Method for inhibiting reduction of transdermal drug movement by inhibiting paths closing

FIELD: medicine.

SUBSTANCE: method involves using known quantity of at least one agent hindering from healing when delivering or selecting an agent (the first agent). The agent hindering from healing is used in a quantity showing effectiveness in reducing transdermal movement of the first agent in comparison to movement of the first agent under practically identical conditions with the exception of absence of the mentioned at least one agent hindering from healing. A special-purpose device is used for applying the method and a set of accessories for setting the device.

EFFECT: enhanced effectiveness of treatment.

48 cl, 8 dwg, 3 tbl

 

The present invention relates to inhibition of reducing transdermal movement of the agent through inhibition of closed paths. In particular, the present invention relates to a method of inhibiting the decrease transdermal movement of the agent, which is delivered through the skin or a sample which is taken through the skin over a long period of time in which the delivery or sampling is accompanied by the violation of the integrity of at least the layer of the skin stratum corneum forming paths through which the agent passes through the joint delivery or joint sampling with a certain amount of at least one agent that prevents healing, in which the quantity of agent that prevents healing, is effective in inhibiting the decrease transdermal movement of the agent, compared to option when shipping or sampling occurs in almost identical conditions except for the absence of the agent (agents)that prevent (inhibit) the healing.

Drugs are usually administered orally or by injection. Unfortunately, many treatments are completely ineffective or drastically reduce its effectiveness when administered orally because they are not absorbed or ispytav who have adverse impacts before reaching the bloodstream and, thus, do not possess the desired activity. On the other hand, direct injection of drugs into the bloodstream, although warrants changes in medicine in the introduction, is inconvenient and uncomfortable procedure that sometimes contributes to non-compliance of the patient circuit and mode of treatment. Transdermal drug delivery offers improvements in this area. However, in many cases, the speed of delivery or movement of many agents via passive flow through the skin is too limited to be therapeutically effective.

One way to increase transdermal movement of the agents is based on the application of an electric current through the surface of the body, called "electric". "Electric vehicle" generally refers to the passage of positively acting agent, such as a medicinal product or precursor drug through the body surface such as skin, mucous membranes, nails, etc. where the agent is induced or enhanced by the application of electric potential. Electrotransport agent through the body surface can be achieved in various ways. One widely applied electrotransport process, iontophoresis is electrically induced transport of charged ion the century Electroosmosis, another type of electrotransport process is the movement of solvent with the agent through the membrane under the influence of an electric field. Electroporation is another type of electrotransport, is the passage of the agent through the pores formed by the application to the membrane electric pulse (pulses) high voltage. In many cases, there may be more than one of these processes simultaneously, in varying degrees. Accordingly, the term "electrotransport" in this document is interpreted in the broadest sense of the word, including the electrically induced or enhanced transport of at least one of a charged or uncharged agent or mixtures thereof, regardless of the specific mechanism or mechanisms by which the agent actually transported. Electrotransport delivery usually increases the movement of the agent during transdermal delivery.

Another way to increase traffic agent includes preliminary effects on the skin beneficial agent or joint delivery with a beneficial agent, an amplifier, the permeability of the skin. Substance that increase the permeability of the skin, when applied to the surface of the body, through which is delivered to the agent increases his movement through it, as well as with increasing selective permeability is/or permeability of the body surface, creating a hydrophilic path through the body surface, and/or decreasing the decomposition agent during transport. This methodology is typically used when the drug is delivered by passive transdermal diffusion.

It was also taken many attempts mechanical penetration through the skin or damaging the integrity, creating, thus, passes into the skin to enhance transdermal movement of the agent. Some of the earliest attempts to enhance transdermal movement of the medicinal product included applying to the skin scratches (e.g., sandpaper) or the scraping of leather strips to divide the stratum corneum. Later there were attempts to puncture or incision in the skin through the stratum corneum using a tiny connectors/cutting elements. See, for example, U.S. patent No. 5879326 issued Godshall et al., 3814097 issued Ganderton et al., 5279544, issued to Gross et al., 5250023, issued to Lee et al., 3964482 issued to Gerstel et al., assigned patent 25637 issued by Kravitz et al., and PCT publication nos WO 96/37155, WO 96/37256, WO 96/17648, WO 97/03718, WO 98/11937, WO 98/00193, WO 97/48440, WO 97/48441, WO 97/48442, WO 98/00193, WO 99/64580, WO 98/28037, WO 98/29298 and WO 98/29365. These devices use the stitching elements of various shapes and sizes to pierce the outermost layer (i.e. stratum corneum) of the skin. Stitching the elements described in these references, usually perpendicular to notonly flat part such as a pad or sheet. Piercing elements or microfactory in some of these devices are extremely small in size, some of the dimensions (i.e. length and width) are approximately only 25-400 μm, and the thickness of Microsystem - only about 5-50 μm. These tiny stabbing/cutting elements respectively carried out small microprotol/micro incisions in the stratum corneum to enhance transdermal delivery through them agent.

It is now established that human skin path created by microprogram/micro incisions, quickly closed and sealed, due to the natural healing process of the skin. Although the process is still not fully understood, I believe that it is closely related to wound healing. Wound healing is a complex phenomenon, involving many biological processes. The first event, which takes place during the first minutes in the wound-healing process, is the formation of a fibrin clot. In addition, during the early phase of wound healing is released or generated a lot of proinflammatory mediators. The release of these factors triggers the migration of keratinocytes, leukocyte infiltration, proliferation of fibroblasts, which leads to protein breakdown, protein synthesis and remodeling aniu tissues. At the end of this process is achieved by restoring the skin barrier. In some cases, enhancing transdermal movement of the agent created by the specified paths, completely stops after a few hours after the formation of the mentioned ways. Thus, there is a need for a method that can prevent or at least slow down the natural healing of skin, to ensure transdermal movement of agents through micro incisions/microprotol for longer periods of time (e.g., approximately more than one hour), when used as a method of delivery using microprocesador elements.

The present invention satisfies the specified and related to her needs.

The present invention relates to a method of inhibiting the decrease transdermal movement of the agent, which is delivered through the skin or a sample which is taken through the skin over a long period of time in which transdermal movement is accompanied by the violation of the integrity of at least the layer of the skin stratum corneum. Specifically, it was found that through joint delivery or joint sampling in the presence of at least one agent that prevents healing, closure of paths in the skin, formed due to the violation of zelos the surface layer of the skin stratum corneum, it is possible to inhibit, inhibition, thus reducing transdermal movement of the agent.

Accordingly, in a first aspect the present invention relates to a method of inhibiting the decrease transdermal movement of the agent, which is delivered through the skin or a sample which is taken through the skin over a long period of time in which the delivery is accompanied by a violation of integrity (for example, by punctures) at least layer of the skin stratum corneum to form a variety of ways, through which the agent; the method includes the joint delivery or joint sampling agent with a certain amount of at least one agent that prevents healing, in which a specified number of the specified agent that prevents healing is effective for inhibiting the reduction transdermal movement of the specified agent in comparison with the delivery or sampling specified agent in almost identical conditions except for absence of the specified agent (agents)that prevent healing.

In a second aspect the present invention relates to a method of transdermal delivery of an agent over an extended period of time, which includes

(i) the formation of many breaks through the skin layer stratum corneum, is obrazovaniya ways, through which the agent, and

(ii) the location of the tank in conditions allowing the transfer agent in respect of microreserves formed in stage (i); the specified tank includes agent and an amount of at least one agent that prevents healing, in which a specified number of the specified agent that prevents healing, is effective in inhibiting the decrease transdermal movement of the specified agent compared to the specified delivery agent in almost identical conditions except for absence of the specified agent (agents)that prevent healing.

In the third aspect of the present invention relates to a method of transdermal sampling agent over an extended period of time, which includes

(i) the formation of many breaks through the skin layer stratum corneum to form paths through which the agent, and

(ii) the location of the tank in conditions allowing the transfer agent in respect of microreserves formed in stage (i); the specified tank includes a quantity of at least one agent that prevents healing, in which a specified number of the specified agent that prevents healing, is effective in inhibiting the decrease transdermal movement of the specified AG the NTA, compared with the sampling of the specified agent in almost identical conditions except for absence of the specified agent (agents)that prevent healing.

In the above methods, at least the layer of the skin stratum corneum punctured, cut or otherwise damaged (e.g., abrasive or scraping strips), and most preferably at least a skin layer stratum corneum perforated using a device for punching leather, with many Microsystem that can penetrate the stratum corneum of the skin with the formation of many ways through which the agent and the agent that prevents healing. Agent (agents)that prevent healing, delivered either before delivery or selection agent sample, either before and during transdermal movement of the agent; or during transdermal movement of the agent; or during and after transdermal movement of the agent.

In the above methods, preferably the agent (agents)that prevent healing, selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit the migration of cells, and osmotic agents, in an amount effective to generate the solution osmotic pressure greater than 2000 kPa, preferably greater than about 3000 kilopascals at 20°who, or mixtures thereof.

Preferably, the anticoagulant selected from the group consisting of heparin with a molecular weight of from 3000 to 12,000 daltons, pentosanpolysulfate, citric acid, citrate salts, EDTA and dextrans with a molecular weight of from 2000 to 10,000 daltons.

