Compositions containing weakly basic drug substances, and controlled-release dosage forms

FIELD: medicine.

SUBSTANCE: this invention aims at pharmaceutical compositions and methods for making these compositions containing a number of controlled-release particles. At least one assembly of said particles comprises a nucleus containing weakly basic drug substance, an alkaline buffer layer above the nucleus, and a controlled-release coating. The weakly basic drug substance contains at least one nitrogen-containing fragment with pKa from approximately 5 to approximately 14, with a solubility from at least 200 mg/ml at room temperature in an aqueous solution at pH approximately pH 1.2-6.8 and solubility of no more than approximately 10 mg/ml at pH 8 and more. The controlled-release coating contains a water-insoluble polymer. The pharmaceutical composition also contains rapidly degrading microgranules. This invention also aims at pharmaceutical dosage forms containing orally degrading tablets, classical tablets and capsules, as well as methods for making them.

EFFECT: invention provides the sustained release of the weakly basic drug substance in the small intestine.

65 cl, 1 dwg, 1 tbl, 7 ex

 

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims the priority of provisional patent application U.S. No. 61/045170 filed April 15, 2008, which reference is hereby incorporated into this description completely in all respects.

Background of the INVENTION

Many therapeutic agents are most effective when they become available with constant velocity in the absorption centers or nearby. Absorption of therapeutic agents made thus available, as a rule, leads to the desired concentrations in plasma, leading to maximum efficacy and minimum toxic side effects. Many efforts have been focused on the development of complex systems of drug delivery, such as osmotic devices for oral use. However, there are cases in which simple systems of drug delivery, such as a matrix tablet comprising polymers that control the rate of dissolution, or monolithic or multi-particle system, coated with functional polymers, unable to meet the target pharmacokinetic (FC) profiles, suitable for single or double modes daily dosing.

For the appropriate absorption of the drug substance from the gastrointestinal tract, the drug substance must� be released from the dosage form and become available in the form of a solution in the absorption center or in its vicinity. The speed at which the medicinal substance goes into solution and is released from the dosage form that are important for the kinetics of absorption of medicinal substance. Pharmaceutical form and, therefore, the active ingredient is exposed to during transit to different pH values varying from pH 1,2 (on empty stomach) to about 7.0 (bile and intestines). In addition, the transit time of the dosage form parts of the digestive tract can vary considerably depending on the size of the dosage form and the local conditions within the digestive tract. Other factors affecting absorption of drug substances, include the physicochemical properties of the drug substance, such as pKa, solubility, crystal lattice energy and specific surface area. Prevailing local conditions within the digestive tract that play an important role include the content properties of the cavities (pH, surface tension, volume, mixing and buffer tank), as well as the changes that occur due to eating. Accordingly, it is often difficult to achieve the release of medicinal substance with constant velocity, especially in the case of extremely soluble or freely soluble weakly basic drug substances, which are released when the acid incredi, that, therefore, leads to the release of the dose. Functional polymer membrane, comprising a suitable combination of synthetic polymers such as water-soluble polymers (e.g., povidone), water-insoluble polymers (e.g., ethylcellulose) and the enteric polymers (e.g., stable in the stomach hypromellose phthalate), are applied to the core tablet or pellet comprising the medicinal substance, to achieve a slow release profiles with limited success.

Oral-disintegrating dosage forms has been steadily gaining popularity as a more convenient and potentially safer alternative to traditional tablets and capsules. These quickly dispersed dosage form disintegrates in the mouth and easy to swallow with water. They are favourable to 50% of the population with difficulties in swallowing traditional tablets and capsules (normal for geriatric and pediatric patients), people who have no free access to water (for example, bedridden or immobile patients, or active people, often far from home), as well as nurses whose patients are reluctant to take medicines. Oral-disintegrating dosage forms help to improve patient compliance with oral modes of dosage because nelegko are introduced, convenient for cautious reception anywhere and difficult to reject after injection. However, these dosage forms require not only rapid disintegration upon contact with saliva in the oral cavity, but also acceptable organoleptic (i.e., pleasant taste) and pharmacokinetic (i.e., the rate and duration of release of medicinal substances) properties corresponding to a particular medicinal substance and a disease whose treatment is performed. These properties are often mutually contradictory. Thus, the development of orally disintegrating tablets (LMP) containing weakly basic drug substances which are freely soluble in the range of physiological pH values of 1.2 and 6.8 for one - and two modes of daily dosage, is very promising.

Weakly basic drug substance is rapidly released in an acidic environment and therefore often not able to provide profiles of FC, suitable for single or double mode of daily dosage. In addition, the main medicinal substance difficult to work with them, and if to obtain a therapeutic effect requires high doses, because their solubility is reduced by 1-2 orders of magnitude during the transit through the stomach to the colon. If applied extremely dense polymeric coating with the intention to slow the release of Les�artenova substances in the area of lower pH values, i.e. at a pH of 1.2 and 6.8, the drug release is by diffusion through the membrane coating with a speed so slow that it will not have practical applicability.

Thoroughly review the published patent application U.S. No. 11/668167 (published as application No. 2007/0190145) and the application for U.S. patent No. 11/668408 (published as application No. 2007/0196491, filed January 29, 2007, disclose pharmaceutical compositions comprising separate layers of weakly basic drugs and organic acids.

BRIEF description of the INVENTION

In one embodiment of the this invention relates to pharmaceutical compositions comprising a plurality of particles with controlled release, where each particle comprises a core comprising a weakly basic substance, a layer of alkaline buffer located above the core of medicinal substances, and coating and controlled release comprising a water-insoluble polymer.

In one embodiment of the this invention relates to pharmaceutical compositions comprising a plurality of particles with controlled release, where each particle comprises a core comprising a weakly basic substance containing at least one nitrogen-containing fragment with a pKa from about 5 to about 14, with a solubility of at least 200 mg/ml at room�temperature in aqueous solution at pH about 1.2-6.8 and a solubility of not more than about 10 mg/ml at pH 8 and above, layer alkaline buffer located above the core of the drug substance, and the coating is a controlled release layer located over the alkaline buffer, where the coating is a controlled release includes water-insoluble polymer.

In another embodiment of the this invention relates to a method for manufacturing a pharmaceutical composition, where the method includes (a) manufacture of the core comprising a weakly basic drug substance, (b) coating the core of step (a) a layer comprising an alkaline buffer, (C) coating the core with a layer of alkaline buffer stage (b) a layer of controlled release.

In another embodiment of the this invention relates to a pharmaceutical dosage form comprising a plurality of particles. Each particle includes a core comprising a weakly basic drug substance, a layer of alkaline buffer located above the core, and the coating is a controlled release layer located over the alkaline buffer, where the coating is a controlled release includes water-insoluble polymer, optionally in combination with enteric or water soluble polymer.

In another embodiment of the this invention relates to a pharmaceutical dosage form comprising at least two sets of particles Leka�governmental substance. The first set of particles of the drug substance includes a core comprising a weakly basic drug substance, and the second set of particles of the drug substance includes a core comprising a weakly basic drug substance, a layer of alkaline buffer located above the core, and the coating is a controlled release layer located over the alkaline buffer, where the coating is a controlled release includes water-insoluble polymer, optionally in combination with enteric or water soluble polymer.

In another embodiment of the this invention relates to a pharmaceutical dosage form comprising at least two sets of particles of the drug substance. One set of particles of the drug substance includes a core comprising a weakly basic drug substance, and the second set of particles of the drug substance includes a core comprising a weakly basic drug substance, a layer of alkaline buffer located above the core of the drug substance, and the coating is a controlled release layer located over the alkaline buffer, where the coating is a controlled release includes water-insoluble polymer alone or in combination with enteric or water soluble polymer.

In another vari�NTE implementation of the present invention relates to a method of manufacturing a pharmaceutical dosage form. In one embodiment, the pharmaceutical dosage form is manufactured by mixing microparticles, as described in the present description, with quickly dispersed granules comprising a saccharide and/or sugar alcohol in combination with disintegrants, with formation of a mixture for pressing and compressing the mixture into a tablet. In another embodiment, the pharmaceutical dosage form is made by filling the capsules described in the present description microparticles.

BRIEF DESCRIPTION of GRAPHIC MATERIALS

FIG. 1 illustrates a cross-sectional MV-granules, coated by alkaline buffer (upper illustration), and SV - and SIV-granules comprising coated by alkaline buffer MV-granules comprising a weakly basic drug substance, in accordance with specific embodiments of the present invention (bottom illustration). Fig.1 (upper schematic) coated by alkaline buffer MV-granule 10 includes a layer of alkaline buffer 72, located on the protective sealing layer 14 which is placed on the layer of weakly basic drug substance 16 located on the inert core 18 comprising the spherical particle of sugar or lactose, microcrystalline cellulose, mannitol-microcrystalline cellulose or silicon dioxide. On the same figure (bottom schematic from�ed), SV - or SIV-granules 20 includes a compressible coating layer 26 located on the coating of controlled release (SV - or SIV-layer) 24, which is located on the sealing layer 22, located on covered with a layer of alkaline buffer MV-granule 10.

DETAILED description of the INVENTION

All cited documents are by reference incorporated into this description fully in all respects; the citation of any document should not be interpreted as recognition of its prototype in relation to the present invention.

The expression "medicinal substance", "active" or "active pharmaceutical ingredient" as used in the present description, include pharmaceutically acceptable and therapeutically effective compound, its pharmaceutically acceptable salts, stereoisomers and mixtures of stereoisomers, solvates (including hydrates), polymorphs, and/or esters. Referring to the medicinal substance in the descriptions of various embodiments of the invention, the reference covers the main medicinal substance, its pharmaceutically acceptable salts, stereoisomers and mixtures of stereoisomers, solvates (including hydrates), polymorphs, and/or esters.

The expression "orally disintegrating tablet" or "LMP" refers to a tablet which rapidly disintegrates in the oral cavity after its introduction without such�p, need chewing. The rate of disintegration can vary, but it is more than the rate of disintegration of traditional solid dosage forms (e.g. tablets or capsules) that, as provided, must proglatavetsa immediately after injection, or chewing solid dosage forms.

The expression "approximately" in the sense that it is used in the present description for the assignment of a numerical value, includes "exactly". For example, "about 60 seconds" 60 seconds exactly, and values close to 60 seconds (e.g., 50 seconds, 55 seconds, 59 seconds, 61 seconds, 65 seconds, 70 seconds, etc.).

