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 exeried 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:
BACKGROUND  
       [0001]     On administering medicinal substances as active substance materials to a patient, a balance is always to be obtained, with the dosage, between desired action and undesired side effects on the body. It is accordingly desirable to bring the medicinal substance as directly as possible to the site of action, in order accordingly to be able to work with minimum total dosages and to place the least possible burden on the body of the patient, and still to achieve the necessary active level at the site of action. This can be achieved by percutaneous administration of medicinal substances.  
         [0002]     The skin, in particular the upper horny layer, represents though a barrier which can be overcome only with difficulty. This applies in particular for water-soluble or sparingly soluble medicinal substances.  
         [0003]     A conventional process for the percutaneous administration of medicinal substances is the application of ointments, creams or gels to the skin. In order to improve the permeation of the active substances, use is made of “penetration promoters”, such as sulfoxides, alcohols, fatty acids, anoids, fusids, and many others. These substances reduce the resistance to penetration of the horny layer and facilitate the permeation of the medicinal substances.  
         [0004]     Dosing possibilities which are only approximate are disadvantages of this process. Because of this, the content of medicinal substances in the preparations has to be kept low as a precaution, resulting in the desired high active level not being reached even in the target tissues. Moreover, despite the use of penetration promoters, the depth of penetration of conventional preparations is only very low.  
         [0005]     Furthermore, different methods are known for overcoming the barrier of the skin (compare  Müller/Hildebrand; Pharmazeutische Technologie: Moderne Arzneiformen [Pharmaceutical Technology: Modern medicinal forms], ISBN  3-8047-1549-4,  chapter  13).  
         [0006]     In particular, transdermal therapeutic systems (TTS) have been developed. TTSs are technical devices which are placed on a specific area of the skin in an adherent fashion and which deliver, by diffusion through the skin, to the body a specific dose of the medicinal substance according to different mechanisms with a specific time-related feed. The objective in this connection is in particular a systemic action with a defined profile of the active level. In order to accelerate the permeation of the medicinal substance into the skin, TTS systems also have ultrasound heads or electrodes, in order to deliver current impulses to the skin and accordingly to promote pore formation in the skin by mechanical or electrical stimuli.  
         [0007]     A disadvantage here is that a targeted local application by means of TTS is not possible. There is the fact that not all medicinal substances can be administered by diffusion. This applies in particular for water-soluble and sparingly soluble medicinal substances.  
         [0008]     Furthermore, medicinal substances are applied to the skin in microemulsions. Because of the low surface tension and large interface in the microemulsion, water-soluble, fat-soluble and sparingly soluble medicinal substances can be dispersed therein. With the help of a microemulsion, success is achieved in introducing the medicinal substances into the horny layer of the skin (stratum corneum) within a short time.  
         [0009]     Even with the help of microemulsions, alone, success is not satisfactorily achieved, though, in temporarily abolishing the barrier function of the skin to the desired extent and in applying all kinds of medicinal substances through the skin.  
         [0010]     It is an object of the invention to remedy the abovementioned disadvantages of the state of the art.  
         [0011]     Specifically, it is an object of the invention to make available preparations (subsequently referred to as medicaments) which satisfactorily penetrate the barrier of the skin.  
         [0012]     Furthermore, it is an object of the invention to make available a system with which it is possible, on any area of the skin, to penetrate the barrier of the skin and to percutaneously apply an active substance or a combination of active substances.  
         [0013]     Furthermore, it is an object of the invention to make available a system with which the medicinal substances to be applied can be accurately dosed.  
         [0014]     It is an additional object of the invention to apply the maximum daily dose locally.  
         [0015]     It has been found, surprisingly, that this and additional unmentioned objects are achieved with the help of a system according to the invention for the percutaneous administration of medicinal substances, exhibiting a microemulsion, into which the medicinal substances are introduced, and a device for the atomization of the microemulsion, preferably in an oxygen-comprising atmosphere (the term “atomization” is to be understood here as the fine dispersing of liquid using a propellant gas).  
         [0016]     Furthermore, these objects are achieved by a microemulsion enriched with oxygen which comprises at least one medicinal substance for percutaneous administration.  
         [0017]     A microemulsion for the percutaneous administration of medicinal substances which exhibit medicinal substances for the improved supply of oxygen to the skin also achieve the object according to the invention.  
         [0018]     The combination of the various mechanisms of the novel process can result in significant synergistic effects in the permeation of active substances into the skin, as is explained subsequently.  
         [0019]     Through the extraordinarily small droplets of the high performance atomizer, the microemulsion charged with active substance is applied to the skin in finely divided form. Because of the low surface tension of the microemulsion, a huge spreading effect arises in this connection. The horny layer of the skin and the microemulsion have similar upper structures, such as lamellae or tubuli, formed from bilipid layers. These upper structures of the horny layer contribute crucially to the resistance to permeation of this layer. The finely dispersed application of the droplets presumably results in “fusion” of the microemulsion with the horny layer according to the principle “similia similibus”. As a result of the fusion, the abovementioned upper structures dissolve and the active substances can diffuse into the skin at a reinforced level. The use of oxygen as propellant gas results in the lipid-comprising droplets of the atomizer being enriched in oxygen. This oxygen is, like the active substances, introduced into the skin layer, which results in an increase in the oxygen partial pressure in the skin. This elevated partial pressure strongly stimulates the microcirculatory flow. Through this, the active substance materials which have diffused in are more strongly entrained convectively inward into the tissue.  
         [0020]     The combined use of microemulsions, fine droplets and oxygen in the process according to the invention also results in an increase in the permeation of active substances in three successive steps: 
        1. The microemulsion and accordingly the active substances are very finely divided and spread over the surface of the skin.     2. The horny layer barrier is overcome and     3. the microcirculatory transport through the skin is increased, namely first by the high performance atomization, secondly by the microemulsion and thirdly by the oxygen.        
 
       DETAILED DESCRIPTION OF THE INVENTION  
       [0024]     The skin is the biggest organ in the body and closes off the outside. It has, in its operation, to perform a number of tasks.  
         [0025]     In first place is the protective function against mechanical effects, such as impacts, pressure or rubbing, and against the penetration of bacteria, viruses and fungi through an acidic sheathing. Furthermore, the skin protects against heat, cold, light and harmful substances.  
         [0026]     The skin is also a sense organ: special sensors detect pressure, temperature, pain and itching.  
         [0027]     The skin also intervenes, by regulation of the water and heat budget, in a regulating fashion in the function of the whole body.  
         [0028]     In broad terms, the skin consists of three layers: of the subcutis, of the corium (dermis) and of the epidermis.  
         [0029]     The subcutis consists of fat, large blood vessels, glands and small muscles. It serves, e.g., as “larder” and for the damping of mechanical effects. The dermis, with its collagen and elastomer fibers, brings about hold and elasticity of the skin and accordingly also resistance to tearing. Sensory cells (sensors) for reception of the abovementioned sensations are also located in the dermis. It comprises much hyaluronic acid and chondroitin sulfate, thus glucosaminoglucans, which make possible, as reversible gels, the transport of biological molecules and cytotaxis.  
         [0030]     The epidermis is of particular importance and particular interest in closing off the body from the outside since this layer altogether guarantees the integrity of the skin, the very outermost layer, the horny layer, playing a crucial role.  
         [0031]     This layer consists of a layer, approximately 10 cells thick, of keratinized, i.e. dead, flat cells (horn cells, stratum corneum); it is divided up yet further into an upper loose layer (stratum disjunctum) and into a lower firmer layer, the stratum conjunctum. The horn cells are constantly peeling off toward the outside and are produced by division in the “stratum germinativum”, the germinative layer, located thereunder.  
