Transdermal plaster

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine. Described is matrix layer, suitable for application in plaster for transdermal delivery, aimed at introduction of biologically active compounds, which includes phosphate compound of tocopherol and polymer carrier. Also described is transdermal plaster and method of its production.

EFFECT: plaster makes it possible to efficiency introduce biologically active compounds.

48 cl, 15 tbl, 13 dwg, 12 ex

 

Area of technology

The present invention relates to compositions suitable for use in plasters for percutaneous delivery (transdermal patches) intended for the introduction of biologically active compounds, and plasters for transdermal delivery containing the composition, or matrix layer.

The level of technology

This detailed description that mentions or discusses a document, act or item of knowledge, this reference or discussion is not an admission that the document, act or item of knowledge or any combination of them were under the priority date, publicly available, widely known, part of common General knowledge; or, as it is known, has to try to solve a problem, which it considers a detailed description.

Delivery of drugs is a method or process of introducing a pharmaceutical compound to achieve a therapeutic effect in humans or animals.

To improve bioavailability, safety, duration, start of the process or release of pharmaceutical compounds developed technology of drug delivery.

When creating the technologies of drug delivery have to deal with the problems, including the compatibility of the system of delivery of medicines�drug and pharmaceutical compounds maintaining appropriate and effective duration, possible side effects and satisfaction of the requirements associated with convenience and the patient's consent. As a result, many technologies drug delivery do not achieve the desired improvements and do not meet the requirements.

Accordingly, there is still a need for alternative delivery systems that would deliver drugs and other bioactive compounds.

Disclosure of the invention

The present invention relates to compositions suitable for use in plaster for percutaneous delivery (transdermal patch) for the purpose of administration of biologically active compounds, and the patch for transdermal delivery containing a composition, or matrix layer.

Accordingly, the first aspect of the present invention provides a matrix layer for use in the transdermal patch with the aim of introducing a biologically active compound, wherein the matrix layer contains a mixture of mono-Tocopheryl phosphate compound and a di-Tocopheryl phosphate compound and a polymeric carrier, wherein the polymeric carrier is present in amounts in the range from about 30 wt./wt.% to 95.5 wt./weight.%.

The present invention also provides the use of compositions or m�technolo layer in the transdermal patch with the purpose of introducing biologically active compounds.

It has surprisingly been found that biologically active compounds can effectively enter it using a transdermal patch.

The second aspect of the present invention provides a transdermal patch for administration of biologically active compounds containing the composition, or matrix layer. The composition, or matrix layer may be solid or semi-solid layer. Transdermal patch may contain additional layers.

The third aspect of the present invention provides a method of manufacturing a transdermal patch designed to deliver the biologically active compound, which includes stages:

(i) combining the polymer carrier and optional inert carrier components with a suitable solvent;

(ii) combining (i) with a dispersion containing a biologically active compound and a mixture of mono-Tocopheryl phosphate compound and a di-Tocopheryl phosphate compound;

(iii) mixing (ii) until complete homogenization;

(iv) placing the composition (iii) in appropriate form or casting compositions (iii) on the surface;

(v) drying of the composition when heated.

The implementation of the invention

The present invention relates to compositions suitable for use in the transdermal patch (a patch for percutaneous delivery) with the aim� administration of biologically active compounds the composition comprises a phosphate compound of tocopherol and a polymer carrier. The composition, or matrix layer, may form part of a transdermal matrix patch. Unexpectedly, it was found that by using a transdermal patch containing the composition, or matrix layer, it is possible to effectively introduce biologically active compounds.

Tocopheryl phosphate compound

The composition, or matrix layer contains a mixture of mono-Tocopheryl phosphate compound and a di-Tocopheryl phosphate compound.

Vitamin E exists in eight different forms, namely in the form of four Tocopherols and four tocotrienols. All are chromanone ring with a hydroxyl group that can give up a hydrogen atom to reduce free radicals and a hydrophobic side chain, which provides the ability to penetrate biological membranes. These derivatives of vitamin E can be classified as "hydroxychromone". And Tocopherols and tocotrienols exist in alpha, beta, gamma and Delta forms, determined by the number and location of methyl groups in hermanova the ring. The tocotrienols differ from the analogous Tocopherols by the presence of three double bonds in the hydrophobic side chain. Different forms of vitamin E shown by the formula (I):

R1R2R3
α-tocopherolCH3CH3CH3
α-tocotrienol
β-tocopherolCH3NCH3
β-tocotrienol
γ-tocopherolNCH3CH3
γ-tocotrienol
δ-tocopherolNNCH3
δ-tocotrienol

In the present invention, the tocopherol can be used in any of four forms. Preferred is alpha-tocopherol form.

The term "phosphate compound" refers to the phosphorylated tocopherol, is formed when a covalent bond between the oxygen atom (usually oxygen hydroxyl gr�PPy) compound of tocopherol and a phosphorus atom of a phosphate group (PO 4).

The phosphate compound can be complicated monophosphate ester, complex diphosphate ether, complex triphosphate ester, complex monoprotonated ether, complex giperfosfatemii ester or its salt or derivative, or their combinations. Complex di - and triesters may contain the same form of tocopherol or different forms of tocopherol.

"Salts" include metal salts, such as salts of alkali and alkaline earth metals, e.g. sodium, magnesium, potassium and calcium. Preferred salts are sodium and potassium.

"Derivatives" include phosphate compounds in which one or more phosphate protons are replaced by a Deputy. Some non-limiting examples of the compounds include derivatives of phosphatidyl where a phosphate proton is substituted amino-alkyl group, derivatives of Sugars, in which the proton of the phosphate is replaced by sugar, such as glucose.

The term "aminoalkyl group" refers to a group containing amino (-NH2group or alkyl group. The term "alkyl" refers to hydrocarbon groups are straight, branched or cyclic chain having from 1 to 8 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclohexyl, heptyl and octyl. Most preferred are proizvodi�e phosphatidylcholine.

Mono-Tocopheryl phosphate compound can be chosen from the group consisting of mono-(Tocopheryl) phosphate monosodium salt, mono-(Tocopheryl) phosphate, the disodium salt of mono-(Tocopheryl) phosphate, montalieu salts of mono-(Tocopheryl) phosphate, and dipotassium salts of mono-(Tocopheryl) phosphate and di-Tocopheryl phosphate compound can be chosen from the group consisting of di-(Tocopheryl)phosphate monosodium salt of di-(Tocopheryl) phosphate and montalieu salt of di-(Tocopheryl) phosphate. These phosphate compounds can be obtained from alpha, beta, gamma or Delta forms of Tocopherols or a combination thereof.

In the case of a combination of complex monophosphate ester and complex diphosphatase ether, i.e. monocomponents and giocovarinatale (in the description of the mixture also can be called tocopherylacetate mixture or just "TRM"), the ratio ( wt./wt.%) is at least 2:1 is in the range of from about 4:1 to 1:4, in the range of from about 6:4 to 8:2. The ratio may be about 2:1, about 6:4 or about 8:2.

A mixture of mono-Tocopheryl phosphate compound and a di-Tocopheryl phosphate compound may be present in an amount in the range of about 0.01 wt./wt.% up to 10 weight./wt.%, in the range of from about 0.1 wt./wt.% to 5 weight./wt.%, in the range of from about 0.1 wt./wt.% to 3 wt./wt.%, in the range of from about 0.1 wt./wt.% up to 2 wt./wt.%, within about� from 0.1 wt./wt.% up to 1 wt./wt.% or in the range of from about 0.1 wt./wt.% to 0.5 wt./wt.% total concentration of the composition, or matrix layer. In some embodiments, a mixture of mono-Tocopheryl phosphate compound and a di-Tocopheryl phosphate compound may be present in an amount in the range of about 0.5 wt./wt.% to 1.5 wt./wt.% or in the amount of about 0.1 wt./wt.% total concentration of the composition, or matrix layer.

A polymeric carrier

The composition, or matrix layer also contains a polymeric carrier.

A polymeric carrier may include natural or synthetic polymers, copolymers or ternary copolymers (terpolymers).

Natural polymers include rubber, elastomers, polysaccharides, such as cellulose, polysaccharides such as cellulose, natural rubber, such as shellac and amber.

Synthetic polymers include, for example, acrylates, polyacrylates, polyalkylacrylate, polyamides, polyesters, polycarbonates, polyimides, polistrole, abs, polyacrylonitrile, polybutadiene, poly(butilstearat), poly(Eversole), poly(ether ketones, polyethylene, poly(ethylene glycol), poly(ethyleneterephthalate), polypropylene, polytetrafluorethylene, styrolacrylonitrile resin, poly(trimethylpentanediol), polyurethanes, polyvinylbutyral, polyvinyl chloride, polyvinylidenedifluoride, povidone, poly(vinylpyrrolidone), polychloroprene, fluoroelastomers, chlorsulfuron rubber, hypromellose, the polyol�new elastomer, polyacrylamide, chlorinated polyethylene, polyethersulfone, nylon, liquid crystal polymers, polyethylene terephthalate (PET), polyphenylsulfone derived politicallynominated alcohol, polyethylene glycols, ethylene vinyl acetate, polymethylmethacrylate, cellulose derivatives, such as, ethylcellulose, hydroxyl propyl methyl cellulose, sugar derivatives (gums) including derivatives of sorbitol and manitol, silicone oil and derivatives, silicone oils, including resistant Amin polysiloxane and siloxanes.

The preferred polymer carriers suitable for use in the composition, or matrix layer of the present invention include acrylates, povidone and siloxanes. Particularly preferred polymeric carriers include polyvinylpyrrolidone (e.g. PVP K90, MW 360,000 Da), polysiloxanes, polyalkylacrylate (e.g., DuroTak) and polymethyl methacrylate (for example, Eudragit E100). In one embodiment of the polymeric carrier is polyvinylpyrrolidone. In an alternative embodiment of the polymeric carrier is a poly (methyl methacrylate).

The polymer carrier used in the composition, or matrix layer, may have a sufficient adhesive to ensure bonding of plaster to the skin. For example, in the composition, or matrix layer, may be used resistant to Aminu �polisiloxana and combinations thereof. The most appropriate would be to use a combination of silicones with moderate stickiness and silicones with high adhesive strength. Polysiloxane can be synthesized from linear and branched bifunctional polyfunctional oligomers. It was found that the ratio of both types of oligomers determines the physical properties of polymers. More polyfunctional oligomers result in further cross-linked polymer with higher traction and reduced stickiness, less polyfunctional oligomers result in a higher stickiness and reduced grip. Variant with highly adhesive must be sufficiently sticky to transdermal patch is glued to the surface of the skin. Variant with moderate stickiness, on the other hand, can be quite sticky, but maybe useful, providing a softening effect to the other components included in the composition, or matrix layer. To increase adhesion of the composition, or matrix layer, you can add silicone oil (such as Dimethicone).

A polymeric carrier may be present in amounts in the range from about 30 wt./wt.% to 95 wt./wt.%, in the range of from about 30 wt./wt.% to 80 wt./wt.% or in the range of from about 55 wt./wt.% to 65 wt./wt.% of the total weight of the composition, or matrix layer.

Polymer �Sitel may also include inert components of the medium, such as, for example, anti-adhesiveness, substances for improving adhesiveness and plasticizers to enhance the softness, flexibility and stickiness of the polymer carrier to enable the composition, or matrix layer attached to the surface of the skin and thus to ensure the proper delivery.

In relation to polymers that are sticky by nature and in need of anti-adhesiveness to obtain a suitable consistency may be suitable anti-adhesive, which is solid if no properties inflexibility (i.e. low ability to retain the solvent dries) and combined (i.e. not able to crystallize when dry) with a polymer carrier. The selection can be based on the type of polymer. Many surfactants are suitable for use as anti-adhesive in combination with a polymeric carrier. A more concrete example of anti-adhesiveness is succinic acid. In specific embodiments, the remedy adhesiveness may be present in amounts of or less than 1 wt./wt.%, about 1 wt./wt.%, or up to about 5 wt./wt.% of the total weight of the composition, or matrix layer.

To increase the ability of the composition, or matrix layer, to adhere to the surface to�LM, it can optionally contain a substance to improve the adhesiveness. Stickiness can be controlled by combining the adhesive materials of different hardness (glass transition temperature or Tg). As a rule, the substance to improve the adhesiveness is a polymer, insoluble in water and composed of a monomer which contains partly or entirely composed of alkylmethacrylamide. Such types of polymers include, but are not limited to, acrylic, N-butyl-methacrylic copolymer (Primal N580NF, sold by Japan Acrylic Chemical Company, Ltd.), methacrylic, 2-ethylhexylacrylate copolymer (Nikasol TS-6520 sold by the company Nippon Carbide Industries Company, Ltd), polyacrylic acid (Jurymer AC-IOLPH sold by Nihon Junyaku Company, Ltd), methacrylic copolymer L (Plastoid L50 sold by Rohm Pharma GmbH) and aminoalkyl-methacrylate copolymer E (Plastoid E35L, Plastoid E35M, Plastoid E35H, all sold Rohm Pharma GmbH). Other non-limiting examples include rosin, gidrirovannoe rosin, dibenzoate DIPROPYLENE glycol and/or mixed hydrocarbon compounds and acrylic copolymers (for example, Flexbond 150 adhesive from Air Products).

