Implanted risperidone delivery system and methods for using it

FIELD: medicine.

SUBSTANCE: invention refers to using a polyurethane polymer as a drug delivery system to provide the biologically active risperidone delivery at a constant speed for a relatively long period of time, as well as to methods for using it.

EFFECT: system provides high biological compatibility and biological stability and is applicable as an implant in patients (humans and animals) for the risperidone delivery to tissues and organs.

25 cl, 13 dwg, 3 tbl, 5 ex

 

The level of technology

Due to the excellent biocompatibility, biostability and physical properties, the polyurethane or the polyurethane-containing polymers used for the manufacture of a large number of implantable devices, including the electrodes of cardiac pacemakers, artificial hearts, heart valves, coatings for stents, artificial tendons, arteries and veins. However, formulations for delivery of active components using polyurethane implantable devices for the diffusion of a drug with a speed of zero order require the use of a liquid medium or media.

Disclosure of inventions

Described here are methods and compositions are based on the surprising discovery that in the core (core) polyurethane implantable device can be applied to solid formulations containing one or more active components, so that the active ingredient was released from the implantable device via a controlled release with zero order kinetics. On the basis of various physical parameters can be selected active ingredients and the polyurethane coating, and then, based on clinical and/or in vitro testing can be optimized the rate of release of the active component of the implantable device to clinically of smackaroonies speed of release.

One embodiment of the invention is directed to a method of delivery to a subject containing an effective amount of risperidone formulation, comprising: implanting the subject of the implantable device, which contains risperidone or its formulation, essentially surrounded by a polymer-based polyurethane. In one preferred embodiment, the polymer-based polyurethane is formed by one or more polyhydric alcohols, while the overall structure of the polyhydric alcohol is selected from the group consisting of

-[O-(CH2)n]x-O-;

O-(CH2-CH2-CH2-CH2)x-O-; and

O-[(CH2)6-CO3]n-(CH2)-O-.

For the here described compositions and methods of size n and x are integers between about 1-1000000; between about 2-500000; between about 5-250000; and between about 10 and 100000. In one preferred embodiment of the polyhydric alcohol contains -[O-(CH2)n]x-O-, with the polymer-based polyurethane has an equilibrium moisture content between about 5%-200%, for example at least about 15%. In one preferred embodiment of risperidone released with a speed of zero order of about 149 g/day per square centimeter of the surface area of the implantable device. In one preferred embodiment of the polyhydric alcohol contains O-(CH2-CH2 -CH2-CH2)x-O-, with the polymer-based polyurethane has a value of modulus of elasticity Flexural strength between about 1000 and about 92000 pounds per square inch, for example, about 2300 pounds per square inch. In one preferred embodiment of risperidone released with a speed of zero order of about 146 g/day per square centimeter of the surface area of the implantable device. In one preferred embodiment of the polyhydric alcohol contains O-[(CH2)6-CO3]n-(CH2)-O-, with the polymer-based polyurethane has a value of modulus of elasticity Flexural strength between about 620 and about 92000 pounds per square inch, for example, about 620 pounds per square inch. In one preferred embodiment of risperidone released with a speed of zero order of about 40 mcg/day per square centimeter of the surface area of the implantable device.

One embodiment is directed to a device for the delivery of drugs for controlled release of risperidone over a long period of time in order to achieve local or systemic pharmacological effects, and contains: a) a polymer-based polyurethane, which is attached to this form in order to limit empty space; and (b) a solid formulation of a medicinal product containing risperidone and possibly one or more pharmaceutically acceptable carriers, when this solid formulation of a drug contained in a blank space and this device provides the desired rate of release of risperidone from the device after implantation. In one preferred embodiment of the device of the drug delivery air-conditioned, and is activated in accordance with the conditions, selected to be compatible with the parameters of the solubility in water of at least one active component. In one preferred embodiment of the pharmaceutically acceptable carrier is stearic acid. In one preferred embodiment, the polymer-based polyurethane is formed by one or more polyhydric alcohols, while the overall structure of the polyhydric alcohol is selected from the group consisting of

-[O-(CH2)n]x-O-;

O-(CH2-CH2-CH2-CH2)x-O-; and

O-[(CH2)6-CO3]n-(CH2)-O-

In one preferred embodiment of the polyhydric alcohol contains -[O-(CH2)n]x-O-, with the polymer-based polyurethane has an equilibrium moisture content between about 5%-43%, for example at least about 15%. In one preferred embodiment of risperidone released with a speed of zero order of about 149 g/day per square centimeter of positiverate of the implantable device. In one preferred embodiment of the polyhydric alcohol contains O-(CH2-CH2-CH2-CH2)x-O-, with the polymer-based polyurethane has a value of modulus of elasticity Flexural strength between about 1000 and about 92000 pounds per square inch, for example, about 2300 pounds per square inch. In one preferred embodiment of risperidone released with a speed of zero order of about 146 g/day per square centimeter of the surface area of the implantable device. In one preferred embodiment of the polyhydric alcohol contains O-[(CH2)6-CO3]n-(CH2)-O-, with the polymer-based polyurethane has a value of modulus of elasticity Flexural strength between about 620 and about 92000 pounds per square inch, for example, about 620 pounds per square inch. In one preferred embodiment of risperidone released with a speed of zero order of about 40 mcg/day per square centimeter of the surface area of the implantable device. In one preferred embodiment in order to establish the desired speed of delivery, at least one active component can be selected the appropriate options air conditioning and activation, and the activation parameters are time, temperature, climate, the environment and energizing environment.

Brief description of drawings

Phi is .1 is a side view of the implant with two open ends.

Figure 2 is a side view of the finished end cap, used for capping of implants.

Figure 3 is a side view of the implant with one end open.

Figa and 4B are graphs of the speed of release of risperidone from polyurethane (mark RS-A Carbothane®) implants (modulus of elasticity in bending of 620 pounds per square inch), made of tube segments, representing the beginning, middle and end of the hose, this graph is part of a study of the homogeneity of the material, taken from a certain party. The samples were evaluated weekly for one year. All implants were equivalent to the geometric characteristics and the magnitude of the load of the medicinal product.

Figure 5 is a graph of the speed of release of risperidone from polyurethane (Carbothane(PC-3575A) implants (modulus of elasticity in bending of 620 pounds per square inch), which is part of a study of the effect of using as an eluting medium saline solution in the aqueous solution oksipropil-beta-cellulose (15% physiological solution with phosphate buffer). The samples were evaluated weekly for 11 weeks. All implants were equivalent to the geometric characteristics and the magnitude of the load of the medicinal product.