         [0032]     The particular microstructure of the stratum corneum consists of flat, brick-like keratinized cells (corneocytes). The intracellular matrix is particularly structured. It consists, approximately parallel to the skin surface, of lipoid bilayers: in the stratum corneum, approximately one hundred aqueous and lipid phases alternate. In the formulation sense, the horny layer represents a “water-in-oil emulsion” in the form of a lamellar bilayer. This constantly regenerating layer, with a thickness of only approximately 12 μm, forms, with the help of its complex two-phase upper structures, secure protection for the cells of the stratum germinativum located thereunder: without the horny layer, a “wound bed” is produced.  
         [0033]     The horny layer of the skin is of particular importance for closing off from the outside, especially in its barrier function. This is the case with regard to the density, the oxygen partial pressure (PO 2 ), the pH and the water content.  
         [0034]     The barrier for hydrogen ions, which form an acidic protective sheathing, is particularly important. Equally important is a barrier for oxygen, by putting up great resistance to the diffusion of this. This results in a decrease in the oxygen partial pressure of the air from 150 torr to approximately 50 torr. Accordingly, the vital cells of the skin epithelium of the intact skin are protected from an excessively high oxidatively damaging oxygen partial pressure.  
         [0035]     So advantageous the effective barrier function in the horny layer is for the body, so disadvantageous it proves to be for transdermal transport of medicinal substances. In such cases, the corneal barrier has to be temporarily abolished.  
         [0036]     It has been found, surprisingly, that the barrier function of the skin, by introduction of oxygen into the horny layer and accordingly the increase in the oxygen partial pressure on the tissue side of the stratum corneum, results in an improved transdermal transport of medicinal substances.  
         [0037]     The transmembrane pressure of the oxygen is increased by the increase in the oxygen partial pressure on the tissue side of the stratum corneum, which is presumably a reason for the improved transdermal transport of medicinal substances.  
         [0038]     Because of the abovedescribed lamellar structure of alternating water and oil phases in the stratum corneum, microemulsions can be particularly suitably introduced into the stratum corneum (compare Müller/Hildebrand; Pharmazeutische Technologie: Moderne Arzneiformen [Pharmaceutical Technology: Modern medicinal forms], ISBN 3-8047-1549-4, chapter 15). In a preferred embodiment of the invention, these are used as vehicle systems for oxygen or medicinal substances and also base materials for medicaments.  
         [0039]     Such microemulsions are known and are used in cosmetics and the pharmaceutical industry. These are available commercially, for example under the trade name “Nanoemulsion” from Sangui A G.  
         [0040]     Microemulsions within the meaning of the invention are thermodynamically stable systems which exhibit at least water, surfactants and lipid. The term “a surfactant” is understood to mean emulsifiers which can be ionic or nonionic. Examples of surfactants which can be used are known under the trade name Tween, Span and Synperonic PEL 101.  
         [0041]     Lipids which can be used are fatty oils or mineral oils, for example isopropyl myristate and isopropyl palmitate.  
         [0042]     Microemulsions which can be used in the context of this invention can be oil-in-water microemulsions or water-in-oil microemulsions. In this connection, oil droplets in a water matrix or water droplets in an oil matrix are formed.  
         [0043]     Such microemulsions exhibit droplet sizes in the range from 10 nm to 1 μm, preferably from 10 nm to 500 nm, particularly preferably from 10 nm to 300 nm.  
         [0044]     The mean droplet size of a microemulsion which can be used in the context of the invention is not limited. The mean droplet size is preferably less than 300 nm, particularly preferably less than 150 nm.  
         [0045]     Such microemulsions preferably exhibit interfaces of more than 200 m 2  per ml, particularly preferably of more than 400 m 2  per ml and very particularly preferably of more than 600 m 2  per ml.  
         [0046]     Because of the hydrophilic and lipophilic portion of the microemulsions and of the low surface tension and of the large interface, it is possible to disperse, in microemulsions, both water-soluble and fat-soluble and/or sparingly soluble medicinal substances. The choice of the surfactants is in this connection made according to the active substance and the effect desired. Ionic surfactants are generally particularly effective, while nonionic surfactants are particularly kind to the skin.  
         [0047]     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 circulatory disorders and for the healing of wounds in degenerated skin, e.g. in elderly people. Medicinal substances based on such microemulsions can, in addition to the parent substances of the microemulsion, exhibit base materials for medicaments and medicinal substances. These base materials and medicinal substances can be of natural and synthetic origin. In the context of this invention, base materials and medicinal substances of natural origin are particularly preferred, without this being limiting.  
         [0048]     Examples of natural base materials and the effect thereof are represented in table 1. Base materials which can be used in the context of this invention are not, however, limited thereto.  
                             TABLE 1                           Natural base materials and the effect thereof                Base materials   Effect                       Aloe vera   favoring the blood flow               contributing to moistness               inhibiting inflammation               removing wrinkles               nourishing the skin           Arnica oil (fat)   alleviating pain               inhibiting inflammation               causing hyperemia               favoring the blood flow               healing wounds           Avocado oil   binding of moisture               regenerating               alleviating itching               healing wounds               nourishing the skin           Borage oil   skin regenerating               alleviating itching           Centella oil   regenerating               regulating connective tissue               (scars)               antiinflammatory               healing wounds           Rose of Sharon oil   antiinflammatory               analgesic               causing hyperemia               antispasmodic           Jojoba oil   inhibiting inflammation               regenerating               healing wounds           Corn oil   antioxidant           Almond oil   regenerating               nourishing           Evening primrose oil   healing wounds               antibacterial               alleviating itching           Neem oil   antibacterial               antimycotic           Olive oil   causing hyperemia               favoring the blood flow               healing wounds           Marigold oil   antiinflammatory               antirheumatic               favoring the blood flow           Shea butter   healing wounds               regenerating           Grapeseed oil   astringent           Wheat germ oil   regenerating               nourishing the skin           Dog rose oil   contributing to moistness           Rose hip oil   skin regenerating               alleviating itching               nourishing               healing wounds                      
 
         [0049]     The medicinal substances which can be used in the context of this invention are not limited. In this connection, natural and synthetic medicinal substances can be used. In the context of this invention, natural medicinal substances obtained from plants are preferred. Essential oils which can be obtained from plant parts are particularly preferred as medicinal substances. Examples of plant species and genera, inclusive of their chemotypes, which comprise essential oils in the most varied plant parts, which can be used as medicinal substances in microemulsions in the context of this invention, and also the therapeutic effect thereof in external application, are represented in table 2; however, these are not limited thereto.  