Plasticizers are additives that increase the plasticity or fluidity of the material to which they are added. Plasticizers can be used in the present invention in order to soften the final product increasing its flexibility� and making it less brittle. Suitable plasticizers include phthalates, esters of polycarboxylic acids with linear or branched aliphatic alcohols of moderate (average) chain length, acetylated monoglycerides, alkilinity, triethylcitrate (TES), acetyltributyl (ATEC), tributyltin (FA), acetyltributyl (ATVs), dioctyltin (CBT), acetylthiocholine (ATOS), tryexecute (THC), acetylsalicylate (ATNS), butyrylthiocholine (VTNS, trihexy-butyrylacetate), trimethylsilyl (TMS), meilleure, lauric acid, laurinlactam, lauryl alcohol, phenyl ester alkylsulfonic acid, the monoethyl ether of diethylene glycol, bis(2-ethylhexyl) phthalate (DEHP), diisooctyl (DIOP), bis(n-butyl)phthalate (DnBP, DBP), Diisobutyl phthalate (DIBP), bis(2-ethylhexyl)adipate (DEHA), dimethyladipate (DMAD), monomethylated (MMAD), dioctyladipate (DOA), ethyloleate, servicemanual, glycerolphosphate, dibutylsebacate (DBS), dibuthylmaleate (DBM), Diisobutylene (DIBM), benzoates, epoxidized vegetable oils, Tris(tromethamine), N-atercolor the sulfonamide (o/p ETSA), N-(2-hydroxypropyl) benzolsulfonat (HP BSA), N-(n-butyl)benzolsulfonat (BBSA-NBBS), tricresylphosphate (TCP), tributyl phosphate (TBP), triethylenemelamine (3G6, 3GH), tetraethylorthosilicate (4G7), 1,3-butyleneglycol, dipropyleneglycol, PEG400, span 80 and polyvinylpyrrolidone. Pre�respectful plasticizers are dibutylsebacate (DBS), servicemanual, meilleures and lauric acid.

Inert media components can be present in an amount in the range of about 0.001 wt./wt.% to about 50 wt./wt.%, in the range of about 0.001 wt./wt.% up to 40 wt./wt.%, in the range of about 0.001 wt./wt.% to about 30 wt./wt.% of the total weight of the composition, or matrix layer. In one embodiment of the composition, or matrix layer contains a remedy stickiness (such as, succinic acid) and a plasticizer (such as, dibutylsebacate) in the total amount of about 35 wt./wt.% of the total weight of the composition, or matrix layer.

The amount of polymer carrier and optional inert component of the carrier present in the composition, or matrix layer will depend on the specific biologically active compounds, which must be entered. However, in most cases, these components may be present in an amount in the range of from about 50 wt./wt.% to 99 wt./wt.%, in the range of from about 80 wt./wt.% up to 98 wt./wt.%, in the range of from about 90 wt./wt.% up to 98 wt./wt.% of the total weight of the composition, or matrix layer. In one embodiment of the composition, or matrix layer contains these components in an amount of about 95 wt./wt.% of the total weight of the composition, or matrix layer.

It should be noted that in some cases in the description of t�pmin "polymeric carrier" may be used collectively for mentioning the polymer carrier and inert components of the media.

Furthermore, the composition, or matrix layer, may optionally contain one or more excipients (excipients) (in addition to the previously discussed inert components of the carrier).

Specialist in the field of technology of the invention will be clear what excipienti are suitable for incorporation into the composition, or matrix layer of the invention. Some examples include, but are not limited to, solvents, thickeners or gelling substances, preserving agents, surfactants, stabilizing agents, buffers, emollients, colorants, flavors and improves the appearance of the substance. It should be understood that any excipient approved by regulatory authorities for use in pharmaceutical products, can be used in the composition, or matrix layer of the present invention. Also, specialists will be clear how many specific excipient or excipients should be used in the composition, or matrix layer of the present invention.

Biologically active compounds

The composition, or matrix layer, may form part of a transdermal matrix patch. It has been surprisingly found that a transdermal patch containing the composition, or matrix layer, can effectively enter the biologically activediary.

The term "biologically active compound" refers to any chemical substance, which has biological effects on humans or animals for therapeutic, cosmetic and veterinary purposes, and includes pharmaceutical products, including medicines, cosmetics, nutraceutical remedies and nutrients. It should be understood that some of biologically active compounds can belong to more than one of these classes.

With the help of a patch for transdermal delivery of the present invention can deliver a wide range of biologically active compounds. Examples include, but are not limited to, drugs for treating cardiovascular diseases, in particular antihypertensive agents (e.g. calcium channel blockers or calcium antagonists and antiarrhythmic agent; pharmaceutical preparations in acute heart failure; inotropic agents; vasodilating agents; ACE inhibitors; diuretics, carbonic anhydrase inhibitors; cardiac glycosides; phosphodiesterase inhibitors; α-blockers; beta-blockers; sodium channel blockers; blockers of potassium channels; β-adrenergic agonists; inhibitors (aggregation) of platelets; antagonists of angiotensin II; protivosvertawati�e tools; thrombolytic means; means for phlebotomy, agents for the treatment of anemia; thrombin inhibitors; antiparasitic agents; antibacterial agents; insulin; human growth hormone and peptides; vaccines; anti-inflammatory agents, in particular non-steroidal anti-inflammatory drugs (NSAID), specifically inhibitors of COX-2; steroid anti-inflammatory drugs; preventive antiinflammatory agent; glaucoma; stabilizers of mast cells; mydriatic agent; drugs affecting the respiratory system; pharmaceutical products for allergic rhinitis; alpha-adrenergic agonists; corticosteroids; pharmaceuticals for chronic obstructive pulmonary disease; xanthine oxidase inhibitors; anti arthritis drug gout; physiologically active substances and antagonists of physiologically active substances; protivopokazaniya funds; antifungal agents; Antiprotozoal agent; sedative; antiviral agents, in particular agents against respiratory viruses, herpes viruses, cytomegalovirus, human immunodeficiency virus and hepatitis infections, agents for the treatment of leukemia and Kaposi's sarcoma; means for pain management, in particular, opioid drugs,�agboluaje and painkillers; neuroleptic drugs; sympathomimetic pharmaceutical drugs; adrenergic agonists; drugs affecting the uptake and release of neurotransmitters; anticholinergic pharmaceutical preparations; remedies for hemorrhoids, remedies for prevention or treatment of effects related to the use of irradiation or chemotherapeutic drugs; drugs in the lipogenesis; funds, reducing fat; peptides against obesity; anti-obesity, such as lipase inhibitors; sympathomimetic funds; funds from inflammation and ulcers of the stomach, such as proton pump inhibitors; prostaglandin inhibitors; VEGF; antihyperlipidemic remedies, in particular statins; drugs, affecting the Central nervous system (CNS) such as antipsychotic, anticonvulsant and antiperoxidative medicines (anticonvulsants), psychotropic drugs, stimulants, sedatives and hypnotics medicines, antidepressants; pharmaceutical anti-Parkinson's disease; hormones and their fragments, such as sex hormones; antagonists of growth hormone; gonadotropin releasing hormones and their analogues; steroid hormones and their antagonists; selective modulators of estrogen; growth factors�; antidiabetic pharmaceutical agents such as insulin, fragments of insulin, insulin analogs, glucagon-like peptides and hypoglycemic agents; H1, H2, H3 and H4 - antihistamines; pharmaceutical products in the form of peptides, proteins, polypeptides, nucleic acids and oligonucleotides; analogs, fragments and variants of natural proteins, polypeptides, oligonucleotides and nucleic acids and similar compounds; agents used in the treatment of migraines; pharmaceutical products for asthma; cholinergic antagonists; glucocorticoids; androgens; antiandrogens; inhibitors of the biosynthesis of adrenocorticoids, agents for the treatment of osteoporosis, such as bisphosphonates; antithyroid pharmaceutical preparations; sunscreens, protective equipment and filters from the sun; agonists of cytokines; antagonists of cytokines of anticancer drugs; drugs for Alzheimer's disease; inhibitors of HMGCoA reductase inhibitors; fibrates; inhibitors of absorption of cholesterol; agents that increase HDL-cholesterol; means for reducing the level of triglycerides; anti-aging products and anti-wrinkle; molecules-precursors for the generation of hormones; proteins, such as collagen and elastin; antibacterial agents; anti-acne (acne); antioxidants; means for ox�with and means whitening the skin; sunscreens, sun filters; variants of human apolipoprotein; molecules-precursors for the generation of hormones; proteins and peptides; amino acids; plant extracts, such as grape seed extract; DHEA; isoflavones; nutrients, including vitamins, phytosterols and iridoid glycosides sesquiterpene lactones, terpenes, phenolic glycosides, triterpenes, derivatives of hydroquinone, phenylalanine; antioxidants such as retinol and other retinoids, including retinoic acid and coenzyme Q10; omega-3 fatty acids; glucosamine; nucleic acids, oligonucleotides, antisense pharmaceuticals; enzymes; cytokines; analogs of cytokines, agonists of cytokines; antagonists of cytokines; immunoglobulins; antibodies; pharmaceutical agents based on antibodies; gene therapy; lipoproteins; erythropoietin; vaccines; low molecular weight and high molecular weight therapeutic substance for the treatment or prevention of human and animal diseases, such as allergies/asthma, arthritis, cancer, diabetes, growth retardation, cardiovascular disease, inflammation, immunological disorders, alopecia, pain, ophthalmological diseases, epilepsy, gynecological diseases, diseases of the Central nervous system, viral infections, bacterial infections, parasitic infections, disease ventricles�part-intestinal tract (GI), obesity and hematologic diseases. Some specific non-limiting examples of suitable biologically active compounds include:

painkillers:

including amino-ether and aminoamide painkillers such as benzocaine, chloroprocaine, cocaine, reserpine, guanethidine, cyclomethycaine, dimethocaine/larocaine, propoxycaine, procaine/novocaine, proparacaine, tetracaine/amethocaine; articaine, bupivacaine, kartikay, qinhokain/dibucaine, etidocaine, levobupivacaine, lidocaine/lignocaine, mepivacaine, piperocaine, prilocaine, ropivacaine, trimekain, propofol, halothane, barbiturates of enflurane, benzodiazepines, neostigmine and ketamine

alkylating agents:

including carmustine, cyclophosphamide, ifosfamide, streptozotocin and mechlorethamine

calcium channel blockers:

including amlodipine, aranidipine, azelnidipine, barnidipine, benidipine, cilnidipine, clevidipine, croyden, durodie, dexniguldipine, efonidipine, einadipine, almodipine, felodipine, floridin, fornicatin, handymen, isradipine, lacidipine, lumisden, lercanidipine, manidipine, methoden, nicardipine, nifedipine, nimodipine, nilvadipine, nimodipine, nisoldipine, nitrendipin, araven, oxazepine, palanivel, pranidipine, changepin, barnidipine, felodipine, Tilden, Cambodian, betanidin, verapamil, gallopamil, benzodiazepin, diltiaz�m, mibefradil, bepridil, fluspirilene and fendiline

antiarrhythmic funds and funds from the strokes:

including amiodarone, disopyramide, acetate flekainida, quinidine sulfate, nitroglycerin, ranolazine, amiodarone, isosorbide and PE Antibacterials, antibiotics and remedies against the window:

including amoxicillin, ampicillin, azithromycin, benethamine penicillin, bleomycin, benzoylperoxide, cinoxacin, chloramphenicol, daunorubicin, plicamycin, fluoroquinolones, ciprofloxacin, clarithromycin, clindamycin, klinges, clofazimine, chlorhexidine gluconate, cloxacillin, demeclocycline, doxycycline, erythromycin, ciprofloxacin, imipenem, indomethacin, lymecycline, minocycline, nalidixic acid, nitrofurantoin, penicillin, rifampicin, spiramycin, sulfacetamide sodium, sulfabenzamide, sulfadoxine, sulfamerazine, sulfacetamide, sulfadiazine, sulfafurazole, sulfamethoxazole, sulfapiridin, tetracycline, cephalexin, cefdinir, triclosan, ofloxacin, vancocin, glyburide, mupirocin, cefprozil, cefuroxime axetil, norfloxacin, isoniazid, lupulin, D-penicillamine, levofloxacin, Gatifloxacin, and trimethoprim

cancer:

including doxorubicin, 6-thioguanine, paclitaxel, docetaxel, camptothecin, megestrol acetate, navelbine, cytarabine, fludarabine, 6-mercaptopurine, 5-fluorouracil, teniposide, wines�the Lastin, vincristine, cisplatin, colchicine, carboplatin, procarbazine and etopside

antidepressants, neuroleptics and sedatives:

