WO1998006409A2 - Composition containing vitamin a and its use, in particular against skin diseases - Google Patents

Composition containing vitamin a and its use, in particular against skin diseases Download PDF

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Publication number
WO1998006409A2
WO1998006409A2 PCT/EP1997/004446 EP9704446W WO9806409A2 WO 1998006409 A2 WO1998006409 A2 WO 1998006409A2 EP 9704446 W EP9704446 W EP 9704446W WO 9806409 A2 WO9806409 A2 WO 9806409A2
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Prior art keywords
composition according
vitamin
polyanion
skin
polysulfate
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PCT/EP1997/004446
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German (de)
French (fr)
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WO1998006409A3 (en
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Albert Landsberger
Malte Landsberger
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Albert Landsberger
Malte Landsberger
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Publication of WO1998006409A2 publication Critical patent/WO1998006409A2/en
Publication of WO1998006409A3 publication Critical patent/WO1998006409A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof

Definitions

  • composition containing vitamin A and its use in particular against skin diseases Composition containing vitamin A and its use in particular against skin diseases
  • the invention relates to a new vitamin A-containing composition and its use.
  • Triggers can be pathogens, such as b eispielnger bacteria, fungi, viruses; Foreign matter, b eispielmud care and drug or Irritation and G iftscher such as insecticides.
  • Be orld Behan d skin diseases both systemic (oral) as well as locally, in particular with Sub b ereitungen in the form of creams, ointments or gels.
  • the drugs used also have a number of undesirable effects.
  • creams administered frequently result in reddening, drying out, itching, desquamation as well as burning and stinging on the treated skin areas.
  • the corticoids administered in a number of dermatoses can lead to changes in skin pigmentation and / or to folliculitis, favor secondary infections and delay wound healing.
  • Oral drugs used to treat severe cornification disorders can, in extreme cases, lead to osteoporosis, onicholysis and epidermal necrolysis.
  • the present invention was based on the technical problem of having a preparation, in particular for skin diseases well tolerated, rapid onset of action possible an d provide higher efficiency than the previously available preparations.
  • composition which contains at least one polyanion, in particular a linear polyanion, a vitamin A and / or a precursor of vitamin A.
  • the basic building block of the polyanion preferably forms a disaccharide, in particular a glycosaminoglycan or derivative thereof. So is preferred as the polyanion
  • Chondroitin polysulfate the atan polysulfate, pentosan polysulfate or heparin are used.
  • High molecular weight poly anions such as chondroitin polysulfates and dermatan polysulfates have an average molecular weight of 20,000 to 60,000 daltons.
  • Further polyanions which can be used according to the invention have a molecular weight of more than 5000 to 15000, in particular in the range from 8000 to 12000.
  • the low molecular weight polyanions which can also be used, such as pentosan polysulfate have a molecular weight in the range from 1500 to 5000 daltons.
  • Vitamin A and provitamin A can be of synthetic or natural origin; According to the invention, retinol, in particular retinol palmitate, is preferably used as vitamin A, and beta-carotene in particular is used as the precursor of vitamin A.
  • the preparation according to the invention is very well suited for the treatment of a number of skin diseases, in particular for the treatment of excessive scarring and cornification, hardening of connective tissue, superficial inflammation (boils), virus-related skin symptoms such as herpes simplex labialis, poorly healing skin tears (Rhagaden) and skin fungus diseases.
  • skin diseases in particular for the treatment of excessive scarring and cornification, hardening of connective tissue, superficial inflammation (boils), virus-related skin symptoms such as herpes simplex labialis, poorly healing skin tears (Rhagaden) and skin fungus diseases.
  • Rhagaden poorly healing skin tears
  • skin fungus diseases at Inflammation of superficial veins, caused by cytostatic chemotherapy drugs, the symptoms subside after an unusually short time. With the rare progressive generalized scleroderma, already hardened skin areas become supple again.
  • composition according to the invention can also be used for the treatment of superficial tissue degeneration: in the case of superficial colonization of organ cancers, an at least partial regression with subsequent normal new skin formation can be achieved.
  • preparation is also suitable as a cosmetic and also has beneficial effects as a body or skin care product.
  • Linear polyanions not only attack tumor cells directly (Landsberger A.: The effect of heparinoids on the Ehrlich ascites tumor in mice; Med. Welt 22, 1963, pages 1222 to 1233), but also enhance the rectified effect of other substances.