Figa and 6B are graphs comparing near the STI release of risperidone from implants, made from polyurethane Carbothane(PC-3595A (modulus of elasticity Flexural strength of 4,500 pounds per square inch), and implants made of polyurethane Tecophilic® HP-60D-20 (EWC (equilibrium moisture content) of 14.9%), which is part of the evaluation release of the active component of any hydrophilic and hydrophobic polyurethane materials. For implant Carbothane® samples were evaluated weekly for 22 weeks. In the case of the implant Tecophilic® samples were evaluated weekly for 15 weeks. All implants were equivalent to the geometric characteristics and the magnitude of the load of the medicinal product.

11 is a graph of the speed of release of risperidone only from polyurethane (Tecophilic® HP-60D-20) implants (EWC 14,9%), the measurements which were made weekly for 15 weeks.

7 is a graph comparing the rate of release of risperidone from implants made of polyurethane, Tecoflex® EG-80A (modulus of elasticity Flexural strength of 1000 pounds per square inch), and two grades of polyurethane Tecophilic®, HP-60D-35 and HP-60D-60 (EWC 23,6% and 30.8%, respectively). The measurements were conducted weekly for 10 weeks. All implants were equivalent to the geometric characteristics and the magnitude of the load of the medicinal product.

Fig is a graph of the speed of release of risperidone from polyurethane (Carbotane® PC-3575A) implants (modulus of elasticity in bending of 620 pounds per square inch), which were used in vitro as a control for implants used in described in example 8 study on dogs breed Beagle. In vitro elution of these implants was initiated on the day of implantation which is the object of the invention implants as part of a study of in vivo - in vitro correlation.

Fig.9 is a graph of in vivo plasma concentrations of risperidone in described in example 8 study on dogs breed Beagle. Located in the lower part of the graph represents the average plasma concentration reached in dogs implanted with one polyurethane (Carbothane®PC-3575A) implant (modulus of elasticity in bending of 620 pounds per square inch). The top graph represents the average plasma concentration reached in dogs implanted with two polyurethane (Carbothane®PC-3575A) implants (modulus of elasticity in bending of 620 pounds per square inch).

Figure 10 is a graph showing in vitro release of risperidone from implants Tecoflex®, Carbothane®. Granules containing the formulation of risperidone, had a diameter of 3.5 mm, a length of about 4.5 mm and a weight of 5.4 mg Implant had a length of reservoir is about 39-40 mm, a wall thickness of 0.2 mm and an inner diameter of 3.6 mm with a total length of about 45 mm

11 is a graph showing in vitro release of risperidone from implants Tecoflex® and Carothane® in comparison with the control. Granules containing the formulation of risperidone, had a diameter of 3.5 mm, a length of about 4.5 mm and a weight of 5.4 mg Implant had a length of reservoir is about 39-40 mm, a wall thickness of 0.2 mm and an inner diameter of 3.6 mm with a total length of about 45 mm

The implementation of the invention

In order to take advantage of the excellent properties of polymers based on polyurethane, the present invention refers to the use of polymers based on polyurethane in the form of a device for drug delivery through the release of drugs with a controlled rate over an extended period of time in order to provide local or systemic pharmacological effect. Device drug delivery may contain a tank of cylindrical shape, surrounded by a polymer-based polyurethane, which controls the delivery rate of the drug in the reservoir. The tank contains a formula, for example, a solid formulation comprising one or more active ingredients and, possibly, pharmaceutically acceptable carriers. Recipe carriers designed to promote diffusion of the active ingredients through the polymer and to ensure the equilibrium content of drug in the reservoir.

Polyurethane is any poly is am, consisting of a chain of organic units connected by urethane bonds. Polyurethane polymers are formed by flowing into the catalyst reaction of the monomer containing at least two isocyanate functional groups with another monomer containing at least two alcohol groups. The polyurethane formulations cover a wide range of indicators of stiffness, hardness and density.

a synthesis reaction is the formation of polyurethane

Polyurethanes are a class of compounds called "reactive polymers", which include epoxy compounds, unsaturated polyesters and phenolic compounds. Urethane bond is formed during the interaction of the isocyanate group,- N=C=O with a hydroxyl (alcohol) group-HE. The polyurethanes obtained by addition polymerization reaction of MDI with a polyol (polyhydric alcohol) in the presence of a catalyst and other additives. In this case, the polyisocyanate is a molecule with two or more isocyanate functional group R-N=C=O)n≥2and the polyhydric alcohol is a molecule with two or more hydroxyl function the functional groups R'-(OH) n≥2. The reaction product is a polymer containing a urethane bond-RNHCOOR'-. Isocyanates enter into reaction with any molecules containing active hydrogen. It is important that the isocyanates interact with water with formation of urea groups and gaseous carbon dioxide; they also react with polyetheramines with the formation of polyurea.

In industry Polyurethanes obtained by reaction liquid isocyanate with a liquid mixture of polyols, a catalyst and other additives. These two components are referred to as polyurethane system or just system. Isocyanate is commonly referred to in North America as "component A" ("A-side") or simply "out" ("iso") and is rigid main chain (or "hard segment") system. The mixture of polyols and other additives commonly referred to as "component B" ("B-side"or "poly" ("poly") and represents the functional area (or "soft segment") system. This mixture can also be referred to as "resin or resin mixture. Additives in the resin mixture may include chain extenders, cross-linking agents, surfactants, fire tools, pore-formers, dyes and fillers. In applications related to the delivery of drugs, "soft segments" are parts of polymer, which give it a quality, ODA shall determine the ability of the active pharmaceutical ingredient (API) by diffusion through a polymer.

Elastic properties of these materials is achieved through the division of solid and soft copolymer of segments of the polymer in such a way that the domains of the hard urethane segments function as cross-linking between the disordered domains of soft polyester segments. This separation of phases occurs because mostly non-polar, low-melting soft segments are incompatible with polar hard segments with a high melting point. Soft segments, which are formed of high molecular weight polyhydric alcohols, are movable and are usually present in compressed form, while the hard segments formed by the isocyanate and chain extenders, are rigid and motionless. As hard segments covalent way connected with soft segments, they prevent plastic deformation of the polymer chains, thereby providing a manifestation of a highly elastic of elasticity. When mechanical deformation of the area with a soft segments undergoes an effort and hard segments are aligned in accordance with the direction of the load. This reorientation of the hard segments and the subsequent formation of strong hydrogen bonds contributes to the achievement of high values of tensile strength, elongation and tear resistance.

