Subcutaneous implant

 

(57) Abstract:

The invention relates to medicine, namely to subcutaneous implants. The implant is protected from overdose, not causing inflammation, biocompatible, not biodegradable subcutaneous polymer implant for long-term controlled release hydromorphone with almost zero kinetics. Also described ways of alleviating cancer pain and treatment of addiction to opioid drugs with this implant. 6 C. and 14 C.p. f-crystals, 14 ill.

The scope of the invention

The invention relates to a unique device for continuous subcutaneous administration of potent opioid in the form, which complicates the leak for illegal drug use and provides a long continuous release of the active agent, thereby providing long term pain relief or treatment of addiction to opioid drugs and preventing potentially lethal consequences unstable release of the drug from the device.

Background of the invention

Approximately 70% of cancer patients experience pain associated with the emergence of neoplasm or its treatment. Increasing the average long-lasting problem. The availability of opioid analgesics, the first therapeutic agent for most caused by cancer pain, varies significantly from country to country. In 1991, 20 developed countries accounted for 86 per cent of the world's morphine, while the remaining 14% of morphine consumed in other countries, with most of the world's population (Joranson D. E., Journal of Pain and Management option, 8 (6): 353-360, 1993).

The scarcity of opiates to alleviate cancer pain for most of the world's population is the result of many factors, including fear of diversion of drugs for illegal use and addiction. Further, many patients with cancer pain origin requires long-term continuous dosage of opioid analgesics, which often necessitates swallowing many pills or tablets several times during the day. Often the adherence doses is unsatisfactory. Further, the release of drug after ingestion poorly tolerated or even prohibited many patients with cancer pain origin, requiring prolonged administration of drugs. However, a long introduction opioid analgesics directly into the body's expensive, difficult and Addictive drugs is an important social problem worldwide. Only in the United States every day in the relevant medical institutions are hundreds of thousands of patients. Most of them are on the "outside support" as the basis of treatment.

The cost of treatment methadone support" is a few hundred dollars per month per patient. A considerable part of it falls on frequent visits to clinics and testing of urine to monitor proper compliance with the dosage of the drug, as well as for payment of the pharmaceutical accounts for sources of methadone.

Systems and devices for the controlled selection of drugs, i.e., for controlled allocation and delayed or prolonged separation, is well known. The literature describes a variety of ways, including physiological modification of absorption or excretion, modification of solvents, chemical modification of drugs, drug absorption in the insoluble carrier, the use of suspensions and implantable pills. Other methods include mixing the drug with a carrier, such as pasta, oil, grease and soluble polymers, which gradually decompose the environment, leading to the excretion of the drug. Considerable attention was directed to devices roar polymer container, allow the preparation to stand out from the tank.

Another type of device for the selection of the drug is of the monolithic type in which the drug is dispersed in the polymer from which it is released upon decomposition of the polymer and/or as the release of the drug from the polymer. A well-known representative of the impermeable polymer is ethylenevinylacetate copolymer (EVA) (Rin C. D. and others Journal of Pharmaceutical Sciences, 69: 265-270, 1980; Newton M. C. and others, Journal of Pharmaceutical Sciences, 73: 1859-1861, 1984; Cohen, J. and other Journal of Pharmaceutical Sciences, 73: 1034-1037, 1973). The kinetics of release of the drug from the polymer system selection depends on the molecular weight of the agent, the solubility of lipoid, quantity of the drug, and the characteristics of the polymer, the percentage of the drug and the characteristics of the matrix coating. The importance of these factors with specific pharmacological, Toxicological and therapeutic purposes leads to the need for careful design of the polymer implant for a specific agent.

Ku and others, Journal of Pharmaceutical Sciences, 74, 926 S. (1985) describes the design with plenty of holes for receiving a zero-order release.

Subcutaneous internal supply of opioid antagonists of Il treatment of dependence on opioid drugs and secondly, the lack of pain is widely recognized in the world.

A. Narcotic antagonist: naltrexone

Over the last two decades has made several attempts to use polymers containing narcotic antagonists, in order to prevent drug addiction. Features of release of such antagonists is less critical than the characteristics of a pure antagonists, as evidenced by references in the literature on the kinetic curves of the first order.

1. Glycerin implants

2. Cholesterol-glyceryltrinitrate in experiments on rats showed the kinetic curve of the first order.

3. Glutamic acid and leucin - biodegradable.

4. Drops polylactic/glucosidases acid (PLGC).

Century Mixed narcotic agonists/antagonists:

Buprenorphine

Kinetic curves of release of the drug first order are obtained by using the agent, which is not preferred for the treatment of chronic pain.

1. Cholesterol-glyceryltrinitrate in experiments on rats showed the kinetic curve of the first order.

C. Narcotic agonist: morphine

Morphine is an excellent contrast ratio is the Eney convenient for long-term subcutaneous implantation. Many of these implants shows the kinetic curve of the release of the drug first order, which can be life-threatening patients receiving implants that contain lethal amounts of opioids.

1. Polymeric silicone elastomer.

2. Silicone with sodium alginate (swells upon contact with water, releasing the drug).

3. Tablets.

4. Polyanhydride connection.

D. EVA-implants

EVA (ethylenevinylacetate) polymers are used to identify many classes of drugs: hormones (for example, prednisone, insulin), antineoplastic agents (e.g., 5FU, adriamycin), proteins (e.g. albumin, immunoglobulins), neurotransmitters (e.g., dopamine) and antibiotics. The release of these agents should not be compared to the consequences of the release of strong opioids.

1. Prednisolone (Miyazaki S. and others , Chem. Pharm. Bull. (Tokyo), 29: 2714-2717, 1981).

2. 5FU (Wyszynski R. E., and others, J. Ocul. Pharmacol., 5:141-146, 1989).

