MX2007004314A - Medicament and system for the percutaneous administration of medicaments - Google Patents

Abstract

The invention relates to an application system provided with a micro emulsion (14) containing a medication, said micro emulsion being contained in a medicament reservoir (12), a first gas connection (18) to which oxygen can be guided, a nozzle head (28) comprising recesses (29) which are arranged on the end of the medicament reservoir (12) and an atomising nozzle (30) which is arranged in the nozzle head (28). Pressure exerted on the microemulsion for atomising as well as the microemulsion emerging therefrom atomises the oxygen into drops by means of a Venturi arrangement in the atomising nozzle (30).

Description

MEDICINE AND SYSTEM FOR THE PERCUTANEOUS ADMINISTRATION OF A MEDICINE FIELD OF THE INVENTION During the administration of drugs as active substances to a patient, always during the dosage should be weighed between the desired effect and undesirable side effects in the body. Therefore, it is desirable to apply the medication as directly as possible to the site of action, in order to be able to work with the minimum possible doses, in order to be able to work with the minimum total doses and with minimum load for the patient, and therefore both obtain or effective levels needed at the action point. This can be obtained by means of the percutaneous administration of the medicines. BACKGROUND OF THE INVENTION The skin, especially the upper horny layer, represents a barrier difficult to traverse. This applies in particular to drugs that are insoluble or poorly soluble in water. A common procedure for the percutaneous administration of medications is the application of ointments, creams or gels on the skin. To improve the permeation of the active substances, so-called penetration promoters are used as sulfoxides, alcohols, fatty acids, anoides, fuses and the like. These substances reduce the resistance to penetration of the stratum corneum and facilitate the permeation of drugs. The advantages of these disadvantages are the inaccurate dosing possibilities. Thus, for safety reasons, the content of the drugs in the preparation must be kept low, so that the target tissues also do not receive the high effective levels desired. Furthermore, despite the use of penetration enhancer, the penetration depth of the conventional preparations is very low. In addition, other different methods are known that overcome the skin barriers. (see: Müller / Hildebrand, Phrmazeutische Technoligie: Moderne Arzeiformen, ISBN 3-8047-149-4, chapter 13). In particular, the transdermal therapeutic systems (TTS) were developed. TTS are technical devices that are placed in an adherent manner on certain parts of the skin and that by means of different periodic mechanisms administer by diffusion to the organism a certain dose of the medicine. The objective here is in particular a systemic effect with a defined profile of the level of effectiveness. To accelerate the permeation of the drug in the skin, the TTS systems also have ultrasound heads or electrodes, to apply touches of current on the skin and with this by means of mechanical or electrical excitation the formation of pores in the skin is promoted. Here it is disadvantageous that specific local use is not possible by means of TTS. Since not all medicines can be administered by diffusion. This is applied by means of insoluble drugs and hardly soluble in water. In addition the drugs are applied in microemulsions on the skin. Due to the low limit surface tension and the large surface area within the microemulsion, water soluble, liposoluble and insoluble drugs can be dispersed therein. With the help of a microemulsion it is possible to apply the medicine in the cornea layer of the skin (Stratum corneum) in a short time. In any case with the help of only the microemulsions it is not possible to temporarily eliminate the barrier function of the skin to a desired degree and apply all kinds of medications through the skin. SUMMARY OF THE INVENTION The task of the invention is to overcome all the aforementioned disadvantages of the state of the art.

In particular, it is the task of the invention to present preparations (hereinafter referred to as medicaments) that pass through the skin barriers in a satisfactory manner. Furthermore, it is the task of the invention to present a system with which it is possible to traverse the skin at any point and apply percutaneously the active substance or a combination of the active substances. It is also the task of the invention to present a system with which the medicine can accurately dose the medicine to be applied. Another task of the invention is to locally apply the maximum daily dose. Surprisingly it was found that this and other tasks not mentioned can be solved with the help of the system according to the invention for the percutaneous administration of drugs, consisting of a microemulsion in which the medicament is introduced and a device for atomising the microemulsion, preferably in an atmosphere containing oxygen (under the term "atomize" is meant here the fine dispersion of a liquid with the help of a propellant gas). In addition, these tasks are solved by means of a microemulsion ion enriched with oxygen, which contains at least one drug for percutaneous administration. A microemulsion for the oral administration of medicaments, which contain the medicaments for a better supply of oxygen to the skin, also solve the task according to the invention. The combination of the different mechanisms of the new process can lead to a considerable effect of synergy during the permeation of the active substances in the skin, as described below. By means of the extraordinarily small droplets of the high-power atomizer, the microemulsion loaded with the finely distributed active substance is applied to the skin. Due to the reduced surface tension of the microemulsion, a huge expansion effect is obtained. The horny layer of the skin and the micro-emulsion have similar upper structures, such as lamellae and tubes, formed of bilipid layers. These superior structures of the corneal layer contribute decisively to the resistance to permeation of that layer. The finely dispersed application of the droplets presumably leads to a "melting" of the micro-emulsion with the stratum corneum according to the principle "Similiar similibus". By means of the fusion the so-called superior structures are weakened and the active substances can be infused deeply into the skin. The use of oxygen as the propellant gas produces an oxygen enrichment in the droplets of the atomization. This oxygen, like the effective substances, is infused into the skin layer, which produces an increase in the partial pressure of oxygen in the skin. This high partial pressure strongly stimulates the microcirculatory flow. With this the active substances infused are absorbed into the tissue in a strongly connective manner. The combined use of the micro-emulsions, the fine droplets and the oxygen in the process according to the invention also produces an increase in the permeation of the active substances in the three sequentially connected stages: 1. There is a very extensive distribution and expansion. fine of the micro-emulsion and with that of the active substances on the surface of the skin. 2. The barrier of the horny layer is overcome and 3. the micro-circulatory transport is elevated through the skin, in fact first through a high-power atomization, secondly by means of the micro-emulsion and in third place by means of oxygen. The skin is the largest organ of the body, which encloses on the outside. During its operation, it must perform a series of tasks. The function of protection against mechanical effects, such as shock, pressure, friction and against the penetration of bacteria, viruses and fungi presents first an acid cover. In addition, the skin protects the skin against heat, cold, light and harmful substances. The skin is also the oregano of the sense of touch, special sensors detect pressure, temperature, pain and itching. The skin also participates in the regulation of the water and heat content regulating the functioning of the whole organism. Crudely seen the skin consists of three layers, the subcutis (inner skin), the Corium (dermis) as well as the epidermis (upper skin). The inner skin consists of fat, large blood vessels, glands and small muscles.