The reaction of the polymer of the organization is catalyzed by tertiary amines, such as, for example, dimethylcyclohexylamine, and ORGANOMETALLIC compounds, such as, for example, dibutyltindilaurate tin or octanoate bismuth. Moreover, the choice of catalysts can be made on the basis of that, do they contribute to the formation by the reaction of urethane gel, as, for example, 1,4-diazabicyclo[2.2.2]octane (also known as DABCO or TEDA), or flowing with the foaming reaction with urea as bis(2-dimethylaminoethyl)ether, or selectively direct the reaction of the isocyanate trimerization, as octoate potassium.

Polyurethane polymer, formed by the interaction of a diisocyanate with a polyhydric alcohol

To obtain polyurethane polymers required isocyanates having two or more functional groups. By volume of aromatic isocyanates represent the vast majority of the total production of diisocyanates. Aliphatic and cycloaliphatic isocyanates are also important components of polyurethane materials, but in much smaller quantities. For this purpose there are many reasons. Firstly, isocyanate group, in connection with aromatic, is much more Rea is cyanopogon, than associated with aliphatic group. Secondly, the use of aromatic isocyanates is more cost-effective. Aliphatic isocyanates are used only in cases when you need to give the final product any special properties. For example, only using aliphatic isocyanates can be obtained permanent coatings and elastomers. Aliphatic isocyanates are also preferred in the production of polyurethane biomaterials due to their inherent stability and elastic properties.

Examples of aliphatic and cycloaliphatic isocyanates include, for example, 1,6-hexamethylenediisocyanate (HDI), 1-isocyanato-3-isocyanatomethyl-3,5,5-trimethylcyclohexane (isophorone diisocyanate, IPDI) and 4,4'-diisocyanatohexane (H12MDI). They will be used for permanent, not subject to yellowing polyurethane coatings and elastomers. The prepolymers H12MDI used to obtain high quality coatings and elastomers having optical transparency and hydrolytic stability. All polyurethane Tecoflex®, Tecophilic®, Carbothane® are made from prepolymers H12MDI.

Polyhydric alcohols are substances with higher molecular weight, derived from the initiator and monomer elementary units, which when embedded in a polyurethane system performance, the keys "soft segments" of the polymer. The easiest way to classify them as polyether polyols obtained by the reaction of epoxides (oxiranes) containing active hydrogen initiator compounds, or the polyether polyols obtained by polycondensation of polyfunctional carboxylic acids and hydroxyl compounds.

Polyurethane Tecoflex®, polyurethanes Tecogel® and polyurethane Tecophilic® are cycloaliphatic polymers and are derived from polyhydric alcohols on polyester basis. Polyurethane Tecoflex® General structure of a segment of a polyhydric alcohol represented as

O-(CH2-CH2-CH2-CH2)x-O-

the increase in "x" represents the increase in elasticity (lower modulus of elasticity in bending "FM"), resulting in receiving FM record in the range from about 1000 to 92000 pounds per square inch. From the point of view of the release of these materials medicinal product, with the increase in FM release relatively hydrophobic API decreases. For the here described compositions and methods values of x are integers between about 1-1000000; between about 2-500000; between about 5-250000; and between about 10-100000. However, in other embodiments, x can be in the range of from about 2 to 500, from about 2 to 100, from about 5 to 50 and from 10 to 30.

Polyurethane Tecophilic® (hydrophilic) or polyurethanes Tecogel® General structure of the segment the polyhydric alcohol represented as

-[O-(CH2)n]x-O-

however, an increase in indices "n" and "x" represents changes in hydrophilicity and lead to the value of the equilibrium moisture content (%EWC) in the range from about 5% to 200%. For the here described compositions and methods of size n and x are integers between about 1-1000000; between about 2-500000; between about 5-250000; and between about 10-100000. However, in other embodiments, the indices n and x can be the same or different values, with values ranging from about 2 to 500, from about 2 to 100, from about 5 to 50 and from 10 to 30. From the point of view of the release of these materials medicinal product, with the increase in %EWC release relatively hydrophilic API increases.

The choice of polyhydric alcohols include, for example, polycarbonate polyols, polycaprolactone polyols, polybutadiene polyols and polysulfide polyhydric alcohols.

Polyurethane Carbothane® are cycloaliphatic polymers and are derived from polyhydric alcohols on the polycarbonate base. General structure of a segment of such a polyhydric alcohol represented as

O-[(CH2)6-CO3]n-(CH2)-O-

the increase in "n" represents the increase in elasticity (decline FM), resulting in receiving FM record in PR the cases from about 620 to 92000 pounds per square inch. For the here described compositions and methods of size n are integers between about 1-1000000; between about 2-500000; between about 5-250000; and between about 10-100000. However, in other embodiments n may be in the range of from about 2 to 500, from about 2 to 100, from about 5 to 50 and from 10 to 30. From the point of view of the release of these materials medicinal product, with the increase in FM release relatively hydrophobic API decreases.

The chain extenders and cross-linking agents are low molecular weight compounds with hydroxyl and amine terminal groups, which play an important role in the morphology of the polymers of polyurethane fibers, elastomers, adhesives and some of foamed porous or with solid surface materials. Examples of chain extenders include, for example, ethylene glycol, butane-1,4-diol (1,4-BDO or BDO), hexane-1,6-diol, cyclohexanedimethanol and hydroquinone bis(2-hydroxyethyl)ether (HQEE). All of these glycols to form polyurethanes well with multiple phases, forming well-defined domains of the hard segments and processed in the melt. All of them are suitable for thermoplastic polyurethanes, with the exception of ethylene glycol, as resulting from it bis-phenylurethane at high levels of hard segment degradation adversely affected the promotion. All polyurethanes Tecophilic®, Tecoflex®, Carbothane® include use as chain extension of 1,4-butanediol.

The present invention provides a device, drug delivery, which can achieve the following goals: speed controlled release (for example, the rate of release of zero order) to maximize therapeutic effects and minimize unwanted side effects, an easy way to remove the device if it is necessary to complete therapy, the increase in bioavailability with reduction of variance in the magnitude of absorption and the absence of presystemic metabolism.

The rate of release of the medicinal product subject to the law of diffusion Fika in the application to the device in the form of a cylindrical tank (cartridge). Correlation between different parameters is described by the following equation

dMdt-2πhpΔClh(r0/ry)

where:

dM/dt: the rate of release of the medicinal product;

h: length of the filled plot device.