                             TABLE 2                           Plant species and genera, inclusive of their chemotypes, which comprise       essential oils in the most varied plant parts, and also the therapeutic       effect thereof in external application                Species/Genus/           Name   Chemotypes   Properties               Angelica oil     Angelica     skin regenerating       Valerian oil     Valeriana     diuretic               skin regenerating       Basil oil     Ocimum     antibacterial           Chemotype   antispasmodic           Methyl chavicol   antiviral               antiinflammatory               analgesic               deblocking               caring for varicose               veins       Bay oil     Pimenta     antibacterial       Pimento oil       antimycotic               antiviral       Mugwort oil     Artemisia     antiviral       Benzoin resin     Styrax     antiinflammatory               antiseptic               skin regenerating               cell renewal       Bergamot oil     Citrus aurantium  var.   antiseptic             Bergamia     epithelizing               healing wounds               skin regenerating       Winter savory     Satureja Montana     analgesic       oil       antibacterial               antimycotic               antiseptic               immunomodulating       Birch oil   Betula   antiinflammatory           98% methyl salicylate   antirheumatic               antispasmodic               alleviating pain               vasodilative       Cajeput oil     Melaleuca     antibacterial               antiviral               caring for varicose               veins       Cassia oil     Cinnamomum cassia     antibacterial               anticoagulant               antimycotic               antiviral               causing hyperemia       Cistus oil     Cistus     antibacterial               antihemorrhagic               antiviral       Eucalyptus oil     Eucalyptus     analgesic               antibacterial               antimycotic               antiinflammatory               antiviral       Fennel oil     Foeniculum     analgesic               dehydrating       Fir needle oil     Abies     antiinflammatory               causing hyperemia       Galbanum oil     Ferula     antiinflammatory               antiseptic               healing wounds       Geranium oil     Pelargonium graveolens     astringent               antibacterial               antimycotic               deblocking               caring for the skin               caring for varicose               veins               healing wounds       Geranium oil     Geranium macrorrhizum     antiseptic       “true geranium”       epithelizing       Clove oil     Eugenia caryophyllata     antibacterial               antimycotic               antiviral       Ho wood oil   Cinnamomum   antibacterial               antimycotic               antiviral       Immortelle oil     Helichrysum     analgesic       Everlasting oil       anticoagulant               epithelizing       Ginger oil     Zingiber     analgesic               causing hyperemia       Blue camomile     Matricaria camomilla     antiinflammatory       oil       healing wounds       Roman camomile     Anthemis nobilis     analgesic       oil       antiinflammatory       Wild camomile     Ormensis mixta     antibacterial       oil       antimycotic               healing wounds       Camphor oil   Cinnamomum   anesthetic               analgesic               antibacterial               antiinfective               antimycotic               antirheumatic               antiviral               diuretic               causing hyperemia               immunomodulating               rheumatic pain               spasmolytic       Pine oil     Pinus     antibacterial               causing hyperemia               protecting from               edema       Mountain pine     Pinus mugo     antiinflammatory       oil       immunomodulating       Lavender oil     Lavendula     analgesic               antibacterial               anticoagulant               antimycotic               antiinflammatory               epithelizing               alleviating itching       Spanish sage     Salvia     analgesic       oil       antiinfective               antispasmodic               tonic       Lemongrass oil     Cymbopogon     antibacterial               antiinflammatory               antiviral               vasodilative               immunomodulating       Laurel oil     Laurus     analgesic               antibacterial               anticoagulant               antispasmodic               mucolytic               protecting from               edema       Marjoram oil     Origanum     analgesic               antibacterial               antispasmodic               diuretic       Manuka oil     Leptospermum     antibacterial               antimycotic               antiinflammatory               antirheumatic               sedative               skin regenerating               alleviating itching       Melissa oil     Melissa     analgesic               antiviral               inhibiting               inflammation               immunomodulating               caring for varicose               veins       Myrrh oil     Commiphora     antibacterial               antiinflammatory               antiviral               epithelizing               skin regenerating       Niaouli oil     Melaleuca     analgesic               antiinfective               antimycotic               antiviral               immunomodulating               caring for varicose               veins       Oregano oil     Origanum     analgesic               antibacterial               antimycotic               antiviral               causing hyperemia               immunomodulating       Patchouli oil     Pogostemon     analgesic               antiinfective               antimycotic               antiinflammatory               diuretic               deblocking               epithelizing               immunomodulating       Petitgrain oil     Citrus aurantium     antiinfective               antiinflammatory               antispasmodic       Balsam Peru oil     Myroxylon     antibacterial               antiinflammatory               antispasmodic       Pepper oil     Piper     analgesic       (black)       antibacterial               antiviral               diuretic               causing hyperemia       Peppermint oil     Mentha     analgesic               anesthetizing               antibacterial               antimycotic               antiparasitic               antiviral               epithelizing               cooling               spasmolytic       Pimento oil     Pimenta     antibacterial               antimycotic               antiviral       Tansy oil     Tanacetum     analgesic               antiallergic               alleviating itching               caring for varicose               veins       Ravensara oil     Ravensara     antibacterial               antimycotic               antiviral       Rose oil     Rosa damaszena     antiinflammatory               antiviral               skin regenerating       Rosemary oil     Rosmarinus     analgesic           Chemotype “Moroccan”   diuretic           Cineol   fungicidal               causing hyperemia       Savin oil     Juniperus     analgesic               causing hyperemia       Sage oil     Salvia     antibacterial               antimycotic               antiviral       Sandalwood oil     Santalum     deblocking               epithelizing       Yarrow oil     Achillea     analgesic               antiinflammatory               epithelizing       Black cumin oil     Nigella     analgesic               antiallergic               antiinflammatory       Spike lavender     Lavendula spica     analgesic       oil       antiinfective               antiviral               fungicidal       Tagetes oil     Tagetes     antimycotic       Tea tree oil     Melaleuca     analgesic               antibacterial               antimycotic               antiparasitic               antiinflammatory               antiviral               epithelizing               immunomodulating               caring for varicose               veins       Texas cedar oil     Juniperus mexicana     deblocking               diuretic       Thuja oil     Thuja     antiinfective               antiviral               diuretic               epithelizing               healing wounds       Thyme oil     Thymus vulgaris     antibacterial           Chemotype Linalool and   antimycotic           Geraniol   antiviral             Thymus     antibacterial           Chemotype Thujanol   antiviral               immunomodulating             Thymus     analgesic           Chemotype Thymol and   antiinfective           Carvacrol   immunomodulating       Vetiver oil     Vetiveria     caring for the skin               causing hyperemia       Juniper oil     Juniperus     antibacterial               antirheumatic               diuretic       Frankincense     Boswellia     antiinflammatory       oil       epithelizing               immunomodulating       Silver fir oil     Abies     antiseptic               causing hyperemia       Wintergreen oil     Gaultheria     antiinflammatory               antispasmodic               alleviating pain               vasodilative       Hyssop oil     Hyssopus     antibacterial               antiviral             Hyssopus  var.   antiinflammatory             Decumbens     antiviral       Cinnamon oil     Cinnamomum verum     antibacterial               antimycotic               antiparasitic               antiviral               causing hyperemia               immunomodulating       Lemon oil     Citrus     astringent               antibacterial               anticoagulant               antiviral               caring for varicose               veins       Cypress oil     Cupressus     astringent               diuretic               deblocking               caring for varicose               veins                  
 
         [0050]     Preferably used medicinal substances and the active properties thereof are listed in table 3. These are subdivided into essential oils, plant extracts and synthetic single substances. The medicinal substances which can be used in the context of this invention are not, though, to be limited thereto.  