It serves, for example, as a "tank chamber" as well as to cushion the mechanical effects. The dermis with its collagen and elastin fibers regulates the elasticity and consistency of the skin and with it the resistance to tearing. Sensory cells (sensors) are also found in the corneal layer to capture sensations. It contains much hyaluronic acid and chondroitin sulfate, that is glucosamino-glucans, which, like reversible gels, allow the transport of biological molecules and cellular movements. To cover the organism from the outside, the epidermis is very important and it has a special interest since that layer generally guarantees the integrity of the skin, for which the outer layer the cornea layer plays a decisive role. This layer consists of approximately 10 cell layers of flat horny cells, that is dead (corneous cells, stratum corneum); an upper loose layer (Stratum disjunctum) and a stronger lower layer, the stratum conjunctum, are divided. The corneous cells are constantly transported outward and formed by division in the so-called Stratum germinat ivum, the germinal layer below.

The special microstructure of Stratum corneum consists of flat cells similar to septa (corneocytes). The intercellular matrix is structured in a special way, consisting of double layers of lipoids approximately parallel to the surface of the skin: in the stratum corneum almost one hundred hydro- and lipophases grow. Seen from the medical point of view, the cornea layer consists of a water-in-oil emulsion in the form of a double lamellar layer. This layer, only approximately 12 μp \ thick, which is constantly regenerated, with the help of its complex biphasic upper structures forms the safe protection for the cells of the stratum germinativum that lie below: without the cornea layer there would be a "bed for injuries. " The corneal layer of the skin is especially important for protection from the outside, especially due to its barrier function. This is applied in reference to the thickness, the partial pressure of oxygen (PO2), the pH value and the water content. Especially important is the barrier for hydrogen ions, which form the protective cover of the acid. Equally important is the barrier to oxygen, before which it has a great resistance to diffusion. This leads to a reduction of the partial pressure of the air oxygen from 150 Torr to approximately 50 Torr. This protects the vital cells of the epithelium of intact skin, especially the high partial pressure of harmful oxygen by oxidation. The effective barrier function in the corneal layer for the organism which is considered disadvantageous for the transdermal transport of drugs is so advantageous. In these cases, the corneal barrier should be temporarily overcome. Surprisingly it was found that the barrier function of the skin by means of the introduction of oxygen into the corneal layer and with this the increase of the partial pressure of oxygen on the tissue side of the stratum corneum leads to a better transdermal transport of the drugs . By raising the oxygen partial pressure of the tissue side of the stratum corneum, the transmembrane pressure of oxygen rises, which is probably the cause of improved improved transdermal transport of the drugs. Due to the laminar structure before descending of alternating phases of water and oil of the stratum corneum, microemulsions are especially suitable for penetrating the Stratum Corneum (see Müller / Hildebran, Pharmazeutische Technologie: Moderne Arzneiformen, ISBN 3-8047-1549-4, chapter 15). These in a preferred embodiment of the invention are used as vehicle systems for oxygen or drugs as well as base materials for medicaments. These microemulsions are known and used in the cosmetic and pharmaceutical industry. These can be obtained, for example, under the trade name "Nanoemulsion" from Sanguei AG. Microemulsions in the sense of the invention are thermodynamically stable systems, which include at least water, surfactants and lipids. Under the term surfactant are meant emulsifiers which may be ionic or non-ionic. Examples of surfactants that can be used are known under the tradenames Tween, Span and Synperonic PEL 101. The lipids which may be used are fatty oils or mineral oils, for example isopropyl myristate and isopropyl palmitate. Microemulsions that can be used in the framework of that invention can be oil-in-water or water-in-oil microemulsions. Thus droplets of oil are formed in a water matrix or water droplets in an oil matrix. These microemulsions have a droplet size in the range of 10 nm to 1 μp, preferably from 10 nm to 500 nm, especially from 10 nm to 300 nm. The average droplet size of a microemulsion that can be used in the invention is not limited. Preferably the average droplet size is less than 300 nm, especially less than 150 nm. These microemulsions preferably have surface areas greater than 200 m2 per mL, especially greater than 400 m2 / mL and more especially higher than 600 m2 per mL. Due to the hydrophilic and lipophilic fraction of the microemulsions as well as the reduced surface tension and the larger limiting surface it is possible to disperse both water-soluble and liposoluble and / or poorly soluble drugs in the microemulsions. Depending on the active substance and the desired effect, the surfactant is selected. Ionic surfactants are generally spatially effective whereas nonionic surfactants are especially protective of the skin. The microemulsions according to the invention relate inter alia to the medicinal use of liquid medicaments based on microemulsions in the therapy of pain, for the treatment of blood supply and for the healing of wounds in degenerated skin, for example in people old age Drugs based on these microemulsions in addition to the base materials of the microemulsion may contain base materials for pharmaceutical materials and medicines. These base materials and pharmaceutical materials can be of natural and synthetic origin. In the context of this invention, the base materials and the drugs of natural origin are especially preferred, without this being considered as limiting. Examples of base materials as well as their effect are presented in Table I. However, the base materials that can be used in the context of this invention are not limited thereto. Table 1 Natural base materials as well as their effect The drugs that can be used within the framework of the invention are not limited. Natural or synthetic medicines can be used. In the context of this invention, natural medicines obtained from plants are preferred. Especially preferred are essential oils, which can be obtained from plant parts. Examples of the species and genera of plants, including their chemotypes, which in different parts of the plants contain etheric oils, which are used as medicaments in the microemulsions according to the invention, as well as their therapeutic effect under external use, are shown in Table 2, however it is not limited to them. Table 2 Species and genera of plants including their chemotypes containing etheric oils in different parts of plants, as well as their therapeutic effect during external use Table 3 shows the drugs that are preferably used as well as their properties. These are divided into etheric oils, plant