Δ is: the concentration gradient across the vessel wall;

ro/ri: the ratio of the magnitude of the external radius of the device to the size of its inner radius; and

p: permeability of the polymer.

The permeability coefficient is determined primarily by the hydrophilicity or hydrophobicity of the polymer, the polymer structure and the interaction between drug and polymer. For the data of a selected polymer and the active ingredient p is a constant, h, roand riare fixed and remain constant after manufacture which has a cylindrical shape of the device. Δ is kept constant.

For keeping the geometry of the device is so accurate as possible, the device, for example, a device with a cylindrical shape can be obtained using methods precise extrusion or precision casting - in the case of thermoplastic polyurethane polymers and methods, reaction injection molding or centrifugal casting - if thermoeconomics polyurethane polymers.

The cartridge can be made either with one closed end or both open ends. The open end can be blocked, for example, pre-fabricated end cap(s) in order to ensure the smoothness of the end and the density of blockage, or, in the case of thermoplastic polyurethanes, using technology the sealing by the sealing, well-known experts in this field. Solid active ingredients and carriers can pressoffice in the form of granules for maximum loading of active ingredients.

To enable identification of the location of the implant into the delivery device may be included radiopaque material by depositing it in a reservoir or production from it end cap, used for capping Chuck.

After plugging both ends of the cartridges filled tank they may be subjected to conditioning and activation within a suitable period of time in order to ensure constant delivery rate.

Air conditioning devices, drug delivery involves loading the active ingredient (the drug) in the polymer-based polyurethane, which surrounds the tank. Activation is performed in order to stop the loading of drug in the polymer-based polyurethane and thereby prevent loss of the active ingredient before the practical application of the implant. The conditions used during conditioning and activation depend on the active ingredient, temperature and environment in which they are implemented. Conditions for running the air conditioning and activation in some of these cases is each can be the same.

Stage conditioning and activation during preparation of the device for drug delivery is to achieve a certain rate of release of a particular drug. Stage conditioning and activation of the implant containing a hydrophilic drug, can be performed in aqueous medium, for example, in physiological solution. Stage conditioning and activating the device to deliver drugs, containing a hydrophobic drug, usually carried out in a hydrophobic environment, such as, for example, the environment oil-based. Stages of conditioning and activation can be performed by controlling the three specific factors, namely, temperature, environment and time period.

The person skilled in the art it is clear that the stages of conditioning and activation devices drug delivery is exposed to the environment in which you place the device. Hydrophilic drug can be subjected to conditioning and activation, for example, in aqueous solution, for example, in physiological solution. The temperature used for the climate control and activation device drug delivery may vary in a wide range of temperatures, comprising, for example, about 37°C.

p> The time interval used for conditioning and activation devices for drug delivery, may vary from about one day to several weeks depending on the speed of release desired for a particular implant or drug. The desired rate of release is determined by the person skilled in the art in accordance with the particular active ingredient used in this recipe granules.

The person skilled in the art it is obvious that the stages of conditioning and activation of the implants are designed to optimize the speed of release of the drug contained within the implant. As such, more a short time air conditioning and activation devices, drug delivery leads to a lower rate of release of the drug compared to the same device, drug delivery, subjected to longer processing at the stage of conditioning and activation.

Temperature during conditioning and activation also affects the rate of release so that the lower temperature leads to a lower rate of release of the drug contained in the device for drug delivery, in comparison with anal is the same device, drug delivery, which have been processed at a higher temperature.

Similarly in the case of aqueous solutions, such as physiological fluids content in the sodium chloride solution defines the rate of release can be achieved for this device drug delivery. More specifically, a lower content of sodium chloride leads to faster release of the drug in comparison with a device, drug delivery, stage-conditioning and activation was higher content of sodium chloride.

Similar conditions apply for hydrophobic drugs, for which the main difference in the implementation phase of conditioning and activation is that the environment for conditioning and activation is a hydrophobic environment, more specifically, the environment oil-based.

Delivery of risperidone may be useful, for example, in the treatment of schizophrenia, manic States of bipolar disorders, anxiety, autism, obsessive-compulsive disorder, severe, are not subject to the treatment of depression with or without psychotic symptoms, Tourette syndrome, disorders of social behavior in children and eating disorders. Risperidone belongs to the class not relationschip drugs known as "atypical neuroleptics". He is a strong antagonist of dopamine. It has a high affinity for dopaminergic B2-receptors. It has the effect on the receptors of several 5-HT (serotonin) subtypes. This 5-NTS associated with increased body mass index, 5-NTA with its antipsychotic action and weakening some of extrapyramidal side effects that occur with typical neuroleptic means" through the action of 5-HT1A. The latter effect leads to an increase in the allocation of mesocortical dopamine from neurons in the brain. Well-known and established effective levels of risperidone in the blood, which can be in the range of, for example, from about 0.1 to about 10 ng/ml, from about 0.5 to about 8 ng/ml, or from about 1.0 to about 5 ng/ml.

The person skilled in the art is able to regulate the release of risperidone by varying different parameters of the implant. For example, as shown in the examples, the use of the polyurethanes of various varieties leads to different rates of release of risperidone. In addition, within the same grade polyurethane of different speed of release of risperidone can be provided by varying the values of EWC and/or modulus of elasticity in bending of polyurethane. Moreover, the person skilled in the art can change the size of the p implant so, to increase or decrease the surface area of the implant and thereby alter the rate of release of risperidone from the implant. Such variation of the terms leads to the speed of release of physiologically-relevant range, for example, from about 0.001 to about 15 mg/day, from about 0.1 to about 15 mg/day, from about 1 to about 12.5 mg/day, from about 7.5 to about 12.5 mg/day or 12.5 mg/day. The rate of release from the implants can also be changed by, for example, regulation of the number and nature contained in the formulation of risperidone inert fillers.

Implants, ensuring the achievement of physiologically significant speed release of risperidone, can vary in size depending on, for example, the nature of the applied polyurethane. The range of the internal diameter of the implant has a cylindrical shape may be, for example, from about 1 mm to about 10 mm, from about 1.5 mm to about 5 mm, from about 1.8 mm to about 3.6 mm, about 3.6 mm, or about 1.8 mm, the Length of the implant may be in the range of from about, for example, 5 mm to about 100 mm, from about 7.5 mm to about 50 mm, from about 10 mm to about 40 mm, from about 15 mm to about 30 mm, 37 mm, about 40 mm, or about 15,24 mm

The present invention focuses on the use of polymers based on polyurethane, thermoplastic or thermosetting Mat is rials, on the creation of implantable devices intended for the delivery of biologically active compounds with adjustable speeds for extended periods of time. Polyurethane polymers can be produced in the form of, for example, hollow cylindrical tubes with one or two open ends by means of extrusion, (reaction) injection molding, extrusion in the form or centrifugal casting (see, for example, U.S. patent No. 5266325 and 5292515), depending on the type of polyurethane.

