Extrusion of hot liquid of multiple particles with modified release

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition with controlled release. Claimed composition includes one or more multiple particles with modified release with dimensions 50-800 mcm, which have effective quantity of one or more therapeutic compounds. Said multiple particles possess known profile of medication release and are subjected to thermal processing into extrudate in thermoplastic polymer matrix or lipid material. Invention also relates to method of obtaining pharmaceutical composition with controlled release and to pharmaceutical hard dosage form, which includes said composition.

EFFECT: invention ensures preservation of predominance of known profile of release of multiple particle medication when it is released from thermoplastic polymer matrix or lipid material.

35 cl, 6 dwg, 12 tbl, 10 ex

 

Technical field of invention

This invention generally relates to the field of controlled release of active agents, and more specifically to compositions and methods for producing hot melt extrusion, comprising multiple particles modified release.

Background of the invention

Without limiting the scope of the invention, its background is described relative to the controlled release of active agents, such as pharmaceuticals.

One such patent is U.S. patent No. 6335033 published Oshlack, et al., for melt extrusion of multiple particles, which describe the standard dose oral pharmaceutical form prolonged release containing multiple particles extruded from the melt, each mainly includes a therapeutically active agent, one or more moderators and the optional water-insoluble binder. The particles have a length of from about 0.1 to about 12 mm and can be of different diameters, and each standard dose provides release of therapeutically active agents for at least 8 hours. Also disclosed are methods of obtaining standard doses, and methods of extrusion and processing methods. However, the release profile is determined by the type of melt extrusion. More t the th, method melt extrusion is not able to meet the needs of the release of drugs that are in fragile plural particles. The release of drugs in this patent is governed by the properties of thermoplastic polymer carrier, and not a particle.

Another patent is U.S. patent No. 6743442 published Oshlack, et al., for extruded from the melt oral input synthetic drug compounds. Briefly described bioavailable oral synthetic narcotic analgesic dosage form for sustained release comprising a set of multiple particles, obtained by methods of extrusion from the melt. This patent claims the pharmaceutical composition of extended release, including extruded mixture of therapeutically active means, one or more hydrophobic materials selected from the group including alkylaryl, acrylic polymers and mixtures thereof; and one or more hydrophobic fusible carriers having a melting point from about 30° to about 200°C. and which is selected from the group comprising natural or synthetic waxes, fatty acids, fatty alcohols and mixtures thereof, the extruded mixture is divided into the standard dose containing an effective amount Ter is piticescu active means to provide the desired therapeutic effect and providing slow release therapeutically active amounts during the period from approximately 8 to approximately 24 hours, with the extruded mixture is formed by mixing therapeutically active means, one or more hydrophobic materials and one or more hydrophobic fusible carriers in the extruder for the formation of the mixture and ekstragiruyut the mixture through the extruder. In addition, the release profile is determined by the type of extrusion from the melt, and he is not able to meet the needs of the release of drugs that are in fragile plural particles. In addition, the release of drugs in this patient is governed by the properties of thermoplastic polymer carrier, and not a particle.

One approach, as disclosed in patent application WO 2008/101743 (Gryczke 2008), involves mixing anionic polymer exhibiting a low glass transition temperature, but too high permeability (Eudragit FS), with water-insoluble polymer (Eudragit RS, RL or NE) to reduce the release of acid.

Description of the invention

This invention provides compositions and methods for their preparation by the inclusion of multiple particles of a modified-release matrix while maintaining the characteristics of the dissolution of the original multiple particles modified release. This invention combines the advantages of a monolithic dosage form that releases multiple the system standard doses after injection. Found that this invention overcomes some or all of the problems that arise when alternative methods that can be used for making multiple particles modified release in monolithic systems, such as compression into tablets or filling into capsules. These disadvantages include one or more of the following: (1) problems of content uniformity of the finished product, especially but not only at low levels of loading; (2) changes in the dissolution profile of the medicinal product the finished product compared with untreated multiple particles due to the interaction with the elements triggering the release, such as a polymer coating or matrix, during the process of embedding; (3) limited loading monolithic system of multiple particles due to the necessity of large quantities of fillers to facilitate the process of embedding or to protect the release characteristics of multiple particles; (4) the sensitivity is ready product to moisture due to the permeability of the elements forming the matrix; and (5) has tampered with the finished product.

In one embodiment, the present invention describes a pharmaceutical composition with controlled release formulation comprising one or more of multiple particles modified visual is born with an effective amount of one or more therapeutic compounds, where multiple particles include known profile of release of the medicinal product and subjected to a heat treatment in the extrudate in a thermoplastic polymer matrix, a lipid material, or in fact, and in another, where the conditions of heat treatment retain the prevalence of known profile of release of the medicinal product multiple particles at the release of thermoplastic polymer matrix or lipid material.

The extrudate as described in this invention, includes at least 80% intact plural particle, where multiple particles include a coating of a polymeric film. In one aspect the pharmaceutical composition of controlled release comprising multiple particles with inherent control release of the drug or the principle of protection of the medicinal product, includes a polymer matrix or a hydrophobic material. In another aspect, multiple particles include intersolubility floor release of the drug. In still another aspect, multiple particles are covered with a long release and protection from moisture one or more therapeutic compounds.

In another aspect, multiple particles of the modified release is covered with a water-soluble or gislators worimi coated and treated to minimize incompatibility between one or more therapeutic compounds and one or more fillers, located in the matrix. Water-soluble or acid-soluble coating comprises a polymer selected from the group including polymethacrylates, cellulose derivatives, polysaccharides, proteins, or vinyl polymers. In other aspects of multiple particles are film-coated granules medicines, film-coated pills, the loaded drug, or covered with a film nonpareil with layered drug. In particular aspects of multiple particles are in the size range 50-800 μm, preferably 300 to 500 μm, and the coating of the polymer film multiple particles comprise from 10% to 60% of polymer(s) (percentage by weight), more preferably 20-50% by weight of multiple particles without coating.

In another aspect, one or more polymers in the coating of a polymeric film selected from the group including polymethacrylates, cellulose derivatives, polysaccharides, proteins or vinyl polymers, and can be plasticized. In another aspect of multiple particles comprise from 5 to 80 weight percent of one or more therapeutic compounds. In another aspect, thermoplastic polymer matrix comprises one or more components, which at least partially are crystalline polymers with a melting point below 80°C. thermoplastic on emery, used in this invention is selected from the group comprising poly(ethylene oxide)-poly(propylene oxide) copolymer, poly(ethylene glycol) or poly(ethylene oxide) with a molecular weight of less than about 1000000. In particular aspects, the weight percentage of multiple particles is from 5 to 70 weight percent. The polymer matrix can dissolve, disintegrate or swell in the environment for dissolution, the aqueous environment to release multiple particles modified release or to make possible the release of drugs from multiple particles through diffusion.

Multiple particles modified release according to this invention are further defined as including intersolubility polymers or water insoluble polymers modified release, which control the release of drug by diffusion or pH-dependent dissolution of the polymer. Products with a long release can be obtained by processing multiple particles of modified release that covered intersolubility coated, with less than 10% of drug is released in the acidic environment of the dosage form, comprising multiple particles modified release to enter solubilis coating, and when the environment changes the pH to a value above 6,8, more than 80% of drug released in 45 minutes in a buffered medium, which is described in U.S.P. (USP)

In one aspect of the multiple particles of modified release include matrix-retarder, where the matrix-moderator breaks down or decomposes with release of multiple particles modified release. In another aspect, as a matrix, and multiple particles modified release coated film coated matrix, or both.