extracts and synthetic monosubstances. Which can be used in the medicines according to the invention however we will not limit ourselves to them. Table 3 Properties of the essential oils, plant extracts as well as the monosubstances isolated from these plant extracts Chamomile oil Herbal oil of • St. John's Roman etenzamide • acid Camphor oil Fructus capsicici acetylsalicylic Aloe oil (Capsaicin) • extra salsalate Oonsoude extract Lavender oil- Extractum symphyti Derivatives of salvia Harpagophum acetic acid, for example: Laurel oil Procumbens Marjoram oil Willow bark • indcmetacin / aceme Citronella oil Tabaco guaiac wood, Niaouli oil Proglumetacin arnica extract Oregano oil • Diclofenac Patchouli oil • Tolmentin Pepper oil • lonazolac • Phenbufeno peppermint oil • aceclofenac, Ethanese oil Etofenamat Rosemary oil Sade tree oil Achillea oil Spiny lavender oil Tea tree oil Thyme oil Pyrrhoic oil Continuation: Acid derivatives Analgesics propionic for example: • ibuprofen • ketorpogen • flurbiprofen • tiaprofen acid ico • Phenophene • Naproxen • Dexketoprofen • Dexibuprofen Heterogenic Acid Oxygen, Oxicam: • Piroxicam • Tenoxicam • Methoxycam • Meloxicam • Lomoxicam Derivatives of anthranilic acid: • Mefenamic acid • Flufenamic acid • Nifluminic acid Continuation of local anesthetics of amide anesthetics • prolocaine • mepivacaine • lidocaine • etidocaine • bupivacaine • levobupivacaine • ropivacaine • articaine • famocaine Antiallergics Cumin oil Glycocorticoids black Antibacterials Pepper oil Evening primrose oil Anti-infective Saturate oil Nem Thymol oil Melaleuca oil Extracts of Stipites Chlorhexidine Cinnamon oil Dulcamara Cassia antibiotics • acid Melodic jara oil Eucalyptus oil • Mupirocin Oil Geranium • Sulfadiazine Clove oil • Erythromycin Tree oil HO Chamomile oil • Clindamycin Camphor oil • Tetracycline Pine oil • Medocicline Garlic oil Lavender oil • Thyrotricin Lavender oil • Extra gentamicin Lavender oil • Bacitracin Sage Tea oil lemon • chloramphenicol Marjoram oil • polymyxin Manuka oil • kanamycin Clove oil Naiaoli oil Oregano oil Patchoili oil Peru balsam Oil di epetit Grain Peppermint oil Black pepper oil Pepper oil Salt oil via Thorny lavender oil Tea tree oil Trujillo oil Thyme oil Juniper oil Hyssop oil Cinnamon oil Lemon oil Anti-hemorrhagic Rock oil Witch hazel extract Antihistamine Cumin oil Glucocorticoids black Antihyperg Salvia Hydrothonic acid canker Walnut Methanamine Oak bark Hexahydrate from Chlorate tanning agents for example oak bark Anticoagulant Always oil Hirudina viva Hirudin derivatives Heparin cinnamon oil, especially Low molecular weight lavender oil Laurel oil Lemon oil Antifungals Pepper oil Nem oil Azole derivatives Pimenta oil Stipite extracts • Clotrimazole Dulcamara sature oil • Bifonazole Cinnamon oil • Econazole cassia • Fenticonazole Eucalyptus oil Geranium oil • Isoconazole Clove oil • Oxiconazole Tree oil HO • Sertaconazole Camphor oil • Tioconazole Cinnamon oil • Miconazole Lavender oil • Ketoconazole Extra lavender oil • Itraconzaol Manche oil • Fluconazole Clove oil • Voriconazole Niaouli oil • Sertaconazole Oregano oil Patchouli oil Peppermint oil Continuation of pepper oil Antifungal inhibitors Squalenepoxid rosemary oil, by Sage oil ejenplo: Lavender oil • Spiny terbinaffin • Naftifine Oil of tagetes orfolins, by tree oil example: te • Amorolfine Thyme oil Other substances with antimicotic effect: • Amphotericin B • Giseofulvin • Flucytosine • Cyclopirox • Nystatin • Natamycin • Thiocarbonate Antiedematous Valerian oil Hyperthotonic Basil oil Decongestant Fennel oil Diuretic Geranium oil Edemoprotector Oil Camphor Oil Pine Oil Bay Oil Marjoram Oil Patchouli Oil Pepper Oil Rosemary Oil Sandalwood Oil Black Cumin Oil Texas Cedar Oil Trujillo Oil Junipere Oil Cypress Oil Antioxidants Flavonoids Selenium Anthocyanins Manganese Proanthoxyanidin Copper Corotinoids Beta-carotene : L-glutathione Licopina L-cysteine Zeaxanthin Coenzyme Q10 Vittamine A, C and E A-lipoic acid Antiparasitic oil Nem Crotaiton oil peppermint Permethrin Cinnamon oil Benzoate and benzyl Alephine tree oil Antiphlogistic Basil oil Melitotus officinaJ is steroids Benzoic resin Ruscus acculeatus Antiphlogistics as birch oil Aesculus glucocorticoids Camphor hippocastanum Bufexamac Eucalyptus oil Herb oil Glycyrheytic acid Spruce oil San Juan Spruce oil Calendula Timol Aloe vera herb oil Cevacrol San Juan Jojoba Camphor Camomile oil Blue Eugenol oval oil Cinnamon aldehyde seed oil Borage chamomile oil Roman capsaicin Cardiospermum Pine helicacabum Aceite bush Tanners as per example lavender oil oak and synthetic extra lavender oil lemon tea oil Continuation of manuca oil antiphlogistic Stipites extract myrrh oil dulcamara oil clove oil Symphyti Extracts de patchouili Witch hazel extract Petit oil Manzanilla grain Arnica oil Peru balm Propolio Rosemary oil Achillea oil Black cumin oil Tea tree oil Thyme oil Olive oil Olive oil Pyrex oil Isopo oil Cinnamon oil Antirheumatic Oil birch Fructus capsici See list of substances Camphor oil Capsaicin Pharmaceutical Manuka oil Nicotinic acid Ichemically effective Rosemary oil Ester of acids as analgesics Allicil juniper oil Pyrolian oil Cortex Salicis Salicin Cinnamon oil Urtica dioica Urtica urens Antiseptics Benzoic resin Oil of bergamot Sature oil Oil splint Geranium oil Camphor oil White pine oil Antispasmodic Basil oil Birch oil Lavender oil - sage Laurel oil Marjoram oil Balsamo from Peru Petit grain oil Antivira pyrrhoic oil l Basil oil Acyclovir extract / Pepper oil Podophyllum valciclovir Pepper oil (podophyllin) Peciclovir / Sature oil Melissa extract Famciclovir Cinnamon oil Fructus capsici idoxuridine / cassia Capivaicina bivudine Rock oil Eucalyptus oil Trifluridine Clove oil Vidarabine Oil of tree HO Tromantadina Inhibitors of Colchicine mitosis Derivatives of colchicine Peripheral relaxants, for example: muscle stabilizers: • tubocurarine chloride • alcuronium chloride Continuation of Tespolarization Relative Inhibitors: Muscles • Pancuronium Bromide • Vecuronium Bromide • Atracurium Besilate • Acurium Chloride • Rocuronium Bromide • Cisatracurium Besilate Repolarizing, for example: • Suxametoni Chloride Skeletal Muscle Tone Reducers: • Dantroles Irreversible inhibition of neuromuscular transmission: • Clorstridium • Botulinum • Botulinum and Cotyllium derivatives (Botox) Na channel inhibitors such as Tolperisone Local anesthetics Quinine sulfate Phlebotics Basil oil Spartaine sulfate extract Melaleuca oil Witch hazel Digitoxin Geranium oil Tuscus acculeatus Hepatine Citronella oil Melitotus albus Claviceps alkaloids Niaouli oil Vine leaves [purpurea Red tansy oil Especially Aesculus tree oil Dihydroergotamine te hypocastanum Diosamina Lemon oil Melilotus Flavonoid derivatives Cypress oil officinalis Centella extract Fagopyrum escalentum Maritime pinus Anti-dandruff Borage oil Evening primrose oil By means of the dissolution or dispersion of the base substances, essential oils, plant extracts and / or synthetic monosubstances mentioned in a microemulsion, the following modular ones can be formulated: Medicament for treating external rheumatic problems, containing active substances with analgesic effect, antiphlogistic, hypertonic and / or spasmolytic.

