Pharmacological composition with swelling coating

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical dosed form, which contains pharmaceutically active substance, unstable in presence of acid, which includes central nucleus, containing active substance and loosening agent, swelling coating, surrounding central nucleus, and enterosoluble coating, surrounding swelling coating. Swelling coating includes prolamin, preferably, zein. Pharmaceutically active substance includes benzimidazole, selected from omeprazole, lansoprazole, rabeprazole and pantoprazole.

EFFECT: invention ensures fast release of pharmaceutically active substance in medium, which has pH value at least 5.

33 cl, 12 ex

 

Prior art

In this description referred to several patents and other documents. The contents of these documents are included in this description by reference.

The invention relates to a solid pharmaceutical dosage form having a coating that protects the pharmaceutically active ingredients contained therein from degradation under the action of the acid gastric juice. In particular, the dosage forms are coated, including substances which swell upon contact with aqueous liquids.

A number of pharmaceutically active ingredients are chemically unstable in acidic environments. Therefore, oral administration cannot be effective without some means of protection substances from contact with gastric juice. It is, however, also leads to a common undesirable effect of slowing access to the substance in the body, because systemic absorption does not begin until the substance will not be released from its dosage form.

Tools were developed to ensure protection of pharmaceutical dosage forms from the action of the acidic contents of the stomach and the transition of active ingredients available only after hitting dosage forms in a more alkaline environment, such as in the duodenum, jejunum or ileum. Typically uh what about the cover dosage forms or particles, containing an active pharmaceutical agent, a material resistant to the action of acid, but soluble or become permeable to a more alkaline environment.

Lovgren et al., in U.S. patent No. 4786505 describe the stable pharmaceutical composition of omeprazole, resistant to acid, but quickly soluble in neutral or alkaline medium. Particles of omeprazole is mixed with water-soluble reactive with respect to alkali substance and cover parts "separating layer", acting as a pH buffer zone, preventing contact of the medicinal product with the acid groups present in the final coating material. Finally, the two-layer composition are coated with Intercollege polymer which does not react with acids.

U.S. patent No. 5035899, to add details name et al., concerns compositions are unstable in the presence of acid medicines protected from contact with gastric juice. On the Central part, containing the drug, causing the first coating of fine particles of a material having a low solubility in water, and then the floor Intercollege film-forming material, such as ethylcellulose.

Mazer et al., in U.S. patent No. 5160742, open the system slow release sensitive to acid medicines Taco is about as β-laktamovogo antibiotic. Particles of a medicinal product with a coating suitable for inclusion in syrups or other composition is prepared by forming a Central core containing the drug, drawing on the engine cover from prolamine and application of the final coating Intercollege substances, such as methacrylic acid copolymer. Optionally, the layer Intercollege coating may be applied an additional coating prolamine. The drug is released over an extended period of time, starting from the moment of contact with the coated particles in an environment with a high pH.

U.S. patent No. 5472712, in the name Oshlack et al., describes the composition of controlled release, having a Central core with a drug and a hydrophobic ethylcellulose floor of supervised release, which optionally contains hydrophilic evaporative substance, such as hypromellose. Optionally, the Central core may have an intermediate barrier coating substances, such as hypromellose, which, preferably, does not affect the dissolution rate of the final product.

In U.S. patent No. 5609909, in the name Meuag et al., oral compositions to disguise the unpleasant taste of the drug substance, in which the drug among the STV becomes bioavailable immediately after contact with the acid fluid in the stomach, receive by drawing on part of the Central core containing the drug, a coating of a mixture of prolamine and polimernogo plasticizer.

U.S. patent No. 5811388, in the name of Friend et al., describes the preparation of dosage forms in which the drug is released in the upper gastrointestinal tract, but is released in the lower gastrointestinal tract for immediate treatment of diseases of the colon. Dosage form comprises a core tablet containing drug and a large number of hydrocolloid vegetable origin, optionally covered with a film Intercollege substances.

Lerner et al describe in U.S. patent No. 5840332, a composition for delivery of drug at a specific site of the gastrointestinal tract, in which a core containing the drug coated with water-insoluble material with permeable particles of water-insoluble hydrophilic substances. The core with the coating may optionally be further coated with intersolubility polymer.

U.S. patent No. 6346269, in the name of Hsiao et al, describes oral compositions sensitive to acid drug in which the drug substance is mixed with an alkaline material, such as trisodium phosphate, which is applied in the form of a coating on the core, such as a tablet, then at the layer of the substance of the medicinal product applied intersolubility floor.

Methods for the manufacture of films, sheets and products of Zein described in U.S. patent No. 6635206 in the name of Padua et al.

There is a need in a unit dosage form containing a drug in which the drug substance is not in contact with the acid in the stomach, but will be quickly released when the dosage form enters in a more alkaline environment.

The invention

In one embodiment, the invention includes a pharmaceutical dosage form containing: solid Central core containing a pharmaceutically active substance and baking powder; swelling of the floor, surrounding the Central core; and intersolubility floor, swelling around the floor. Dosage form can have different options for implementation, including coated tablets or capsules containing granules coated or minitablets coated.

A preferred aspect of the invention is a dosage form in which the pharmaceutically active substance is largely held until the dosage form is in the stomach, but where the pharmaceutically active substance is rapidly released after dosage form is adjudged to be in an environment having a pH value in men is her least 5.

The invention also includes a pharmaceutical dosage form that contains solid Central core, which includes sensitive to acid pharmaceutically active substance and baking powder; swelling of the coating containing the component, forming hydrocolloid, and surrounding the Central core; and intersolubility floor, swelling around the floor.

The invention further includes a pharmaceutical dosage form having a solid Central core containing the benzimidazole and baking powder; swelling of the coating containing one or more substances forming hydrocolloids selected from Zein, crosspovidone and hydroxypropylcellulose, and surrounding the Central core; and intersolubility coating containing a copolymer of methacrylic acid and ethyl acrylate, swelling around the floor.

Another aspect of the invention is a method of treatment when there are medical indications, including oral introduction of the pharmaceutical dosage form according to any one of the above aspects and embodiments, in which: dosage form remains essentially unchanged during the passage through the stomach; intersolubility coating is removed in environments digestive system with pH values above about 5; water liquid penetrate into areas of dosage forms with shock is i.i.d. intersolubility coating, causing the formation of hydrocolloid swelling in the floor; water fluid pass through the hydrocolloid and hydratious Central core; and hydrated Central core is segmented, releasing a pharmaceutically active substance from the dosage form.

Further, the invention includes a method of manufacturing a pharmaceutical dosage form, comprising the stage of: mixing components, including pharmaceutically active substance and baking powder, and forming a solid Central core; applying to the Central core of swelling of the coating containing the component, forming hydrocolloid; and applying an external coating containing resistant to acids intersolubility substance.