In another embodiment, this invention represents a pharmaceutical composition with controlled release formulation comprising one or more of multiple particles modified release with an effective amount of one or more therapeutic compounds, where multiple particles include known profile of release of the medicinal product and subjected to a heat treatment in the extrudate in a thermoplastic polymer matrix, a lipid material, or in fact, and the other in the heat-treated conditions that preserve the integrity of multiple particles during processing. The extrudate as described in the embodiment of the present invention, includes at least 80% intact multiple particles

In another embodiment, the invention discloses pharmaceutical composition of controlled release comprising one or more pills of modified release with an average particle size of 300 to 3000 μm, where one or more pills of modified release include pharmaceutically active substance included in the matrix of one or more anionic polymers, and technological additives. In one aspect less than 10% of the pharmaceutically active substance is released after 2 hours in simulated gastric fluid pH 1.2 and at least 40% after 2 additional hours in the buffer with a pH of 6.8 or buffer with a pH of 7.4. In another aspect, more than 60% of the pharmaceutically active substance is released after 2 hours in a buffer with a pH of 6.8 or buffer with a pH of 7.4.

In a separate aspect, the average particle size of one or more pills of modified release ranges from 500 to 1000 μm. The particle size of one or more pills of modified release, as described in the embodiment of the present invention, is 200, 300, 400, 500, 600, 750, 800, 1000, 1500, 2000, 2500, 3000 and 5000 microns.

In one aspect, the weight percentage of pharmaceutically active substances is 0.1-70%. In another aspect, the weight percentage of the pharmaceutically active substance is 5-40%. In another aspect of the weight ol the interest content of the pharmaceutically active substance is 0.1, 0,5, 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70 and 80%. One or more anionic polymers comprise a copolymer of methacrylate and methacrylic acid in which one or more anionic polymers selected from the group comprising acrylic acid, methacrylic acid, vinyloxy acid, crotonic acid, allyloxy acid, 4-methyl-4-Antonovo acid, vinylsulfonate, styrelseledamot and acrylamidophenylboronic acid. The copolymer contains at least 20% of methacrylic acid.

In one aspect, one or more pills of modified release can withstand a load of at least 10 N without having to undergo cracking or deformation. In another aspect, one or more pills of modified release moved in a monolithic system, including tablet, capsule, or any combination of them.

In one embodiment, the invention describes a method of obtaining a pharmaceutical composition of controlled release, which includes the step of mixing one or more of multiple particles modified release comprising an effective amount of a therapeutic compound with a known profile of release of the medicinal product, with a thermoplastic polymer matrix or hydrophilic wax, including the matrix, via the heat is th processing under conditions who hold controlling release of drugs, the characteristics of the protection of the medicinal product or the one and the other at multiple particles. In one aspect of thermal processing performed by hot melt extrusion, which is held by a single screw or twin screw extruder at temperatures of not less than 100°C.

In another aspect, plural particle includes a film coating, which is applied by way of the dry coating, the method of the aqueous coating or coating solvent. In another aspect of multiple particles cover device for coating fluidized bed. Multiple particles slow release can be obtained by coating at least one of hydrophobic polymers, hydrophilic polymers, gums, materials derived from proteins, waxes, shellac, oils and mixtures thereof.

In another embodiment, the invention describes a pharmaceutical solid dosage form provides controlled release of therapeutic compound and comprising a pharmaceutical composition obtained by the method according to this invention. In one aspect of the preferred injection compositions described in this invention was orally path. In another aspect controlled visual the discussion further defined as immediate, prolonged or extended release.

In another embodiment, this invention discloses a method of obtaining a pharmaceutical composition with controlled release formulation comprising one or more cylindrical pills, modified release, including the stages of: (i) mixing a pharmaceutically active substance, one or more anionic polymers and process additives for the formation of the mixture, (ii) processing the mixture by the method of hot melt extrusion for the formation of one or more extruded filaments, and (iii) cutting the extruded filaments into one or more cylindrical pills modified release. The method as described in the embodiment of the present invention, further includes the steps of coating of a polymeric film on one or more cylindrical pill modified release and spheroidization one or more cylindrical pills modified release.

In one aspect, the temperature during the extrusion method of the hot melt does not exceed 200°C. In another aspect, the temperature of the at least one of the zones of heating during extrusion method hot melt exceeds the glass transition temperature of the polymer, of at least 10°C.

In one embodiment, this image is the buy is a method of determining one or more parameters of the extrusion process for obtaining a pharmaceutical composition of controlled release, comprising: selecting one or more of multiple particles modified release with an effective amount of one or more therapeutic compounds with a known profile of release of the medicinal product, the mixing of one or more of multiple particles modified release with a thermoplastic polymer matrix or hydrophilic wax containing matrix, extruding multiple particles with a thermoplastic polymer matrix or hydrophilic wax containing matrix under different conditions for the formation of the extrudate, the definition of the profile of release of the medicinal product for the extrudate and the choice of thermoplastic polymer matrix or hydrophilic wax containing matrix, and conditions of extrusion, in which at least 80% of one or more multiple particles modified release retains the known profile of release of the drug.

Description of graphic materials

For a more complete understanding of the characteristics and advantages of the present invention reference is made to the detailed description of the present invention together with the accompanying figures, in which:

FIGURE 1 depicts the cross-section of an illustrative case for extruded from a hot melt composition as provided given the first invention;

FIGURE 2 is a graph of the release profiles of the medicinal product for the compositions prepared according to Examples 2, 4 and 7 and analyzed according to Example 9;

FIGURE 3 is a graph of the release profiles of the medicinal product for the compositions prepared according to Examples 2, 4 and 7 and analyzed according to Example 9. Download the pill in the matrix was 30%;

FIGURE 4 depicts the release of the drug after 2 hours in an environment with a pH of 1.2 for various multiple particles, in accordance with Examples 1-4 and investigated in Example 9, before extrusion after extrusion 30%multiple particles in Poloxamer 407 according to Example 7;

FIGURE 5 is a graph of the release profiles medicines for compositions prepared with 30% granules as defined in Example 1 and coated according to Example 4 after processing according to Example 7 in Poloxamer 407 or Example 8 in the study in Example 9; and

6 is a graph of the release profiles medicines for compositions prepared with 30% granules as defined in Example 1 and coated according to Example 4 after processing according to Example 7 in Poloxamer 407, in the study in Example 9 directly after preparation and after 1 year of storage at room temperature (22±1°C) and relative humidity surrounding the Reda.

The description of this invention

While the execution and application of the various embodiments of the present invention is discussed in more detail below, it should be noted that this invention provides many applicable ideas of the invention, which can be realized in a wide variety of specific contexts. Some variants of implementation discussed in this document are only to illustrate specific ways of implementing the present invention and do not limit the scope of the present invention.

To facilitate understanding of the present invention below defines a number of expressions. Expressions that are defined in this document have the meanings that are commonly understood by a specialist in the areas related to this invention. Expression of the form of the singular is not intended to apply only to a single object, but include the General class in which a specific example may be used for illustration. Terminology this document is used to describe specific embodiments of this invention, but their use does not limit this invention except as set forth in the claims.

This invention includes compositions and methods of making the pharmaceutical composition of the modified h is obozrenie and execution method for embedding multiple particles of the modified release polymer or wax-like matrix. Polymer matrix comprises a thermoplastic polymer or lipophilic carrier or their mixture, which softens or melts at a high temperature and allows the distribution of multiple particles of the modified-release polymer matrix during thermal processing.

The invention additionally describes in detail the composition and method of producing pills, having an average particle size of 300 to 3000 μm, containing a pharmaceutically active substance in a matrix containing anionic polymer and one or more plasticizers. Pills provide release of drugs less than 10% in a simulated gastric environment for 2 hours and the release of at least 40% after 2 hours in a buffer with pH 6.8 and/or a pH of 7.4.