Medication for the treatment of the peripheral pain syndrome complex, which contains active substances with an analgesic, antioxidant, antiphlogistic, spasmolytic, muscular relaxant, hypertonic and / or local anesthetic effect. Medicine for the treatment of wounds, contusions, jerks, sports injuries and edema, containing active substances with a healing effect, analgesic, thrombolytic, fibrinolytic, epithelial, anticoagulant, antiphlogistic, antibacterial, antiviral, antifungal, diuretic, nutritious skin and / or anti-itraumatic. Medicament for the treatment of chronic wounds containing active substances with an antioxidant, analgesic, antiphlogistic and / or curative effect. Medicine for the treatment of hair loss. Medicine for the treatment of erectile dysfunction. Medicine for the treatment of excessive sweating.

Medicament for the treatment of neuralgia containing active substances with analgesic and / or local anesthetic effect. Drug for the treatment of diabetic neuropathies, which contains active substances with an analgesic, hypertonic, antipruritic and / or curative effect for burns. Medicine for the treatment of varicosis, phlebitis, which contains phlebotonic active substances, edemoprotective, antipruritic, anticoagulant, fibrinolytic, antispastic, diuretic, decongestant, antioxidant and / or hemolytic. Medicine for the treatment of hemorrhoids containing active substances with a phlebotonic, diuretic and / or epithelizing effect. Medicine for the treatment of gout attacks that contains active substances with an inhibitory effect on mitosis, antiphlogistics, antioxidants and / or diuretics. Medicine for the treatment of mycosis that contains active substances with an antifungal effect. Medicine for the treatment of neurodermatitis or eczemas containing active substances with an antiphlogistic, antipruritic, immunomodulatory, skin regenerating, antioxidant, astringent and / or antiallergic effect. Medicine for the treatment of keratosis containing active substances with keratolytic effect. Medicament for the treatment of psoriasis containing active substances with a keratolytic, antiphlogistic, antipruritic, skin regenerative and / or antioxidant effect. Medicine for the treatment of acne that contains active substances with a keratolytic, antibacterial, antiphlogistic, antioxidant and / or cicatrizing effect. Medicine for the treatment of viral diseases that contains active substances with an analgesic, antiphlogistic, keratolytic and / or antioxidant effect. Medicament for the treatment of bruises containing active substances with fibrinolytic effect. Medicament for the treatment of couperose that contains active substances with an antiphlogistic and / or antioxidant effect.

Drug for the treatment of scratches containing active substances with antiparasitic and / or antipruritic effect. Medicament for the treatment of degenerated skin containing active substances with antiphlogistic, antimicrobial, nutritional and / or local anesthetic effects. Medicament for the treatment of angina pectoris - pains in the chest - containing active substances of hypertonic effect and (or spasmolytic) Medicine for the treatment of pruritus containing active substances with a cooling effect, local anesthetic, analgesic, antiphlogistic and / or astringent drug for the treatment of scars and keloids containing active substances with regulating effects of the connective network In a particularly preferred embodiment, several drugs based on the same microemulsions can be combined to form combined preparations. In the microemulsions, guidelines and guidelines recommended for therapy and in the amounts of microemulsions common in practice are revealed.