Thermoplastic polyurethane can be processed by extrusion, injection molding or extrusion in the form. Thermosetting polyurethane can be processed by reaction injection molding, molding to form or centrifugal casting. The values of dimensions of a hollow cylindrical pipe should be maintained as accurate as possible.

Polymers based on polyurethane synthesized from polyfunctional polyols, isocyanates and chain extenders. The characteristics of each of the polyurethane can be determined by its structure.

Thermoplastic polyurethanes are made from Makrigialos, diisocyanate and a bifunctional chain extenders (e.g., U.S. patent No. 4523005 and 5254662). Macrodiol are soft domains. The diisocyanates and chain extenders are also die domains. The hard domains are used in polymers as areas that are physically engaged in cross-linking. The variation of the ratio of these two types of domains can change the physical properties of polyurethanes, for example, the modulus of elasticity Flexural strength.

Thermosetting polyurethanes can be prepared from polyfunctional (more than bifunctional) polyols and/or isocyanates and/or chain extenders (e.g., U.S. patent No. 4386039 and 4131604). Thermosetting polyurethanes may also be prepared by incorporating into the polymer chain unsaturated bonds and of suitable cross-linking agents and/or originators to provide a chemical cross-linking (for example, U.S. patent No. 4751133). Controlling the number of stations of the cross-linking and their distribution, it is possible to regulate the rate of release of the active component.

Depending on the desired properties through the modification of the main chain polyhydric alcohols in the polymer chain of the polyurethane can be of various functional groups. In cases where the device is used for delivery of drugs, soluble in water, polyhydric alcohols to increase the hydrophilicity of the polymer are introduced hydrophilic side groups, such as ion, carboxyl, ether and hydroxyl groups (EmOC is emer, U.S. patent No. 4743673 and 5354835). When the device is used to deliver hydrophobic drugs, to increase the hydrophobicity of the polymer polyols include hydrophobic side groups, such as alkyl, siloxane groups (e.g., U.S. patent No. 6313254). The speed of release of the active components can also be controlled by regulating the hydrophilicity/hydrophobicity of polyurethane polymers.

For thermoplastic polyurethanes preferred choice when receiving hollow tubes (Figure 1) with two open ends and constant physical size is accurate extrusion or injection molding. The tank can be freely filled with suitable formulations containing active ingredients and carriers, or ready to fill pellets in order to ensure maximum loading of active ingredients. First, before you download recipes in the hollow tube, one open end must be sealed. To seal both open ends can be used two finished end caps (Figure 2). Stage clogging can be performed by applying heat treatment or solvent, or any other means for capping the ends, preferably providing a permanent closure.

In the case of thermoreactor the data polyurethanes depending on the curing mechanism of the preferred choice is the exact reactive injection molding or centrifugal casting. Reactive injection molding is used, if the curing mechanism is realized through the application of heat and centrifugal casting is used, if the curing mechanism is implemented by means of light and/or heat. For example, hollow tubes with one open end (Figure 3) can be produced by centrifugal casting. Hollow tube with two open ends can be manufactured using, for example, reactive injection molding. The tank may be filled in the same manner as in the case of thermoplastic polyurethanes.

For capping the open end can be used suitable initiated by light and/or initiated by the warmth formulation of thermosetting polyurethane, which fills the open end and which then hardens under the action of light and/or heat. For capping the open end may also be used, for example, the finished end cap by application to the surface between the finished end cap and an open end suitable initiated by light and/or initiated by the warmth of the formulation of thermosetting resin and curing it under the action of light and/or heat, or can be used in any other way obstruct ends, preferably providing a permanent closure.

The final process involves conditioning and Akti is the situation of implants to achieve speeds of delivery, the required data for the active components. Suitable for air conditioning and activation environment are selected depending on the type of active ingredient is hydrophilic or hydrophobic. For hydrophilic active ingredients are preferred aquatic environment, and for hydrophobic active ingredients preferred environment oil-based.

As it is quite clear to the person skilled in the art, in the preferred embodiment of the invention, without departing from the scope of the claims, may be made many changes. This means that all material contained herein should be considered in relation to this invention as illustrative and not limiting it.

Explanatory examples

Example 1

Tubes of polyurethane polymer Tecophilic® were supplied by Thermedics Polymer Products obtained by way of exact extrusion. Polyurethane Tecophilic® represents the group of aliphatic thermoplastic polyurethane on polyester basis, the formula of which can be developed with different indicators of the equilibrium water content (EWC), constituting up to 150% by weight of dry polymer. Compounding extrusion of the brand are designed for maximum physical properties termoformovannyh pipes or other components. Constructs used in the examples is Bristow pipes and plugs are depicted in figure 1-3.

Presented below are data on the physical properties of the polymers provided by Thermedics Polymer Product (the tests were performed according to the guidelines of the American society for testing materials (ASTM), table 1).

Example 2

Table 2 a-C present data on rates of release of risperidone from polyurethane materials three different classes (Tecophilic®, Tecoflex®, Carbothane®). Speed of release were subjected to normalization by surface area of the implant, thereby making the amendment, taking into account the small differences in the sizes of various implantable devices. Risperidone is considered as being hydrophobic (not water soluble) substance index what is the value of LogP; in the context of the data provided value LogP greater than about 2.0, is considered as an indicator of low solubility in aqueous solution. Polyurethanes were chosen in such a way as to have differing indices of affinity for water-soluble active ingredients and different elasticities (which displays different values of modulus of elasticity in bending).

For the application of polyurethanes suitable for described here are devices and methods, the polyurethane must demonstrate physical properties suitable for the formulation of risperidone, prednaznachendlya delivery. Available for purchase or can be prepared polyurethanes with a wide range of indicator EWC or modulus of elasticity in bending (table 2). In Tables 2 a-C shows the normalized speed of release of different active ingredients of polyurethane compounds. Table 2 D-F show not subjected to the normalization of the data on rates of release of the same active ingredients in comparison with the compositions of the implants.