The expression "weakly basic drug substance" includes medicinal substances containing one or more nitrogen fragments with a pKa in the range of from about 5 to about 14, which is very soluble or easily soluble in acidic conditions and neutral pH values (i.e. pH from about 1.2 to about 6.8), but poorly soluble above pH 6.8. Expressions related to solubility (e.g., "very soluble", "soluble", "slightly soluble", etc.) have the same meaning as in the United States Pharmacopoeia (Vol. 26, NF 21, 2003) with the understanding that we bring to the solubility limits represent approximate border. For example, "very soluble" means having a solubility of at least 1 g of races�voennogo substance in 1 ml of water or aqueous solution at room temperature and the specified pH; "soluble" means having a solubility of from about 100 mg to about 1000 mg of solute per 1 ml of water or aqueous solution at room temperature and the specified pH; "slightly soluble" means having a solubility of less than about 100 mg of solute per 1 ml of water at room temperature.

In the same sense as it is used in the present description, the expression coverage "controlled release" encompasses coatings that delay release, slow release, prevent release, and/or otherwise prolong the release of drug substance from the particles covered with a coating of controlled release. The phrase "controlled release" includes the expression "sustained release" and "synchronous pulsed release". Coating controlled release can also be called in the present description coating that provides a "lag time".

In the same sense as it is used in the present description, the expression "the core of instant release" refers to a core containing a medicinal substance, optionally coated with a sealing substance, but not covered with a coating of controlled release. The expression "the core of instant release" may include crystals �cartonnage substances (or amorphous particles), pellets of the drug substance with one or more excipients or inert core (e.g., a spherical particle of sugar), coated with a medicinal substance (and optionally a binding agent), protective sealing coating and, optionally, a layer of alkaline buffer. "Kernel with instant release" would have the properties of instant release as described in the present description. Particles extended-release (for example, POLLUTANTS-particles, SIV-particles, etc.) can be produced by coating cores with instant release coating of the extended release.

In the same sense as it is used in the present description, the term "immediate release", or MB, refers to the release of more than or equal to about 50% (especially in the case of masking of taste for the introduction of the dosage form orally disintegrating tablets), preferably more than about 75%, more preferably more than about 90%, and, in accordance with some embodiments of the invention, more than about 95%, of active substance within about 2 hours, more particularly within about 1 h, after administration of the dosage form.

The expression "CIV-particle" or "CIV-granule" refers to a particle that contains a drug substance, for example, to pellets, covered with a layer of ve medicinal�society, the pellet containing the medicinal substance, or a particle of the drug substance, covered with SIV-coating (coating "synchronous pulsed release"), SIV-coating provides impetus to the sudden release of a medicinal substance or a sustained release profile of the drug substance after the expiration of a predetermined time delay. The term "latency" refers to the time period after oral administration of the particles containing the medicinal substance, or after storage in two-stage solvent environment or simulated (s) or biological (-) fluid (s), during which the particles containing the medicinal substance is released in less than about 10% of the drug. In one embodiment, the term "latency" refers to the time period during which the medicinal substance is practically not released from the particles, or after storage in two-stage solvent environment or simulated biological fluids. In some embodiments, the lag time of about 1-10 hours, is achieved by coating the particles, for example, a combination of at least one water-insoluble polymer and at least one intersolubility� polymer (e.g., a combination of ethyl cellulose and hypromellose phthalate). In one embodiment, the time delay is in the range from about 2 days to about 10 days. CIV-layer optionally may contain a plasticizer.

Expression coverage "sustained release" or "SV-coating" refers to a coating that provides the sustained release properties, for example, to the coating that slows the release of drug substance from the particles containing the medicinal substance, however, does not provide a significant "lag time". In one embodiment of the invention SV-coating includes a water-insoluble polymer and optionally a water-soluble polymer.

The expression "substantially disintegrates" means the level of decay that comprises at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or about 100% dissolution of the TMP files.

The expression "substantially masks the taste against taste masking layer MV-particles (if present) refers to the ability of the taste masking layer to substantially prevent the release of drug substance, having a bitter taste in the patient's mouth. Masking the taste of the layer "a significantlargely masks" the taste of the drug substance, typically, releases less than about 10% of the drug in the patient's mouth, in other embodiments less than about 5%, less than about 1%, less than about 0.5%, less than about 0.1%, less than about 0.05%, less than about 0.03%, less than about 0.01% of the drug. Masking the taste properties of the taste masking layer compositions according to the present invention can be measured in vivo t (for example, using traditional organoleptic testing methods known in the art) or in vitro (e.g., as described in the present description of the dissolution test). Specialists in the art knows that the amount of released drug substance associated with taste masking layer, which "substantially masks" the taste of the drug; substances, not limited to the intervals explicitly disclosed in the present description, and may vary depending on other factors, such as susceptibility to bitter taste of the drug substance and, for example, the presence of flavoring agents in the composition.

The expression "the time dependence of the plasma concentration", "Cmax", "AUC", "Tmah" and "half life" have their ordinary meanings, defined by the FDA Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products (March 2003).

<> If not stipulated otherwise, the number of different coatings or layers described in the present description ("coating weight") is represented as the percentage weight gain of the particles or pellets, are equipped with the dried coating, in relation to the initial weight of the particles or granules before the layering of the coating. Thus, the coating weight of 10% refers to the dried coating, which increases the weight of the particles by 10%. If not stipulated otherwise, the relationship is given in wt.%.

In one embodiment of the this invention relates to pharmaceutical compositions comprising a plurality of particles with controlled release, where each particle comprises a core comprising a weakly basic substance, a layer of alkaline buffer located above the core of the drug substance, and the coating is a controlled release layer located over the alkaline buffer. In specific embodiments, the coating is a controlled release includes water-insoluble polymer. In accordance with some embodiments of implementing the present invention, a pharmaceutical composition includes any weakly basic drug substance having at least one nitrogen-containing fragment, pKa from about 5 to about 14, a solubility of at least 200 mg/ml at room temperature in aqueous solution at pH �Colo 1,2-6,8 and solubility less than about 10 mg/ml at pH 8 and above. Without being bound to theory describing the mechanism of regulation of release of medicinal substance, a layer of alkaline buffer, located in the core containing a weakly basic drug substance, creates a microenvironment with alkaline pH on the border with the drug substance, drug substance, in the best case, malorastvorima even when the external environment granules coated governing the release, is acidic, and the medicinal substance in it lagoratory that, thus, avoids the ejection of the dose after oral administration.

In some embodiments, the implementation of the weakly basic drug substance according to the present invention can be selected from the following non-limiting examples of classes of drugs: analgesics, anticonvulsants, antidiabetic remedies, anti-microbial agents, antitumor agents, antiparkinsonian funds, Antirheumatic agents, cardiovascular agents, Central nervous system stimulants (CNS), agonists of dopamine receptors, antiemetics, gastrointestinal agents, psychotherapeutic means (e.g., antipsychotics), opioid agonists, opioid antagonists, anti-epileptic agents, histamine H2antagonists, procious�MATIC means, the skeletal muscle relaxants.

Examples of weakly basic drugs include as non-limiting examples butyrophenone derivatives, nitrogen containing fragment, phenyliminomethyl (for example, clonidine, an antihypertensive agent), (e.g. fenoterol, a bronchodilator agent), fenoximetilpenitsillina (for example, β-adrenolytic dinitrogen), proximinality (e.g., antiarrhythmic mexiletine), aminoethylethanolamine (antihypertensive and antianginal drugs), or their pharmaceutically acceptable salts, solvates, esters and polymorphs, and mixtures thereof. In some embodiments, weakly basic drug substance has a half-life of about 2 h to about 7 h.

The expression "located above" means that the second material is applied to the first material, wherein the second material may be or may not be in physical contact with the first material. Thus, it is possible, but not necessary, to between the first and second material lying intermediate material.

A layer of alkaline buffer, as expected, creates an alkaline microenvironment on the surface of the drug substance particles inside with controlled release. Because the weakly basic drug prophetic�tvo has a lower solubility in such a microenvironment, layer alkaline buffer effectively delaying the release of drug substance under acidic and neutral pH of the gastrointestinal tract, in which the medicinal substance otherwise would be to dissolve quickly. The introduction of a layer of alkaline buffer in the composition according to the present invention can achieve a pharmacokinetic profile suitable for one - and two single modes daily dosage. Non-limiting examples of alkaline buffers that are suitable for the compositions according to the present invention include sodium hydroxide, monolatry dihydrogen phosphate, disodium hydrogen phosphate, trinacria phosphate, sodium acetate, sodium carbonate or bicarbonate, monogalia dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium carbonate or bicarbonate, magnesium phosphate, magnesium acetate, magnesium carbonate, magnesium oxide, magnesium hydroxide, sodium silicate, calcium silicate, complex metasilicate of magnesium-aluminum, and mixtures thereof. Layer alkaline buffer optionally comprises a polymer binding agent. The polymeric binder can be selected from the group consisting of gidroksipropilzelluloza, povidone, methylcellulose, hydroxypropylmethylcellulose, karboksimetsiltsellyulozy, polyethylene oxide, and polysaccharide.

Inside of the particles with controlled release layer alkaline buffer RA�relies on a layer of sealing substance, which, in turn, is located on the core comprising the weakly basic drug substance. In one embodiment, a layer of alkaline buffer may include a polymeric binding agent, if necessary. Non-limiting examples of suitable polymeric binders include hydroxypropyl cellulose, povidone, methylcellulose, hydroxypropyl methylcellulose, carboximetilzellulozu, polyethylene oxide, starch, and polysaccharide. In some embodiments, the ratio of alkaline buffer and weakly basic drug substance is in the range from about 5:1 to approximately 1:5, including from about 3:1 to about 1:3.

The compositions according to the present invention can, in some embodiments, to enable the sealing layer located on the core containing a medicinal substance, under a layer of alkaline buffer. This protective sealant layer separates the core containing a medicinal substance layer from an alkaline buffer and may provide one or more advantages: the prevention (or minimization) of contact between the drug substance and the alkaline buffer during processing or storage, the prevention (or minimization) of a static property, the prevention (or minimization) of abrasion particles, avoid potential destabi�enosti, which may be the result of finding medicinal substances close to alkaline buffer during the laying of the drug substance and storage (for example, the formation of additional connections between the acid and buffer), a guarantee that the alkaline buffer and weakly basic drug substance not form a direct contact until the dosage form does not form contact with the solvent medium or biological fluid during oral intake. In one embodiment the sealant layer includes a hydrophilic polymer. Non-limiting examples of suitable hydrophilic polymers include hydrophilic hydroxypropyl cellulose (e.g. Klucel®LF), hydroxypropyl cellulose, or hypromellose, (for example, é®Clear or Pharmacoat™ 603), the copolymer vinylpyrrolidone and vinyl acetate (e.g., Kollidon® VA 64, BASF) and ethylcellulose low viscosity (for example, with a viscosity of 10 SP or less in a 5% solution in a mixture of 80/20 toluene/ethanol at 25°C when measured using Ubbelohde viscometer). The sealing layer may comprise from about 1% to about 20% by weight containing the medicinal substance and covered with a protective layer of the kernel, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17%, about 20%, including all intervals and subintervals between him�.

