Implanted octreotide delivery device and method for using it

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine and concerns a method for the delivery of octreotide or its pharmaceutically acceptable salt into an individual, involving implanting the implanted device comprising a polyurethane polymer into the individual; the implanted drug delivery device for the octreotide acetate release by diffusion through a polyurethane polymer.

EFFECT: group of inventions provides high biocompatibility and biostability when used as an implant for the patients for the octreotide delivery to tissues or organs.

4 cl, 3 dwg, 5 tbl, 2 ex

 

The technical field to which the invention relates

This invention relates to the use of the polymer-based polyurethane as a device for delivering medicines for delivering biologically active octreotide constant speed for an extended period of time and to the means of obtaining it. The device vysokorychlostniho and biostacis and usable as an implant for patients (humans and animals) for the delivery of octreotide to tissues or organs.

The level of technology

Thanks to their excellent biological compatibility, biological stability and physical properties of the polyurethane or poliuretanowej polymers used for the manufacture of a large number of suitable for use as implant devices, including a pacemaker, artificial heart, heart valves, coatings of stents, artificial tendons, arteries and veins. However, the compositions for delivery of active agents using polyurethane implantable devices require a liquid medium or carrier for the diffusion of the drug at zero order.

Disclosure of the invention

Described herein methods and compositions based on the unexpected discovery that solid compositions comprising one or more active agents, mo�ut to be used in the core (the core) polyurethane implantable devices, the active agent is released from the implantable device with adjustable constant over time speed. Active agents and a polyurethane coating may be selected on the basis of various physical parameters and then the rate of release of active agent from an implantable device can be optimized to a clinically relevant release rate on the basis of clinical trials and/or in vitro tests.

One of the embodiments of the invention relates to a method of delivering to a subject an effective amount of octreotide, including implantation to a subject the implantable device, wherein the implantable device comprises octreotide surrounded by a polymer based on polyurethane. In a particular embodiment the polymer is a polyurethane selected from the group consisting of polymer Tecophilic®, Tecoflex polymer® and polymer Carbothane®. In a particular embodiment, the polymer-based polyurethane is a polymer Tecophilic® content equilibrium moisture of at least about 24%. In a particular embodiment, the polymer-based polyurethane is a polymer Tecoflex® modulus of elasticity in bending about 2,300.

One of the embodiments of the invention relates to a device for delivery of the drug for the controlled release of octreotide for a long period of time for h�Oba to provide local or systemic pharmacological effect, comprising a) a polymer based on polyurethane, molded to form the cavity; and (b) a solid composition of the medicinal product, including octreotide and optionally one or more pharmaceutically acceptable carriers, wherein the solid composition of the drug is in the cavity of the tank is cylindrical in shape and wherein the device provides a desired release rate of octreotide from the device after implantation. In a special embodiment of the device for delivery of the drug condition and primed under conditions selected as appropriate to the characteristics of water solubility, at least one active agent. In a special embodiment of the pharmaceutically acceptable carrier is a stearic acid. In a particular embodiment the polymer is a polyurethane selected from the group consisting of polymer Tecophilic®, Tecoflex polymer® and polymer Carbothane®. In a particular embodiment, the polymer-based polyurethane is a polymer Tecophilic® content equilibrium moisture of at least about 24%. In a particular embodiment, the polymer-based polyurethane is a polymer Tecoflex® modulus of elasticity on bending, equal to about 2300. In a particular embodiment may be selected the appropriate settings for the conditioning and priming for establishing the desired speed �of retirement, at least one active agent, wherein the priming parameters are time, temperature, environment for conditioning and environment for priming.

Brief description of the drawings

Fig.1 is a side view of an implant with two open ends. Fig.2 is a side view of the finished end caps used for capping implants.

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

The implementation of the invention

In order to benefit from the excellent properties of polymers based on polyurethane, the present invention relates to the use of polymers based on polyurethane as devices for drug delivery for the release of drugs with adjustable speeds for an extended period of time to produce local or systemic pharmacological action. A device for drug delivery may include a cylindrical tank surrounded by a polymer based on polyurethane, which regulates the rate of delivery of the drug inside the reservoir. The reservoir contains a composition, for example a solid composition comprising one or more active ingredients and, optionally, pharmaceutically acceptable carriers. The media include to facilitate the diffusion� active ingredient through the polymer and guarantees the stability of drugs inside the tank.

Polyurethane is any polymer consisting of a chain of organic units connected by urethane linkages. Polyurethane polymers prepared by reacting a monomer containing at least two isocyanate functional groups with another monomer containing at least two alcohol groups in the presence of a catalyst. Characteristics of stiffness, hardness and density of the polyurethane compositions are in an extremely wide range.

The reaction of obtaining the polyurethane in General

Polyurethanes belong to the class of compounds called reaction polymers, which include epoxies, unsaturated polyesters, and formaldehyde resin. Urethane group prepared by reacting an isocyanate group-N=C=O with a hydroxyl (alcohol) group. Polyurethanes receive polyaddition reaction of the polyisocyanate with a polyhydric alcohol (polyol) in the presence of a catalyst and other additives. In this case, a polyisocyanate is a molecule with two or more isocyanate functional groups, R-(N=C=O)n≥2and �of Olia is a molecule with two or more hydroxyl functional groups, R'-(OH) n≥2. The reaction product is a polymer containing the urethane group-RNHCOOR'-. Isocyanates react with any molecule that contains an active hydrogen. It is important that the isocyanates react with water to form a urea group and carbon dioxide; they also react with polyetheramines with the formation of polyurea.

