Pellet in enterosoluble shell, including ixabepilone, and method of its obtainment

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention claims pellet with enterosoluble shell, including ixabepilone with structure (A). Also a capsule containing multiple pellets with enterosoluble shell is claimed. Pellet includes particle with coating, containing main particle and active component layer distributed completely or partially on or in the main particle. Active component layer includes ixabepilone of structure (A) and binding agent. In addition, versions of obtaining pellet with enterosoluble shell are claimed.

EFFECT: reduced or prevented ixabepilone powder flaking, possible oral administration of ixabepilone without combined acid-neutralising buffer administration.

14 cl, 4 tbl, 3 ex

 

The SCOPE TO WHICH the INVENTION RELATES.

This invention in General relates to a granule covered intersolubility shell containing ixabepilone. There is also a method of preparation of this granule covered intersolubility shell. There is also a method of treating cancer or other proliferative diseases with the use of pellets coated with intersolubility shell.

BACKGROUND of INVENTION

Ixabepilone is a macrocyclic compound having the following structure:

Ixabepilone shows the effect of stabilizing micro canals, like Taxol TAXOL®and therefore possesses cytotoxic activity against rapidly proliferating cells, such as those formed with cancer and other hyperproliferative cellular disease (see Angew. Chem. Int. Ed. Engl., Vol.35, No. 13/14, 1996 and D.M.Bollag, Exp. Opin. Invest. Drugs, 6 (7): 867-873, 1997).

However, before ixabepilone can be used to treat diseases in patients, based on it must be obtained pharmaceutical composition that can be administered to the patient, for example, in the form of a dosage form suitable for oral administration, injection through the mucous membrane (for example by nasal, sublingual, vaginal, buccal, or rectal), a pair of Teroldego (for example, subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration. Especially preferred are formulations for oral administration, as they are more convenient and easy to enter than other formulations. In addition, the oral route of administration avoids the pain and discomfort inherent in parenteral introduction. Patients also prefer oral administration, it leads to better tolerance by the patient schemes medication.

Oral administration includes the passage of ixabepilone through the stomach, where it is exposed to gastric fluids with low pH and then enters the small intestine, where ixabepilone absorbed by the blood stream. The time of passage through the stomach is approximately two hours. The pH in the stomach is approximately 1-3. The small intestine consists of the duodenum, skinny intestine and terminal ileum, the pH in these areas ranges from about 5 to about 7.2. However, ixabepilone labile in acidic environment with maximum stability in aqueous solution in the range of pH between 7 and 8.5. Thus, ixabepilone subject to decomposition, decay or deactivation in aqueous solution, especially in acidic solutions, such as in the stomach. When administered orally, the bioavailability of ixabepilone depends on minimizing the Sabayon in acidic conditions, observed during the passage through the stomach.

In U.S. patent No. 6576651 described by way of oral administration of ixabepilone. The method includes oral introduction of ixabepilone and oral administration of one or more pharmaceutically acceptable buffers, neutralizing the acid. A buffer, neutralizing the acid may be introduced to, simultaneously with or after the introduction of ixabepilone. The described method allows delivery of ixabepilone the mammal, thus it is possible to reduce or avoid decay, decomposition or deactivation of ixabepilone in the gastrointestinal system, especially under the action of gastric fluid in the stomach. In addition, cancer patients are often forced to take other medicines, some of which may be undesirable alkaline conditions in the stomach. Therefore, the desired oral dosage form and method of oral administration of ixabepilone, which does not require neutralization of acid in the stomach.

One way to protect ixabepilone from contact with the contents of the stomach is to supply particles of ixabepilone intersolubility coating. Ixabepilone usually obtained in the form of a fine powder, and before applying Intercollege coating small particles of ixabepilone need granulation to obtain large particles containing the drug. However ixabel the n represents the active drug, and any dry process involving ixabepilone, including how dry granulation, will require special precautions in the process of getting the dosage form. For example, you may need to install containment and production equipment with special technical control to reduce or eliminate dust generated during the stages of the "dry" process. Such installation and equipment require planning and a large investment. You must create a dosage form, which may be prepared in a way that minimizes the presence of dry ixabepilone.

The wet method of obtaining granules ixabepilone with intersolubility coating can reduce or eliminate the generation of dust from the dry ixabepilone. However, ixabepilone prone to decay, decomposition or deactivation in the presence of water and/or by heating. The required wet method, in particular water-way, obtain granules containing intersolubility shell and containing ixabepilone.

In accordance with this invention provides a method of producing granules with intersolubility shell, which allows you to reduce or eliminate dusting powder ixabepilone. Additionally, there are pellet with intersolubility membrane, which is suitable for oral administration ixabel is on without joint injection buffer, neutralizing the acid.

The INVENTION

This invention relates to a granule with intersolubility envelope that includes a particle with a coating containing the primary particle and the layer of the active ingredient, located on the main part, with a layer of active ingredient contains ixabepilone or its pharmaceutically acceptable salt, MES, clathrate, hydrate or prodrug and one or more binders, as well as intersolubility coating encapsulating the particle is coated.

Also provided is a method of obtaining granules with intersolubility shell capsules containing granules with intersolubility shell, and a method of treating cancer or other proliferative diseases, including oral administration of granules with intersolubility shell to a patient in need of it.

DETAILED description of the INVENTION

Definition

In the description of this invention, the following definitions apply different terms.

The term "ixabepilone covers ixabepilone or its pharmaceutically acceptable salt, MES, clathrate, hydrate or prodrug, this term is used throughout the description.

Used in this description, the term "mainly containing no moisture" refers to compositions containing less than about 4% by weight water, preferably less than PR is about 3% by weight of water and more preferably less than about 2% by weight of water per weight of the composition. Examples of quantities that fall under the definition of "not mainly containing water includes the water content of from zero to less than approximately 4% by weight, preferably from zero to less than approximately 3% by weight and more preferably from zero to less than about 2% by weight based on the weight of the composition.

Receiving, composition and application of ixabepilone described in U.S. patent No. 6365749 B1, U.S. patent No. 6518421 B1, U.S. patent No. 6576651 B1, U.S. patent No. 6605599 B1, U.S. patent No. 6686380 B1; in the application of the U.S. patent No. 20030073677 A1, in the application of the U.S. patent No. 20040024032 A1 and in the application of the U.S. patent No. 2004026254 A1.

This invention relates to a granule with intersolubility shell containing ixabepilone which is suitable for oral administration to a patient. The pellet with intersolubility coating includes particles with a coating layer which contains the active ingredient, located on the core particle; and intersolubility coating that encapsulates the particle with the coating. The layer of the active ingredient contains ixabepilone and at least one binder. Intersolubility coating can protect ixabepilone, which has a tendency to decay, decomposition or deactivation during exposure to acidic conditions of the gastric fluids with low pH values normally encountered during passage through the stomach into the intestine. Intersolubility floor --- the but to minimize or prevent the action of the acid on the layer of the active ingredient in the stomach. This prevents ixabepilone from release in the stomach or acid in the stomach from penetration through the layer of active ingredient. When hit granules with intersolubility sheath in the small intestine intersolubility coating partially or completely dissolved in an environment with a higher pH in the intestine, which leads to the release of ixabepilone and its penetration into the blood stream of the patient.