Preferred agents swelling in swelling the coating include prolamins, vinylpyrrolidone polymers; cellulose derivatives; starches; carboxyvinyl polymers; alginates; pectins; agar and resin. More preferred for use as swelling agents are Zein, crosspovidone or hydroxypropylcellulose.

A detailed description of the invention

This invention provides a pharmaceutical dosage form including a Central core containing a pharmaceutically active ingredient, and swelling of the floor, surrounding the Central core. The Central core is smaller is her least 50%, at least 60%, at least 70%, preferably at least 80%, preferably at least 82.5 percent, preferably at least 85%, preferably at least 87%, preferred at least 88%, preferred at least 89%, from the pharmaceutical compositions in General. The Central core may also comprise at least 90%, at least 91%, at least 92%, or at least 93% of the pharmaceutical composition as a whole.

In this application, the terms "pharmaceutically active ingredient", "pharmaceutically active ingredient" and "active agent" are used interchangeably to denote the component pharmaceutical dosage form providing a therapeutic effect when administered to a subject. This invention is particularly applicable to sensitive to acid pharmaceutically active substances exhibiting instability in environments with low pH, such as benzimidazole derivatives, including their optically active isomers.

Specific examples of useful benzimidazole compounds include rabeprazole, omeprazole, esomeprazole, lansoprazole and pantoprazole. Other medicines, for which the invention will be useful include, without limitation: pharmaceutically active substances reacting with components Intercollege coverage examples to the verge are medicines forming insoluble complexes with intersolubility coating, such as fluoxetine and DULOXETINE; and strongly alkaline medicines that can react with acid groups, reducing the insolubility of the coating in acid, such as diclofenacgel and piroxicam.

Used here meaning "swelling coating" is a coating which increases in volume upon contact with aqueous fluids. This swelling usually occurs due to absorption of water. Swelling coating adds 0,1-10%, 0,5-8%, 0,7-7%, 1-5%, 1,3-3%, 1,5-2%, about 2% or about 1.5% of the weight of the Central core. In another embodiment, the swellable coating adds 0,1-5%, 0,1-4%, 0,1-3%, 0,1-2% or 0.1-1% by weight of the Central core.

In General, swelling the coating when wetted becomes a hydrocolloid, which is a gel-like suspension of microscopic particles in the water. Preferably, the hydrocolloid is formed from prolamine, such as gliadin, hordein or, more preferably, the Zein. Zein is extracted from corn in the form of a granular amorphous powder from straw to pale yellow or small flakes, and various industrial produce extracts have a molecular weight in the range 25000-35000. Zein is insoluble in water and insoluble in alcohols, but soluble in aqueous alcohol is. Chemically Zein has a fairly high content of glutamine and does not contain lysine and tryptophan. Zein contains approximately 20-22% glutamic acid and glutamine, 17-20% leucine, 5-9% Proline, 8-10% of alanine, 4-7% phenylalanine, 3-7% isoleucine, 4-6% serine, 4-5% asparagine and 3-5% tyrosine. The content of the remaining amino acids in the Zein is less than 3% each.

The Zein was granted the status of a substance recognized completely safe (GRAS) by the Management under the control over products and medicines of the United States from March 1985 for use in food and pharmaceutical products. Zein is commercially available from several sources, including Freeman Industries LLC, Tuckahoe, New York USA); commercial Seidovym products marketed by the company, owned by Zein F4000, Zein 4400, Zein F6000, Zein G-10, Aqua and Aqua Zein Zein Neutral.

Preferred at this time, the Zein for the purposes of this invention is Zein F6000, which is subjected to re-extraction to reduce its color (caused by xanthophyllum). Zein F6000 is a granulated powder is very light yellow color with a molecular weight of about 35,000 and a bulk density 0,125-0.21 g/ml It contains 90-96% Zeinalova protein, calculated on the dry substance.

The hydrocolloid may also be formed from hydroxypropylmethylcellulose.

Viscosity of 2 wt.% aqueous solution of different hydroxypropyl who ethylcellulose products varies in the range of from about 4000 MPa·s to about 100,000 MPa·S.

In one embodiment, hypromellose is a product of type substitution 2208 (Substitution Type 2208) according to the USP, which is also called hypromellose 2208 having a viscosity of about 15000 MPa·s, commercially available as Methocel KM. In another embodiment, hypromellose is a product of type substitution 2910 (Substitution Type 2910) USP, also known as HyperMethod 2910, with a viscosity of about 4000 MPa·s, sold under the name Methocel E4M.

METHOCEL is a trademark owned by Dow Chemical Company (Midland, Michigan USA).

Other materials suitable for forming hydrocolloid include, without limitation, crosspovidone; sodium salt croscarmellose; cellulose derivatives such as hydroxyethylcellulose, hydroxypropylcellulose or methylcellulose; gums, such as seaweed extracts, plant extracts, plant exudates, extracts of plant seeds and the products of bacterial fermentation; starches, including petizione and modified starch; and synthetic materials such as carboxyvinyl polymers, including carbopol.

More specific examples include alginates, pectins, pectin with a low content of methoxypropyl, agar, carrageenan, gum Arabic (plus arabic), tragakant, karaya, Gatti,resin carob (carob), guar, dextran, xanthan gum, carrageenan, Tara (tara), Khaya grandfolia, 'gellan (gellan), Konjac mannan, galactomannan, resin funorb (funoran), aceton (acetan), Whelan (welan), Raman (rhamsan), furcelleran (furcelleran), succinogenes, stearopten, sizofiran (schizophylan), curdlan (curdlan), pullulan (pullulan), karaya and tamarind.

In addition to the pharmaceutically active substance, the Central core further includes a leavening agent, which in the aquatic environment promotes physical fragmentation of the material with which it is mixed. Baking powder does not cause dissolution or chemical changes fragmented material. Examples of suitable disintegrating agents include: starches, such as potato or manioc starch, modified starches such as sodium salt starch glycolate) and partially petizione starch (such as Starch 1500); polyvinylpyrrolidone, including the modified polyvinylpyrrolidone (such as crosspovidone, polymerized under conditions conducive to binding); cellulose, such as microcrystalline cellulose, modified cellulose, such as hydroxypropylcellulose with a low degree of substitution, sodium salt croscarmellose and calcium carboxymethyl cellulose); formaldehyde-casein compounds (such as Esma-Spreng R™, resins, such as polacrilin-potassium sold Rohm and Haas Company (Philadelphia, Pennsylvania USA under the trademark AMBERLITE IRP88; low fat soy extracts; alginic acid; agar-agar; calcium carbonate; calcium phosphate and sodium carbonate. In U.S. patent No. 6696085, in the name Rault et al., indicated that the acrylic polymers are suitable for use as a baking powder tablets.