  • Appropriate therapeutic preparations containing anionic linear polymers and cytostatic chemotherapeutics have already been patented (DE 3220326C2 and 3249658C2, US-A-4, 710, 493 and 4,738,955; CDN-B-1227427; EP 0176769B1) and are currently in clinical pharmacology h en testing (Landsberger A., M. Landsberger.:.
  • the diverse, experimentally proven effects of anionic linear polymers include: inhibiting the multiplication of certain viruses (Baba M. et al.: Sulfated Polysaccharides are Potent and Selective Inhibitors of Various Enveloped Viruses, Including Herpex Simplex Virus, Cytomegalovirus, Vesicular Stomatitis Virus, and Human Immunodeficiency Virus; Antimicrobial Agents and Chemoth. 32, 11, 1988, pages 1742 to 1745; Museteanu C, H.
  • Voss Sulfated glycosaminoglycans as virus inhibitors, 3rd communication: to determine the basics of a therapy for viral diseases with glycosaminoglycan polysulfates in animal experiments; Zbl. Bakt. Hyg., I. Dept. Orig. A231, 1975, pages 375 to 388), enhancing the effect of growth factors (Nagasaki T., MA Lieberman: Heparin Potentiates the Action of Plasma Membrane-Associated Growth Stimulatory Activity; J. of Cellular Phys. 133, 1987, pages 365 to 371) and the blocking of enzymes which spread to the inflammation and tumor contribute by breaking down constituents of the basic substance of the connective tissue (Greiling H., M. Kaneko: The inhibition of lysosomal enzymes by a glycosaminoglycan polysulfate; Pharm. Forsch. (Drug Res.) 23, 593, pages 597 to 1973).
  • linear polyanions from disaccharide units are themselves an essential component of the basic substance. They are found in the connective tissue of humans as
  • Glycosaminoglycans especially chondroitin sulfate, predominantly bound to protein bodies to form proteoglycans or glycoproteins. They influence the entire mass exchange between the supplying blood vessels and the cells, determine with the water content, the ion and metabolite concentration, act as a selective filter and have a defense function. They promote the cohesion of the fibers of the basic substance and are probably also involved in the formation of collagen fibers from microfibrils (Bucher 0., H. Wartenberg: Cytology, Histology and Microscopic Anatomy of Humans; pages 146 to 163, publisher Hans Huber, Bern, Stuttgart, Toronto 1989; Junqueira, L. C, J. Carneiro: Histology, cytology, histology and microscopic human anatomy; pages 151 to 171, Springer Verlag, Berlin, Heidelberg, New York, Tokyo 1991).
  • heparin and heparin-like substances are mainly used in the prevention and treatment of diseases.
  • the substances are injected for prophylaxis against thrombosis and embolism, for the treatment of fresh vascular occlusions, for coagulation inhibition during operations with extracorporeal circulation, for consumption coagulopathy, for circulatory disorders and hyperlipidemia; They are administered locally for superficial vein changes, including inflammatory in nature, circulatory disorders, blunt trauma, frost damage, hemorrhoids, tendonitis, insect bites and for herpes simplex labialis, especially in the early stage of development.
  • Fixed combinations e.g. B. with zinc sulfate or anti-inflammatory plant extracts (Federal Association of the Pharmaceutical Industry (ed.): Red List 1996; ECV, Editio Cantor, Aulendorf / Württ. 1996).
  • vitamin A regulates the growth of superficial tissues (epithelia) and connective tissue cells and supports the regular differentiation of the cell organelles. Vitamin A is also an essential component of the cell membrane and influences the formation of mucus-secreting cells. These cells produce glycoproteins, the sugar content of which is mainly derived from glycosaminoglycans (formerly known as mucopolysaccharides referred to). The sulfur required for the biosynthesis of anionic linear polymers may be activated by vitamin A (Sailer S .: Digestion, Vitamins; in: Functional Pathology; Ed .: Wick G.
  • Vitamin A deficiency symptoms include night blindness, excessive cornification of the skin surfaces, drying out of the conjunctiva and cornea of the eye, clouding and softening of the cornea, infection, blindness, growth disorders, inability to conceive, malformations.
  • overdosing of vitamin A can also lead to disorders such as headache, nausea, nausea, itching, detachment of the skin and mucous membranes and malformations (Wolfram G.: body and environment, nutrition; in: Hierholzer K., RF Schmidt ( Ed.): Pathophysiology of humans; pages 38.1 to 14, Ed.Medicine, VCH publishing company, Weinheim, Basel, Cambridge, New York 1991).