3. Adriamycin (Lin C. Y. and others, Biomat Art Cells Art Org., 17:189-203, 1989).

4. Insulin (brown L. et al. Diabetes, 35:692-697, 1986; brown L. et al. Diabetes, 35: 684-691, 1986) - covered EVA and with a hole on one side of a polymer, which gave nearly constant speed vysvobozhdavshej (Radomski M L. et al., Biomaterials, 11:619-624, 1990).

7. Albumin (Niemi, S. M. and other Lab. Anim. Sci., 35:609-612, 1985).

8. Dopamine/Levodopa (Dühring M. J. and others, Ann. Neurol., 25:351-356, 1989; Sabel B. A. et AL., Ann. Neurol., 28:714-717, 1990).

Mechanisms for EVA polymers and tests for biocompatibility and absence of inflammatory actions described in the literature. Brown L. R., and others, J. Pharm. Sci. , 72:1181-1185, 1983; Langer P., and others, J. Biomed. Mater. Res., 15: 267-277, 1981; Niemi, S. M. and other Lab. Anim. Sci., 35:609-612, 1985, all describe newsplease nature of the polymer and the technique of its manufacture.

Critical factors influencing the change of the release characteristics of drugs from EVA-polymer, also described in the literature (brook, I. M., and others, Br. Den. J., 157:11-15, 1984).

U.S. patent US 5153002 included in this description by reference thereto, describes a cube, five sides of which are covered with an impermeable layer, and the cylinder, which covered all sides, except for one end. The hemisphere with impermeable (paraffin) coating, except for the indentation on the front surface, provided the zero release kinetics of albumin (Hsieh D. C., and others , L. Pharm. Sci., 72:17-22, 1982). EVA with an impermeable coating polymer with a hole in the center of one of the surfaces provided zero cinena affects the kinetics of release (Rin C. D. and others, J. Pharm. Sci., 69:265-270, 1980).

Grossman and others (Proceedings ASCO), T. 19, S. 337, 1991) describes the allocation system, in which hydromorphone enclosed in a matrix controlled release from poly[vinyl acetate].

The purpose of the invention

The aim of the present invention is to provide an implantable, biocompatible polymer, which subcutaneously continuously emit a stable concentration of opioid analgesic in the periods from two weeks to over six months.

Another objective of the present invention is to provide means receiving relieves pain hydromorphone in the form of complicating diversion for illicit use.

The invention

The present invention relates to a system subcutaneous selection, including: i) a polymeric matrix material, ii) a therapeutic agent, a prisoner in the above-mentioned matrix, and (iii) a coating surrounding said matrix, characterized by the fact that this allocation system is adapted to provide a virtually constant allocation of hydromorphone.

The invention also includes a method of manufacturing the allocation system, including: (i) the location of therapeutic agent in a polyethylene vinyl acetate matrix, (ii) giving a cylindrical hole along the axis of the cylindrical matrix, forming an internal wall in said matrix, characterized in that the inner wall has no cover.

The invention relates also to method ensure the continued easing of pain in a mammal suffering from pain, including subcutaneous administration to the mammal at least one device (and when you enter two or more devices, they either joined together or introduced separately), and also relates to a method for treatment of dependence on opioid drugs in mammals suffering from such dependence, including subcutaneous administration to the mammal at least one device.

Brief description of drawings

In Fig.1 presents a General view of the device according to the present invention.

In Fig. 2 shows a cross-section of the ejector along the line 2-2 in Fig.1. The thickness of the coating is shown most illustrative purposes.

In Fig. 3 shows a General view of the device according to the present invention, made in the shape of a hemisphere.

In Fig. 4 shows a General view of the device according to the present invention in a cubic form.

In Fig. 5 presents a General view of the device aguideline hydromorphone inside (in vitro) of poly-(methyl methacrylate) coating with a Central hole and without it compared to the allocation of uncovered solid device.

In Fig. 7 shows the influence of the height of the cylindrical device with a poly-(methyl methacrylate) coating and the same center hole diameter allocation hydromorphone inside (in vitro).

Fig.8 illustrates up to four weeks almost zero kinetics of release hydromorphone inside (in vitro) of the ejector according to the invention. Excluded the initial release of release, complicating action many devices controlled dispensing.

Fig. 9 shows that a simple modification of the device issuing allows you to easily vary the amount of hydromorphone released per hour, and the duration of release hydromorphone inside (in vitro).

Fig. 10 shows that the two ejector placed subcutaneously to each of the 5 rabbits, provide consistently supported the concentration of hydromorphone in plasma up to four weeks. Concentrations in plasma are in the range of therapeutic doses to humans.

Fig. 11 shows the projected release of hydromorphone from multiple implanted devices, issuing and observed concentrations of hydromorphone in plasma of rabbits over time. The increase in the number subcutaneously, implanter is the AZM rabbits. The General toxicity of 6 implants (approximately 900 micrograms of hydromorphone per hour) was evident in the passing of time, depression and loss of appetite.

Fig. 12 shows that subcutaneously implanted osmotic pumps that produce approximately the same amount of hydromorphone per hour, and two ejector according to the invention, produce comparable concentrations of hydromorphone in plasma of rabbits.

Fig. 13 shows that intravenous administration of a 50% (600 μg) and 100% (1200 mcg) total number of hydromorphone released two devices issue within 4 hours (typical interval dosage for humans) leads to the peak concentration in plasma of rabbits within one minute followed by rapid decline to background within a few hours. Peak concentrations of hydromorphone clearly manifested and were at least 4 times higher constant concentrations obtained with the aid of the device according to the invention.