In addition to the above, the Central core may contain any desirable components, such as binders, lubricants, antioxidants, etc. as well known in the art and discussed below.

Pharmaceutical dosage form further includes intersolubility floor, swelling around the floor. "Intersolubility coating" is a coating that is essentially insoluble at acid pH values in the stomach, but essentially soluble or water-permeable at higher values of pH in the intestine. In this invention, intersolubility coating protects swelling the coating from contact with acidic gastric environment, but does not prevent the contact swellable coating with more alkaline intestinal juice. Intersolubility coating can be selected for targeted release in a particular Department of the intestine. For example, intersolubility coating can provide delivery to the duodenum (pH>5,5), the jejunum (pH 6-7) or ileum (pH 7.5). Intermediate point dostavka may be achieved by combining different coating materials or change the thickness of the coating. Materials Intercollege coverage include coverage based on cellulose, such as acetated cellulose phthalate of hydroxypropylmethylcellulose, floor-based methacrylate, based coating polivinilatsetatftalat and floor-based shellac.

In this invention, preferred are coatings based on acrylic, and several useful products are commercially available from the company Rohm GmbH & Co. (Darmstadt, Germany) under the trade name EUDRAGIT. Especially preferred is Eudragit L100-55. Eudragit L100-55 is a dried atomization powder Eudragit L30D-55, which can be restored. Eudragit L30D-55 is a water dispersion of the pH-dependent polymer soluble at pH of at least 5.5, designed for targeted delivery into the duodenum. Eudragit L100-55 pH-dependence of Eudragit L30D-55 and, thus, is soluble at pH of at least 5.5 and ensures the delivery into the duodenum.

Eudragit L100-55 and Eudragit L30D-55 are copolymers of methacrylic acid and ethyl acrylate in a ratio of 1:1. They have a molecular formula: (C5H2About2·4H6About2)xand registration number CAS (Chemical Abstracts) 25212-88-8. Eudragit L100-55 also meets the requirements of United States Pharmacopeia to the methacrylic acid copolymer type C.

In one embodiment, the implementation of whom tvline, intersolubility coating comprises 1-40%, 3-35%, 5-30%, 6-20%, 7-10%, or 8% of the total composition. In another embodiment, intersolubility coating includes less than 20%, not more than 17.5%, less than 15%, not more than 12.5%, not more than 10%, not more than 9%, no more than 8%, no more than 7%not more than 6%not more than 5% or no more than 4% of the total composition.

Optional, swelling the coating add excipient, which modulates the release of pharmaceutically active substances. Modulation can be done by facilitating or impeding the access of water to the Central core. Suitable excipients include plasticizers, such as lactic acid, ndimethylacetamide lactic acid, glycerin, glycerylmonostearate, triacetin, sorbitol, triethylcitrate, pyrrolidone, triethylene glycol, tricresylphosphate, dibutylated, etilenglikolevye, palmitic acid, stearic acid, oleic acid, dibutylsebacate, acetylated monoglycerides and other oils and waxes, and polyethylene glycol 300, 400, 600, 1450, 3350 and 8000. Additional excipients, modulating the rate of release of active substances include water-soluble surfactants such as sodium lauryl sulfate and sodium docusinate, and materials Intercollege coatings, such as Eudragit L100-55, which domeshivat swelling in the floor.

B is C limitations of any particular theory of action is considered, what material Intercollege floor, included in swelling the coating dissolves upon contact with gastrointestinal fluid and forms channels in swelling the coating that facilitates access intestinal fluids to the Central core. In one embodiment, the material Intercollege floor is approximately 0,1-30%, 0,5-20%, 1-17,5%, preferably 5-15% or, more preferably, 5-10% from the swelling of the coating. In another embodiment, the material Intercollege cover 10-50%, 15-40%, preferably 20-30% of the swelling of the coating.

Also without limitation, any theory argues that water-soluble surface-active agent causes rapid wetting and swelling of the coating upon contact with intestinal fluids, thereby contributing to the flow of fluid to the Central core. In the case of using water-soluble surface-active substances, it is approximately 0,001-30%, 0,005-20%, 0,01-10%, 0,03-8%, 0,05-6%, 0,07-4%, 0,09-2% or 0.1-1 wt.% from the swelling of the coating. The preferred range is from 0.01 to 10%.

For example, if the swelling Zein coating is used, the amount of swelling and controls the permeability and the permeability is achieved when the greatest amount of swelling. For more information on diffusion through the hydrate is rowanne film Zein see Y.K. Oh et al., "Swelling and Permeability Characteristics of Zein Membranes", PDA Journal of Pharmaceutical Science and Technology, Vol.57, pages 208-217 (2003).

Adding plasticizers for Zein affect its permeability to water. The combination of Zein with hygroscopic plasticizers, such as glycerin, triethylene glycol and levonova acid, leads to an increase of water absorption compared to the unplasticized Zein. However, the introduction of Zein hydrophobic plasticizers, such as dibutylated and oleic acid, leads to the reduction of water absorption compared to the unplasticized Zein.

The greater the degree of penetration of the water, the smaller will be the tensile strength and the coating can simply be destroyed, leading to the full release of pharmaceutically active substances. Discussion photoabsorption characteristics of cast plasticized sainovich films, see J.W. Lawton, "Plasticizers for Zein: Their Effect on Tensile Properties and Water Absorption of Zein Films", Cereal Chemistry, Vol.81, pages 1-5 (2004).

The modulation profile release of pharmaceutically active substances by excipients, such as a plasticizer, is not limited to Zein. In General, changing the amount and type of plasticizer affects the tensile strength of the coating. The use of hygroscopic excipients instead hydrophobic also affects the release profile in the same way as described for Zein.

The Central core according to the invention can be in the form of tablets, minitablets, granules, solid dispersed particles of arbitrary or rounded. Tablets and minitablets can be made by direct extrusion or any other method known to specialists in this field. Formation of granules can be used dry granulation, wet granulation, dry granulation of the melt, or any other method known to specialists in this field. Solid dispersion particles of arbitrary or rounded shape can be manufactured by any method known to specialists in this field, such as extrusion or spheronization. Particles of rounded shapes can also be produced by granulation of the melt or coating dispersion germ particles. Wet Central core is dried using conventional drying procedures, such as air drying or drying by heating and/or under reduced pressure. On the Central core according to the invention cause swelling of the floor, and then the external intersolubility floor. In General, the coating can the t to be inflicted by any means, known in the art, such as drazhirovanie (including perforated closed system drazhirovanija), coacervation or coating in the fluidized bed. Fluidized bed may have a rotary sleeve and/or the sleeve-top. Coatings can be broadly classified according to their polymer-based, for example: on the basis of cellulose, including acetated cellulose phthalate of hydroxypropylmethylcellulose, hypromellose, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose; carrageenan; based on acrylic or methacrylic acid, such as methacrylic acid, methacrylate, acrylate, ethacrylate, methyl methacrylate or copolymers; or on the basis of polivinilatsetatftalat. Typically, the polymer is mixed with a solvent, such as water, and a plasticizer such as polyethylene glycol, lactic acid, ndimethylacetamide, glycerin, glycerylmonostearate, triacetin, sorbitol, triethylcitrate, pyrrolidone, triethylene glycol, tricresylphosphate, dibutylated, etilenglikolevye, palmitic acid, stearic acid, oleic acid or dibutylsebacate. Optional, can be added to any of these components: release agent, non, filler, surfactant, dye, Kosovo the substance, and combinations of any two or more of these components.