                                 TABLE 3                           Active properties of essential oils, plant extracts and       single substances isolated from these plant extracts                        Chemically/pharmaceutically                   active       Properties   Essential oils   Plant extracts   substances               Astringent   Geranium oil   Tannins, e.g.               Lemon oil   Quercus           Cypress oil   Extract from               Stipites               Dulcamarae               Hamamelis extract       Acne           Azelain                   Tretinoin                   Isotretinoin                   Adapalene                   Benzoyl peroxide       Analgesic   Basil oil   Rose of Sharon oil   Carboxylic acids,           Winter savory   Fructus Capsici   e.g.:           oil   (capsaicin)   Salicylic acid           Birch oil   Comfrey extract   Diflunisal           Fennel oil   Symphytum extract   Salicylamide           Fir needle oil   Harpagophytum   Ethenzamide           Ginger oil   Procumbens   Acetylsalicylic           Roman camomile   Willow bark   acid           oil   Guaiacwood   Salsalate           Camphor oil   Arnica extract   Acetic acid           Extra lavender       derivatives, e.g.:           oil       Indomethacin/           Spanish sage       Acemetacin,           oil       Proglumetacin           Laurel oil       Diclofenac           Marjoram oil       Tolmetin           Melissa oil       Lonazolac           Niaouli oil       Fenbufen           Oregano oil       Aceclofenac           Patchouli oil       Etofenamate           Pepper oil           Peppermint oil           Tansy oil           Rosemary oil           Savin oil           Yarrow oil           Spike lavender           oil           Tea tree oil           Thyme oil           Wintergreen           oil       Continuation:           Propionic acid       Analgesic           derivatives, e.g.:                   Ibuprofen                   Ketoprofen                   Flurbiprofen                   Tiaprofenic                   acid                   Fenoprofen                   Naproxen                   Dexketoprofen                   Dexibuprofen                   Heterocyclic                   ketoenol acids                   Oxicams:                   Piroxicam                   Tenoxicam                   Metoxicam                   Meloxicam                   Lornoxicam                   Anthranilic acid                   derivatives:                   Mefenamic acid                   Flufenamic acid                   Niflumic acid       Continuation:           Other derivatives:       Analgesic           Nabumetone                   Azapropazone                   Aceclofenac                   Caffeine                   Pyrazolidiones:                   Azapropazone                   Oxyphenbutazone                   Phenylbutazone/                   Mofebutazone                   Azapropazone                   Additional                   substance                   categories:                   Paracetamol                   Niflumic acid                   Bufexamac       Neuropathies           Pyrazolinones:       Neuropathic           Propylphenazone                   Metamizole                   Cox-2 inhibitors,                   e.g.                   Celecoxib                   Rofecoxib                   Valdecoxib                   Etoricoxib                   Parecoxib                   Vitamin B                   complex                   α-Lipoic acid                   L-Camithin                   Peripheral                   sympathetic                   blockers:                   Clonidine                   Homeopathic                   preparation       Anesthetizing   Camphor oil       Ester local           Peppermint oil       anesthetics           Thyme oil       Benzocaine                   Procaine (0)                   Tetracain (0)                   Thymol       Continuation:           Amide local       Anesthetizing           anesthetics                   Prilocaine                   Mepivacaine                   Lidocaine                   Etidocaine                   Bupivacaine                   Levobupivacaine                   Ropivacaine                   Articaine                   Fomocaine       Antiallergic   Black cumin       Glucocorticoids           oil       Antibacterial   Bay oil   Evening primrose   Urea       Antiinfective   Winter savory   oil   Thymol           oil   Neem oil   Chlorhexidine           Cajeput oil   Extracts from   Antibiotics:           Cassia oil   Stipites   Fusidic acid           Cistus oil   Dulcamarae   Mupirocin           Eucalyptus oil       Sulfadiazine           Geranium oil       Erythromycin           Clove oil       Clindamycin           Ho wood oil       Tetracycline           Camomile oil       Medocycline           Camphor oil           Pine oil           Garlic oil           Lavender oil       Tyrothricin           Extra lavender       Gentamycin           oil       Neomycin           Spanish sage       Bacitracin           oil       Chloramphenicol           Lemongrass oil       Polymyxin           Marjoram oil       Kanamycin           Manuka oil           Carnation oil           Niaouli oil           Oregano oil           Patchouli oil           Balsam Peru           oil           Petitgrain oil           Peppermint oil           Black pepper           oil           Pimento oil           Sage oil           Spike lavender           oil           Tea tree oil           Thuja oil           Thyme oil           Juniper oil           Hyssop oil           Cinnamon oil           Lemon oil       Anti-   Cistus oil   Hamamelis extract       hemorrhagic       Anti-   Black cumin       Glucocorticoids       histaminic   oil       Anti-       Sage   Camphoric acid       hyperhydrotic       Walnut leaves   Methenamine               Oak bark   Aluminum chlorate               Tannins, e.g. oak   hexahydrate               bark       Anticoagulant   Immortelle oil       Hirudin           Everlasting       Hirudin           oil       derivatives           Cinnamon oil       Heparins,           Lavender oil       in particular also           Laurel oil       low molecular           Lemon oil       weight       Antimycotic   Bay oil   Neem oil   Azole derivatives:           Pimento oil   Extracts from   Clotrimazole           Winter savory   Stipites   Bifonazole           oil   Dulcamarae   Econazole           Cassia oil       Fenticonazole           Eucalyptus oil       Isoconazole           Geranium oil       Oxiconazole           Clove oil       Sertaconazole           Ho wood oil       Tioconazole           Camphor oil       Miconazole           Cinnamon oil       Ketoconazole           Lavender oil       Itraconazole           Extra lavender       Fluconazole           oil       Voriconazole           Manuka oil       Sertaconazole           Carnation oil           Niaouli oil           Oregano oil           Patchouli oil           Peppermint oil       Continuation:   Pimento oil       Squalene epoxidase       Antimycotic   Rosemary oil       inhibitors, e.g:           Sage oil       Terbinafin           Spike lavender       Naftifin           oil       Morpholines, e.g.:           Tagetes oil       Amorolfin           Tea tree oil       Other antimycotically           Thyme oil       effective                   substances, e.g.:                   Amphotericin B                   Griseofulvin                   Flucytosin                   Ciclopirox                   Nystatin                   Natamycin                   Thiocarbonates       Combating   Valerian oil   Aesculus       edema   Basil oil   hippocastanum       Diuretic   Fennel oil   Ruscus aculeatus       Deblocking   Geranium oil   Melilotus       Dehydrating   Camphor oil   officinalis       Protecting   Pine oil   Fagopyrum       from edema   Laurel oil   esculentum           Marjoram oil   Red vine leaf           Patchouli oil   extract           Pepper oil   Solidago virgaurea           Rosemary oil   Stinging nettle           Sandalwood oil           Black cumin           oil           Texas cedar           oil           Thuja oil           Juniper oil           Cypress oil       Antioxidant       Flavonoids   Selenium               Anthocyans   Manganese               Proanthoxy-   Copper               cyanidines   L-Glutathione               Carotenoids   L-Cysteine               β-carotene:   Coenzyme Q 10                 Lycopene   α-Lipoic acid               Zeaxanthin               Vitamin A, C and E       Antiparasitic   Peppermint oil   Neem oil   Crotamiton           Cinnamon oil       Permethrin           Tea tree oil       Benzyl benzoate                   Allethrin       Antiinflammatory   Basil oil   Melilotus   Steroidal antiinflammatories,           Benzoin resin   officinalis   such as           Birch oil   Ruscus aculeatus   glucocorticoids           Camphor oil   Aesculus   Bufexamac           Eucalyptus oil   hippocastanum   Glycyrrhetinic           Fir needle oil   Rose of Sharon oil   acid           Galbanum oil   Marigold   Thymol           Rose of Sharon   Aloe vera   Cavacrol           oil   Jojoba   Camphor           Blue camomile   Evening primrose   Eugenol           oil   oil   Cinnamaldehyde           Roman camomile   Borage oil   Capsaicin           oil   Cardiospermum           Mountain pine   halicacabum           oil   Tannins, e.g. from           Lavender oil   Quercus and           Extra lavender   Synthetica           oil           Lemongrass oil       Continuation:   Manuka oil   Extracts from       Antiinflammatory   Myrrh oil   Stipites           Carnation oil   Dulcamarae           Patchouli oil   Symphytum extracts           Petitgrain oil   Hamamelis extract           Balsam Peru   Camomile           oil   Arnica oil           Rosemary oil   Propolis           Yarrow oil           Black cumin           oil           Ledum palustre           oil           Tea tree oil           Thyme oil           Frankincense           oil           Wintergreen           oil           Hyssop oil           Cinnamon oil       Antirheumatic   Birch oil   Fructus Capsici   See list           Camphor oil   Capsaicin   analgesically           Manuka oil   Nicotinic acid   chemically/           