delaying or continuing the release of the active ingredient, such as a "pH-dependent soluble layer" or "diffusion-controlling layer", or acting by means of an erosion or decomposition mechanism.

The term "pH-dependent soluble release control coating layer" according to this invention means a coating layer that does not dissolve and does not decompose in the acidic pH conditions of the stomach, but dissolves or decomposes in the intestine.

The term "diffusion-controlling coating layer" according to the present invention means a coating layer that does not dissolve itself, and which releases the active ingredient through the pores that are formed in the layer.

The term "gelling polymer coating layer" according to this invention

Zo means a coating layer that quickly forms highly viscous gels on contact with water and prolongs the retention time in the digestive tract.

The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, such as a filler, diluent, carrier, etc. Excipients that are useful in the preparation of a pharmaceutical composition are generally safe, non-toxic and are not undesirable from a biological or any other point of view, and are acceptable for veterinary use as well as for human pharmaceutical use. "Excipient" or "pharmaceutically acceptable excipient" as used herein includes both one and more than one such excipient.

The term "acid-labile compound" means any compound that is not stable under acidic conditions, or that undergoes decomposition or hydrolysis by acid or proton-catalyzed reactions.

A polymeric substance that "dissolves" or is "soluble" under certain aqueous conditions, facilitating the release of the drug from the composition, or under certain pH conditions, or regardless of pH, may not actually form a solution. It is said to dissolve or is soluble if it swells enough to have the characteristics of a solute, decomposes, or forms a solution.

Some specific aspects and embodiments are described in more detail in the following examples, while they are presented solely for illustrative purposes, and the scope of this invention is not limited to them.

Example 1: Pellets containing omeprazole.

Sugar spherical particles (25-30 mesh)

Hypromellose, 5 cPz (Mefshose E5 Rgetiit) HER 7777777777111718611717Сс21 "Evaporates during processing.

Obtaining procedure:

A. Protective Coating 1. Hypromellose is dissolved in water and sprayed onto the sugar spherical particles using a fluidized bed (FB) device, obtaining a mass increase of 5 95 after drying, and the coated spherical particles are dried.

B. Load of medicinal product 1. Gpromellose, poloxamer 407 and meglumine are mixed with water. 2. Omeprazole is added to the substance obtained in stage 1, with stirring for at least 15 minutes. 3. Pellets with a protective coating from the AT stage are coated with the substance obtained at stage 2 using EVR.

C. The coating that forms the sublayer 1. Hydroxypropyl methylcellulose is dissolved in water. 2. Talc and titanium dioxide are homogenized in water. 3. The dispersion obtained in stage 2 is mixed with the polymer solution from stage 1 and mixed. 4. The dispersion is sprayed on pellets with a drug loaded on them from the VZ stage using EVR, while obtaining an increase in mass by 16 95 after drying. Enteric coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etzagadia? |. 100 55 is added to the solution obtained at stage 1, while stirring.

C. Talc is added to the solution obtained in step 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage 3 is sprayed onto the pellets from stage C4, which have a coating in the form of a sublayer, thus obtaining an increase in mass by 45595 after drying, using EVR (spraying from below). 5. The pellets are hardened in the EVR for 2 hours at 40 "C. 6. The hardened pellets are sieved through a 16-mesh sieve and then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing.

Zo E. Lubricant 1. The pellets obtained at the Ob stage are mixed with talc.

Example 2: Pellets containing omeprazole.

Sugar spherical particles (25-30 mesh)

o Triethylcitrate/////777777777111111111111111111111111111111111Ї11111111111161ссСсСсС in "Evaporates during processing.

Obtaining procedure:

A. Protective coating 1. Hypromellose is dissolved in water and sprayed onto sugar spherical particles using a fluidized bed (FB) device, obtaining a mass increase of 5 95 after drying.

B. Load of medicinal product 1. Gpromellose, poloxamer 407 and meglumine are dissolved in water. 2. Omeprazole is added to the dispersion obtained in stage 1, with stirring for at least 15 minutes.