Getting intersolubility pills usually involves several processing steps, including wet granulation mass and extrusion, spheronization and functional coverage. These methods require the use of organic or aqueous solvents and lengthy and costly procedures of drying. Pills made these traditional methods usually exhibit low mechanical strength and high brittleness. Method of extrusion hot melt of the present invention enables the manufacture intersolubility matrix of pills in a single step and continuous way, avoiding the using serial coating film and refraining from the use of organic solvent. The powder mixture containing the drug, anionic polymer, and optional processing AIDS, mix, melted and transferred inside the heated cylinder with one or two rotating augers before going through formosanus stamp product. In addition to the technological advantages extruded from a hot melt pills allow the inclusion of higher downloads medicines while protecting properties of controlled release, because of the low porosity extruded from the hot solution matrices compared with pills, prepared by the usual methods of granulation wet mass [1]. Extruded from a hot melt pills additionally exhibit low friability, high mechanical strength and high resistance properties release during subsequent processing, such as direct compression in a single tablet [2].

On successful receipt of pills sustained release by hot melt extrusion has been reported in several publications [3-5] and patents [6-7]. However, the manufacture of intersolubility pills manifesting release less than 10% after 2 hours in simulated gastric environment, remains promising. Due to the greater surface area of the small pills the release of drug from the estva in acid will be increased compared to tablets as previously shown for extruded from the melt matrix Eudragit L100-55, containing 20% of drugs [8]. Another aggravating circumstance, which must be overcome is the opposite trend between the polymer permeability and workability. Anionic polymers with a low glass transition temperature and low melt viscosities give pills that are too permeable to acid and release more than 10% of the content of the medicinal product. On the other hand, polymers exhibiting low permeability and good protection in acid, it is difficult to process by extrusion hot melt because of their high glass transition temperature and high melt viscosity.

Dosage forms containing multiple particles, provide an advantage over monolithic dosage forms. These advantages include improved distribution along the gastro-intestinal tract and the possibility of increased biological availability and more constant levels in the blood plasma, avoiding high local and possible toxic concentrations of drugs reduced the risk of falling dosage, reduced susceptibility to absorption of drug influence food intake or physiological factors, faster and less variable pharmacological effects due to more playback IMEI : the led of times of passage through the gastrointestinal tract and enhanced flexibility of the composition due to the mixing of particles, providing a variety of active substances or speed of release. Subsequent processing of multiple particles is necessary to ensure the patient is injected dosage forms. Monolithic systems such as tablets or capsules, can be used as finished dosage form and such solid compositions offer the advantage over liquid formulations regarding the storage stability, security and the degree of consent of the patient with the prescribed regime.

The two most common techniques include the backfilling of multiple particles in capsules or compressed into tablets. The applicability of both procedures is threatened due to significant shortcomings. Capsules are more expensive than tablets and can be less secure because of the high susceptibility to spoofing. The capsule shell are gigroskopicheskimi and provide little protection from light, oxygen and moisture. They are difficult to open, and, therefore, they provide less flexibility in dosage.

Tableting include effects on multiple particles high unidirectional forces tightening that can cause the break of the coating and/or deformation of the particles and cracking. It was reported that a solid core particles is necessary to prevent fracture coatings Surelease E-7-7050 and Methocel AS, naneseny is on containing theophylline pills [9]. Applying a film coating did not change the strength of the pills medicines regardless of the thickness of the coating. The core of multiple particles were subjected to cracking before the destruction of the coating and subsequent break cover when crushed core deformed under compressive load. Beckert and staff reported an increased release of Bisacodyl of pills with intersolubility coating in an acid environment when using soft pills low at crushing strength compared to solid pills[2].

Sufficient strength to rupture the coating is additionally necessary to resist damage to the film at low degrees of deformation of the particles. Therefore, brittle polymers do not meet the requirements for use as coating materials, if you do not use a high coverage levels. Alternatively, the high amount of plasticizer should be added to increase the elasticity of the film during compression, but these substances can vydeliajutsia of the product during storage. The elasticity of the films of Eudragit L30D-55 can be further improved by mixing them with Eudragit NE 30 D, but the release of drug during the buffer stage may not meet the requirements of the USP (USP) [10]. The film, made only with Eudragit L30D-55, were too fragile for the resistance to compression, which caused damage despite the plasticization of using a TEC (triethylcitrate) and a relatively high level of coverage (25%). Pills, covered only Kollicoat 30D MAY 30 DP, lost intersolubility properties after compression due to the properties of the fragility of this polymer, but a mixture of Kollicoat 30D MAE 30 DP and Kollicoat EMM 30D provided sufficient protection in acidic environment [11]. Altaf and staff reduced the cracking of coatings Aquacoat ECD-30 by spraying the coating on the pill with an additional layer REO [12] (the polyethylene anoxic). Nabuhay polymer was gidratirovana at the time of dissolution and, as was made without evidence, acted as a sealant for cracks formed in the coating during compression.

It is shown that the addition of shock absorbing means, such as spheres wax/starch obtained by granulation of the melt at a concentration of 50% percentage weight in the finished tablet, reduces damage pills diltiazem hydrochloride coated with Eudragit NE 30D [13]. The behavior was used Debunne and colleagues to save the dissolution characteristics of coated pills of piroxicam after compression [14]. Intersolubility pills covered only plasticized Eudragit L30D 55, provided sufficient gastric protection within 2 hours, but the required amount of wax pills exceeded the loading functional pills [15]. Also, these shock-absorbing particles is difficult and expensive and may prevent the disintegration of the tablets. The use of pellets with high porosity as tabletiruemogo filler for pills have also been shown to reduced the formation of recesses in the surface of the pill, but could not prevent deformation when flattening surfaces during compression16. Efficiency tabletiruemyh additives to act as a shock absorbing means is further limited by the size of their particles. The study conducted by Yao et al. with teofilina powder coated ethylcellulose demonstrated that tabletiruemye fillers with smaller particle size have been better to protect the film from damage because of their shock-absorbing ability during compression [17].

As described in detail above, the deformation of the particles during compression causes the crack of functional films. Cracking film depends on the load of particles in the tablet and limits the applicability of compression methods for high downloads of multiple particles. It was reported that approximately 30% of the percentage weight load only particles of multiple particles on the surface are subjected to deformation and, consequently, damage to the film [10]. The high amount of load will cause additional deformation of the particles in NR the internal part of the tablets, that the surface of solid particles in contact with each other. The disintegration into separate multiple particles will be further suppressed by the merging of the particles during compression. This phenomenon also limits the applicability of high loads of particles.

Tableting of multiple particles additionally difficult due to the differences in particle size, the particle shape and the true density between the particles and tabletiruemye additives. The uniformity of content of the finished dosage form can be broken by separation of the mixture and a weak flow of powder during tableting. Used different algorithms to overcome the shortcomings of the relative homogeneity of content, such as floor tabletiruemyh fillers directly on coated pills [18], processing tabletiruemyh fillers in the placebo pills of the same size [19] or the use of fillers with a small particle size [20]. Most of these approaches include additional stages of cooking, resulting in increased operational costs. Beckert and staff investigated the influence of the percentage of pills in the composition of the tablets on the uniformity of content [21]. The uniformity of content improved by increasing the load of pills to 70%, and it ceased to depend on the size of the filler particles due to the formation of percolation cluster pills that prevent separation during compression. High boot preparation of tablets becomes problematic and was possible only when used fillers with high binding capacity. However, tablets containing 10% percentage weight pills, showed high variation in the content medicines and did not meet the USP requirements for content uniformity.

Alternatively, intersolubility pills can be included in an insert in the form of tablets alternating injection of the molten media and pills in shape with cavities [22]. The reported method was performed manually interrupted and had to stop to allow the media to harden and prevent the deposition of pills. The study is further limited to polyethylene glycol as a carrier and a load of pills 8-12% in the matrix.