The pellet with intersolubility coating contains a particle coated, encapsulated in intersolubility the floor. The particle with the coating contains the primary particle, which is embryonic particle for applying a layer of the active ingredient. The core particle made of a pharmaceutically acceptable material which is capable of carrying the layer of the active ingredient. Usually the particle contains, for example, pharmaceutically inert material such as, for example, sugar, starch, microcrystalline cellulose, lactose or a combination thereof. The core particle may also contain one or more active ingredients. Main particle usually has a spherical or hemispherical shape, although other shapes. The average diameters of the core particles are typically in the range from about 0.1 mm to about 5 mm Examples of suitable core particles include Nu-Pareil™ Sugar Spheres NF (Chr. Hansen, Inc., WI), Celhere™ representing the sphere of microcrystalline cellulose (Asahi Kasei Kogyo Kabushiki Kaisha a Corp., Japan). Usually the pellet with intersolubility shell contains, for example, from about 10 to about 80 wt.% primary particles, preferably from about 15 to about 70 wt.% the primary particles, and more preferably from about 20 to about 65 wt.% the primary particles based on the weight of the granules with intersolubility shell. Preferably, the primary particle mainly contains no moisture. More preferably, the primary particle contains less than 3 wt.% water based on the weight of the primary particles.

A particle with a coating layer contains an active ingredient that is located on the primary particle. The layer of active ingredient is applied to the core particle and may form the surface layer on the surface of primary particles, absorbed the core particle, or may occur and that, and another. The layer of the active ingredient may be fully or partially distributed, and/or under the surface of the core particles. Preferably, the layer of the active ingredient evenly arranged on the surface of the primary particles.

The layer of the active ingredient contains ixabepilone or its pharmaceutically acceptable salt, MES, clathrate, hydrate and its prodrug. In addition ixabepilone layer of the active ingredient can be the t contain at least one additional active agent, such as anticancer agent. One of the options layer of the active ingredient may contain a mixture of ixabepilone and its pharmaceutically acceptable salts, MES, clathrate, hydrate or prodrug. For example, a layer of active ingredient can include a mixture of ixabepilone and clathrate of ixabepilone. The appropriate number of ixabepilone include, for example, a number in the range from about 0.1 wt.% up to about 10 wt.%, preferably from about 0.2 wt.% to about 5 wt.% and more preferably from about 0.5 wt.% to about 4 wt.% based on the weight of the granules with intersolubility shell.

The layer of the active ingredient also contains a binder. A binder can be applied to improve the adhesion of ixabepilone to the core particle and/or to ensure the cohesion of the layer of the active ingredient. Materials suitable as the binder include, for example, starch, gelatin, sugars such as sucrose, glucose, dextrose, molassy, lactose; natural and synthetic resins, such as resin acacia, sodium alginate, methylcellulose, carboxymethylcellulose and polyvinylpyrrolidone (PVP) and copolymers of vinylpyrrolidone such as polyvinylpyrrolidone/polyvinyl acetate (PVP-PVA); cellulose, such as ethylcellulose, hydroxypropylcellulose or hypromellose; the polyethylene glycol and waxes. For example, the approach is the following commercially available materials include cellulose crystalline materials Avicel PH 101, Avicel RC 591 and Avical™ CL 611 (FMC Corp., PA). In the layer of the active ingredient can be applied to one or more different binders. One or more of the possible ingredients that can be included in a layer of active ingredient, are, for example, buffers, anti-foam agents and plasticizers. The pellet with intersolubility shell can contain, for example, from about 2 to about 80 wt.% a layer of active ingredient, preferably from about 10 to about 70 wt.% layer the active ingredient and more preferably from about 20 to about 60 wt.% a layer of active ingredient based on the weight of the granules with intersolubility shell. Preferably, the layer of the active ingredient basically did not contain moisture.

The pellet with intersolubility shell has intersolubility floor, in which the encapsulated particle is coated. Intersolubility coating is insoluble or has low solubility in acidic solutions, characteristic of gastric fluids encountered in the stomach, the pH-value of less than about 3. At higher pH value, such that occurs in the small intestine, intersolubility shell dissolves, leading to the release of ixabepilone. Examples of the higher pH values observed in the small intestine include the value of R is more than about 4.5, preferably more than about 5 and most preferably, the pH was in the range of from about 5 to about 7.2.

Suitable materials for education intersolubility membranes include, for example, polymers to obtain intersolubility coatings, such as, for example, hydroxypropylmethylcellulose phthalate, polyvinylacetate, acetated cellulose, copolymers of acrylic acid, acetylsuccinate hydroxypropylmethylcellulose and copolymers of methacrylic acid. One example of suitable copolymers of methacrylic acid is Eudragit™ L-30-D 55 in the form of an aqueous dispersion of the copolymer, which is an anionic copolymer derived from methacrylic acid and ethyl acrylate with a ratio of free carboxyl groups to the ethyl ester groups of approximately 1:1, and with an average molecular weight equal to approximately 250000, and comes in the form of an aqueous dispersion containing 30% by weight solids. Aqueous dispersion of a copolymer Eudragit™ L-30-D 55 comes Röhm-Pharma Co., Germany.

The pellet with intersolubility shell can contain, for example, from about 5 to about 55 wt.% Intercollege coating, preferably from about 10 to about 45 wt.% Intercollege coating, and more preferably from about 15 to about 40 wt.% enterocoelous the high coverage based on the weight intersolubility shell. Preferably, intersolubility coverage basically does not contain moisture.

Intersolubility coating may contain other materials such as plasticizers, dyes, anti-foam agents, and agents that prevent adhesion. The pellet with intersolubility coating may contain one or more sublayers, which are located between the primary particle and the layer of the active ingredient or the layer of the active ingredient and intersolubility shell. The sublayer can be used to minimize contact between ixabepilone contained in the layer of the active ingredient, and intersolubility coating containing acid groups, for example, methacrylic acid copolymer. For example, the granule with intersolubility shell can contain from about 0.1 to about 10 wt.% sublayer, preferably from about 0.5 to about 5 wt.% sublayer and more preferably from about 2 to about 4 wt.% substrate based on the weight of the granules with intersolubility shell. Suitable materials for the substrate include starch, gelatin, sugars such as sucrose, glucose, dextrose, molasse and lactose; natural and synthetic resins, such as resin acacia, sodium alginate, methyl cellulose, carboxymethyl cellulose, and polymers and copolymers of vinylpyrrolidone (PVP), such as copolymers of PVP-PA; cellulose, such as ethylcellulose, hydroxypropylcellulose and hypromellose; the polyethylene glycol and waxes. The underlayer may also contain one or more plasticizers, such as polyethylene glycol, propylene glycol, triethylcitrate, triacetin, diethylphthalate, tributylamine or combinations thereof.

One of the options pellet with intersolubility shell contains sub-layer located between the layer of the active ingredient and intersolubility coating. In this embodiment, the granule with intersolubility shell can contain from about 0.1 to about 10 wt.% sublayer, preferably from about 0.5 to about 5 wt.% sublayer and, more preferably, from about 2 to about 4 wt.% substrate based on the weight of the granules with intersolubility shell. Preferably, the sublayer essentially does not contain moisture.

The pellet with intersolubility shell may contain other components such as fragrances, preservatives and dyes, if it is necessary or desirable.

One of the options, without limiting the invention, the granule with intersolubility coating essentially does not contain moisture. Preferably, the granule with intersolubility coating contains less than about 4 wt.% water, preferably less than about 3 wt.% water and more prefer the LNO less than 2 wt.% water based on the weight of the granules with intersolubility shell.