Polyurethanes receive commercial interaction liquid isocyanate with a liquid blend of polyols, catalyst, and other additives. These two components are referred to as a polyurethane system, or simply system. In North America the isocyanate is commonly referred to as "A-side" or simply "out" and it represents a rigid substrate (or "hard segment") of the system. The mixture of polyols and other additives usually referred to as "In-side" or as "poly" and it represents the functional part (or "soft segment") of the system. Such a mixture may also be referred to as "resin" or "resin mixture". Additives of the resin mixture may include chain extenders, crosslinking agents, surfactants, flame retardants, blowing agents, pigments and fillers. In applications for drug delivery "soft segments" represent a part of the polymer, which gives the characteristics that determine the ability of diffusion of the active pharmaceutical ingredient (API) through this �of OLIMAR.

The elastic properties of such materials is determined by the phase separation of the hard and soft copolymer of segments of the polymer, so that the domains of the hard urethane segments serve as linkers between the domains of soft segments of amorphous polyether (or polyester). This separation of phases occurs because mostly non-polar low-melting soft segments are incompatible with polar high-melting hard segments. The soft segments are formed from high molecular weight polyols, movable and normally present in the folded form, while the hard segments, which are formed from the isocyanate and chain extenders, rigid and motionless. Since the hard segments are covalently bound with soft segments, they inhibit plastic flow of the polymer chains, thus creating elastomeric elasticity. When mechanical deformation of the soft segments is subjected to tension by deploying and hard segments oriented in the load direction. This reorientation of the hard segments and the subsequent formation of numerous hydrogen bonds contribute to the high values of tensile strength, elongation and tear resistance.

The reaction catalyze the polymerization of tertiary amines, such as, for example, dimethylcyclohexylamine�, and ORGANOMETALLIC compounds, such as, for example, dilaurate dibutylamine or octanoate bismuth. In addition, catalysts can be selected on the basis of whether they are urethane (gel) reaction, such as 1,4-diazabicyclo[2.2.2]octane (also called DABCO or TEDA), or the urea (blow) reaction, such as bis(2-dimethylaminoethyl) ether, or specifically contribute to the reaction trimerization isocyanate, such as, e.g., potassium octoate.

Polyurethane polymer formed by the interaction of a diisocyanate with a polyol

For the formation of polyurethanes are required isocyanates with two or more functional groups. Within reasonable limits aromatic isocyanates determine the large majority of world production of diisocyanates. Aliphatic and cycloaliphatic isocyanates are also important building blocks for polyurethane materials, but in much smaller amounts. This is for several reasons. First, an isocyanate group, associated with the aromatic group is considerably more reactive than aliphatic isocyanate group. In�second aromatic isocyanates are more economical to use. Aliphatic isocyanates are used, if only for the final product requires special properties. For example, light-resistant coatings and elastomers can be obtained only with aliphatic isocyanates. Aliphatic isocyanates also promoted the production of polyurethane biomaterials because of 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 (diisocyanate, IPDI), and 4,4'-diisocyanatohexane (H12MDI). They are used to obtain permanent negatiwa polyurethane coatings and elastomers. The respectively H12MDI used to produce optically transparent and resistant to hydrolysis coatings and elastomers with high performance. All polyurethanes, Tecoflex®, Tecophilic® and Carbothane® is produced from respectively H12MDI.

Polyols are higher molecular weight materials produced from the initiator and monomer building blocks, and when included in the polyurethane systems are a "soft segments" of the polymer. Their most easily be classified as simple polyether polyols, which is obtained by interaction of epoxy polymers (oxir�new) with initial connections containing active hydrogen, or the polyesters of polyols, which are obtained by polycondensation of multifunctional carboxylic acids and hydroxyl compounds.

Polyurethanes, Tecoflex® polyurethanes, Tecophilic® represent a cycloaliphatic polymers and are compounds of the type which are obtained from polyols based on polyethers. Polyurethane Tecoflex® General structure of the polyol segment is

O-(CH2-CH2-CH2-CH2)x-O-, in accordance with the increase in "x" reflects the increase in elasticity (low modulus of elasticity in bending"; "FM") and leads to FM, fluctuating in the range of about 6895-634330 kPa (1000-92000 f/d2). From the point of view of release of the drug from such materials the release of a relatively hydrophobic API decreases with increasing FM.

Polyurethane Tecophilic® (hydrophilic) General structure of the polyol segment is

-[O-(CH2)n]x-0-,

in accordance with the increase in "p" and "x" reflects the change in hydrophilicity and leads to the equilibrium content of moisture (%EWC), oscillating in the range of about 5%-43%. From the point of view of release of the drug from such materials release relatively hydrophilic API increases with increasing %EWC.

Special polyols include, for example, polycarbonate polyols, the polyols polycaprolactone, the polyols polybutadiene and polyols polysulfides.

Polyurethanes, Carbothane® represent a cycloaliphatic polymers and are a type of polymers obtained from polyols based polycarbonates. The General structure of the polyol segment is

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

in accordance with the increase in "n" represents an increase in elasticity (reduced FM) and leads to FM in the range of about 4275-634330 kPa (620-92000 f/d2). From the point of view of release of the drug from such materials the release of a relatively hydrophobic API will decrease with increasing FM.