In some embodiments, the microparticles according to the present invention include coating a controlled release comprising a water-insoluble polymer, and laminated on the layer of alkaline buffer. In some embodiments, the coating is a controlled release includes water-insoluble polymer in the absence of water-soluble or enteric polymer. In this latter embodiment the coating is a controlled release slows the release of drug substance from more than about 8 h to about 20 h when tested by the method of two-stage dissolution (700 ml of 0.1 n Hcl (hydrochloric acid) during the first 2 h, and then 900 ml at pH 6.8 obtained by adding 200 ml of pH modifier), and is suitable for one - and two-regime daily dosage.

Non-limiting examples of suitable water-insoluble polymers include ethylcellulose, cellulose acetate, cellulose acetate-butyrate, polyvinyl acetate, neutral copolymers of methacrylic acid and methylmethacrylate, and mixtures thereof. In one embodiment the water-insoluble polymer includes ethylcellulose. In another embodiment the water insoluble polymer includes ethylcellulose with an average viscosity of 1 CP in 5% solution in a mixture of 80/20 toluene/alcohol, measured at 25°C. by Ubbelohde viscometer. Water-insoluble polymer coating controlled release provides a weight gain from about 3% to about 30%, including about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17%, about 20%, about 22%, about 25%, about 27%, about 30%, about 35% and about 40%, including all intervals and subintervals between them. In one embodiment, the microparticle with a slow release can contain a sustained release coating of plasticized water-insoluble polymer, such as ethylcellulose (EU-10), in an amount of about 5-50% by weight to slow the release of medicinal substance for more than about 4-20 hours

In one embodiment, the implementation of the water-insoluble polymer coating controlled release additionally includes a plasticizer. Non-limiting examples of suitable plasticizers include triacetin, tributyltin, triethylcitrate, acetyl-tri-n-butylnitrite, Deerfield, castor oil, dibutylsebacate, monoacetylmorphine and diacetylmorphine diglycerides (e.g., Myvacet® 9-45), and mixtures thereof. When used in one embodiment of the present invention, the plasticizer may be from about 3% to about 30% by weight in the calculation of the water-insoluble polymer. In another embodiment, the implementation of the Fig�message plasticizer is from about 10% to about 25% by weight in the calculation of the water-insoluble polymer. In other embodiments, the amount of plasticizer relative to the weight of the water-insoluble polymer is about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17%, about 20%, about 22%, about 25%, about 27% and about 30%, including all intervals and subintervals between them. The person skilled in the art it is clear that the type (s) and amount (s) of plasticizer (s) are selected based on the polymer, or polymers, and the nature of the coating system (e.g., coatings based on water or solvent, the solution or dispersion, and total solids contents). In one embodiment of the invention, if the plasticizer is used in the controlled coating of the release, the plasticizer does not contain phthalates.

In one embodiment of the present invention in each of the layers of coatings that also contains a plasticizer, the plasticizer (s) does not contain phthalates.

In some embodiments, the coating is a controlled release layer located on the alkaline buffer comprises a water-soluble polymer in combination with a water-soluble polymer and provides sustained release of the drug substance. In one embodiment, the implementation of the ratio of water insoluble polymer and a water-soluble polymer is in the range from about 95/5 to about 50/50, VK�including the interval from about 90/10 to about 60/40. In another embodiment of the water-insoluble polymers in combination with water-soluble polymers comprise from about 3% to about 50% by weight in the calculation covered the core, including the intervals from about 10% to about 50%, from about 3% to about 30%, and from about 5% to about 30%. In other embodiments, the amount of water-insoluble polymer in combination with a water-soluble polymer is about 3%, about 5%, about 7%, about 10%, about 12%, about 15%, about 17%, about 20%, about 22%, about 25%, about 27%, about 30%, about 35%, about 40%, about 45%, about 50% by weight based on the core with an instant release, including all intervals and subintervals between them.

Water-soluble polymers used in accordance with some embodiments of implementation of the present invention comprise water-soluble polymers. Non-limiting examples of suitable water-soluble polymers include polyvinylpyrrolidone (e.g., Povidone K-25), a glycol (e.g., PEG 400), hydroxypropyl methylcellulose and hydroxypropyl cellulose. In one embodiment, the implementation of the sustained release coating provides a release of drug substance, slow for more than about 12 hours to about 16 hours when tested by the method of two-stage dissolution (700 ml of 0.1 n Hcl (hydrochloric acid) during the first 2 h, and then 900 ml �ri pH 6.8 by the addition of 200 ml of pH modifier), and is suitable for single or double mode of daily dosage.

In another embodiment the coating is a controlled release includes water-insoluble polymer in combination with soluble in the stomach of a blowing agent and provides sustained release of the drug substance. Example soluble in the stomach of the blowing agent is calcium carbonate. Other suitable soluble in the stomach blowing agents include sodium chloride, calcium carbonate, calcium phosphate, calcium saccharide, calcium succinate, calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium phosphate, etc.

In some embodiments, the coating is a controlled release includes water-insoluble polymer in combination with an enteric polymer and provides a delayed or synchronized pulsed release (CIV) of medicinal substance. This type of coating controlled release (i.e., the combination of a water-insoluble polymer and enteric polymer) here also called coating that provides "time lag", and microparticles covered with a coating that provides a time delay may also be called SIV-particles. The expression "time delay" on�Xia time period after oral administration of the particle, containing the medicinal substance, or after storage in two-stage solvent environment or simulated (s) or biological (-) fluid (s), during which the particles containing the medicinal substance is released in less than about 10% of the drug. In one embodiment, the implementation of the expression "delay time" refers to the time period during which the medicinal substance is practically not released from the particles, or after storage in two-stage solvent environment or simulated (s) or biological (-) fluid (s). In one embodiment of the coating, providing the time delay, is applied directly to the layer of alkaline buffer. In another embodiment of the coating, providing the time delay, is applied directly to one or more layers (for example, the sealing layer) which are laminated on the layer of alkaline buffer. In some embodiments, the ratio of water insoluble polymer and enteric polymer is in the range from about 10:1 to about 1:4, including the intervals from about 9:1 to about 1:3 and about 3:1 to about 1:1. In other embodiments, water-insoluble and enteric polymers in combination constitute from about 5% to approximately 60% by weight based on the core of mgno�enny release including intervals from about 10% to about 60%, and from about 10% to about 50%. Non-limiting examples of suitable enteric polymers include cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, pH sensitive copolymers of methacrylic acid and methylmethacrylate, shellac, and mixtures thereof. (The term "pH sensitive" refers to polymers with pH-dependent solubility). These enteric polymers can be used in the form of a dry powder or an aqueous dispersion. Some commercially available materials that may be used are methacrylic acid copolymers, commercially available under the trademark Eudragit (L100, S100, L30D) manufactured by Rohm Pharma, Cellacefate (cellulose acetate phthalate) from Eastman Chemical Co., Aquateric (water dispersion of cellulose acetate phthalate) from FMC Corp. and Aqoat (water dispersion of hydroxypropylmethylcellulose acetate-succinate) from Shin Etsu K. K. In one embodiment, the implementation of SIV-coating includes ethylcellulose (e.g. EU-10) as a water-insoluble polymer and hypromellose phthalate (e.g., HP-55) as the enteric polymer.

In one embodiment, the implementation of SIV-microparticles can provide a lag time of from about 1 h to about� 10 h, including from about 2 h to about 7 h, about 2 h to about 4 h ("low latency"), and from about 7 hours to about 8 hours ("long delay"). In another embodiment of the SIV-release microparticles of drug substance during the period of time from about 4 hours to about 16 hours in the gastro-intestinal tract after the expiration of the delay time from about 1 h to about 10 h after oral administration.

In another embodiment, the microparticles contain the outer cover, providing the time delay, which is located on the coating controlled release. In an embodiment, this type of release of drug substance starts at a higher pH in the intestine with subsequent slow release of the drug substance.

Release profiles of drug substances 3 In - and SIV-microparticles can be determined by dissolution test according to USP in the Device 1 or 2 using a two-stage solvent medium (first 2 hours in 700 ml of 0.1 n Hcl at 37°C, followed by dissolution test at pH 6.8 by the addition of 200 ml of pH modifier). The release of drug substance over time can be determined by various methods, for example by HPLC on the samples taken at selected time points.

SV or SIV-coating contributes to the regulation of the dissolution of the drug substance on the surface of the drug substance and, therefore, the release of drug substance from the microparticles. The achievable time delay, or time delayed release, depends on the composition and coating thickness of sustained release and/or the composition and thickness of the coating, providing the time delay. Specific factors that affect the achievement of an optimal two - or one-day dosage forms, include as non-limiting examples of RCA therapeutic agent (and its solubility, i.e. the medicinal substance, easily soluble in acid and neutral conditions of pH, malorastvorima at pH 8.0 and above), the half-life and decrease the solubility in a microenvironment with an alkaline pH that are created with an alkaline buffer.

In another embodiment, the microparticles contain a compressible coating, located on the coating controlled-release (or placed in the outer coating, if the coating is a controlled release additionally covered with SIV-coating). Compressible coating comprises a hydrophilic polymer. In one embodiment the hydrophilic polymer is selected from the group which consists of hydroxyprop�of icellulse, poly(vinyl acetate and vinyl pyrrolidone), and plasticized polyvinyl acetate latex dispersion of ethyl cellulose with low viscosity. This coating can be applied, for example, by coating in a fluidized bed plasticized aqueous dispersion of ethyl cellulose. Its purpose is the maintenance of membrane integrity during extrusion with quickly dispersed microgranules.

The core of the microparticles include weakly basic drug substance. In some embodiments, the core may take the form of inert granules, micro-granules or crystals of the drug substance. In one embodiment, the implementation of the core comprises an inert bead coated with a medicinal substance, comprising the weakly basic drug substance. Inert granule can include sugar, microcrystalline cellulose, mannitol-microcrystalline cellulose, silicon dioxide etc. the Core has an average particle size of not more than 400 μm, or in another embodiment of the invention, not more than 350 μm. In one embodiment, the implementation of the medicinal substance layer includes a polymeric binder. The polymeric binder can be selected from a group which contains hydroxypropyl cellulose, povidone, methylcellulose, hydroxypropyl methylcellulose, carboximetilzellulozu,�ethylenoxid, starch (e.g. corn starch and gelatinizing corn starch and polysaccharide. The ratio of drug and polymer binding substances may be in the range of from about 85:15 to about 100:0 (binding agent is absent).