Preferably an anti-inflammatory agent selected from the group consisting of hydrocortisone nativespace, betamethasone of nativespace and triamcinolone of nativespace.

Preferably, the agent that inhibits the migration of cells, which are selected from the group consisting of laminin and related peptides.

Preferably, the osmotic agent is a biologically compatible salt, such as sodium chloride, or neutral compound, such as glucose, or zwitterionic connection, such as glycine, having a sufficiently high concentration to provide the solution osmotic pressure exceeding 2000 kilopascals, more preferably about 3000 kilopascals.

Preferably the agent is delivered transdermal, is a macromolecular agent selected from the group consisting of polypeptides, proteins, oligonucleotides, nucleic acids and polysaccharides.

Preferably the polypeptides and proteins are selected from the group consisting of desmopressina, luteinizing releasing hormone (LHRH) and obtained the s LHRH (for example, goserelin, leuprolide, buserelin, triptorelin), PTH, calcitonin, interferon-α, interferon-β, interferon-γ, follicle-stimulating hormone (FSH), hGH, insulin, insulinotropic and erythropoietin.

Preferably the oligonucleotide is chosen from the group consisting of ISIS 2302, ISIS 15839 and other fosforilirovannyh oligonucleotides and other detoxicification oligonucleotides, and the polysaccharide is chosen from the group consisting of low molecular weight heparin having a molecular weight of from 3000 to 12,000 daltons, and pentosanpolysulfate.

Preferably the agent of the samples taken transdermal, is an analyte of the body. Preferably the analyte of the body is glucose.

Preferably, the agent and the agent (agents)that prevent healing, delivered by passive transdermal diffusion and/or by electric.

In the fourth aspect of the present invention relates to a device for transdermal delivery of an agent over an extended period of time; the specified device includes

(i) an item that has many connectors skin Microsystem, for the formation of numerous micro incisions through the skin layer stratum corneum to form paths through which the agent, and

(ii) a reservoir comprising the agent and the number n is at least one agent, preventing healing, in which a specified number of the specified agent that prevents healing, is effective in inhibiting the decrease transdermal movement of the specified agent, compared with the specified delivery agent in almost identical conditions except for absence of the specified agent (agents)that prevent healing.

In the fifth aspect of the present invention relates to a device for transdermal sampling agent over an extended period of time; the specified device includes

(i) an item that has many connectors skin Microsystem for the formation of numerous micro incisions through the skin layer stratum corneum to form paths through which the agent, and

(ii) a reservoir comprising an amount of at least one agent that prevents healing, in which a specified number of the specified agent that prevents healing, is effective in inhibiting the decrease transdermal movement of the agent, compared to the sampling agent in almost identical conditions except for absence of the specified agent (agents)that prevent healing.

In the sixth aspect of the present invention relates to a kit for transdermal delivery or sampling of an agent is for an extended period of time; the specified set includes

(i) the device with many Microsystem, for the formation of micro incisions through the skin layer stratum corneum to form paths through which the agent, and

(ii) an applicator for placing first specified element of the specified device on the skin to form the above-mentioned injuries.

Preferably the agent (agents)that prevent healing, selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit the migration of cells, and osmotic agents, in an amount effective to generate the solution osmotic pressure greater than about 2000 kPa, preferably greater than about 3000 kilopascals at 20°or mixtures thereof.

Preferably, the anticoagulant selected from the group consisting of heparin with a molecular weight of from 3000 to 12,000 daltons, pentosanpolysulfate, citric acid, citrate salts, EDTA and dextrans with a molecular weight of from 2000 to 10,000 daltons.

Preferably an anti-inflammatory agent selected from the group consisting of hydrocortisone nativespace, betamethasone of nativespace and triamcinolone of nativespace.

Preferably, the agent that inhibits the migration of cells, which are selected from the group consisting of laminin and related to him peptide is.

Preferably, the osmotic agent is a biologically compatible salt, such as sodium chloride, or neutral compound, such as glucose, or zwitterionic connection, such as glycine, having a sufficiently high concentration to provide the solution osmotic pressure in excess of about 2000 kPa, preferably greater than about 3000 kilopascals.

Preferably the agent is delivered transdermal, is a macromolecular agent selected from the group consisting of polypeptides, proteins, oligonucleotides, nucleic acids and polysaccharides.

Preferably the polypeptides and proteins are selected from the group consisting of desmopressina, luteinizing releasing hormone (LHRH) and LHRH analogs (such as goserelin, leuprolide, buserelin, triptorelin), PTH, calcitonin, interferon-α, interferon-β, interferon-γ, follicle-stimulating hormone (FSH), hGH, insulin, insulinotropic and erythropoietin.

Preferably the oligonucleotide is chosen from the group consisting of ISIS 2302, ISIS 15839 and other fosforilirovannyh oligonucleotides and other detoxicification oligonucleotides, and the polysaccharide is chosen from the group consisting of low molecular weight heparin having a molecular weight of from 3000 to 12000 gave the tone, and pentosanpolysulfate.

Preferably the agent of the samples taken transdermal, is an analyte of the body. Preferably the analyte of the body is glucose.

The present invention will be described hereinafter in more detail with reference to the accompanying drawings.

FIGURE 1 is a graph showing the effect of inhibitors closing track on passive transdermal movement pentosanpolysulfate.

FIGURE 2 is a graph showing the effect of inhibitors of closed paths on the passive transdermal delivery pentosanpolysulfate.

FIGURE 3 is a graph showing the effect of inhibitors closing track on passive transdermal movement pentosanpolysulfate.

FIGURE 4 is a graph showing the effect of inhibitors of closed paths on the passive transdermal delivery pentosanpolysulfate.

FIGURE 5 is a graph showing the effect of inhibitors of closed paths on the passive transdermal delivery pentosanpolysulfate.

6 is a graph showing the effect of inhibitors of closed paths on the passive transdermal delivery pentosanpolysulfate.

FIG.7 is a graph showing the effect of inhibitors of closed paths on the passive transdermal delivery of DNA.

FIG is a schematic side image device for transdermal delivery and or sampling of an agent according to the present invention.

Definition

Unless otherwise stated, the following terms used in this application, have the following meanings.

The term "transdermal movement" means the rate of passage of any agent in the skin and through the skin of the individual or the rate of passage of any agent through the skin of the individual outside.

The term "transdermal" means the delivery or extraction agent through the skin.

The term "path" refers to the passages formed in the stratum corneum of the skin by disrupting its integrity, which helps to enhance transdermal movement of the agent. The integrity of the stratum corneum of the skin can be broken by methods well known in the art such as treatment with sandpaper, scraping strips, applying micropores etc. Other methods described in U.S. patent No. 6022316, 5885211 and 5722397, the description of which is entirely incorporated herein as references. Preferably the passages are formed by breaking the skin using a device that has many Microsystem, these stratum corneum, which creates micro incisions in the stratum corneum.

The term "Microsystem", as used herein, refers to very small elements, connectors stratum corneum, which typically have a length of less than 500 micrometers, preferably less than 250 micrometers, which penetrate through the stratum corneum. The purpose is to proniknoveniya through the stratum corneum of microfactory preferably have a length of at least 50 micrometers. Microsystem can be any shape, such as needles, hollow needles, blades, pins, punches, and combinations thereof.

The term "many Microsystem", as used herein, refers to the set of Microsystem with an ordered arrangement, which are designed to pierce stratum corneum. Many Microsystem can be formed by engraving blades on thin paper and wrapping each blade outwards with respect to the plane of the plate to form the configuration shown in FIG. Many Microsystem can be formed in other ways, such as connecting a set of strips having microfactory along the edge of each strip. Many Microsystem may include a hollow needle that injected liquid composition. Examples of sets of Microsystem described in U.S. patent No. 5879326 issued Godshall et al., 3814097 issued Ganderton et al., 5279544, issued to Gross et al., 5250023, issued to Lee et al., 3964482 issued to Gerstel et al., assigned the patent 25637 issued by Kravitz et al., and PCT publication nos WO 96/37155, WO 96/37256, WO 96/17648, WO 97/03718, WO 98/11937, WO 98/00193, WO 97/48440, WO 97/48441, WO 97/48442, WO 98/00193, WO 99/64580, WO 98/28037, WO 98/29298 and WO 98/29365, each of which is incorporated herein by reference.

The term "extended delivery", as used herein, means the period of delivery, which lasts at least p is Lhasa, preferably from a few hours to about 24 hours, more preferably from about 8 to 24 hours.

The term "co-delivery", as used herein, means that the agent (agents)that prevent healing, enter transdermal to the delivery agent; before and during transdermal movement of the agent during transdermal movement of the agent and/or during and after transdermal movement of the agent.

The term "joint sampling", as used herein, means that the agent (agents)that prevent healing, enter transdermal to the selection of the sample agent through transdermal movement; before and during transdermal movement of the agent during transdermal movement of the agent and/or during and after transdermal movement of the agent.