After applying Intercollege coating on the pharmaceutical compositions can be printed identifying information using printing ink and procedures known in the art, such as deep offset printing. Pharmaceutically acceptable printing inks, which can be used for deep offset printing include Markem™ 2200, 2202, 2212 and 2222 production company Markem Corporation, Keene, New Hampshire, USA). These printing inks are typically made on the basis of shellac and contain pigments. Any of these printing inks can be added as diluents to increase or decrease the speed of drying and/or adjusting the viscosity. After applying these printing inks are usually dried in the air.

Other pharmaceutically acceptable printing inks include products under the names d™ and Opacode™ WB, which both contain pigments, titanium dioxide and the solvent and is produced by the firm use (West Point, Pennsylvania, USA). Many other printing inks known to experts in this field, and any of them will be suitable for dosage forms according to the invention.

Optional, dosage forms with intersolubility coating may be a coating of thin films. Often the film will be painted for the region is Genia identification of the product and for aesthetic reasons; in this case, print any desired information can be performed after film coating. Many products suitable for film coating are commercially available, including the proposed company use (West Point, Pennsylvania, USA) under the trademarks OPADRY and OPAGLOS. These products Colorcon are dry powders containing polymer, a plasticizer and a pigment that is mixed with water or solvent, such as alcohol, and nabryzgivajut on tablets or other solid dosage forms. This procedure of coating film and alternative products for film coating.

Coated tablets, round pellets, granules or solid particles can be placed in capsules for easy introduction. The space in the shell can be any known in the art, such as filling pre-formed capsules. Such capsules can contain gelatin or any other material known to specialists in this field.

Without limiting any theory argues that after the dissolution of Intercollege coverage in the intestine swelling the coating absorbs intestinal fluid and expands outward. Thus, the first swelling the coating expands like a balloon, blowing the t, not being destroyed. When the swelling of the coating its permeability to water increases. It is assumed that the swelling coating contains microchannels, through which the water by diffusion goes to the Central core.

Water is the cause of the fragmentation of the Central core. Some of these fragments can pierce swelling the coating, leading to intake more water. Additional water causes even greater fragmentation of the Central core, which is believed to trigger a piercing cover other fragments. It is believed that this cycle continues until the full release of pharmaceutically active substances or up until swelling the coating will not weaken so that collapses under the action of absorption.

Further, without limitation to any theory, it is believed that the release of the active substance can be modulated by other factors besides the availability of Intercollege coverage. One such factor is the choice of substances forming hydrocolloid, swelling in the floor. Hydrocolloids have different ability to swell and, therefore, the permeability of the intestinal fluid. It is argued that the permeability of hydrocolloid affects the rate of hydration of the Central core and the resulting fragmentation of the Central core. Hydro is oloidi also have different tensile strength, which, as it affects the proportion of fragments of the Central core, capable of penetrating into the fragmentation swellable coating. The number of fragments that can come out that has a direct impact on the release of pharmaceutically active substances. It is also believed that the number of holes formed in swelling the coating additionally affects the release of the active substance by increasing revenues in the Central core of intestinal fluid, which causes more fragmentation. From the tensile strength additionally depends when and will collapse if any swelling of the coating due to the attenuation caused by absorption of water, leading to a complete release of the active substance. In addition, some hydrocolloids erogenous swelling that affects the ease of perforation swelling of the coating fragments of the Central core.

Another factor may be an optional addition to swelling the coating excipient, modulating the release of pharmaceutically active substances. Such agents can increase or decrease the permeability of hydrocolloid for intestinal fluid.

This permeability affects the amount of intestinal fluid, which is in contact with the core and leads to fragmentation. There is an assumption that the result is e fragmentation fragments pierce the swelling floor, thereby affecting the release of pharmaceutically active substances. Further, it is believed that the holes formed in swelling the coating, to form passages for admission of additional amount of intestinal fluid to the Central core, further accelerating fragmentation.

The third factor is the use of baking powder in the Central core. The use of baking powder increases the rate of fragmentation of the Central core, which supposedly increases the frequency of formation of fragments of holes swelling in the floor.

Itself only increasing the number of fragments that go out through the swelling of the coating increases the rate of release of pharmaceutically active substances. Additionally it is believed that a greater number of holes formed in swelling the floor, allows more water to enter the Central core, causing an even stronger fragmentation of the active substance. In addition, the baking powder can affect the force with which the fragments of the Central nucleus of pressure on swelling the surface, which can cause the formation of holes in swelling covering a large number of fragments. This intensive destruction will further increase the rate of release of pharmaceutically active substances, allowing a greater number of fragments in the Central core, p is ahadith through the swellable coating. These leavening agents also form additional openings through which intestinal fluid hydrates and fragments of the active substance, leading to additional release of the active substance. Although the rate of release of the pharmaceutically active substance can be modulated, as described above, this invention is not intended to create compositions with delayed release, in which the pharmaceutically active substance is released from the controlled rate over an extended period of time, such as 12 or 24 hours. On the contrary, the sign of this invention is the slow release taken orally pharmaceutically active substance up until the dosage form reaches the intestinal tract, where alkaline pH values that do not affect sensitive to acid pharmaceutically active substance, cause rapid, essentially complete release of the pharmaceutically active substance for systemic absorption.

The following examples are intended to help understanding of the invention and are not intended and should not be interpreted as in any way limiting the invention defined in the attached claims. In the examples, the ingredients that are volatile during drying and therefore are not in the final product, nicklachey in tabular lists of ingredients; however, these ingredients are referred to as solvents, etc. in the description of the procedures of preparation. In addition, weight gain when printing information on the finished dosage form is insignificant and therefore not included in the final total weight. Percentages are given in terms of weight, unless the context clearly indicated otherwise.