including alprazolam, amoxapine, bentazepam, bromazepam, claripen, clobazam, clonazepam, diazepam, lorazepam, flunitrazepam, flurazepam, lormetazepam, medazepam, nitrazepam, oxazepam, temazepam, maprotiline, mianserin, nortriptyline, risperidone, sertraline, trazodone, aloperidin, trimipramine maleate fluoxetine, ondansetron, midazolam, chlorpromazine, haloperidol, triazolam, clozapine, fluororesin, fluphenazine decanoate, fluanisone, perphenazine, pimozide, prochlorperazine, sulpiride, thioridazine, paroxetine, citalopram, bupropion, phenelzine, olanzapine, divalproex sodium and venlafaxine

tritsiklichesky antidepressants:

including azathioprin, amitriptyline, famotidine, promethazine, paroxetin, oxcarbazepine and mirtazapine

antidiabetic drugs:

including acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, Metformin, tolazamide, glyburide, glimepiride and tolbutamide

anti-convulsants:

including beclamide, carbamazepine, gabapentin, tiagabine, vigabatrin, topiramate, clonazepam, ethotoin, Metin, methsuximide, methylphenobarbital, oxcarbazepine, paramethadione, phenacemide, fenobarbiton, Fenelon, phensuximide, primidone, sultiame, phenytoin sodium, �Irapuato monohydrate, gabapentin, lamotrigine, zonisamide, ethosuximide and valproic acid

hypnotics/sedatives and muscle relaxants:

including zolpidem tartrate, amylobarbitone, Barbican, butobarbital, pentobarbital, brotizolam, carbromal, chlordiazepoxide, chlormethiazole, ethinamate, meprobamate, methaqualone, cyclobenzaprine, cyclobenzaprine, tizanidine, baclofen, butalbital, zopiclone, atracurium, tubocurarine and phenobarbital

antifungal, Antiprotozoal and antiparasitic agents:

including amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, Itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terconazole, tioconazole and undecanoyl acid; benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate dinitolmide, furazolidone, metronidazole, nimorazole, nitrofurazone, Ornidazole, terbinafine, clotrimazole, chloroquin, mefloquin, Itraconazole, drug, praziquantel, quinacrine, mebendazole and tinidazole antihypertensive and cardiac medications:

including candesartan, hydralazine, clonidine, triamterene, felodipine, gemfibrozil, fenofibrate, nifedical, prazosin, mecamylamine, doxazosin, dobutamine and cilexetil

protivomigrenoznae means:

including dihydroergotamine mesilate, erg�taming tartrate, methysergide maleate, pizotifen maleate and sumatriptan succinate

antimuscarinic means:

including atropine, benzhexol, biperiden, ethopropazine, hyoscyamine, mepenzolate bromide, oxybutynin, oxyphencyclimine and Tropicamide

anticancer drugs or immunosuppressive agents):

including aminoglutetimid, amsacrine, azathioprine, busulfan, chlorambucil, cyclosporine, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine, tamoxifen citrate, testolactone, tacrolimus and sirolimus

anti-Parkinsonian agents:

including bromocriptine mesilate, levodopa, tolcapone, ropinirole, bromocriptine, hypoglycemic drugs such as sulfonylureas, biguanides, inhibitors of α-glucosidase, a thiazolidinedione, cabergoline, carbidopa and lisuride maleate

antithyroid drugs:

including carbimazole and p.

antiviral agents:

including amantadine, ritonavir, cidofovir, acyclovir, famciclovir, ribavirin, amprenavir, indinavir, rimantadine and efavirenz, penciclovir, ganciclovir, vidarabine, abacavir, adefovir, amprenavir, delavirdine, didanosine, stavudine, zalcitabine, zidovudine, enfuvirtide and interferon

cardiac inotropic agents:

including amrinone, milrinone, digitoxin, d�goxin, enoximone, lanatoside With and methoxy

hypolipidemic drugs and remedies hyperlipidemia:

including fenofibrate, clofibrate, probucol, ezetimibe and torcetrapib

anti-inflammatories:

including meloxicam, triamcinolone, cromolyn, nedocromil, hydroxychloroquine, montelukast, zileuton, zafirlukast and meloxicam

antihistamines:

including Fexofenadine, chloral hydrate, hydroxizin, promethazine, cetirizin, cimetidine, lilitin, meclizine, dimenhydrinate, loratadine, nizatidine and promethazine

antiulcer drugs:

including omeprazole, lansoprazole, pantoprazole and ranitidine

diuretics:

including hydrochlorothiazide, amiloride, acetazolamide, furosemide and torsemide

opioid drugs:

including natural opiates, for example, the alkaloids contained in the resin of the opium poppy, such as morphine, codeine and thebaine; palpitations opioids created from the natural opiates, such as hydromorphone, hydrocodone, oxycodone, Oxymorphone, desomorphine, diacetylmorphine (heroin), Nicomorphine, dipropanoylmorphine, benzylmorphine and Ethylmorphine; fully synthetic opioids such as fentanyl, pethidine, methadone, tramadol and dextropropoxyphene; endogenous opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dinary�s, and endomorphin; opioid painkillers including agonists of opioid receptors, partial agonists of opioid receptors, opioid antagonists or mixed agonists-antagonists of opioid receptors; agonists of opioid receptors, including morphine, apomorphine, Etorphine, heroin, hydromorphone, Oxymorphone, Levorphanol, methadone, levomethadyl, meperidine, fentanyl, Sufentanil, Alfentanil, codeine, hydrocodone, oxycodone and the mixture vysheperechislennogo; antagonists of opioid receptors, including naloxone and naltrexone; mixed agonists-antagonists of opioid receptors, oblada mixed agonistic/antagonistic activity, or receptor, demonstrating only partial agonist activity, including buprenorphine, nalbuphine, butorphanol, pentazocine, and mixtures of such compounds; opioids, exhibiting partial agonist activity, including ethylketocyclazocine; opium alkaloids including phenanthrene that are natural in opium, such as codeine, morphine, thebaine and oripavine (the active metabolite of thebaine); synthetic derivatives such as diacetylmorphine (heroin), Dihydrocodeine, hydrocodone, hydromorphone, Nicomorphine, desmartin, Ethylmorphine, dipropanoylmorphine, oxycodone and Oxymorphone; synthetic opioids, including anilinopyrimidines such as fentanyl, alphamethylthiofentanyl, alfenta�Il, Sufentanil, Remifentanil, carfentanil and ohmefentanyl, phenylpiperidine, such as pethidine (meperidine), Ketobemidone MRRR, allylprodine, prodyn and RARER; derivatives of diphenylpropylamine such as propoxyphene, dextropropoxyphene, dextromoramide, Bezitramide, Piritramide, methadone, Dipipanone, levomethadyl acetate (LAAM), Difenoxin, Diphenoxylate and loperamide; derivatives of benzomorphans, such as dezocine, pentazocine and phenazocine; oripavine derivatives such as buprenorphine, dihydroetorphine and Etorphine; derivatives morphinan, such as butorphanol, nalbuphine, Levorphanol and levomethorphan, and others, such as lefetamine, meptazinol, Tilidine, tramadol and tapentadol; antagonists of opioid receptors, including nalmefene, naloxone and naltrexone

NSAID (nonsteroidal anti-inflammatory drugs):

including derivative arylalkenes acid, diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indometacin, indometacin farnesyl, nabumeton, exaltation, proglumetacin, sulindac and tolmetin; derivatives of 2-arylpropionic acids (profenov), which include alminoprofen, benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen, Ketoprofen, Ketorolac, loxoprofen, miroprofen, naproxen, oxaprozin, pirprofen, suprofen, t�replumbed and tiaprofenic acid; and derivatives N-orientalibus acid (fenomenologi acid), which include flufenamic acid, meclofenamic acid, mefenamic acid and tolfenamic acid, tromethamine, celecoxib, nepafenac, aspirin, rofecoxib, naproxen, sulindac, piroxicam, phenylbutazone, tolmetin, indomethacin, acetaminophen (paracetamol), tramadol and propoxyphene

retinoids:

including retinoids first generation, such as retinol, retinal, tretinoin (retinoic acid, Retin-A), isotretinoin and alitretinoin; the second generation retinoids such as etretinate and its metabolite acitretin; the third generation retinoids such as tazarotene, bexarotene and adapalene

hormones and steroids:

including adrenocorticotropic hormone (ASTN), antidiuretic hormone (vasopressin), atrial natriuretic factor (ANF), atrial natriuretic peptide (ANP), beclomethasone, cortisone, scopolamine, dopamine, epinephrine, catecholamines, cholecystokinin, clomiphene citrate, danazol, dexamethasone, diethylstilbestrol (DES), ethinyl estradiol, fludrocortisone, finasteride, follicle stimulating hormone, gastrin, hydroxyprogesterone, growth hormone, insulin, leptin, luteinizing hormone, medroxyprogesterone acetate, mestranol, quinestrol, methyltestosterone, nandrolone, norethindrone, norethisterone, norgestrel, estradiol, conjugar�bathrooms estrogens, Oxandrolone, oxytocin, prednisone, progesterone, prolactin, prostaglandins, somatostatin, stanozolol, stilbestrol, thyroxine, prednisolone phosphate, triamcinolone, mifepristone acetonide, budesonide, levothyroxine, testosterone, testosterone cypionate, fluoxymesterone, flutamide, mometasone furoate, ciproteron, formation, goserelin, leuprolide, calcitonin, halobetasol, hydrocortisol and tibolona

statins and derivatives:

including atorvastatin, fluvastatin, lovastatin, nystatin, rosuvastatin, pravastatin, orlistat and simvastatin

excitatory (stimulating) means:

including amphetamine, phentermine, tyramine, ephedrine, metaraminol, phenylephrine, dexamfetamine, deksfenfluramin, fenfluramine, nicotine, caffeine and mazindol

vasoconstrictors:

including desmopressin

vasodilators:

including carvedilol, terazosin, phentolamine and menthol

funds for Alzheimer's:

including levetiracetam, levetiracetam and donepezil

the ACE inhibitors(angiotensin converting enzyme):

including benzapril, enalapril, ramipril, fosinopril sodium, lisinopril, Minoxidil, isosorbide, ramipril and quinapril

antagonists of beta-adrenergic receptors:

including atenolol, timolol, pindolol, propanolol hydrochloride, bisoprolol, esmolol, metoprolol succinate, metoprolol and metoprolol TA�expenses

antagonists of angiotensin II:

including losartan

inhibitors of platelets:

including abtsiksimab, clopidogrel, tirofiban and aspirin

alcohols and phenols:

including tramadol, tramadol hydrochloride, allopurinol, calcitriol, Cilostazol, santalol, Ursodiol bromperidol, droperidol, flupentixol decanoate, albuterol, albuterol sulfate, carisoprodol, clobetasol, ropinirol, labetalol and Methocarbamol

ketones and esters:

including amiodarone, fluticasone, spironolactone, prednisone, trazodone, desoximetasone, methyl prednisone, nabumetone and buspirone

antiemetic:

including metoclopramide

ophthalmological preparations:

including dorzolamide, brimonidine, olopatadine, cyclopentolate, pilocarpine and echothiophate

anticoagulant and antithrombotic means:

including warfarin, enoxaparin, and lepirudin

remedies for the treatment of gout:

including probenecid and sulfinpirazon

remedies for the treatment of COPD and asthma:

including ipratropium

remedies for the treatment of osteoporosis:

including raloxifene, pamidronate and risedronate

cosmetic peptides:

including acetyl Hexapeptide-3, acetyl Hexapeptide-8, acetolactate and 1-carnosine

vaccine:

including vaccines containing toxoids (inactivated toxic compounds); proteins, subunits of proteins, polypeptide; polynucleotides such as DNA and RNA; conjugate; adjuvant such as saponins, virosomes, inorganic and organic adjuvant, for example, zostavax

nutraceutical and cosmetic active substances:

including coenzyme Q10(or ubiquinone), ubiquinol or resveratrol; a carotenoid, such as α, β, or γ-carotene, lycopene, lutein, zeaxanthin and astaxanthin; phytonutrients such as lycopene, lutein and zeaxanthin; unsaturated fatty acid such as linoleic acid, conjugated linoleic acid, linolenic acid, omega-3 fatty acids, including, but not limited to, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and their glycerol esters; fat-soluble vitamins including vitamin D (D2, D3 and their derivatives), vitamin E (α, β, γ, δ - tocopherol or α, β, γ, δ - tocotrienols), vitamin a (retinol, retinal, retinoic acid and derivatives), vitamin K (K1, K2To3and their derivatives) of capric/Caprylic triglycerides, folic acid, iron, Niacin, glitserillinoleat, omega-6 fatty acids, vitamin F, selenium, cyancobalamin, aloe Vera, beta-glucan, bisabolol, an extract of camellia thea (green tea) extract, centella asiatica (sciolistic Asian), Cetearyl oleate, chlorophyll, oil of citrus sinensis (orange), Cocoyl Proline, dicaprylyl ether, disodium lauramidopropyl of Tocopheryl phosphates (phosphatidycholine (E), glycerin, glyceridae, licorice root (glycyrrhiza glabra) extract, witch hazel (hamamelis virgiana), lactic acid, lecithin, lutein, oil seeds, macadamia (macadamia integrifolia), chamomile extract (matricaria chamomilla), evening primrose oil (oenothera biennis) extract, olive leaf (olea europaea), rice oil, avocado oil (persea gratissima) extract, Polygonum (polygonum multiflorum), pomegranate sterols, resveratrol, rosehip oil (rosa eglanteria), sandalwood oil (santalum spicatum), titanium dioxide, folic acid, glycerin, glitserillinoleat (omega-6 fatty acids vitamin F), vitamin a palmitate, grape seed oil (vitis vinifera), halobetasol, adenosine, adenosine triphosphate, alpha-hydroxy acid, allantoin, hyaluronic acid and its derivatives, solutal, tranexamic acid, glycolic acid, arginine, ascorbylpalmitate, ascorbyl palmitate, salicylic acid, carious acid, alpha lipoic acid, gamma-linolenic acid (GLA), panthenol, retailpoint, remineralised, furfuryladenine, retinaldehyde, copper peptides, idebenone, dimethylaminoethanol (DMAE), Niacinamide, beta-glucan, polymethylpentene-4, palmitoylated/tetrapeptide-7, ethocyn, ceramides, phenylalanine, glucuronolactone, L-carnitine, hydroxyapatite, palmitoleate-3, Forskolin, zinc oxide, α-bisabolol, eugenol, silybin, isoflavones, aucubin, catalpol, pseudoguainolides from Ar�IKI Chamisso (Arnica chamissonis), rosmarinic acid, Rosana, salicylates, such as salicin, saligenin and salicylic acid, taxaction, α-lecturera, isolateral, taraxatone, ceramides, arbutin, gingerale, sagauli, hypericin, elastin, collagen and peptides.