The pellet with intersolubility membrane may be contacted with a hydrophobic material such as talc, magnesium stearate or colloidal silicon dioxide, to form a hydrophobic layer on the surface of the granules with intersolubility shell. The hydrophobic layer is needed to reduce agglomeration of the individual granules with intersolubility shell and/or to reduce static electricity during handling of the granules with intersolubility shell.

One variant of the invention the granule with intersolubility shell contains a particle with coating and intersolubility coating encapsulating the particle is coated.

According to another variant of the invention the granule with intersolubility shell contains: a particle with a coating comprising a primary particle sublayer located on the core particle, and a layer of active ingredient, located on the sublayer, and intersolubility shell that encapsulates the particle is coated.

By the third variant of the invention the granule with intersolubility shell includes: a particle with a coating sublayer located on the particle surface, and intersolubility floor, in which the encapsulated particle is coated.

According to the fourth variant of the invention the granule with intersolubility coating includes: a particle with a coating, sotiriadou the core particle, the first sublayer located on the core particle, and a layer of active ingredient, located at this sublayer, the second sublayer located on the particle surface, and intersolubility floor, in which the encapsulated particle is coated.

According to the fifth variant of the invention the pellet containing intersolubility floor, includes: a particle with a coating, in which the core particle contains a second pharmaceutically active ingredient, intersolubility floor, in which the encapsulated particle is coated.

The pellet with intersolubility sheath according to the invention may contain the first sublayer located between the primary particle and the layer of the active ingredient, and a second sublayer located between particle coated and intersolubility coating. Second pharmaceutically active ingredient may be ixabepilone or pharmaceutically active salt, MES, clathrate, hydrate or prodrug. Or the second pharmaceutically active ingredient may be another active agent such as a second anti-cancer agent.

Granules with intersolubility shell can be obtained in a way that reduced the influence of moisture, heat or a combination of moisture and heat on ixabepilone. This method provides high activity and good uniformity sports the pharmaceutical agent, as ixabepilone prone to decay, decomposition in the presence of water and especially the combination of moisture and heat.

One aspect of this invention provides a method of producing granules with intersolubility shell, including:

a) obtaining a core particle;

b) applying the mixture of the active ingredient and a binder on the core particles, the mixture based on the active ingredient contains:

i) ixabepilone or its pharmaceutically acceptable salt, MES, clathrate, hydrate or prodrug and

ii) a solvent, water or a mixture thereof;

C) drying the core particles, which caused the mixture on the basis of active ingredient order to obtain particles coated and

g) applying Intercollege coating on the particles coated with the aim of producing granules with intersolubility shell.

According to the method of producing granules with intersolubility membrane in this invention the mixture on the basis of active ingredient may also contain a binder that allows the joint application of the same mixture. Or a mixture of the active ingredient and a solution containing a binder that can be pre-mixed immediately before application. A mixture on the basis of active ingredient contains ixabepilone in solvent, water or mixtures thereof. A mixture on the basis of active ingredient may submit, the better a solution, containing ixabepilone dissolved in the solvent, water or mixtures thereof. Or a mixture on the basis of active ingredient may be a suspension of the active agent containing particles of ixabepilone dispersed in solvent, water or mixtures thereof.

Suitable solvents include, for example, alcohols such as methanol, ethanol, n-propanol and isopropanol, and acetone. A mixture on the basis of active ingredient can be prepared by mixing ixabepilone with the solvent, water or mixtures thereof. In the mixture based on the active ingredient can be included binder. Ixabepilone and possible binding can be connected in any order with the solvent, water or mixtures thereof. Typically requires mixing to minimize any localized concentrations of ixabepilone or potential binder in the solvent, water or mixtures thereof. The mixing may be performed using a mechanical device, such as magnetic or outboard mixer.

One of the options pellet with intersolubility coating according to this invention is obtained by applying a suspension of the active ingredient and a binder on the core particles. Preferably, the suspension of the active ingredient was water suspension of active ingredient containing particles of ixabepilone dispersed in the aquatic environment. Water is the ed contains more than about 50 wt.% water and perhaps one or more miscible with water solvent based on the weight of the water environment.

Preferably, the aqueous medium containing at least about 65 wt.% water, more preferably at least about 75 wt.% water and most preferably at least about 85 wt.% water based on the weight of the water environment. Aqueous suspension of particles of ixabepilone reduces contact between the aqueous medium and ixabepilone compared with a solution of ixabepilone and thus reduces the rate of decay or decomposition ixabepilone. Aqueous suspension of the active ingredient can be prepared by mixing particles of ixabepilone and possibly a binder in water and possibly mixing with the water solvent. Particles ixabepilone and potential binders can be combined with water and/or with possible mixing with the water solvent in any order. Typically, for a dispersion of particles of ixabepilone and minimize any localized concentrations of particles ixabepilone or possible binding requires mixing. Suitable particle sizes of ixabepilone comprise, for example, less than approximately 1000 microns, preferably less than about 500 microns and more preferably less than about 250 microns. Particles ixabepilone can be amorphous or crystalline. Preferred and are crystalline particles ixabepilone. Examples of the crystalline forms of ixabepilone, such as Form a or Form B, described in U.S. patent No. 6689802. Suspension of the active ingredient may contain from about 1 to about 50 wt.% particles ixabepilone, preferably from about 2 to about 30 wt.% particles ixabepilone and more preferably from about 3 to about 20 wt.% particles ixabepilone based on the weight of the suspension of the active ingredient. Preferably, the pH of the suspensions of the active ingredient was in the range of from about 6 to about 9, more preferably in the range from about 6.5 to about 8 and most preferably in the range from about 6.5 to about 7.5. Suspension of the active ingredient may contain other components such as buffering agents, dispersing agents such as surfactants or low molecular weight polymers, anti-foam agents, and agents that regulate the pH value, such as acids and bases.

A binder may be in the form of a solution or dispersion in water.

One of the options the mixture on the basis of active ingredient may contain, for example, from about 1 to about 30 wt.% at least one binder, preferably from about 2 to about 20 wt.% at least one binder, or more preferably from about 3 to about 10 wt.% at the ore one binder based on the weight of the mixture based on the active ingredient.

The mixture is based on the active ingredient and the binder solution can be deposited on the core particles using a spray or stream of basic particles in motion. Preferably, the conditions were under control to minimize the agglomeration of the core particles. The solvent and/or water is then removed from the mixture on the basis of active ingredient to obtain particles with a coating containing layer of the active ingredient, located on the core particles.

Intersolubility the coating can be applied to particles with a coating by applying a composition for Intercollege coating in the form of a spray or stream on the motion of the particle is coated. Mixture to obtain Intercollege coating may be a solution or suspension. It is preferable to control the process conditions in order to minimize agglomeration of the particles. Mixture for Intercollege coating contains a material forming the coating in an aqueous or nonaqueous solvent, or mixtures thereof. Suitable solvents include, for example, alcohols such as methanol and isopropanol, and acetone. Can be applied to the mixture of solvents or a mixture of water and one or more miscible with water solvents.

The material forming intersolubility floor, can be dissolved in p is storytale with obtaining a solution or may be in the form of a dispersion of particles to obtain a suspension, such as aqueous dispersion of a copolymer. Usually the mixture for Intercollege coating may contain, for example, from about 5 to about 50 wt.% the material forming intersolubility coating, and preferably from about 10 to about 40 wt.% the material forming intersolubility floor, based on the weight of the mixture for Intercollege coverage.