Example 1

Manufactured tablets containing 20 or 40 mg of pantoprazole, using such components and procedure:

IngredientsAmount (mg) per tablet 20 mgAmount (mg) per tablet 40 mg
The Central core tablets
Dry mixing
Pantoprazole sodium22,5545,1
Mannitol (Pearlitol SD 200)110,95221,9
Crosspovidone8,2516,5
Sodium carbonate3,757,5
Granulation
Sodium carbonate anhydrous3,757,5
Hydroxypropylcellulose (Klucel LF)48
Grease
Crosspovidone8,2516,5
Talc1,53
Calcium stearate24
Only165330
Swelling floor
Zein F60002,074,13
Methacrylic acid copolymer (Eudragit L100-55)0,410,82
Growing up167,48334,95
Intersolubility floor
Methacrylic acid copolymer (Eudragit L100-55)a 9.25be 18.49
Triethylcitrate0,931,85
Titanium dioxide1,83the 3.65
Talc1,412,81
Growing up180,83361,65
Film coating
Opadry Yellow OY-52945to 4.529,04
Growing up185,42370,79
Printing
Opacode Black S-1-8152 HVq.s. (sufficient quantity)q.s.

The Central core tablets prepared by dry granulation of a mixture of pantoprazole sodium, mannitol, crosspovidone and sodium carbonate with an aqueous solution of hydroxypropy the cellulose (Klucel LF) and anhydrous sodium carbonate. The granules are dried using conventional drying methods. The dried granules are then smeared with crosspovidone, talc and calcium stearate. The lubricated granules are pressed into the Central core. The Central core is applied to the primary coating of a mixture of Zein, Eudragit L100-55, water and isopropyl alcohol and dried. Put intersolubility coating over the primary coating using Eudragit L100-55 with isopropyl alcohol as a solvent and triethylcitrate as a plasticizer. Talc and titanium dioxide is used as the lubricant agent and impart opacity, respectively. After drying, a tablet with intersolubility coating is applied film coating using Opadry Yellow OY-52945 and printed information using Opacode Black S-1-8152 HV.

Example 2

Tablets containing 20 or 40 mg of pantoprazole, manufactured with the use of such components and procedures:

IngredientsAmount (mg) per tablet 20 mgAmount (mg) per tablet 40 mg
The Central core tablets
Dry mixing
Pantoprazole-potassium22,5545,1
Mannitol (Pearlitol SD 200)110,95221,9
Crosspovidone8,2516,5
Sodium carbonate3,757,5
Granulation
Sodium carbonate anhydrous3,757,5
Hydroxypropylcellulose (Klucel LF)48
Grease
Crosspovidone8,2516,5
Talc1,53
Calcium stearate24
Only165330
Swelling covered is e
Zein F60002,074,13
Methacrylic acid copolymer (Eudragit L100-55)0,410,82
Growing up167,48334,95
Intersolubility floor
Methacrylic acid copolymer (Eudragit L100-55)a 9.25be 18.49
Triethylcitrate0,931,85
Titanium dioxide1,83the 3.65
Talc1,412,81
Growing up180,83361,65
Film coating
Opadry Yellow OY-52945to 4.529,04
In zestawy total 185,42370,79
Printing
Opacode Black S-1-8152 HVq.s.q.s.

The Central core tablets are manufactured by dry granulation of a mixture of pantoprazole sodium, mannitol, crosspovidone and sodium carbonate with an aqueous solution of hydroxypropylcellulose (Klucel LF) and anhydrous sodium carbonate. The granules are dried using conventional methods. The dried granules were lubricated with crosspovidone, talc and calcium stearate. The lubricated granules are then pressed into the Central core. The Central core is applied to the primary coating of a mixture of Zein, Eudragit L100-55, water and isopropyl alcohol. After drying, put intersolubility coating over the primary coating using Eudragit L100-55 with isopropyl alcohol as a solvent and triethylcitrate as a plasticizer. Talc and titanium dioxide is used as a lubricating agent and the agent imparting opacity, respectively. Then dried tablet with intersolubility coating is applied film coating using Opadry Yellow OY-52945 and print information using Opacode Black S-1-8152 HV.

Example 3

Capsules containing 40 mg Wes is asola, manufactured using such components and procedures:

IngredientsQuantity/capsule (mg)
The Central core of the granules
Omeprazole40
Mannitol236
Crosspovidone18
The hypromellose, 5 SP·8
Poloxamer 4075
Meglumin3
Only310
Swelling floor
Zein F60006,2
Growing up316,2
Intersolubility floor
Phthalate of hydroxypropylmethylcellulose (HP 55)63,24
Triethylcitrateof 6.31
Talc9,45
Growing up395,25

The Central core of omeprazole pellets prepared by mixing omeprazole, mannitol, crospovidon, meglumine and poloxamer and granulating the mixture with hypromellose as a binder. Thus obtained granules are extruded and spheronization to obtain spherical granules. The granules are then dried by conventional drying methods. Granules cause swelling coating containing Zein and sodium lauryl sulfate dissolved in a mixture of isopropyl alcohol and water, and then vyscheperelichene coating is prepared by dissolving phthalate of hydroxypropylmethylcellulose and triethylcitrate in a mixture of isopropyl alcohol and acetone and dispersing talc in this solution, which is then applied to the intermediate coating.

Granules coated Packed by weight in gelatin capsules.

Example 4

Tablets containing 40 mg of omeprazole, made using the ingredients and procedures:

IngredientsQuantity/tablet (mg)
The Central core tablets
Omeprazole40
Mannitol (Peartitol SD-200)231.3 of which
Crosspovidone6
Meglumin3
Poloxamer 4075
The hypromellose, 5 MPa·s8
Magnesium stearatethe 3.8
Talc3
Only300
Swelling floor
Zein F60002,73
Sodium lauryl sulfate0,27
Growing up303
Intersolubility floor
Phthalate of hydroxypropylmethylcellulose (HP 55)24
Triethylcitrate2,4
Talc3,6
333

The Central core tablets omeprazole is prepared by mixing omeprazole, mannitol, crospovidon, meglumine and poloxamer and granulating the mixture with hypromellose as a binder. The granules are dried in a fluidized bed dryer, and dry granules pressed into tablets or minitablets. On these tablets or minitablets Central core of the solution is applied intermediate layer containing Zein and sodium lauryl sulfate dissolved in a mixture of isopropyl alcohol and water, and then dried. Intersolubility coating is prepared by dissolving phthalate of hydroxypropylmethylcellulose and triethylcitrate in a mixture of isopropyl alcohol and acetone and dispersing talc in this solution, the layer is then applied on the intermediate floor.