Heat treatment in the main and the hot melt extrusion in particular borrowed from the plastics industry for the manufacture of matrix systems for pharmaceutical purposes. therapeutic compound is usually included in the form of powder or granules in the composition and dispersed in the molten thermoplastic medium such as wax or polymers during processing. Thermal methods include elevated temperature and applying shear forces. The extrusion hot melt typically sportsouth for solid dispersions of slightly soluble compounds. Depending on the solid state of the drug and the number of distinct phases in the product extrusion in the scientific literature have been described solid solutions, amorphous mixture or solid suspension. In most cases, the particles of the drug are reduced particle size, melting and/or dissolution in situ, leading to modified properties of the active compounds in a solid dispersion in comparison with the basic material. Amorphization, the reduction of particle size and hydrophilic coating material media are most suitable explanations profiles increased dissolution observed in most solid dispersions. The patent, filed Miller, et al., discloses a composition and method of preparation of the hot melt extrusion for separation of secondary agglomerates of crystalline or amorphous pre-made particles medicines and dispersion of the individual particles in the media while preventing changes in the solid state or rearrangements during processing or storage[23]. After solidification, the material should be ground into powders for subsequent processing or cut into tablets, mini-blocks, or cylinders for subsequent spheronization. The kinetics of release of the medicinal product is mainly controlled by the kinetics nabahani and erosion of the material of the carrier, the geometry of the dosage form and the particle size and solid-state active connection.

As a first step to prepare multiple particles modified release containing therapeutic compound. Further, these multiple particles of the modified release is mixed with one or more extrudable funds and ekstragiruyut, for example ekstragiruyut from the hot liquid in the finished composition, in which at least, 50, 60, 70, 80, 90 or more percentage of multiple particles modified release release its active or therapeutic agent with the same or equivalent profile release, as before extrusion with the release of the extruded matrix. Alternatively, the release of drugs may additionally be controlled by the nature of the extruded matrix. For example, if the finished composition includes an extrudable matrix that releases multiple particles modified release after, for example, the passage of the stomach, the release of active ingredient is controlled by the matrix or the properties of multiple particles modified release.

As used herein, the expression "multiple particles" refers to one or more systems standard the eskers, such as, but without limitation, pills, spheres, pellets, mini-tablets, granules, spheroids or pellets with a modified release profile of the drug. Multiple particles contain film or matrix, controlling the release of drugs and/or protecting drug, such as polymer film or matrix, integrity or effectiveness of which is susceptible to certain conditions, such as heat or mechanical forces that may occur during subsequent processing. The term "core material" describes the nature of the internal parts of multiple particles, which may also include functional coverage. Exemplary materials of the core can be pills (spherical matrix system, which contain the drug and optional excipients), granules (less spherical particles, which almost entirely consist of medicines) or nonpareil (spherical particles without the drugs).

The expression "therapeutic compound", "drug" and "active pharmaceutical ingredient" are used interchangeably regarding chemical objects that exhibit certain pharmacological effects in the body and are introduced for such purpose.

Non-limiting examples terapeuticas the x compounds include, but without limitation, antibiotics, analgesics, vaccines, anticonvulsants; antidiabetic agents, fungicide, antineoplastic agents, antiparkinsonian tools, Antirheumatic remedies, appetite suppressors, biological response modifiers, cardiovascular drugs, Central nervous system stimulants, contraceptives, dietary supplements, vitamins, minerals, lipids, saccharides, metals, amino acids (and predecessors), nucleic acids and precursors, contrast agents, diagnostic agents, agonists dopamine receptor means of erectile dysfunction, treatment for infertility, gastrointestinal remedies, hormones, immunomodulators, means against hypercalcemia, stabilizers mastocytes, muscle relaxants, nutritional agents, ophthalmic assets, osteoporosis, psychotherapeutic tools, parasympathomimetics funds parasympatholytics means, respiratory means, sedative hypnotics, means for skin and mucous membrane, means for Smoking cessation, steroids, sympatholytic assets, urinary tract, uterine relaxants, vaginal funds, the vasodilator, antihypertensive, hypertension, protivogistaminnye, protivostat the definition and remedies against vertigo. In certain embodiments implement one or more therapeutic compounds are water-soluble, slightly soluble in water drug or a drug with a low, medium or high melting point. Therapeutic compounds can be provided or not provided with a stabilizing salt or salts.

As used herein, the term "fragility" refers to the tendency of multiple particles or particles of the present invention to break, to break, to crack or trend coatings damaged or colored due to abrasion during processing or handling. In this invention, if there is the fragility of multiple particles, such particles will not be able to provide the necessary release of therapeutic compound (or drug) and dosage form to be unsuitable. This invention provides a significant advantage over the prior art, since thermal conditions selected for co-extrusion thermal matrix and multiple particles, often reduce or eliminate the fragility of multiple particles, extruded in the extrusion matrix, thus having the advantage of combining release profiles as extruded matrix, and multiple particles. In particular the i.i.d. cases, the fragility of multiple particles will determine the way which was processed or formed of multiple particle so that multiple particles have been coated or composition of the coating (if any). Accordingly, the composition of the coating (or shell), for example, the powder(s), shell(-s), floor(-s), binder(s), polymer(s) or filler(s), chosen so that the finished product has at least a moderate amount of resistance to chipping, breaking, abrasion, friction and the like. Election material to achieve this are known in the prior art and is additionally described in the examples.

Different ways of getting you can use for the manufacture of a medicinal product containing particles, and high mechanical strength are not necessary. Exemplary methods of obtaining includes the extrusion of the wet mass and spheronization, wet granulation and layering spray. You can use other methods, including hot melt extrusion, molding by extrusion or similar thermal processes.

The polymer coating can be applied onto the core material to modify the release of drugs and/or to separate the drug from its environment to protect. Coverage level must be greater than 10% and more preferably more than 20% of the percentage weight gain by the of iMER to ensure its stability during heat treatment. The use of polymers with glass transition temperatures above the temperature of thermal treatment, it may be necessary to prevent in-situ mitigation of the coating. However, optimization of composition is to minimize the period of exposure to multiple particles of a high temperature and to pay this need in excess. Optional, additional water-soluble or kislotorastvorimuu coating can be applied over modifying the release coating so that it acted as a barrier between modifying the release coating and the matrix carrier. Non-limiting examples of polymers that can be included in the upper floor are hydroxypropylcellulose, hypromellose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium salt, a copolymer of dimethylaminoethylmethacrylate and methyl methacrylate, chitosan, polyvinyl alcohol or polyvinylpyrrolidone.

All fillers and therapeutic compounds present in plural particles must also have sufficient thermal stability at the applied temperatures.

Requirements for the particle size for multiple particles strongly depend on the selected method and processing conditions and, in the case of extrusion hot melt, from hardware configuration to extras is I. Particles not exceeding about 800 microns with a preferred range of approximately 300-500 μm, are most suitable for processing by hot melt extrusion. Single-screw extruders can have certain advantages over the twin-screw extruders, however, the aim is to preserve the original characteristics of the particles during thermal processing.

The matrix carrier includes at least one thermoplastic polymer or fusible lipid and may also contain additional functional excipients, such as disintegrant, glidant, plasticizers, antioxidants, retarders or other means of modifying the release, surfactants, stabilizing means or processing AIDS. The term "matrix" refers to a material that surrounds multiple particles to provide the dosage form with multiple particles.