During and/or after applying for Intercollege coating can be applied to drying to remove solvent. By one of the following drying conditions include the temperature of the drying air at the inlet equal to from about 20°With up to about 70°C, the relative humidity of the inlet air is less than approximately 50%, the temperature of the layer of product, in the range of about 20°With up to about 40°and applying a flow of air sufficient to remove a pair of free water.

For spraying suspensions of the active agent in the core particles and/or for spraying the mixture for Intercollege coating on the particles with the coating can be used in devices for spraying liquid layer tangential nozzle or rotary atomizer tray-type.

The device for applying the coating liquid layer is a device, which may dilute particles, such as granules, while their location is population and drying the film coating. The dilution air is heated to the desired temperature, and air flow is fed at a speed suitable for the appropriate dilution and drying.

Bin machine for coating is a device in which particles are processed in the tray when spraying with the formation of a film coating. At the same time the air with the appropriate temperature and flow rate passes through a layer of particles for drying the applied film coating.

According to one aspect of the present invention provides a capsule containing many granules with intersolubility coating which is suitable for oral administration of ixabepilone. The capsule is produced by filling of the capsule's shell, such as shell gelatin capsules, granules with intersolubility shell. The capsule is easier to swallow oral introduction of granules with intersolubility the floor.

The capsule may include at least one hydrophobic material to reduce agglomeration of the individual granules with intersolubility coating in the capsule and/or to reduce static electricity during loading pellets with intersolubility shell in the capsule. Usually the number of such hydrophobic material is preferably maintained at a level that is sufficient to prevent adhesion part is after dissolution of the capsule's shell, but not too high to cause a slow dissolution.

Examples of suitable hydrophobic materials include talc, magnesium stearate, stearic acid, glycerinated, gidrirovannoe cottonseed oil, trimyristin, tripalmitin, tristearin and colloidal silicon dioxide. Examples of commercially available hydrophobic materials include Lubrital™ (Penwest Pharmaceutical Co., NJ), Dynasan™ 114, Dynasan™ Dynasan 116 and™ 118 (Sasol North America, TX) and Compritol™ 888 ATO (Gattefosse Co., France). The preferred hydrophobic material is talc.

APPLICATION

Ixabepilone used as agent, stabilizing micro canals. Ixabepilone suitable for the treatment of various types of cancer and other proliferative diseases including, but without limitation, the following:

- carcinoma, including carcinoma of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin, including squamous cell carcinoma;

- gemopoeticescoe tumors of the lymphatic system, including leukemia, acute lymphocytic leukemia, acute lymphoblastic, lymphoma B-cell lymphoma T-cell, Hodgkin's lymphoma non-Hodgkin's lymphoma, lymphoma "hairy" cells, Burkitt's lymphoma;

- gemopoeticescoe tumor myeloid system, including acute and chronic myelogenous leukemias and promyelocytic leiko is;

- other tumors, including melanoma, seminoma, teratocarcinoma, neuroblastoma and glioma;

- tumors of the Central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and swannery;

- tumor messenging origin, including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma, and

- other tumors, including melanoma, xeroderma pigmentation, keratoakantoma, seminoma, thyroid follicular cancer cancer and teratocarcinoma.

Ixabepilone suitable for the treatment of patients who have previously undergone treatment for cancer, and those patients who were not treated for cancer. The methods and compositions according to this invention, using granules with intersolubility shell, can be used in the treatment of cancer medicines of the first row and second row. In addition, granules with intersolubility shell suitable for the treatment of refractory or resistant cancer.

Ixabepilone will inhibit the development of blood vessels, thereby affecting the growth of tumors and providing treatment of tumors and disorders associated with tumors. These properties are useful in the treatment of other conditions that respond to the action of agents that prevent the development of blood vessels, including, but not limited to, certain forms of blindness related to retinal neoplasm of blood from the vessels, arthritis, especially inflammatory arthritis, multiple sclerosis, restenosis, and psoriasis.

Ixabepilone induces or inhibits apoptosis, a physiological process of cell death is critical for normal development and homeostasis.

Changes in apoptotic pathways involved in the pathogenesis of various diseases in humans. The claimed compounds as modulators of apoptosis useful in the treatment of various diseases in people with aberration of apoptosis, including, but without limitation, cancer and precancerous disorders, diseases associated with immune response, viral infections, kidney diseases, and degenerative diseases of the musculoskeletal system.

Granules with intersolubility shell can be together or be administered in conjunction with other therapeutic agents that are selected for their acceptability in the treatment of the above conditions. Granules with intersolubility shell can be combined with agents to prevent nausea, hypersensitivity and irritation of the stomach, such as anti-emetics and H1and H2-antihistamines. The above-mentioned therapeutic agents when used in combination with ixabepilone can be entered in the amounts indicated in the Physicians′ Desk Reference (PDR) or determined by the expert in this field.

In addition, granules with intersolubility blockimage to be introduced in combination with other anti-cancer and cytotoxic agents and treatments, used in the treatment of cancer or other proliferative diseases. The introduction of granules with intersolubility shell can be performed before, during or after administration of other anti-cancer agents, cytotoxic agents and/or methods of treating cancer or other proliferative diseases. Especially useful in combination with anti-cancer and cytotoxic drugs, when the selected second drug works differently or to a different phase of the cell cycle, for example, the S phase, compared to ixabepilone, which exerts its action on G2- M-phase. Examples of classes of anti-cancer and cytotoxic agents include, but without limitation, alkylating agents, such as mutiny, alkyl sulphonates, nitrosamine, ethylenimine and triazine; antimetabolites such as folate antagonists, purine analogues, and pyrimidine analogues; antibiotics such as anthracyclines, bleomycin, mitomycin, dactinomycin, and plicamycin; enzymes such as L-asparaginase; inhibitors farnesyl - protein transferase; hormonal agents such as glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens, progestins, and antagonists hormone releasing luteinizing hormone, octreotide acetate, agents that Deplete micro canals such as ecteinascidins or their analogs and derivatives; agents, stabilizing is their micro canals, such as paclitaxel (TAXOL®), docetaxel (TAXOTERE®); products of vegetable origin, such as Vinca alkaloids, epipodophyllotoxins and taxanes; topoisomerase inhibitors; inhibitors prenyl - protein transferase and mixed agents, such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, coordination complexes of platinum, such as cisplatin and carboplatin, and other agents used as anti-cancer and cytotoxic agents such as biological response modifiers, growth factors; immune modulators and monoclonal antibodies. Granules with intersolubility shell can be used in combination with radiation therapy.

Representative examples of these classes of anti-cancer and cytotoxic agents include, but without limitation, mechlorethamine hydrochloride, cyclophosphamide, chlorambucil, mephalan, ifosfamide, busulfan, carmustin, lomustin, semustine, streptozocin, thiotepa, dacarbazine, methotrexate, tioguanin, mercaptopurine, fludarabine, pentostatin, cladribine, cytarabine, fluorouracil, doxorubicin (including its salt, such as doxorubicin hydrochloride, daunorubicin, idarubitsin, neomycine sulfate, mitomycin C, actinomycin D, saracini, saframycin, chinacartimes, discodermolide, vincristine, vinblastine, vinorelbine tartrate, etoposide (vklyuchayaego salt, such as etoposide phosphate), teniposide, paclitaxel, tamoxifen, estramustine, sodium salt of estramustine phosphate, flutamide, buserelin, leuprolide, pteridine, dinnes (diynesis), levamisole, flacon, interferon, interleukins, aldesleukin, filgrastim, sargramostim, rituximab, BCG, tretinoin, irinotecan hydrochloride, betamethasone, capecitabine, gemcitabine hydrochloride, altretamin and topotek and their analogues and derivatives.