Specifically, the concentration of the drug in the microemulsion can be between 0 and 100%, the concentrations being preferred between 10 ~ 8% and especially preferred between 10"6 and 5%, through the enrichment with oxygen of these and other medicines based on of microemulsions, medicaments are obtained according to the invention for percutaneous application This enrichment can be carried out during the production of the medicaments Under the term microemulsions enriched with oxygen microemulsions are understood, which are a suitable stage of the process are enriched with oxygen. Such a process step is represented, for example, by the atomization of the microemulsion in an oxygen-containing atmosphere, wherein the oxygen content of that atmosphere is preferably greater than 25 volume percent, more preferably greater than 50 volume percent and especially greater than 90 percent by volume, preferably the microemulsion ion enriched with oxygen has an oxygen concentration greater than 10"3 mol / L, especially greater than 5x10" 3 mol / L. To prevent the oxygen from being expelled again during the production of microemulsions enriched with oxygen, these microemulsions are preferably gas-tightly packed. Also other additives to these drugs, as well as to other medicaments based on microemulsions, which improve the oxygen supply to the skin, lead to the drugs according to the invention. Examples of additives that improve the oxygen supply to the skin are the natural carriers of oxygen, such as myoglobin and / or hemoglobin as well as fluorocarbons. An enrichment of the microemulsion with oxygen can also be carried out directly by administering the microemulsion with the aid of an application system for the percutaneous administration of medicaments, which has at least one microemulsion containing a medicament and a device for atomizing the microemulsion. Preferring oxygen enrichment directly during administration. In a system according to the invention, the microemulsion is preferably contained in a container to which an atomization unit is connected, a source of gas under pressure being connected to the atomization unit, and the microemulsion is atomized by means of the effect of the gas that is under pressure. It is also possible to temporarily eliminate the barrier function of the stratum corneum by means of the application of a microemulsion according to the invention without medicaments, which has been enriched with oxygen and / or which contains an additive that improves the oxygen supply to the body. skin. This is achieved by means of the application of a suitable microemulsion without drugs, for example with an application system according to the invention. The drugs that are going to be administered then in another stage are applied to the part of the skin in question. During the use of the system according to the invention in which an oxygen-containing propellant gas is used, the microemulsions that are applied are enriched with oxygen directly before entering the stratum corneum. This leads to an increase in the partial pressure of the oxygen on the tissue side of the stratum corneum and with this to a stimulation of the cutaneous microcirculation and to an improved transdermal transport of the medicaments. The transdermal transport of the drugs can also be produced, for example, also by means of a high transmembrane pressure, caused here by the rise of the oxygen concentration on the tissue side of the stratum corneum. The use of this system is especially appropriate in the case of medicines that possess oxidatively sensitive substances and therefore can be enriched with oxygen directly before the application. It is possible with an application system according to the invention to dose exactly the dose of the drug to be applied, with which the maximum daily dose can also be applied. For this a microemulsion which presents the maximum daily dose of one or several drugs, is introduced into the system for percutaneous administration and with this system is administered to a patient. Another effect of atomization, which can contribute to a better transdermal transport of drugs, is the expansion effect. This is based on the fine distribution of droplets during atomization. Thus the microemulsion in the form of small droplets reaches less furrows, folds and holes in the skin. The aforementioned medicament based on microemulsions represents a preferred embodiment of a system for the percutaneous administration of drugs within the framework of this invention. Next, the application system according to the invention for atomizing liquid medicaments for the percutaneous administration of medicaments will be described. The reaction of the application system is carried out according to the invention with the characteristics given in the claims. In the application system according to the invention for atomizing liquid medicaments for the percutaneous administration of medicaments, a liquid medication dosed in an exact manner, especially a medicament containing a microemulsion, to be applied to the skin by means of a propellant gas, preferably highly concentrated oxygen, is compressed through a microdoser nozzle and preferably using a suction effect based on the Venturi effect. A spectrum of droplet sizes can be generated with the microdosing nozzle of the application system, whereby the cross section of the outlet of the microdosing nozzle can be varied with the tip of an adjustable needle and with this the droplet size can be modified . The diameter of the droplets that can be obtained by atomization is in the nanometer range, the measured mean droplet size being less than 1 μm, preferably less than 400 nm, especially less than 300 nm. The reproducibility of the droplet size spectrum with the application system can be determined by non-contact measurement methods and laser optics measurement methods. The individual droplet sizes and their frequency can be determined from the plurality of different droplets of a liquid sprayed by means of laser diffraction spectroscopy. Here the monochromatic light of a laser beam is diffracted more or less in an elevated way through the individual droplets through an atomizing liquid, in which the photomultipliers found in a detector register the different impulses and intensities. A subsequent electronic circuit with special software evaluates and calculates the actual droplet size distribution. With the application system according to the invention, all liquid medicaments prepared and to be atomized, preferably medicaments based on microemulsion ions, with certain rheological properties, such as viscosity, density of the liquid, surface tension but also below A dynamic viscosity can be sprayed on the place of the skin to be treated. In addition to highly concentrated oxygen, air, nitrogen or a noble gas (helium, argon) can alternatively be used as the propellant gas. Here under the highly concentrated oxygen is meant a gas which is enriched with at least 90% by volume. If propellant gases are used that do not contain oxygen, the microemulsion is enriched with oxygen and / or contains additives that improve the oxygen supply to the skin. During atomization the prepared drug is wrapped in the propellant gas and mixed with it. This dissolves the propellant gas in the liquid medication under pressure, which can produce a positive property of the skin together with the liquid active substance that stimulates oxygen. A positive effect of the extremely fine atomization in the case of the application of medicaments is the pleasant refreshing effect of the atomized medicament produced by the cold evaporation. Due to the highly concentrated oxygen reactivity for the individual components of the application system, materials that can withstand oxygen must be used., such as glass, clinically accepted special synthetic materials or stainless steel. During the evaporation of the microemulsion depending on the daily dose and the part of the body to be treated, a volumetric flow of 1.5 to 5 ml / 20 min or 4.5 to 15 ml / h is expelled through the outlet cross section of the micro dosing nozzle. The propellant gas can be taken from a gas tank and conducted to the application system through a hose connection. The gas container itself can be a part of the installation for the production of oxygen (O2 plant), in which oxygen is taken from the ambient air and enriched. Alternatively, in a further embodiment of the application system and the gas source, one can think of a self-sufficient gas container or a gas connection in a clinic. In a preferred embodiment of the invention, the application system is formed as an autonomous system filled with a liquid medicament and connected to a propellant gas system. BRIEF DESCRIPTION OF THE FIGURES Now referring to FIGS. 1, 2 3, the application system according to the invention for the percutaneous administration of medicaments, in particular liquid medicaments based on microemulsions, will be described in detail. Figure 1 shows a schematic representation of an application system; Figure 2 shows an enlarged schematic representation of the area near the nozzles of the application system according to Figure 1 and its operating principle, and Figure 3 is a schematic representation of another application system, Figure 4 is a schematic representation of another application system. DESCRIPTION OF THE INVENTION Figure 1 shows an application system 10 in a simplified schematic representation of the individual components. The application system includes a reservoir for the medication 12, which is placed in a gas