The expression "thermoplastic", with the description of a polymer, refers to one or more polymers which melt and/or soften upon the application of heat to allow the melt while maintaining good chemical stability. Illustrative examples of thermoplastic polymers that can be used as the matrix material include, but without limitation, poly(ethylene oxide)-poly(Pro is lanoxin) copolymer, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), carbomer, polycarbophil, cellulose derivatives, natural gum, povidone, poly(vinyl acetate), alginates, acrylic and methacrylic polymers. Lipids include the types of wax, such as beeswax, Carnauba wax, glycerides (mono-, di - and tri-), GMS (glycerylmonostearate), GMO (glycerolphosphate), sucrose stearate. As foreseen and included in the scope of the present invention, the combination of suitable polymers and/or lipids can be used as a matrix material for the formation of copolymers or physical blends.

Multiple particles can be mixed with the polymer carrier before extrusion or dosed in the media during the extrusion method using a separate port along with the cylinder. Submission of multiple particles through the port, which is located adjacent to area heads can reduce the impact on the particle thermal load and shear forces and can support the physical and functional integrity of multiple particles.

Under conditions of thermal treatment of multiple particles can remain generally not physically damaged, so that the characteristics of the release of drugs initial particles are stored in a matrix product. This is achieved by use of the polymer carrier, which corresponds to one who does more of the following requirements:

the melting or softening at relatively low temperatures so that the integrity of multiple particles is not disturbed thermally induced processes such as softening, deformation, dissolution in the carrier polymer or chemical degradation, the probability of which increases as a function of temperature;

the low viscosity of the melt to provide a low resistance relative to the rotation of the screw during extrusion hot melt and to minimize shear forces acting on multiple particle;

good flowability in the solid state and low melt viscosity to facilitate the rapid transition through the cylinder of the extruder; reducing the residence time of the composition within the extruder barrel and, consequently, the time of exposure of the material to elevated temperatures. Mainly, the size of the pellets give excellent flowability;

like many particles as particle size, spherical shape and the true density to avoid segregation of the mixture and ensure content uniformity of the finished product;

the low degree of intermolecular interaction with fillers in the plural particles that are in direct contact with thermoplastic carrier during the extrusion process.

The obtained matrix system can be formed in the threads of the cylinder, t is blackah, thin-walled tubes or films. Paleorrota may include various methods of shaping products, such as granulation or other techniques of cutting, calendering, molding or spheronization, to obtain a dosage form required geometry.

Finished dosage form will show the properties that are comparable with untreated multiple particles, which relates to a controlled release drug and/or protect it from environmental influences. As used herein, the expression "modified-release" and "controlled release" are used interchangeably and are intended to describe the immediate, prolonged or extended release profiles of the medicinal product, as used in USP 31 [24], and the need for the presence of the element that controls the release. The element that controls the release, may be a functional coating; and/or it is possible to provide a matrix material.

The invention additionally discloses a composition and method for producing extrusion hot melt intersolubility matrix of pills. Pills, as described in this invention have an average particle size of from 500 to 3000 μm, preferably from 500 to 1000 microns and contain a pharmaceutically active substance (drug) is plasticized anionic polymer matrix. Disclosed here pills release less than 10% drug 2 hours in simulated gastric environment with a pH of 1.2 and more than 40% after an additional 2 hours in a buffer with a pH of 6.8 or 7.4, respectively. Disclosed herein pills additionally exhibit high mechanical strength and low brittleness, which makes them more suitable for further processing than pills, obtained in the usual way. Examples of further processing include the functional coating film, direct compression, filling in capsules and extrusion of the melt in a monolithic system.

Anionic polymers containing anionic groups, which proteinous during the acid phase, but are ionized after increasing pH. Anionic polymer, which is used as a matrix controlled release, is not soluble at low pH and exhibits low permeability to the drug in the acidic phase of the study on dissolution. During the buffer stage of ionization of the acid groups of the polymer will increase the release of drugs by swelling and/or erosion of the matrix. Particularly suitable are copolymers of methacrylate and methacrylic acid in different ratios (Eudragit S and Eudragit L), or a mixture thereof.

Pharmaceutically acceptable anionic polymers used in ways the e melt extrusion, possess high glass transition temperatures and high viscosities of the melt during processing. According to this invention an acceptable plasticizer or mixture of plasticizers is added to the composition in sufficient quantity to reduce the glass transition temperature and melt viscosity of the polymer in order to avoid thermal decomposition occurring at elevated temperature processing. Acceptable plasticizers are non-toxic and are safe, have shown an increased plasticization efficiency for anionic polymer and do not increase the release of drugs above 10% during the acid phase.

Pills can include one or more pharmaceutically active substances at the joint level of from about 0.1 to 70%, preferably from 5 to 40% of the medicinal product. The composition of the pill may optionally contain additional fillers and/or processing AIDS, improved chemical stability, machinability or property release pills, such as thermal grease, glidant and/or antioxidants.

How hot melt extrusion of this invention is predominant over the traditional methods of obtaining pills, because it is a one-step continuous process that avoids the use of solvents or t is udoamaka methods of drying. The components of the disclosed composition can be reduced in particle size and/or mix before extrusion, using commonly available equipment for grinding and mixing. According to this invention can be applied to commonly used single - or twin-screw extruders of different sizes and with one or more temperature zones. The temperature, at least one of the heating zones must be selected, at least 10, preferably at least 30°C above the glass transition temperature of the plasticized polymer to produce the polymer melt sufficiently low melt viscosity. The temperature of extrusion, in addition, must be below the temperature of thermal decomposition of polymer or other components of the composition. The diameter and shape of the extruded filament is mainly governed by the diameter and geometry of the output part of the decoration of the channel head of the extruder, but they can also influence the viscoelastic properties of the polymer melt. Circular head with a diameter of 500 to 1000 microns are preferred for this invention. Extruded filaments can be cut into cylindrical pills while hot or after cooling to room temperature, and optionally spirolateral. Developed several techniques for consistent granulation in pellets and speronis is the continuous or semi-continuous method [25-27].

The expression "the study of dissolution in the intestine and released into the intestine medicines," you see, as described in USP 31, Chapter <711> dosage forms, extended release [24].

The expression "long-term release of drugs" was used, as described in USP Chapter <711> dosage forms, extended release [24].

EXAMPLE 1

Materials nucleus

EXAMPLE 2

Getting pills

The following procedure can be used to obtain pills with particles of the required size. Drug and microcrystalline cellulose was placed in the tank and thoroughly mixed for 10 minutes. PVP (polyvinylpyrrolidone) C dissolved in water and this binder solution was added dropwise to the powder when mixing. Wet the collected material is then moved to table the pellet mill LCI and extrudible through a 0.6 mm sieve when the speed of rotation of the blades 50 revolutions per minute. The extruded filament was placed in spheronization model 120, Caleva, and was rotated at 700 rpm for 3 minutes. Received the pills were dried at 40° oven for 24 hours and sieved. Fraction from 300 to 500 μm was used for subsequent coating intersolubility the floor.

the table 2
Composition to obtain pills
ComponentAmount [g]Percentage
Anhydrous theophylline90,030,0%
Microcrystalline187,562,5%
cellulose (RN)
PVP K2522,57,5%
Water dist.180,0

EXAMPLE 3

Layering a drug nonpareil

Layered active tool nonpareil with the desired range of particle sizes obtained by applying the following procedure.

Table 3
Dispersion coatings for weight gain drugs 30% 250 g party
ComponentAmount [g]
Anhydrous theophylline75,0
A receiver array (hypromellose) E3 (Pharmacoat 603)8,0
Talc20,0
Water diets.425,3

250 g batch of nonpareil derived from 100% microcrystalline cellulose NF, and having a particle size of 300-500 μm (Celphere® CP 305, Asahi Kasei America, Inc.), introduced into the device for coating in the fluidized bed Strea-1 (Aeromatic-Fielder) and layered aqueous dispersion of theophylline and E3 receiver array using the following conditions:

Table 4
Process parameters for a device for coating in the fluidized bed Strea-1 (Aeromatic-Fielder)
Lot size250 g
Theoretical weight gain medications30%
Pressure spray air1,5-1,8 bar
Fan performance3-6
The nozzle diameter1.0 mm
Inlet temperature75-80°C
Outlet temperature45-50°C
The application rate2.0 g/min or 8.0 g/min*kg
The spraying modeThe lower column Wurster

The obtained layered particles were dried (24 hours at 40°C. oven) and screened before coating intersolubility the floor.