Described in the present description, the pharmaceutical compositions can also include quickly dispersed granules comprising a saccharide and/or sugar alcohol in combination with disintegrants. Disintegrant can be selected from the group which comprises copovidone, sodium chromalveolata, crosslinked sodium carboxymethylcellulose and hydroxypropyl cellulose with a low degree of substitution. Saccharide and/or sugar alcohol may be selected from the group which includes lactose, energy, sucrose, maltose, mannitol, sorbitol, xylitol and maltitol.The ratio of disintegrant and of saccharide and/or sugar alcohol in quickly dispersed the microgranules is in the range of about 1/99 to about 10/90, and in some embodiments is about 5/95 (by weight). In some embodiments, disintegrant or saccharide and/or sugar alcohol, or both, may be present in the form of microparticles having an average size of about 30 μm or less. The ratio of microparticles containing a drug substance, and quickly dispersed granules can be difficult to� in the range of from about 1:6 to about 1:2.

In another embodiment of the this invention relates to pharmaceutical dosage forms, including microparticles described here. Pharmaceutical dosage forms include orally disintegrating tablets (LMP), traditional tablets and capsules (for example, capsules of hard gelatin, hydroxypropylmethylcellulose (HPMC) or polysaccharides). If the pharmaceutical dosage form takes the form of the got, the got substantially disintegrates within about 60 seconds after contact with saliva in the oral cavity or with simulated salivary fluid. In another embodiment, the implementation of LMP substantially disintegrates within about 30 seconds. The disintegration is tested in accordance with the disintegration test No. 701 according to the USP monograph. In one embodiment, the implementation of the TMP includes a therapeutically effective amount of weakly basic drugs, where after the introduction of LMP substantially disintegrates in the oral cavity with the formation of a homogeneous, easy-to-swallow suspension, not having a sandy texture or flavor, and provides the desired profile of FC (i.e., a graph of plasma concentration against time) of the said weakly basic drug substances suitable for single or double mode of daily dosage.

EU�and pharmaceutical dosage form is a tablet, it preferably has an abrasion resistance less than about 1%. If the pharmaceutical dosage form is got, the tablet may also include pharmaceutically acceptable excipients suitable for use in the compositions of disintegrating tablets, such as compressible diluents, fillers, coloring tools, and, optionally, a lubricant.

In some embodiments, the weight of the got is not more than about 2000 mg, for example, 2000 mg or less, 1500 mg or less, 1000 mg or less, 500 mg or less. In some embodiments, the weight of the got is not more than about 1600 mg. In another embodiment of the weight got is no more than about 800 mg. In another embodiment of the weight got is not more than about 500 mg.

The got include one or more sets of 3 - and/or one or more sets of SIV-microparticles described in the present description, or their mixtures, in combination with quickly dispersed microparticles. The got may additionally include MV-particles. For example, the pharmaceutical dosage form may include: SV-microparticles in combination with quickly dispersed granules; CIV-microparticles in combination with quickly dispersed granules, MV-particulates, POLLUTANTS-particulates and quickly dispersed granules; MV-microparticles With�In-microparticles and quickly dispersed granules; MV-particulates, POLLUTANTS-particulates and one or more sets of SIV-microparticles, which may be the same or different lag times (for example, SIV-microparticles with low latency and SIV particles with a long time lag), in combination with quickly dispersed granules. These various combinations of microparticles can achieve different desired release profiles of the drug substance. For example, a dosage form for single daily dosage of the active substance with a half-life of about 7 h may contain a mixture of aggregate MV-granules, providing impetus to the instant of release, the second set of 3 - or SIV-granules with a small time delay (about 2-4 hours) that provide a quick sustained release profile, and a third set of SIV-granules with a long lag time (about 7-8 hours), which allows to obtain the profile of a delayed, sustained release through about 8-12 hours to maintain acceptable plasma concentrations within 12-24 h.

If the pharmaceutical dosage form is present MV-particles, the ratio MV-particle and 3 - and/or SIV particles is in the range from about 0:100 (MV-particles are absent) to about 50:50. Taste MV-particles may be masked by layering taste masking layer, to�which substantially masks the taste of the drug substance, contained in the particle. Data MV-particles with taste masking release no more than 10% for 3 minutes (the longest retention time expected for the got in the mouth) when tested for dissolution in simulated salivary fluid (pH ~ 6.8 cm), while about 75% of the dose is released within about 60 minutes when tested for dissolution in 0.1 n Hcl.

MV-particles comprise a core containing a medicinal substance, optionally, coated water-insoluble polymer (e.g., ethylcellulose), providing a taste masking layer. Coating of water-insoluble polymer may include a plasticizer. In addition, it can include soluble in the stomach, a blowing agent (e.g., calcium carbonate), for example, in accordance with the disclosure in jointly considering the application for U.S. patent No. 11/213266, filed August 26, 2005(published application No. 2006/0105038, published may 18, 2006), or by layering in a fluidized bed water-insoluble polymer (e.g. ethyl cellulose with an average viscosity of 10 CP) by itself or in combination with soluble in the stomach by a polymer (e.g., Eudragit El 00 or EPO), for example, in accordance with the disclosure in jointly considering the application for U.S. patent No. 11/248596, filed on October 12, 2005(published application No. 2006/0078614 published 13 April 2006), or soluble in �elude the blowing agent (for example, calcium carbonate), for example, in accordance with the disclosure in jointly considering the application for U.S. patent No. 11/256653, filed on October 12, 2005(published application No. 2006/0105039, published may 18, 2006). Each of the above applications reference is hereby incorporated into this description completely in all respects.

Described in the present description may have got one or more of the following advantages: (i) disintegrate upon contact with saliva in the oral cavity within about 60 seconds, forming a homogeneous, easy-to-swallow suspension comprising particles with taste masking and/or containing the medicinal substance; (ii) disintegrate within 30 seconds when tested for dissolution in accordance with the disintegration test No. 701 according to the United States Pharmacopoeia; (iii) MV-particle masking of taste, if present, provide fast, substantially complete release of the dose when injected into the stomach (e.g., typically more than about 75% within 60 min); (iv) SV - or SIV-particles provide sustained and/or delayed release of drug substance from the gastrointestinal tract.

In another embodiment of the this invention relates to methods of manufacturing pharmaceutical compositions of microparticles described in the present description. In one embodiment of the method includes (a) manufacture of the core, containing weakly basic drug substance, (b) coating the core containing a medicinal substance, the step (a) with a sealing layer, (C) coating the core, covered with an insulating layer of step (b) a layer comprising an alkaline buffer, and (d) coating the core with a layer of alkaline buffer of step (C) layer controlled release with the formation of microparticles. The fabrication stage of the nucleus can be performed by any known in this art ways; for example, by layering on inert pellet (e.g., sugars, microcrystalline cellulose, mannitol-microcrystalline cellulose, silicon dioxide, etc.) of solutions containing the medicinal substance, and, optionally, a polymer binder (for example, in a fluidized bed or in a coating plant); granulating the drug substance with an appropriate diluent (e.g., microcrystalline cellulose and/or lactose); extrusion and spheronization of a mixture containing a medicinal substance; pressing medicinal substance in minitablets diameter of about 1-2 mm; or obtain crystals of the drug substance with the required average particle size (e.g., about 50-500 μm, including 100-400 μm).

In one embodiment, the implementation uses a method of making microparticles coated delayed VisualAge�message. In this embodiment, the coating controlled-release stage (d) comprises coating water-insoluble polymer and optionally a water-soluble polymer to a weight gain from about 3% to about 30% with the formation of POLLUTANTS-particulates. In another embodiment of the method of manufacture of microparticles coated with synchronized pulsed release (SIV-coating). In this embodiment of the coating controlled-release stage (d) comprises water-insoluble polymer and the enteric polymer to a weight gain of from about 10% to about 60% with the formation of SIV-microparticles. In another embodiment, the implementation uses a method of making microparticles of a sustained release coating lying beneath the outer coating synchronized pulsed release. In this embodiment of the coating controlled-release stage (d) includes the layering of the coating water-insoluble polymer and optionally a water-soluble polymer to a weight gain from about 3 to about 30% with the formation of particles with a slow release. The micro-particle with a slow release then covered with a layer comprising a water-insoluble polymer and the enteric polymer with the formation of SV/CIV-microparticles.

In another embodiment of the present invention relative�consistent with the method of manufacturing a pharmaceutical dosage form, where the method includes: mixing the microparticles, as described in the present description, with quickly dispersed granules comprising a saccharide and/or sugar alcohol in combination with disintegrants; and pressing the resulting mixture into a tablet with the formation of the got. In another embodiment of the pharmaceutical dosage form can be manufactured by filling hard gelatin capsules are described in the present description microparticles.

In one embodiment the method includes the following steps:

(a) the manufacture of particles of a weakly basic drug substances (crystals, microgranules, granules, or pellets with an average particle size of 50-500 μm, particularly 100-400 μm, in particular, 100-350 μm) and layering a protective sealing layer on the granules coated with a medicinal substance, with the formation of MV-granules;;

(b) superimposition of a layer of alkaline buffer MV-granules from a solution of a polymeric binding agent, if necessary, and then layering protective sealing coating on the buffer layer;

(c) superimposition of the sustained release coating comprising a water-insoluble polymer or water-insoluble polymer in combination with a water-soluble polymer to a weight gain of about 3-30% with the formation of POLLUTANTS-particles;

and/or

(d) superimposition of the coating, providing time�I lag, on SG-particles or particles coated with a layer of alkaline buffer, and a combination of water-insoluble polymer and enteric polymer in a weight ratio of about 10:1-1:4 to weight gain of about 10-60% by weight in the calculation of covered' the pellet with the formation of SIV particles;

e) optionally, the superimposition of a layer of hydrophilic polymer on SV-layer or SIV-layer; and

f) filling the appropriate quantities of 3 - and SIV-particles in the presence or in the absence of MV particles of hard gelatin capsules; or their compaction in conventional or orally disintegrating tablets (LMP) after mixing with pharmaceutically acceptable excipients and one or more sets of granules (for example, the combination of MV-pellet, 3-pellet and/or SIV-granules in the desired ratio).

Perhaps the manufacture of pellets coated with a medicinal substance, using Granurex by controlled spheronization and create a layer of alkaline buffer located above covered with an insulating coating MV-pellets in the same Granurex, and then layering the coating controlled-release equipment fluidized bed with the formation of SV-, RO - or SIV-granules.