Rosemary oil   Salicylate   pharmaceutically           Juniper oil   Cortex Salicis   effective           Wintergreen   Urtica dioica   substances           oil   Urtica urens   Salicin           Cinnamon oil       Antiseptic   Benzoin resin           Bergamot oil           Winter savory           oil           Galbanum oil           Geranium oil           Camphor oil           Silver fir oil       Antispasmodic   Basil oil           Birch oil           Spanish sage           oil           Laurel oil           Marjoram oil           Balsam Peru           oil           Petitgrain oil           Wintergreen           oil       Antiviral   Basil oil   Extractum   Aciclovir/           Bay oil   podophyllum   Valciclovir           Pimento oil   (podophyllin)   Penciclovir/           Cajeput oil   Extractum Melissae   Famciclovir           Cassia oil   Fructus Capsici   Idoxuridine/           Cistus oil   Capsaicin   Bivudine           Eucalyptus oil       Trifluridine           Clove oil       Vidarabine           Ho wood oil       Tromantadine           Camphor oil       Foscarnet           Cinnamon oil       Interferon-β           Lemongrass oil       Podophyllotoxin           Melissa oil           Myrrh oil           Niaouli oil           Oregano oil           Pepper oil           Peppermint oil           Pimento oil           Sage oil           Spike lavender           oil           Tea tree oil           Thuja oil           Thyme oil           Hyssop oil           Lemon oil       Regenerating       Allium cepa   Heparin       connective       Centella asiatica   Asiaticoside       tissue       Erectile           Alprostadil       dysfunction           (PGE 1)                   Sildenafil citrate                   Vardenafil                   Tadalafil                   Favoring the blood                   flow, such as                   benzyl nicotinate       Epithelizing   Bergamot oil           Geranium oil           Immortelle oil           Everlasting           oil           Lavender oil           Extra lavender           oil           Myrrh oil           Patchouli oil           Peppermint oil           Sandalwood oil           Yarrow oil           Tea tree oil           Thuja oil           Frankincense           oil       Binding of       Avocado oil   Urea       moisture       Dog rose   Glycerol               Aloe vera   Glycine       Vasodilative   Lemongrass oil       Nitro preparations       Hair loss           Finasteride                   Minoxidil       Nourishing   Angelica oil   Dog rose   Amino acids       the skin   Valerian oil   Almond oil   Vitamins       Caring for   Benzoin resin   Wheat germ oil       the skin   Bergamot oil   Avocado oil       Regenerating   Geranium oil   Aloe vera       the skin   Manuka oil   Borage oil           Myrrh oil   Jojoba oil           Vetiver oil   Almond oil               Shea butter               Dog rose       Cardiotonic       Arnica flowers               Hawthorn extract       Causing   Cassia oil   Arnica oil   Nicotine       hyperemia   Birch oil   Peanut oil   salicylate       Favoring the   Ginger oil   Olive oil   Capsaicin       blood flow   Camphor oil       Capsaicinoids           Pine oil       Caffeine           Oregano oil       Benzyl nicotinate           Black pepper       Nonivamide           oil       Nicobexil           Rosemary oil       Methyl salicylate           Savin oil           Vetiver oil           Eucalyptus oil           Turpentine oil           Camphor           Silver fir oil           Cinnamon oil       Immunomodulating   Camphor oil   Extracts from           Cinnamon oil   Stipites           Lemongrass oil   Dulcamarae           Melissa oil   Viola tricolor           Niaouli oil   Similax species           Oregano oil   Phytolacca           Patchouli oil   americana           Tea tree oil   Glycyrrhiza glabra           Thyme oil   Mistletoe extract           Frankincense   Bryonia alba           oil   Echinacea extract       Alleviating   Lavender oil   Melilotus   Bufexamac       itching   Manuka oil   officinalis   Synthetic tannins               Ruscus amleatus   Glycyrrhetinic               Fructus Capsici   acid               Capsicum               (capsaicin)               Borage oil               Avocado oil               Evening primrose               oil               Dog rose oil               Tannins, e.g. from               Quercus               Hamamelis extract       Keratolytic       Mahonia aquifolium   Vitamin A acid       Antipsoriatic           Urea                   Salicylic acid                   Tazarotene       Cooling   Peppermint oil       Menthol       Antimitotic           Colchicine                   Colchicine                   derivatives       Muscle           Peripheral, e.g.:       relaxant           Stabilizing:                   Tubocurarine                   chloride                   Alcuronium                   chloride       Continuation:           Preventing       Muscle           depolarization:       relaxant           Pancuronium                   bromide                   Vecuronium                   bromide                   Atracurium                   besylate                   Mivacurium                   chloride                   Rocuronium                   bromide                   Cisatracurium                   besylate                   Repolarizing,                   e.g.:                   Suxamethonium                   chloride                   Reduction of                   elevated skeletal                   muscle tone:                   Dentrols                   Irreversible                   inhibition of                   neuromuscular                   transmission:                   Clostridium                   Botulinum                   Botulin and                   derivatives                   Cotylinum (botox)                   Sodium channel                   inhibitors, such                   as tolperisone                   Local anesthetics                   Quinine sulfate       Caring for   Basil oil   Hamamelis extracts   Spartine sulfate       varicose   Cajeput oil   Ruscus aculeatus   Digitoxin       veins   Geranium oil   Melilotus albus   Heparin           Melissa oil   Red vine leaf   Ergot alkaloids,           Niaouli oil   Aesculus   in particular           Tansy oil   hypocastanum   dihydroergotamine           Tea tree oil   Melilotus   Diosmin           Lemon oil   officinalis   Flavonoid           Cypress oil   Centella extract   derivatives               Fagopyrum               esculentum               Pinus maritima       Scale-   Borage oil       inhibiting   Evening           primrose oil       Sedating       Extractum               Valerianae               Melissa oil       Spasmolytic   Peppermint oil           Camphor oil           Fir needle oil       Vasodilative   Birch oil   Hawthorn extract   Nitroglycerin           Wintergreen       Benzyl nicotinate           oil       Healing   Bergamot oil   Dog rose       wounds   Galbanum oil   Shea butter       Antitraumatic   Geranium oil   Olive oil           Rose of Sharon   Evening primrose           oil   oil           Camomile oil   Arnica oil           Thuja oil   Avocado oil               Aloe vera               Jojoba oil               Calendula oil               Camomile oil               Hamamelis extract               Hypericum oil               Tannins               Calendula extract               Symphytum extract               Hypericum extract                  
 
         [0051]     By dissolution or dispersion of the abovementioned base materials, essential oils, plant extracts and/or synthetic single substances in a microemulsion, it is possible, inter alia, to formulate the following medicaments:  
         [0052]     Medicaments for the treatment of external rheumatic pain which exhibit medicinal substances with an analgesic, antiinflammatory, hyperemia-causing and/or spasmolytic effect.  
         [0053]     Medicaments for the treatment of complex peripheral pain syndrome which exhibit medicinal substances with an analgesic, antioxidant, antiinflammatory, spasmolytic, muscle-relaxing, hyperemia-causing and/or local anesthetic effect.  
         [0054]     Medicaments for the treatment of wounds, contusions, strains, sports injuries and edemas which exhibit medicinal substances with a wound-healing, analgesic, thrombolytic, fibrinolytic, epithelizing, anti-coagulant, antiinflammatory, antibacterial, antiviral, antimycotic, diuretic, skin-nourishing and/or antitraumatic effect.  
         [0055]     Medicaments for the treatment of chronic wounds which exhibit medicinal substances with an antioxidant, analgesic, antiinflammatory and/or healing effect.  
         [0056]     Medicaments for the treatment of hair loss. Medicaments for the treatment of erectile dysfunction. Medicaments for the treatment of excess secretion of sweat.  
         [0057]     Medicaments for the treatment of neuralgia which exhibit medicinal substances with an analgesic and/or local anesthetic effect.  
         [0058]     Medicaments for the treatment of diabetic neuropathy which exhibit medicinal substances with an analgesic, hyperemia-causing, alleviating of itching and/or alleviating of burning effect.  
         [0059]     Medicaments for the treatment of varicosis or phlebitis which exhibit medicinal substances with a caring for varicose veins, protecting from edema, alleviating of itching, anticoagulant, fibrinolytic, antispasmodic, diuretic, deblocking, antioxidant and/or hemolytic effect.  
         [0060]     Medicaments for the treatment of hemorrhoids which exhibit medicinal substances with a caring for varicose veins, diuretic and/or epithelizing effect.  
         [0061]     Medicaments for the treatment of acute attacks of gout which exhibit medicinal substances with an antimitotic, antiinflammatory, antioxidant and/or diuretic effect.  
         [0062]     Medicaments for the treatment of mycosis which exhibit medicinal substances with an antimycotic effect.  
         [0063]     Medicaments for the treatment of neurodermatitis and/or eczema which exhibit medicinal substances with an anti-inflammatory, alleviating of itching, immunomodulating, skin-regenerating, antioxidant, astringent and/or antiallergic effect.  