EXAMPLE 4

Floor intersolubility coated core material

The following composition and processing method can be used to provide core material (pills, granules, nonpareil) intersolubility coating. You can use alternative functional polymers, plasticizers or facilities to prevent sticking. Particles coated film can be dried overnight in a 40°C oven or inside the unit for coating, sift and the fraction with a particle size of 300-500 μm can be used for subsequent extrusion hot melt.

Table 5
Dispersion coatings for 200 g party
CompositionPercentageAmount [g]
Eudragit® L30D-5512% of the polymer in disperse the 400 (120 g of polymer)
A TEC10% of the content of the polymer12
GMS7.5% of the content of the polymer9
Tween 8040% of GMS3,6
Water575,4
The solids contentof 14.46%

Table 6
The process parameters for the functional coating device for coating in the fluidized bed Strea-1 (Aeromatic-Fielder).
Gain20-50%
Inlet temperature36-38°C
Outlet temperature32-33°C
The nozzle diameter1.0 mm
The application rate10 g/(min*kg)
Installation Wurster, the lower spray

Additional polymer top coating can be applied to multiple particles with intersolubility coating to improve their resistance to high temperatures and/or shear forces during subsequent extrusion method hot melt.

EXAMPLE 5

Extrusion hot melt intersolubility matrix pills

The following structures and procedures can be applied to obtain intersolubility matrix of pills with the desired particle size. Powder mixture for extrusion received preliminary blending of the polymer with the plasticizer and the subsequent mixing with the drug, using the appropriate equipment for mixing. Mini-extruder, equipped with two rotating in one direction screws and o-ring cylinder, 500 μm (Haake Minilab, Rheomax ARTICLE W5, Thermo Electron, Germany), can be applied for the preparation of loaded drug, polymer filaments, which are then cut to obtain a cylindrical pills. Pills can be spheronization at a later stage using the appropriate equipment for spheronization.

Table 7
Examples for composition intersolubility m is trionyx pills.
The plasticizerThe amount of plasticizer [%]Eudragit® S 100 [%]Theophylline [%]Temperature te [°C]
No07030220
A TEC106030180
A TEC205030140
PEG
(polyethylene glycol) 8000106030180
PEG 8000205030140
Methylparaben106030180
Methylparaben205030140

EXAMPLE 6

Study of the release of a medicinal product by way of in vitro intersolubility matrix pills

Properties of release of drug from the pills can be defined, as described in USP 31, fashion <711> for a method And dosage forms of extended release. Used blade unit (unit 2) with a water bath to maintain a temperature of 37±0.5°C, and the ow rate was set at 50 rpm. The compositions were placed in 750 ml of simulated gastric fluid (SGF) with a pH of 1.2 (without pepsin, called the acid stage) for 2 hours and an aliquot of the liquid was collected at the end of this period. Volume 250 ml of 0.20 M trehosnovnogo phosphate, which was balanced to 37±0.5°C, was added over 2 hours to increase the pH of the medium to 6.8 or 7.4, respectively (buffer stage). After completion of the study period remaining particles completely destroyed by stirring in a homogenizer with large shear effort to fully release the residual medicines, an aliquot of the liquid was filtered and analyzed to determine the released total number using the approved method HPLC (high is the effective liquid chromatography). All the average values obtained from at least n=3 and reported as % released of the total released quantity.

EXAMPLE 7

The hot melt extrusion of multiple particles modified release

The following is an example of a hot melt extrusion of the solid matrix with included intersolubility particles using a Randcastle Microtruder RCP-0750. You can apply different polymer carriers and you can change the loading of multiple particles.

Table 9
Composition for extrusion hot melt matrix with multiple particles.
ComponentAmount [g]
Multiple particles modified release30,0
Polymer-media70,0

Multiple particles and the polymer mixed in the mixer with a V-hull or alternative mixing device. The composition exhibits excellent fluid properties and served through the hopper into the cylinder by gravity without additional application is silt. The separation of the components of the mixture within the extruder hopper or decreased due to the spherical nature of the particles and the similarity of the particle size and the true density. The following process conditions were used for the extruder. Possible changes in extrusion equipment, speed screw, the set temperature and the load/torque of the engine.

EXAMPLE 8

Direct compression of multiple particles

Functionally coated particles (30%), microcrystalline cellulose (Ceolus™ KG-802, 65%) and superdisintegrants (Ac-Di-Sol®, 5%) can be directly compressed into round tablets (333 mg, equivalent to 100 mg of particles) using a single stationary manual Carver Press, equipped with a concave surface with a head diameter of 10 mm. pressure was 5 kN, and the hardness of the tablets was 17.1±1,6 kPa.

EXAMPLE 9

Study of the release of a medicinal product by way of in vitro intersolubility multiple particles and extruded from a hot melt matrix

Properties of release of drug from the particles or extruded from a hot melt matrix can be defined, as described in USP 31, fashion <711> for a method And dosage forms of extended release. Used blade unit (unit 2) with a water bath to maintain the pace of the atmospheric temperature environment 37±0.5°C and the ow rate was set to 100 rpm. The compositions were placed in 750 ml of simulated gastric fluid with a pH of 1.2 (without pepsin, called the acid stage) for 2 hours and an aliquot of the liquid was collected at the end of this period. Volume 250 ml of 0.20 M trehosnovnogo phosphate, which was balanced to 37±0.5°C, was added over 2 hours to increase the pH of the medium to 6.8 or 7.4, respectively (buffer stage). After completion of the study period remaining particles completely destroyed by stirring in a homogenizer with large shear effort to fully release the residual medicines, an aliquot of the liquid was filtered and analyzed to determine the released total number using the approved method HPLC. All the average values obtained from at least n=3 and reported as % released of the total released quantity.

Characteristics of dissolution of multiple particles before and after extrusion in a monolithic matrix shown in Fig. 2-5.

EXAMPLE 10

Determination of tensile strength of multiple particles

The mechanical strength of the core material covered with multiple particles and pills, extruded from a hot melt, was determined using the universal device for testing the tension/compression Chatillon model TCD-200. Flat round steel plate secured on the digital device DL is measuring the strength of DFGS 50 and lowered in the diametrical direction to separate the particle at the speed of the RAM to 2.5 mm/min Data of deflection under load was collected using the software for research power Chatillon Nexygen TCD. Mechanical strength was reported as the tensile strength and calculated using the following equation:

σ=2Pπdl

Samples with diameters (d), equal to the length (l), was chosen for the experiment and the maximum load (P), which were brittle fragmentation of particles used for calculations.

Table 11
Tensile strength extruded from the melt Eudragit® S100 pills containing 30% theophylline, as a function of the type and level of plasticizer. Analysis of the diametral compression of individual pills (mean ± SD (standard deviation), n=6).
The concentration of plasticizerThe tensile strength of methylparaben ± SD [MPa]The tensile strength of the TEC ± SD [MPa]The tensile strength of PEG 8000±SD [MPa]
0%40,4±5,240,4±5,240,4±5,2
10%30,0±3,027,0±1,733,6±2,1
20%29,5±4,529,7±2,417,4±3,4

Table 12
The tensile strength of uncoated core material and coated with multiple particles. Analysis of the diametral compression of individual pills (mean ± SD, n=20).
Tensile strength before coating ± SD [MPa]Tensile strength after coating ± SD [MPa]
Granules7,3±2,29,5±2,8
Pills21,5±3,020,0±3,4
Globule MCC33,6±5,424,1±4,5

Assume that any variant of implementation discussed in this description may be made with respect to any method, the set, the reagent or composition of the present invention and Vice versa. In addition, the compositions of this invented what I can be used to implement the methods of this invention.