Other examples of these classes of anti-cancer and cytotoxic agents include, but without limitation, cisplatin, carboplatin, karminomitsin, aminopterin, methotrexate, methopterin, ecteinascidin 743, porfiromycin, 5-fluorouracil (5-FU), 6-mercaptopurine, gemcitabine, cytosine arabinoside, paclitaxel, doxorubicin, daunorubicin, mitotyping With, podophyllotoxin or derivatives podofillotoksina, such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leirosidin, bendectin and Larsen. Obviously, ixabepilone can be introduced in combination with specific anti-cancer and cytotoxic agents related to these classes of agents, for example, ixabepilone can be introduced in combination with any 5-FU agents and/or their prodrugs, including, but without limitation, capecitabine (XELODA®).

Other examples of anticancer and other cytotoxic agents are following the existing substances: inhibitors of cyclin-dependent kinase, such as described in the application WO 99/24416, and inhibitors prenyl - protein transferase, such as described in applications WO 97/30992 and WO 98/54966.

Not wanting to be limited to any mechanism or any morphology, expect the granules with intersolubility shell, which contain ixabepilone, can be applied also to treat conditions that are different from cancer or other proliferative diseases. Such conditions include, but without limitation, viral infections such as caused by the herpes virus, se-virus, Epstein-Bar virus Sindbis and adenovirus; autoimmune diseases such as systemic lupus erythematosus, immunopositivity glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus; neurodegenerative diseases such as Alzheimer's disease, dementia associated with AIDS′MD, Parkinson's disease, amyotrophic lateral sclerosis, pigmentary retinopathy, spinal muscular atrophy, cerebellar degeneration; AIDS; myelodysplasia syndromes; aplastic anemia, myocardial infarction associated with coronary artery disease; the impact and damage during reperfusion injury; restenosis, arrhythmia, atherosclerosis, liver disease caused by toxins or alcohol; hematologic diseases, such as chronic anemia and aplastic enemy is; degenerative diseases of the musculoskeletal system, such as osteoporosis and arthritis; rhinosinusitis sensitive to aspirin; cystic fibrosis, multiple sclerosis, kidney diseases and pain in cancer.

An effective amount of ixabepilone may be determined by the person skilled in the art, for humans in the treatment of cancer or other proliferative diseases, it is from about 1 to 500 mg/m2and may be given as a single dose or in the form of individual divided doses, for example, from 1 to 4 times a day. For example, metastasis breast cancer can be treated by a dose of 40 mg/m2ixabepilone once a day every 21 days. It should be borne in mind that the value of a specific dose and frequency of use for any particular patient may vary and depend on various factors, including metabolic stability and duration of ixabepilone, species, age, weight, General health, sex, diet of the subject and the method and time of administration, rate of excretion, combination of drugs, and severity of the particular condition.

Preferred subjects for treatment include animals, most preferably mammals, such as humans, and domestic animals such as dogs, cats, etc. subject to the above diseases.

Usually ixabepilone enter up until I get an answer from PAC is enta, for example, a decrease in tumor size, or until you reach the dose that causes toxicity. The person skilled in the art can easily determine when a response is received from the patient or the toxic dose. The usual dose of ixabepilone limited by toxicity results, but without limitation, to the appearance of fatigue, arthalgia/myalgia, anorexia, hypersensitivity, neutropenia, thrombocytopenia, or neurotoxicity.

As discussed above, the granules with intersolubility shell administered orally. The method according to this invention comprises a dosing protocols, such as taking one or two times daily. Oral administration can be daily continuously, weekly, or can be interrupted, for example, the interval between the introduction may be equal to 3-4 weeks.

One of the options daily, a dose from about 1 to about 50 mg/m2.

Alternatively a dose of from about 2 to 150 mg/m2enter weekly, for example, daily for 2 days, then in 5 days do not perform oral administration of granules with intersolubility the floor.

According to another variant, a dose equal to from about 10 to 300 mg/m2enter for a period of time equal to from about 3 to about 4 weeks, for example, 1 day, and then within 20 days not impose granules with ENT is resolubilize the floor.

EXAMPLES

Below are the following examples are not limiting, but only to illustrate the invention.

Example 1

Preparation of suspension of the active ingredient

Received a suspension of the active ingredient, representing ixabepilone [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2(2-methyl-4-thiazolyl)ethynyl]-4-Aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione. First mixed 2,783 g of Tris-powder (Tris(hydroxymethyl of aminomethane)), 500 ml of water and HCl IN obtaining 0,046 M solution of Tris buffer having a pH value equal to 8.1. Then I prepared the mixture of 43.5 g of a solution of Tris-buffer (43,5 g) and 2.5 g of powder Opadry™ Clear Coat (use, Inc., PA) as a binder. To this mixture was added 4 g of ixabepilone in the form of crystals and was stirred for about 30 min to obtain a suspension of the active ingredient. Suspension of the active ingredient was passed through a sieve of 60 mesh to remove possible agglomerates.

Obtaining particles with a coating

Particles with a coating obtained by applying a suspension of the active ingredient in the core particles. Primary particles represented the sugar granules 18/20 mesh Sugar Spheres, NF particles (Chr. Hansen, Inc., WI)) with particle diameters of more than 0.85 mm and less than 1 mm.

Suspension of the active ingredient were applied to the core particles by spraying with a device for applying a Jew in the th layer, which was used as the system Wuster spray coating. This system for coating by spraying included Aeromatic - Fielder MP - MICRO™ the device (Nitro Inc., Maryland), equipped with a nozzle for spraying (0.8 mm).

In this device was loaded to 90 g sugar granules and then pre-heated to a temperature equal to about 50°in a few minutes. Suspension of the active ingredient were applied to the core particles with the following parameters: spray rate of 1.1 g/min at a pressure atomization 1.8 bar (180 kPa), the temperature at the inlet 68°C, the temperature at the outlet 32°C, the temperature of the layer of product 32°and With the fan speed 4 m3/am In the process of applying a suspension of the active ingredient slowly stirred.

After application of the suspension of the active ingredient of the final temperature at the inlet was maintained up until the temperature of the layer of the product has not reached 40°C.

Particles obtained by coating contained a 2.75 wt.% ixabepilone based on the weight of the particles are coated.

The underlayer coating

For particles with a coating was applied sublayer. Solution the substrate was prepared by combining 5 g of powder Opadry™ Clear Coat and 95 g of water and stirring to obtain a clear solution.

In the process of applying a sublayer used the device for drawing in a liquid layer, use aleesa upon receipt of the particles with the coating. This device, which contained 80 g of the particles coated, pre-heated to a temperature equal to about 50°in a few minutes. The sublayer was applied using the coating method and the settings application and drying described above to obtain particles with a coating. During the process of applying the solution to obtain sublayer slowly stirred. After completion of the application process sublayer final temperature at the inlet was maintained up until the temperature of the layer of the product has not reached 40°C. the Obtained particles with a coating comprising a sublayer, contained about 2 wt.% substrate based on the total weight of the obtained particles is coated.