Detailed description of the invention

The invention relates to biocompatible non-inflammatory and biologically not degradable implantable device 2, which provides controlled release of potent opioid with packager, polyethylenterephtalate, and this polymer is biocompatible cover and impervious to hydromorphone polymer 12, for example poly(methyl methacrylate). Typical implant has a cylindrical geometry with a diameter of the upper 4 and lower 6 cross sections of the cylinder, substantially exceeding the height of the outer wall 8 of the cylinder. The implant 2 perforated with the formation of the openings 10 in the upper 4 and lower 6-section device 2 and uncovered the inner cylindrical wall 16. This structure provides a constant release of hydromorphone.

The dispenser in accordance with the present invention minimizes the possibility of leakage of the drug, improves compliance with the prescribed dosage and eliminates the costly need to attract staff and use of equipment, and the need for costly and not always available external catheters and pumps for patients with cancer pain requiring continuous infusion of opiates. The device allocates a fixed amount of hydromorphone in vitro and in vivo for extended periods of time. Levels of hydromorphone in plasma achieved by using the present invention are not significantly toxic. Achieved stable UB is risovaniya, achieved using implants, quite similar to the values obtained using osmotic pumps.

The floor 12 of the EVA polymer containing the drug, effectively eliminates the initial peak of the issuance of the drug observed in many other devices issued. Unlike intravenous injection levels of hydromorphone in plasma obtained after implantation of this device remain stable and are therapeutically acceptable limits throughout the dosing interval.

By varying the thickness (i.e. height of the wall 8) and diameter (i.e. the diameter of the upper 4 and lower 6 sections) of these devices, as well as variation in the number of implantable devices, is achieved by regulation of the quantity of hydromorphone released into the hour, and the duration of the selection hydromorphone, and values of the obtained levels of hydromorphone in plasma.

The present invention solves the problem of "peak effect" hydromorphone, eliminates the need for repetitive injections of hydromorphone, provides long-term relief of persistent or chronic cancer pain, provides the means to treat dependence on opioid drugs and prevent drug risk, i.e. the leak according to the invention.

Opiod

Hydromorphone (including hydromorphone hydrochloride) is a water-soluble strong opioid (6-7 times more potent than morphine), allowed for subcutaneous use and is usually prescribed to patients with cancer pain. Cm. The Wallner and others, J. Clin. Pharmacol., 21:152-156, 1981; Bruera etc. , J. Natl. Cancer Inst., 80:1152-1154, 1988; Reidenberg and others, Clin. Pharmacol. Ther. , 44:376-382, 1988; Moulin and others Can. Med. Assoc. J., 146: 891-897,1992; Moulin and others, Lancet, 337:465-468, 1991. Restrictions on the sizes of hypodermic devices issue, make a preferred use of this opioid. Hydromorphone is perfectly soluble in water and give a satisfactory release of the hydrophobic polymer EVA.

Matrix

Ethylene vinyl acetate (EVA) copolymer is biocompatible, non-inflammatory and biologically not degradable polymer. In the present invention is used not biologically degradable polymer to provide localization. Further, if any adverse circumstance will force the doctor to remove the implant 12 from the patient, it can be removed intact. Biodegradable implant over time softens and loses its structural integrity, making the possibility of immediate removal zatrudnieniu solution. The pre-polymer is dissolved in an organic solvent, preferably in a solvent with a low boiling point, for example, methylene chloride or chloroform, to facilitate subsequent removal of the solvent by evaporation. The concentration of polymer in the solution is preferably from five to fifteen percent by weight. Too weak solution leads to the formation of bubbles during casting, and too difficult concentrated dispersion of particles of the drug in solution.

The drug introduced in the EVA matrix, dissolve, and in the case of high load level drug dispersed in the polymer solution. The drug can be released by penetration through the polymer phase, and if the drug has low solubility in the polymer by diffusion through pores and channels. As particles of the drug near the surface of the matrix is dissolved and released, they remain pores and channels through which are released when the particles of the drug. Preferably sift particles of the drug, because of their size should be determined by the size of the pores and channels. However, this is not absolutely necessary, if only particles of the drug are not stuck with the formation of large lumps, naweglanie) is achieved with micronized particles of a commercially available drug.

The solution of the polymer with the drug is poured into the form required type and size. After a slow (to prevent the formation of bubbles) evaporation of the solvent molecules or particles of the drug are embedded in the polymer matrix. Molding is usually carried out at low temperature to prevent precipitation of the particles of the drug during evaporation of the solvent. Typically, the polymer solution containing the drug is poured into the mold, which is cooled to a temperature below the melting temperature of the solvent. The solution thus quickly freezes, providing uniform distribution of the particles of the drug in the target matrix.

Other materials that can be used as a matrix include silicone rubbers, hydrogels, for example, poly-(vinylalcohol) and poly-(hydroxyethylmethacrylate) with cross-links.

Floor

Floor EVA polymer-matrix excludes potentially dangerous "peak effect" usually seen in devices managed issue. Uncoated polymer allocates hydromorphone peak in the first two days of using the drug, and then reduces the issue to a minimum in the following days (see Fig. 6). This is a key problem in the use of Poggiomarino. To exclude peak effect and a more stable and permanent kinetics allocation without manipulating heterogeneous distribution of the drug in the matrix EVA-polymer 14 containing a drug is covered, except for the small holes 10 in the middle of the floor 12, impermeable to the drug and the biocompatible with the tissues, causing only minimal encapsulation of the implant 12 densified tissue. Preferably hydromorphone used bone cement poly-(methyl methacrylate). The coating 12 should be thick enough taking into account of their estimated time of service of the implant, typically about 100 microns.