Z. Pellets with a protective coating from stage AT and are coated with dispersion from stage 2 using EVR.

C. The coating that forms the sublayer 1. Hydroxypropyl methylcellulose is dissolved in water. 2. Talc and titanium dioxide are homogenized in water. 3. The dispersion obtained in stage 2 is mixed with the polymer solution obtained in stage 1 and mixed. 4. The dispersion is sprayed onto pellets with the drug loaded on them from the VZ stage using EVR, while obtaining an increase in mass by 16 95 after drying. Enteric coating 1. Triethyl citrate is dissolved in isopropyl alcohol. 2. Etzagadia? |. 100 55 is added to of the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and continuously stirred throughout the coating process. 4. The dispersion from stage C is sprayed onto the pellets from stage C4, which have a coating in the form of a sublayer , obtaining at the same time an increase in mass by 205 95 after drying, using EVR (spraying from below). 5. Pellets are hardened in EVR for 2 hours at 40 "С. 6. The hardened pellets are sieved through a 16-mesh sieve, then through a 24-mesh sieve and particles that

Zo is retained on a 24-mesh sieve, used for additional processing.

E. Lubricant 1. The pellets obtained at the Ob stage are mixed with talc.

Example 3: Omeprazole drug in the form of capsules. today, for example 1, 77.95

"Evaporates during processing.

Obtaining procedure:

A. Enteric coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etsyadgadiya? I. 100 55 is added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage C is sprayed onto the pellets, which have a coating that forms a sub-layer, with the target weight increase of 95 bOzh5 after drying, using EVR (spraying from below). 5. The pellets are cured in EVR for 2 hours at 4090. 6. The dried pellets are sieved through a 16 mesh screen, then through a 24 mesh screen, and the particles retained on the 24 mesh screen are used for further processing.

B. Outer coating 1. Triethylcitrate is dissolved in methanol. 2. Etsyagadiy? 1100-55 and Eshdgady BI RO are added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion from stage C is sprayed onto pellets with an enteric coating to achieve the target weight increase of 15:25 95 after drying, using EVR (spraying from below). 5. The pellets are cured in EVR for 2 hours at 4090. 6. The dried pellets are sieved through a 16 mesh screen, then through a 24 mesh screen, and the particles retained on the 24 mesh screen are used for further processing.

C. Lubricant and encapsulation 1. Pellets from stage Bb are mixed with talc. 2. Fill the capsule using 114 mg pellets from Example 1 and 145 mg pellets from stage 1.

Capsules are tested for dissolution characteristics using the OBR method by

By immersing the capsules in a pH 6.5 buffer medium, and periodically analyzing the content of the drug in the medium. Fig. C represents the results, where the y-axis represents the cumulative percentage of drug present that dissolves and the x-axis represents minutes.

Example 4: Omeprazole drug in the form of capsules.

"Evaporates during processing.

Obtaining procedure:

A. Enteric coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etsyadgadiya? I. 100 55 is added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage C is sprayed on pellets having a coating that forms a sub-layer, thus obtaining an increase in mass of 6bOzh5 95 after drying, using EVR (spraying from below). 5. The pellets are hardened in the EVR for 2 hours at 40 "C. 6. The dried pellets are sieved through a 16-mesh sieve and then through a 24-mesh sieve and the particles retained on the 24-mesh sieve are used for additional processing.

B. Outer coating 1. Triethylcitrate is dissolved in methanol. 2. Etsyagadiy? 1100-55 and Eshdgady BI RO are added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage 3 is sprayed onto enteric coated pellets from stage Ab, obtaining an increase in mass by 15:33 95 after drying, using

EVR (sprinkling from below). 5. The pellets are cured in EVR for 2 hours at 4090. 6. The dried pellets are sieved through a 14 mesh screen, then through a 24 mesh screen, and the particles retained on the 24 mesh screen are used for further processing.

C. Lubricant and encapsulation 1. Pellets from stage Bb are mixed with talc. 2. Fill the capsule using 114 mg pellets from example 1 and 145 mg pellets from stage 1.

Example 5: Omeprazole drug in the form of capsules.

Koo) today, the sublayer is 77.95

"Evaporates during processing.

Obtaining procedure:

A. Enteric coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etsyadgadiiye I. 100-55 is added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage C is sprayed on pellets having a coating that forms a sub-layer, thus obtaining an increase in mass by 6bOzh5 95 after drying, using EVR (spraying from below). 5. The pellets are hardened in the EVR for 2 hours at 40 "С. 6. The dried pellets are sieved through a 16-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing.

B. Outer coating 1. Triethylcitrate is dissolved in methanol. 2. Etsyagadiy? 1100-55 and Eshdgady BI RO are added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage 3 is sprayed on enteric-coated pellets, obtaining an increase in mass by 15:53 95 after drying, using

EVR (sprinkling from below). 5. The pellets are cured in the EVR for 2 hours at 40 "С. 6. The dried pellets are sieved through a 14-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing.