It should be understood that the specific embodiments of described herein, shown as illustrations and not limitations of this invention. The main features of the present invention can be applied in different implementation without deviating from the scope of this invention. Specialists in this prior art will recognize, or be able to determine with nothing more than a simple experiment, many equivalents of the specific procedures described in this document. Such equivalents are considered as being within the scope of this invention and covered by the claims.

All publications and patent applications mentioned in the description, indicate the level of qualification of specialists in the prior art to which the invention belongs. All publications and patent applications are incorporated herein by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to activate the link.

Application forms singular when used in combination with the expression "comprising" in the claims and/or description, can mean "one", but it is also combined with the designation of "one or more", "at least one" and "one or more than one." The use of expressions or formulas the invention is used to mean "and/or", if it is not listed as a reference only alternative, or alternatives are mutually exclusive, even if the disclosure supports a definition that refers to only alternatives and "and/or". Throughout this application the terms "approximately" is used to indicate that a value includes the inherent deviation error device, method used to determine the value, or the deviation that exists among the objects of study.

As used in this description and the item(s) of the claims, the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "comprising" (and any form of comprising, such as "contains" and "contain"or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or unlimited and do not exclude additional, non-listed elements or stages of the method.

The expression "or combinations thereof", as used herein, applies to all transformations and combinations of the above points, the preceding expression. For example, "a, b, C, or combinations thereof" is meant to include at least one of: a, b, C, AB, AC, BC, or ABC, and if order is important in a particular context, also WA, SA,SV, IAS, SU And DIA, YOU or CAB. In continuation of this example clearly include combinations that contain repetitions of one or more item or expression, such as BB, AAA, MB, air force, AAASSS, SWAA, SAWAW and so on. Specialist in this field will understand that, as a rule, there is no limit on the number of items or expressions in any combination, unless otherwise clear from the context.

All compositions and/or methods disclosed and claimed herein can be made and executed without undue experiment in the light of this disclosure. While the compositions and methods of this invention have been described through preferred embodiments, it will be obvious to experts in this field that you can apply variations to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without deviating from the idea, the essence and scope of this invention. All such substitutions and modifications, obvious to the skilled in the art are anticipated as being within the entity, the amount and ideas of the present invention, as defined by the attached claims.

Sources of information

1. The pharmacy is systematic composition of controlled release, comprising one or more of multiple particles modified release with an effective amount of one or more therapeutic compounds, where multiple particles include known profile of release of the medicinal product and subjected to a heat treatment in the extrudate in a thermoplastic polymer matrix, a lipid material, or in fact, and in another, where the conditions of heat treatment retain the prevalence of known profile of release of the medicinal product multiple particles at the release of thermoplastic polymer matrix or lipid material, where the pharmaceutical composition of controlled release retains the prevalence of known profile of release of the medicinal product multiple particles at the release of thermoplastic polymer matrix or lipid material, and where multiple particles are in the size range 50-800 microns.

2. The pharmaceutical composition of controlled release according to claim 1, where multiple particles are in the size range of 300-500 μm.

3. The pharmaceutical composition of controlled release according to claim 1, where the extrudate comprises at least 80% intact multiple particles.

4. The pharmaceutical composition of controlled release according to claim 1, where multiple parts of the s include a coating of a polymeric film.

5. The pharmaceutical composition of controlled release according to claim 1, where controlling the release of drugs or the principle of protection of medicines inherent in the multiple particle includes a polymer matrix or a hydrophobic material.

6. The pharmaceutical composition of controlled release according to claim 1, where multiple particles include intersolubility floor release of the drug.

7. The pharmaceutical composition of controlled release according to claim 1, where multiple particles are covered for prolonged release of one or more therapeutic compounds.

8. The pharmaceutical composition of controlled release according to claim 1, where multiple particles are covered to protect from moisture for one or more therapeutic compounds.

9. The pharmaceutical composition of controlled release according to claim 1, where multiple particles of the modified release is covered with a water-soluble or kislotorastvorimuu upper floors.

10. The pharmaceutical composition of controlled release according to claim 9, where the additional water-soluble or acid-soluble top coat comprises a polymer selected from the group including polymethacrylates, cellulose derivatives, polysaccharides, proteins or poly vinyl is a career.

11. The pharmaceutical composition of controlled release according to claim 1, where multiple particles are processed to minimize incompatibility between one or more therapeutic compounds and one or more fillers in the matrix.

12. The pharmaceutical composition of controlled release according to claim 1, where multiple particles are film-coated granules medicines, film-coated pills, the loaded drug, or covered with a film nonpareil with layered drug.

13. The pharmaceutical composition of controlled release according to claim 4, where the coating of the polymer film multiple particles comprise from 10% to 60% of polymer(s) (percentage of weight), more preferably 20-50% by weight of multiple particles without coating.

14. The pharmaceutical composition of controlled release according to claim 4, where one or more of the polymers in the coating of a polymeric film selected from the group which includes polymethacrylates, cellulose derivatives, polysaccharides, proteins, or vinyl polymers.

15. The pharmaceutical composition of controlled release according to claim 4, where the coating of the polymer film includes a plasticizer.

16. The pharmaceutical composition of controlled release according to claim 1, where multiple particles include from 5 to Wes.% one or more therapeutic compounds.

17. The pharmaceutical composition of controlled release according to claim 1, where thermoplastic polymer matrix comprises one or more components, which at least partially are crystalline polymers with a melting point below 80°C.

18. The pharmaceutical composition of controlled release according to claim 1, where thermoplastic polymer is selected from the group comprising poly(ethylene oxide)-poly(propylene oxide) copolymer, poly(ethylene glycol) or poly(ethylene oxide) with a molecular weight of less than approximately 1000000.

19. The pharmaceutical composition of controlled release according to claim 1, where the weight percentage of multiple particles is from 5 to 70 wt.%.

20. The pharmaceutical composition of controlled release according to claim 1, where multiple particles modified release dissolve or disintegrate in water in less than two hours to release multiple particles modified release.

21. The pharmaceutical composition of controlled release according to claim 1, where multiple particles modified release further defined as including intersolubility polymers or water insoluble polymers modified release, which release the drug by diffusion or pH-dependent dissolution of the polymer.

22. The pharmaceutical composition of controlled release according to claim 1, where multiple particles modified release coated intersolubility coating, and where less than 10% of the drug will be released in the acidic environment of the dosage form, comprising multiple particles modified release with intersolubility the floor, and when the environment changes the pH to a value above 6,8, more than 80% of drug released for 45 min in a buffer environment.

23. The pharmaceutical composition of controlled release according to claim 1, where multiple particles of modified release include matrix-retarder, where the matrix-moderator breaks down or decomposes with release of multiple particles modified release.

24. The pharmaceutical composition of controlled release according to claim 1, where the matrix and multiple particles modified release coated film coated matrix, or both.

25. The pharmaceutical composition of controlled release according to claim 1, where multiple particles are subjected to a heat treatment in the heat-treated conditions that preserve the integrity of multiple particles during processing.

26. A method of obtaining a pharmaceutical composition with controlled high what opozdaniem, including the stage at which mix one or more of multiple particles modified release comprising an effective amount of a therapeutic compound with a known profile of release of the medicinal product, with a thermoplastic polymer matrix or hydrophilic wax containing matrix, using a heat treatment under conditions which retain the control of release of the medicinal product, the characteristic of the protection of the medicinal product or the one and the other at multiple particles.