The coating matrix preferably carried out by coating by immersion. For example, floor exercise, putting the disk on the needle from the syringe to the desired diameter and immersing it in a solution of polymer. By applying several layers of repeated dipping and drying, the needle is removed, revealing a bare cylindrical hole. On the contrary, the hole axis of the matrix can be performed after the coating matrix. The drug is released only through this hole. This configuration receive almost constant release of the drug in the absence of the castle is biodegradable (negligible splitting patterns of the polymer and loss of mass for a two-month period), it is soluble in the solvent, which is not a good solvent for the selected matrix. Otherwise, the matrix is partially dissolved least in the process of coating by immersion and some of the molecules or particles of the drug could be embedded in the floor. The solubility parameter of poly(methylmethacrylate) lies in the range of 9-9,5 [cal/cm3]0,5. A suitable coating for polymer EVA-hydromorphone may be other polymers, impervious to hydromorphone and having the same solubility parameter.

Load drug

The ratio of hydromorphone to the EVA polymer can comprise from 10 to 90 percent of hydromorphone by weight, preferably from 30 to 70 percent. The mixture of the drug with EVA homogeneous. Large concentrations of hydromorphone use usually with small holes 10 (see below).

The geometry of the implant

It is preferable to use the implant has a cylindrical shape (see Fig.1 and 2). Can be used by other geometry in which the distance between the uncovered wall and covered by a wall (opposite the uncovered wall) is constant or substantially constant (+-20%) on the implant, for example, a hemisphere with a bare wall in the form Pol provide almost constant release rate over the lifetime of the implant.

The cylindrical implant is performed with a diameter of 5 to 100 mm, preferably from 10 to 25 mm and a height (thickness) of from 1 to 20 mm, preferably from 1 to 2 mm.

One round or almost round hole 10 in diameter from 50 μm to 3 mm, preferably from 0.5 to 1.5 mm forms an inner cylindrical uncovered region 16, through which the drug is excreted. The orifice device is cylindrical, cubic, hemispherical or other shape should be less than 10%, and preferably less than 1% of the surface area of the top of the device.

Multiple device according to the invention is formed by overlapping a cylindrical implant (or implant other forms), i.e., when the axes of the device perpendicular to the axis of the multi-section device (see Fig. 5). When applying the contact area (i.e., which components are connected) individual component (i.e., separate cylinders or cubes) can be covered or uncovered.

In another embodiment, a multi-section device is formed so that the axes of the devices (e.g., cylindrical or cubic) coincide with the axis of the multi-section device. To connect the individual devices and thus provide new separators are one or more items, extending parallel to the axis multiple devices, where each element is bonded with the outer wall of each individual device. In another embodiment, between the individual devices placed porous elements (providing the connection devices). In another embodiment, for the formation of multiple devices use small separators in contact (and connecting) the bottom one single device and the top of the neighboring device. It is preferable to manufacture the separator made of the coating material, i.e., from poly-(methylmethacrylate). In another embodiment, the separator can be used popoloca covered with this material.

Introduction implant

The device according to the invention 12 is implanted subcutaneously, preferably into the upper arm or in the abdominal region, using techniques known to experts in this field. Dosage choose safe and effective for a particular patient. Too low dosage leads to inadequate sedation pain, and too high can lead to depression and respiratory failure. For example, in the treatment of cancer pain using the visual analogue scale for smerek with the appropriate dosage.

For the treatment of cancer pain usually use implants that produce from 0.1 to 25 mg/h, preferably from 0.1 to 10 mg/h (for example, 0.25 mg/h, 1 mg/h and 4 mg/h). The patient usually implanted from one to three implants. Dosage (mg/h) preferably adjust the height of the cylindrical disk or hole diameter, i.e., the increase in the height or diameter of the hole means higher speed selection (a large area of the uncovered surface 16 is exposed to the external environment). Cm. Fig. 7. The use of multiple devices, or separate, or superimposed one upon the other, as described above, increases the dosage. In addition, the dosage increases, increased loading of the drug.

For the treatment of opioid dependence usually use implants that produce subcutaneously from 0.1 to 0.5 mg/h hydromorphone. Discussion methadone support, see Strain and others, Ann. Intern. Med., 119:23-27, 1993, and Gerstein, and Levin, N. Engl. J. Med., 323, 844-848, 1990.

The device according to the invention may be controlled to select hydromorphone to maintain the desired level in the blood from two weeks to over six months. The implant preferably is adjustable by selection of the diameter (the larger the diameter, the more time deià cancer pain the preferred implant, designed for four weeks, because oncologists usually to inspect their cancer patients at least once a month. The pain may increase as the result of progressive tumor growth, which will require an increase in dosage. Moreover, there is the addiction to hydromorphone, so that higher dosage may be required for relief of pain the same force in the next month.

The device according to the invention provides an almost constant allocation of hydromorphone. "Almost constant" refers here to plus or minus five times (500%), preferably plus or minus two times (200%) the change, and most preferably plus or minus one-time (100%) speed change selection (in vivo or in vitro). More than five-fold change results in a "peak effect", which could cause a threat or even the death of the recipient.

In one of the embodiments of the invention the selection of the drug from the implant accompany additional technique (oral, rectal), when the patient experiences increased pain.

Treatment pain

The implant according to the invention can be used in all cases when the internal receiving opiates. Internal intake of opiates, the OSC, when ingestion is not suitable or not available or if there is toxicity associated with intermittent reception. The implant according to the invention can be used in the treatment of cancer pain in humans and in other animals. The implant can find application in the treatment of other types of chronic pain, such as chronic severe pain associated with degenerative musculoskeletal diseases or diseases of the nervous system.