C. Lubricant and encapsulation 1. Pellets from stage Bb are mixed with talc. 2. Fill the capsule using 114 mg pellets from Example 1 and 145 mg pellets from stage 1.

Example 6: Omeprazole drug in the form of capsules.

Coo) sauteed Gollia sublayer 77.95 "Evaporates during processing.

Obtaining procedure:

A. Enteric coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etsyadgadiiye I. 100-55 is added to the solution obtained in stage 1, while stirring.

3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage C is sprayed on pellets having a coating that forms a sub-layer, thus obtaining an increase in mass by 6bOzh5 95 after drying, using EVR (spraying from below). 5. The pellets are hardened in the EVR for 2 hours at 40 "С. 6. The dried pellets are sieved through a 16-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing.

B. Outer coating 1. Triethylcitrate is dissolved in methanol. 2. Etsagadiy? 1100-55 and Etsagadi KI RO are added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage 3 is sprayed onto enteric coated pellets from stage Ab, obtaining an increase in mass by 15:33 95 after drying, using

EVR (sprinkling from below). 5. The pellets are cured in the EVR for 2 hours at 40 "С. 6. The dried pellets are sieved through a 14-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing.

C. Lubrication and encapsulation 1. Pellets obtained at stage Bb are mixed with talc. 2. Fill the capsule using 114 mg pellets from Example 1 and 145 mg pellets from stage 1.

Example 7: The preparation of omeprazole in the form of capsules lU sublayer 77.95 "Evaporates during processing.

Obtaining procedure:

A. Enteric coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etzadgadiya? |. 100 55 is added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage C is sprayed onto pellets having a coating that forms a sub-layer, while obtaining an increase in mass of 60595 after drying, using EVR (spraying from below). 5. Pellets are hardened in EVR for 2 hours at 40 "С.

6. The dried pellets are sieved through a 16-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for further processing.

B. Outer coating 1. Triethylcitrate is dissolved in methanol. 2. Etsyadgadi? 1100 55 ii of Etsagadiy KI RO are added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage 3 is sprayed onto the coated pellets from stage Ab, obtaining a mass increase of 15395 after drying, using EVR (spraying from below). 5. The pellets are cured in the EVR for 2 hours at 40 "С. 6. The dried pellets are sieved through a 14-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing.

C. The last layer of coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etsyadgadiiye I. 100-55 is added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage 3 is sprayed onto the pellets, which have an outer coating, while obtaining an increase in mass of 103595 after drying, using EVR (spraying from below). 5. The pellets are cured in the EVR for 2 hours at 40 "C. 6. The dried pellets are sieved through a 14-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing. r. Lubricant and encapsulation 1. Pellets from stage Sb are mixed with talc 2. Fill a capsule using 114 mg of pellets from Example 1 and 165.3 mg of pellets from stage 1.

From Example 8: Omeprazole drug in the form of capsules. sublayer "Evaporates during processing.

Obtaining procedure:

A. Enteric coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etsyadgadiya? I. 100 55 is added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion from stage C is sprayed onto pellets having a coating that forms a sub-layer, while obtaining a mass increase of 70595 after drying, using EVR (spray from below). 5. Pellets are cured in EVR for 2 hours at 40 "c.

6. The dried pellets are sieved through a 16-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for further processing.

B. Outer coating 1. Triethylcitrate is dissolved in methanol. 2. Etsagadi? 1100 55 ii of Etsagadiy KI RO are added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage 3 is sprayed onto the enteric-coated pellets from stage Ab, obtaining at the same time an increase in mass by 10:22 95 after drying, using

EVR (sprinkling from below). 5. The pellets are cured in the EVR for 2 hours at 40 "С. 6. The dried pellets are sieved through a 14-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing.

C. Lubricant and encapsulation 1. Pellets from stage Bb are mixed with talc. 2. Fill the capsule using 114 mg pellets from Example 1 and 146.5 mg pellets from stage 1.

Example 9: Omeprazole drug in the form of capsules.

Pon inii iavi i NN PIY sublayer 77.95 o ЕЕвааойВЕРО /(/(//СС711111111111111111111111111Ї11111111111811111 o Enagaoi С 300 55....7777711111111111Ї1111111811111 ". Evaporates in the processing process

Obtaining procedure:

A. Enteric coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etsyadgadiya? I. 100 55 is added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage C is sprayed on pellets having a coating that forms a sub-layer, obtaining at the same time an increase in mass of 702595 after drying, with

With the use of EVR (spraying from below). 5. The pellets are cured in EVR for 2 hours at 40 "C. 6. The dried pellets are sieved through a 16-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing.