EXAMPLES

Example 1:

Deployed release profiles of drug substances in vitro to weakly basic drug substances

Pharmacokinetic �analysis was undertaken to identify the set of theoretical release profiles of drug substances in vitro which takes into account single or twice daily dose dosage forms of weakly basic drugs. Used data on the time dependence of the concentration in human plasma after oral disposable the introduction, or at homeostasis, and/or intravenous (IV) profile, single or dvukhkomponentnye pharmacokinetic (FC) model (e.g. two-component model shown in the schematic picture below). To the FC model can simultaneously be approximated as oral (PO) and BB data. Using software WinNonlin parameter estimation of FC and predictions data - and/.or BB data is carried out with the aim of generating equations for model profiles. Developed formulations with release profiles of drug Substances in vitro that mimic model, i.e. deployed, profiles in vitro or cover the target window profile. These compounds are then tested in FC research on healthy adults objects.

Example 2

2.And MV-granules containing weakly basic drug substance

Linking the polymer was slowly added to the system of solvents (e.g., water, acetone, ethanol or mixtures thereof) for the manufacture of a solution of a binding agent. Weakly basic drug substance was slowly added to the system RA�creators until dissolved. A solution of a binding agent was then added to the drug solution and then stirred. In an alternative embodiment, the binding substance and the medicinal substance are sequentially added until dissolved. In the installation for layering coatings in a fluidized bed, e.g., a Glatt GPCG 3 (e.g., equipped with a 7 13/16"column of Wurster with 7" bottom nozzle, 'C" plate for air distribution on the bottom, covered with a sieve for holding the product size of 200 mesh) were loaded spherical particles of sugar (for example, the size of 60-80 mesh), which are then sprayed with a solution of a binding agent and a medicinal substance. Coated spherical particles of sugar then dried to remove residual solvents (including moisture) and sifted (for example, through a sieve 35 and 80 mesh) to get rid of particles larger and smaller size.

2.In Layering a base layer of anhydrous denetria phosphate (DP (A)

Anhydrous, denetria phosphate was added to purified water with stirring until dissolved. In the installation for layering coatings in a fluidized bed, e.g., a Glatt GPCG 3 (e.g., equipped with 13 6" column of Wurster from the lower nozzle 8", "C" plate for air distribution on the bottom, covered with a sieve for holding the product size of 200 mesh and spray nozzle with a hole diameter of 1.0 mm) were loaded MV-granules (for example, in Example 2.�). On MV-granules were sprayed buffer solution. After optionally rinsing solvent is covered with a buffer granules, applied at about 2% by weight of the insulation coating. Dried MV-granules can be sieved (e.g., use of screens 35 and 80 mesh) to get rid of granules larger and smaller size.

2.With SV-granules. containing weakly basic drug substance

Covered with buffer pellets of Example 2.In were covered in the installation for layering coatings in a fluidized bed SV-plated, optional, plastifitsirovannoj (for example, 10% weight/weight of triethylcitrate from ethyl cellulose) water-insoluble polymer (e.g. ethyl cellulose). The solution of compressible coating (e.g., hydroxypropyl cellulose such as Klucel® LF), dissolved in a solvent was sprayed over the coated buffer pellets to a weight gain of about 2% by weight. The resulting SV-granules can be dried to remove residual solvent.

2.D Quickly dispersed microbeads

Quickly dispersed microbeads are manufactured in accordance with the procedure disclosed in jointly considering the application for U.S. patent No. 10/827106 (published as published application for U.S. patent No. 2005/0232988, October 20, 2005, the contents of which reference is hereby incorporated into this description in all respects). D-mannitol with an average of reseraches about 20 μm or less (for example, Pearlitol 25, Roquette, France) was mixed with 8 kg of cross-linked povidone (e.g. Crospovidone XL-10, ISP) in the granulator with a large shear force (GMX 600, Vector) and granulated with purified water and subjected to wet-milled using Comil (Quadro) and dried in trays until the loss on drying (LOD) of less than about 1%. The dried granules were sifted, and the material was larger razmalyvanija quickly with the formation of dispersed micro-particles with an average particle size in the range of approximately 175-300 mm.

2.E ORT with controlled release containing SV-granules

Quickly dispersed microbeads (-1200 g) was mixed with 3-granules weakly basic drug substance (-850 g) and other pharmaceutically acceptable ingredients, such as corrigent (-25 g), sweetener (e.g., Sucralose, -10 g), additional polyplasdone (-125 g) and microcrystalline cellulose (e.g., Avicel PHI 01, -250 g), with the ratio quickly dispersed microbeads and SV-granules of about 3:2 in a V-shaped blender with double hulls in a period of time sufficient for the formation of homogeneously distributed blend for compression. The got, including 50 mg weakly basic drug in the form of STAR-pellets were pressed using an industrial tablet press equipped with an external lubrication system, the following condition�ies: instrument - circle 15 mm, flat surface, edge radius; compressive strength of 16 kN; the average weight is 1000 mg; mean hardness: 46 N; and friability: 0,28%. Thus obtained LMP (dosage 50 mg) rapidly disintegrate in the oral cavity, forming a homogeneous, easy-to-swallow suspension, which comprises coated granules and provides a release profile of the drug substance is suitable for single mode daily dosage.

Example 3

3.And MV-granules containing weakly basic drug substance

Linking the polymer was slowly added to the system of solvents (e.g., water, acetone, ethanol or mixtures thereof) for the manufacture of a solution of a binding agent. Weakly basic drug, clonidine, derived phenylaminopyrimidine, was slowly added to a solution of a binding agent with stirring until dissolved. In the installation for layering coatings in a fluidized bed, e.g., a Glatt GPCG 3 (e.g., equipped with a 7 13/16"column of Wurster with 7" bottom nozzle, 'C" plate for air distribution on the bottom, covered with a sieve for holding the product size of 200 mesh) were loaded spherical particles of microcrystalline cellulose (for example, Cellets 100, Glatt), which are then sprayed with a solution of a binding agent and a medicinal substance. MV-granules are then dried to remove residual Rast�of aricela (including moisture), and sieved (e.g., through the screens 40 and 100 mesh) to get rid of granules larger and smaller size.

3.In Layering a base layer of anhydrous denetria phosphate (DPA)

Anhydrous disodium phosphate was added to purified water with stirring until dissolved. In the installation for layering coatings in a fluidized bed, e.g., a Glatt GPCG 3 (e.g., equipped with 13 6" column of Wurster from the lower nozzle 8", "C" plate for air distribution on the bottom, covered with a sieve for holding the product size of 200 mesh and spray nozzle with a hole diameter of 1.0 mm) were loaded MV-granules (for example, from Example C (A). On MV-granules were sprayed buffer solution. After optionally rinsing with a solvent coated buffer granules was applied about 2% by weight of the insulation coating. Dried MV-granules can be sieved (e.g., use of screens 35 and 80 mesh) to get rid of granules larger and smaller size.

3.With the Coating CIV-layer:

Covered with buffer pellets of Example C was covered In a layers of coatings in a fluidized bed SIV-coating comprising ethylcellulose (Ethocel Premium 10 SP), hypromellose phthalate (HP-55) and ten (triethylcitrate) in the ratio 55/30/15 dissolved in a mixture of 90/10 acetone/water, till weight gain of 30% by weight in the calculation of the coated granule. The solution of compressible coating (e.g., hydroxypropyl cellulose such as Klucel® LF), dissolved�CSOs in the solvent, sprayed over the coated buffer pellets to a weight gain of about 2% by weight. The resulting SIV-granules can be dried to remove residual solvent.

3.D got with controlled release containing SIV-granules:

Quickly dispersed microbeads from Example 2.D mixed with SIV-granules from Example C and With other pharmaceutically acceptable ingredients, such as corrigent, sweetener (e.g., Sucralose), additional polyplasdone and microcrystalline cellulose (e.g., Avicel PHI 01), with the ratio quickly dispersed microbeads and SIV-granules of about 3:2 in a V-shaped blender with double hulls in a period of time sufficient for the formation of homogeneously distributed blend for compression. The got, including 50 mg weakly basic drug in the form of SIV-granules, was pressed using an industrial tablet press equipped with an external lubrication system. Thus obtained LMP (dosage 50 mg) rapidly disintegrate in the oral cavity, forming a homogeneous, easy-to-swallow suspension, which comprises coated granules and provides a release profile of the drug substance, suitable for single mode daily dosage. Example 4

4.And MV-granules. containing weakly basic drug substance:

Solution for naselenie� coating of the drug substance in an appropriate solvent system was prepared by adding, in the first place, polymeric binders to dissolve, and then weakly basic drug. Then the solution was applied on Cellets 100 (spherical particles of microcrystalline cellulose with an average particle size of 100-200 µm). Received MV-granules are then dried to remove residual solvents (including moisture) and sifted (for example, through a sieve of 40 and 100 mesh) to get rid of particles larger and smaller size.

4.In Layering a base layer of magnesium oxide:

Micronized magnesium oxide was added to a solution of polymeric binders in the system of solvents on the Basis of ethanol under stirring to form a uniform dispersion. Device for layering coatings in a fluidized bed, e.g., a Glatt GPCG 3, loaded MV-granules (e.g., that of Example 4.A), and sprayed a solution of magnesium oxide and polymer binding substances on MV-granules. After optionally rinsing solvent is covered with a buffer granules, applied at about 2% by weight of the insulation coating. Dried MV-granules can be sieved to get rid of granules larger and smaller size.

4.With the Coating CIV-layer:

Covered with buffer granules of Example 4.In were covered in the installation for layering coatings in a fluidized bed SV-coating comprising ethylcellulose (EU-10) and ten in the ratio�Institute 90/10, dissolved in a mixture of 95/5 acetone/water, till weight gain of 10% by weight in the calculation of the coated granule.

Pellets coated SV-coating, and then further covered with a solution of SIV-coating, including the EU-10, HP-55 and TES at a ratio of 60/30/10, and then - compressible coating Klucel® LF to gain about 2% by weight. Received SIV-granules can be dried to remove residual solvent.

4.D MV-granules with masked taste

MV-granules of example 4.And was subjected to disguise the taste by covering the EU-10, Eudragit® El 00, TES and magnesium stearate in the installation Glatt GPCG 3 to gain about 15% by weight.

i 4.E ORT with controlled release containing MB - and SIV-granules:

Quickly dispersed microbeads from Example 2.D, SIV-granules and MV-granules weakly basic drug substances by taste masking of Example 4.D in the ratio 2:1 mixed with other pharmaceutically acceptable ingredients, such as corrigent, sweetener (e.g., Sucralose), additional polyplasdone and microcrystalline cellulose (e.g., Avicel PHI 01). SIV-granules and MV-granules with masked taste combined with quickly dispersed granules in the ratio quickly dispersed microbeads and covered with granules of about 3:2 in a V-shaped blender with double hulls in a period of time sufficient for the formation of uniformly distributed with�art for pressing. The got, including 50 mg weakly basic drug in the form of 3 - and SIV-granules, was pressed using an industrial tablet press equipped with an external lubrication system. Thus obtained LMP (dosage 50 mg) rapidly disintegrate in the oral cavity, forming a homogeneous, easy-to-swallow suspension, which comprises coated granules and provides a release profile of the drug substance, suitable for single mode daily dosage.