  • vitamin A and its derivatives are used therapeutically, especially when there are changes in the outer and inner skin surfaces, e.g. B. acne, seborr oe, hyperkeratosis and dyskeratosis, injuries to the cornea of the eye and to promote wound healing. Attempts are also being made to increase the sensitivity of malignant tumors to ionizing radiation and cytostatics through vitamin A. Vitamin A is administered both systemically (orally) and topically (drops, oils, ointments). Fixed combinations are common, e.g. B.
  • composition according to the invention is preferably administered cutaneously, ie externally by application to the skin, in particular in the form of a dermatological preparation.
  • Dermatological preparations include, for example, envelopes and pastes, but preferably ointments, gels, lotions or powders, optionally with additional auxiliaries. When such preparations are applied topically, the active ingredients are absorbed by the cornea in a concentration which is sufficient, for example, to reduce excessive cornification to a normal level.
  • the required dosage of the active ingredients is determined by the doctor depending on common factors, such as the nature and severity of the disease.
  • the composition according to the invention preferably contains 10 to 15000 mg, in particular 50 to 1000 mg, very particularly preferably 100 to 300 mg polyanion per 250,000 I.U. up to 10 million IU Vitamin A.
  • a further preferred embodiment relates to compositions which can be administered parenterally, such as solutions which are suitable for injection and which contain the composition according to the invention.
  • solutions which are suitable for injection and which contain the composition according to the invention.
  • solutions can be introduced into the body by intravenous infusion. This type of administration is particularly indicated for the treatment of cancer.
  • Effective dosages for, for example, patients with advanced epithelial and esenchymal tumors ranged from 50,000 to 2,000,000 IU of vitamin A, preferably 150,000 to 1,200,000 IU of vitamin A, in an oily solution for intramuscular injection, still 50 to 1000 mg, preferably 200 to 600 mg of pentosan polysulfate are present in the infusion solution.
  • the vitamin-containing solution and the pentosan polysulfate-containing solution can also be administered separately from one another. When the vitamin A solution and the pentosan polysulfate solution are administered separately, the latter is, for example, in 250 ml 5% glucose or 250 ml isotonic saline infused.
  • the vitamin A-containing solution is administered intramuscularly while the pentosan polysulfate solution is administered intravenously.
  • the number of repetitions of the injections depends on the patient's condition, but a regimen with administration 1 to 2 times a week for 4 to 12 weeks has proven successful. In individual cases, treatments over a longer period are required.
  • Adverse effects were rare and were usually limited to skin symptoms such as itching or scaling, increased liver enzymes, GOT, GPT and ⁇ GT, and moderate pain symptoms that persisted for about 1 to 2 days. All undesirable side effects were fully reversible.

Abstract

The invention concerns a composition which contains at least one polyanion, in particular a linear polyanion, a vitamin A and/or a vitamin A precursor. The novel composition is suitable in particular for use against skin diseases.

Description

Vitamin A-haltige Zusammensetzung und deren Verwendung insbesondere gegen Hauterkrankunqen Composition containing vitamin A and its use in particular against skin diseases
Die Erfindung bezieht sich auf eine neue Vitamin A-haltige Zusammensetzung und deren Verwendung.The invention relates to a new vitamin A-containing composition and its use.
Krankhafte Veränderungen der Haut sind auf die verschiedensten Ursachen zurückzuführen und zeigen die unterschiedlichsten Ausprägungen. Auslöser können Krankheitserreger sein, wie beispielsweise Bakterien, Pilze, Viren; Fremdstoffe, beispielsweise Pflege- und Arzneimittel oder Reiz- und Giftstoffe, wie beispielsweise Insektengifte. Hinzu kommen bösartige Gewebeentartungen, die entweder ihren Ursprung im Bereich der Haut haben oder Absiedelungen von Organkrebsen sind. Verbunden sind Hauterkrankungen mit Symptomen, wie Veränderungen der Farbe und Form, von der einfachen Rötung bis zur tiefen Geschwürbildung, mit Mißempfindungen und Schmerzen. K rank-like changes in the skin are on a variety of U RSAC h en due usprägungen and show a wide variety of A. Triggers can be pathogens, such as b eispielsweise bacteria, fungi, viruses; Foreign matter, b eispielsweise care and drug or Irritation and G iftstoffe such as insecticides. Added b ösartige tissue degeneration, or have either originated in the area of skin metastases of organ cancers. Skin diseases are associated with symptoms such as changes in color and shape, from simple reddening to deep ulceration, with sensations and pain.