         [0064]     Medicaments for the treatment of keratosis which exhibit medicinal substances with a keratolytic effect.  
         [0065]     Medicaments for the treatment of psoriasis which exhibit medicinal substances with a keratolytic, antiinflammatory, alleviating of itching, skin-regenerating and/or antioxidant effect.  
         [0066]     Medicaments for the treatment of acne which exhibit medicinal substances with a keratolytic, antibacterial, antiinflammatory, antioxidant and/or wound-healing effect.  
         [0067]     Medicaments for the treatment of viral infections which exhibit medicinal substances with an antiviral, analgesic, antiinflammatory, keratolytic and/or antioxidant effect.  
         [0068]     Medicaments for the treatment of hematomas which exhibit medicinal substances with a fibrinolytic effect.  
         [0069]     Medicaments for the treatment of rosacea which exhibit medicinal substances with an antiinflammatory and/or antioxidant effect.  
         [0070]     Medicaments for the treatment of scabies which exhibit medicinal substances with an antiparasitic and/or alleviating of itching effect.  
         [0071]     Medicaments for the treatment of degenerated skin which exhibit medicinal substances with an antiinflammatory, antimicrobial, nourishing and/or local anesthetic effect.  
         [0072]     Medicaments for the treatment of angina pectoris or chest pains which exhibit medicinal substances with a hyperemia-causing and/or spasmolytic effect and medicinal substances which interrupt pain stimuli.  
         [0073]     Medicaments for the treatment of pruritus which exhibit medicinal substances with a cooling, local anesthetizing, analgesic, antiinflammatory and/or astringent effect.  
         [0074]     Medicaments for the treatment of scars and keloids which exhibit medicinal substances which regulate connective tissue.  
         [0075]     In a particularly preferred embodiment, several medicaments based on the same microemulsions can be combined to give combination preparations.  
         [0076]     The concentration of the medicinal substances in the microemulsions results from the recommended guidelines of the therapy and the amount of microemulsion which can be handled in practice.  
         [0077]     In concrete terms, the concentration of the medicinal substance in the microemulsion can be between 0 and 100%, concentrations between 10 −8 % and 50% being preferred and concentrations between 10 −6  and 5% being particularly preferred.  
         [0078]     Medicaments according to the invention for percutaneous administration are obtained by enriching, with oxygen, these and other medicaments based on microemulsions.  
         [0079]     This enriching can take place in the preparation of the medicinal substances.  
         [0080]     The term “microemulsions enriched with oxygen” is understood to mean microemulsions which are enriched with oxygen in a suitable processing stage. Such a processing stage is represented, for example, by the atomization of the microemulsion in an oxygen-comprising atmosphere. In this connection, the oxygen content of this atmosphere is preferably greater than 25 percent by volume, particularly preferably greater than 50 percent by volume and in particular greater than 90 percent by volume.  
         [0081]     Preferably, the microemulsion enriched with oxygen exhibits an oxygen concentration of greater than 10 −3  mol/l, in particular of greater than 5×10 −3  mol/l.  
         [0082]     In order to prevent microemulsions enriched with oxygen in the preparation from re-releasing the oxygen up to the time of application, these microemulsions are preferably packaged in gastight containers.  
         [0083]     In addition, other additives to these medicaments, and to other medicaments based on microemulsions, which improve the oxygen supply of the skin, result in medicaments according to the invention.  
         [0084]     Examples of additives which improve the oxygen supply of the skin are natural oxygen carriers, such as myoglobin and/or hemoglobin, and also fluorocarbons.  
         [0085]     An enriching of the microemulsion with oxygen can also be carried out directly in the administration of the microemulsion with the help of an application system for the percutaneous administration of medicinal substances exhibiting at least one microemulsion comprising medicinal substance and a device for the atomization of the microemulsion. In this connection, enriching with oxygen directly in the administration is preferred.  
         [0086]     In such a system according to the invention, the microemulsion is preferably present in a container which is connected to an atomizing unit, a gas source under pressure being connected to the atomizing unit, and the microemulsion is atomized through the action of the pressurized gas.  
         [0087]     It is likewise possible to at times abolish the barrier function of the stratum corneum by application of a microemulsion according to the invention without medicinal substances which is enriched with oxygen and/or which exhibits an additive which improves the oxygen supply of the skin. This also succeeds by application of a suitable microemulsion without medicinal substances, for example with an application system according to the invention. The medicinal substances to be administered are then applied to the relevant part of the skin in an additional stage.  
         [0088]     On employing the system according to the invention, an oxygen-comprising propellant gas being used, the microemulsions which are applied are enriched with oxygen directly before the entry thereof into the stratum corneum. This results in an increase in the oxygen partial pressure on the tissue side of the stratum corneum and accordingly in stimulation of the cutaneous microcirculation and in improved transdermal transport of the medicinal substances. Likewise, the transdermal transport of medicinal substances can, for example, also be partly caused by an increased transmembrane pressure, here caused by the increase in the oxygen concentration on the tissue side of the stratum corneum.  
         [0089]     The use of this system is particularly suitable with medicaments which exhibit substances sensitive to oxidation and which accordingly can be enriched with oxygen only directly before application.  
         [0090]     It is possible, with an application system according to the invention, to accurately dose the dose of medicinal substance which is to be applied, through which the maximum daily dose can then also be applied. For that, a microemulsion which exhibits the maximum daily dose of one or more medicinal substances is sent into the system for the percutaneous administration of medicinal substances and is administered with this system to a patient.  
         [0091]     An additional effect of the atomizing, which can contribute to improved transdermal transport of medicaments, is the spreading effect. This is based on the fine distribution of the droplets in the atomization. As a result, the microemulsion in the form of small droplets is more effective in falling into depressions, folds and openings in the skin.  
         [0092]     The abovementioned medicaments based on microemulsions form preferred embodiments of a system for the percutaneous administration of medicinal substances in the context of this invention.  
         [0093]     The application system according to the invention for the atomizing of liquid medicaments for the percutaneous administration of medicaments is explained more fully subsequently.  
         [0094]     The implementation of the application system takes place according to the invention with the characteristics given in the patent claims.  
         [0095]     In the application system according to the invention for the atomizing of liquid medicaments for the percutaneous administration of medicaments, a precisely dosed liquid medicament, in particular a microemulsion comprising the medicinal substance, for application to the skin by means of a propellant gas, preferably highly concentrated oxygen, is squeezed under pressure through a microdosing nozzle and is as finely atomized as possible, preferably through use of a suction action established through the Venturi effect.  
         [0096]     A spectrum of droplet sizes can be generated with the microdosing nozzle of the application system, the outlet cross section of the microdosing nozzle being varied by a positionable needle point and accordingly it being possible to change the droplet size. The diameter of the droplets which can be obtained by the atomizing lies in the nanometer range, the mean droplet size measured being less than 1 μm, preferably less than 400 nm, in particular less than 300 nm. The reproducibility of the spectrum of droplet sizes with the application system can be demonstrated by noncontact measuring methods using laser optics.  
         [0097]     From the multitude of the different droplets of an atomization liquid, the individual droplet sizes and the frequency thereof can be determined using laser diffraction spectroscopy. In this connection, the monochromatic light of a laser beam is diffracted more or less strongly by the individual droplets of an atomization liquid, the photomultipliers located on a detector registering different signals and intensities. In line electronics with specific software evaluate these and calculate from this the actual droplet size distribution.  
         [0098]     All liquid medicaments prepared and to be atomized, preferably medicaments based on microemulsions, with particular Theological properties, such as, e.g., viscosity, liquid density, surface tension but in particular below a certain dynamic viscosity, can be sprayed onto the site of the skin to be treated using the application system according to the invention.  