Example 5

5.And MV-granules containing propiverine Hcl

Propiverine HC1 (308 g) was slowly added to purified water (2054,7 g) with stirring until dissolved. In a pre-warmed install Glatt 3 downloaded Cellets 100 (900 g) and sprayed with a drug solution at a rate of 4 ml/min with a step increase of speed up to 12 ml/min and the inlet volume flow of 8 cubic feet per minute, the product temperature 50±2°C. the Spray system was then rinsed with 40 g of water was applied to the 2% coating é Clear (6% solids in water) received MV-granules were dried to remove residual solvents (including moisture), and sieved (e.g., through a sieve of 40 and 100 mesh) for getting rid of particles larger and smaller size.

5.In Layering the buffer layer denetria phosphate

Denetria phosphate (113,9 g) was slowly added to the polymer concerned�the present substance aqueous solution (2278 g of water) povidone (2.3 g), with stirring until dissolved. In a pre-warmed install Glatt GPCG 3 downloaded MV-granules (e.g., in Example 5.A, 1000 g) and sprayed on MV-Granada buffer solution similar to the disclosure of Example 3.B. After optionally rinsing of the spray system 40 g of water, was applied a 2 wt.% insulating coating é Clear. Dried MV-granules can be sieved to get rid of granules larger and smaller size. 5. With SV-granules of propiverine (30% coverage)

Covered with buffer granules (900 g) from Example 5.In was covered in a pre-warmed install for layering coatings in Presidium layer SV-layer, including ethylcellulose (357,4 g) and TES (39,7 g) in a ratio of 90/10 dissolved in a mixture of acetone (3375 g)/water (596 g), to gain 30% by weight in the calculation of the coated granule. Granules with SV-coating is additionally covered with a compressible coating Klucel® LF (26,5 g) until a weight gain of about 2% by weight. Received SV-granules were dried to remove residual solvents. SV-granules with 20%, 25% and 30% by weight of the coating was subjected to the dissolution test according to the method of two-stage dissolution (USP, Apparatus 2, blade at 50 rpm.min, solvent medium: 700 ml of 0.1 n HCl for first 2 hours, then at a pH of 6.8 obtained by adding 200 ml of the modifier buffer at 37°C). Data before dissolution�taulani in Table 2 below. The table shows that the level of coverage must be substantially reduced.

Table 2:
Release profiles of drug substances in vitro to SV-granules of propiverine·HCl
Time (h)The release of drug substance (%)
20% coverage25% coverage30% coverage
1,03,71the 1.650,91
2,09,925,093,08
4,015,87,744,26
8,026,112,87,29
12,032,1a 16.49,49
16,035,819,211,2
24,040,522,713,6

Example 6

6.And MV-granules containing propiverine·HCl

Propiverine HCl(256,5 g) was slowly added to a mixture of 50/50 acetone/water (855 g of each) with stirring until dissolved and then added sodium fumarate (PRUV, 28.5 g) under vigorous stirring until a uniform dispersion. Preheated Glatt 3 uploaded spherical particles of sugar 45-60 mesh (972 g) and the drug solution (continuously stirred during spraying) was sprayed at a rate of 4 ml/min with a step increase to 8 ml/min and the inlet volume flow of 10 cubic feet per minute, the product temperature 45±2°C. After rinsing, the spray system 40 g of acetone was applied insulating coating with a 2% é Clear (6% solids in water) received MV-granules were dried to remove residual solvents (including moisture), and sieved (e.g., through a sieve of 40 and 80 mesh) to get rid of particles larger and smaller size.

6.In Layering a base layer dibasic sodium phosphate

Layer dibasic sodium phosphate (113,9 g) was layered on MV-granules (e.g., in Example 5.A, 1000 g) in a pre-warmed Glatt GPCG 3 in accordance with the procedures disclosed in Example 5.In. After optional rinsing systems� spray 40 g of acetone was applied to 2 wt.% insulating coatings é Clear. Dried MV-granules can be sieved to get rid of granules larger and smaller size. 6.With SV-granules of propiverine (10% coverage)

Covered with buffer granules (850 g) from Example 6.In was covered in a pre-warmed the installation for coating in the fluidized bed 3 In the layer including ethylcellulose (of 86.9 g) and TES (9.7 g) in a ratio of 90/10 dissolved in a mixture of acetone (821 g)/water (145 g), weight gain in 10 wt.% in the calculation of the coated granule. Covered 3 In the pellets was then covered with a compressible coating with Klucel® LF (19,3 g) for a weight gain of about 2 wt.%. Received SV-granules were dried to remove residual solvent.

6.D got propiverine"NC1 CR

Quickly dispersed microbeads (43,68 parts) from example 2.D, SV-granules of propiverine"HC1 (34,97 parts) from example 6.C and a previously prepared mixture of microcrystalline cellulose (Ceolus KG 802+Avicel PHI 01, 7.5 parts of each), polyplasdone (5 piece), Sucralose (0.35 parts), corrigent with the taste of peppermint (1.0 part) were mixed and passed through a sieve of 40 mesh to obtain a homogeneous mixture) were mixed in a V-shaped blender as disclosed in Example 4.E. Tablet got, comprising 50 mg of propiverine*HC1 in the form of STAR-pellets were pressed using an industrial tablet press equipped with an external lubrication system: thus received ORT (dosage 50 mg fast raspados� in the oral cavity, forming a homogeneous, easy-to-swallow suspension comprising coated pellets, and the time of decay, when tested by method No. 701 according to the US Pharmacopoeia was less than 30 seconds.

Example 7

7.And Pellets of propiverine"NC1 by controlled spheronization

Povidone (PVP K-30, 111,1 g) and propiverine*HC1 (particle size distribution - D(0,l): 2.6 m; D(0,5): to 10.38 µm; D(0,9): 42,52 mm; 1000 g) were mixed together and loaded into the bowl Granurex GX-35 from Vector Corporation (Iowa, USA). In rotating a substrate for the material with variable speed are dispensed purified water. Optimized parameters during forming of pellets: the temperature of the process - -19-20°C; product temperature 16±2°C; rotor speed is about 425./min; external air supply - 150 l/min; spraying speed is 15 rpm.min (~8 ml/min), the pressure drop from edge to edge of the slit - 1,3-11 mm in water; and during drying, the pellets: air volume process - 30 cubic feet/min, the temperature of the process ~60°C, product temperature of 35°C (to the date of termination of drying), the rotor speed of 180 rpm.min, the volume of air supplied through the slit - 10 cubic feet/min, the treatment time is 40 minutes thus Produced pellets contain about 65% of the particles in the size range of 40-80 mesh.

7.In MV-pellets of propiverine"NC1 with masking of taste

Pellets (970 g) from Example 7.And covered with an insulating coating Klucel LF (30 g), RAS�varenum in a mixture of acetone/water (7.5% of solids), for weight gain of 3%. Ethylcellulose (EU-10, Ethocel Premium 10, from Dow Chemicals, 159.1 g) was slowly added to a mixture of 85/15 acetone/water (10% solids) with constant stirring until dissolved. Triethylcitrate (ten, to 15.9 g) was slowly added until dissolved. Masking of taste MV-pellets was performed in a Glatt GPCG 3 by spraying the above solution for a weight gain of 20%.

7.With the Superimposition of a layer of magnesium oxide on the pellets of propiverine by powder layering

Povidone (11.9 g) was slowly added to purified water (5% solids) while stirring until dissolved. Pellets of propiverine in Example 7.A (2000) or pellets of propiverine covered with an insulating coating from example 7.In (2000 g) were loaded into the bowl Granurex GX-35 from Vector Corporation (Iowa, USA). In rotating the substrate material with adjustable speed was sprayed a solution of povidone, while at the same time the powder (229,3 g of magnesium oxide) is sprayed into the apparatus by the device for powder layering (K-Top) with adjustable speed. Optimized parameters during powder layering: product temperature: 22-25°C; rotor speed: 300 rpm.min; external air supply: 150-320 l/min and a temperature of 100°C; pressure drop from edge to edge gap of 1-2 mm of water; spray rate of the solution - 3-5 ml/min (air through the nozzle: 20 lb/sq ft); and the rate of spraying of the powder - 5 g/min (pressure at�of the spirit of 12.5 psi ft). Pellets covered with an insulating coating by spraying the same solution of a binding agent or mortar Opandry Clear (5% solids) at an operating air volume of 70 cubic feet/min, and covered with an insulating coating with layered buffer layer pellets were dried for about 5 min to reduce the moisture content.

Ground or finely ground medicinal substance can be mixed with granular excipients, such as colloidal silica or magnesium stearate.The binding agent in an amount up to 10% may be partially mixed with powder of the drug substance and partly dissolved in the sprayed liquid. Solvents such as acetone, ethanol or a mixture) can be used in suitable for use with solvents apparatus Granurex. Can also be used an alternative binding agent such as Klucel LF, polymer. On spheronization pellets in the Granurex or for layering coatings in a fluidized bed, as disclosed in Example 6.In the above, can be applied a protective insulating coating é Clear or Klucel LF.

7.D CR-pellets of propiverine"HC1 (25% CIV/10% SV-coating)

As disclosed in Example 2.With covered with buffer pellets of propiverine in Example 7. In (900 g) was covered in a pre-heated device for layering coatings in a fluidized bed, GPCG 3, SV-�freight with 10 wt.%, including ethylcellulose (Ethocel Premium 10 SP; of 128.6 g), plasticized triethylcitrate (14.3 g), and then covered SIV-coating comprising ethylcellulose (214,3 g), hypromellose phthalate (HP-55, 107,2 g) and TES (triethylcitrate, to 35.7 g) in a ratio of 60/30/10 dissolved in 85/15 acetone/water for a weight gain of 25 wt.% in the calculation of the coated pellets.The solution of compressible coating Klucel® LF (a 7.5% solids) was sprayed on the coated CIV pellets for a weight gain of about 2 wt.%. The resulting CR-pellets for 5 minutes, dried in the apparatus for removal of residual solvent.