reservoir 16 of the application system 10. One end of the reservoir for the medicament 12, in the area near the nozzle 40 of the application system 10, is thins forming a capillary tube. Depending on the daily dose to be applied, the drug device 12 contains between 1.5 and 5 ml of a medication 14. The front end of the drug reservoir 12 and the gas reservoir 16 of the application system 10 are formed coaxially seen in the position of use and are joined together through a bypass or compensation conduit 26. Likewise at the upper end there is an inlet 18 for venting a medicament 14 in the reservoir for medicament 12 and an inlet 20 for venting the gas reservoir 16 with a propellant gas. The gas reservoir 16 of the application system 10 is connected to a hose connector 22 to a gas container 24. In the area near the nozzles 40, the application system 10 is formed as a rotating body with a cross-section that thins in the direction of jaca the outlet of the nozzle 50. The drug reservoir 12 with its thinned end is connected to the atomization nozzle 30, which is placed inside the nozzle head 28. The nozzle head 28 has along its axis of rotation has orifices 29, through which a flow connection is formed between the gas reservoir 16 and the environment. A needle 32 that is inserted into the atomization nozzle 30, which is led into the upper part of the gas reservoir 16, reduces its circular cross-section. By means of the rotation of a knob 3 the needle can be positioned vertically and with this adjusting the transverse constriction of the atomization nozzle. In the following, the operation of the application system 10 represented in FIG. 1 will be described in detail for the atomization of a drug prepared for the percutaneous administration of a medicament. Depending on the size of the surface of the part of the body to be treated, in the drug reservoir 12 through the entrance of the drug reservoir 18 of the application system 10, a liquid medicament 14 is introduced exactly dosed, in particular a liquid medication based on a microemulsion, preferably in an amount of 1.5 to 5 ml. To atomize the liquid medicament 14, the gas reservoir 16 is constantly filled with propellant gas and an overpressure is formed in a gas reservoir 16. The propellant gas is withdrawn from the gas reservoir 24 and under a predetermined pressure, for example approximately 2 bar, is conveyed to the application system 10. For this the gas reservoir 16 is connected via a hose connector 22 to the connection for gas 20 of the application system 10. By means of the overpressure in the gas reservoir 16 the propellant gas is led to the outlet 50 of the atomizing nozzle 30 (micro-dosing nozzle). Since the gas tank 16 of the application system 10 in the area 40 near the nozzle is formed as a rotating body, with a cross-section that is thinned in the direction of the outlet of the nozzle 40, the propellant gas by means of the overpressure is accelerated towards the gas reservoir 16 in the flow direction. The suction pressure that is formed due to the transverse constriction within the gas reservoir 16, it is diverted through a diversion conduit 26 to produce the delivery of the liquid medicament 14 onto the reservoir of the medicament 12, whereupon the suction pushes the liquid medicament through the atomization nozzle 30. With this a discharge is ensured uniform. The end of the medication reservoir which thins in the area 40 near the nozzle is formed inside the gas reservoir 16 in such a way that leakage of the medicament is avoided. The holes 29 in the interior of the nozzle head 28 ensure that the propellent gas accelerated in the direction of the thinned rotation body 16, flows from the atomization nozzle 30 to the exit point 50 of the nozzle head 28. In the exit position 40 of the atomization nozzle 30, the liquid medicament is suctioned by means of the underpressure present at the exit point (by the effect of Venturi) and there atomized. During atomization the prepared drug 14 is wrapped by the propellant gas and mixed with it. Here the propellant gas is dissolved in the liquid medication 14. This produces a high action of the liquid drug 14 on the microcirculation, especially in the case of a liquid drug based on microemulsions, which produces the percutaneous administration of the drugs . The diameter of the droplet size during atomization of the liquid medicament 14 can be varied through the needle 32 inside the atomization nozzle 30, for which the needle 32 is finely adjusted by means of the knob 38. If the nozzle The atomization 30 is completely closed by means of the needle 32, in such a way that the massive passage of the liquid medication 14 is prevented through the atomization nozzle 30, and thus the atomized medicament is deposited. The propellant gas then flows mainly through the outlet point 60 of the nozzle head 27, along the atomization nozzle 30 thanks to the holes 29 placed inside the head of the nozzles 28. On the other hand in a form of embodiment not shown can be used a nozzle with a predetermined internal diameter without adjustment needle, when the desired droplet profile has already been obtained. Figure 2 shows the operating principle of the atomization represented schematically in simplified form in Figure 1, the area near the nozzle 40 of the application system 10 being represented enlarged to improve clarity. Here the arrows indicate the direction of gas flow. Figure 3 shows another embodiment of an application system 70 in cross section. The application system 70 includes a reservoir for medicament 12, which is surrounded by a gas reservoir 16 of the application system 70. The reservoir of medicament 12 at the end in the area near the nozzles of the application system 70, is formed or it thins in the form of a capillary tube. Depending on the daily dose to be administered in the drug store 12 there are between 1.5 and 5 ml of a medicine 14. The tank of the drug 12 and the gas tank 16 of the application system 70 are formed coaxially and are united each other through a bypass conduit 26. At the upper end of the application system 70 there is an entrance to the medicament reservoir 18 for introducing a medicament 14 and an entrance to the medicament reservoir 20 for filling the gas reservoir 16 with a propellant gas. Both inputs can be closed with plugs not shown. The entrance to the drug reservoir 18 is formed in such a way that the liquid medicament 14 in no case reaches the diverting conduit 26 and thereby be able to flow out of the application system 70. In order to prevent this, the diverting end 27 is formed of such that it penetrates deeply into the inlet duct of the medicament tank 12. The gas tank 16 of the application system 70 is connected through a hose connector 22 to a gas tank 24. In the area near the nozzles the application system 7 is formed as rotation body, with a cross section that is thinned in the direction towards the outlet of the nozzle 50. The medicament tank 12 closes with it connects with its thinned end to the atomization nozzle 30, which is positioned inside the nozzle head 28. nozzle head 28 has slots 29 along its axis of rotation, so that the gas reservoir 16 has a flow connection with the environment. A needle 32 that is inserted into the dosing nozzle 30, which is inserted into the upper part of the application system, reduces its round cross section. By turning an adjusting screw (knob) positioned on the knob head the needle 32 can be adjusted vertically and with this the transverse constriction of the atomization nozzle 30 can be adjusted. Next, the operation of another system will be described in detail. of application 70 for the atomization of the medicament prepared for the percutaneous application represented in figure 3. Depending on the dimensions of the part of the body to be treated, the dosed medication 14 is introduced precisely in a microemulsion, preferably 1.5 to 5 ml, in the tank for medication 12 through an inlet for the drug reservoir 18 of the application system 70. To atomize the liquid medication 14 the gas reservoir 16 is constantly filled with propellant gas forming in a reservoir of 16 gas an overpressure. The propellant gas is withdrawn from the gas reservoir 24 and, under a predetermined pressure, is conveyed to the application system 70. For this, the gas reservoir 16 is connected via a hose connector 22 to the gas connection 20 of the gas system. application 70. By means of the overpressure in the gas reservoir 16 the propellant gas is led to the outlet 50 of the atomizing nozzle 30 (micro-dosing nozzle). Since the gas tank 16 of the application system 70 in the area 40 near the nozzle is formed as a rotating body, with a cross section that is thinned in the direction of the outlet of the nozzle 40, the propellant gas by means of the overpressure is accelerated towards the gas reservoir 16 in the flow direction. The suction pressure that is formed due to the transverse constriction within the gas reservoir 16, is diverted through a bypass conduit 26 to cause the liquid medicament 14 to be pushed over the reservoir of the medicament 12, whereby the suction pushes the liquid medication through the spray nozzle 30. This ensures a uniform flow. The end of the drug reservoir 12 in the form of a capillary tube inside the gas reservoir 16 is formed in such a way that drug leaks are prevented. The slots 29 in the interior of the nozzle head 28 ensure that the accelerating propellent gas in the direction of the thinned rotating body 16 flows from the atomizing nozzle 30 to the exit point 50 of the nozzle head 28.