Behandelt werden Hauterkrankungen sowohl systemisch (Präparate zum Einnehmen) als auch lokal, hier insbesondere mit Zubereitungen in Form von Cremes, Salben oder Gelen. Häufig weisen die eingesetzten Arzneimittel jedoch auch eine Reihe von unerwünschten Wirkungen auf. So haben beispielsweise bei virusbedingten Hauterscheinungen, wie zum Beispiel Herpes, verabreichte Cremes häufig Rötungen, Eintrocknungen, Juckreiz, Abschuppung sowie Brennen und Stechen auf den behandelten Hautstellen zur Folge. Die bei einer Reihe von Dermatosen verabreichten Kortikoide können zur Änderung der Hautpigmentierung und/oder zu Folliculitis führen, Sekundärinfektionen begünstigen sowie die Wundheilung verzögern. Oral verabreichte Medikamente zur Behandlung schwerer Verhornungsstörungen führen im Extremfall zu Osteoporose, Onicholyse und epidermaler Nekrolyse .Be orld Behan d skin diseases both systemic (oral) as well as locally, in particular with Sub b ereitungen in the form of creams, ointments or gels. Often, however, the drugs used also have a number of undesirable effects. For example, in the case of virus-related skin symptoms such as herpes, creams administered frequently result in reddening, drying out, itching, desquamation as well as burning and stinging on the treated skin areas. The corticoids administered in a number of dermatoses can lead to changes in skin pigmentation and / or to folliculitis, favor secondary infections and delay wound healing. Oral drugs used to treat severe cornification disorders can, in extreme cases, lead to osteoporosis, onicholysis and epidermal necrolysis.
Der vorliegenden Erfindung lag das technische Problem zugrunde, eine Zubereitung, insbesondere gegen Erkrankungen der Haut, mit guter Verträglichkeit, möglichst raschem Wirkungseintritt und höherer Effektivität als die bislang zur Verfügung stehenden Zubereitungen bereitzustellen.The present invention was based on the technical problem of having a preparation, in particular for skin diseases well tolerated, rapid onset of action possible an d provide higher efficiency than the previously available preparations.
Dieses Problem wird erfindungsgemäß durch eine Zusammensetzung gelöst, die mindestens ein Polyanion, insbesondere ein lineares Polyanion, ein Vitamin A und/oder eine Vorstufe von Vitamin A enthält .According to the invention, this problem is solved by a composition which contains at least one polyanion, in particular a linear polyanion, a vitamin A and / or a precursor of vitamin A.
Den Grundbaustein des Polyanions bildet vorzugsweise ein Disaccharid, insbesondere ein Glykosaminoglykan oder Derivat davon. So wird als Polyanion vorzugsweiseThe basic building block of the polyanion preferably forms a disaccharide, in particular a glycosaminoglycan or derivative thereof. So is preferred as the polyanion
Chondroitinpolysulfat, Der atanpolysulfat , Pentosanpolysulfat oder Heparin eingesetzt.Chondroitin polysulfate, the atan polysulfate, pentosan polysulfate or heparin are used.
Hochmolekulare Polyanionen, wie Chondroitinpolysulfate und Dermatanpolysulfate, weisen ein mittleres Molekulargewicht von 20000 bis 60000 Dalton auf. Weitere, erfindungsgemäß einsetzbare Polyanionen besitzen ein Molekulargewicht von mehr als 5000 bis 15000, insbesondere im Bereich von 8000 bis 12000. Die ebenfalls einsetzbaren, niedermolekularen Polyanionen, wie Pentosanpolysulfat, weisen ein Molekulargewicht im Bereich von 1500 bis 5000 Dalton auf.High molecular weight poly anions such as chondroitin polysulfates and dermatan polysulfates have an average molecular weight of 20,000 to 60,000 daltons. Further polyanions which can be used according to the invention have a molecular weight of more than 5000 to 15000, in particular in the range from 8000 to 12000. The low molecular weight polyanions which can also be used, such as pentosan polysulfate, have a molecular weight in the range from 1500 to 5000 daltons.