The chain extenders and crosslinkers are low molecular weight hydroxyl - and aminobenzamide compounds that play an important role in the polymer morphology of polyurethane fibers, elastomers, adhesives, and some solid films and microporous foams. Examples of chain extenders include, for example, ethylene glycol, 1,4-butanediol (1,4-BDO or BDO), 1,6-hexandiol, cyclohexanedimethanol and bis(2-gidroksiètilovyh) ether of hydroquinone (HQEE). All of these glycols to form polyurethanes, the phases of which are well separated, form a well-defined domains of the hard segments and can be processed in the melt. They are suitable for all t�moplastic polyurethanes with the exception of ethylene glycol, as obtained from biphenylmethane undergo undesirable degradation at high hard segment. All polyurethanes, Tecophilic®, Tecoflex® and Carbothane® include the use of 1,4-butanediol as an extension chain.

The present invention relates to a device for drug delivery, which you can use to achieve the following goals: adjustable speed release (e.g., release rate of a zero order) to maximize therapeutic action and minimize unwanted side effects, an easy way to remove the unit, if you need to finish the treatment, the increase in bioavailability with less variation in absorption and no first pass metabolism.

The rate of release of the drug obeys the law of diffusion Fick in relation to the device in the form of a cylindrical tank (cartridge). The following equation describes the relationship between various parameters:

dMdt=2πhpΔCln(ro/ri)

where dM/dt: the rate of drug release means�a;

h: length of the filled part of the device;

Δ with: a concentration gradient across the vessel wall;

rabout/ri: the ratio of the outer radius of the device to the internal; and

p: permeability of polymer used. Permeability is primarily governed by the hydrophilicity or hydrophobicity of the polymer, the polymer structure and the interaction between drug and polymer. After the polymer and the active ingredient are selected, p is a constant value, h, raboutand r; are fixed and remain constant once the device is of cylindrical shape is obtained. The value of δ with constant support.

In order to preserve the geometry of the device as accurately as possible, the device, for example, the device of cylindrical shape precision can be obtained by extrusion or precision casting in the case of thermoplastic polyurethanes and reaction injection molding or centrifugal casting in the case of thermoset polyurethanes.

The cartridge can be made or with one closed end or both open ends. The open end may be sealed, for example, finished end plug (end caps) to provide a smooth finish and tight insulation or, in the case of thermoplastic polyurethanes, the use�m methods for heat sealing, known to those skilled in the art. Solid active ingredients and carriers can be compacted into the form of granules to maximize the load of active ingredients.

In order to identify the location of the implant delivery device may be included impervious to the rays of the material by introducing it into the tank or its inclusion in end cap used to seal the cartridge.

Once the cartridges are sealed at both ends of the reservoir, optionally condition and primed (primed) within a reasonable period of time in order to ensure a constant delivery rate.

Air conditioning devices for drug delivery includes the loading of active ingredients (drugs) into the polymer-based polyurethane, which surrounds the reservoir. Priming is carried out in order to stop the loading of the drug in the polymer based on polyurethane and thus to prevent the loss of active ingredient to the actual use of the implant. Conditions applicable to the stage of conditioning and priming depend on the active ingredient, temperature and environment in which implement them. The conditions for the conditioning and priming can be in some cases identical.

With�adiya conditioning and priming in the process of receiving devices for drug delivery is performed to obtain the desired release rate of a specific drug. Stage of conditioning and priming of the implant containing a hydrophilic drug can be carried out in an aqueous medium, for example in a saline solution. Stage of conditioning and priming of the device for drug delivery comprising a hydrophobic drug, usually carried out in a hydrophobic environment, such as environment-based oils. The stage of conditioning and priming can be performed by adjusting three specific factors, namely temperature, environment, and time interval.

Specialist in the art it is clear that at the stage of conditioning and devices for drug delivery is influenced by the environment in which the device is placed. Hydrophilic drug can be air-conditioned and primed, for example, in aqueous solution, e.g. a saline solution. Implants octreotide, for example, can be air conditioned and primed in saline solution, more specifically, air-conditioned in saline solution containing sodium chloride 0.9% and primed in saline solution containing sodium chloride 1.8 per cent.

The temperature used for conditioning and prime devices for drug delivery, can vary in a wide interval of temperatures, for example, may be about 37°C.

The time interval used for �of kondicionirovanija and priming devices for drug delivery, can vary from about one day to several weeks depending on the release rate needed for a particular implant or drug. The desired rate of release is determined by the person skilled in the art, taking into account the particular active agent used in the composition of the granules.

Specialist in the art will realize that the stage of conditioning and priming of the implants must optimize the rate of release of the drug contained in the implant. Namely a shorter period of time spent on the conditioning and priming devices for drug delivery, leads to a lower release rate of the drug compared with the same device to deliver the drug, which undergoes a longer stage of conditioning and priming.

The temperature at the stage of conditioning and priming will also affect the rate of release so that lower temperature leads to a lower release rate of the drug contained in the device to deliver the drug, compared with the same device to deliver a drug that is treated at a higher temperature.

<> Also in the case of aqueous solutions, for example saline solutions, the content of sodium chloride in the solution determines which type release rate is obtained for the device to deliver the drug. More specifically, the lower content of sodium chloride leads to a higher release rate of the drug when compared with the device for delivery of the drug, which is undergoing a stage of conditioning and priming, when the content of sodium chloride is higher.

The same conditions apply for hydrophobic drugs, where the main difference at the stage of conditioning and priming is that the environment for conditioning and priming is hydrophobic environment, specifically the environment of oil-based.