Particularly preferred biologically active compounds include alprazolam, donepezil, risperidone, lorazepam, nicotine, lidocaine, diclofenac, felodipine, insulin, ketoralac, prilocaine, halobetasol, hydrocortisol, opioids such as oxycodone and dihydrohydroxycodeinone (of oxycodone base).

It is clear that pharmaceutically, nutriceuticals or cosmetically acceptable derivatives of biologically active compounds included in the scope of the present invention.

The term "pharmaceutically, nutriceuticals or cosmetically acceptable derivative" includes, but is not limited to, pharmaceutically, nutriceuticals or cosmetically acceptable salts, esters, salts of such esters, ethers or any other derivative, including prodrugs and metabolites, which after administration to a subject (e.g. patient, human or animal) in need, is able to provide, directly or indirectly, a biologically active compound, as described elsewhere in the description.

When used in the description, the term "pharmaceutically, nutraceutic�ski or cosmetically acceptable salt" refers to salts, in the framework of a thorough medical evaluation are suitable for use in contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., in accordance with an acceptable ratio of benefit/risk. Pharmaceutically, nutriceuticals or cosmetically acceptable salts are well known in the art. For example, S. M. Berge, et al. details pharmaceutically, nutriceuticals or cosmetically acceptable salts in J. Pharmaceutical Sciences, 66:1-19, 1977. Examples of pharmaceutically, nutriceuticals or cosmetically acceptable non-toxic salts accession acids are salts formed by interaction of amino groups with inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzolsulfonat, benzoate, bisulfate, borate, butyrate, comfort, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecenal�at, aconsultant, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, idgital, 2-hydroxy-econsultant, lactobionate, lactate, laurate, lauryl, manat, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like salts. Typical salts of alkali and alkaline earth metals include sodium, lithium, potassium, calcium, magnesium, etc. Additional pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, Quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

The term "pharmaceutically, nutriceuticals or cosmetically acceptable ester" refers to esters that are hydrolyzed in vivo and include those that are easily destroyed in the human body with the provision of the parent compound or its salts. Suitable ether groups include, for example, groups derived from pharmaceutically, nutriceuticals or cosmetically acceptable aliphatic carbon�o acids, in particular, alkane, alkinoos, cycloalkanones acid and alcantarilla, in which each alkyl or alkenyl fragment preferably has not more than six carbon atoms. The examples of esters include formate, acetate, propionate, butyrate, acrylate and ethylsuccinate.

The term "pharmaceutically, nutriceuticals or cosmetically acceptable prodrug" when used in the description refers to the prodrug is biologically active compounds, which, under careful medical assessment, are suitable for use in contact with tissues of a subject without excessive toxicity, irritation, allergic response, etc., in accordance with an acceptable ratio of benefit/risk and effective against their intended use, as well as the zwitterionic forms (if possible) of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo with obtaining the parent compound of the above formula, for example, by hydrolysis in blood. A complete discussion is provided in T. Higuchi and V. Stella, Pro-dmgs as Novel Delivery Systems, Vol.14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.

In addition, the present invention is not limited to introducing only one biologically active compounds�Oia: in the composition, or matrix layer can include more than one biologically active compound or other therapeutic compounds.

Biologically active compound may be present in a therapeutically effective amount, i.e. in an amount necessary to achieve the desired therapeutic effect. In most cases, the biologically active compound will be present in an amount in the range of from about 0.1 wt./wt.% to 30 wt./wt.%, in the range of from about 0.1 wt./wt.% up to 20 wt./wt.%, in the range of from about 0.1 wt./wt.% up to 10 weight./wt.% with all the concentration of the composition, or matrix layer. In one embodiment of the matrix layer will have a concentration of biologically active compounds in the range of from about 3.0 wt./wt.% to 15.0 wt./wt.% with all the concentration of the composition, or matrix layer.

The ratio of biologically active compound: TR ( wt./wt.%) may be in the range of from about 5:5 to 5:0,5, with the most preferred value is about 5:1. The ratio of polymeric carrier: [biologically active compound and TR] can be in the range of from about 1:1 to 3:1, the most preferred value is in the range of about 7:6 to 7:3.

Fabrication of transdermal patch

The composition, or matrix layer, may form part of a transdermal matrix patch. Transdermal patch can be made using a variety of methods.

Od�n method involves the Union of the polymer carrier and any inert components, media, for example, anti-adhesiveness and/or plasticizer with a suitable solvent (for example, 50% water, 50% ethanol). This mixture is combined with the dispersion containing the biologically active compound and a mixture of mono-Tocopheryl phosphate compound and a di-Tocopheryl phosphate compound, and stirred to achieve complete homogenization. In one embodiment, after the implementation of this composition is placed in the appropriate form and dried. In a preferred embodiment of the composition is dried by heating to about 90°C, preferably for from 0.5 to 24 hours. However, preparation of the mixture and/or drying may be carried out at a temperature in the range of from about 30°C to 90°C. it Was found that the composition of the mixture and/or drying at a temperature of about 75°C results in improved delivery of bioactive compounds. In an alternative embodiment of the composition may be deposited on the surface (e.g., a roller) and then dried by heating.

A composition comprising a mixture of mono-Tocopheryl phosphate compound and a di-Tocopheryl phosphate compound and the polymer carrier is suitable for use as the matrix layer. The matrix layer may be solid or semi-solid layer.

In addition, the Transdermal patch in most cases�EV may contain a protective layer. The protective layer serves as a substrate or base for the composition, or matrix layer. If you manufacture a transdermal patch form is used, the protective layer can be placed in the form before adding of the composition, or matrix layer.

Accordingly, the composition, or matrix layer mainly has two surfaces: a first surface and a second surface opposite the first surface, the first surface is in contact with the protective layer and the second surface is intended for diffusive contact with the skin of the subject. A subject can be human or animal.

Preferably, the protective layer is occlusive or impermeable to protect the composition, or matrix layer from the external environment. However, can also be used reocclusion protective layer, if the packaging of transdermal patch is completely sealed to prevent the destruction of the composition, or matrix layer. Preferred is an occlusive protective layer.

The protective layer may be any thickness, but in the art of the protective layer generally has a thickness of approximately from 0.0005 inches to 0.01 inches.

In addition, the transdermal patch may contain "lining", which is a removable protective or impermeable with�OEM, in most cases, but not necessarily, it does not have adhesive properties, i.e. it is "readhesion (non-stick)" in order not to stick to the composition, or matrix layer. This "lining", which is also referred to as a coating film that protects the transdermal patch during storage. When using the patch, a cover film is removed.

The cover film may be made of the same material as the protective layer, however, it can also be a metal foil, Mylar (officially registered trademark), polyethylene terephthalate, siliconized polyester, colloidal silica in silicone rubber, polytetrafluoroethylene, cellophane, paper sizing organosilicon compounds, aluminized paper, polyvinyl chloride film, composite foils or films containing polyester such as polyglycolether, polyester or aluminized polyester, polytetrafluoroethylene, thermoplastic elastomers, block copolymers of polyethylene and methyl methacrylate, polyurethanes, polyvinylidene chloride, nylon, silicone elastomers, kouchakzadeh polyisobutylene, styrene, copolymers of butadiene and styrene and copolymers of isoprene and styrene, polyethylene and polypropylene.

The cover film may be any thickness, but in this area� technology of covering film, typically has a thickness from about 0.01 mm to 2 mm.

Transdermal patch may also contain an adhesive layer (adhesive, adhesive layer). The adhesive layer may constitute an additional layer in the composition, or matrix layer, or may be applied to the outer edge of the protective layer, wherein the protective layer extends beyond the edges of the composition, or matrix layer. Polymeric adhesives are suitable for transdermal patches include polyacrylate polymers, adhesives based on rubber and polysiloxane adhesive. These types of materials, as well as others, are described in the work Van Norstrand (The Handbook of Pressure Sensitive Adhesive Technology Second Edition 1989), included in the description by reference. Examples of commercially available adhesives include, but are not limited to, polyacrylate adhesives sold under the brand name DUROTAK (registered trademark) companies National Starch and Chemical Corporation, Bridgewater, new Jersey, as well as GELVA-MULTIPOLYMER SOLUTION (registered trademark) from the company Cytek Surface Specialties, Smyrna, GA.

Advantages

It has surprisingly been found that biologically active compounds can effectively enter it using a transdermal patch containing the composition, or matrix layer, which contains a mixture of mono-Tocopheryl phosphate compound and a di-Tocopheryl phosphate compound and �alimamy media.

Funds (options) transdermal delivery include, for example, creams and gels for topical application and skin patches.

Creams and gels can create difficulties in respect of compliance with the prescribed requirements and control the dosage, and may be perceived by patients as dirty or unpleasant.

There are different forms of skin patches, including "reservoir" patches and "matrix" patches. Patches can also be single or multilayer. "Reservoir" patch basically has a reservoir with a liquid or gel containing a solution or suspension of the drug separated by a membrane or layer of sticky substance. In "matrix" patch, the variance of the medicinal product is semi-solid or solid layer, which may contain or not contain a sticky substance.

"Reservoir" patches overcome some of the difficulties associated with the dosage (as when using local creams and gels), however, the delivery may be uneven or unstable, and there is some risk of compromising the integrity of the tank. An additional problem relates to the delivery of assigned drugs that can cause addiction in a subject and misuse. Gels, creams, and "reservoir" patches provide limited barriers to extra�tion of the drug substance, while the inclusion of the drug substance in the composition, or matrix layer, represents a significant or even a nearly impenetrable barrier for extraction of medicinal substances.

Delivery of the active substance perorally by or by injection, typically results in a non-linear profile of delivery. Transdermal delivery provides a non-invasive method of achieving a lasting unchanging delivery.

Without wanting to be bound by theory, it is believed that the presence of a mixture of mono-Tocopheryl phosphate compound and a di-Tocopheryl phosphate compound increases the skin penetration of biologically active compounds. It was also found that the components of the composition, or matrix layer is not very well prepared in the mixture without the presence of a mixture of mono-Tocopheryl phosphate compound and a di-Tocopheryl phosphate compound. It was also found that the presence of a phosphate compound of tocopherol reduces skin irritation caused by many biologically active compounds.

Figures

Examples will be described with reference to the accompanying figures:

figure 1 - schematic representation of the transdermal patch of one embodiment of the present invention;

figure 2 is a graph representing the result of comparing the delivery of oxycodone transder�xual patches of the present invention, manufactured under different drying modes;

figure 3 is a graph representing the result of comparing the delivery of oxycodone transdermal patches of the present invention, fabricated with and without adhesive).

figure 4 is a graph representing the result of comparing the delivery of oxycodone transdermal patches of the present invention, fabricated with and without occlusion of the protective layer;

figure 5 is a graph representing the result of the study of pharmacokinetic parameters was performed after the application of transdermal patches of the present invention;

figure 6 is a graph representing the result of the study of pharmacokinetic parameters was performed after the application of transdermal patches of the present invention;

figure 7 is a graph representing the result of comparing the delivery of oxycodone transdermal patches of the present invention containing different plasticizers;

figure 8 is a graph representing the result of comparing the delivery of oxycodone transdermal patches of the present invention containing different plasticizers and polymeric carriers;

figure 9 - graph showing the mean value of changes in the content of glucose in the blood after applying a transdermal patch of the present invention each animal;

figure - graph showing the area under the curve, calculated from data presented in the graph of figure 9;

figures 11 and 12 graphs that compare the deposition in the skin of diclofenac when using two transdermal patches for the delivery of diclofenac; and

figure 13 is a graph comparing the penetration of lidocaine from two transdermal patches for the delivery of lidocaine.