For the purposes of transdermal delivery, the term "agent"as used herein refers to an agent, drug, compound, composition of matter or mixture thereof which have some pharmacologic, often beneficial, effect. It is used in its broadest interpretation as any pharmaceutically acceptable substance that can be delivered to a living organism to obtain a desired, usually beneficial, effect. Typically, this includes therapeutic Agay is you in all major therapeutic areas, including, without limitation, anti-infective agents such as antibiotics and antiviral agents; analgesics such as fentanyl, Sufentanil and buprenorphine and analgesic combinations; anesthetics; anorexic; antiarrhythmic agents; anti-arthritis agents; anti-asthma agents such as terbutaline; anticonvulsants agents; antidepressants; antidiabetic agents; agents against diarrhoea; antihistamine agents; antiinflammatory agents; drugs against migraine; drugs against kinetosis, such as scopolamine and ondansetron; anti-nausea agents; agents against tumors; drugs against Parkinson's disease; antipruritic agents; antipsychotic agents; antipyretic agents; antispasmodics, including acting on the gastrointestinal tract and urinary system; anticholinergic agents; sympathomimetic agents; xantinove derivatives; cardiovascular preparations, including calcium channel blockers such as nifedipine; beta-agonists such as dobutamine and ritodrin; beta-blockers; antiaritmiki; antihypertensive agents, such as atenolol; ACE inhibitors such as ranitidine; diuretics; vasodilators, including General, coronary, peripheral and cerebral; Central nervous system stimulants; cough and p is study; protivostoyanie agents; diagnostic agents; hormones such as parathyroid hormones; hypnotics agents; immunosuppressive agents; muscle relaxants; parasympatholytics; parasympathomimetic; prostaglandins; proteins; peptides; psychoactive agents; vaccines; sedative agents and tranquilizers.

The present invention is particularly suitable for the controlled delivery of peptides, polypeptides, proteins or other macromolecules that are difficult to deliver transdermal due to their large size. These macromolecular substances usually have a molecular weight of at least about 300 daltons, and more often in the range from about 300 to 40,000 daltons. Examples of polypeptides and proteins that can be delivered in accordance with the present invention include, without limitation, LHRH, LHRH analogues such as goserelin, leuprolide, buserelin, triptorelin, gonadorelin, nafarelin and leuprolide), GHRH, GHRF, insulin, insulinotropic, calcitonin, octreotide, endorphin, TRH, NT-36 (chemical name: N-[[(s)-4-oxo-2-azetidine]carbonyl]-L-histidyl-L-prolinamide), leprecon, pituitary hormones (e.g., HGH, HMG, HCG, desmopressina acetate and the like), follicular luteola, α-ANF, a growth factor, such as growth hormone-releasing factor (GFRF), β-MSH, GH, somatostatin, bradykinin, somatotropin, a growth factor derived from platelets, asparaginase is, bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, corticotropin (ACTH), erythropoietin, epoprostenol (inhibitor of platelet aggregation), glucagon, hirudin and analogs of hirudin, such as hirulog, hyaluronidase, interleukin-2, menotropin (urofollitropin (FSH) and LH), oxytocin, streptokinase, tissue activator of plasminogen, urokinase, vasopressin, desmopressin, ACTH analogs, ANP, inhibitors clearance of ANP, antagonists of angiotensin II, antidiuretic hormone agonists, antagonists antidiuretic hormone antagonists of bradykinin, CD4, Ceredase, CSI, enkephalins, FAB fragments, the suppressor of the IgE peptide, IGF-1, neurotrophic factors, colony stimulating factors, parathyroid hormone agonists, antagonists, parathyroid hormone antagonists, prostaglandin, pentigetide, protein C, protein S, renin inhibitors, thymosin alpha-1, thrombolytics, TNF, PTH, heparin with a molecular weight of from 3000 to 12,000 daltons, vaccines, analogues of vasopressin antagonist, interferon-α, -β and -γ, antitripsin alpha-1 (recombinant) and TGF-beta.

It should be understood that the composition of the agent in the method according to the present invention can include more than one agent, and that the use of the term "agent" in no way excludes the use of two or more of these agents or drugs.

Agents mo is ut can take various forms, such as free bases, acids, charged or uncharged molecules, components of molecular complexes or non-irritating, pharmacologically acceptable salts. You can also use a simple derivative agents (such as ethers, esters, amides and the like), which are easily hydrolyzed, pH, enzymes, etc. in the body. In the reservoir for a drug agents can be in solution, in suspension, or a combination of them. Alternative agent may be in the form of a set of particles.

The amount of agent that is used in the device for delivery shall constitute such number, which is necessary to deliver a therapeutically effective amount of the agent to achieve the desired result. In practice, this number will vary widely depending on the specific agent, the site of delivery, the severity of the condition and the desired therapeutic effect. Thus, identification of specific limits for therapeutically effective amount of the agent used in the method is impractical.

For the purposes of the transdermal sampling, the term "agent"as used herein, refers to an analyte of the body subject to selection. The term "analyte"as used herein means any hee is practical or biological material or compound, suitable for passage through a biological membrane using methods outlined in the present invention, or by using previously known methods, the concentration or activity of the organism of which the individual may wish to learn. Glucose is a concrete example of the analyte, because it is a sugar, suitable for passing through the skin, and individuals, for example, suffering from diabetes may wish to know the levels of glucose in their blood. Other examples of analytes include, without limitation, such compounds as sodium, potassium, bilirubin, urea, ammonia, calcium, lead, iron, lithium, salicylates, alcohol permitted substances, prohibited drugs, etc.

The term "therapeutic" amount or rate refers to the number or speed of the agent required to produce a desired pharmacologic, often beneficial, result.

The term "passive transdermal delivery is used herein to describe the passage of the agent through the body surface, for example the skin by passive diffusion. Typically, devices for passive delivery have a tank that contains a high concentration of the drug. The device is placed in contact with the surface of the body for an extended period of time, and it allows drug is redtwo to diffuse from the reservoir into the patient, in which the drug concentration is much lower. The main driving force for the passive delivery of drugs is the gradient of concentration of drug along the skin. With this type of delivery of the drug reaches the bloodstream by diffusion through the layers of the skin. Preferred agents for passive delivery are hydrophobic non-ionic agents, suggesting that the drug must diffuse through the lipid layers of the skin.

The term "electric vehicle" is used herein to describe the passage of substances such as drugs or prodrugs, through a body surface or membrane, such as skin, mucous membrane, or nails, induced at least partially by the application of an electric field through the surface of the body (e.g. skin). Widespread electrotransport process, iontophoresis involves the electrically induced transport of therapeutic agents in the form of charged ions. An ionisable therapeutic agents, for example, in the form of a salt which, when dissolved forms ions agent, are preferred for ionophoretically delivery, because ions agent moving through electromigration within the applied electric field. E is chaosmos, another type of electrotransport process, involves the movement of fluid containing dissolved charged and/or uncharged therapeutic agent through a biological membrane (e.g., the skin) under the action of an electric field. Another type of electrotransport, electroporation, involves the formation of temporarily existing pores in living biological membrane through the application of high voltage pulses and delivery through them therapeutic agent. However, in all of these transport processes to some extent may be more than one process simultaneously. Accordingly, the term "electric vehicle" is used herein in its broadest sense and includes electrically induced or enhanced transport of at least one agent, which may have charge, i.e. it must be in the form of ions, or may not have a charge, or mixtures thereof, regardless of the specific mechanisms through which the agent is transported to the fact.

The term "agent that prevents healing" refers to the agent who individually or in combination operates in such a way that prevents or reduces the natural healing processes of the skin, preventing, thus, closing of the paths formed by the violation of its integrity, such as ICRI the punctures/micro incisions in the stratum corneum of the skin. Examples of suitable agents that prevent healing, include, without limitation,

(1) osmotic agents, which include neutral compounds such as glucose, salts such as sodium chloride, and zwitterionic compounds such as amino acids.

Composition (as such or re-dissolved dry composition) must have an osmotic pressure greater than about 2000 kPa, and more preferably greater than about 3000 kilopascals at 20°C. the Osmotic pressure is calculated from the following relationship:

P=iMRT,

where i is a factor of the van't Hoff, M represents both molarity of the solute, R is the universal gas constant (8,314 J K-1mol-1), and T represents the temperature in degrees Kelvin.

For neutral compounds i is equal to 1, and the concentration at 2000 kPa 0.8 M; approximately at 3000 kPa it is 1.2 M

The neutral compound include

(a) organic solvents, such as dimethylsulfoxide,

(b) acid in a neutral state, such as boric acid and the like,

(C) the ether alcohols and polymers of ethylene oxide, comprising at least one alcohol group and having a molecular weight in the range from 92 to 500.

Compounds of this group include ethoxalyl the Col, diethylene glycol, dipropyleneglycol, triethylene glycol, PEG-4, PEG-6, PEG-8, PEG-9, etc.;

(d) aliphatic alcohols, including two alcohol groups, such as propylene glycol and butanediol, and the like;

(e) aliphatic alcohols, including three alcohol groups, such as glycerol and 1,2,6-hexanetriol, etc.;

(f) chetyrehtomnik alcohols, such as erythritol and threitol, etc.;

(g) a pentabasic alcohols, such as adonit, xylitol and Arabic, etc.;

(h) setiathome alcohols, such as sorbitol, mannitol, galactic, etc.;

(i) aliphatic compounds containing one ketone or aldehyde group and at least two alcohol groups. Compounds of this group include deoxyribose, ribulose, xylulose, psicose, sorbose etc.;

(j) cyclic polyols, such as Inositol, and the like;

(k) monosaccharides, such as apiose, arabinose, lyxose, ribose, xylose, digitoxose, fucose, cortical, Hinojosa, rhamnose, allose, altrose, fructose, galactose, glucose, gulose, Hamamelis, idose, mannose, tagatose, etc.;

(l) disaccharides, such as sucrose, trehalose, primaveras, Vicenza, rutinose, syllabize, cellobiose, gentiobiose, lactose, lactulose, maltose, melibiose, sophorose and turanose, etc.