Octreotide is a OCTA-peptide that mimics the action of natural somatostatin, although it is a stronger inhibitor of growth hormone, glucagon, and insulin than the natural hormone. Octreotide can be used to treat, for example, acromegaly, diarrhea and episodic febrile conditions associated with carcinoid syndrome, and diarrhea in patients with tumors secreting vasoactive intestinal peptide (VIPoma), severe persistent diarrhoea of other origin, prolonged recurrent hypoglycemia following overdose �of sulfonylation, children with hyperplasia of pancreatic islets to promote the reduction of hypersecretion of insulin, varicose veins of the esophagus, chronic pancreatitis, thymic neoplasms, hypertrophic pulmonary osteopathy (NRAA), secondary to non-small cell lung carcinoma, and pain associated with NROA. Effective levels of octreotide in the blood known and established and can range, for example, from about 0.1 to about 8 ng/ml, from about 0.25 to about 6 ng/ml, or from about 0.3 to about 4 ng/ml.

The present invention focuses on the use of polymers based on polyurethane, thermoplastic or thermoset, to create implantation devices for drug delivery, delivering a biologically active compound with adjustable speeds for a long time. Polyurethanes can be processed, for example, in a cylindrical hollow tube with one or two open ends through extrusion, (reaction) injection molding, direct pressing or centrifugal casting (see, e.g., us Pat. U.S. No. 5266325 and 5292515) depending on the type of polyurethane.

Thermoplastic polyurethane can be processed by extrusion, injection molding or direct compression. Thermoset, poliur�tan can be processed by reaction injection molding, direct pressing or centrifugal casting. The dimensions of the cylindrical hollow tube must be met as best as possible.

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

Thermoplastic polyurethanes prepared from macrodiols, diisocyanates, and difunctional chain extenders (e.g., us Pat.U.S. No. 4523005 and 5254662). Macrodiol create a soft domains. The diisocyanates and chain extenders create a rigid domains. The hard domains serve as physical crosslinking sites for the polymers. Changing the ratio of these two domains, you can modify the physical characteristics of polyurethanes, for example the modulus of elasticity in bending.

Thermoset polyurethanes can be obtained from polyfunctional (higher than bifunctional) polyols and/or isocyanates and/or chain extenders (e.g., us Pat. U.S. No. 4386039 and 4131604). Thermoset polyurethanes can also be obtained by the introduction in the chain of the unsaturated bonds of polymers and related cross-linking agents and/or initiators for chemical crosslinking (e.g., us Pat. U.S. No. 4751133). Adjusting the number of places of formation of cross-links and how they are distributed, you can adjust the speed vysvobozhdeny� active ingredients.

Depending on the desired properties in the chain of the polyurethane by means of modifications of the main chain of the polyol can be introduced various functional groups. When the device is used to deliver water-soluble drugs, the polyols include hydrophilic side groups, such as ionic, carboxyl, simple ether and hydroxyl groups, to increase the hydrophilicity of the polymer (for example, us Pat. U.S. No. 4743673 and 5354835). When the device is used to deliver hydrophobic drugs, the polyols include hydrophobic side groups, such as alkyl, siloxane groups, to increase the hydrophobicity of the polymer (for example, us Pat. U.S. No. 6313254). Release rate of active ingredients also can be adjusted by the ratio of the hydrophilicity/hydrophobicity of polymers based on polyurethane.

In the case of thermoplastic polyurethanes, precision extrusion and injection molding are the preferred choice for obtaining a hollow tube with two open ends (Fig.1) and corresponding physical dimensions. The tank can be freely downloaded corresponding compositions containing the active ingredients and carriers, or filled with pre-obtained pellets to maximize loading with active ingredients. It is necessary that before downloading the compositing�tion in a hollow tube one of the open ends of the first was corked. In order to seal the two open ends, ready to use two end caps (Fig.2). Stage clogging can be performed through the application of heat or solvent, or any other method of plugging the ends, preferably permanently.

In the case of thermoset polyurethane is the preferred choice for precision reaction injection molding or centrifugal casting, depending on the curing mechanism. Reaction injection molding is used, if the mechanism of curing is carried out through heating, and centrifugal casting is used if the curing mechanism is due to the lighting and/or heating. Hollow tubes with one open end (Fig.3) can be obtained, for example, using centrifugal casting. A hollow tube with two open ends can be obtained, for example, using reaction injection molding. The tank can be loaded in the same manner as thermoplastic polyurethanes.

In order to seal the open end, it is possible to use the corresponding composition thermoset polyurethane, the curing of which is initiated by light and/or heated, and harden it with the light and/or heat. Also, for example, you can use �finished end caps for capping the open end, applying the appropriate composition thermoset polyurethane, the curing of which is initiated by light and/or heat at the site of contact between the finished end plug and the open end, and cure her by means of light and/or heat or any other means for capping the ends, preferably permanently.

The final process involves the conditioning and priming of the implants to achieve the speed of delivery required for active ingredients. Depending on the types of the active ingredient is hydrophilic or hydrophobic choose the appropriate environment for the conditioning and priming. Aquatic environment preferred hydrophilic active ingredients, and environment-based oils are preferred for hydrophobic active ingredients.

How easy it can be to find out a specialist in the art can make many modifications of the preferred embodiments of the invention without deviation from its volume. It is assumed that all the examples contained in this document, are considered to illustrate the invention and not in the sense of its limitations.

Explanations with examples

Example 1

Tube of polyurethane Tecophilic® provided by Thermedics Polymer Products and manufactured precision extrusion. Polyurethanes, Tecophilic are a family of aliphatic thermoplastic �of poliuretano on the basis of polyethers, which can be compiled for different content equilibrium moisture (EWC) - up to 150% by weight of dry resin. Created by extrusion of the composition of different brands for maximum physical properties of thermoformed tubing or other components. An example of a device handset and charging plug shown in Fig.1-3.