Treatment of opioid dependence

The implant according to the invention may be useful in the treatment of dependence on opioid drugs (such as heroin). Hydromorphone given in small doses, for a long time is an effective treatment for addiction. The implant according to the invention can be used in any situation where it may be used methadone program support. The implant ensures compliance with low dosages of the drug for long periods without relying on patient compliance schedule dosages when administered. Further, when using the implant, the drug is available in a form which virtually eliminates the possibility of illegal use.

The trail of the present invention are, and other suitable modifications and adaptations to different conditions and parameters normally encountered in clinical therapy, obvious to a person skilled in this field.

EXAMPLES

Example 1

The formation of polymer

In these experiments for the formation of hydromorphone implant used method of low-temperature casting solution. EVA (with a molecular weight of approximately 250,000)(Elvax-40W DuPont) with 40% by weight of vinyl acetate was washed with water and dissolved in methylene chloride (CH2CL2) to obtain a 10% solution. To remove dirt and antioxidants polymer could be purified by extraction with distilled water for three days in a Soxhlet extractor, with subsequent extraction with acetone for another four days. Matrix with the inclusion of hydromorphone were prepared by casting a solution. 10% (weight per volume) solution of EVA was obtained by dissolving 2 g of pure EVA in 20 ml of methylene chloride.

To 10% EVA at room temperature was added whole powder hydromorphone hydrochloride (Knoll Pharmaceuticals) before the formation of 50% by weight solution which was then subjected to magnetic stirring for about 10 minutes. Powder hydromorphone could mechanically prostiutes to a certain particle size and to form a suspension in a solution of EVA. Visible makrana suspension was quickly applied to the recrystallization saucer 14 cm in diameter, pre-cooled with dry ice to -78oC. the Plate was covered to reduce condensation. After solidification, which took place within 15 minutes, the sample was dried for two 48 hour periods: in the first at -20oC, and then in vacuum at room temperature.

From the dried round plate pervym drill # 7 cut out about 15 polymer disks hydromorphone of 0.27 cm thick and 1.05 cm in diameter. For experiments, indicating the possibility of variations in the number of hydromorphone released per hour, were made of polymer disks double and triple thickness (respectively 0,55-0,65 cm and 0,83 cm) by doubling or tripling the amount of the mixture EVA with hydromorphone placed in the form. Polymer disks 2,13 cm in diameter to demonstrate variations in the duration of release of the drug were cut from the dried plate EVA with hydromorphone pervym drill N 15.

Example 2

Polymer coating

Before coating each polymer EVA disk with hydromorphone approximately the center of its circular side punctured hollow steel needle 18 size. Then each polymer disk was coated by immersion in a 10% solution of poly-(methylmethacrylate) with the molecular the ear at room temperature for 24 hours, then the needle was removed, the polymer disk was upside down and the needle was inserted with the other hand. The procedure was repeated two more times to obtain an impervious coating of a poly (methylmethacrylate) triple thickness, which is completely surrounded by the polymer except for the cylindrical holes 18 size (about 1.25 mm in diameter) passing through the center of each polymer disk, like the hole in the button. The coating thickness was achieved approximately 100-200 μm. The solubility parameter of the coating material was 9-9,5 [cal/cm3]0,5.

Example 3

Test selection in vitro

The allocation of hydromorphone from covered EVA polymer with hydromorphone was tested in vitro at the location of each polymer sample in a glass the acquired scintillation vial containing quality buffer 10 ml of 0.1 mol of sodium phosphate with a pH of 7.4, warmed to 37oC. All vials were placed in a water bath at 37oC. at appropriate intervals, the buffer of each bubble were selected and placed in a centrifuge tube and the vial was added 10 ml of fresh phosphate buffer at 37oC. Samples together was periodically measured with a UV spectrophotometer at a wavelength of 254 nm in parallel cells with the concentrations of hydromorphone and, if necessary, samples were diluted with buffer, so that their absorption could be measured on the linear part of the calibration curve.

Covered EVA polymers with hydromorphone allocated hydromorphone with a constant average speed of 164 µg/hour starting from the fourth day after the beginning of the release in vitro over a period of 4 weeks. The coating of these polymers impermeable layer of poly(methylmethacrylate), except for the center hole full thickness excludes the initial "peak", which complicates the use of many other devices with adjustable selection. The variation in the number of hydromorphone released into the hour, and the duration of excretion of the drug is easily achieved by varying the thickness and diameter of the coated polymer EVA with hydromorphone. Cm. Fig. 9.

Examples of in vivo

Example 4A

The release of polymer

Two covered EVA polymer with hydromorphone were placed under General anesthesia in subcutaneous pouches of each of the five adult rabbits. Each rabbit was kept in a cage and got rabbit feed and water without restrictions. For each animal were taken and blood samples before implantation and at certain intervals up to 6 weeks after placing. Blood samples were tsentrifugirovanie and plasma were collected and stored in the refrigerator PR is the ATA and reference hydromorphone samples. To demonstrate the ratio of the number of implanted hydromorphone and the resulting level of the drug in the blood plasma of two additional rabbit got three portions by two polymer sequentially implanted at intervals of about one week. Previously implanted coated with polymers that were kept, so these rabbits had the first 2, then 4 and then 6 polymers, simultaneously emitting hydromorphone. Blood samples were taken and plasma was tested as described above.

Two devices simultaneously implanted in rabbits, produce stable and long-lasting levels of hydromorphone in plasma 23-27 ng/ml up to four weeks (see Fig.10). The increase in the number of subcutaneous implants in rabbit produces long-term and predictable increase in the concentration of hydromorphone in plasma of rabbit (see Fig. 11). In these experiments, animals were not observed appreciable toxicity, except for a weak passing of depression after implantation of two devices and increase of depression with reduced appetite, also going after implantation of a larger number of devices.