For salts with i=2, the concentration of salt at approximately 2000 kPa is about 0.4 M; approximately at 3000 kPa she is about 0.6 M of the criminal code of the above salts include sodium chloride, salt forms of acetic acid, propionic acid, glycolic acid, pyruvic acid, gerasimovoj acid, lactic acid, pavlinovoi acid, beta-hydroxybutiric acid, glyceric acid, sorbic acid, almond acid, atrractive acid, tropovoy acid, Hinn acid, glucuronic acid, gluconic acid, gulonovoy acid, glucoheptonate acid, benzyl acid, ammonium, monoethanolamine, diethanolamine, aminomethylpropanol, tromethamine, triethanolamine, galactosamine and glucosamine.

For salts with i=3, the concentration of salt at approximately 2000 kPa is about 0.3 M; approximately at 3000 kPa she is about 0.4 M Above the salt include salt forms of phosphoric acid, malonic acid, fumaric acid, maleic acid, succinic acid, Castronovo acid, oxaloacetic acid, malic acid, alpha-Ketoglutarate acid, citramalic acid and tartaric acid.

For salts with i=4, the concentration of salt at approximately 2000 kPa is approximately 0.2 M; approximately at 3000 kPa she is about 0.3 M Above the salt include a salt form amanitowoc acid, citric acid, solimano acid.

For zwitterionic compounds i is equal to approximately 1, and the concentration at approximately 2000 kPa is about 0, M; approximately at 3000 kPa she is about 1.2 M

Zwitterionic compounds include amino acids such as glycine, alanine, Proline, threonine and valine, diaminobutane, such as glycylglycine, buffers, such as 4-morpholinepropanesulfonic acid (MOPS), (2-{[Tris(hydroxymethyl)methyl]amine}-1-econsultancy acid (TES), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), monohydrate β-hydroxy-4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPPSO), tricin, bitin, CHES, and CAPS etc.

(2) Anticoagulants, such as citric acid, citrate salts (e.g., sodium citrate), textresult-sodium EDTA, pentosanpolysulfate, oligonucleotides, aspirin, low molecular weight heparin and liepolt sodium.

(3) anti-Inflammatory agents, such as salt centripetal-21 betamethasone, centripetal-21 triamcinolone acetonide, hydrochloride hydrocortamate, salt centripetal-21 hydrocortisone, salt centripetal-21 methylprednisolone, salt nutriactive-21 methylprednisolone, centripetal of paramethasone, salt nutriactive-21 prednisolone, salt nitrosulfonic-21-m prednisolone hydrochloride 21-diethylaminoacetate prednisolone nutrifaster prednisolone hydrochloride 21-diethylaminoacetate of prednisolone, centripetal-21 triamcinolone acetonide; salt form NSAIDs, such as aspirin or others with whom literacy, bromfenac, diclofenac, diflunisal, etodolac, fenoprofen, ibuprofen, indomethacin, Ketoprofen, Ketorolac, meclofenamate, mefenamovaya acid, naproxen, oxaprozin, piroxicam, sulindac, tolmetin, and anti-inflammatory peptides, such as antiplasmin 1 and antiplasmin 2.

(4) Agents that affect cell migration, such as laminin and related peptides, fibronectin and related peptides.

The limits of concentration for anticoagulants, anti-inflammatory agents and agents that inhibit cellular migration, range from 0.1 to 10% in the composition.

The main barrier properties of the skin, such as resistance to diffusion of drugs associated with the outermost skin layer, the stratum corneum. The inner part, i.e. subject to layers of the epidermis, usually consists of three layers, called the stratum granulosum, stratum malpighii, and stratum germinativum. Through these layers, the resistance to transport or adsorption agent is very small or non-existent. Therefore, to enhance transdermal movement, microfactory used to create paths on the surface of a body, in accordance with the present invention should only penetrate through the stratum corneum, so the agent was delivered or transdermal selected his sample with little or no resistance from the skin.

There have been many priests is OK mechanical penetration or violation of the integrity of the skin to create, thus, openings in the skin to enhance transdermal movement.

However, the passages created by microprogram/micro incisions, quickly closed and sealed with natural healing process of the skin. Accordingly, enhancing transdermal movement of the agent, provided these passages, completely stops after a few hours of creating data paths. The present invention inhibits the reduction of transdermal movement of the agent because of the closure of ways after they are created.

In one of the embodiments of the present invention the skin is treated using a device that contains many Microsystem, for the formation of small cuts, slits or holes, called paths, in the most external layer of the body surface, with limited depth. Microsystem can be given various shapes, such as needles, hollow needles, blades, pins, punches, and combinations thereof. The reservoir for delivery or sampling of an agent is placed in contact with the pre-treated portion of the surface of the body for delivery or sampling of an agent. The reservoir for delivery or sampling of an agent contains the agent (agents)that prevent healing, which is delivered together with the agent. The specified agent that prevents healing, prevents or less the th least inhibits the closure of roads and therefore, inhibits the reduction of transdermal movement of the agent that is delivered or samples which are selected. Alternative tank with an agent that prevents healing, and a reservoir for delivery or sampling of an agent can be a different tanks.

FIG illustrates a patch for transdermal delivery or sampling of 10, including many Microsystem 12, a reservoir 14 and adhesive backing layer 16, and an impermeable backing layer 18. Although the tank 14 was shown the distal side relative to the skin of Microsystem 12, it should be understood that the tank may also be located in other positions. For example, the reservoir 14 may be provided with a discrete layer proximally relative to the skin or distal relative to the skin relative to the main sheet, which supports microfactory 12. The tank 14 may be provided with a coating Microsystem and/or the reservoir may be provided with a coating for other parts of the patch 10. Although the present invention is described as including the agent and the agent that prevents healing, it should be understood that the agent and the agent that prevents healing, can be placed in the same tank or in different reservoirs of the device.

The device according to the present invention can be used in conjunction with DOS is avcoi agent, sampling agent or both. In particular, the device according to the present invention is used in connection with the transdermal drug delivery, transdermal sampling of the analyte or so, and with others. Device for transdermal delivery for use in the present invention include, without limitation, passive devices, transport devices, osmotic devices, and working under pressure. Device for transdermal sampling for use in the present invention include, without limitation, passive devices, reverse electrotransport device operating under negative pressure, and osmotic device. Transdermal device according to the present invention can be used in combination with other ways of increasing traffic agent, such as amplifiers permeability of the skin.

EXAMPLES

The following preparations and examples are given for better understanding and practical implementation specialists of the present invention. They should not be construed as limiting the scope of the present invention, but serve only for illustration of the present invention.

Example 1

Less traffic drugs were studied in three models is karstenii funds with different properties in terms of electrical charge: pentosanpolysulfate (PPS), a connection with a large negative electric charge, DECAD, synthetic model Decapeptide carrying two positive electric charge at pH 5.5, and inulin, a neutral polysaccharide. These compounds do not penetrate substantially through the skin without the use of penetration enhancers or physical damage of the skin barrier.

In this experiment, PPS, DECAD and inulin were delivered by passive diffusion through the path in the skin formed by pre-processing device with many Microsystem. Pre-treatment involves placing a device with many Microsystem on the skin with enough force to create a variety of microprogram/micro incisions through the stratum corneum of the skin. Device with many Microsystem then removed from the skin, and then on top of the generated paths are placed one form of device for delivery to an agent or vessel agent with the aim of influencing the delivery agent or sampling. Pre-processing was used instead of the integrated system, since the closure of ways, as it turned out, there is faster and more reproducible manner after pre-treatment than in the case when microfactory leave on the skin in the time which I deliver medicines. The PPS concentration was below the concentration required for the anticoagulant effect. All drugs were dissolved in water and the solution turned into a gel using 2% of hydroxyethyl cellulose. The concentration of PPS, DECAD and inulin was 0.1 mg/ml, 13 mg/ml and 2.5 mg/ml, respectively. PPS and DECAD received radioactive tritium label. Inulin received radioactive tag14C.

Hairless Guinea pigs (HGP) skin one side manually bilateral stretched for time overlay system. Overlay multiple Microsystem was performed using the drum applicator. The overlay system included foam double adhesive ring (diameter 3.8 cm, a thickness of 0.16 cm) with a reservoir area of 2 cm2in the middle, containing many Microsystem, with an area of 2 cm2and included a plate of stainless steel with a thickness of 0.025 mm, blade trapezoidal shape, curved at an angle of approximately 90° to the plane of the plate; microfactory had a length of 545 μm and the density Microsystem 72 microvista/cm2. After applying tensile weakened. Sticky ring remained glued to the skin, and the device with many Microsystem removed. The composition of the medicinal product (350 ál) was placed in the office for drugs and put the lining of memb the Anu on the tacky outer surface of the ring, to pressurize the system. For each composition of the medicinal product used in a total of six HGP. After 1 hour and 24 hours after applying the 3 HGP from each group system was removed, and the remaining drug was washed off from the skin. The quantity of a drug, which is specified intervals penetrated through the skin was determined by measuring the excretion of radioactivity in urine within two days after removal of the patch, and resolved it by percentage, excreted after/in the injection site (earlier studies have shown that3H-PPS3H DECAD and14With inulin percentage excreted through two days after injection, was 32%, 65% and 94%, respectively). The results (table I) show that between 1 hour and 24 hours movement of medicines has decreased by at least one order of magnitude for all medicines that indicates at least partial closing of paths generated by the punctures of the skin with the help of Microsystem.