The solubility of the active component in the aquatic environment can be measured or predicted based on the distribution coefficient (defined as the ratio of the concentration of the compound in the aqueous phase to its concentration in immiscible solvent). The distribution coefficient (P) is a measure of how well a substance is divided between the lipid (oil) and water. Based on the measure R measure solubility is often represented in the form of LogP. In General, the solubility is determined by LogP and melting temperature (which depends on the size and structure of the connection). As a rule, the lower the LogP value, the higher the solubility of compounds in water. Od is ako possible cases, when compounds with a high LogP values are, however, soluble due to, for example, their low melting point. Similarly, a compound with high melting point may be of low magnitude LogP and to be completely insoluble.

The modulus of elasticity in bending for this polyurethane is the ratio of stress to strain. It is a measure of the "stiffness" of the connection. This hardness is usually expressed in Pascals (PA) or in pounds per square inch (psi).

The rate of elution of the active component of the polyurethane compounds may change under the influence of various factors, including, for example, the relative hydrophobicity/hydrophilicity of the polyurethane (shown, for example, the metric logP), the relative hardness of the polyurethane (denoted, for example, the modulus of elasticity in bending) and/or the molecular weight of the active component, intended for release.

Example 3. Elution of risperidone from polyurethane implantable devices.

5 to 10 are graphs illustrating the elution profiles of risperidone from various implantable devices through different periods of time.

Data were obtained for the speed of release of risperidone from polyurethane (mark RS-A Carbothane®) implants (F.M. (modulus of elasticity in bending) 620 pounds is rather square inch), made from segments of the tube, representing the beginning, middle and end of the hose, this graph is part of a study of the homogeneity of the material taken from a specific party (Figure 5). The samples were evaluated weekly for one year. All implants were equivalent to the geometric characteristics and the magnitude of the load of the medicinal product.

Data were obtained for the speed of release of risperidone from polyurethane (Carbothane® PC-A) implants (F.M. 620 pounds per square inch), which is part of a study of the effect of using as an eluting medium saline solution in the aqueous solution oksipropil-beta-cellulose (15% in saline phosphate buffer) (6). The samples were evaluated weekly for 11 weeks. All implants were equivalent to the geometric characteristics and the magnitude of the load of the medicinal product.

Were compared speeds release of risperidone from implants made of polyurethane Carbothane®PC-3595A (F.M. 4500 pounds per square inch), and implants made of polyurethane Tecophilic® HP-60D-20 (EWC (equilibrium moisture content) of 14.9%), which is part of the evaluation of the release of active ingredient from any hydrophilic and hydrophobic polyurethane materials (Figa and 7B). In the beam of the implant Carbothane® samples were evaluated weekly for 22 weeks. In the case of the implant Tecophilic® samples were evaluated weekly for 15 weeks. All implants were equivalent to the geometric characteristics and the magnitude of the load of the medicinal product.

Were compared speeds release of risperidone from implants made of polyurethane, Tecoflex® EG-80A (F.M. 1000 pounds per square inch) and two grades of polyurethane Tecophilic®, HP-60D-35 and HP-60D-60 (EWC 23,6% and 30.8%, respectively) (Fig). The measurements were conducted weekly for 10 weeks. All implants were equivalent to the geometric characteristics and the magnitude of the load of the medicinal product.

Were obtained velocities of release of risperidone from polyurethane (Carbothane® PC-3575A) implants (F.M. 620 pounds per square inch), which were used in vitro as a control for implants used in described in example 8 study on dogs breed Beagle. In vitro elution of these implants was initiated on the day of implantation which is the object of the invention implants as part of a study of in vivo - in vitro correlation.

Example 4. Assessment polyurethane implantation subcutaneous devices, contains risperidone, dog breed Beagle.

This study determines the levels of risperidone in the blood achieved by using one or two implants, and lifespan is here time-release implants of the medicinal product. The implantable device based on polyurethane, containing granules with risperidone, were implanted dog breed Beagle with the aim of determining the velocity of release of risperidone in vivo. The sampling results are summarized in table 3 and figure 10. Risperidone was still present in high levels in the plasma of the dog at the end of the third month. The study was conducted in accordance with established WCFP standard operating procedures (SOP), the Protocol and any amendments to the Protocol. All procedures were performed in accordance with the Guidance on the content and use of laboratory animals (National Research Center, National Academy Press, D.C., 1996) and approved by the Institutional Committee for animal care and use in the WCFP.

The original implants contain about 80 mg of risperidone and was intended to ensure delivery of approximately 130 ág/day for 3 months. The samples before applying stored at temperatures between 2 and 8°C. the Animals were as follows:

Type: dog

Breed: Beagle

Source: Pharm. Industrial Research Institute, Guangzhou

Certificate number SCXK(YUE)2003-0007

Age at start of treatment: 6~9 months

Weight: 8~10 kg

The number and sex: 6 males.

Before the beginning of the research animals were assigned identification numbers pre-treatment. Centuries before the vision all animals were weighed weekly during the acclimatization period was exposed in places of detention a daily inspection by a qualified veterinarian. Before selection of studies all animals underwent clinical examination. Animals with any signs of disease or physical abnormalities for research were not selected. In the 3rd and 2nd day before implantation of the implant was performed by sampling the blood, the results of which were considered as the source. Then the animals were randomized in 2 groups with the following dosing schedules:

GroupMethod of making doseThe number of animalsDosageTotal dose (mg)
Males(μg/day)
1Subcutaneous implant313023 (single implant)
2Subcutaneous implant326046(double implant)

Each animal for implantation of the device was shot General anesthesia with sodium phenobarbital at a dose of 30 mg/kg of the drug high is was obaidalla with uniform speed in a few months. Half of the animals was implanted one implant (group 1), while others received two implants (group 2). On his shoulder was vapiwala plot 5 cm2and to ensure the loss of sensitivity of this area subcutaneously administered 2 ml of marcaine. On his shoulder and made a small incision and the device wdialog under the skin. A small incision was stitched, the animal was allowed to recover and returned to his pen. Over the next five to seven days place of implantation of the implant was observed in order to detect symptoms of infection or any reactions. Astringent skin brackets were removed when the skin is sufficiently healed. At the end of the period of three months the device has been removed, as it must make in the clinical setting.