         [0099]     Apart from highly concentrated oxygen, air, nitrogen or a noble gas (helium, argon) can alternatively be used as propellant gas. In this connection, the term “highly concentrated oxygen” is understood to mean a gas which is enriched with at least 90% by volume of oxygen. If propellant gases are used which comprise no oxygen, the microemulsion is already enriched with oxygen and/or comprises additives which improve the oxygen supply of the skin.  
         [0100]     In the atomizing, the medicament prepared is surrounded by propellant gas and mixed with this. In this connection, the propellant gas dissolves in the liquid medicament under pressure, through which a positive property of the liquid active substance stimulating the skin in connection with oxygen can be produced.  
         [0101]     A positive effect of the extremely fine atomizing is the pleasantly cooling action, because of the cold due to evaporation, of the finely atomized medicament in the percutaneous administration of medicaments.  
         [0102]     Because of the reactivity of the highly concentrated oxygen, materials which withstand oxygen are to be used for the individual components of the application system, such as, e.g., glass, special hospital-grade plastics or high-grade steel.  
         [0103]     In the atomizing of the microemulsion, it is advantageous to achieve, depending on the daily dose and body part to be treated, a volumetric flow rate of 1.5 to 5 ml/20 min or 4.5 to 15 ml/h through the outlet cross section of the microdosing nozzle.  
         [0104]     The propellant gas can be withdrawn from a gas container and can be conveyed to the application system via a hose connection. The gas container itself can be a constituent of an oxygen preparation plant (O 2  plant), in which oxygen is obtained from ambient air and is enriched in this.  
         [0105]     Alternatively, in an additional embodiment of application system and gas source, a self-sufficient gas container or a gas connection is also conceivable in a clinic.  
         [0106]     In a preferred embodiment of the invention, the application system is in the form of a self-sufficient system filled with liquid medicament and connected to a propellant gas system.  
         [0107]     The application system according to the invention for the percutaneous administration of medicinal substances, in particular of liquid medicaments based on microemulsions, is more fully explained below with reference to  FIGS. 1, 2  and  3 . 
     
    
       [0108]      FIG. 1  shows a diagrammatic representation of an application system,  
         [0109]      FIG. 2  shows an enlarged diagrammatic representation of the region of the application system according to  FIG. 1  in the vicinity of the nozzle and the operating principle thereof, and  
         [0110]      FIG. 3  shows a diagrammatic representation of an additional application system,  
         [0111]      FIG. 4  shows a diagrammatic representation of an additional application system. 
     
    
       [0112]      FIG. 1  shows an application system  10  in simplified diagrammatic representation of the individual components. The application system comprises a medicament reservoir  12  which is arranged in a gas reservoir  16  of the application system  10 . The medicament reservoir  12  is tapered at its end in the region  40  of the application system  10  in the vicinity of the nozzle to give a capillary. Depending on the daily dose to be administered, between 1.5 and 5 ml of a medicament  14  are located in the medicament reservoir  12 . The upper end of the medicament reservoir  12  and the gas reservoir  16  of the application system  10  are in the normal position seen to be coaxially formed and are connected to one another via a bypass line  26  or an equalizing pipe  26 . An inlet  18  for filling the medicament reservoir  12  with a medicament  14  and an inlet  20  for filling the gas reservoir  16  with a propellant gas are likewise located at the upper end. The gas reservoir  16  of the application system  10  is connected via a hose connection  22  to a gas container  24 . In the region  40  in the vicinity of the nozzle, the application system  10  has the form of a solid of rotation with a cross section tapering in the direction of the nozzle outlet  50 . The medicinal substance reservoir  12  connects with its tapered end to the atomizing nozzle  30 , which is arranged inside the nozzle head  28 . The nozzle head  28  exhibits, along its axis of rotation, openings  29  via which the gas reservoir  16  is connected flow wise with the surroundings. A needle  32  carried in the upper part of the gas reservoir  16  projects into the atomizing nozzle  30  and narrows the annular cross section thereof. The needle can be vertically positioned by turning a knurled head  34  and the narrowing of the cross section of the atomizing nozzle  30  can thereby be adjusted.  
         [0113]     The manner of operation of the application system  10  represented in  FIG. 1  for the atomizing of a prepared medicament for the percutaneous administration of medicaments is more fully described below.  
         [0114]     Depending on the size of the area of the body part to be treated, the medicament reservoir  12  is filled, via the medicament reservoir inlet  18  of the application system  10 , with a precisely dosed liquid medicament  14 , in particular a liquid medicament based on a microemulsion, preferably from 1.5 to 5 ml.  
         [0115]     For the atomizing of the liquid medicament  14 , the gas reservoir  16  is continuously filled with propellant gas, preferably oxygen, through which an excess pressure builds up in the closed gas reservoir  16 . The propellant gas is withdrawn from the gas container  24  and conveyed to the application system  10  under a predetermined pressure, in the example approximately 2 bar. For this, the gas reservoir  16  is connected via a hose connection  22  to a gas connection  20  of the application system  10 .  
         [0116]     The propellant gas is transported, by the excess pressure in the gas reservoir  16 , up to the outlet  50  of the atomizing nozzle  30  (microdosing nozzle). Since the gas reservoir  16  of the application system  10  in the region  40  in the vicinity of the nozzle has the form of a solid of rotation with a cross section tapering in the direction of the nozzle outlet  40 , the propellant gas is accelerated by the excess pressure in the gas reservoir  16  in the flow direction. The dynamic pressure appearing inside the gas reservoir  16  as a result of the narrowing in the cross section is diverted via a bypass line  26  to bring about the advance of the liquid medicament  14  in the medicament reservoir  12 , the dynamic pressure squeezing the liquid medicament through the atomizing nozzle  30 . A uniform advance is provided by this.  
         [0117]     The end of the medicament reservoir tapering in the region  40  in the vicinity of the nozzle inside the gas reservoir  16  is shaped in such a way that the liquid medicament is prevented from breaking off.  
         [0118]     The openings  29  inside the nozzle head  28  guarantee that the propellant gas accelerated in the direction of the tapering solid of rotation  16  flows around the atomizing nozzle  30  up to the outlet  50  of the nozzle head  28 .  
         [0119]     Having arrived at the outlet  50  of the atomizing nozzle  30 , the liquid medicament is sucked in by the negative pressure appearing in the outlet (Venturi effect) and is at the same time atomized.  
         [0120]     In the atomizing, the prepared medicament  14  is surrounded by the propellant gas and is mixed with this. In this connection, the propellant gas dissolves in the liquid medicament  14 . This results in a strengthened effect of the liquid medicament  14  on the microcirculation, in particular in a liquid medicament based on microemulsions, which can result in percutaneous administration of medicinal substance. The droplet size diameter in the atomizing of the liquid medicament  14  can be varied via the needle  32  inside the atomizing nozzle  30 , by finely positioning the needle  32  by turning the knurled head  38 . If the atomizing nozzle  30  is completely closed by the needle  32 , SO that the mass flow of the liquid medicament  14  through the atomizing nozzle  30  is prevented, the atomizing of the medicament comes to a standstill. Then simply propellant gas flows through the outlet  60  of the nozzle head  28 , because of the openings  29  arranged inside the nozzle head  28  along the atomizing nozzle  30 .  
         [0121]     On the other hand, in an additional embodiment not represented, a nozzle with a predetermined internal diameter without an adjusting needle can be used if through this the desired droplet profile is already achieved.  
         [0122]      FIG. 2  shows the operating principle of the atomizing represented diagrammatically in simplified form in  FIG. 1 , the region  40  of the application system  10  in the vicinity of the nozzle being represented for clarification on an enlarged scale. In this connection, the arrows indicate the direction of flow of the gas.  