Table I

Movement model drugs after pre-processing device with many Microsystem
Movement of drug (ág/(sup> 2h))
1 h24 hours
PPS0,177±0,0390,015±0,002
0.05 mg/ml
DECAD1,77±0,390,097±0,035
12 mg/ml
Inulin13,9±1,60,489±0,123
2.5 mg/ml

Example 2

Inhibition of spadine ways using chemical agents studied after pretreatment of the skin with a device with many Microsystem and application of compositions containing an agent for 24 hours. Quantitative determination was carried out by assessing the impregnation ways dye.

The HGP skin one side manually bilateral stretched at the time of blending. The overlay device with many Microsystem was performed using the drum applicator. The overlay system included foam double adhesive ring (diameter 3.8 cm, a thickness of 0.16 cm) with a reservoir area of 2 cm2in the middle, containing many Microsystem, with an area of 2 cm2and included a plate of stainless steel with a thickness of 0.025 mm, blade trapezoidal shape, curved at an angle of approximately 90° to the plane of the plate. Microfactory had a length of 545 μm and the density of the mi is rovisteto 72 microvista/cm 2. After applying tensile weakened. Sticky ring remained glued to the skin, and the device with many Microsystem removed. Composition (350 μl)containing the test compound in water and optionally a gelling agent is hydroxyethylcellulose (BORE) with a concentration of 2% or silica gel with a concentration of 50%), was placed in the reservoir for drugs and put the lining membrane on sticky outer surface of the ring to pressurize the system. On the opposite side of the Guinea pig was placed second system containing a different composition. Twenty-four hours after applying, on three systems from each group was removed, and the remaining composition is washed from the skin. The skin was stained with 1% solution of methylene blue. Excess paint was carefully removed with swabs moistened with 70% isopropyl alcohol, and photographed the site. Pictures were evaluated using a scoring system from 0 to 5 points, 5 points were awarded if the paint absorption was observed immediately after blending device with many Microsystem, and 0 points were awarded if the paint absorption was observed after 24 h of contact with the control composition. Scores of 0.5 or more was considered significant. Studied various osmotic agents, anticoagulants, anti-inflammatory agents, generous the e agents, and also gels with different pH values and different additives (table II). Additional osmotic agents, the most effective agents were polyol 1,2,6-hexanetriol, glucuronic acid, a polymer of ethylene oxide and diethylene glycol, a pentabasic alcohol adonit, chastity alcohol sorbitol, a polyol-amine tromethamine and the monosaccharide glucose. Among anticoagulants citric acid, EDTA, and dextran 5000 were the most effective agents in preventing the closure of ways. Anti-inflammatory agents centripetal betamethasone and sodium salt of Ketoprofen showed a reliable effect. Keratolytic agent salicylic acid also influenced the closing of ways. Low pH also inhibited the closing of ways. Surfactants (anionic, cationic and non-ionic) in non-irritating concentrations actions are not provided. Inert agents did not prevent the closure of ways. Areas that are affected by glycerol and citric acid, were also stained with Indian ink to ensure that the paths were opened for connections larger.

0±0 0,025%
Table II

Inhibition of closed paths of chemical agents on the assessment with methylene blue after pre-treatment device is istom with many Microsystem
Class SupplementAdditiveConcentrationPoints
Osmotic agentsThe sulfoxide10% (1.3 M)1,0±0,0
Ethanol0% (4.3 M)0±0
Isopropyl alcohol30% (5 M)0,2±0,2
Propylene glycol70% (9.2 Meters)1,0±0,6
50% (6.6 M)1,3±0,1
30% (3.9 M)0,7±0,2
1-3 butanediol50% (5.5 M)0,2±0,2
2-3 butanediol50% (5.5 M)2,2±0,2
1-2 butanediol50% (5.5 M)2,0±0,8
1-4 butanediol50% (5.5 M)3,0±0,3
Diethylene glycol50% (4.7 M)3,2±0,2
Thiodiglycol50% (4.1 M)0,3±0,3
Etokxidiglicol50% (3.7 M 0,5±0,3
Triethylene glycol50% (3.3 M)3,7±0,3
30% (2 M)3,3±0,3
10% (0.7 M)1,3±0,3
PEG-450% (2.6 M)2±0,6
PEG-1250% (0.9 M)0±0
PEG-35050% (0.03 M)0±0
Glycerin70% (7.6 M)2,7±0,3
50% (5,4 M)3,0±0,2
30% (3.3 M)2,7±0,2
1,2,6-hexanetriol50% (3.7 M)3,8±0,2
23% (1.7 M)3,0±0,5
11% (0.8 M)2,0±0,3
Inositol10% (0.6 M)1,5±0,3
Erythritol30% (2.5 M)3,3±0,4
Adonit50% (3.3 M) 3,7±0,3
23% (1.5 M)3,5±0,3
11% (0.7 M)3,0±0,3
Sorbitol50% (2.7 M)3,3±0,3
23% (1.3 M)3,3±0,3
11% (0.6 M)1,3±0,6
Ribose50% (3.3 M)2,3±0,3
D-glucose50% (2.8 M)4,0±0,3
23% (1.3 M)3,5±0,5
11% (0.6 M)1,8±0,6
5% (0.3 M)1,5±0,0
L-glucose23% (1.3 M)3,5±0,3
Sucrose50% (1.5 M)1,7±0,6
Trehalose50% (1.5 M)1,5±0,0
NaCl3,5% (0.6 M)1,8±0,2
Sodium acetateof 4.9% (0.6 M) 1,7±0,1
Ammonium acetateof 4.9% (0.6 M)2,1±0,1
Sodium salt of glycolic acid24% (2.4 M)2,7±0,1
12% (1.2 M)2,6±0,1
6% (0.6 M)1,7±0,1
Sodium salt of gluconic acid30% (1.4 M)4,5±0,0
13% (0.6 M)3,3±0,0
10% (0.5 M)2,7±0,2
Sodium salt of glucuronic acid13% (0.6 M)3,0±0,3
10% (0.5 M)3,5±0,3
5% (0.2 M)1,0±0,0
Ammonium chloride3,2% (0.6 M)2,6±0,1
Hydrochloride tromethamine50% (3.2 M)3,7±0,3
9,5%(0.6 M)2,3±0,3
Hydrochlo the ID galactosamine 50% (2.3 M)2,8±0,3
The disodium salt of malic acid11% (0.6 M)2,1±0,3
The disodium salt of tartaric acid12% (0.6 M)1,5±0,4
Glycine9% (0.2 M)1,8±0,3
SurfactantsSodium dodecyl sulphate0,01%0±0
Chloride of cetylpyridinium0,01%0±0
Tween 201%0,2±0,2
Inert agentsObtained by sublimation of silicon dioxide (Cab.O.Sil®)14%0±0
Silica gel (2-25 ?m)50%0±0
Hydroxyethylcellulose3%0±0
2%0±0
0,75%0±0
pH4,5Acetate buffer 0.15 M0,8±0,4
7The MOPS buffer 0.15 M
9The buffer is boric acid 0.15 M0,3±0,2
AnticoagulantsEDTA5%1,3±0,2
The disodium salt of citric acid3%1,2±0,2
1%0,3±0,2
0,5%0±0
Dextran 50005%2,2±0,4
Oligonucleotide (ISIS 2302)5%0,7±0,2
Pentosanpolysulfate5%0,5±0,0
0,01%0±0
Heparin2%0,3±0,2
Anti-inflammatory agentsBetamethasone Na phosphate2%2,3±0,4
Ketoprofen Na2%2,3±0,6
Calcium SupplementCalcium chloride2%0,7±0,4
The inhibitor of actin polymerizationCytochalasin D1,5±0,0
Laminin and related peptidesLaminin0,05%1,0±0,3
Ser-Ile-Lys-Val-Ala-Val0,05%0,5±0,5
Tyr-Ile-Gly-Ser-Arg-NH20,05%0,3±0,3
Peptides related to fibronectinArg-Gly-Asp1%0,7±0,4
VariousInsulin3 mm0,2±0,2

Example 3

Pentosanpolysulfate (PPS), a compound with high negative electric charge, does not penetrate substantially through the skin without the use of penetration enhancers or physical disruption of the skin barrier. In this experiment, PPS was delivered by passive diffusion through the path in the skin created by the device with many Microsystem. The PPS concentration was below the concentration required for inhibition of spadine ways (see table II). Thus, at the concentrations used in this experiment, PPS behaved as a drug that does not have any activity in relation to the closure of ways. The purpose of this experiment was to show that the inhibitors spadine ways identified in example 2, the e improved the movement of drugs through the skin in vivo.