In the exit position 40 of the atomization nozzle 30, the liquid medicament is suctioned by means of the underpressure present at the exit point (by the Venturi effect) and atomized there. The diameter of the droplet size during atomization of the liquid medicament 14 can be varied through the needle 32 inside the atomization nozzle 30, for which the needle 32 is finely adjusted by means of the knob 38 placed on the screw of knob 36 which moves needle 32. If the atomization nozzle 30 is completely closed by means of needle 32, in such a way that massive passage of liquid medicament 14 is prevented through spray nozzle 30, and thus the atomized medicine is deposited. The propellant gas then flows mainly through the outlet point 60 of the nozzle head 27, along the atomization nozzle 30 thanks to the holes 29 placed inside the head of the nozzles 28. The conicity of the needles 32 in comparison with the conicity of the atomizing nozzle 30 it is greater in order to produce a wider atomization or a wider atomization angle. A wider atomization angle can be produced by means of the placement on the nozzle head 28 of a rotating means. According to another embodiment, shown in Figure 4, the drug reservoir is directly connected to the gas source in its upper zone, for which it has another entrance. Here the Venturi conformation of the nozzle can be omitted, if this seems to be advantageous. However, if a Venturi spray nozzle is used, a gas line corresponding to that of FIG. 2 is placed on the outside of the nozzle. A gas tank can also be omitted even in the nozzle zone, provided that only a gas conduit is provided in the nozzle area, as shown in figure 4. Next, with the help of examples, the microemulsions and their production, microemulsions which, in the context of the invention, can be enriched with oxygen, will be described. example during the application with the application system according to the invention. Example 1: Production of a water-in-oil emulsion (I) 5 g of Tween® 80 are mixed with 10 g of Span® 20 and 5 g of ethanol and 75 g of isopropyl myristate are added. To this mixture, 5 g of water are added dropwise with stirring. This produces 100 g of a water-in-oil microemulsion (I). Example 2: Production of a water-in-oil emulsion (II) 14 g of Span® 20 are mixed with 21 g of Synperonic® PEL 101. To this is added 60 g of isopropyl palmitate. To this mixture, 5 g of water are added dropwise with stirring. This produces 100 g of a water-in-oil (II) microemulsion. Example 3: Production of a water-in-oil (III) emulsion 4 g of Tween® 80 are mixed with 12 g of Synperonic® PEL 101 and 5 g of isopropyl myristate are added. To this mixture, 79 g of a water / polypropylene glycol mixture (1.2) (weight ratio) are added under stirring. This produces 100 g of a water-in-oil (III) microemulsion. Example 4: Preparation of a medicament with procaine active substance to locally combat pain based on an oil-in-water microemulsion: 2 g of procaine chloride are dissolved in 5 ml of water. The solution is added under agitation to 93 g of the microemulsion III. This produces 100 g of the medication.