Before sampling the blood of animals received no food for at least four hours. As the blood collection was performed in the morning, food was given during the night. Blood samples were taken by using a 20G needle and was going directly into 5 ml test tubes with heparin sodium and before centrifugation was kept chilled. Then the samples were tsentrifugirovanie for 5 minutes at 4°C and a speed of 5000 rpm Separated plasma was then transferred into two 3 ml cryoprobes. The samples were marked on the actual date of selection of the sample, the appropriate day of the study, and is edificatory dogs and the index of the duplicate samples (And or or). Until ready for analysis, the samples were kept at -20°C.

Initial blood samples were taken in two consecutive days prior to implantation of the delivery device. In addition, blood samples were taken daily for the first week and weekly blood samples were taken for three months after implantation. Each time from each dog received 2 blood sample volume of 5 ml blood Samples were taken primarily from the head of Vienna, as the backup was used hypodermic vein of a foot, or jugular vein. For both groups, both single and double implants, blood samples were collected at appropriate time points indicated below in Table 3. For the analysis required at least 2 ml of plasma, for which it was necessary to obtain in the case of each sample at least 10 ml of blood. The analysis of parameters of plasma concentrations of risperidone was performed using the method LC/MS (liquid chromatography / mass spectrometry), extended for this connection. For each sample was carried out on one test. The samples were taken were stored under suitable conditions and analyzed by the parties.

td align="center"> 1,29 3,25
Table 3
The concentration of risperidone in plasma dogs
DateWeekDayGroup 1 (single implant)Group 2 (dual implant)Group 1Group 2
M 1M 2M 3M 1M 2M 3AverageArticle deviationAverageArticle deviation
-3------------------
-2------------ ---
1.2911BLQBLQ0,26BLQ0,54BLQ0,26/0,54/
1.30120,77BLQ0,240,53to 1.860,460,510,370,950,79
1.31131,160,780,371,152,700,920,770,401,590,97
2.01141,260,790,661,213,850,940,900,322,001,61
2.02151,150,661,031,023,130,770,950,261,641,30
2.03161,140,580,520,972,960,790,750,34of 1.571,20
2.04171,170,720,44 0,89with 3.270,730,780,371,631,42
2.112141,261,030,381,152,811,010,890,461,661,00
2.183211,090,700,621,383,090,910,800,251,791,15
2.25428of 1.340,841,021,713,551,101,070,252,12 1,28
3.035352,072,231,651,974,541,121,980,302,541,78
3.106421,531,131,87to 1.863,341,401,510,372,201,01
3.177491,331,091,161,672,231,291,190,121,730,47
3.248561,561,301,282,091,541,380,151,640,41
3.319631,060,831,391,132,270,971,090,281,460,71
4.0710701,391,001,361,423,511,481,250,222,141,19
4.1411771,231,151,411,613,471,071,26/td> 0,132,051,26
4.2112841,291,101,211,233,471,231,200,101,981,29
4.2813911,380,881,101,093,221,381,120,251,901,16
5.0514981,941,011,321,283,761,191,420,472,081,46
5.1215/td> 1051,540,981,231,373,481,311,250,282,051,24
5.19161121,610,941,301,223,981,591,280,34of 2.261,50
5.26171191,360,971,491,482,661,651,270,271,930,64
6.02181261,400,930,950,991,161,090,271,801,26
6.09191331,471,191,331,363,360,981,330,141,901,28
6.16201401,161,250,853,2*of 3.461,031,090,212,251,72
6.23211471,161,231,261,175,561,531,220,052,75,44
6.30221541,632,02the 1.441,41to 5.21of 1.341,540,132,65of 2.21
7.07231611,261,040,921,4144,82*1,361,070,171,390,04
7.14241681,850,9BLQ1,53,781,261,380,672,181,39
7.21251751,691 BLQ1,29of 3.461,31,350,492,021,25
7.28261821,421,090,341,74,481,820,880,76to 2.67of 1.57
* re-analysis
** re-analysis, unusual data

Fig.9 is a graph of in vivo plasma concentrations of risperidone in research on the breed Beagle. Located in the lower part of the graph represents the average plasma concentration reached in dogs implanted with one polyurethane (Carbothane®PC-3575A) implant (F.M. 620 pounds per square inch). The top graph represents the average plasma concentration reached in dogs implanted with two polyurethane (Carbothane®PC-3575A) implants (F.M. 620 pounds per square inch).

Example 5. Assessment floor is urethane implantation subcutaneously devices contains risperidone, dog breed Beagle.

When expanding on the data presented in example 4, this study determines the levels of risperidone in the blood achieved by using one or two larger implants, as well as the length of time of the release implants of the medicinal product. The implantable device based on polyurethane, containing granules with risperidone, were implanted dog breed Beagle with the aim of determining the velocity of release of risperidone in vivo. The results for larger implants in the summary as presented in Figure 10 (in vitro elution profile) and 11 (elution dogs breed Beagle).

Used in this study, the granules containing the formulation of risperidone, had a diameter of 3.5 mm, a length of about 4.5 mm and a weight of 5.4 mg Implant had a length of reservoir is about 39-40 mm, a wall thickness of 0.2 mm and an inner diameter of 3.6 mm with a total length of about 45 mm, originally contained about 80 mg of risperidone and was intended to deliver approximately 130 ág/day for 3 months.

Equivalents

The present disclosure should not be construed as limited as described in this application the preferred embodiments, are intended to illustrate various objects of the invention. Specialists in this field it is obvious that without derogating from creatures and amount of claims of the present disclosure in this invention can be made many modifications and changes. In addition to listed here from the foregoing descriptions of the professionals in this field is obvious and other functionally equivalent methods, systems and devices that are within the scope of this disclosure. Such modifications and changes are intended to fall within the volume covered by the attached claims. The present disclosure should be considered as limited only by the attached claims, covering the full scope of equivalents to which the claims distributes its rights. It should be understood that this disclosure is not limited to particular methods, reagents, compositions, compounds or biological systems, which can, of course, subject to change. It should also be understood that the terminology used here is used only for the purpose of describing particular embodiments and is not intended to be restrictive purposes. Specialists in this field it is clear that in all cases, for example, for the purpose of providing a written description, all disclosure here ranges also cover all possible subranges and combinations of subranges.

Despite the fact that there are disclosed various objects and embodiments, the experts in this field is obvious and other objects and embodiments. All used in the examination of the application materials JW is Auda included here in its entirety by reference.

1. The method of delivery to the subject an effective amount of risperidone, including: the introduction of the implantable device to a subject, which contains:
a) polymer-based polyurethane, which is attached to this form in order to limit empty space; and
b) a solid formulation of a medicinal product containing risperidone and possibly one or more pharmaceutically acceptable carriers, with a solid formulation of a medicinal product containing risperidone, contained in the specified blank space.