Examples

Now different implementation options/aspects of the present invention will be described with the following non-limiting examples.

Example 1. Fabrication of transdermal patch

Final composition, or matrix layer
ComponentsThe weight percentage after drying
The combination of mono-(Tocopheryl) phosphate and di-(Tocopheryl) phosphate in a ratio 6:41.1 wt./wt.%
Oxycodone5,5 weight./wt.%
Eudragit E100 (polymethyl methacrylate)60,6 weight./wt.%
Dibutylsebacate27.3 wt./wt.%
Succinic acidSmall scale laboratory production

Components dissolved in a solvent (acetone: isopropanol: ethanol 60:6,6:33,5% by weight).

Then the solution was poured in a separate form (containing suitable protective layers) at room temperature and the solvent evaporated at 75°C for 1.5 hours.

Large-scale production

All components of the composition, or matrix layer combined at a suitable temperature to obtain a homogeneous molten mass. Then the molten mass is inflicted on a cold surface (for example, rotating mill (rotating mill) or a sheet coated with a suitable protective layer) and allowed to harden. You can then cut the individual transdermal patches of different sizes.

When applying both methods, the composition, or matrix layer may be relatively thin; however, the thickness of the composition, or matrix layer can vary depending on desired properties of the transdermal patch. Figure 1 is an example of a transdermal patch of one embodiment of the present invention.

Example 2. An alternative method of manufacturing a transdermal patch

Transdermal patches were made by dissolving 20 wt./wt.% solid mixture of the granules Eudragit E100, dibutylsebacate, amber� acid (except TPM and oxycontin components in the composition, or matrix layer may together be referred to as "polymeric carrier"); a combination of mono-(Tocopheryl)phosphate and di-(Tocopheryl) phosphate in a ratio of 6:4 (TRM); and oxycodone in a mixture of 60:6,6:33,4 acetone/isopropyl alcohol/ethyl alcohol. Then this mixture was transferred to a 6 cm2round aluminum form posted below (at the bottom) polyester "lining" (of 1.66 ml, 3M Scotchpak™, 3M, MN) and the evaporated solvent in a drying Cabinet or at 45°With during the night or at 75°C for 1.5 hours. When using glue, it was the adhesive DuroTak, and in this example succinic acid was not included in the composition.

Table.
The composition, the ratio of excipients and conditions for the manufacture of a transdermal patch
PatchThe ratio (RS:O:TRM)*Oxycodone (mg)Mixture volume (ml)Temp. visus./timeSuccinic acidglue
110:5:110245°C/nightYes No
214:5:110245°C/nightYesNo
314:5:15145°C/nightYesNo
414:5:15175°C/1.5 hYesNo
514:10:250,575°C/1.5 hNoYes
* Refers to the ratio of polymeric carrier: oxycodone:TRM

Example 3. Compare the used drying temperatures

Transdermal patches for the delivery of oxycodone were manufactured in accordance with example 1 (small scale production) to test the two different temperature regimes. Transdermal patches were glued to the samples of human skin full thickness�s, using the methodology of diffusion Franz cell filled with PBS. Then using HPLC-determined concentrations of oxycodone in the solution of the recipient (the number of oxycodone has passed through the skin) at certain intervals of time- 18, 22, 24, 42, 44, 68 and 75 hours.

Table.
Characteristics of the test patches
PatchThe ratio (RS:O:TRM)*Oxycodone (mg)Mixture volume (ml)Temp. visus./timeSuccinic acidglue
And14:5:110245°C/nightYesno
In14:5:110275°C/1.5 hYesno
* Refers to the ratio of polymeric carrier: oxycodone:TRM

The results predstavljen�e in figure 2, show that the transdermal patch is manufactured by using higher temperature (drying) during drying, there is an increase transdermal delivery compared to the transdermal patch is manufactured using a lower temperature during drying.

Example 4. Comparative testing to determine the impact of the external adhesive layer

Produced transdermal patches, and investigated the solution of the recipient, as described in example 3, and the validation was carried out after 0.5; 1, 3, 4 and 20 hours.

Table.
Characteristics of the test patches
PatchThe ratio (RS:O:TRM)*Oxycodone (mg)Mixture volume (ml)Temp. visus./timeSuccinic acidglue
14:5:110275°C/1.5 hYesno
D14:5:1 10275°C/1.5 hnoYes
* Refers to the ratio of polymeric carrier: oxycodone:TRM

The results of this comparison, presented in figure 3 clearly show that the use of a transdermal patch comprising an adhesive layer, leads to reduced penetration of oxycodone through the skin compared with self-adhesive transdermal patches.

Example 5. Comparative testing to determine the effect of occlusive protective layer in comparison with the absence of the protective layer

Produced transdermal patches, and investigated the solution of the recipient, as described in examples 3 and 4, the checks were performed after 1, 2, 3, 4 and 5 hours.

Table.
Characteristics of the test patches
PatchThe ratio (RS:O:TRM)*Oxycodone (mg)Mixture volume (ml)Temp. drying/timeOcclusive protective layerGlue
E14:5:110275°C/1.5 hYesno
F14:5:110275°C/1.5 hnono
* Refers to the ratio of polymeric carrier: oxycodone:TRM

The results presented in figure 4 clearly show that transdermales penetration of oxycodone is much better when using occlusive protective layer compared to tape without adhesive protective layer.

Example 6. Pharmacokinetic testing

In this example a comparison was made of the RK parameters in plasma with the use of patches No. 1, 2, 4 and 5 in example 2.

Transdermal patches are cut from a polyester substrate and glued to the shaved and washed the back of male rats line Sprag-doli 10-12 weeks of age using a 6×7 cm adhesive dressings Tegaderm HP™ (3M, MN) or left in its place a protective layer or a remote protective layer (see table below). Tegaderm served to hold the occlusive protective layer in place or if there is no�AI protective layer to keep himself transdermal patch.

The day after the attachment of the transdermal patch to the shaved area, took blood samples from the tops of the tail after amputation (~1 mm of the tip of the tail, on certain terms.

Quantitatively evaluated the following RK-options:

Cmaxthe observed maximum concentration of oxycodone.

AUC0-4: Area under the curve between 0 and 4 hours (the duration of the experiment was 4 hours) is a measure of the total amount of the delivered drug.

The results presented in figure 5 and the table below show that the Transdermal patches of the present invention with different compositions are able to effectively deliver oxycodone rats, as evidenced by the results of pharmacokinetic studies.

Table.
Estimated pharmacokinetic parameters in rats
PatchDose of oxycodone (mg/kg)Occlusive layernCmax(ng/ml)AUC0-4(ng.ml/min)
141,8±0,4no 1793±1613681±2367
245,0±2,1Yes992±2711959±2910
421,7±0,1Yes5144±3321637±5189
518,1±0,3Yes574±2911161±4636
'n' = number of animals

Example 7. Testing pharmacodynamics

Rats were prepared and gave them doses of the drug, in the same way as in example 6 using the patches No. 1, 3 and 5 in example 2.

The next day, after adhesion of transdermal patches for the shaven area of the skin have evaluated antinociceptive hind feet with plantar analgesiometer provided with the infrared source, calibrated to 190 Mu/cm2.

Were evaluated the following PD parameters:

Maximum: the maximum time taken is the time required for the rat removed its paw in response to thermal effects. Higher h�the word means the rat took a longer time to respond, and a deeper analgesia caused by oxycodone.

AUC: a Measure of General anesthesia during the observed time period is the area under the curve between 0 and 4 hours, which is used to compare the response in different actions.

Initial response time is shown in figure 6, with 1=(-0.5 hours) and t=0.

The results presented in the table below and in figure 6 show that was held effective analgesia in rats using a range of compositions of the present invention.

Table.
Pharmacodynamic parameters in rats after using transdermal patches
PatchDose of oxycodone (mg/kg)nMax (C)AUC0-4(h/h)
141,0±0,8520,7±3,557,6±9,1
321,8±0,6522,3±3,376,8±13,1
521,6±0,5420,5±2,364,0±6,4
n = number of animals

Example 8. Alternative plasticizers

The following compositions were prepared as described in example 2. Composition 1 was poured onto the workpiece (die), and the composition was poured onto 2 sheet. The following percentages reflect the composition when the plaster is dry.

Composition 1 (1% T80, dbs)weight./wt.%
Eudragit 10060,59
DBS (dibutylsebacate)26,28
Succinic acid5,46
OxycodoneThe 5.56
Tocopheryl phosphate0,67
Di-Tocopheryl phosphate0,44
Tween 801,00
100,00

Composition 2 (3% ML, 25% T) weight./wt.%
Eudragit 10060,59
transcutol26,28
Succinic acid5,46
OxycodoneThe 5.56
Tocopheryl phosphate0,67
di-Tocopheryl phosphate0,44
Meilleures3,00
100,00

Transdermal patches were glued to the samples of human skin full thickness, using the methodology of diffusion Franz cell filled with PBS. Then using HPLC-determined concentrations of oxycodone in the solution of the recipient (the number of oxycodone has passed through the skin) through certain time intervals - 1, 2 and 4 hours.

The results presented in figure 7 show that delivery of oxycodone may occur when using alternative plasticizers.

Example 9. Alternative polymeric carrier

The following compositions were prepared as in example 1, but the composition was poured onto a flat surface or a sheet instead of blanks.

20% tran, 3% ML, 1% span20% tran, 1% Lau, 1%span20% tran, 1% span3% ML1% of span
20 wt./wt.% transcutol20 wt./wt.% transcutol20 wt./wt.% transcutol3 wt./wt.% Meilleures1 wt./wt.% Span 80
3 wt./wt.% Meilleures1% Lauric acid1 wt./wt.% Span 80DuroTak to 100 wt./wt.%DuroTak to 100 wt./wt.%
1 wt./wt.% Span 801 wt./wt.% Span 80DuroTak to 100 wt./wt.%5,5 weight./wt.% Oxycodone5,5 weight./wt.% Oxycodone
DuroTak to 100 wt./wt.%DuroTak to 100 wt./wt.%5,5 weight./wt.% Oxycodone1.1 wt./wt.% TRM1.1 wt./wt.% TRM
5,5 weight./wt.% Oxycodone5,5 weight./wt.% Oxycodone1.1 wt./wt.% TRM
1.1 wt./wt.% TRM1.1 wt./wt.% TRM

Transdermal patches were glued to the samples of human skin full thickness, using the methodology of diffusion Franz cell filled with PBS. Then using HPLC-determined concentrations of oxycodone in the solution of the recipient (the number of oxycodone has passed through the skin) through certain time intervals - 1, 2 and 4 hours.

The results presented in figure 8 show that delivery of oxycodone may occur when using alternative polymer carrier.

Example 10. The study of pharmacodynamics of insulin included in a transdermal patch

Four transdermal patch of the present invention were tested in comparison with gel (positive control).

The table below presents the composition, or matrix layer in each of the four transdermal patches. It was found that polyvinylpyrrolidone adds to the composition, or matrix layer sufficient "stickiness" that makes it possible to avoid the inclusion of any inert component carrier. The dry weight of each skin patch was 60 mg.

PatchTRMPolyvinylpyrrolidoneInsulin
11.2 mg (2 wt./wt.%)54.8 mg (91,33 weight./wt.%)4 mg (6.67 cm weight./wt.%)
20.6 mg (1 wt./wt.%)Of 55.4 mg (92,33 weight./wt.%)4 mg (6.67 cm weight./wt.%)
30.6 mg (1 wt./wt.%)56.4 mg (94,0 wt./wt.%)3 mg (5 wt./wt.%)
41.2 mg (2 wt./wt.%)50,8 mg (84,6 weight./wt.%)8 mg (13,33 weight./wt.%)

The components of the composition, or matrix layer dissolved in a solvent (50% water, 50% ethanol). Then the solution was poured in a separate form (containing suitable protective layers) at room temperature, and the solvent evaporated at 75°C for 1.5 hours.

As a positive control used 300 mg of gel containing 2,25 mg/ml insulin, 2% TPM (2:1), 30% ethanol, 1% carbopol 934 in water at pH=4,7.

Research plan

This study had a cross-d�Zayn to test the effect of transdermal patch of the present invention compared to the gel. In this study, each animal received four of the five treatment options throughout the study. In the experiment, the males took 10-12 weeks of age. In each treatment group consisted of 11 animals. All animals were >300 g by weight, and the concentration of glucose in the blood stream in a state of "fasting" was >10 mmol/l (average concentration of glucose "fasting" was 21,37±0.85 mmol/l). Key expected result of the study, the levels of glucose in the blood during a 5 hour test in tolerance to insulin, which was performed as described below.