         [0123]      FIG. 3  shows an additional exemplary embodiment of an application system  70  in cross section. The application system  70  comprises a medicament reservoir  12  which is surrounded by a gas reservoir  16  of the application system  70 . The medicament reservoir  12  is, at its end in the region of the application system  70  in the vicinity of the nozzle, shaped or tapered to give a capillary. Depending on the daily dose to be administered, between 1.5 and 5 ml of a medicament  14  are located in the medicament reservoir  12 . The medicament reservoir  12  and the gas reservoir  16  of the application system  70  are formed coaxially and are connected to one another via a bypass line  26 . A medicament reservoir inlet  18 , for filling with a medicament  14 , and a gas reservoir inlet  20 , for filling the gas reservoir  16  with propellant gas, are located on the upper end of the application system  70 . Both inlets can be closed by caps, not shown.  
         [0124]     The medicament reservoir inlet  18  is shaped in such a way that the liquid medicament  14  can in no case reach the bypass  26  and accordingly run out from the application system  70 . In order to prevent this, the bypass end  27  was shaped in such a way that it projects far into the inlet line of the medicament reservoir  12 .  
         [0125]     The gas reservoir  16  of the application system  70  is connected via a hose connection  22  to a gas container  24 . In the region in the vicinity of the nozzle, the application system  70  has the form of a solid of rotation with a cross section tapering in the direction of the nozzle outlet  50 . The medicinal substance reservoir  12  connects with its tapered end to the atomizing nozzle  30 , which is arranged inside the nozzle head  28 . The nozzle head  28  exhibits, along its axis of rotation, recesses  29  so that the gas reservoir  16  is connected flow wise with the surroundings. A needle  32  carried in the upper part of the application system projects into the atomizing nozzle  30  and narrows the annular cross section thereof. The needle  32  can be positioned vertically by turning the adjustable screw (knurled screw) arranged in the knurled head  34  and through this the narrowing in cross section of the atomizing nozzle  30  can be adjusted.  
         [0126]     The manner of operation of an additional application system  70 , represented in  FIG. 3 , for the atomizing of a prepared medicament for the percutaneous administration of medicaments is described more fully below.  
         [0127]     Depending on the size of the area of the part of the body to be treated, the medicament reservoir  12  is filled, via the medicament reservoir inlet  18  of the application system  70 , with a precisely dosed medicinal substance  14 , in particular in a microemulsion, preferably from 1.5 to 5 ml.  
         [0128]     For the atomizing of the liquid medicament  14 , the gas reservoir  16  is continuously filled with propellant gas, preferably oxygen, through which an excess pressure builds up in the gas reservoir  16 . The propellant gas is withdrawn from a gas container  24  and conveyed to the application system  70  under a predetermined pressure. For this, the gas reservoir  16  is connected via a hose connection  22  to a gas connection  20  of the application system  70 .  
         [0129]     The propellant gas is transported, by the excess pressure in the gas reservoir  16 , up to the outlet  50  of the atomizing nozzle  30  (microdosing nozzle). Since the gas reservoir  16  of the application system  70  in the region  40  in the vicinity of the nozzle has the form of a solid of rotation with a cross section tapering in the direction of the nozzle outlet  40 , the propellant gas is accelerated by the excess pressure in the gas reservoir  16  in the flow direction. The dynamic pressure appearing inside the gas reservoir  16  as a result of the narrowing in the cross section is diverted via a bypass line  26  to bring about the advance of the liquid medicament  14  in the medicament reservoir  12 , the dynamic pressure squeezing the liquid medicament through the atomizing nozzle  30 . A uniform advance is provided by this.  
         [0130]     The end of the medicament reservoir  12  inside the gas reservoir  16 , which end is shaped in the region in the vicinity of the nozzle as an internal capillary, is shaped in such a way that the liquid stream  14  is prevented from breaking off.  
         [0131]     The recesses  29  inside the nozzle head  28  guarantee that the propellant gas accelerated in the direction of the tapering solid of rotation  16  flows around the atomizing nozzle  30  up to the outlet  50  of the nozzle head  28 .  
         [0132]     Having arrived at the outlet  50  of the atomizing nozzle  30 , the liquid medicament is sucked in by the negative pressure appearing in the outlet (Venturi effect) and is at the same time atomized.  
         [0133]     The droplet size diameter in the atomizing of the liquid medicament  14  can be varied via the needle  32  inside the atomizing nozzle  30 , by finely positioning the needle  32  by turning the knurled screw  36  arranged in the knurled head  38 . If the atomizing nozzle  30  is completely closed by the needle  32 , so that the mass flow of the liquid medicament  14  through the atomizing nozzle  30  is prevented, the atomizing of the medicament comes to a standstill. Then simply propellant gas flows through the outlet  60  of the nozzle head  28 , because of the recesses  29  arranged inside the nozzle head  28  along the atomizing nozzle  30 .  
         [0134]     The conicity of the needle  32  is more strongly developed in comparison with the conicity of the atomizing nozzle  30  for the purposes of a broader atomizing or a broader atomizing angle.  
         [0135]     A broader atomizing angle can furthermore be pursued by the incorporation in the nozzle head  28  of a helix-producing means.  
         [0136]     According to an additional embodiment—shown in  FIG. 4 —the medicament reservoir is combined on its upper side directly with the gas source and accordingly has an additional inlet. In this connection, the Venturi formation of the nozzle can be dispensed with if this appears advisable. If, however, Venturi atomizing nozzle is used, a gas supply arrangement corresponding to  FIG. 2  is provided on the outside of the nozzle. A gas reservoir can thus be dispensed with except for the region of the nozzle, if only a gas supply in the region of the nozzle is provided, as is represented in  FIG. 4 .  
         [0137]     Microemulsions and the preparation thereof are described below from examples, which microemulsions can in the context of this invention be enriched with oxygen, for example in the administration in the application system according to the invention. These examples are not to have a limiting effect.  
       EXAMPLE 1  
     Manufacture of a Water-In-Oil Micro-Emulsion (I)  
       [0138]     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. 5 g of water are added dropwise to this mixture with stirring. This gives 100 g of a water-in-oil microemulsion (I).  
       EXAMPLE 2  
     Manufacture of a Water-In-Oil Micro-Emulsion (II)  
       [0139]     14 g of Span® 20 are mixed with 21 g of Synperonic® PEL 101. 60 g of isopropyl palmitate are added thereto. 5 g of water are added dropwise to this mixture with stirring. This gives 100 g of a water-in-oil microemulsion (II).  
       EXAMPLE 3  
     Manufacture of an Oil-In-Water Micro-Emulsion (III)  
       [0140]     4 g of Tween® 80 are mixed with 12 g of Synperonic® PEL 101. 5 g of isopropyl myristate are added thereto. 79 g of a water/polypropylene glycol (1:2) (weight ratio) mixture are added to this mixture with stirring. This gives 100 g of an oil-in-water microemulsion (III).  
       EXAMPLE 4  
     Preparation of a Medicament with the Medicinal Substance Procaine, for the Local Combating of Pain, Based on an Oil-In-Water Microemulsion  
       [0141]     2 g of procaine chloride are dissolved in 5 ml of water. The solution is added to 93 g of the microemulsion III with stirring. This gives 100 g of the medicament.  
       EXAMPLE 5  
     Preparation of an Additional Medicament with the Medicinal Substance Procaine, for the Local Combating of Pain, Based on a Water-In-Oil Micro-Emulsion  
       [0142]     2 g of procaine chloride are dissolved in 5 g of 0.01M NaOH. The solution is added dropwise with stirring to 93 g of the microemulsion I. This gives 100 g of the medicament.  
       EXAMPLE 6  
     Preparation of a Medicament with the Medicinal Substance Lidocaine, for the Local Combating of Pain, Based on a Water-in-Oil Microemulsion  
       [0143]     2 g of lidocaine are dissolved in 98 ml of the microemulsion II. This gives 100 g of the medicament.  
       EXAMPLE 7  
     Preparation of a Medicament with the Medicinal Substance Diclofenac, for the Local Combating of Painful Inflammation, Based on a Water-In-Oil Microemulsion  
       [0144]     2 g of lidocaine, 2 g of diclofenac and 0.05 g of capsaicin are successively dissolved in 95.95 g of the microemulsion (II). This gives 100 g of the medicament.