Example 4B

Issuance of osmotic pump

For you the political pumps company Alzet, outstanding approximately the same amount of hydromorphone per hour, and that the two devices according to the invention. Each of the four rabbits under General anesthesia were placed subcutaneous Alzet osmotic pump (average speed pump was $ 2,08 ál/h, the average amount of fill - 2073 μl); the sampling of blood was performed as described above. Plasma preparation and analysis was carried out as described above.

Osmotic Alzet pumps that produce 297 µg/h hydromorphone, provided the mean levels of hydromorphone in plasma of rabbits from 28 to 51 ng/ml within two weeks (see Fig. 12).

Example 4C

Intravenous hydromorphone

Two rabbits was injected intravenously at a single dose of 600 mcg and 1200 mcg, respectively (which was equal to 1/2 and 1 dose total amount allocated subcutaneously polymers or pumps for 4 hours, typical interval dosing for humans); samples were taken at intervals 0, 1, 2, 5, 10, 20, 30, 45, 60, 90, 120, 150, 180, 210 and 240 minutes.

Six hundred and 1200 μg injections of hydromorphone produced peak levels of hydromorphone in plasma of rabbits almost 200 and 250 ng/ml for one minute with fast decay to background within 4 hours (see Fig. 13).

For the light is I, the system can be modified and updated without departing from the disclosed invention.

1. The device subcutaneous injection containing (a) a matrix containing polyethylenterephthalat, (b) hydromorphone, uniformly nourishing this matrix, (b) the floor of this matrix of polymethylmethacrylate, wherein the device is adapted to obtain a hydromorphone and has perforations along the Central axis geometric shape and contains a coating of the outer wall and the inner wall has no cover.

2. The device under item 1, characterized in that the geometric shape of the device is such that the distance between the uncovered wall and covered the wall opposite the uncovered wall, is almost constant throughout the device introduction.

3. The device under item 1, characterized in that it has a cylindrical shape and has an axis of cylindrical hole, which forms the inner wall of the device's introduction.

4. The device under item 1, characterized in that the thickness of the coating is from 0.1 to 1.0 mm

5. The device under item 1, characterized in that the matrix contains 50% by weight of hydromorphone and 50% by weight of polyethylenterephtalate.

6. The device under item 5, characterized in that hydromorphone is distributed homogeneously in the matrix.

>8. The device according to p. 3, characterized in that the cylindrical hole has a diameter of from 0.05 to 3 mm

9. A method of obtaining a device for subcutaneous injection under item 1, comprising dispersing hydromorphone in polyethylenepolyamines matrix, forming a cylinder from it, coating the matrix with polymethylmethacrylate and the perforation is covered with a matrix along its Central axis.

10. Device for subcutaneous injection containing polymer matrix, hydromorphone, including the matrix, and a coating surrounding the matrix, is not permeable to hydromorphone, characterized in that the device is cylindrical in shape and has a cylindrical hole along the axis of the device, forming internal bare wall for emission hydromorphone.

11. The device according to p. 10, characterized in that the polymeric matrix material is polietilentereftalata.

12. The device according to p. 10, characterized in that the coating is made of polymethylmethacrylate.

13. The device according to p. 10, characterized in that the thickness of the coating is from 0.1 to 1.0 mm

14. The device according to p. 10, characterized in that the matrix contains 50% by weight of hydromorphone and 50% by weight of polyethyleneamine.

16. The device according to p. 10, characterized in that the cylinder has a height of from 1 to 20 mm and a diameter of 5 to 100 mm

17. Multicell device for subcutaneous injection containing at least two devices introduction by p. 1, connected one with the other.

18. The way to ensure long-term weakening of the pain mammal suffering from pain, including subcutaneous administration to a mammal of the device under item 1.

19. The method according to p. 19, characterized in that the said pain is cancer pain.

20. A method for the treatment of opioid drug dependence mammals with such dependence, including subcutaneous administration to a mammal of the device under item 1.

 

Same patents:

--isomer of 2,5-dimethyl-4 - hydroxypiperidine - intermediate in the production of mestoobitaniyakh drug rihlokain" target="_blank">

The invention relates to a method of obtaining-isomer of 2,5-dimethyl-4-hydroxypiperidine - intermediate in the production of mestoobitaniyakh drug rihlokain recovery 2,5-dimethyl-4-Ketobemidone by sodium borohydride in the presence of a mineral acid while maintaining the pH of 4.5 - 6.0, and the temperature of the reaction mixture to 0 - 5oC

The invention relates to a piperidine derivative of General formula (I) where Z represents the group -(CH2)m-CH(OR3) or a carbonyl group, R1is hydrogen or (C1- C3)alkyl, R2- (C1- C3)alkyl, or R1and R2together form a chain -(CH2)n, where n is the number of 3 - 5, or -(CH2)2-O-(CH2)2-, m = 0 - 1, n = 1 - 2, R3- hydrogen or-COCH3and R4- hydrogen, -CH3, -OH or-OCH3provided that when Z represents a carbonyl group, h = 2, or their pharmaceutically acceptable salts

FIELD: medicine.

SUBSTANCE: the present innovation deals with the method to accelerate mucosal healing due to the following technique: one should apply a membrane consisted of purified collagenic material obtained out of natural collagen-containing tissue onto the part of affected mucosa to provide the chance for mucosal reconstruction in this part and, also, it deals with mucosa-regenerating preparation and application of purified collagenic material obtained out of collagen-containing natural tissue for preparing mucosa-regenerating preparation. The innovation provides more modified method that accelerates mucosal regeneration, as a whole, and, particularly, after surgical operations associated with the plasty of oral fornix.