All cavies skin one side manually bilateral stretched for time overlay system. The overlay device with many Microsystem was performed using the drum applicator. The overlay system included foam double adhesive ring (diameter 3.8 cm, a thickness of 0.16 cm) with a hydrogel containing a drug having a contact area with the skin 2 cm2in the mid-contained unit with many Microsystem, with an area of 2 cm2and included a plate of stainless steel with a thickness of 0.025 mm, blade trapezoidal shape, curved at an angle of approximately 90° to the plane of the plate; microfactory had a length of 545 μm and the density Microsystem 72 microvista/cm2. After applying tensile weakened. Sticky ring remained glued to the skin, and the device with many Microsystem removed. The hydrogel containing 3H-PPS in water (concentration of PPS 0.1 mg/ml, 2%, 350 ml), was placed in the office for drugs and put the plastic cover on the sticky outer surface of the ring to pressurize the system. Additional groups HGP treated similarly, except that the composition contained 3% chinatravel salt of citric acid or 50% 1,2,6-hexanetriol). After 1 and 24 h after the application of three systems and what each group were removed, and the remaining drug was washed off from the skin. The quantity of a drug, which is specified intervals penetrated through the skin was determined by measuring the concentration of tritium in urine (earlier studies have shown that the HGP 32% tritium extracted from3H-PPS, injected intravenously, are excreted in the urine). The results presented in figure 1 show that between 1 hour and 24 hours movement of medicines has decreased by about 12 times, which indicates the closing of ways. Citric acid and 1,2,6-hexanetriol inhibited the decrease movement. The movement in the presence of 1,2,6-hexanetriol between 1 hour and 24 hours was reduced to less than 2 times. Total transported quantity was increased by approximately 4 and 7 times in the presence of citric acid and 1,2,6-hexanetriol, respectively, compared to controls, as shown in figure 2.

Example 4

The second experiment was performed with PPS. Conditions were identical to the conditions described in example 3, except that the device with many Microsystem had a shorter blade length 194 micrometers, and a higher density Microsystem (190 Microsystem/cm2). The PPS concentration was 0.16 mg/ml and was still below the concentration that was required to spadine ways. Assessment of the implementation of the Lyali after 45 min, instead of 1 o'clock in Addition, an additional group of animals received a composition comprising a mixture of 3% trinational salt of citric acid and 50% 1,2,6-hexanetriol. As in the previous example, the results presented in figure 3 show that between 0.75 and 24 h movement decreased sharply, demonstrating the close of ways. Used additive did not affect the movement of PPS after 45 min, which indicates a lack of properties enhance the penetration and the way significantly is not closed within this time period. After 24 hours, citric acid and 1,2,6-hexanetriol significantly inhibited the decrease in movement. Motion in the presence of a mixture trinational salt of citric acid and 1,2,6-hexanetriol led to complete inhibition of the reduction of motion PPS observed between 45 min and 24 h Total number of transported PPS is shown in FIGURE 4. The effect observed in the presence of 3% trinational salt of citric acid and 50% 1,2,6-hexanetriol, was more pronounced than in the presence of additives. This fact, perhaps, is an indication that these two agents are effective against different mechanisms of wound healing (citric acid, may prevent the formation of blood clot, while 1,2,6-hexanetriol possibly prevents another process of regeneration, such as migration of keratinocytes).

Example 5

With PP was performed an additional experiment. Conditions were identical to the conditions described in example 4. Sodium salt of gluconic acid, sodium salt of glucuronic acid and glucose were evaluated at a concentration of 0.6 M, in the presence or in the absence of 3% citric acid. As in the previous example, the results presented in FIGURE 5, show that between 1 hour and 24 hours movement decreased sharply, demonstrating the close of ways. After 24 hours all the connections and combinations significantly increased the movement PPS. The total number of transported PPS is shown in FIG.6. These results confirm the findings presented in example 4, and show that lower concentrations of agents that prevent healing, are still very effective in inhibiting the closed paths formed by mikrosysteme.

Example 6

On hairless Guinea pig (HGP) were performed research regarding the feasibility of using Macroflux passive intradermal vaccine delivery of plasmid DNA (pCMV-AYW-Hbs-Mkan), which encodes the surface antigen of hepatitis b [HbsAg]. All cavies skin one side manually bilateral stretched for time overlay system. The overlay device with many Microsystem was performed using the drum applicator. The overlay system included foam double adhesive ring (diameter 2.5 cm, the thickness of the as of 0.08 cm) with a reservoir area of 1 cm 2middle.

Used one of the two device configurations with many Microsystem. Description of two sets is given in table III. Each configuration had a total surface area of 2 cm2and the total active surface area of the blades 1 cm2.

Table III

TypeLength microvistaThe number of projections/cm2
8-1A545 microns72
21-A430 microns190

Many Microsystem type selected was glued to the sticky foam and covered the bottom of the tank (after applying many Microsystem is in contact with the skin). After applying tensile weakened, and the device with many Microsystem left in situ. Liquid composition (90 μl)containing 3.5 mg/ml vaccine of plasmid DNA in buffer (5 mm TRIS, pH 7,6), was placed in the reservoir for drugs and put the lining membrane on sticky outer surface of the ring to pressurize the system. Other HGP treated in the same way, except that the composition contained 1% Tween 80 or 3% chinatravel salt of citric acid, in addition to plasmid DNA and TRIS buffer. After 1 hour after applying for the two systems from each group was removed, and the OS is asuza composition was washed off from the skin. The number of drugs that have penetrated into the skin for a specified time, determined by biopsy of the involved area of the skin full-thickness, diameter 6 mm Biopsy was dissolved in digest buffer (sodium dodecyl sulphate/proteinase K) and the content related with the experiment, DNA was evaluated using polymerase chain reaction (PCR) followed by electrophoresis of the PCR product. In the experiment included a positive control group, which consisted of animals treated with 10 μg of plasmid DNA by intradermal injection. Negative controls consisted of animals that were applied to the skin of plasmid DNA without the use of devices with many Microsystem. The results showed that plasmid DNA can be successfully delivered using devices with many Microsystem by passive delivery (FIG.7). Plasmid DNA was not detected in the skin when plasmid DNA was applied to the skin without the use of devices with many Microsystem (negative controls). Comparison between groups showed that the most effective composition contained chinatravel salt of citric acid. After one hour in the presence of trinational salt of citric acid was delivered more than 10-fold more plasmid DNA compared with the control composition. To the reliable amplification of delivery of plasmid DNA in the compositions, containing Tween 80, was not observed. When using citric acid using a device with many Microsystem 21-10A led to the increase in the number of delivered plasmid DNA in 2.5 times compared with the device with many Microsystem 8-1A, which is consistent with a large number of tabs in the device 21-10A.

Example 7

Examples 2-6 show that the medicinal product of interest can increase their movement through the joint delivery of inhibitors of closed paths. In particular, it was shown that the compounds having the properties of anticoagulants are effective in preventing the closure of ways. If these compounds can prevent losing ways and, therefore, to extend the time of delivery of molecules of drugs, obviously, if they are delivered in concentrations high enough locally to show their anticoagulant activity, they will prolong your own delivery. Experiments for the delivery of drugs having the properties of anticoagulants, were performed on animals HGP using PPS and fosforilirovanija of the oligonucleotide ISIS 2302. PPS is a drug that is used in the treatment of inflammatory conditions such as interstitial C is stith, and fosforilirovannyh oligonucleotide ISIS 2302 is a desensitizing drug relative to mRNA that encodes a molecule ICAM1, and has anti-inflammatory properties. Both molecules have a high negative electric charge and do not penetrate through the skin to a large extent, without the use of penetration enhancers or physical damage of the skin barrier.

Using PPS at a concentration of 300 mg/ml total dose of 6.5±1.1 mg was taken for 24 hours at HGP from the system area of 2 cm2passive pre-processing identical to that which was described in example 3 (overlay was performed manually, using a device with many Microsystem, with an area of 2 cm2and including a plate of stainless steel with a thickness of 0.025 mm, blade trapezoidal shape, curved at an angle of approximately 90° to the plane of the plate; Microsystem had a length of 430 μm and a density Microsystem 190 Microsystem/cm2). The dose excreted in the urine (2 mg)was found, was more than 85% intact. This contrasts with oral introduction of PPS, when 300 mg daily dose is the bioavailability of from 1 to 3% (from 3 to 9 mg is absorbed). In addition, after oral delivery of less than 5% stimulate dose was found intact in MOC is, that indicates that transdermal introduction of PPS using a device with many Microsystem effectively bypasses the liver.

With PPS were performed additional experiments to test alternative delivery methods. With PPS at a concentration of 50 mg/ml was delivered total dose of 1.9±0.1 to 4 hours by means of electric current of 100 μa/cm2and using a device with many Microsystem, with an area of 2 cm2and including a plate of stainless steel with a thickness of 0.025 mm, blade trapezoidal shape, curved at an angle of approximately 90° to the plane of the plate; microfactory had a length of 480 mm and a density Microsystem 241 Microsystem/cm2. For comparison with the same device with many Microsystem and the same concentration of PPS total dose of transdermal devices with many Microsystem with integrated reservoir for drugs, pre-processing device with many Microsystem and the subsequent imposition of a reservoir for drugs amounted to 2.2±0.2 mg and 1.4±0.2 mg, respectively. Collectively, these results indicate that PPS can be effectively delivered through the skin for extended periods of time, likely due to its anticoagulation its Tam.