Application Intercollege coverage

Intersolubility the coating was applied on the particles with a coating containing underlayer. The solution is to get Intercollege coating was prepared by filtration of the dispersion of polymer Eudragit™ L30D55 (Röhm GmbH and Co., Darmstadt, Germany) through a sieve of 60 mesh. The dispersion polymer Eudragit™ L30D55 is an aqueous suspension containing a methacrylic acid copolymer. The filtered dispersion polymer Eudragit (200 g) was diluted to 89.5 g of water. Then this diluted dispersion polymer Eudragit was added 9 g of diethylphthalate, then 9.5 g of 1 N NaOH solution. The pH of the obtained solution for applying intersolubility shell was equal to 5.0#x000B1; 0,1.

In the process of applying Intercollege film coatings applied the same device for applying a liquid layer that upon receipt of the particles with the coating. This device, which contained 70 g of the particles coated, pre-heated to a temperature of about 50°within a few minutes. The solution for Intercollege coating was applied using the following parameters application and drying:

the tip of the nozzle 0.8 mm

the spray rate of 1.1 g/min,

pressure atomization 1.8 bar

inlet temperature 65°C

the exit temperature of 30°C

the temperature of the layer of product 30°C

the fan speed is 3.5 m3/PM

In the process of applying the solution to obtain Intercollege coating slowly stirred. After completion of the application process sublayer final temperature at the inlet was maintained up until the temperature of the layer of the product has not reached 40°C. the Obtained pellets with intersolubility membrane had an average particle diameter of 1 mm.

Table 1 lists the composition of the granules with intersolubility coating obtained in this example. In composition, the content of each ingredient specified in% (based on the total weight of the granules containing intersolubility shell.

Table 1
Ingredients% weight/weight
A. Particles coated
Sugar spheres55,49
Ixabepilone1,60
Binder1,00
Tris(hydroxymethyl)aminomethan0,10
Century Sublayer
The sublayer1,80
C. Intersolubility floor
Copolymer of methacrylic acid34,59
Diethylphthalate5,19
NaOH0,22
ONLY100,00

Example 2

Obtaining suspensions of the active ingredient

Received a suspension of the active ingredient, representing ixabepilone [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2(2-methyl-4-thiazolyl)ethynyl]-A-Aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione. First mixed 2,7832 g of Tris-powder (Tris(hydroxymethyl)aminomethane)), 484,5 g of water and 12.7 g IN HC1 with getting 0,046 M solution of Tris-buffer, and then were added 4 g of ixabepilone in the form of crystals and stirred. To this mixture was added 2.4 g of powder Opadry™ Clear Coat (use, Inc., PA) as a binder and was stirred for about 30 min to obtain a suspension of the active ingredient. Suspe is the Zia active ingredient was passed through a sieve of 60 mesh to remove agglomerates.

Obtaining particles with a coating based drugs

Particles with a coating obtained by applying a suspension of the active ingredient in the core particles. Primary particles represented granules of sugar (14/18 mesh) (Sugar Spheres, NF particles (Chr. Hansen, Inc., WI)) with particle diameters greater than 1 mm and less than 1.4 mm

Suspension of the active ingredient were applied to the core particles by spraying with a device for drawing in a liquid layer, which was used as the system Wuster spray coating. This system for coating by spraying included Aeromatic - Fielder MP - MICRO™ the device (Nitro Inc., Maryland), equipped with a nozzle for spraying (0.8 mm). The device was loaded 70 g sugar granules and then pre-heated to 30-50°C. Suspension of the active ingredient were applied to the core particles with the following parameters of application and drying:

the spray rate of 1.0 to 1.2 g/min at a pressure atomization 1.8 bar (180 kPa),

the inlet temperature of 65-70°C

the exit temperature of 28-32°C

the temperature of the layer of product 27-32°C

the fan speed of 3.8-4.2 m3/hour.

In the process of applying a suspension of the active ingredient slowly stirred. After application of the suspension of the active ingredient of the final temperature at the inlet was maintained up until the temperature of the layer of the product has not reached 38-2° C. Another alternative is the immediate continuation of the spray composition for formation of a substrate and drying at the end of the process.

The underlayer coating

For particles with a coating based medicine inflicted sublayer. Solution the substrate was prepared by mixing 8 g of powder Opadry™ Clear Coat and 92 g of water and stirring to obtain a clear solution.

In the process of applying a sublayer used the device for drawing in a liquid layer that was used to obtain particles with a coating. Particles with a coating based medicine (65 g) was heated in a device for applying to a temperature of about 30-50°C. In the process of applying a sublayer used the device for drawing in a liquid layer that was used to obtain particles with a coating. This device, which contained 80 g of the particles coated, pre-heated to a temperature equal to about 50°in a few minutes. The sublayer was applied using the coating method and the settings application and drying described above to obtain particles with a coating. During the process of applying the solution to obtain sublayer slowly stirred. After completion of the application process sublayer final temperature at the inlet was maintained up until the temperature of the layer of the product has not reached 38-42°C.

Application Intercollege coverage

Intersol is stable coating was applied on the particles with a coating, containing underlayer. The solution is to get Intercollege coating was prepared by filtration of the dispersion of polymer Eudragit™ L30D55 (Röhm GmbH and Co., Darmstadt, Germany) through a sieve of 60 mesh. The dispersion polymer Eudragit™ L30D55 is an aqueous suspension containing a methacrylic acid copolymer. The filtered dispersion polymer Eudragit (133,34 g) was diluted 55,61 g of water. Then this diluted polymer Eudragit dispersion were added 6 g of diethylphthalate and then of 5.05 g of 1 N NaOH solution. The pH of the obtained solution for applying intersolubility shell was equal to 5.0±0,1.

In the process of applying Intercollege film coatings applied the same device for applying a liquid layer that upon receipt of the particles with the coating. This device, which contained 65 g of particles with a sub-layer, pre-heated to a temperature of 30-50°C. the Solution Intercollege coating was applied using the following parameters application and drying:

the tip of the nozzle 0.8 mm

the spray rate of 1.1 g/min,

pressure atomization 1.8 bar

the inlet temperature of 65-70°C

outlet temperature 30-36°C

the temperature of the layer of product 28-32°C

the fan speed of 3.9-4.1 m3/PM

In the process of applying the solution to obtain Intercollege coating slowly stirred. After okoncane the coating solution to obtain Intercollege cover kept the temperature at the inlet equal to the final temperature until while the temperature of the product reaches 38-42°C. the Obtained pellets with intersolubility shell had the average particle diameter equal to 1.4 mm

Table 2 shows the composition of the granules with intersolubility membrane obtained in this example. The composition is indicated in wt.% each ingredient is calculated on the total weight of the granules with intersolubility shell.

/table>

Example 3

Granules with intersolubility shell containing ixabepilone received, as described below.

Table 3 shows the composition of the granules with intersolubility shell.

Table 2
Ingredients% weight/weight
A. Particles coated
Areas of sugar71,0538
Ixabepilone2,2220
Opadry Clear1,3332
Tris(hydroxymethyl)aminomethan (TV.)0,1039
1 N HCl (TV.)0,0171
Century Sublayer
Opadry Clear3,1100
C. Intersolubility floor
Methacrylic acid copolymer (Eudragit L30D55)19,0017
Diethylphthalate2,8501
1 N NaOH (TV.)0,1082
D. Adding talc
Talc0,2000
ONLY100,00
Table 3
ExamplePre-coatingThe layer of the active ingredientThe sublayerInteroperate
3.1Bufferer.Bufferer.YesYes
3.2NoBufferer.YesYes
3.3NoBufferer.NoYes
3.4.NoNebuhaler.YesYes
3.5NoNebuhaler.NoYes

All coatings were obtained on the installation Aeromatic - Fielder Type MP Micro in the liquefied layer, provided with a sprayer, sprayer, located at the bottom. Scheme coatings: download (50-90 g), the location in column (1 cm), the diameter of the nozzle for spraying (0.8 mm), pressure atomization (1.8 bar), spraying speed (0.9-1.1 g/min), fan speed (3,5-4,0 m3/HR), inlet temperature (58-72°C), so the temperature value layer (30-33° C). At the end of each stage of coating the product dried up until the temperature reached about 40°C.