Example 5: Preparation of a medicament with procaine active substance to locally combat pain based on an oil-in-water microemulsion: 2 g of procaine chloride are dissolved in 5 ml of 0.01M NaOH. The solution is added under agitation to 93 g of the microemulsion I. This produces 100 g of the medicament. Example 6: Preparation of a medicament with the active substance lidocaine to locally combat pain based on an oil-in-water microemulsion: 2 g of lidocaine are dissolved in 98 ml of microemulsion II. This produces 100 g of the medication. Example 7: Preparation of a drug with the active substance diclofenac to locally fight painful inflammations based on a water-in-oil microemulsion: 2 g of lidocaine, 2 g of diclofenac and 0.05 g of capsaicin are sequentially dissolved in 95.95 g of the microemulsion ( II). This produces 100 g of medication.

Claims (34)

1. NOVELTY OF THE INVENTION Having described the invention as above, property is claimed as contained in the following: CLAIMS 1. A microemulsion enriched with oxygen, characterized in that it contains at least one drug for percutaneous application.
2. 2. A microemulsion for the percutaneous administration of at least one medicament, characterized in that the microemulsion includes an additive to improve the oxygen supply to the skin.
3. 3. A medicine for treating external rheumatic problems, containing active substances of analgesic, antiphlogistic, hypertonic and / or spasmolytic effect, characterized in that it contains a microemulsion according to claim 1 or 2..
4. A medicament for the treatment of the peripheral pain syndrome complex, which contains active substances of analgesic, antioxidant, antiphlogistic, spasmolytic, muscular relaxant, hypertonic and / or local anesthetic characterized, because it contains a microemulsion according to claim 1 or 2.
5. 5. A medicine for the treatment of wounds, contusions, jerks, sports injuries and edema, containing active substances with healing effect, analgesic, thrombolytic, fibrinol, itching, epithelial, anticoagulant, antiphlogistic, antibacterial, antiviral, antifungal, diuretic, nutritious the skin and / or antitraumatic, because it contains a microemulsion according to claim 1 or 2.
6. 6. A medicament for the treatment of chronic wounds containing active substances of antioxidant, analgesic, antiphlogistic and / or curative effect, because it contains a microemulsion according to claim 1 or 2.
7. 7. A medicament for the treatment of neuralgia containing analgesic and / or local anesthetic active substances, because it contains a microemulsion according to claim 1 or 2.
8. 8. A medicament for the treatment of diabetic neuropathies, containing active substances of effect analgesic, hypertonic, antipruritic and / or curative for burns, because it contains a microemulsion according to claim 1 or 2.
9. 9. A medicament for the treatment of varicosis, phlebitis, which contains phlebotonic active substances, edemoprotective, antipruritic, anticoagulant, fibrinolytic, antispastic, diuretic, decongestant, antioxidant and / or hemolytic, because it contains a microemulsion according to claim 1 or 2.
10. 10. A medicine for the treatment of hemorrhoids containing active substances of phlebotonic, diuretic and / or epithelizing, because it contains a microemulsion according to the r claim 1 or 2.
11. 11. A medicament for the treatment of attacks of gout containing active substances with an inhibitory effect on mitosis, antiphlogistics, antioxidant and / or diuretic, because it contains a microemulsion according to claim 1 or 2.
12. 12. A medicament for the treatment of mycosis containing active substances with antifungal effect, because it contains a microemulsion according to claim 1 or 2.
13. 13. A medicament for the treatment of neurodermatitis or eczema containing active substances with an antiphlogistic, antipruritic, immunomodulatory effect , skin regenerator, antioxidant, astringent and / or antiallergic, because it contains a microemulsion according to claim 1 or 2.
14. 14. A medicine for the treatment of keratosis containing active substances with keratolytic effect, because it contains a microemulsion according to the claim 1 or 2.
15. 15. A medication for the treatment of psoriasis containing active substances with a keratolytic, antiphlogistic, antipruritic, skin regenerative and / or antioxidant effect, because it contains a microemulsion according to claim 1 or 2.
16. 16. A medicine for the treatment of acne containing active substances with a keratolytic effect, antibacterial, antiphlogistic, antioxidant and / or cicatrizant, because it contains a microemulsion according to claim 1 or 2.
17. 17. A medicament for the treatment of viral diseases that contains active substances with an analgesic, antiphlogistic, keratolytic and / or antioxidant effect. , because it contains a microemulsion according to claim 1 or 2.
18. 18. A medicament for the treatment of hematomas containing active substances with fibrinolytic effect, because it contains a microemulsion according to claim 1 or 2.
19. 19. A medicament for the couperose treatment containing active substances with an antiphlogistic and / or antioxidant effect, because it contains a microemulsion according to claim 1 or 2.
20. 20. A medicament for the treatment of scratches containing active substances with antiparasitic and / or antipruritic effect, because contains a microemulsion according to claim 1 or 2.
21. 21. A med an agent for the treatment of degenerated skin containing active substances with antiphlogistic, antimicrobial, alimentary and / or local anesthetic effects, because it contains a microemulsion according to claim 1 or 2.
22. 22. A medicament for the treatment of angina pectoris - pains in the chest - containing active substances with hypertonic effect and (or spasmolytic), because it contains a microemulsion according to claim 1 or 2.
23. 23. A medicine for the treatment of pruritus containing active substances with a cooling effect, local anesthetic , analgesic, antiphlogistic and / or astringent, because it contains a microemulsion according to claim 1 or 2.
24. 24. A medicine for the treatment of scars and keloids containing active substances with regulating effects of the connective network, because it contains a microemulsion of according to claim 1 or 2.
25. 25. An application system for the administration percutaneous drug, which has at least one microemulsion containing a drug and a device for atomizing the microemulsion.
26. 26. The application system according to claim 25, characterized in that it presents: a) has a reservoir for medicament (12) which contains the liquid medicament (14) in the form of microemulsion, b) a first connection for gas (18) ), in which gas can be fed at a predetermined pressure through a gas conduit (22) to drug reservoir (12), c) an inlet for the drug reservoir (18), into which the liquid medicament (14) can be introduced, d) a nozzle head (28) with slots (29), which are formed at the end of the medicament device (12), and atomization (30) which is placed in the nozzle head (28) and which is flow-linked with the reservoir for the medicament (12), and because with it a spectrum of droplet sizes, the nozzle head (28) can be produced. ) and the atomization nozzle (30) form a Venturi system, and the nozzle head (28) has an annular chamber around the atomization nozzle (30) and f) a second gas connection (29) that is in the area of the nozzle head (28) and is in flow contact with the annular chamber and the slots (29), and at the point of exit of the atomizing nozzle (30) the droplets generated under pressure are atomized by means of the Venturi effect .
27. 27. The application system according to claim 25 or 26, characterized in that to adjust the droplet size an axially displaceable needle (32) is inserted into the cross section of the atomizer nozzle orifice (30), the needle being provided (32) with a knob on the end of the needle (34), such that the cross-section of the orifice of the atomizing nozzle (30) can be adjusted exactly by means of an adjusting screw (36) in the head of the knob (38).
28. 28. The application system according to one of the preceding claims, characterized in that the gas reservoir is connected to a drug reservoir (12) by means of a bypass conduit (26).
29. 29. The application system according to one of the preceding claims, characterized in that the pressurized gas is oxygen, air, nitrogen or a noble gas (helium, argon), preferably it is oxygen.
30. The application system according to one of the preceding claims, characterized in that the mean droplet size that can be adjusted by means of the adjustment screw (36) is less than 1 μ? T ?, preferably less than 400 nm, especially lower than 300 nm.
31. 31. The application system according to one of the preceding claims, characterized in that the application system is made of glass and stainless steel.
32. 32. The application system according to one of the above indications, characterized in that the application system consists of a special clinical synthetic material.
33. The application system (10) according to one of the preceding claims, characterized in that it can be connected to the gas source (24) by means of a hose connection (22) via a gas connection (20). .
34. 34. The system according to one of claims 25 to 33, characterized in that the microemulsion is a medicament according to claims 3 to 24.