B. Outer coating 1. Triethylcitrate is dissolved in methanol. 2. Eiadgadiya? I. 100-55 and Etsagaodii VI. PO is added to the solution from stage 1 while stirring. 3. Talc is added to the solution from stage 2 and constantly stirred throughout the coating process. 4. Dispersion from stage C is sprayed onto pellets with an enteric coating from stage Ab, obtaining an increase in mass by 15395 after drying, using EVR (spraying from below). 5. Pellets are hardened in EVR for 2 hours at 40 "С.

6. The dried pellets are sieved through a 14-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for further processing.

C. Lubricant and encapsulation 1. Pellets from stage Bb are mixed with talc. 2. Fill the capsule using 114 mg pellets from Example 1 and 152.7 mg pellets from stage 1.

Example 10: Omeprazole drug in the form of capsules. sooiyatzhnetetnui | lU sublayer 77.95 "Evaporates during processing.

Obtaining procedure:

A. Enteric coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etsyadgadiya? I. 100 55 is added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage C is sprayed onto pellets that have a coating that forms a sub-layer, thus obtaining an increase in mass of 80x3 95 after drying, using EVR (spraying from below). 5. The pellets are hardened in the EVR for 2 hours at 40 "С. 6. The dried pellets are sieved through a 16-mesh sieve and then a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing.

B. Outer coating 1. Triethylcitrate is dissolved in methanol. 2. Etsyagadi? 1100-55 and Eshdgady BI RO are added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained at stage C is sprayed onto pellets with an enteric coating, thus obtaining an increase in mass by 10:53 95 after drying, using

From EVR (sprinkling from below). 5. The pellets are hardened in the EVR for 2 hours at 40 "С. 6. The dried pellets are sieved through a 16-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing.

C. Lubrication and encapsulation 1. Pellets obtained at stage Bb are mixed with talc. 2. Fill the capsule using 114 mg pellets from Example 1 and 153.6 mg pellets from stage 1.

Example 11: Formulation of omeprazole. sub layer

"Evaporates during processing.

Obtaining procedure:

A. Enteric coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etsyagadiy? I. 100 55 is added to the solution from stage 1 while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage C is sprayed onto pellets that have a coating that forms a sub-layer, thus obtaining an increase in mass of 80x3 95 after drying, using EVR (spraying from below). 5. The pellets are hardened in the EVR for 2 hours at 40 "С. 6. The dried pellets are sieved through a 16-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing.

B. Outer coating 1. Triethylcitrate is dissolved in methanol. 2. Etsyagadiy? 1100-55 and Eshdgady BI RO are added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage 3 is sprayed on enteric-coated pellets, obtaining an increase in mass by 10:53 95 after drying, using

EVR (sprinkling from below). 5. The pellets are cured in EVR for 2 hours at 4090. 6. The dried pellets are sieved through a 14 mesh screen, then through a 24 mesh screen, and the particles retained on the 24 mesh screen are used for further processing.

C. Lubricating and filling capsules 1. Pellets are mixed with talc. 2. Fill the capsule using 114 mg pellets from example 1 and 155 mg pellets from stage 1.

Example 12: Omeprazole drug in the form of capsules.

Coo)

"Evaporates during processing.

Obtaining procedure:

A. Sublayer 1 1. Hypromellose is dissolved in water. 2. Talc and titanium dioxide are homogenized in water. 3. The dispersion obtained in stage 2 is mixed with the polymer solution obtained in stage 1. 4. The dispersion is sprayed onto the pellets from example C using EVR, obtaining an increase in mass by 16:22 95 after drying.

B. Load of medicinal product 1. Dissolve hypromellose, poloxamer 407 and meglumine in water. 2. Omeprazole is added to the dispersion obtained in stage 1, with stirring for at least 15 minutes.

C. Pellets that have a coating that forms a sub-layer from stage A4 are coated with the dispersion obtained in stage 2 using EPR.

C. Sublayer 2 1. Hypromellose is dissolved in water. 2. Talc and titanium dioxide are homogenized in water. 3. The dispersion obtained in stage 2 is mixed with the polymer solution obtained in stage 1. 4. The solution is sprayed onto the pellets with the drug loaded on them, using EVR, while obtaining an increase in mass by 12 95 after drying. r. Enteric coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etzadgadiya? I. 100 55 is added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage 3 is sprayed onto the pellets from stage C4, which have a coating that forms a sub-layer, while obtaining an increase in mass of 172 95 after drying, using EVR (spraying from below). 5. Pellets are hardened in EVR for 2 hours at 4090.