27. The method according to p, where heat treatment is performed by hot melt extrusion.

28. The method according to p, where the hot melt extrusion is conducted single-screw or twin-screw extruder.

29. The method according to p, where multiple particles include film coating, which is applied by way of the dry coating, the method of the aqueous coating or coating solvent.

30. The method according to p, where multiple particles cover a device for coating the fluidized bed.

31. The method according to p, where heat treatment is performed at a temperature less than approximately 100°C.

32. The method according to p, where multiple particles modified release form part of a slow-release by coating, at least, one of them from hydrophobic polymers, hydrophilic polymers, gums, materials derived from proteins, waxes, shellac, oils and mixtures thereof.

33. The pharmaceutical solid dosage form provides controlled release of therapeutic compound and comprising a pharmaceutical composition obtained by p.

34. The pharmaceutical solid dosage form according p, where the preferred site of administration is the oral route.

35. The pharmaceutical solid dosage form according p controlled release, further defined as immediate, prolonged or extended release.



 

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EFFECT: dosage form of erectile dysfunction under the invention having the greater particles shows high dissolution rate when approximately 60%, preferentially 68% or more of tadalafil is released for 20 minutes if taken in a dose of 20 mg of tadalafil.

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FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of pharmaceutics. Claimed is method of obtaining drug form, which include: a) placement inside depression of friable material, including at least approximately 5 wt % of at least one hydrated salt and pharmaceutically active agent, and where at least one hydrated salt is characterised by temperature of dehydration from 20 to 120°C; b) heating friable material in depression to temperature higher than said temperature of dehydration of at least one hydrated salt for time period sufficient for fusion of material with formation of aggregate, and heating is performed by radio-frequency or microwave heating; and c) cooling aggregate in depression until aggregate hardens in dosed form. Friable material can additionally contain carbohydrate. Claimed is drug form, obtained by said method. In order to obtain drug form, which includes external edible part and internal part, disintegrating in oral cavity, said friable material is placed inside depression in preliminarily created external edible form, with depression having required shape and volume, sufficient for placement of part of drug form, disintegrating in oral cavity.

EFFECT: method makes it possible to create dosed drug forms avoiding production stage of pressing, which in its turn improves integrity of particles, which contain pharmaceutically active agent and are sensitive to forces of compression.

16 cl, 3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for the correction of cerebrovascular disease accompanying cardiovascular diseases which contains the active ingredients presented by atorvastating or pharmaceutically acceptable salt thereof and nicergolin in the therapeutically effective amounts.

EFFECT: pharmaceutical composition is characterised by high stability and bioavailability.

8 cl, 8 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an oral solid dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt wherein an active ingredient makes more than 46 wt % of total weight of the oral dosage form. The oral dosage form is presented in the form of a tablet or a film-coated tablet, and contains an internal phase containting aliskiren or its pharmaceutically acceptable salt, an excipient, a binding agent and a disintegrant, and an external phase containing a disintegrant, an excipient, a glidant and a lubricant.

EFFECT: invention provides administration of the active ingredient aliskiren in the small oral dosage form; it is characterised by an acceptable disintegration time.

32 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to an agent to be used for treating arterial hypertension and congestive cardiac failure. A pharmaceutical composition contains ramipril, a combination of sodium bicarbonate and arginine as a stabiliser, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium croscarmellose, glidant and a lubricant and optionally a dying agent. A method for preparing the pharmaceutical composition involves moisturising of a mixture of ramipril, lactose monohydrate, microcrystalline cellulose, sodium bicarbonate, and optionally the dying agent in a solution of hypromellose and arginine, granulation, drying, dry granulation, addition of sodium croscarmellose, glidant and the lubricant, and tableting of the prepared mixture. The pharmaceutical composition in the form of a solid dosage form is characterised by decreased formation of all impurities, including ramiprilate and diketopiperazine ramipril, fast release of the active substance, high strength and storage stability of the quality characteristics guaranteed within more than 2 years of shelf life.

EFFECT: preparing the agent for treating arterial hypertension and congestive cardiac failure.

11 cl, 2 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely pharmacy and may be used for creating an oral solid dosage form. The dosage form contains a pharmaceutically acceptable salt of an alkaline-earth metal of 5-methyk-(6S)-tetrahydrofolic acid and granules containing progestogen, oestrogen and microcrystalline cellulose. What is also presented is a pharmaceutical kit for females for providing the concentrations or treating the diseases, conditions or symptoms associated with endogenous oestrogen deficiency.

EFFECT: group of inventions provides the good storage stability of tetrahydrofolic acid, and at the same time provides rapid and reliable release of oestrogen and progestogen being parts of the composition.

13 cl, 3 dwg, 4 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and deals with combined pharmaceutical composition, which possesses anti-tuberculosis action. Composition is made in form of solid drug form, which contains combination of levofloxacin, protionamide, pyrazinamide, ethambutol hydrochloride and pyridoxine hydrochloride ad active ingredient, and pharmaceutically acceptable auxiliary substances.

EFFECT: composition is characterised by high therapeutic activity.

10 cl, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to tablet, which is decomposed in mouth, containing D-mannite, active ingredient, disintegrating preparation, selected from crospovidone and carmellose, lubricant, selected from sodium stearylfumarate and sucrose esters of fatty acids, binding agent and starch. D-mannite has average size of particles larger than 30 mcm and specific surface larger than 0.40 m2/g.

EFFECT: claimed tablet has time of decomposition in oral cavity within 30 seconds, excellent sensation in oral cavity and sufficient strength, as a result of which tablet is not decomposed in the process of distribution.

28 cl, 1 dwg, 12 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry and represents a pharmaceutical composition containing: {1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3;4-difluorophenyl)cyclopropyl]amino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol; an excipient representing mixed mannitol and dibasic calcium phosphate dihydrate; a binding agent representing hydroxypropyl cellulose; a disintegrant representing sodium starch glycolate; and one or more lubricating agents.

EFFECT: invention provides preparing the composition of the active compound possessing high stability and high bioavailability of the active agent.

12 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a drug preparation containing 97.0-59.5 wt % of naltrexone base, 0.5-3.0 wt % of corticosteroid specified in triamcinolone, betamethasone or dexamethasone, 2.0-37.0 wt % of a nitrogen-containing polymer composition and 0.2-0.5 wt % of stearic acid or magnesium stearate. The nitrogen-containing polymer composition contains N-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymer or a salt of branched oligomers hexamethylene diamine and guanidine, and polyvinylpyrrolidone. The drug preparation may be used in addictology for treating the alcohol- or opioid-dependent patients.

EFFECT: invention provides prolonged and uniform naltrexone release with a lower probability of the implant rejection caused by an inflammatory response.

2 cl, 3 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutical industry and deals with solid pharmaceutical composition, possessing high physical strength. Claimed invention also presents method of manufacturing solid pharmaceutical composition. Claimed pharmaceutical composition contains 7 varicoloured types of granules in form of capsule. Granules contain, wt %: nikotinamide 1-35; pyridoxine 0.1-8; calcium pantitenate 0.1-15, thiamin 0.1-30; tryptophan 1-30; tocoferol 0.5-5; ascorbic acid 0.1-50; 5-hydroxyanthranyl acid 0.01-10; Riboflavin 0.1-10; folic acid 0.1-6; cyanocobalomin 0.001-6; isoleucin 0.5-10; leucin 0.5-15; lysine 0.5-20; phenylalanine 0.1-5; threonine 0.1-5.0; valin 0.1-8.0; methionine 0.1-15; lactose 1-4.0; ergocalcioferol 1-95.0 and auxiliary substances for obtaining granules.

EFFECT: claimed composition possesses excellent properties of medication release and digectionin application composition possesses hepatoprotective hypolipidemic immunostimulating and normalising kidney activity action.

2 cl. 2 ex. 5 tbl

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