Following are the physical characteristics of the polymers provided by Thermedics Polymer Products (tests were carried out in accordance with the recommendations of the American society for testing and materials (ASTM), table 1).

Table 1. Typical results of physical-mechanical tests for Tecophilic
ASTMHP-60D-20HP-60D-35HP-60D-60HP-93A-100
The Durometer (shore hardness)D224043D42D41D83A
Relative densityD7921,121,121,151,13
The modulus of elasticity in bending (kPa/f/d2)D790~29650/4300~27580/4000~27580/4000~19995/2900
The limit of tensile strength for dry matter (kPa/f/d2)D412~61360/8900~53780/7800~57230/8300~15170/2200
The limit of tensile strength for wet substances (kPa/f/d2)D412~35160/5100~33780/4900~21375/3100~9655/1400
Elongation for dry matter (%)D4124304505001040
Elongation for wet matter (%)D412390390300620

Example 2

In tables 2A-D shows the release rate of octreotide from three different classes of polyurethane (Tecophilic®, Tecoflex® and Carbothae®). Release rate to normalize the surface area of the implant, and through this correct for minor differences in the amount of various implantable devices. Octreotide is vodorastvorimoe connection, as shown by the Log P value; for the purposes of the data provided the value of Log P of greater than about 2.0 is considered as a low solubility in aqueous solution. Polyurethanes are chosen so as to obtain a varying affinity for water soluble active agents and changing the elasticity (as indicated by the change of the modulus of elasticity in bending).

For applications of polyurethanes applicable to devices and methods described in this document, polyurethane detects physical properties that are suitable for delivery of the composition with octreotide. Polyurethanes are available or can be obtained, for example, with an interval of values of EWC or modules of elasticity in bending (table 2). Table 2 shows the normalized release rate for various active ingredients of polyurethane compounds. Table 2C-D show the normalized release rate for the same active ingredients together with the composition of the implant.

Table 2A
The type of polyurethaneTecophilic
Mark polyurethaneHP-60D-60HP-60D-35HP-60D-20HP-60D-10HP-60D-05
%EWC/Modulus of elasticity in bending31% EWC24% EWC15% EWC8.7% of EWC5.5% of EWC
Active ingredientRelative solubility in water
Octreotide acetate (M. W. 1019)Soluble,Log P=0,43-2022 mg/day/cm22% SA, 50 mg API758 mg/day/cm25% HPC,2% SA,50 mg API11 mg/day/cm210% HPC,2% SA,50 mg API0 10% HPC,2% SA, 50 mgor

fl
Table 2B
The type of polyurethane
Mark polyurethaneEG-85AEG 100AEG-65D
%EWC / Modulus of elasticity in bendingF. M.:2300 (sl5860 kPa)P. M.:10000 C=68950 kPa)F. M.: 37000 (=;255110)
Active ingredientRelative solubility in water
Octreotide acetate (M. W. 1019)Soluble Log P=0,4316 mg/day/cm210% HPC, 2% SA, 50 mg API--

Table 2C

PolyurethaneTecophilic
MarkHP-60D-60HP-60D-35HP-60D-20HP-60D-10HP-60D-05
%EWC31% EWC24% EWC15% EWC 8.7% of EWC55% EWC
Active ingredientRelative solubility in water
Octreotidesee (M. W. 1019)Soluble, Log P=0,43-4000 mcg/day 1.80 mm ID, wall 0.30 mm, L 30 mm, 1,978 cm21500 mcg/day 1.80 mm ID, wall 0.30 mm, L 30 mm, 1,978 cm225 mcg/day ID of 1.83 mm, a wall 0.30 mm, L 34 mm, 2,274 cm20

Table 2D

The type of polyurethaneTespih
Mark polyurethaneEG-85AEG 100AEG-65D
The modulus of elasticity in bendingF. M.: 2,300 15860 kPa)F. M.:10000 (≈68950 kPa)F. M.: 37000 (≈255110 kPa)
Active ingredientThe relative�nd solubility in water
Octreotide acetate (M. W. 1019)Soluble, Log P=0,4330 mcg/day ID of 1.85 mm, wall of 0.20 mm,L 30 mm, 1,931 cm2--

The solubility of the active agent in an aqueous environment can be measured and predicted based on the distribution ratio (defined as the ratio of concentration of compound in aqueous phase to the concentration in the immiscible solvent). The distribution coefficient (P) is a measure of how well the agent is distributed between the lipid (oil) and water. The measure of solubility on the basis of P is often expressed as Log P. in General, the solubility is determined using Log P and melting temperature (which affects the size and structure of the compounds). Usually the lower the Log P value, the more soluble compound in water. However, it is possible to obtain compounds with high Log P values, which are still soluble, for example, because of their low melting temperature. In this way it is possible to have a connection with low Log P with a high melting point, which is very insoluble.

The modulus of elasticity in bending for a given polyurethane is the ratio of voltage�of Azania to deformation. It is a measure of the "stiffness" of the connection. This stiffness is usually expressed in Pascals (PA) or pounds per square inch (f/d2).

The rate of elution of active agent from polyurethane can vary depending on many factors, including, for example, the relative hydrophobicity/hydrophilicity of the polyurethane (indicated, for example, logP), the relative "stiffness" of polyurethane (indicated, for example, the modulus of elasticity in bending) and/or molecular weight of the active agent that is released.