From 6. The dried pellets are sieved through a 12-mesh sieve, then through a 20-mesh sieve, and the particles retained on the 20-mesh sieve are used for further processing.

E. Lubrication and encapsulation 1. The pellets obtained at the Ob stage are mixed with talc. 2. Fill the capsules with the pellets obtained in stage 1.

In each of the examples 3-11, the combination of Esgady Her 100 55 and Etsagady KI RO polymers is used for the outer coating. These polymers can be used in mass ratios from 1:9 to 9:1 in composition variants. In addition, in these examples Etsagadiya I. 100 55 can be replaced by Eshyagadiya Y 100, and Etsagadiya KI RO can be replaced by Etsagadiya KZ RO, and they can be used in the same proportions.

In some embodiments, the pellets of example 1 or example 2 can be combined with pellets obtained in any of examples 3-11, and these pellet mixtures can optionally be mixed with polyethylene oxide and used to fill capsules.

This application also covers compositions comprising the enteric coated pellets obtained in Example 1, equivalent to 10-20 mg of active substance, and the pellets obtained in any of Examples 3-8, equivalent to 20-50 mg of active substance, where these pellets combine and fill the capsule with them. Various changes and combinations are possible, taking into account the desired mass of the active substance in the standard dosage form, for example, in the range of 40-60 mg.

Example 13: The drug omeprazole in the form of capsules 60 mg.

E5 Rgetiit " "

ST B---- -LIY NYN necessary

Hydroxypropylmethylcellulose, 5 cPz (Meiyosei tli: LY YN is not necessary

E5 Rgetiit ' necessary necessary

Copolymer of methacrylic acid, type C isopropyl alcohol : : necessary necessary

BE sini UNN NIE ZNO

Etsagadiy VI RO "shi r

Eshpagadi I. 100-55 '

MOSTI PN KO NO I: IN UDO o Triethylcitrate/////77777777771111111111111111111111 11111111 2621 - 222222 r necessary "Evaporates during processing.

Obtaining procedure:

A. Application of protective coating 1. Hypromellose is dissolved in water and sprayed onto sugar spherical particles using a fluidized bed (FBD) device.

B. Load of medicinal product 1. Gpromellose, poloxamer 407 and meglumine are mixed with water. 2. Omeprazole is added to the dispersion obtained in stage 1.

Z. Pellets with a protective coating from stage AT and are coated with dispersion from stage 2 using EVR.

C. Sublayer 1. Hydroxypropylmethylcellulose is dissolved in water. 2. Talc and titanium dioxide are homogenized in water.

3. The dispersion obtained in stage 2 is mixed with the polymer solution obtained in stage 1 and mixed. 4. The dispersion is sprayed onto the pellets loaded with the medicinal product from the stage

VZ, using EVR, while obtaining an increase in mass by 16 95 after drying. r. Enteric coating 1. Triethylcitrate is dissolved in isopropyl alcohol. 2. Etsyadgadiya? I. 100 55 is added to the solution obtained in stage 1, while stirring.

C. Talc is added to the solution obtained in step 2 and the mixture is constantly stirred throughout the coating process. 4. The dispersion from stage C is sprayed onto the pellets from stage C4, which have a coating that forms a sub-layer, while obtaining a mass increase of 20:x5 95 after drying, using EVR (spraying from below). 5. The pellets are cured in the EVR for 2 hours at 4096. 6. The cured pellets are sieved through a 16 mesh screen, then through a 24 mesh screen, and the particles retained on the 24 mesh screen are used for further processing.

E. Sustained release coating 1. Triethylcitrate is dissolved in methanol. 2. Etsagadiy? And 100 55 and Etsgadiy KI RO are added to the solution obtained in stage 1, while stirring. 3. Talc is added to the solution obtained in stage 2 and constantly stirred throughout the coating process. 4. The dispersion obtained in stage 3 is sprayed onto the pellets from stage Ob which have a coating, thus obtaining a mass increase of 1553595 after drying, using EVR (spraying from below). 5. The pellets are cured in the EVR for 2 hours at 40 "С. 6. The dried pellets are sieved through a 14-mesh sieve, then through a 24-mesh sieve, and the particles retained on the 24-mesh sieve are used for additional processing.

E. Lubricant 1. The pellets obtained at stage OB and stage E are mixed with talc.

From b. Encapsulation 1. Lubricated pellets of type A and type B are filled with capsules.