2. The method according to claim 1, wherein the polymer-based polyurethane is formed by one or more polyhydric alcohols, while the overall structure of the polyhydric alcohol is selected from the group consisting of
-[O-(CH2)n]x-O-;
O-(CH2-CH2-CH2-CH2)x-O-; and
O-[(CH2)6-CO3]n-(CH2)-O-.

3. The method according to claim 2, in which the polyhydric alcohol contains -[O-(CH2)n]x-O - and in which the polymer-based polyurethane has an equilibrium moisture content of between about 5-200%.

4. The method according to claim 3, in which the polymer-based polyurethane has an equilibrium moisture content of at least about 15%.

5. The method according to claim 2, in which risperidone is released with a speed of zero order of about 149 g/day per square centimeter of area and the surface of the implantable device.

6. The method according to claim 2, in which the polyhydric alcohol contains -[O-(CH2)n]x-O - and in which the polymer-based polyurethane has a modulus of elasticity Flexural strength between about 1000-92000 pounds per square inch.

7. The method according to claim 6, in which the polymer-based polyurethane has a modulus of elasticity in bending about 2300 pounds per square inch.

8. The method according to claim 6, in which risperidone is released with a speed of zero order of about 146 g/day per square centimeter of the surface area of the implantable device.

9. The method according to claim 2, in which the polyhydric alcohol contains O-[(CH2)6-CO3]n-(CH2)-O - and in which the polymer-based polyurethane has a modulus of elasticity Flexural strength between about 620-92000 pounds per square inch.

10. The method according to claim 9, wherein the polymer-based polyurethane has a modulus of elasticity in bending about 620 pounds per square inch.

11. The method according to claim 9, in which risperidone is released with a speed of zero order of about 40 mcg/day per square centimeter of the surface area of the implantable device.

12. Device drug delivery designed for a controlled release of risperidone over a long period of time in order to achieve local or systemic pharmacological effects, contains:
a) polymer clay is based on the polyurethane, which is attached to this form in order to limit empty space; and
b) a solid formulation of a medicinal product containing risperidone and possibly one or more pharmaceutically acceptable carriers, with a solid formulation of a drug contained in the empty space and thus the device provides a desired rate of release of risperidone from the device after implantation.

13. The device according to item 12, which is air-conditioned and is activated under conditions selected so as to be compatible with the parameters of the solubility of risperidone in the water.

14. The device according to item 13, in which the pharmaceutically acceptable carrier is stearic acid.

15. The device according to item 12, in which the polymer-based polyurethane is formed by one or more polyhydric alcohols, while the overall structure of the polyhydric alcohol is selected from the group consisting of
-[O-(CH2)n]x-O-;
O-(CH2-CH2-CH2-CH2)x-O-; and
O-[(CH2)6-CO3]n-(CH2)-O-.

16. The device according to item 15, in which the polyhydric alcohol contains -[O-(CH2)n]x-O - and in which the polymer-based polyurethane has an equilibrium moisture content of between about 5-200%.

17. The device according to clause 16, in which the polymer-based polio ETANA has an equilibrium moisture content, at least about 15%.

18. The device according to item 15, in which risperidone is released with a speed of zero order of about 149 g/day per square centimeter of the surface area of the implantable device.

19. The device according to item 15, in which the polyhydric alcohol contains -[O-(CH2)n]x-O - and in which the polymer-based polyurethane has a modulus of elasticity Flexural strength between about 1000-92000 pounds per square inch.

20. The device according to claim 19, in which the polymer-based polyurethane has a modulus of elasticity in bending about 2300 pounds per square inch.

21. The device according to claim 19, in which risperidone is released with a speed of zero order of about 146 g/day per square centimeter of the surface area of the implantable device.

22. The device according to item 15, in which the polyhydric alcohol contains O-[(CH2)6-CO3]n-(CH2)-O - and in which the polymer-based polyurethane has a modulus of elasticity Flexural strength between about 620-92000 pounds per square inch.

23. The device according to item 22, in which the polymer-based polyurethane has a modulus of elasticity in bending about 620 pounds per square inch.

24. The device according to item 22, in which risperidone is released with a speed of zero order of about 40 mcg/day per square centimeter of the surface area of the implantable device.

25. The device according to item 12, to which the PRS in order to establish the desired speed of delivery of risperidone can be selected the appropriate options air conditioning and activation while the activation parameters are time, temperature, climate, the environment and energizing environment.



 

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16 cl, 8 ex

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 medicine and chemical-pharmaceutical industry, namely to using ipidacrine as an agent for treating disturbed potency.

EFFECT: pharmaceutical composition of ipidacrine represents a tablet, including a prolonged action tablet, or a solid gel capsule.

4 cl, 4 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents an implanted depot of a therapeutic agent for relieving, preventing or treating pain in a patient in need thereof, containing clonidine in the amount of 1 wt % to 15 wt % of the depot of the therapeutic agent, and at least one biodegradable polymer; the above depot of the therapeutic agent has a surface that provides releasing a peak dose of clonidine in the amount of 5 wt % to 20 wt % of total amount of clonidine in the above depot for 24 hours and releasing the effective amount of clonidine for a period of at least three days; the above polymer has characteristic viscosity 0.45 dl/g to 0.55 dl/g and contains poly(D,L-lactide), while said clonidine contains clonidine hydrochloride.

EFFECT: invention extends the range of products for relieving pain.

9 cl, 2 ex, 5 tbl, 34 dwg

Drug form // 2493830

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to drug form, preferably, to pill for per oral application, for pain treatment with controlled release of pharmacologically active composition (A), which it contains. Drug form contains pharmacologically active composition (A), which is potential for abuse, representing opioid or opioid derivative, and hydrophilic polymer (C). Part of surface of drug form by invention is convex, and the other part of its surface is concave. Drug form has tensile strength B1, at least, 500 H in direction of tension E1 and has tensile strength B2 lower than 500 H in direction of tension E2.

EFFECT: drug form by invention is stable to rupture and stable against abuse.

16 cl, 21 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. What is described is an implanted drug delivery device on the basis of polyurethane for the delivery of biologically active compounds at a constant speed for a long period of time, and a method for preparing it. The device is high biocompatible and bioresistant, and applicable as an implant for patients (human and animals) for the delivery of biologically active compounds to tissues and organs.

EFFECT: implanted device provides the delivery at a constant speed for a long period of time.

26 cl, 5 tbl, 14 dwg, 8 ex

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