Example 5

Tablets containing 40 mg of pantoprazole, made using the ingredients and procedures:

IngredientsQuantity/tablet (mg)
The Central core tablets
Pantoprazole sodium sesquihydrate45
Mannitol (Pealitol SD-200) 143,18
Mannitol (Pearlitol DC-400)47,72
Crosspovidone16,5
Plasdone S-63030
Sodium lauryl sulfate2,5
Meglumin3
Calcium stearate6
Talc6
Only300
Swelling floor
Zein4,5
Growing up304,5
Intersolubility floor
Methacrylic acid copolymer (Eudragit L100-55)the value of 16,81
Triethylcitrate1,68
Titanium dioxide3,39
Talcof 2.51
Growing up 328,89

The Central core tablets are made by mixing pantoprazole-sodium-sesquihydrate with mannitol, crosspovidone, Plasdone S630, talc and magnesium stearate, and direct compression into tablets. These Central core tablets cause swelling solution coating, which contains Zein and sodium lauryl sulfate dissolved in a mixture of isopropyl alcohol and water, and then dried. Intersolubility coating is prepared by dissolving phthalate of hydroxypropylmethylcellulose and triethylcitrate in a mixture of isopropyl alcohol and acetone and dispersing talc in this solution, the layer which is applied then on the middle floor.

Example 6

Capsules containing esomeprazole, made using the ingredients and procedures:

IngredientsQuantity (g)
Granules
Esomeprazole-magnesium trihydrate178
Mannitol938
Crosspovidone72
Sodium lauryl sulfate20
Kapawi is it 32
Only1240
Swelling floor
Zein16,2
Sodium lauryl sulfate1,62
Growing up1257,82
Intersolubility floor
Methacrylic acid copolymer type C110
Triethylcitrate11
Titanium dioxide15,29
Talc16,5
Growing up1410,61

The Central core is made by mixing esomeprazole-three-hydrate magnesium, mannitol, crosspovidone and sodium lauryl and granulating the mixture with an aqueous solution of copovidone. The pellets are then extruded and spheronization to obtain spherical granules. The granules are dried by conventional methods of drying. On dry granules put a solution of the intermediate coating containing Zein and Lauri is sodium sulphate, dissolved in a mixture of isopropyl alcohol and water, and then dried. Intersolubility coating is prepared by dissolving a copolymer of methacrylic acid type and triethylcitrate in isopropyl alcohol, and the dispersion of talc and titanium dioxide in the solution.

Granules coated fill gelatin capsules, receiving 4000 capsules, each containing 40 mg of esomeprazole.

Example 7

Made tablet esomeprazole using the ingredients and procedures:

IngredientsQuantity (mg/tablet)
The Central core tablets
Esomeprazole-magnesium trihydrate44,5
Magnesium oxide20
Plasdone S-630of 17.5
Crosspovidone10
Mannitol (Pearlitol SD 200)227
Colloidal silicon dioxide3,5
The sodium fumarateof 17.5
Always the 340
Swelling floor
Zein F60006,8
Growing up346,8
Intersolubility floor
Eudragit L100-5519,1
Triethylcitrate1,9
Titanium dioxidethe 3.8
Talc2,9
Growing up374,5

Esomeprazole-magnesium trihydrate, magnesium oxide, copovidone, crosspovidone, mannitol and silica are mixed, then add the sodium fumarate, continuing the stirring. From this mixture is pressed the Central core tablets. The tablets covered with a water-alcohol solution of Zein, and then dried. Finally, the ingredients Intercollege coating is dispersed in water and applied on the tablets with Seidovym the floor, and then finally dried.

Example 8

Tablets containing rabeprazole-sodium, made using the ingredients and procedures:

IngredientsQuantity/tablet (mg)
The Central core tablets
Rabeprazole sodium20
Mannitol (Pearlitol SD 200)97,2
Mannitol (Pearlitol DC 400)28
Meglumin5,1
Crosspovidone3,4
Plasdone S-63010,5
Talc3,4
Magnesium stearate2,4
Only170
Swelling floor
Zein F60004,25
Triethylcitrate0,2
Growing up174,45
Intersolubility floor
Methacrylic acid copolymer (Eudragit L100-55) of 12.26
Triethylcitrate1,224
Talc0,68
Growing up188,614

Rabeprazole-sodium, crosspovidone, Plasdone S630 and mannitol (Peariitol SD 200) mixed with mannitol (Pearlitol DC 400) for 20 minutes. Then add to the mixture of talc and magnesium stearate and mix for 5 minutes. This lubricated mixture is then pressed into tablets. On the Central core tablets is applied to the primary coating is a water-alcohol solution of Zein (weight gain of 2.5±0.5%) and dried. On tablets with the primary coating applied solution Intercollege coating (weight gain 8-9%).

Example 9

Pills rabeprazole-sodium is produced using the ingredients and procedures:

IngredientsQuantity/tablet (mg)
The Central core tablets
Rabeprazole sodium20
Mannitol (Pearlitol SD 200)97,01
Hydroxypropylcellulose with a low degree of substitution LH21 (L-HPC) 14.4V
Magnesium oxide40
Sodium lauryl sulfate1,8
The hypromellose, 5 MPa·s3
Talc1,54
Magnesium stearate2,25
Only180
Swelling floor
Zein 6000a 4.9
Triethylcitrate0,49
Growing up185,39
Intersolubility floor
Eudragit L100-55of 14.46
Triethylcitratethe 1.44
Talc0,79
Growing up202,08
Film coating
Opadry Yellow OY-52945of 5.05
Growing up207,13
Printing
Opacode Blackq.s.

Magnesium oxide is sifted through a sieve of 60 mesh (250 microns). Rabeprazole-sodium, L-HPC, mannitol SD 200) and sifted magnesium oxide sieved through a sieve of 40 mesh (425 microns). Then the materials are mixed for 30 minutes in the mixer-granulator Rapid. Sodium lauryl sulfate (SLS) is dissolved in purified water and hypromellose (receiver array) is dissolved in warm purified water. A mixture of rabeprazole-sodium is mixed with a solution of SLS and a receiver array. The wet mass is dried in a fluidized bed dryer and the dried granules are sieved through a 20 mesh (850 microns). The sifted granules mixed with L-HPC in the double-cone mixer for 5 minutes. Added to a mixture of magnesium stearate (screened through a sieve of 60 mesh) and stirred for 5 minutes. Then pressed from the lubricated mixture of the Central core tablets. On the Central core tablets is applied aqueous-alcoholic solution Zeinalova coating (weight gain of 2.5±0.5%) and dried. On coated tablets next put a solution Intercollege coverage (increase weight 8,0±1,0%). Tablets with intersolubility coating is additionally coated with Opadry solution with the increase in ve is and 2,0±0,5%. Then on the film-coated tablets printed information using ink Opacode black.

Example 10

Tablets pantoprazole-sodium, manufactured according to Example 5, is subjected to the test method 724 "Release drugs" United States Pharmacopeia, 24th edition (United States Pharmacopeial Convention, Inc., Rockville, Maryland USA, pp.1944-1947, 2000), using the Method and Apparatus 1 (described in the Method 711 "Dissolution" on page 1942). The tablet is first dipped in a 0.1 n hydrochloric acid with stirring for two hours at 37°C. Then the tablet is immersed in phosphate buffer, pH 6.8, with stirring, and selected samples of the buffer solution for analysis after a certain period of time to determine the amount of drug that is released from the pill.