Equivalents

The present disclosure is not limited from the point of view of certain embodiments described in this application, which are intended to illustrate different aspects. Can be made many modifications and variations without deviating from the essence and scope of the disclosure, as will be clear to experts in this field of technology. Functionally equivalent methods, systems and devices within the scope of disclosure, except for those listed in this document will be clear to experts in the art from the descriptions above. It is assumed that such modifications and variations are included in the scope of the appended claims. The present disclosure should be limited only by the terms of appended claims along with the full scope of equivalents DL� which such claim is authorized. It should be understood that this disclosure is not limited to specific methods, reagents, compounds compositions or biological systems, which can, of course, subject to change. It should also be understood that the terminology used in this document is intended to describe certain embodiments and is not intended to be limiting. As will be clear to a person skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges.

Although this document discloses various aspects and embodiments, other aspects and embodiments will be obvious to those skilled in the art. All references cited in this document included therein by reference.

1. Delivery method the subject of octreotide or its pharmaceutically acceptable salt, comprising implanting in the subject an implantable device comprising a polymer based on a polyurethane polyol having a fragment of the General formula -(CH2-CH2-CH2-CH2)x-O - the modulus of elasticity in bending 2300, and this polymer is formed to provide cylindrical tank, wherein the reservoir is sealed after loading efficiency�active amount of a solid composition, comprising octreotide acetate, so that the release of octreotide acetate occurs essentially at the speed of zero order in vitro and the rate of diffusion through the polymer-based polyurethane is 16 mg/day/cm2.

2. A method according to claim 1, wherein the solid composition further comprises stearic acid (SA), hydroxypropyl cellulose (HPC), or a combination.

3. Implantable device for delivery of medicament to release of octreotide acetate at a speed of essentially zero-order in vitro by diffusion through the polymer-based polyurethane over an extended period of time when the rate of diffusion through the polymer 16 mg/day/cm2and specified implantable device for delivery of the medicinal product contains a polymer based on a polyurethane polyol having a fragment of the General formula -(CH2-CH2-CH2-CH2)x-O-, with the modulus of elasticity in bending 2300, and this polymer is formed to provide cylindrical tank, wherein the reservoir is sealed after loading an effective amount of a solid composition comprising octreotide acetate.

4. Implantable device according to claim 3, wherein the solid composition further comprises stearic acid (SA), hydroxypropyl cellulose (HPC), or a combination. /p>

 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medical equipment, namely to devices delivering therapeutic agents through the user's skin by means of a set of tiny needles inserted into the device. The transdermal delivery device comprises a bearing piece, a set of microneedles and a path. The bearing piece comprises the first surface and the second surface. The set of microneedles projects from the second surface of the bearing piece. At least one microneedle comprises a base, a tip and an outer surface. The path comprises a hole extending between the first surface of the bearing piece and the second surface of the bearing piece, and a port on the outer surface of at least one microneedle. The port at the base is aligned with at least a section of the hole to form a connection through which substances can flow. The connection is formed in a cavity of the second surface at the base of the mictoneedle. At least one microneedle has a cylindrical section on which a tipped conical section is formed. According to the second embodiment, the device comprises a compound formed in a plane of the second surface at the base of the microneedle by crossing at least one hole and at least one port; the compound has a sectional area, which exceeds or is equal to about 100 mcm2.

EFFECT: invention provides reliable control of an amount of the delivered or digestible substance with a lesser failure and/or corking probability.

14 cl, 8 dwg

FIELD: medicine.

SUBSTANCE: treating postoperative corneal erosions following pterygium removal. That is ensured by postoperative instillations of drug preparations for corneal erosion. Additionally, the final stage of pterygium removal operation involves administering ozone-oxygen mixture in the concentration of 2 mg/l in an amount of 0.5 ml subconjunctivally. The injection is repeated in the same concentration and amount on the following postoperative day. The method increases the operation effectiveness by reducing postoperative complications and negative symptoms in the patient, including by a compensatory increase of antioxidant enzyme activity, reducing tissue and recovering metabolic processes in the involved tissues, reducing a probability of coarse cicatrisation in the operation region.

EFFECT: method is easy and accessible to implement.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to treating diabetes. That is ensured by the method for transdermal administration of insulin. The method involves placing a flat applicator pre-soaked in an insulin solution in the form of a porous titanium nickelide plate of the thickness of 0.2 to 1 mm on skin. The plate and skin are heated by an infrared light source, while a procedure length is specified within 30 to 120 minutes. A device used for implementing the method comprises a body with a power supply, a heating element and the flat applicator pre-saturated with insulin. The applicator represents the removable porous titanium nickelide plate of the thickness of 0.2 to 1 mm forming one of the body walls. The heating element is represented by the infrared light source in the form of a light-emitting diode set integrated into the body above the plate.

EFFECT: invention provides the more comfortable procedure by eliminating injuring factors, simplifying the power supply configuration, as well as making the applicator process more ordinary, including a possibility to implement the process in everyday life.

2 cl, 1 ex, 3 dwg

Tattoo machine // 2532522

FIELD: medicine.

SUBSTANCE: invention refers to medical equipment and can be used for decorative and cosmetic tattooing. A tattoo machine comprises a frame and a permanent magnet. The permanent magnet is mounted to polarise a magnetic flow generated by an inductance coil. The frame of the tattoo machine is made of a non-magnetic material and comprises a holed projection. The inductance coils are arranged on both sides from the projection of the frame. The permanent magnet is cylindrical and integrated into the hole of the projection of the frame so that a magnetic axis is perpendicular to axes of the inductance coils.

EFFECT: enlarging the controlled power range of the device, stabilising operation conditions and reducing heating after the long-term continuous use.

2 cl, 2 dwg

FIELD: medicine.