Fosforilirovannyh oligonucleotide ISIS 2302 was delivered within 24 hours using a device with many Microsystem, with an area of 2 cm2the length of Microsystem 480 μm and a density Microsystem 241 Microsystem/cm2. Evaluated the effect of drug concentration, pre-treatment device with many Microsystem, compared with integrated effects and passive delivery compared to electric. The results, summarized in table IV, show that this compound can be effectively delivered through the skin for extended periods of time, likely due to its anti-clotting properties.

Table IV

Transdermal delivery of ISIS 2302

The total dose delivered (mg)
Conc. drugs. means (mg/ml)Pre-treatment mikrosystemeIntegrated impact
Passive deliveryTransportPassive deliveryTransport
50,17±0,020,47±0,050,20±0,040,35±0,05
50 2,6±0,76,4±0,57,4±1,58,3±1,4
20010,0±1,915,6±3,814,0±3,215,2±1,8

Drugs of interest, which could be delivered in therapeutic levels using technology Microsystem, for extended periods of time (i.e. 24 hours), and without the aid of auxiliary substances, which prevent losing ways, include all compounds that have anti-clotting properties during local delivery and having a molecular weight of about 2000. These compounds include pentosanpolysulfate, oligonucleotides, low molecular weight heparin, hirudin and analogs of hirudin, such as hirulog.

Specialists will appreciate the fact that the present invention can be implemented in other specific forms without departure from its ideas or essential nature. The above embodiments of the present invention, therefore, in all senses considered as illustrative, and not limiting it. Scope of the present invention, as described more in the attached claims than in the foregoing description, and all changes which come within the meaning and equivalent is intesti, also covered by the present invention.

1. Method of inhibiting the decrease transdermal movement of the first agent, comprising the stage of:

formation damage in at least the layer of the skin stratum corneum, for the formation of many ways in which damage to the skin are micro incisions, caused by one or more connectors stratum corneum of Microsystem;

induction of movement of the first agent and at least one agent that prevents healing, through the specified path; wherein the number of the specified agent, preventing the healing that moves through these paths, is effective for inhibiting decrease transdermal movement of the specified first agent, compared with the movement of the specified first agent under practically identical conditions except for the absence of the specified at least one agent that prevents healing.

2. The method according to claim 1, wherein the agent that prevents healing, selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit cellular migration, and osmotic agents and mixtures thereof.

3. The method according to claim 2, wherein the specified anticoagulant selected from the group consisting of heparin with a molecular weight of from 3000 to 12,000 daltons, pantazopoulou is that, citric acid, citrate salts, EDTA and dextrans with a molecular weight of from 2000 to 10,000 daltons, aspirin and laposata sodium.

4. The method according to claim 2, wherein the specified anti-inflammatory agent selected from the group consisting of hydrocortisone sodium phosphate, betamethasone sodium phosphate and triamcinolone sodium-phosphate.

5. The method according to claim 2, in which the specified agent that inhibits the migration of cells, is a laminin.

6. The method according to claim 2, wherein the specified osmotic agent is a biologically compatible salt osmotic agent.

7. The method according to claim 2, wherein the specified osmotic agent in the solution generates osmotic pressure in excess of about 2000 kPa at 20°C.

8. The method according to claim 1, wherein the first agent is a therapeutic agent that is delivered in transdermal skin.

9. The method of claim 8, wherein the agent comprises a macromolecular agent.

10. The method according to claim 9, wherein the macromolecular agent selected from the group consisting of polypeptides, proteins, oligonucleotides, nucleic acids and polysaccharides.

11. The method according to claim 8, in which damage to represent one or more micro incisions through the skin layer stratum corneum, which form the path, and additionally includes a step of placing the tank in position, soleidae transfer agent, regarding micro incisions; the specified tank includes first agent and the agent that prevents healing.

12. The method according to claim 1, wherein the first agent is an analyte of the body, examples of which are selected transdermal.

13. The method according to item 12, wherein the analyte of the body represents glucose.

14. The method according to item 12, wherein damage to represent one or more micro incisions through the skin layer stratum corneum, which form the path, and additionally includes a step of placing the tank in a position that allows the transfer agent relative to the micro incisions; the specified tank includes first agent.

15. The method according to claim 1, wherein the agent that prevents healing, delivered (a) to any transdermal movement of the first agent; (b) before and during transdermal movement of the first agent; (c) during transdermal movement of the first agent; or (d) during and after transdermal movement of the first agent.

16. The method according to claim 1, wherein microfactory have a length of less than 0.5 mm.

17. The method according to 14, wherein microfactory and reservoir are part of a single device for sampling.

18. The method according to claim 1, wherein the first agent is selected from the group consisting of heparin with a molecular weight of from 3000 to 12,000 daltons, pentosanpolysulfate, citric acid, citrate what's salts, EDTA and dextrans with a molecular weight of from 2000 to 10,000 daltons.

19. The method according to p, in which the first agent is identical to at least one of these agents that prevent healing.

20. The method according to claim 2, wherein the specified osmotic agent is a neutral connection.

21. The method according to claim 1, in which the first agent and the agent that prevents healing, represent a dry coating on one or more specified Microsystem.

22. The method according to claim 1, wherein the first agent is a therapeutic agent applied in the form of a coating on these microfactory, wherein said first agent is delivered in transdermal skin.

23. The method according to item 22, further including the state space of individual tanks in position, allowing the transfer agent relative to the skin; the specified tank includes an agent that prevents healing.

24. The device for transdermal movement of the agent, including the first element capable of forming damage for at least the stratum corneum of the skin, to form paths passing through it, and at least one reservoir comprising a first agent and at least one agent that prevents healing, specified at least one reservoir is able to be placed in put the e, allowing the transfer agent relative to the skin and the specified paths; in which the number of the specified at least one agent that prevents healing is effective for inhibiting decrease transdermal movement of the agent, compared with transdermal movement of the specified first agent under practically identical conditions except for the absence of the specified at least one agent that prevents healing.

25. The device according to paragraph 24, wherein said first element includes one or more connectors stratum corneum of Microsystem who are capable of forming micro incisions in the skin.

26. The device according to paragraph 24, in which the agent that prevents healing, selected from the group consisting of anticoagulants, anti-inflammatory agents, agents that inhibit cellular migration, and osmotic agents and mixtures thereof.

27. The device according to p, wherein said anticoagulant selected from the group consisting of heparin with a molecular weight of from 3000 to 12,000 daltons, pentosanpolysulfate, citric acid, nitrate salts, EDTA and dextrans with a molecular weight of from 2000 to 10000 Da, aspirin and laposata sodium.

28. The device according to p, wherein said anti-inflammatory agent selected from the group consisting of hydrocortisone sodium phosphate, betamethasone sodium-f is state and triamcinolone sodium-phosphate.

29. The device according to p, wherein said agent that inhibits the migration of cells, is a laminin.

30. The device according to p, wherein said osmotic agent is a biologically compatible salt osmotic agent.

31. The device according to p, wherein said osmotic agent in the solution generates osmotic pressure in excess of about 2000 kPa at 20°C.

32. The device according to paragraph 24, in which the first agent is a therapeutic agent, and the specified device delivers the first transdermal agent into the skin.

33. The device according to p in which the agent comprises a macromolecular agent.

34. The device according to p, in which the macromolecular agent selected from the group consisting of polypeptides, proteins, oligonucleotides, nucleic acids and polysaccharides.

35. The device according to p, wherein said first element includes one or more connectors stratum corneum of Microsystem, which can damage the skin by forming micro incisions in the skin.

36. The device according to paragraph 24, in which the first agent is an analyte of the body, examples of which are selected transdermal.

37. The device according to p, in which the analyte of the body represents glucose.

38. The device according to p, wherein said first element includes one or is more connectors stratum corneum of Microsystem, which can damage the skin by forming micro incisions in the skin.

39. The device according to paragraph 24, in which the agent that prevents healing, delivered (a) to any transdermal movement of the first agent; (b) before and during transdermal movement of the first agent; (c) during transdermal movement of the first agent; or (d) during and after transdermal movement of the first agent.

40. The device according A.25, in which microfactory have a length of less than 0.5 mm.

41. The device according to § 38, in which microfactory and reservoir represent a single element.

42. The device according to paragraph 24, in which the first agent is selected from the group consisting of heparin with a molecular weight of from 3000 to 12,000 daltons, pentosanpolysulfate, citric acid, nitrate salts, EDTA and dextrans with a molecular weight of from 2000 to 10,000 daltons.

43. The device according to § 42, in which the first agent is the same agent that prevents healing.

44. The device according to p, wherein said osmotic agent is a neutral connection.

45. The device according A.25, in which the first agent and the agent that prevents healing, represent a dry coating on one or more specified Microsystem.

46. The device according A.25, in which the first agent is a therapeutic agent applied in the form of the aircraft the Oia these microfactory, in which the specified device is capable of delivering the specified first transdermal agent into the skin.