Below is data obtained by testing six tablets. The amount of drug that is released in the acid is not specified, but it was minor. In General, the release of the acid up to 10% of the medicinal product is considered acceptable for dosage forms with intersolubility coating. For purposes of this invention it is considered that the pharmaceutically active substance is essentially retained in the dosage form, if less than approximately ten percent of the mass is released in 0,1N chloris vodorodnoy acid when tested according to USP.

Time (min)The percentage of release of the medicinal product
Tablet 1Tablet 2Tablet 3Tablet 4Tablet 5Tablet 6Average
00000000
1529182221181721
3061626557555860
458286848481 7983
6092949192898891

These results show that the medicinal product is essentially completely released within sixty minutes at pH 6.8.

Example 11

As in Example 10, test tablets rabeprazole-sodium, manufactured according to Example 9 by the Method 724 Release of drugs (USP). However, as the alkaline solution for the second part of the trials used a phosphate buffer with a pH of 8.0, which also contained 0.5 wt.% lauryl sodium. The following results were obtained.

Time (min)The percentage of release of the medicinal product
Tablet 1Tablet 2Tablet 3Tablet 4TabletkiTablet 6Average
00 000000
100000000
200000000
301837124302823
4582947494939288
6091919290929291

These results show that the medicinal product is essentially completely released within sixty minute at pH 8.0.

Example 12

Made tablet esomeprazole using following ingredients and procedure.

IngredientsQuantity/tablet (mg)
The Central core tablets
Esomeprazole-magnesium trihydrate44,5
Magnesium oxide20
Plasdone S-630of 17.5
Mannitol (Pearlitol SD 200)237
Colloidal silicon dioxide3,5
The sodium fumarateof 17.5
Only340
Swelling floor
Zein F60006,8
Growing up346,8

Esomeprazole-magnesium trihydrate, magnesium oxide, Plasdon S-630, silicon dioxide and mannitol sift and mix, then add the sodium fumarate, the mixture is stirred and finally formed into tablets by direct compressing the mixture. Zein is dissolved in a water-alcohol mixture and apply the coating on the pill. The coated tablets are then dried.

Made the same way for more number of tablets, optionally containing 7 mg or 10 mg of the ingredient powder of crospovidon in the Central core of the composition, with a corresponding decrease in the amount of mannitol to maintain a constant weight of tablets. Put pill testing to determine characteristics of dissolution at pH 6.8 using the procedure of Example 10 (except that was omitted stage of contact with the acid), obtaining the following results.

Time (min)The percentage of release of the medicinal product
Without baking powderBaking powder 7 mgBaking powder 10 mg
150061
3001 80
450386
600689
900-88
1201--

For this particular composition 10 mg powder provide the desired rapid release of drug at pH 6.8. However, other compositions may have the desirable characteristics of release of drugs with different concentrations of baking powder, depending on the views of different components of the composition, physical methods used for the manufacture of Central nuclei (such as pressure tablets), and the presence of additional coverage. Thus, it is necessary to test each proposed compositions using different amounts of the selected components of baking powder to determine the exact composition that provides the desired release characteristics of the drug.

1. Pharmaceutical dosage form, which on the replies:
a) a solid Central core containing a pharmaceutically active substance and baking powder;
b) swelling the coating comprising prolamin, surrounding the Central core; and
c) intersolubility floor, swelling around the floor.

2. The pharmaceutical dosage form according to claim 1, in which the Central core is a tablet.

3. The pharmaceutical dosage form according to claim 1, including many of the Central core with a coating that is placed in the capsule.

4. The pharmaceutical dosage form according to claim 1, in which the pharmaceutically active substance is unstable in the presence of acid.

5. The pharmaceutical dosage form according to claim 1, in which the pharmaceutically active substance is reactive with respect to the component Intercollege coverage.

6. The pharmaceutical dosage form according to claim 1, in which the pharmaceutically active substance comprises a benzimidazole.

7. The pharmaceutical dosage form according to claim 1, in which the pharmaceutically active substance comprises a benzimidazole, which is one or more members selected from the group consisting of omeprazole, esomeprazole, lansoprazole, rabeprazole and pantoprazole.

8. The pharmaceutical dosage form according to claim 1, in which the baking powder includes one or more components selected from the group, with the standing of the starch; polyvinylpyrrolidone; formaldehyde-casein compounds; resins; low-fat soy extracts; alginic acid; agar-agar; calcium carbonate; calcium phosphate; sodium carbonate and acrylic polymers.

9. The pharmaceutical dosage form according to claim 1, in which the swellable coating includes one or more hydrosolidarity components selected from the group consisting of vinylpyrrolidone polymers; cellulose derivatives; starches; carboxyvinyl polymers; alginates; pectins; agar, and resins.

10. The pharmaceutical dosage form according to claim 1, in which the swellable coating comprises Zein.

11. The pharmaceutical dosage form according to claim 1, in which the swellable coating comprises hypromellose.

12. The pharmaceutical dosage form according to claim 1, in which the swellable coating includes excipient, modulating the release of pharmaceutically active substances from the Central core of hydration.

13. The pharmaceutical dosage form according to item 12, in which excipient includes one or more components selected from the group consisting of plasticizers, water-soluble surface-active substances and materials Intercollege coverage.

14. The pharmaceutical dosage form according to claim 1, in which intersolubility floor includes the OS is ove cellulose, on the basis of methacrylate-based polivinilatsetatftalat, or on the basis of shellac.

15. The pharmaceutical dosage form according to claim 1, in which intersolubility coating includes a copolymer of methacrylic acid and ethyl acrylate.

16. The pharmaceutical dosage form according to claim 1, in which the Central core is at least 50 wt.% from dosage forms.

17. The pharmaceutical dosage form according to claim 1, in which the swelling of the coating is from about 0.1 to 10 wt.% from dosage forms.

18. The pharmaceutical dosage form according to claim 1, in which intersolubility coating is from about 0.1 to 30 wt.% from dosage forms.

19. The pharmaceutical dosage form according to claim 1, in which the pharmaceutically active substance is essentially retained in the dosage form until the dosage form is in the stomach, and released after getting dosed form in the environment of the digestive system with pH value of at least 5.

20. Pharmaceutical dosage form, including:
a) a solid Central core containing sensitive to acid pharmaceutically active substance and baking powder;
b) swelling the coating containing the prolamin surrounding the Central core; and
c) intersolubility floor, swelling around the floor.