EFFECT: higher efficiency.

12 cl, 3 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: method involves mechanically cleaning biological connective tissue and treating animal or human connective tissue with solutions. After mechanical cleaning, the animal or human connective tissue is hold in 3-6% hydrogen peroxide solution 2-4 h long, frozen at temperature below 0°C in wet state, thawed and treated with alkaline detergent solution of pH 7.0-14.0. Then, it is treated with 3-6% hydrogen peroxide solution 2-4 h long , heat treated at 40-90°C, shaped as required and sterilized.

EFFECT: improved quality of allergen-free biomaterial.

14 cl

FIELD: abdominal surgery.

SUBSTANCE: invention relates to manufacturing prostheses for abdominal surgery based on synthetic polymeric complex threads with coating, whose composition, in order to impart antimicrobial properties to allotransplant, is completed with various-type chemiotherapeutical materials, in particular antiseptic substance (Poviargol). Prosthesis of invention is designed for plastics of hernial defects of abdominal wall. Mesh prosthesis with antimicrobial properties for hernioplasty is manufactured as follows: polymeric composite consisting of (i) Poviargol substance, which is metal-polymer composition of ultrafine metallic silver stabilized with synthetic polymer Collidon, 40-45%, and (ii) medical-grade high-molecular weight polyvinylpyrrolidone, 55-60%, is applied onto synthetic polymer mesh, after which mesh with dispersion applied thereon is dried by way of blowing with hot air (60-80°C) for 20-30 min.

EFFECT: simplified manufacturing procedure and enhanced antimicrobial efficiency.

2 tbl, 8 ex

FIELD: polymer materials.

SUBSTANCE: invention concerns amorphous light-sensitive cross-linked polymeric structure and provides structure including (i) amorphous cross-linked structure formed from matrix based on acrylate and/or methacrylate compound and cross-linking agent and (ii) photoreactive component capable of undergoing reversible photodimerization reaction. Cross-linked structures are characterized by good properties with shape-memory effect.

EFFECT: increased mechanical strength of material with desired property profile.

21 cl, 4 dwg, 2 tbl, 12 ex

FIELD: medicine, in particular tubular polyurethane articles (guides, suction drainages, catheters) having aseptic coat.

SUBSTANCE: claimed articles are produced by providing of article elements followed by assembly thereof and application of aseptic coat by impregnation of catheter surface with chlorohexidine and/or salts thereof (e.g., dihydrochloride, or diacetate, or bigluconate, etc.), by article treatment for 14-180 min with aqueous-alcohol solutions of chlorohexidine and/or salts thereof at 20-60°C, containing (mass %): chlorohexidine and/or salts thereof 1-5; ethanol or methanol 75-85; water 15-25.

EFFECT: prolonged anti-microbial activity; protection against body contamination during catheterizing.

5 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: described method of implant material production on basis of pored polytetrafluorethylene includes processing of base surface which serves as a substrate, deposition of surface layer modified with alloying elements onto processed substrate by magnetron deposition of one of targets selected from the following metals: titanium, zirconium, hafnium, niobium, tantalum, mainly titanium, carbides of mentioned metals, mainly titanium carbide of TiC0.5; compound ceramic materials from the following group: TiC0.5+10 mass.% CaO; TiC0.5+10 mass.% CaO+2 mass.% KMnO4; TiC0.5+10 mass.% ZrO2; TiC0.5+10 mass.% hydroxyapatite (Ca10(PO4)6(OH)2, deposition of one of mention targets at that is carried out at pressure 1-2x10-1 Pa, at substrate temperature between 150-170°C, in argon or argon and nitrogen medium at nitrogen partial pressure 14%. Implant material includes base of polytetrafluorethylene of porosity 3.0-40.0%, and surface layer of thickness not less than 50 nm modified with alloying elements composing mentioned targets. Surface layer at deposition of metal target in argon medium contains mentioned metal as alloying element mainly titanium. Surface layer at deposition of metal carbide in argon and nitrogen medium contains Ti-C-N as alloying elements. Surface layer at deposition of ceramic target TiC0.5+10 mass.% CaO in argon and nitrogen medium contains Ti-Ca-C-O-N as alloying elements. Surface layer at deposition of ceramic target TiC0.5+10 mass.% CaO+2 mass.% KMpO4 in argon and nitrogen medium contains Ti-Ca-Mn-K-C-0-N as alloying elements. Surface layer at deposition of ceramic target TiC0.5+10 mass.% ZrO2 in argon and nitrogen medium contains Ti-Zr-C-O-N as alloying elements. Surface layer at deposition of ceramic target TiC0.5+10 mass.% (Ca10(PO4)6(OH)2, in argon and nitrogen medium contains Ti-Ca-P-C-O-N as alloying elements.

EFFECT: method of implant materials production as a substrate for hybrid implants characterized by improved physicochemical, biomechanical properties and enhanced biological activity to biotissues.

10 cl, 1 dwg

FIELD: medicine.

SUBSTANCE: method implies use of high-tensile knitted armature, binding agent based on polyurethane components VILAD A-11k-3, VILAD-17, polyisocyanate of "B" mark, solvent acetone and pigment paste of corporal colour at following mass parity: (95-105):(9-11):(70-80): (9-11):(4-6) respectively, and mass parity of binding agent and knitted armature is (185-213):(74-85.2), and composition is hardened at temperature 60-65°C within 2-2.5 hour.

EFFECT: extended range of elasticity; prosthesis reliability and improved injured limb support ability and walking pattern.