The introduction of streptozotocin

Diabetes was induced by the introduction with a single intraperitoneal injection of streptozotocin (STZ) 50 mg/kg (Sigma Chemicals) dissolved in sodium citrate buffer (0.1 mol/l, pH 4.5) immediately before administration. Believed that rats developed diabetes and has included them in the study, if the level of glucose in the blood was greater than 16 mmol/l within 24 hours after STZ injection. Measurement of blood glucose in all groups were in the blood sample in the form of drops, taken from the tip of the tail. Test animals were performed after 5 days after administration of STZ.

Processing

24 hours before application of the gel and transdermal patches anesthesia was performed and animals were shaved ~30 cm2the fur on the back, avoiding any damage to the skin, which can �velocity absorption compositions. The gel was applied in a dose of 12 mg/cm2all over the shaved area. Transdermal patches were glued to the shaved area and protected by adhesive tegaderm dressings. The test for tolerance to insulin was performed 24 hours after removal of the fur. After each treatment the animal was allowed to recover for 3 days before the next treatment.

ITT (Test for tolerance to insulin)

Animals were not given food for 2 hours prior to the application of insulin or test compounds. Blood samples were taken from the tail using 0, 30, 60, 90, 120, 180, 240 and 300 minutes after applying the gel and transdermal patches. The levels of blood glucose were determined at the same moments of time, using test strips to determine the level of glucose (AccuChek, Roche Diagnostics).

Results

Gel and transdermally patches caused a significant reduction in the concentration of blood glucose in rats with diabetes (see figures 9 and 10). After 30 minutes after application, the level of blood glucose was significantly decreased (p<0.05) from baseline values and remained low throughout the experiment. There were no statistically significant differences in lowering glucose levels in the blood between the tested patches and gel at this point, as demonstrated by the calculation of the area under the curve (see figure 10). Apparently, transdermal patch is effe�tive for delivery of insulin this transdermal patch described herein provides many advantages in comparison with gel or other delivery methods.

Example 11. Transdermal patch for the delivery of diclofenac

Produced Transdermal patches for the delivery of diclofenac diethylamine, having the following composition:

200 mg diclofenac diethylamine
20 mg TPM (8:2)
168 mg Eudragit
200 mg diclofenac diethylamine
168 mg Eudragit

Transdermal patches for the delivery of diclofenac diethylamine had a surface area of 120 cm2.

Method of production

The components listed in the table above, was dissolved in 30 ml of a mixture of isopropanol :acetone (1:1) at 45°C. Then the mixture was subjected to casting to the surface of the adhesive tape type "Scotch" brand 3M and dried for 90 minutes at 75°C.

Testing in vitro (Diffusion)

Transdermal patches cut in the form of round discs (7 cm2) and placed on the skin of rats. The receiving volume of the solution was 12 ml and had effective�active surface with the skin, equal to about 1.76 cm2. After the time of the experiment the skin (about 7 cm2) was removed, the surface cleaned (excess gel) and was extracted with 10 ml of solvent.

Results

The results are shown in figures 11 and 12.

DiffusionDose: 2,92 mg/1,76 cm2
Extraction through the skinDose: 11,78 mg/7,06 cm2

Example 12. Transdermal patches for the delivery of lidocaine

Produced Transdermal patches for delivery of lidocaine, having the following composition:

100 mg lidocaine the basics
20 mg TPM (8:2)
168 mg Eudragit
100 mg lidocaine the basics
168 mg Eudragit

Transdermal patches for the delivery of lidocaine had a surface area of 120 cm2.

Method of production

The components listed in the table above, was dissolved in 30 ml of a mixture of isopropanol: acetone (1:1) at 45°C. �ATEM mixture was subjected to casting to the surface of the adhesive tape type "Scotch" brand 3M and dried for 90 minutes at 75°C.

Testing in vitro (Diffusion)

Transdermal patches cut in the form of round discs (7 cm2) and placed on the skin of rats. The receiving volume of the solution was 12 ml and had an effective surface with the skin equal to about 1.76 cm2. After the time of the experiment the skin (about 7 cm) was removed, the surface cleaned (excess gel) and was extracted with 10 ml of solvent.

Results

The results are presented in figure 13.

DiffusionDose: 1,46 mg/1,76 cm2
Extraction through the skinDose: of 5.89 mg/7,06 cm2

In this description, except where the context requires otherwise, the word "contain", "contains" and "containing" mean "include", "includes" and "including", respectively, i.e. when the invention is described or defined as containing specific symptoms, different embodiments of the same invention can also include additional features.

Although this invention is described by way of example and with reference to its possible implementation option, it is clear that can be done its modifications or improvements without deviation from the substance and scope of the present�status (active or inactive of the invention.

1. Matrix layer, suitable for use in plaster for percutaneous delivery (transdermal patch) for the introduction of biologically active compounds, which comprises a mixture of mono-tocopherylacetate compounds and di-tocopherylacetate compound and a polymeric carrier selected from the group consisting of polyacrylates, siloxanes, resistant to Aminu polysiloxanes and polymers on the basis of rubber, which is present in the amount from about 30 wt./wt.% to 95 wt./wt.% from the total concentration of the matrix layer.

2. The matrix layer according to claim 1, wherein the mono-tocopherylacetate compound selected from the group consisting of mono-(Tocopheryl)phosphate monosodium salt, mono - (Tocopheryl)phosphate, the disodium salt of mono - (Tocopheryl)phosphate, montalieu salt of mono - (Tocopheryl)phosphate dipotassium salt of mono - (Tocopheryl)phosphate and di-tocopherylacetate compound selected from the group consisting of di - (Tocopheryl)phosphate monosodium salt of di - (Tocopheryl)phosphate and montalieu salt of di - (Tocopheryl)phosphate.

3. The matrix layer according to claim 1, wherein the ratio (wt./wt.%) mixture of mono-Tocopheryl phosphate compound and a di-tocopherylacetate connection is at least 2:1.

4. The matrix layer according to claim 1, wherein the mixture of mono-tocopherylacetate compounds and di-tocopherylacetate compound is present in amounts � the range of about 0.01 wt./wt.% up to 10 weight./wt.% from the total concentration of the matrix layer.

5. The matrix layer according to claim 1, wherein the mixture of mono-tocopherylacetate compounds and di-tocopherylacetate compound is present in amounts in the range of about 0.5 wt./wt.% to 1.5 wt./wt.% of the total concentration of the matrix layer.

7. The matrix layer according to claim 1, wherein the polymeric carrier is present in amounts in the range from about 85 wt./wt.% to 95 wt./wt.% of the total weight of the matrix layer.

8. The matrix layer according to claim 1, wherein the polymer carrier further comprises an inert media components selected from the group consisting of anti-adhesiveness, substances for improving adhesiveness and plasticizers.

9. The matrix layer of claim 8 in which the anti-adhesiveness is succinic acid.

10. The matrix layer of claim 8, in which the tool against the stickiness is present in amounts less than about 5 wt./wt.% of the total weight of the matrix layer.

11. The matrix layer of claim 8 in which the substance to increase the stickiness is insoluble in water and consists of a monomer, which is partly or entirely composed of ester of alkylmethacrylamide.

12. The matrix layer of claim 8 in which the substance to increase the stickiness is selected from the group consisting of acrylic, N-butyl-methacrylic copolymer, methacrylic and 2-ethylhexylacrylate copolymer, polyacrylic acid, methacrylic �of polimera L, aminoalkyl-methacrylate copolymer E, esterified rosin, hydrogenated rosin, dibenzothiophenes, mixed hydrocarbon compounds and acrylic copolymers.

13. The matrix layer of claim 8, wherein the plasticizer is selected from the group consisting of phthalates, esters of polycarboxylic acids with linear or branched aliphatic alcohols of moderate chain length of acetylated monoglycerides, alkyl citrates, triethyl citrate (TEC), acetyl triethyl citrate (ATEC), tributyl citrate (TBC), acetyl tributyl citrate (ATVs), trioctyl citrate (TOC), acetyl trioctyl citrate (ATOS), tridecyl citrate (THC), acetyl trihexy citrate (ATNS), butyryl trihexy citrate (VTNS, trihexy about butyryl citrate), trimethyl citrate (TMC), methyl laurate, lauric acid, lauryl lactate, lauryl alcohol, phenyl ether alkylsulfonic acid, the monoethyl ether of diethylene glycol, bis(2-ethylhexyl) phthalate (DEHP), diazoacetate (DIOP), bis(n-butyl)phthalate (DnBP, DBP), Diisobutyl phthalate (DIBP), bis(2-ethylhexyl)adipate (DEHA), of dimethyl adipate (DMAD), of monomethyl adipate (MMAD), of dioctyl adipate (DOA), ethyloleate, sorbitanoleat, glycerol monooleate, dibutylsebacate (DBS), dibutyl maleate (DBM), Diisobutyl maleate (DIBM), benzoate, epoxidized vegetable oils, Tris(tromethamine)a, N-ethyl toluene sulfonamide� (o/p ETSA), N-(2-hydroxypropyl) benzene sulfonamida (HP BSA), N-(n-butyl) of benzene sulfonamide (BBSA-NBBS), tricresylphosphate (TCP), tributyl phosphate (TBP), triethylenemelamine (3G6, 3GH), tetraethylorthosilicate (4G7), 1,3-butyleneglycol, dipropyleneglycol, PEG400, Span 80 and polyvinylpyrrolidone.

14. The matrix layer of claim 8 in which the inert components of the carrier are present in amounts in the range of about 0.001 wt./wt.% to 50 wt./wt.%, of the total weight of the matrix layer.

15. The matrix layer of claim 8, in which the matrix layer contains a remedy tack and a plasticizer in a total amount of about 35 wt./wt.% of the total weight of the matrix layer.

16. The matrix layer according to claim 15, in which the tool against the stickiness is a succinic acid and the plasticizer is dibutylsebacate.

17. The matrix layer according to claim 1, wherein the polymer carrier and optional inert components of the carrier are present in amounts in the range from about 50 wt./wt.% to 99 wt./wt.% of the total weight of the matrix layer.

18. The matrix layer of claim 1, further comprising one or more excipients.

19. Application of the matrix layer according to any one of claims.1-18 in the transdermal patch for administration of biologically active compounds.

20. Transdermal patch for administration of biologically active compounds, including matrix �LOI according to any one of claims.1-18.

21. Transdermal patch according to claim 20, in which the matrix layer is a solid or semi-solid layer.

22. Transdermal patch according to claim 20 or 21, further comprising one or more occlusive or impermeable layers and/or one or more reocclusion layers.

23. Transdermal patch according to claim 22, in which an impermeable or occlusive layer is a protective layer.

24. Transdermal patch according to claim 22, in which reocclusion layer is a protective layer.

25. Transdermal patch according to claim 20 or 21, in which the thickness of the protective layer is approximately from 0.0005 inch to 0.01 inch.

26. Transdermal patch according to claim 22, in which the impermeable layer is removed, a cover film.

27. Transdermal patch according to claim 22, in which impermeable layers are made from metal foil, Mylar (officially registered trademark), polyethylene terephthalate, siliconized polyester, colloidal silica in silicone rubber, polytetrafluoroethylene, cellophane, paper sizing organosilicon compounds, aluminized paper, polyvinyl chloride film, composite foils or films containing polyester such as polyglycolether, polyester or eliminated polyester, polytetrafluoroethylene, thermoplastics�x elastomers, block copolymers of polyethylene and methyl methacrylate, polyurethanes, polyvinylidene chloride, nylon, silicone elastomers, kouchakzadeh polyisobutylene, styrene, copolymers of butadiene and styrene and copolymers of isoprene and styrene, polyethylene, polypropylene or combinations thereof.

28. Transdermal patch according to claim 26 or 27, in which the thickness of the coating film is from about 0.01 mm to 2 mm.

29. Transdermal patch according to claim 20, further comprising an adhesive layer.

30. Transdermal patch according to claim 29, in which the adhesive layer is a polymeric adhesive selected from the group consisting of polyacrylate polymers, adhesives based on rubber and polysiloxane adhesives; commercially available adhesive is selected from the group consisting of polyacrylate adhesives.

31. Transdermal patch according to claim 20, in which the biologically active compound selected from the group of pharmaceutical products, including medicines, cosmetics, nutraceutical remedies and nutrients.