7.E CR-LMP propiverine HC1. 200 mg

Quickly dispersed microbeads (57,2 parts) from example 2.D, CR-pellets (of 15.6 parts) from Example 6.C and MV-pellets with the masking of the taste (of 12.8 parts) from Example 6.In mixed with pre-prepared mixture comprising other pharmaceutically acceptable ingredients, such as corrigent (part 1), sweetener (e.g., Sucralose, and 0.35 parts), additional polyplasdone (5 parts) and microcrystalline cellulose (e.g., Avicel PHI 01, 10 parts) and was pressed at 200 mg CR-LMP-tablets weighing about 1250 mg using industrial tablet press equipped with an external lubrication system: the result thus obtained LMP (dose 100 mg) can quickly disintegrate in the oral cavity, forming a homogeneous, easy-to-swallow WM�enzio, comprising coated granules and provide the expected release profile of the drug substance suitable for the dosing regimen once a day.

Specialists in this field should understand that the above procedure and composition can be appropriately modified to ensure the adequate dosage weakly basic drug substances.

1. Pharmaceutical composition comprising a plurality of particles with controlled release, where at least one of the set of particles includes:
(a) a core comprising a weakly basic drug substance or its pharmaceutically acceptable salt, where the weakly basic drug substance contains at least one nitrogen-containing fragment with RKafrom about 5 to about 14, with a solubility of at least 200 mg/ml at room temperature in aqueous solution at pH about 1.2-6.8 and a solubility of not more than about 10 mg/ml at pH 8 and above;
(b) a layer of an alkaline buffer, positioned over the core and comprising an alkaline buffer; and
(c) coating a controlled release layer located over the alkaline buffer, where the coating is a controlled release includes water-insoluble polymer,
this pharmaceutical composition also contains fast-disintegrating microgranules.

2. Pharmaceutical �omposite according to claim 1, where the specified weakly basic drug substance is selected from the group which contains analgesics, anticonvulsants, anticholinergics, anti-diabetic remedies, anti-microbial agents, antitumor agents, antiparkinsonian funds, Antirheumatic agents, cardiovascular agents, Central nervous system stimulants, agonists of dopamine receptors, antiemetics, gastrointestinal agents, psychotherapeutic agent, opioid agonists, opioid antagonists, anti-epileptic agents, histamine H2antagonists, anti-asthmatic means and skeletal muscle relaxants.

3. Pharmaceutical composition according to claim 1, further comprising at least one sealing layer comprises a hydrophilic polymer.

4. Pharmaceutical composition according to claim 3, where said at least one sealing layer separates the weakly basic drug substance and the alkaline layer of the buffer.

5. Pharmaceutical composition according to claim 1, further comprising a compressible coating, located on the specified coating controlled release.

6. Pharmaceutical composition according to claim 5, where the specified compressible coating comprises a polymer selected from the group that contains hydroxyprop�cellulose, hydroxypropyl methylcellulose, poly(vinyl acetate-vinylpyrrolidone), poly (vinyl acetate) and ethylcellulose.

7. Pharmaceutical composition according to claim 1, where the specified water-insoluble polymer is selected from the group which contains ethylcellulose, cellulose acetate, cellulose acetate-butyrate, polyvinyl acetate, neutral copolymers of methacrylic acid and methyl methacrylate and mixtures thereof.

8. Pharmaceutical composition according to claim 1, wherein the water-insoluble polymer includes ethylcellulose.

9. Pharmaceutical composition according to claim 1, where the specified coating controlled release additionally includes a plasticizer.

10. Pharmaceutical composition according to claim 8, wherein the said plasticizer is selected from the group which contains triacetin, tributyltin, triethylcitrate, acetyl-tri-n-butylnitrite, diethyl, castor oil, dibutylsebacate, monoacetylmorphine diglycerides, diacetylmorphine glycerides and mixtures thereof.

11. Pharmaceutical composition according to claim 9, where the specified plasticizer does not contain phthalates.

12. Pharmaceutical composition according to claim 3, wherein the hydrophilic polymer is selected from the group which contains hydroxypropyl cellulose, hydroxypropyl methylcellulose, copolymer of vinyl-pyrrolidone-vinyl acetate, ethylcellulose low viscosity and a mixture of hydroxypropyl cellulose and ethyl cellulose.

13. Headlights�aseptically composition according to claim 1, where specified alkaline buffer is selected from the group which contains sodium hydroxide, monolatry dihydrogen phosphate, disodium hydrogen phosphate, trinacria phosphate, sodium acetate, sodium carbonate, sodium bicarbonate, monogalia dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, potassium acetate, potassium carbonate, potassium bicarbonate, magnesium phosphate, magnesium acetate, calcium silicate, complex metasilicate magnesium-aluminum, magnesium carbonate, magnesium oxide, magnesium hydroxide, sodium silicate and mixtures thereof.

14. Pharmaceutical composition according to claim 1, wherein the ratio of said alkaline buffer to the specified weakly basic drug substance is in the range from about 5:1 to about 1:5.

15. Pharmaceutical composition according to claim 1, wherein the coating is a controlled release additionally includes a water soluble polymer.

16. Pharmaceutical composition according to claim 15, where the specified water-soluble polymer is selected from the group which contains povidone, polyethylene glycol, hydroxypropyl methylcellulose and hydroxypropyl cellulose.

17. Pharmaceutical composition according to claim 15, where the ratio of said water-insoluble polymer to a specified water-soluble polymer is in the range from about 95:5 to about 50:50.

18. Pharmaceutical composition according to claim 1, where the specified coating controlled release additional�about includes the enteric polymer.

19. Pharmaceutical composition according to claim 18, where specified the enteric polymer is selected from the group which contains hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, pH sensitive copolymers of methacrylic acid and methylmethacrylate, shellac and mixtures thereof.

20. Pharmaceutical composition according to claim 18, where the ratio of said water-insoluble polymer to a specified enteric polymer is in the range from about 9:1 to about 1:3.

21. Pharmaceutical composition according to claim 1, further comprising providing the outer lag time of coating, located above the specified coating controlled release.

22. Pharmaceutical composition according to claim 21, where the outer providing a lag time coating comprises a water-insoluble polymer in combination with an enteric polymer at a ratio of the specified water-insoluble polymer to the specified the enteric polymer in the range of about 9:1 to about 1:3.

23. Pharmaceutical composition according to claim 22, where the specified water-insoluble polymer is selected from the group which contains ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral copolymers of metacrilato� acid and methyl methacrylate and mixtures thereof, and the enteric polymer is selected from the group which contains hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, pH sensitive copolymers of methacrylic acid and methylmethacrylate, shellac and mixtures thereof.

24. Pharmaceutical composition according to claim 22, where the specified water-insoluble polymer is ethylcellulose, and the enteric polymer is hydroxypropylmethylcellulose phthalate.

25. Pharmaceutical composition according to claim 1, wherein the core comprises an inert bead coated with a medicinal substance, comprising the weakly basic drug substance.

26. Pharmaceutical composition according to claim 25, where the specified inert granule includes sugar, microcrystalline cellulose, mannitol-microcrystalline cellulose or silicon dioxide.

27. Pharmaceutical composition according to claim 1, where the specified core has an average particle size of not more than about 400 microns.

28. Pharmaceutical composition according to claim 25, where the specified medicinal substance layer further includes a polymeric binding agent.

29. Pharmaceutical composition according to claim 28, where the specified polymer binder is selected from the group which contains hydroxypropyl cellulose, povidone, methylcellulose, HYDR�nsiproperties, carboximetilzellulozu, polyethylene oxide, starch, and polysaccharide.

30. Pharmaceutical composition according to claim 28, where the ratio of the specified medicinal substance to a specified polymer binding substance is in the range from about 85:15 to about 100:0.

31. Pharmaceutical composition according to claim 1, where said layer of alkaline buffer additionally includes a polymeric binding agent.

32. Pharmaceutical composition according to claim 31, where the specified polymer binder is selected from the group which contains hydroxypropyl cellulose, povidone, methylcellulose, hydroxypropyl methylcellulose, carboximetilzellulozu, polyethylene oxide, starch, and polysaccharide.

33. Pharmaceutical composition according to claim 1, wherein the fast-disintegrating pellets include saccharide and/or sugar alcohol in combination with baking powder.

34. Pharmaceutical composition according to claim 33, where
the specified disintegrant is selected from the group which contains copovidone, sodium chromalveolata, crosslinked sodium carboxymethylcellulose and hydroxypropyl cellulose with a low degree of substitution;
the specified saccharide and/or sugar alcohol is selected from the group which contains the energy, lactose, sucrose, maltose, mannitol, sorbitol, xylitol, maltitol, and mixtures thereof;
the ratio of the specified disintegrant to the specified saccharide and/or sugar alcohol at�situated in the range from about 10:90 to about 1:99.

35. Pharmaceutical composition according to claim 33, where the specified disintegrant, and specified a sugar alcohol and/or the said disaccharide is present in the form of microparticles having an average particle size of about 30 μm or less.

36. Pharmaceutical composition according to claim 33, where the ratio of these particles with controlled release to the instant granules is in the range from about 1:6 to about 1:2.

37. Pharmaceutical dosage form comprising the composition according to claim 1.

38. Pharmaceutical dosage form comprising the composition according to claim 15.

39. Pharmaceutical dosage form comprising the composition according to claim 18.

40. Pharmaceutical dosage form comprising the composition according to claim 21.

41. Pharmaceutical dosage form according to claim 37, where the specified dosage form is a capsule.

42. Pharmaceutical dosage form according to claim 37 in the form of a pill.

43. Pharmaceutical dosage form according to claim 33, where the specified dosage form is an orally disintegrating tablet.

44. Pharmaceutical dosage form according to claim 43, where the specified orally disintegrating tablet disintegrates within about 30 seconds after contact with saliva in the oral cavity or with simulated salivary fluid.

45. Pharmaceutical dosage form according to claim 37, d�effector comprising particles with an instant release, which include a core comprising a weakly basic drug substance.

46. Pharmaceutical dosage form according to claim 45, where the ratio of these particles with an instant release of these particles with controlled release is in the range from about 0:100 to about 50:50.

47. Pharmaceutical dosage form according to claim 45, where said particles with an instant release release at least about 85% of the drug contained in the specified particle with an instant release, within 15 minutes when tested for dissolution in the Device 1 according to the US Pharmacopoeia (baskets at 100 rpm) or Apparatus 2 (the blade at 50 rpm) in 900 ml of 0.1 n HCl at 37°C.

48. Pharmaceutical dosage form according to claim 38, further comprising particles with an instant release, where each particle with an instant release includes a core comprising a weakly basic drug substance.

49. Pharmaceutical dosage form according to claim 48, where said particles with an instant release release at least about 85% of the drug contained in the specified particle with an instant release, within 15 minutes when tested for dissolution in the Device 1 according to the US Pharmacopoeia (baskets at 100 rpm) or Apparatus 2 (the blade at 50 rpm) in 900 ml of 0.1 n HCl at 37°C.