SUBSTANCE: there are presented versions of a method for a penetrant delivery involving creating a number of delivery openings. An opening depth makes from approximately 40 to approximately 90 micron. The above delivery openings are characterised by a distribution resultant in a normal distribution curve. There are also presented versions of a method for assessing the effectiveness of the penetrant delivery through a biological membrane, involving measuring the fixed penetrant concentration, measuring a transepidermal water loss through a mammalian membrane and comparing the measurement results to the known values for each providing the desired results.

EFFECT: inventions provide the optimum percutaneous substance delivery to the body by determining the optimum depth range of the delivery openings providing the effective absorption of the therapeutic substances.

25 cl, 10 tbl, 9 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: lipoaspiration cannula of the diameter of up to 1.2 mm is used to sample primary aspirate from subcutaneous fat of an anterior abdominal wall. The produced aspirate is washed with 5% glucose to prepare a lipid fraction to be diluted with 5% glucose in ratio 1:1 of glucose-fat, agitated to prepare a suspension. The skin is punctured to insert a blunt-ended injection cannula of the diameter of up to 1.2 mm into soft tissues surrounding an ulcer and immediately under an ulcerous defect. The cannula is delivered to an end of each marked beam, and the prepared suspension is administered at the output by removing the cannula gradually by simultaneous pressing on a syringe piston. Up to 5 insertions of the suspensions are fan-shaped from one puncture herewith creating a perifocal cushion of the thickness of up to 0.7 cm. A distance of passage beams shall not exceed 2-3 mm.

EFFECT: higher quality of treatment of this pathology by forming the normotrophic scar tissue by stimulating regional microcirculation.

3 tbl, 1 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medical equipment, namely to drug delivery control units using a magnetic body. The magnetic body comprises a magnet and a coating element attached to an end surface of the magnet. The coating element consists of a material with high magnetic permeability; a length-to-radius ratio of the coating element makes 10:1 to 7:3; the side surface of the coating element is longitudinally tapered, and the upper end of the tapered side surface of the coating element is spherical. The drug delivery control unit comprises the magnetic body, a supporting head for the magnetic body and a head drive mechanism which actuates the head along the projected portion formed by the injured region in relation to the tissues surface.

EFFECT: using the invention enables more effective and adjustable drug delivery.

6 cl, 14 dwg

FIELD: medicine.

SUBSTANCE: treating trophic corneal erosion is ensured by processing the corneal erosion structures with ozone-oxygen mixture with the ozone concentration of 1.5 mg/l. The mixture is administered subconjunctivally in a dose of 0.5 ml per one injection. The therapeutic course involves at least 5 procedures and depends of a degree of manifestation of corneal erosion.

EFFECT: method is easy to implement; it requires no specific skills and special laboratory equipment, provides the scar-free corneal epithelium recovery over a relatively short period of time by stimulating proper regeneration.

1 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medical equipment and describes versions of a sprayer for subcutaneous liquid injection and a needle unit. According to the first version, the sprayer comprises a body, a needle unit and a rubber element. The body comprises a drive, a cam turned by the drive, and a connection element reciprocated by the cam. The needle unit is detachably connected to the front end of the body. The rubber element is provided in the needle unit to block a leak-off of blood and liquid from a patient's skin flowing into the needle unit during a medical procedure. The needle unit comprises a needle holder, a liquid container, a movable rod and a lid. The needle unit of the sprayer for subcutaneous liquid injection, including a drug or a tattoo pigment applied on the skin, comprises a needle holder, a liquid container, a movable rod and a lid. The needle holder comprises needles and outlets for a liquid injection. The liquid container is connected to the needle holder via one hole and contains a liquid. One side of the movable rod is connected to the liquid container, and the other side thereof is detachably connected to one end of the drive in the above sprayer. The lid encloses the needle holder and the liquid container and comprises a support unit which the movable rod passes through. The group of inventions also involves a version of the sprayer and a version of the needle unit.

EFFECT: invention enables blocking a leak-off of the patient's blood and liquid flowing into the needle unit during a medical procedure.

16 cl, 9 dwg

Tattoo machine // 2519425

FIELD: mechanics.

SUBSTANCE: tattoo machine frame consists of a side wall made of one piece and an S-shaped fin. The side wall is adjacent to the S-shaped fin for at least 70% of its length. The S-shaped fin is made with a boss. The boss is made with a hollow groove. The clamp is made in the form of a flat bolt pin with an opening and a threaded stud and is mounted in the closed groove of the boss of the S-shaped fin with the ability to move in a direction perpendicular to the side wall. The threaded stud passes through the opening of the frame. The nut is mounted on a threaded stud at the side wall can have a thumbscrew shape. The frame can be made of aluminium alloy.

EFFECT: weight reduction of tattoo machine due to increasing the frame flexural rigidity and torsional rigidity, increasing the reliability of the holder due to more rigid structure of the clamp.

3 cl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular to a pharmaceutical composition in the form of the extrudate, containing at least one pharmaceutically active substance in the form of needles, characterised by the fact that the ratio of the particle size of the needle-like active substance to the diameter of strands constitutes at least 1:25.

EFFECT: invention makes it possible to obtain the more homogeneous extrudate.

11 cl, 13 ex, 10 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition containing N-[3-chlor-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5[[[2-(methylsulphonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine or its pharmaceutically acceptable salt as an active pharmaceutical ingredient in an amount of more than 60 wt % to less than 85 wt % as related to total weight of the composition. The active pharmaceutical ingredient is characterised by a wetting angle of less than 55°.

EFFECT: method for preparing the pharmaceutical composition involves the stage of grinding or milling the above pharmaceutical ingredient in the presence of one or more excipients.