32. Transdermal patch according to claim 31, in which the biologically active compound is selected from the group consisting of drugs for the treatment of cardiovascular diseases, in particular antihypertensive agents (e.g. calcium channel blockers or antagonists �Alicia) and antiarrhythmic agents; pharmaceutical preparations in acute heart failure; inotropic agents; vasodilating agents; ACE inhibitors; diuretics, carbonic anhydrase inhibitors; cardiac glycosides; phosphodiesterase inhibitors; α-blockers; beta-blockers; blockers of sodium channels; blockers of potassium channels; β-adrenergic agonists; inhibitors (aggregation) of platelets; antagonists of angiotensin II; anticoagulants; thrombolytic means; means for phlebotomy; agents for the treatment of anemia; inhibitors of thrombin; antiparasitic agents; antibacterial agents; insulin; human growth hormone and peptides; vaccines; anti-inflammatory agents, in particular nonsteroidal anti-inflammatory drugs (NSAID), specifically the COX-2 inhibitors; steroidal anti-inflammatory agents; prophylactic anti-inflammatory agents; agents glaucoma; stabilizers of mast cells; mydriatic funds; agents that affect the respiratory system; pharmaceutical agents for allergic rhinitis; alpha-adrenergic agonists; corticosteroids; pharmaceuticals for chronic obstructive pulmonary disease; xanthine oxidase inhibitors; anti-arthritis drugs from gout; physiologically active substances and ant�of honesto physiologically active substances; protivopokazaniya funds; antifungal agents; Antiprotozoal funds; antihelmintic drugs; antiviral agents, in particular agents against respiratory viruses, herpes viruses, cytomegalovirus, human immunodeficiency virus and hepatitis infections; remedies for the treatment of leukemia and Kaposi's sarcoma; agents for the treatment of pain, in particular opioid drugs, painkillers and analgesics; neuroleptics; sympathomimetic pharmaceutical drugs; adrenergic agonists; drugs affecting the uptake and release of neurotransmitters; anticholinergic pharmaceutical preparations; agents for hemorrhoids; agents for the prevention or treatment of effects related to the use of irradiation or chemotherapeutic drugs; medicines while lipogenesis; funds, reducing fat; peptides against obesity; agents against obesity, such as lipase inhibitors; sympathomimetic funds; funds from inflammation and ulcers of the stomach, such as proton pump inhibitors; prostaglandins; VEGF inhibitors; antihyperlipidemic agents, particularly statins; drugs affecting the Central nervous system (CNS), such as antipsychotic, anticonvulsant and antiperoxidative medication�funds (anticonvulsants), psychotropic drugs, stimulants, sedatives and hypnotics medicines, antidepressants; pharmaceutical drugs against Parkinson's disease; hormones and their fragments, such as sex hormones; antagonists of growth hormone; gonadotropin releasing hormones and their analogues; steroid hormones and their antagonists; selective modulators of estrogen; growth factors; anti-diabetic pharmaceuticals, such as insulin, fragments of insulin, insulin analogues, glucoheptonate peptides and hypoglycemic agents; H1, H2, H3 and H4 antihistamines; pharmaceutical products in the form of peptides, proteins, polypeptides, nucleic acids and oligonucleotides; analogs, fragments and variants of natural proteins, polypeptides, oligonucleotides and nucleic acids and similar compounds; agents used in the treatment of migraines; pharmaceutical drugs in asthma; cholinergic antagonists; glucocorticoids; androgens; antiandrogens; inhibitors of the biosynthesis of adrenocorticoids; agents for the treatment of osteoporosis, such as bisphosphonates; antithyroid pharmaceutical preparations; sunscreens, protective equipment and filters from the sun; agonists of cytokines; antagonists of cytokines; anti-cancer drugs; medicines from the disease �of lzheimer; inhibitors of HMGCoA reductase inhibitors; fibrates; inhibitors of absorption of cholesterol; agents that increase HDL-cholesterol; agents that reduce levels of triglycerides; anti-aging and anti-wrinkle; precursor molecules for generation of hormones; proteins, such as collagen and elastin; antibacterial agents; anti-acne (acne); antioxidants; hair products and tools, whitening the skin; sunscreen filters, from the sun; variants of human apolipoprotein; precursor molecules for generation of hormones; proteins and peptides; amino acids; plant extracts such as grape seed extract; DHEA; isoflavones; nutrients, including vitamins, phytosterols and iridoid glycosides sesquiterpene lactones, terpenes, phenolic glycosides, triterpenes, derivatives of hydroquinone, phenylalanine; antioxidants such as retinol and other retinoids, including retinoic acid and coenzyme Q10; omega-3 fatty acids; glucosamine; nucleic acids, oligonucleotides, antisense pharmaceuticals; enzymes; cytokines; analogues of cytokines, agonists of cytokines; antagonists of cytokines; immunoglobulins; antibodies; pharmaceutical drugs based on antibodies; gene therapy; lipoproteins; erythropoietin; vaccines; molecular and crepemaker�'s therapeutic substances for the treatment or prevention of human and animal diseases, such as allergies/asthma, arthritis, cancer, diabetes, growth retardation, cardiovascular disease, inflammation, immunological disorders, alopecia, pain, ophthalmological diseases, epilepsy, gynecological diseases, diseases of the Central nervous system, viral infections, bacterial infections, parasitic infections, diseases of the gastrointestinal tract (GI), obesity, and hematologic diseases.

33. Transdermal patch according to claim 32, in which the biologically active compound is selected from the group consisting of alprazolam, donepezil, risperidone, lorazepam, nicotine, lidocaine, diclofenac, felodipina, insulin, ketoralac, prilocaine, halobetasol, hydrocortisol, opioids, including oxycodone and dihydrohydroxycodeinone (of oxycodone base).

34. Transdermal patch according to claim 33, in which the biologically active compound is present in amounts in the range of from about 3.0 wt./wt.% to 15.0 wt./wt.% from the total concentration of the matrix layer.

35. Transdermal patch according to claim 20, in which the ratio (wt./wt.%) biologically active compound: a mixture of Tocopheryl phosphate is in the range of from about 5:5 to 5: 0,5.

36. Transdermal patch according to claim 20, in which the ratio (wt./wt.%) a polymeric carrier:[biologically active compound and a mixture of Tocopheryl phosphate] is in the range of from about 1:1 to 3:1.

37. �tricky layer according to claim 1 in which the polymeric carrier is present in amounts being in the range of from about 55 to about 65 weight./wt.% of the total weight of the matrix layer.

38. The matrix layer according to claim 1, wherein the polymeric carrier is present in an amount in the range of from about 90 to about 95 wt./wt.% of the total weight of the matrix layer.

39. Transdermal patch according to claim 20, in which the biologically active compound is present in an amount in the range of from about 0.1 to about 10 weight./wt.% from the total concentration of the matrix layer.

40. Transdermal patch according to claim 20, in which the biologically active compound is present in an amount in the range of from 0.1 to about 20 wt./wt.% from the total concentration of the matrix layer.

41. Transdermal patch according to claim 32, in which the biologically active compound selected from the group consisting of calcium channel blockers, calcium antagonists, NSAIDs, COX-2 inhibitors, lipase inhibitors, proton pump inhibitors, statins, antipsychotic drugs, antiepileptic drugs, antiparazitarnyh medicines, protivokomarinye, sex hormones, hypoglycemic drugs, bis-phosphonates, collagen, elastin, grape seed extract, vitamins, retinol, retinoids, retinova acid and coenzyme Q10.

42. Tr�sternally the patch according to claim 20, in which the ratio (wt./wt.%) biologically active compound: a mixture of Tocopheryl phosphate is about 5:1.

43. Transdermal patch according to claim 20, in which the ratio (wt./wt.%) a polymeric carrier: [biologically active compound and a mixture of Tocopheryl phosphate] is in the range of about 7:6 to 7:3.

44. A method of manufacturing a transdermal patch according to claims.20-43 intended for the introduction of biologically active compounds, which includes stages:
(i) combining the polymer carrier and optional inert component of the carrier with a suitable solvent;
(ii) combining (i) with a dispersion containing a biologically active compound and a mixture of mono-Tocopheryl phosphate compound and a di-Tocopheryl phosphate compound;
(iii) mixing (ii) until complete homogenization;
(iv) placing the composition (iii) in appropriate form or casting compositions (iii) on the surface;
(v) drying of the composition when heated.

45. A method according to claim 44, wherein the drying is conducted at a temperature of about 90°C.

46. A method according to claim 44, wherein the drying is conducted for about 0.5 to 24 hours.

47. A method according to claim 45, wherein the drying is conducted at a temperature from about 30°C to 90°C.

48. A method according to claim 45, wherein the drying is conducted at a temperature of about 75°C.



 

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27 cl, 23 tbl, 371 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinolines substituted by phosphorus-containing group of formula and applicable in medicine, wherein Z represents V1 and V2 are independently specified in hydrogen or halogen; one of R and R` represent phosphorus-containing substitute Q; the other one is specified in hydrogen or methoxyl; wherein the phosphorus-containing substitute Q represents A represents O; L represents C1-6alkyl; J represents NH or C3-6heterocycloalkyl and J is optionally substituted by G3; X is absent or represents -C(=O)-; X is absent or represents C1-6alkyl; each of R1 and R2 are independently specified in C1-6alkyl or C1-6alkoxy; G3 represents C1-6alkyl, R3S(=O)m-, R5C(=O)- or R3R4NC(=O)-; R3, R4 and R5 are independently specified in 3 or C1-6alkyl; m is equal to 0-2.

EFFECT: there are presented new protein kinase inhibitors effective for treating the diseases associated with abnormal protein kinase activity.

20 cl, 42 ex, 8 tbl, 3 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to endocrinology, and deals with stimulation of insulin secretion. For this purpose 2 ml of concentrated nitro-glycerine solution are diluted with distilled water, cotton swab is soaked with obtained solution, stretched to 10-12 cm long and 3-4 cm wide size, applied perpendicular to spine on the left at the level of Th12, covered with cellophane and sealed with self-adhering plaster, with patient being turned onto back with preservation of said position for 1 hour.

EFFECT: method provides enhancement of insulin secretion by pancreas due to improvement of its blood supply.

2 ex, 2 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new substituted aminotetrahydropyranes of structural formula or to their pharmaceutically acceptable salts , and , wherein V is specified in groups having the formulas below, Ar represents phenyl unsubstituted or substituted by one to five halogen atoms, each of R1 and R2 is independently specified in C1-C6alkyl; R3 is specified in a group consisting of C1-C6alkyl; cyano; tetrazolyl; -C(O)OC1-C6alkyl and -C(O)NH2; wherein C1-C6alkyl is substituted by 1-4 substitutes independently specified in a group consisting of OH; -C(O)NH2 and -CO2H. The declared compounds can be dipeptidylpeptidase-IV inhibitors and can be applicable in treating or preventing diseases involving the enzyme dipeptidylpeptidase-IV, such as diabetes, and especially type 2 diabetes mellitus.

EFFECT: invention also refers to a pharmaceutical composition containing the above compounds, and using the above compounds and compositions for preventing or treating the diseases involving the enzyme dipeptidylpeptidase-IV.

12 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to derivatives of diaza-spiro[4.5]decan-1-one of formula (I) or to their pharmaceutically acceptable salts, where. R1 is a substituted phenyl, which contains one substituent, selected from the group, including C1-4-alkyl, C3-6-cycloalkyl halo-C1-4-alkyl and halo -C1-4-alkoxy, and which can additionally contain one substituent, selected from a halogen; R2 is hydrogen, C1-4-alkyl, phenyl, substituted phenyl, with the substituted phenyl containing one substituent, selected from the group, including C1-4-alkoxy; R3 is -R4, -C(OH)R5R6 or -C(O)NR7R8; R4 is phenyl, phenyl-C1-4-alkyl, substituted phenyl, substituted phenylcarbonyl, with the substituted phenyl, substituted phenylcarbonyl containing from one to two substituents, selected from the group, including a halogen, halo-C1-4-alkyl; one of R5 and R6 is hydrogen, C1-4-alkyl, and the other is aminocarbonyl, phenyl, substituted phenyl or substituted phenyl-C1-4-alkyl, with the substituted phenyl or substituted phenyl-C1-4-alkyl containing from one to two substituents, independently selected from the group, including a halogen; one of R7 and R8 is hydrogen C1-4-alkyl, and the other is C1-4-alkyl, C3-6-cycloalkyl, C1-4-alkoxy-C1-4-alkyl, phenyl-C1-4-alkyl, substituted phenyl or substituted phenyl-C1-4-alkyl, with the substituted phenyl or substituted phenyl-C1-4-alkyl containing one substituent, selected from the group, including a halogen, halo-C1-4-alkyl; or R7 and R8 together with a nitrogen atom, which they are bound to, form pyrrolidinyl; n equals zero or 1/ The invention also relates to a pharmaceutical composition based on the compound of formula (I), application of the formula (I) compound and a method of treatment.

EFFECT: obtained are novel heterocyclic compounds, useful as an inhibitor of hormone-sensitive lipase.

17 cl, 57 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry and represents a formulation specially adapted for insulin transformation into the aerosol state, containing insulin in water from 100 IU/ml to 1,200 IU/ml and 2 to 4 Zn2+ ions per the insulin hexamer, wherein the formulation is preservative-free and wherein the formulation is able to transform into the aerosol state as an aerosol spray when using a holed vibration plate with no foaming of the formulation, when the formulation is kept on a back surface of the holed plate by gravity, and the spray is ejected from the front surface of the holed plate entirely by vibrating the holed plate.

EFFECT: invention provides reducing the foaming of the formulation, the time of transformation into the aerosol state and providing the more effective administration of an insulin dose.