47. The device according to item 46, further including the state space of individual tanks in position, allowing the transfer agent relative to the skin; the specified tank includes an agent that prevents healing.

48. Set to overlay device for receiving transdermal movement of the agent, including the device according to point 24 and the applicator for the premises specified in the first element of the specified device on the skin, with the aim of forming the above-mentioned injuries.



 

Same patents:

FIELD: medicine.

SUBSTANCE: apparatus has threaded rod positioned for performing shuttle-type micro motions of bushing projecting from casing of mechanized perforator, to which needle base is coupled. Rod is passing through casing of mechanized perforator through opening provided within its extension part and/or bushing. Needle base consists of disk-shaped case with threaded opening provided on one of end surfaces of said case and adapted for cooperation with rod thread. Disk-shaped case has elongated edge for defining hollow covering cylindrical part to be mated around extension part and/or perforator casing bushing for forming of covering hollow cylindrical part which is to be put onto extension part and/or perforator casing bushing. Other end surface of disk-shaped case has central projecting portion with non-detachable needle casing fixed therein. Edges of disk-shaped case are made elongated for defining fluid receptacle.

EFFECT: increased efficiency owing to reduced back flow of organism's liquid.

3 cl, 3 dwg

FIELD: medical equipment.

SUBSTANCE: medical gas insufflator has high-pressure source which output is connected with decreasing reduction gear, first and second safety valves and line for supplying gas into cavity. Output of device for gas preparation is connected with pressure stabilizer and gas discharge meter. Output of gas discharge meter is connected with first safety valve, controlled pressure stabilizer and controlled discharge throttle. Output of controlled discharge throttle is connected with controlled valve. Output of safety valve is connected with second safety valve and line for feeding gas into cavity. The latter is made in form of receiver connected with pneumatic toggle switch. Output of receiver is connected with input of comparison circuit. First input of comparison circuit is connected with output of controlled pressure stabilizer. Output of comparison circuit is connected with control input of controlled valve.

EFFECT: improved reliability of operation; higher non-volatility.

3 cl, 1 dwg

FIELD: medicine, arthrology.

SUBSTANCE: the present innovation deals with treating arthritis of different etiology. For this purpose one should introduce medicinal preparation into articular cavity and immediately after introduction one should periodically change spatial articular position at the interval of 20-30 min. The present innovation provides efficient and safe treatment of arthritis due to steady distribution of medicinal substance along the whole area of articular surface.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex

FIELD: medicine.

SUBSTANCE: means has crushed schungite mineral and mint, chamomile, Saint-John's wort and valerian taken in weight proportion of 1:2.25:2.25: 2.25:2.25, respectively. Method involves treating reflexogenic zones with vegetative applicator composed of mint, chamomile, Saint-John's wort, valerian and crushed schungite mineral taken in the amount of 20-40 g. Treatment time is not less than 15-20 days at least 6 h per day. Device has blank produced from laminated material having flexible fabric base and additionally has inlay impregnated with the abovementioned therapeutic prophylactic means. Pocket for placing the inlay is placed on internal base side. The elements defining form are arranged between base layers, fastening members are fixed on one of lateral base sides and have fixing members. Control members are available on the other side as buckles.

EFFECT: enhanced effectiveness in treating nervous system, locomotor apparatus, gastrointestinal tract and urogenital system diseases.

4 cl

The invention relates to medicine and can be used for the treatment of angina

The invention relates to medicine, in particular for treatment
The invention relates to medicine, in particular to Oncology

The invention relates to medicine, in particular to devices for drug delivery in various areas of the body and cells using various types of energy, including laser radiation

The invention relates to medicine and the performance of the sensor for placement in the cavity of a tubular organ of the body

FIELD: veterinary science.

SUBSTANCE: preparation for treatment and prophylaxis of endometritis in cows comprises antibacterial substance dioxydin, gelatin, glycerol and distilled water wherein food or medicinal gelatin is used as gelatin source, distilled glycerol if the 1-st grade is used glycerol source and comprises additionally resorcinol and veterinary algalipin in the following ratio of components, g: dioxydin, 0.1-0.3; resorcinol, 0.01-0.02; veterinary algalipin, 0.9-1.1; food or medicinal gelatin, 1.5-2.0; distilled glycerol of the 1-st grade, 5.0-5.4, and distilled water, 2.1-2.6. Invention provides enhancing effectiveness of the preparation and fertilization in cows.

EFFECT: improved and valuable veterinary properties of preparation.

3 tbl

FIELD: veterinary science.

SUBSTANCE: preparation for treatment and prophylaxis of endometritis in cows comprises antibacterial substance dioxydin, gelatin, glycerol and distilled water wherein food or medicinal gelatin is used as gelatin source, distilled glycerol if the 1-st grade is used glycerol source and comprises additionally resorcinol and veterinary algalipin in the following ratio of components, g: dioxydin, 0.1-0.3; resorcinol, 0.01-0.02; veterinary algalipin, 0.9-1.1; food or medicinal gelatin, 1.5-2.0; distilled glycerol of the 1-st grade, 5.0-5.4, and distilled water, 2.1-2.6. Invention provides enhancing effectiveness of the preparation and fertilization in cows.

EFFECT: improved and valuable veterinary properties of preparation.

3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds able to prevent the extracellular release of inflammatory cytokines. Proposed compounds including their diastereomeric forms and their pharmaceutically acceptable salts correspond to the formula: wherein R means: (a) -O[CH2]kR3 or (b) -NR4aR4b; R3 means a substituted or unsubstituted (C1-C4)-alkyl, a substituted or unsubstituted phenyl wherein substitutes are taken among halogen atom, cyano-group, trihalidemethyl, (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein R3 means hydrogen atom each among R4a and R4b means independently hydrogen atom or (C1-C4)-alkyl-CO- or benzo(1,3)dioxol; index k has a value from 0 to 5; each among R4a and R4b means independently: (a) hydrogen atom or (b) -[C(R5aR5b)2]mR6 wherein each Ra means hydrogen atom, and R5b means hydrogen atom, linear or branched (C1-C)-alkyl; R6 means vinyl, the group -OR7, -CO2R7, cyclic (C3-C)-alkyl, unsubstituted phenyl or phenyl substituted with (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein each among R3, R4a and R4b means independently hydrogen atom, or unsubstituted 6-membered nitrogen-containing heteroaryl; R7 means hydrogen atom, water-soluble cation or (C1-C4)-alkyl; index m has a value from 0 to 5. Also, invention relates to a pharmaceutical composition comprising the effective dose of compounds corresponding to abovementioned formula, and to a method for inhibition of extracellular release of inflammatory cytokines.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 sch, 6 tbl, 3 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to crystalline polymorphic modifications of strong acting epotilone analog of forma A and forma B represented by the formula (I): Invention proposes a crystalline substance representing a mixture of form A and form B of epotilone analogs. Invention proposes two variants of a method for preparing crystalline polymorphic modification representing form A. Also, invention proposes a pharmaceutical composition inhibiting angiogenesis and comprising an active component that represents crystalline polymorphic modification of epotilone analog of form A, form B or a crystalline polymorphic modification of epotilone analog of the formula (I) wherein this modification has no amorphous component, and a pharmaceutically acceptable carrier. Also, invention proposes a method for treatment of cancer comprising administration in mammal the effective dose of crystalline polymorphic modification of epotilone analog. Invention provides preparing crystalline polymorphic modifications of strong acting epotilone analog of the formula (I) characterizing by improved properties for using in therapy of cancer species.

EFFECT: improved preparing methods, valuable medicinal properties of compounds and composition.

16 cl, 9 dwg, 7 tbl, 5 ex

FIELD: organic chemistry, medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I): or its pharmaceutically acceptable salt. Indicated compounds stimulate release of growth hormone from hypophysis and can be used in medicine.

EFFECT: improved stimulating method, valuable medicinal property of compound and composition.

4 cl, 1 dwg, 1 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I): representing such compound as 2-(2,6-dichlorophenylamino)-1H-benzimidazol-4-ol and others. Also, invention relates to using these compounds for preparing a medicinal agent used in treatment of diseases associated with inhibition of [Na+/H+]-exchange. Proposed compounds can be used, in particular, in treatment and prophylaxis of impairment of respiratory impulse, acute and chronic renal diseases.

EFFECT: valuable medicinal properties of compounds.

17 cl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-hydroxypiperidine of the general formula (I): wherein R means (a): -C(O)(CH2)nC(O)OH; (b): wherein R1 means -N(R2)(R3); each R2 and R3 means hydrogen atom, lower alkyl or cyclic tertiary amine; (c): -P(O)(OH)2 or (d): -C(O)(CH2)n and -NHC(O)(CH2)nN(R2)(R3) wherein n means a whole number 1-4. Indicated compounds can be used as prodrugs in preparing medicinal agents used in treatment of diseases associated with blocking agents for receptors of subtype NMDA.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 1 tbl, 20 ex

FIELD: medicine.

SUBSTANCE: method involves carrying out hernia removal in intralaminar way. Posterior longitudinal ligament defect is covered with Tacho-Comb plate after having done disk cavity curettage. Subcutaneous fat fragment on feeding pedicle is brought to dorsal surface of radix and dural sac.

EFFECT: enhanced effectiveness of treatment; reduced risk of traumatic complications.

1 dwg

Up!