5. Pharmaceutical dosage form according to claim 48, where the ratio of these particles with an instant release of these particles with controlled release is in the range from about 0:100 to about 50:50.

51. Pharmaceutical dosage form according to claim 39, further comprising particles with an instant release, where each particle with an instant release includes a core comprising a weakly basic drug substance.

52. Pharmaceutical dosage form according to claim 51, where the ratio of these particles with an instant release of these particles with controlled release is in the range from about 0:100 to about 50:50.

53. Pharmaceutical dosage form according to claim 51, where said particles with an instant release release at least about 85% of the weakly basic drug substance contained therein within 15 minutes when tested for dissolution in the Device 1 according to the US Pharmacopoeia (baskets at 100 rpm) or Apparatus 2 (the blade at 50 rpm) in 900 ml of 0.1 n HCl at 37°C.

54. Pharmaceutical dosage form according to claim 37, further comprising a second set of particles with controlled release, where each particle with controlled release include:
(a) a second core comprising the weakly basic drug substance;
(b) second �Loy alkaline buffer located on the second core and comprising an alkaline buffer;
(c) a second coating of controlled release, located above the second layer of an alkaline buffer, where the second coating controlled release includes water-insoluble polymer and the enteric polymer.

55. Pharmaceutical dosage form according to claim 38, further comprising a second set of particles with controlled release, where each particle of the second sphere includes:
(a) a second core comprising the weakly basic drug substance, and a second layer of an alkaline buffer, located on the second core and comprising an alkaline buffer;
(b) a second coating of the controlled release layer located over the second alkaline buffer, where the second coating controlled release includes water-insoluble polymer and optionally a water soluble or enteric polymer.

56. Pharmaceutical dosage form according to claim 55, where each of the coatings controlled release of the first and second sets of particles with controlled release includes water-insoluble polymer and the enteric polymer, and where two sets of particles with controlled release have different lag times.

57. A method of manufacturing a pharmaceutical comp�posture, containing many particles with controlled release, in which:
(a) make the core comprising a weakly basic drug substance;
(b) covering a core containing a medicinal substance, stage (a) a layer comprising an alkaline buffer; and
(c) covering the core with a layered alkaline buffer stage (b) layer with controlled release comprising a water-insoluble polymer.

58. A method according to claim 57, where in step (a) further applied the sealing layer comprises a hydrophilic polymer

59. A method according to claim 57, where the specified stage (a) carry out the layering on inert pellet of solutions containing the indicated weakly basic drug substance and, optionally, a polymeric binding agent.

60. A method according to claim 57, where said layer of controlled release at a specified stage (C) additionally includes a water soluble polymer or enteric polymer.

61. A method according to claim 57, which further perform the specified coating of the second layer of microparticles with controlled release comprising a water-insoluble polymer and optionally a water-soluble polymer or enteric polymer.

62. A method according to claim 57, further comprising stages on which:
(d) mixed particles with bystromenyayuschimsya granules comprising a saccharide and/or sakaryspor in combination with disintegrants, and, thus, form the mixture for compaction; and
(e) extrude this mixture for pressing in orally disintegrating tablet.

63. A method according to claim 57, further comprising stages on which:
(d) mixed particles with particles with an instant release, which include a core containing a weakly basic drug substance, and quickly dispersed granules comprising a saccharide and/or sugar alcohol in combination with disintegrants, and, thus, form the mixture for compaction;
(e) extrude this mixture for pressing in oral-disintegrating tablet,
where said particles with an instant release and particles with controlled release have different release rate.

64. A method according to claim 57, further comprising stages on which:
(d) mixed particles with particles with an instant release, which include a core containing a weakly basic drug substance, and quickly dispersed granules comprising a saccharide and/or sugar alcohol in combination with disintegrants, and, thus, form the mixture for compaction;
(e) extrude this mixture for pressing in oral-disintegrating tablet,
where said layer of controlled release in step (C) further includes the enteric polymer, and where said particles � instant release and these particles with controlled release have different lag times.

65. A method of manufacturing a pharmaceutical dosage form, wherein the capsule fill microparticles according to claim 1.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to producing drug preparations, namely represents a process of producing microcapsules of the antiseptic Dorogov's stimulator (ADS fraction 2). The process of microencapsulation represents a method of a non-solvent addition; a microcapsule coating is kappa-carageenan, while a core is the ADS fraction 2.

EFFECT: implementing the invention provides simplifying and accelerating the process of microencapsulation, reduces the microencapsulation loss (higher weight yield).

1 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of invention refers to medicine, namely to oncology, and can be used in treating cancer in a patient. The method involves administering at least one encapsulated chemotherapeutic agent, and at least one amphiphilic block copolymer in this patient. What is also presented is a composition, a kit for treating cancer in the patient and using the amphiphilic block copolymer.

EFFECT: group of inventions provides potentiating the encapsulated chemotherapeutic agent by stimulating the active chemotherapeutic agent release from liposomes by the use of the amphiphilic block copolymer, which is poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer, in the composition.

10 cl, 11 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

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EFFECT: developing the method for ensuring the uniform dissolution profile of the pharmaceutical composition.

53 cl, 6 ex, 5 dwg, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to field of microcapsulation of heterocyclic compounds of triazine series, applied in pharmaceutical industry and agriculture as pesticides. Method of obtaining microcapsules includes physical-chemical method of precipitation with non-solvent with application of polyvinyl alcohol as microcapsule envelope. Carbinol and acetone are used as non-solvent. Preparation E 472c is used as emulsifier.

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3 ex

FIELD: chemistry.

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EFFECT: simple and faster process of producing microcapsules and higher mass output.

2 ex

FIELD: chemistry.

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3 dwg, 3 ex

FIELD: chemistry.

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EFFECT: simple and faster process of producing microcapsules and higher mass output.

2 ex

FIELD: chemistry.

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FIELD: chemistry.

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3 dwg, 3 ex

FIELD: medicine, pharmaceutics.

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22 cl, 5 ex

FIELD: medicine.

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11 cl, 3 tbl

FIELD: chemistry.

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EFFECT: obtained solid medication forms satisfy the requirements of the State Pharmacopoeia.

7 cl, 2 dwg, 3 tbl, 14 ex

FIELD: medicine, pharmaceutics.

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EFFECT: pharmaceutical composition according to the invention is storage-stable and releases the active substance quickly in the gastrointestinal tract.

10 cl, 9 tbl, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claim describes a standard solid dosage form for oral administration which represents a mini-tablet having a core and an outer coating, wherein the core contains a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt, while the outer coating represents a film coating containing a taste masking material specified in polyacrylates, and/or a release modifying ingredient of the coating specified in cellulose derivatives and acryl copolymers, and a mixture thereof. The above mini-tablet has a size of 1 mm to 4 mm and contains aliskiren in an amount making 2 mg/tablet to 4 mg/tablet. The oral solid dosage form is preferentially applied in paediatrics.

EFFECT: according to the invention, the dosage form of aliskiren can be dosed and possesses a taste that makes it applicable for children, and maintains a biological availability at a level comparable to that of the available medicinal product for adults.

19 cl, 13 dwg, 5 tbl, 3 ex

FIELD: chemistry.

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EFFECT: invention provides fast disintegration of the compositions in a medium with different pH (less than 30 minutes) and satisfactory characteristics of the anti-moisture barrier.

18 cl, 1 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of modifying envelopes of polyelectrolyte capsules with magnetite nanoparticles. The disclosed method involves producing a container matrix in form of porous calcium carbonate microparticles, forming envelopes of polyelectrolyte capsules by successive adsorption of polyallyl amine and polystyrene sulphonate and modifying with magnetite nanoparticles on the surface of the container matrix or after dissolving the matrix through synthesis of magnetite nanoparticles via chemical condensation.

EFFECT: invention enables to obtain modified polyelectrolyte capsules, designed to deliver medicinal substances which do not harm the human body.

3 cl, 4 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention is aimed at pharmaceutical compositions and methods of producing such compositions, where compositions include combination of particles with synchronised impulse release (SIR-particles) and particles with fast release (FR-particles). Each SIR-particle includes core, covered with SIR-layer; core includes weakly basic poorly soluble medicinal substance and pharmaceutically acceptable organic acid, which are separated from each other by layer with delayed release. Each FR-particle includes granule, which contains weakly basic poorly soluble medicinal substance, pharmaceutically acceptable binding substance, at least, one auxiliary substance and, at least, one backing powder. As organic acid, fumaric acid is preferably applied. FR-granules are conjoined with SIR-granules in single pharmaceutical formula, for example, in capsule.

EFFECT: medical form by invention has improved profile of release of weakly basic poorly soluble medicinal substances and is suitable for oral introduction once per day.

32 cl, 11 dwg, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and concerns a solid dosage form containing azithromycin dihydrate as an active substance in the amount of 83.2-93.2% and pharmaceutically acceptable target additives. A tablet core is film-coated in the amount of 2.5-5.0% of tablet weight. The new dosage form of azithromycin contains the high absolute (1000 mg) and relative (88.2%) concentration of the active substance that enables reaching the immediate therapeutic effect.

EFFECT: therapeutic preparation is storage-stable and complies with the Pharmacopoeia requirements.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmacology, and concerns solid dosage forms of taurine. The dosage forms are applicable in treating type I and II diabetes mellitus, cardiovascular insufficiency and hepatobilliary systems. The dosage forms of taurine contain pharmaceutically acceptable carriers, excipients and additives differing by the fact that such forms have an external coating; as taurine promotors, they contain potassium chloride and N-vinylpyrrolidone copolymer.

EFFECT: solid dosage forms possess the improved pharmacological properties and improved efficacy in cardiovascular insufficiency, diabetes mellitus and hepatobilliary systems.

5 cl, 6 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a solid oral pharmaceutical formulation containing a hydrolised form of 5-chloro-M-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide in the amount of 1 to 60%. The formulation contains sodium lauryl sulphate as a wetting agent and hydroxypropylmethyl cellulose as a hydrophilic binding agent. The pharmaceutical formulation is presented in the form of a tablet.

EFFECT: formulation according to the invention provides higher biological availability of the active ingredient.

17 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: therapeutic agent contains anastrozole, poly(lactic-co-glycolic acid), polyvinyl alcohol and D-mannitol. The therapeutic agent represents sub-micron particles and can be presented in the form of capsules, granules, powder, as well as a suspension for injections.

EFFECT: using the developed therapeutic agent enables achieving the therapeutic effect with lower therapeutic doses and making the antitumour therapy more comfortable for the patient.

2 cl, 1 tbl, 2 dwg, 3 ex

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