19 cl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the pharmaceutical industry, namely to a medication for the complex therapy of patients with type 2 diabetes mellitus and a method of the complex therapy of patients with type 2 diabetes mellitus. The medication for the complex therapy of patients with type 2 diabetes mellitus contains a cleaned and dried rhizome of Curcuma longa in the form of powder with the specified size of particles. The method of the complex therapy of patients with type 2 diabetes mellitus consists of the daily intake of the cleaned and dried rhizome of Curcuma longa in the form of powder with the specified size of particles twice per day after dinner and supper at the background of the intake of pelleted hypoglycaemic agents without changing the dose and scheme of the drug therapy.

EFFECT: medication produces a direct stimulating impact on β-cells of the pancreas and ensures the development of a hypoglycaemic effect, including early stages of the disease development.

3 cl, 1 dwg, 5 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to therapy and endocrinology, and can be used in treating patients suffering type 2 diabetes mellitus. That is ensured by a continuous exenatide delivery by implanting into a patient into an osmotic delivery device comprising an impermeable container, a semi-permeable membrane, an osmotic mechanism integrated into the container and adjoining the semi-permeable membrane, a piston adjoining the above osmotic mechanism; the above piston forms a movable seal with an inner surface of the container and divides the container into a first chamber comprising the osmotic mechanism, and a second chamber comprising a suspension formulation, and a diffusion adjustor. The suspension formulation contains a particle formulation containing exenatide particles having a diameter of less than 10 to 30 mcm. The delivery formulation contains a solvent specified in a group consisting of benzyl benzoate, lauryl lactate and lauryl alcohol, and polyvinylpyrrolidone polymer. The delivery formulation has a viscosity of approximately 10,000 poise to approximately 20,000 poise at 37°C. The continuous exenatide delivery in the therapeutic concentration is ensured for 5 days or less. The continuous exenatide delivery from the osmotic delivery device in a dose of exenaide of 10 mcg/day, 20 mcg/day, 30 mcg/day, 40 mcg/day, 60 mcg/day, and 80 mcg/day can be effected through at least three months.

EFFECT: method enables the effective treatment of the given pathology by the fast achievement and long maintenance of the exenatide concentration to be completed rapidly with no constant injections or oral administration.

15 cl, 20 tbl, 21 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: suppositories, containing uniformly distributed in one suppository recombinant human interferon-alpha-2b in an amount of 400000-600000 IU and immunoglobulins IgA, IgM and IgG in an amount of 0.1-0.3 g, are additionally rectally introduced as the second medication to an adult patient in case of the long-term introduction of an opioid-containing medication. The dose constitutes 2-3 suppositories 2-3 times per day with the reduction of the daily dose by 1-3 suppositories in case of the reduction of pain sensation to 2-3 points by a ten-point scale and expressed sedation. If pain sensation increases to 6-8 points by the ten-point visual analogue scale, the daily dose is increased by 1-3 suppositories.

EFFECT: application of the claimed method makes it possible to ensure the prevention of the opioid dose increase and an increase of the level of antibodies to interferon-alpha in the patients' blood serum in case of the long-term application of opioids.

5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a therapeutic agent for treating or preventing neuropathic pain containing active ingredients in the form of a cyclohexane derivative presented by the following formula, or its pharmaceutically acceptable salt, and a calcium channel α2δ ligand which represents pregabalin or gabapentin.

EFFECT: therapeutic agent possesses the synergistically increased analgesic action in a dose which prevents any side effects of the calcium channel α2δ ligand, and which prevents any side effects of the agent on the central nervous system .

3 cl, 5 dwg, 5 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to pyrazine derivatives of formula I, as well as to their enanthiomers, diastereomers and pharmaceutically acceptable salts, wherein R1 is specified in a group consisting of ii) pyridinyl optionally having one substitute specified in a group consisting of C1-4alkoxy and cyano; and iii) pyrimidin-5-yl; or R1 optionally represents methoxymethyl, when Y represents ethinyl; Y represents ethinyl or a bond; R2 represents phenyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzo[1,3]dioxol-5-yl, indolyl or pyridinyl substituted by methyl, phenyl has one to two substitutes independently specified in a group consisting of C1-4alkyl, C1-4alkoxy, fluorine, chlorine, cyano, cyanomethyl, difluoromethyl, trifluoromethyl and hydroxy; or R2 represents phenyl having one C1-4alkylcarbonylamino or 1H-imidazol-1-yl substitute; X represents O or CH2; L is absent, and R3 represents 4-aminocyclohexyl, or L represents methylene, while R3 is specified in a group consisting of i) pyrrolidin-2-yl; ii) 1-aminoeth-1-yl; and iii) 1-aminocyclopent-1-yl; or R3 is combined into one cycle with L nitrogen atom to which L is attached to form piperazinyl. Besides, the invention refers to specific compounds, a pharmaceutical compound based on a compound of formula I, a method of treating pain and some neurodegenerative diseases.

EFFECT: there are produced new pyrazine derivative effective in treating pain and some neurodegenerative diseases.

21 cl, 3 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a compound of formula (I) and its isomers, using them for treating a condition associated with P2X3 activity, to a pharmaceutical composition based on the compound of formula (I) or its isomers, and to a method of treating.

EFFECT: what is prepared is the new heterocyclic compound possessing the effective biological properties.

16 cl, 1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutics, namely to pharmaceutical drug forms, containing poly-ε-caprolactone, and methods of obtaining them, an application and methods of treatment with their application.

EFFECT: application of a poly-ε-caprolactone matrix makes it possible to provide properties, constraining from abuse (such as resistance to crushing or grinding).

32 cl, 14 dwg, 14 ex, 14 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula R1 is H or (1-6C alkyl); R2 represents NRbRc, (1-4C)alkyl, (1-4C)fluoroalkyl, CF3, (1-4C)hydroxyalkyl, -(1-4Calkyl)hetAr1, -(1-4Calkyl)NH2, -(1-4C alkyl)NH(1-4Calkyl), -(1-4Calkyl)N(1-4Calkyl)2, hetAr2, hetCyc1, hetCyc2, phenyl substituted where applicable by NHSO2(1-4Calkyl) or (3-6C)cycloalkyl, substituted where applicable by (1-4C alkyl), CN, OH, OMe, NH2, NHMe, N(CH3)2, F, CF3, CO2(1-4C alkyl), CO2H; C(=O)NReRf or C(=O)ORg; Rb is H or (1-6C alkyl); Rc represents H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr3 or phenyl, wherein the above phenyl is substituted where applicable by one or more substitutes independently from halogen, CN, CF3 and -O(1-4C alkyl); Re represents H or (1-4C)alkyl; Rf represents H, (1-4C)alkyl or (3-6C)cycloalkyl; Rg represents H or (1-6C)alkyl; X is absent or represents -CH2-, -CH2CH2-, -CH2O- or -CH2NRd; Rd represents H or (1-4C alkyl); R3 represents H or (1-4C alkyl); and n is equal to 0-6. The radical values NRbRc, Y, hetAr1, hetAr2, hetAr3, hetCyc1, hetCyc2, NReRf, R4 are specified in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds, to a method of treating Trk kinase mediated diseases and conditions, such as pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection, osteolytic disease, and to a method of preparing the above compounds.

EFFECT: invention refers to new derivatives of pyrazolo[1,5-a]pyrimidines possessing an inhibitory activity on tropomyosin-related kinases (Trk).

42 cl, 1 tbl, 105 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: a peroral pharmaceutical composition with an instant release for treating pain in patients or for titration of a dose for the patients, suffering from pain, which contains at least oxicodon or its pharmaceutically acceptable salt and naloxon or its pharmaceutically acceptable salt in an approximate weight ratio oxicodon or its pharmaceutically acceptable salt: naloxon or its pharmaceutically acceptable salt 2:1 (versions), its application for obtaining medication for titration of the dose for the patients, suffering from pain, its application for obtaining medication for treatment of breakthrough pain, a method of titration of the dose in the patient, suffering from pain, and a method of treating breakthrough pain.

EFFECT: achievement of the claimed results with absence of undesirable side effects of opioid is demonstrated, with levels of naloxon in the blood plasma being extremely low, bioavailability of oxicodon constituting 96.3 or 99.2%, and tablets being stable in storage.

30 cl, 9 dwg, 15 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to buprenorphine analogues of formula , where R1 is selected from -(C1-C10)alkyl, -(C2-C12)alkenyl, -(C3-C12)cycloalkyl, ((C3-C12)cycloalkyl)-(C1-C6)alkyl-; any of which is optionally substituted with 1 or 2 substitutes selected from OH and -(5-12-member)heterocycle, wherein at least one carbon atom is substituted with a nitrogen heteroatom; R2 and R8 each independently is hydrogen, -(C1-C10)alkyl, -(C2-C12)alkenyl, -(C2-C12)alkynyl, -(C3-C12)cycloalkyl, -(5-9-member)heteroaryl, where in the 5-9-member heteroaryl, at least one carbon atom is substituted with a nitrogen, oxygen or sulphur heteroatom, phenyl and naphthyl; any of which is optionally substituted with one or two substitutes selected from OH, halo, -C(halo)3, -(C1-C6)alkyl, phenyl, NH2, CN, OR4 and COOR7; at least one of R2 or R8 is not hydrogen; R3a and R3b are independently selected from hydrogen and -(C1-C6)alkyl; R4 is selected from -(C1-C6)alkyl, -C(halo)3 and phenyl; R7 is hydrogen; X is selected from (C1-C6)alkoxy or OH; Z is (CH2)m; Y is (CH2)n-CH or a direct bond, under the condition that when Y is a direct bond, R8 is absent; m equals 1 and n equals 0. The invention also relates to a pharmaceutical composition which modifies opioid receptor function and is intended to treat pain, which contains compounds of formula I, a method of preparing said composition, a method of modulating an opioid receptor and a method of treating pain.

EFFECT: compounds of formula I as opioid receptor function modulators.

37 cl, 11 dwg, 7 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to methods of obtaining a lyophilised preparation of tetrodotoxin and to a tetrodotoxin preparation for relief of the drug withdrawal in case of addiction to opiates. The method of obtaining the lyophilised preparation of tetrodoxin includes the following stages: 0.1-20 mcg/dose of tetrodotoxin is dissolved with 0.1% solution of citric acid to regulate pH within the range of 3.5-4.5 in injection water and filtered to remove pyrogen; separately dissolved are: a stabiliser - dextran or trehalose - and a filling agent, representing an isotonic solution of sodium chloride or mannit in injection water. After that, 0.1% solution of citric acid is added to regulate pH within 3.5-4.5, then, activated carbon is added with keeping at a temperature of 60°C and mixing for more than 30 minutes, filtering to remove pyrogen and cooling to room temperature. After homogeneous mixing of the obtained solutions and realisation of ultrafiltration, lyophilic drying is carried out. Lyophilic drying consists in preliminary freezing, drying under vacuum at reduced temperature, drying under vacuum at increased temperature, with each drying being performed at a certain temperature for the specified time period. After that, filling with inert gas is performed with control of water content at 3% level, with further sealing. Another version includes addition of additional solution of lidocaine chloride to the solution of tetrodotoxin and citric acid at the first stage. Also disclosed is the tetrodotoxin preparation for relief of the drug withdrawal in case of addiction to opiates, obtained by the said method, which is characterised by the weight ratio tetrodotoxin:filling agent:stabiliser, equal to 1:(150-3000):(50-6000).

EFFECT: claimed group of inventions ensures obtaining the stable tetrodotoxin solution with accurate dosage, which is used for introduction into the human organism.

25 cl, 9 tbl, 14 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: a combination possessing analgesic action of at least one sigma ligand and at least one opioid or opiate compound specified in morphine and its structural derivatives, phentanyl and tramadol for simultaneous, separate or sequential administration; the sigma ligand has the general formula ;

using it for preparing a therapeutic agent potentiating analgesic action of morphine or its structural derivatives, phentanyl and tramadol and/or relieving addiction thereto. What is also presented is using the combination of at least one sigma ligand and at least one opioid or opiate compound for preparing the therapeutic agent for potentiating analgesic action of opioids or opiates and for relieving addiction thereto; the opiate is specified in a group of: hydromorphone, oxymorphone, desomorphine, diacetylmorphine, nicomorphine, dipropanoylmorphine, benzylmorphine and ethylmorphine.

EFFECT: what is shown is the synergetic analgesic action of the morphine and compound 63 combination; the compound appeared to relieve the effects of positive stimulation caused by morphine with establishment of behaviour reflex.

16 cl, 10 dwg

FIELD: medicine.

SUBSTANCE: what is described is an antiseptic sorption material having the anti-inflammatory, wound-healing, absorbent, astringent and antiseptic action representing a microfiber matrix with a disperse adsorbent attached to its fibres and containing highly porous alumina hydrate particles and zinc oxide particles. A method for making the same and a based dressing are also described.

EFFECT: material is applicable for making wound dressings having additional functional properties and maintaining the absorbing properties of the material absorbing the wound discharge, inhibiting bacterial growth inside the dressing and preventing the wound re-infection.

15 cl, 4 dwg, 2 tbl, 3 ex

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