21. Farmatsevticeski the dosage form according to claim 20, which is sensitive to acid pharmaceutically active substance comprises a benzimidazole.

22. The pharmaceutical dosage form according to claim 20, in which the baking powder includes one or more components selected from the group consisting of starches; polyvinylpyrrolidones; formaldehyde-casein compounds; resins; low-fat soy extracts; alginic acid; agar-agar; calcium carbonate; calcium phosphate; sodium carbonate and acrylic polymers.

23. The pharmaceutical dosage form according to claim 20, in which hydrochorothiazide component includes one or more members selected from the group consisting of vinylpyrrolidone polymers; cellulose derivatives; starches; carboxyvinyl polymers; alginates; pectins; agar, and resins.

24. The pharmaceutical dosage form according to claim 20, in which intersolubility floor includes a component on the basis of cellulose-based methacrylate, based polivinilatsetatftalat based or shellac.

25. The pharmaceutical dosage form according to claim 20, in which intersolubility coating includes a copolymer of methacrylic acid and ethyl acrylate.

26. Pharmaceutical dosage form, including:
a) a solid Central core containing the benzimidazole and baking powder;
b) swelling the coating comprising one or more materials forming hydrocolloid, containing Zein and optional crosspovidone and hydroxypropylcellulose, and surrounding the Central core; and
c) intersolubility coating comprising a copolymer of methacrylic acid and ethyl acrylate and swelling around the floor.

27. The pharmaceutical dosage form according p, in which the baking powder includes one or more components selected from the group consisting of starches; polyvinylpyrrolidones; formaldehyde-casein compounds; resins; low-fat soy extracts; alginic acid; agar-agar; calcium carbonate; calcium phosphate; sodium carbonate and acrylic polymers.

28. The pharmaceutical dosage form according p, in which the swellable coating includes crosspovidone.

29. The pharmaceutical dosage form according p, in which the swellable coating includes hydroxypropylcellulose.

30. A method of manufacturing a pharmaceutical dosage form, comprising the steps:
a) mixing components comprising a pharmaceutically active substance and baking powder, and forming a solid Central core;
b) applying to the Central core of the swelling coatings comprising prolamin; and
c) applying an external coating containing resistant to acids intersolubility substance.

31. The method according to item 30, in which the prolamin contains Zein.

32. The method according to item 30, in which the solid center is the core material is formed into tablet form.

33. The method according to item 30, further comprising the stage of filling capsules with numerous Central cores coated.
Priority items:

17.07.2003 according to claims 1 to 33;

30.12.2003 according to claims 1 to 33;

20.04.2004 according to claims 1 to 33.



 

Same patents:

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SUBSTANCE: invention relates to new derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I) or to its salts: , where R1 is ,, in which n is an integer ranging from 0 to 6; Y is aryl, where the said aryl is optionally substituted at a substitutable position with one or more substitutes selected from a group which consists of halogen or C1-6alkyl, optionally substituted with mono-, di- or trihalogen; R2 is hydrogen; R3 is hydrogen or halogen; and R4 is hydrogen. The invention also relates to derivatives of imidazo[1,2-c]pyrimidinyl acetic acid of formula (I-i) or to its salts, to a drug, to use of compounds in paragraph 1, as well as to a drug in form of a standard single dosage.

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25 cl, 13 ex

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20 cl, 80 ex, 9 tbl

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3 ex

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49 cl, 10 dwg

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12 cl, 7 dwg, 6 tbl, 2 ex

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11 cl, 30 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes solid dispersed measured drug including a core with pharmacological agent dispersed in the first matrix for controlled liberation at relatively low speed; and coating covering the core and including the agent dispersed in the second matrix for controlled liberation at relatively high speed. The first matrix can be represented by cross-linked starch with high amylose content, and the second matrix can be represented by polyvinylacetate and polyvinylpyrrolidone mix. Solid measured drug is preferably a pill.

EFFECT: reduced administration frequency, relatively stable medicine concentration in organism for a given time period and reduced undesired side effect frequency and intensity due to reduction of high concentrations in plasma.

19 cl, 5 dwg, 4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: claimed composition contains core including Rabeprasol or pharmaceutically acceptable salt thereof as acid secretion inhibitor in stomach and basic compound, intermediate coat coating the core, and overcoat applied on intermediate layer and containing water insoluble polymer and enterosoluble polymer. Also described is method for production of composition containing said preparation.

EFFECT: composition of prolonged storage time providing effective concentration of Rabeprasol in blood for long period of time.

16 cl, 5 dwg, 14 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to solid medicinal formulations covered by enterosoluble envelope. Enterosoluble envelope represents a polymeric derivative as conglomerate of hydroxypropylcellulose and acetatephthalatecellulose in the presence of wax and Tween. Envelope has 1-10 layers and its mass is 0.1-10% of the solid pharmaceutical composition mass in the definite ratio of component in envelope. Also, invention represents methods for coating a pharmaceutical composition by such enterosoluble envelope. Invention provides the required disintegration of envelope for capsules as a whole and expanding assortment of active components among medicinal agents useful for applying the claimed cover and with inclusion to this enumeration of thermolabile medicinal immunobiological preparations.

EFFECT: improved and valuable properties of envelope, improved coating method.

9 cl, 7 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a composition comprising as active components pyridoxine hydrochloride and doxylamine succinate and a disintegrating agent that provide the following dissolving pattern: 20-90% of the total amount of each component among pyridoxine hydrochloride and doxylamine succinate are dissolved in 5-120 min. The composition is made preferably as a tablet with an enterosoluble envelope. The tablet has a core comprising pyridoxine hydrochloride and doxylamine succinate, and inactive excipients also. The composition is used in treatment of nausea, vomiting being especially in pregnancy. The composition provides rapid and simultaneous release of synergetic pair of indicated active components.

EFFECT: improved and valuable properties of composition.

24 cl, 2 dwg, 9 tbl, 3 ex

The invention relates to pharmaceutical compositions cefuroxime aksetila in the form of particles
The invention relates to chemical-pharmaceutical industry, namely intersolubility shell of solid dosage forms having two layers, one of which contains a film-forming component, and a second plasticizer, dye and technological additives

The invention relates to the field of pharmacology, and relates to a composition containing diphosphonic acid

FIELD: medicine.

SUBSTANCE: claimed invention relates to pharmaceutical medicinal forms, which are applied for controlled and/or directed delivery of active substance to definite part of gastrointestinal tract of human or animals. Pharmaceutical medicinal forms preferably include active substance N-(2-(2-phthalimidoetoxy)acetyl)-L-alanyl-D-glutamic acid (LK 423).

EFFECT: also described are methods of treating chronic inflammatory diseases of gastrointestinal tract of human and/or animals applying pharmaceutical medicinal forms of claimed invention.

21 cl, 5 ex, 3 tbl, 7 dwg

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