The capsules are packaged in aluminum foil blister packs and stored for one month at 409 and 75 95 relative humidity. Samples are analyzed before and after storage and the results obtained are presented in the table below. Quantitative analysis values for the medicinal product and impurities represent percentages of the content of the medicinal product indicated on the label, and losses on drying are expressed as a percentage of the mass of the composition. o Admixture A //-/-:777777777771111111111111111111111111111001111111111711111100611

The identified impurities have the following structures.

Basic

НС хи SN N

M-oxide admixture | o M (Impurity 1) - SHI u ten-5- c) M osn n s. . M

Benzimidazole admixture (Impurity 2) nv-k Fe

M basic

Osn"

Not sia SN

Sulfone impurity | o) H (Impurity 3) ro by mM sna-5-K o M Osn

NzS or SN N

Desmethoxy impurity | ru o M (Admixture 4) bombs Zsn,-8-K pf

M osn" osn

Us. them and SN

Sulfide impurity | n i - (Admixture 5) MU tsne-8-5, LO

M osn nos n

M pl-

Desmethoxy dehydro impurity (Impurity A) is ri to M ny

Oh--

M-methyl impurity o / (Impurity C) t is Xx

In whether or not;

M. U

N

M

N

And M

Des-sulfur admixture (It/7 a M 283) o (c)

Six of the obtained capsules, after storage for one month at 402C and relative humidity of 75 95, were subjected to a drug dissolution test in 500 ml of other solutions

NSII for 2 hours, then in 900 ml of pH 7.0 phosphate buffer with 5 mM 515 for 105 minutes, stirring with a paddle mixer at 75 rpm, the results are presented in the table below.

Sample 1 2 Z 4 5 b o Output value| 90 | 88 | 88 | 89 | 88 | 88 | 89

T1 months// | 90 | 90 | 90 | 91 | 90 | 89 | 90

The dissolution profile of the resulting composition is shown in Fig. 2 based on the test data according to the OR method using 0.1 N HCI solution for the first 2 hours, then pH 6.5 RazvBIb buffer for the rest of the test time, with 900 ml of medium and stirring using a paddle mixer at 75 rpm . The y-axis represents the cumulative percent of drug present that dissolves, and the x-axis represents minutes.

Claims (11)

FORMULA OF THE INVENTION 1. A pharmaceutical composition that includes, in combination: a) particles that contain omeprazole or its salt and have a controlled release polymer coating containing a combination of at least one pH-independent polymer and at least one pH-dependent polymer, while the coating is soluble at pH values from 5 to 7.5; and p) particles that contain omeprazole or its salt and have a polymer coating that is soluble at pH values from 5 to 6. 2. Pharmaceutical composition according to claim 1, where particles a) are tablets or granules or pellets. 3. The pharmaceutical composition according to claim 1, where the particles of BYU) are tablets or granules or pellets. 4. Pharmaceutical composition according to claim 1, where particle a) and BYU) are tablets or granules or pellets. 5. Pharmaceutical composition according to claim 1, where the particles a) and B) have intermediate coatings, which essentially do not affect the release of the drug, on which the polymer coating is applied. 6. Pharmaceutical composition according to claim 1, where the polymer coating a) includes a pH-dependent polymer, soluble at pH values from 5 to 6. 7. Pharmaceutical composition according to claim 1, containing from 20 to 60 mg of omeprazole. 8. Pharmaceutical composition according to claim 1, containing 40 mg of omeprazole. 9. Pharmaceutical composition according to claim 1, where a) contains 20 mg of omeprazole and B) contains 20 mg of omeprazole. 10. The pharmaceutical composition according to any of the previous items, where the pH-dependent polymer is selected from the group consisting of cellulose acetophthalates, cellulose acetosuccinates, polyvinylacetophthalates, polyvinylacetophthalates, hydroxypropylmethylcellulose phthalates, hydroxypropylmethylcellulose acetosuccinates, hydroxypropylmethylcellulose succinates, copolymers of methyl methacrylate and methylmeth methyl acrylate, copolymers of methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride, copolymers of ethyl methacrylate-methyl methacrylate-ethyl acrylate chlorotrimethylammonium, copolymers of methyl methacrylate and methacrylic acid, copolymers of methacrylic acid and ethyl acrylate acid, copolymers of methacrylic acid and methyl acrylate-methyl methacrylate and their mixtures. 11. The pharmaceutical composition according to any of the previous items, where the pH-independent polymer is an ammonium methacrylate copolymer. Zo