2 cl, 1 dwg, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to the method of obtaining polymer materials, suitable for use in medicine. The proposed method of obtaining elastomer material involves a stage where polyurethane reacts with polydimethylsiloxane, with 4 acetoxy groups, 2 for each end part, in the presence of a solvent at temperature lower than 100°C. Concentration of polydimethylsiloxane ranges from 20 to 40 mass %. Material obtained using the described method is proposed, as well as its use in vascular prosthesis as material for making or covering prosthetic devices.

EFFECT: creating a method of obtaining bio-compatible, haemo-compatible and bio-stable elastomer material.

14 cl, 8 dwg

FIELD: medicine.

SUBSTANCE: composition of black-reinforced plastic for bone defect correction contains carbon-base material "ТГН"-2M and polyamide film 12/10. Additionally composition contains powdered silicon at following ratio of components wt %: carbon-base material "ТГН"-2M 57.5-62.5, powdered silicon 2.5-7.5, and polyamide film 12/10 - the rest. Particle size of powdered silicon is 20-50 mcm.

EFFECT: higher radiopacity and biocompatibility, reduced toxicity and carcinogenicity of material.

2 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: composition of black-reinforced plastic for bone defect correction contains carbon-base material "ТГН"-2M and polyamide film 12/10. Additionally composition contains powdered titanium and silicon at following ratio of components, wt %: carbon-base material "ТГН"-2M 60-64.5, powdered titanium 1.25-3.75, powdered silicon 1.25-3.75, and polyamide film 12/10 - the rest. Particle size of powdered silicon and titanium is 20-50 mcm.

EFFECT: higher radiopacity and biocompatibility, reduced toxicity and carcinogenicity of material.

3 cl, 1 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes implant prepared by mixing a carrier material with components of the preparation antibiotic/antibiotics with delayed release of an active substance (aminoglycoside, lincosamide antibiotics, 4-quinolone antibiotics and tetracyclines), and a method for preparing the implant. Release of an active substance from implant during from some days to some weeks doesn't dependent from a carrier material and adsorption effects of a carrier-material surface.

EFFECT: improved and valuable properties of preparation.

13 cl, 1 tbl, 6 ex

FIELD: medicine; therapeutic dentistry.

SUBSTANCE: new biological material for layer has low antigeny properties and keeps physical and mechanical properties of initial donor tissue. Biological laying has powder-like modified dentine with unblocked chemical bonds among collagen, chondrointin sulfates and mineral salts and Alloplant biological materials which have to be osteogeny stimulator, vasculogeny stimulator, phagocytosis stimulator at definite content of components. Laying for curing pulpitis has biological active matters to stimulate angiogenesis, dentinogenesis which matters activate phagocytosis.

EFFECT: improved efficiency of treatment.

1 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: bone-and-mineral product contains porous bone mineral particles produced from natural bone and having crystalline structure practically corresponding to natural bone structure and practically containing no endogenous organic material. The particles have fibers of physiologically compatible type II resorbable collagen at least on their surface. Mass proportion of type II collagen fibers and porous bone mineral is at least equal to approximately 1:40.

EFFECT: enhanced effectiveness in recovering combined injuries of cartilage and bone tissue in articulations having defects.

8 cl, 6 dwg

FIELD: medicine, in particular tubular polyurethane articles (guides, suction drainages, catheters) having aseptic coat.

SUBSTANCE: claimed articles are produced by providing of article elements followed by assembly thereof and application of aseptic coat by impregnation of catheter surface with chlorohexidine and/or salts thereof (e.g., dihydrochloride, or diacetate, or bigluconate, etc.), by article treatment for 14-180 min with aqueous-alcohol solutions of chlorohexidine and/or salts thereof at 20-60°C, containing (mass %): chlorohexidine and/or salts thereof 1-5; ethanol or methanol 75-85; water 15-25.

EFFECT: prolonged anti-microbial activity; protection against body contamination during catheterizing.

5 cl, 1 tbl

Transplant mixture // 2301684

FIELD: medicine.

SUBSTANCE: transplant mixture has liophylized allogenic bone tissue and allogenic hydroxyapatite and patient autoblood platelets gel with Metronidazole, taken in the following components proportions (%): liophylized allogenic bone tissue - 65; allogenic hydroxyapatite - 10; patient autoblood platelets gel - 20; Metronidazole - 5.

EFFECT: enhanced effectiveness of treatment; no clamps required; reliably and tightly closed bone tissue defect; accelerated regenerate reorganization; improved antiseptic and immunomodulating action.

FIELD: medicine.

SUBSTANCE: method involves introducing proper mesenchyme stem cells separated from marrow and cultivated in vitro. The cells are implanted on a carrier into cerebral cortex region planned in advance. To do it, the mesenchyme stem cells are preliminarily introduced into modified resorbable stent (carrier). The number of cells to be introduced is equal to 7-12 mln per one Brodman zone selected for transplanting autologic mesenchyme stem cells. Marked anatomical changes in brain regions being the case, the same quantity of cells are inravascularly (intravenously or intra-arterially) introduced. The treatment is carried out in particular cases in concurrently introducing the mesenchyme stem cells in intraperenchymatous or intravenous way.

EFFECT: enhanced effectiveness of treatment in cognitive-mnestic function disorder cases.

10 cl

FIELD: medicine.

SUBSTANCE: the present innovation deals with a medicinal prosthesis that contains metallic material, such as titanium or its alloy, in which surface parts of metallic material area covered with the layer of the corresponding hydroxide material, such as titanium hydroxide. Preferably, hydroxide layer contains one or more biomolecular substances being connected with it. Also, the innovation in question refers to electrolytic process for obtaining a medicinal prosthesis. Metallic prostheses are of improved biological compatibility.

EFFECT: higher efficiency.

24 cl, 8 ex, 3 tbl

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