7 cl, 7 dwg, 5 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a balanced fat composition, suitable for probe feeding. The fat composition, suitable for the probe feeding, contains from 8 to 15 wt % of linoleic acid (LA); from 3.0 to 6.0 wt % of a mixture, consisting of ω-3 polyunsaturated fatty acids, alpha-linolenic acid (ALA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), where the quantity of ALA>2.5 wt % and the mixed quantity of DHA and EPA≤2.5 wt %l from 10 to 20 wt % of at least one medium-chain fatty acid (MCFA); and from 35 to 79 wt % of one monounsaturated fatty acid (MUFA). Claimed is a liquid nutritional composition, containing the said fat composition. Claimed is a method of supplying enteral feeding to patients, which includes the introduction of an effective quantity of the said liquid nutritional composition, containing the balanced fat composition by the invention.

EFFECT: invention makes it possible to obtain the balanced nutritional composition for long enteral feeding.

27 cl, 1 dwg, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, namely represents pharmaceutical formulations containing 9-cis-retinyl esters in a lipid excipient. The pharmaceutical formulations containing 9-cis-retinyl esters are described to be applicable in a retinoid replacement therapy for treating retinal degenerations in individuals.

EFFECT: using the formulations for the retinoid replacement therapy for treating retinal degenerations in individuals.

73 cl, 14 dwg, 2 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: composition includes glutaryl histamine in an amount of 18.0-75.0 wt % as an active substance, and as auxiliary substances: microcrystalline cellulose in an amount of 18.0-71.0 wt %, sodium croscarmellose in an amount of 0.25-1.0 wt %, colloidal silicon dioxide in an amount of 0.5-2.0 wt %, calcium stearate in an amount of 0.5-2.0 wt % and lactose monohydrate. The invention also relates to a method of obtaining the said composition.

EFFECT: invention is characterised by the high bioavailability of the active component and high pharmacological activity.

4 cl, 6 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: method for preparing a gel for wound and burn healing involving diluting chitosan in an organic acid, combining it with a biologically active substance and water; chitosan is diluted in citric or lactic acid; mussel hydrolysate is used as the biologically active substance; the hydrolysate is added to the chitosan solution before PEG 600 and calcium alhylose are added in the certain environment.

EFFECT: method enables preparing the new effective wound-healing agent.

2 dwg, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. There are described implanted devices with various versions of biologically active ingredient loading with the version selectable and applicable for creating a prolonged-release profile or a release profile having a low initial ejection of the biologically active ingredient from the implanted device.

EFFECT: there are described the implanted devices with various versions of biologically active ingredient loading.

11 cl, 2 dwg

FIELD: medicine.

SUBSTANCE: what is described is a mesh bioactive wound coating with its base containing disintegrated bacterial cellulose comprising antimicrobial and antioxidant ingredients: silver-modified montmorillonite and fellerenol aiming at optimising the course of the wound process, preventing the development and suppression of a wound infection. The mesh bioactive wound coating is used for treating gunshot wounds, severe mechanical injuries, uninfected and infected wounds, including septic and persistent wounds, granulating wounds following deep thermal, chemical and radiation burns, for conducting the integrated treatment of trophic ulcers and bedsores in hospital, out-patient and field settings.

EFFECT: mesh bioactive wound coating is non-toxic; it causes no local irritant and skin re-absorption action, possesses elasticity, a high degree of wound modelling; it is not fragmented that facilitates a wound care.

5 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compositions for local application for the prevention and treatment of local eye pathologies, in particular inflammatory keratites and conjunctivitis and the dry eye syndrome, which contain as active ingredients polyunsaturated fatty acids of the omega-3 and omega-6 type, namely, EPA (eicosapentaenoic acid), DHA (docosahexaenoic acid) and GLA (γ-linolenic acid), mixed with vitamin E acetate and combined into a stable composition in a hydrogel, that is in the disperse form in a water solution, containing one or more gel-forming polymers. The claimed compositions are especially recommended for application as artificial tears.

EFFECT: invention provides an increased efficiency of the prevention and treatment of eye pathologies.

15 cl, 15 tbl, 3 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: what is described is a medical semisynthetic biological adhesive based on biopolymer nanocomposites as a semisynthetic polymer matrix containing a substrate presented by low-molecular polyisobutylene, collapan as an excipient, human immunoglobulin, castor aerosol lubricant as a binding agent; faster setting of the microporous sandwich adhesive is ensured by performing an operation by means of a repetitively pulsed laser (CO2 laser) scalpel in a combination with a semiconductor laser. A polyacrylamide hydrogel placed into a polymer bath is used as a setting agent of an upper layer that is a polymer plaster tape.

EFFECT: medical semisynthetic biological adhesive has high adhesion characteristics.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a peptide, a peptide mimetic or an amino acid derivative, which contain di-substituted β-amino acid, wherein each of substituting group in the β-amino acid, which can be identical or different, contains at least 7 non-hydrogen atoms, is lipophilic and contains at least one cyclic group; one or more cyclic groups in the substituting group can be bound or condensed with one or more numbers of cyclic groups in the other substituting groups, and when the cyclic groups are fused so that an aggregate total number of non-hydrogen atoms for these two substituting groups makes at least 12, wherein the above peptide, peptide mimetic or amino acid derivative consist of 1-4 amino acids or length-equivalent sub-units.

EFFECT: preparing the peptide, peptide mimetic or amino acid derivative, which contain the di-substituted β-amino acid.

17 cl, 4 dwg, 10 tbl, 4 ex

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