The size of sugar granules was 18/20 mesh. We used the following solutions and suspensions for coating.

Preliminary buferizovannogo based coating Opadry: it was 8% (weight/weight) solution of Opadry®Clear (YS-1-19025 And 0,046 M Tris buffer (pH 8.1±0,1). Was applied to obtain gain of approximately 4%.

The sublayer based Opadry: it was 8% (weight/weight) solution of Opadry®Clear in MilliQ water. Was applied to obtain gain of approximately 4%.

Buferizovannogo coating based medicine: it was 5% (weight/weight) Opadry®Clear in 0,046 M Tris buffer (pH 8.1±0,1) contained 12% (weight/weight) of ixabepilone. Was applied to obtain gain of approximately 3.7%.

Nebuferizirovannoj coating based medicine: it was 5% (weight/weight) Opadry Clear in MilliQ water, contained 12% (weight/weight) of ixabepilone. Was applied to obtain gain of approximately 3.7%.

Intersolubility floor: it was 66,67% (weight/weight) solution of Eudragit®L30D55 (30% solids), 3% of diethylphthalate in MilliQ water, the pH of the suspension was brought to 5.0±0,1 using 1 N NaOH. Was applied to obtain gain of about 35%.

Granules with intersolubility membrane obtained in examples 3.1-3.5, were placed in test tubes from scintillation the aqueous glass and kept at 40° With over 8 weeks. Then analyzed granules with intersolubility shell method GHUR using the following conditions.

Column - UMS - Pack Pro C8, 150*4.6 mm, 3 mm S/N.

The mobile phase A: 10 mm NH4SLA in a mixture of water: acetonitrile (90:10) (NH4OAc, Sigma).

Mobile phase b: 10 mm NE4SLA in a mixture of water: acetonitrile (30:70) (CAN:EM Science).

The flow rate: 1.5 ml/min

Detection: UV at a wavelength of 240 nm.

Volume of injection: 10 ml

The rinse solution of the needle: water: acetonitrile (50:50).

The column temperature: room temperature.

Sample temperature: 4°C.

Gradient:% mobile% mobile
Time (min)Phase aPhase
0-28020
2-3680-69,520-30,5
36-5169,5-2030,5-80
51-5620-8080-20
56-718020

Diluent: acetonitrile (EM Science).

Standard solution: (0.2 mg/ml, ixabepilone, purity of 99.2%).

Standard solution was prepared by weighing ˜50.0 mg of ixabepilone, placing it in a flask with a volume of 250 ml) followed by addition of 100 ml of diluent. The mixture was treated at what travelcom for about 5 min or until the dissolution of solids.

Granules with intersolubility shell were prepared for analysis using the Tablet Process Workstation (Caliper Lifescience, Hopkinton, MA). Preparation of sample: (0.2 mg/ml).

Table 4
The results of the analysis of the pellets obtained in examples 3.1-3.5 after storage at a temperature of 40°C for 8 weeks.
ExampleDescription% remaining ixabepiloneDecayed componentsUserisloggedin components and impurities
Buferizovannogo preliminary floor
3.1Buferizovannogo coating based medicinesfor 95.22,162,54
The sublayer
Interoperate
3.2Buferizovannogo coating based medicines98,41,291,75
The sublayer
Interoperate
3.3Buferizovannogo coating based medicines94,52,442,93
Interoperate
3.4Nebuferizirovannoj coating based medicines98,51,271,74
The sublayer
Interoperate
3.5Nebuferizirovannoj coating based medicinesto 97.12,753,26
Interoperate

1. The pellet with intersolubility shell, including

a) a particle with a coating containing

i) a core particle and

ii) a layer of active ingredient, fully or partially distributed on or in the core particle, with a layer of active ingredient contains

1) a compound having the formula

or its pharmaceutically acceptable MES or hydrate and

2) at least the bottom binder and

b) intersolubility shell that encapsulates the particle is coated.

2. The pellet with intersolubility sheath according to claim 1, in which the membrane is applied on the particle coated to minimize or prevent the effects of stomach acid on the layer of the active ingredient in oral patient.

3. The pellet with intersolubility sheath according to claim 1, in which the layer of the active ingredient partially distributed under the surface of the core particles.

4. The pellet with intersolubility sheath according to claim 1, in which the binder is a starch, gelatin, sucrose, dextrose, molassy, modified dextrin, lactose, resin acacia, sodium alginate, potassium alginate, methylcellulose, hydroxyethylcellulose, hypromellose, hydroxypropylcellulose, hydroxyethyl cellulose, guar gum, xanthan resin, polyvinylpyrrolidone, copoly(vinyl pyrrolidone-vinyl acetate) or a mixture.

5. The pellet with intersolubility sheath according to claim 1, characterized in that it has a diameter ranging from 0.5 mm to 7 mm

6. A method of producing granules with intersolubility shell, comprising preparing particles with a coating, which contain a mixture on the basis of active ingredient deposited on the core particles, the mixture of the active ingredient contains a compound having the formula

or its pharmaceutically acceptable MES or hydrate in a solvent, water or mixtures thereof, possibly in the presence of a binder, and applying intersolubility shell particles coated with obtaining granules with intersolubility shell.

7. The method according to claim 6, wherein the mixture is based on the active ingredient has a pH value ranging from 6 to 9, more preferably from 6.5 to 8.

8. The method according to claim 6, wherein the mixture is based on the active ingredient further comprises a binder, which is mixed with the active ingredient to be applied on the core particles.

9. The method according to claim 6, in which the mixture on the basis of active ingredient applied to the core particles by spraying with a device for spraying liquid layer.

10. The method according to claim 9 which further includes drying the core particles with the mixture of the active ingredient with obtaining particles with a coating before applying intersolubility shell.

11. A method of producing granules of ixabepilone with intersolubility shell for oral administration by a patient, comprising preparing a mixture on the basis of active ingredient containing particles of ixabepilone with a diameter of less than 500 microns, more preferably less than 250 μm, in water, solvent, or mixture of solvent and water, contacting the core particles with a mixture on the basis of active ingredi the NTA in the presence of a binder to obtain particles with a coating, and encapsulating particles coated in intersolubility shell with obtaining granules of ixabepilone with intersolubility shell.

12. A method of producing granules of ixabepilone with intersolubility shell for oral administration by a patient, comprising preparing a mixture on the basis of active ingredient containing particles of incubation in water, solvent, or mixture of solvent and water, and the mixture is based on the active ingredient has a pH value ranging from 6 to 9, more preferably from 6.5 to 8, the contacting core particles with a mixture on the basis of active ingredient in the presence of a binder to obtain particles with a coating, and encapsulation of the particles coated in intersolubility shell with obtaining granules of ixabepilone with intersolubility shell.

13. Granules ixabepilone with intersolubility membrane obtained by the method according to any of PP-12.

14. Capsule containing many granules with intersolubility sheath according to any one of claims 1 to 5 or 13.



 

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9 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention concerns enantiomers of thiophene hydroxami acid derivatives of general formula I and their pharmaceutically acceptable salts. , where Ar is aryl or heteroaryl group selected out of thiophene, morpholine, which can be non-substituted or mono-, di- or trisubstituted by halogen, phenyl, alkyl, -O-alkyl, -OH; R1 is hydrogen, phenyl or alkyl; together with Ar-group R1 forms tetrahydronaphthaline or indane cycle; R2 is hydrogen or alkyl; and their pharmaceutically acceptable salts.

EFFECT: application as histondesacetylase inhibitors in obtaining medicine for neoplasm treatment in hemopoietic and lymphatic system.

29 cl, 10 ex

FIELD: medicine; oncology.

SUBSTANCE: method includes radical operation and intraoperative radiation therapy within regional lymphatic cancer spread dosed 10 Gy, in cys-platinum radiosensitisation. It is accompanied with two additional courses of neoadjuvant chemotherapy ensured with intravenous drop-by-drop one-day introduction of Taxol dosed 175 mg/m2 and Carboplatine AUC 6 every 3 weeks.

EFFECT: reduced rate of local recurrences, lower number of postradiation complications.

2 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new composition of antifungal and fungicidal action, and applied for treatment of diseases caused by bacterial and fungal infection. Composition of prolonged action contains active substances antibacterial (chlorhexidine 0.02-0.05 mass%), antifungal (clotrimasole - 0.4-0.6 mass%), dimexide (7.0-27.0 mass%) as potentiator intensifying penetration of active substances, and also the stabiliser based on polyvinyl alcohol solution in physiologic saline, and structurally represents polymeric matrix with immobilised active components made as gel or a film from which active components are gradually released during application.

EFFECT: invention provides reduction of treatments time for ENT-diseases and dermal diseases of both candidal and mixed aetiology.

3 cl, 1 tbl

The invention relates to a metered composition of extended release within 24 h and a single dosage form of the composition in the form of capsules, including spheroids containing venlafaxine hydrochloride, microcrystalline cellulose and hypromellose

The invention relates to the field of medicine and veterinary medicine, namely to pharmacology, in particular, probiotics, and can be used in the correction of microbiocenosis of an organism of the person (adults and children) and animals

FIELD: agriculture.

SUBSTANCE: method implies production of dry enzyme-containing granulate and coating thereof with dispersion, which contains particles of hydrophobic substance. The latter is a polyolefine with monomers of 2 to 10 carbon atoms, dispergated in a suitable solvent. Enzyme-containing granulate coated with particle dispersion, which consists mainly of hydrophobic substance.

EFFECT: high enzyme stability under granulation conditions and during storage; improved enzyme bioavailability due to short time of granule dissolving.

14 cl, 6 tbl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention claims method of forming a mass containing a) 50 to 99.4 wt % of at least one cross-linked non-thermoplastic carrier selected out of group including cross-linked polyvinylpyrrolidone and cross-linked sodium carboxycellulose, b) 0.5 to 30 wt % of at least one adjuvant selected out of group including thermoplastic polymers, lipids, polyatomic alcohols forming monosaccharide by oxidation, derivatives of polyatomic alcohols forming monosaccharide by oxidation, and solubilisators, and c) 0.1 to 49.5 wt % of bioactive substance with 1 mg/ml solubility in water at 25°C; at temperature of adjuvant softening or higher, at least 70°C, then the mass is cooled down. Measured forms are rapidly dissipating in water medium.

EFFECT: fast-releasing measured forms for low-soluble bioactive substances without the use of organic solvents or bioactive substance melting.

8 cl, 7 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention includes as active substances one or several fibrates and one or several statins or their pharmaceutically comprehensible salt, in carrier chosen from group, consisting of i) admixtures of polyethyleneglycol and poloxamer in the ratio from 2:1 to 3:1 and with the subsequent dispersion on lactose, ii) glyceryl monostearate with the subsequent spraying on lactose or on an admixture of lactose and hydroxypropymethylcellulose; and iii) polyethyleneglycol, with subsequent spraying on Aeroperl. Besides, the invention concerns firm dosed out forms including specified material and way of their obtaining.

EFFECT: possibility to establish suitable biological availability of both active ingredients at peroral insertion.

56 cl, 15 tbl, 15 ex

FIELD: medicine; pharmacology.

SUBSTANCE: obtain the mixed solution containing oltipraz and soluble polymer in water, for example in the purified water, or insoluble polymer in water in solvent, thus the solvent is organic solvent; and obtaining of solid oltipraz dispersion in polymer. At obtaining of a solid dispersion, the mixed solution can be exposed to spray-type drying at use of the spray-type dryer or granulating at use of the granulator with a fluidised layer.

EFFECT: increase in solubility and biological availability of oltipraz.

18 cl, 2 tbl, 16 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: according to novel method liquid medium, containing at least one dissolved organic or inorganic compound, which is subject to solidification, is forced through membrane into one or several anti-solvents, or one or few anti-solvents are forced through membrane into liquid medium, which contains at least one organic or inorganic compound. Membrane is located in membrane module, has pores with size to 3mcm, membrane form is selected from pipe, fibre or spiral winding. Method is realised as continuous process. Method ensures obtaining solid particles, which include organic or inorganic compound, which are non - agglomerated. Method can be used for large volumes and allows controlling particle size.

EFFECT: obtaining possibility of application for large volumes and ensuring control of particle size.

15 cl, 2 dwg, 2 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: preparation method of ball shaped pellets, containing (a) water soluble active ingredient, that is soluble, freely soluble or very soluble in the water and preferably has water solubility equal to ≥0.5 g/ml; (b) agent, providing ball shape; (c) mono-, di- or triglycerides or their mixture. Indicated method comprises preparation of mixture, containing the active ingredient, agent, providing the bal shape, mono-, di- ot triglycerides or their mixture; and water volume less than of mixture full weight; extrusion of the indicated mixture with extrudate generation; and extrudate spheronization for preparation of the ball shaped pellets. Also invention relates to pellets, preparated by way of the indicated method, and measured dosage bands with sustained release for peroral intake, containing the indicated pellets. The method allows to prepare ball shaped pellets, containing water soluble medications, that allows to regulate release of active ingredient sample, providing a long-lasting powerful therapeutic effect.

EFFECT: provision long-lasting powerful therapeutic effect.

12 cl, 2 ex

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to method of preparation of hard medicinal form of desmopressin or its pharmaceutically acceptable salt, which includes granulation of said desmopressin or its pharmaceutically acceptable salt and at least one excipient selected from cellulose, starch and lactose, or their mixture, in apparatus for granulation in pseudoliquefied layer. Obtained granulate containing said desmopressin is suitable for being pressed into pharmaceutically acceptable tablet.

EFFECT: obtaining stable preparation of desmopressin.

15 cl, 1 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns drugs, particularly a water-soluble granulate and its application for treatment of pain, inflammation, fever and respiratory diseases of animals, the granulate containing meloxicam, linking agent, sugar or sweetener, carrier, salt-forming component to form meglumine, sodium, potassium or ammonium meloxicam salt, optional aromatiser, and other optional auxiliary substances. The invention also concerns method for obtaining the claimed granulate.

EFFECT: possibility of optical control of completely dissolved active substance due to absolute solubility of the granulate in water.

16 cl, 4 ex

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