Vitamin A und Provitamin A können synthetischen oder natürlichen Ursprungs sein; erfindungsgemäß wird als Vitamin A vorzugsweise Retinol, insbesondere Retinolpalmitat , und als Vorstufe des Vitamins A insbesondere Beta-Carotin eingesetzt .Vitamin A and provitamin A can be of synthetic or natural origin; According to the invention, retinol, in particular retinol palmitate, is preferably used as vitamin A, and beta-carotene in particular is used as the precursor of vitamin A.
Es zeigte sich überraschenderweise, daß die erfindungsgemäße Zubereitung für die Behandlung einer Reihe von Hauterkrankungen sehr gut geeignet ist, insbesondere für die Behandlung überschießender Narbenbildungen und Verhornungen, Bindegewebsverhärtungen, oberflächlichen Entzündungen (Furunkel) , virusbedingten Hauterscheinungen, wie beispielsweise Herpes simplex labialis, schlecht heilenden Hautrissen (Rhagaden) und Hautpilzerkrankungen. Bei Entzündungen oberflächlicher Venen, ausgelöst durch zytostatische Chemotherapeutika, klingen die Symptome nach ungewöhnlich kurzer Zeit ab. Bei der seltenen fortschreitenden generalisierten Sklerodermie werden bereits verhärtete Hautstellen wieder geschmeidig. Darüberhinaus ist die erfindungsgemäße Zusammensetzung aber auch zur Behandlung von oberflächlichen Gewebeentartungen einsetzbar: So kann bei oberflächlichen Absiedelungen von Organkrebsen eine zumindest teilweise Rückbildung mit anschließender normaler Hautneubildung erreicht werden. Desweiteren eignet sich die Zubereitung auch als Kosmetikum und zeigt als Körper- bzw. Hautpflegemittel ebenfalls günstige Effekte.Surprisingly, it was found that the preparation according to the invention is very well suited for the treatment of a number of skin diseases, in particular for the treatment of excessive scarring and cornification, hardening of connective tissue, superficial inflammation (boils), virus-related skin symptoms such as herpes simplex labialis, poorly healing skin tears (Rhagaden) and skin fungus diseases. at Inflammation of superficial veins, caused by cytostatic chemotherapy drugs, the symptoms subside after an unusually short time. With the rare progressive generalized scleroderma, already hardened skin areas become supple again. In addition, however, the composition according to the invention can also be used for the treatment of superficial tissue degeneration: in the case of superficial colonization of organ cancers, an at least partial regression with subsequent normal new skin formation can be achieved. Furthermore, the preparation is also suitable as a cosmetic and also has beneficial effects as a body or skin care product.
Die bekannteste und sehr genau untersuchte Wirkung anionischer Linearpolymere ist die Hemmung der Blutgerinnung. Je nach Struktur des Polymers werden unterschiedliche Faktoren des Gerinnungssystems mit unterschiedlicher Intensität beeinflußt (Schmutzler W. : Störungen der Blutgerinnung, in: Pharmakotherapie Klinische Pharmakologie; Herausgeber: Füllgraf G. , D. Palm, Seite 145 bis 154, Gustav Fischer Verlag, Stuttgart, New York 1986). Bei der tumorzellzerstörenden Wirkung dieser Substanzen scheint die gerinnungshemmende Aktivität nur eine untergeordnete Rolle zu spielen (Paresh C. R. et al . : Evidence that Sulfated Polysaccherides Inhibit Tumor Metastasis by Blocking Tumor-Cell-Derived Heparanases; Int. J. Cancer 40, 1987, Seite 511 - 518) . Wegen der dadurch erforderlichen Dosisbegrenzung bei systemischer Anwendung ist sie zum Teil sogar ein unerwünschter Effekt .The most well-known and very carefully investigated effect of anionic linear polymers is the inhibition of blood coagulation. Depending on the structure of the polymer, different factors of the coagulation system are influenced with different intensity (Schmutzler W.: disorders of blood coagulation, in: pharmacotherapy clinical pharmacology; publisher: Füllgraf G., D. Palm, pages 145 to 154, Gustav Fischer Verlag, Stuttgart, New York 1986). The anticoagulant activity appears to play only a minor role in the tumor cell-destroying effect of these substances (Paresh CR et al.: Evidence that Sulfated Polysaccherides Inhibit Tumor Metastasis by Blocking Tumor-Cell-Derived Heparanases; Int. J. Cancer 40, 1987, page 511 - 518). Because of the required dose limitation for systemic use, it is even an undesirable effect in some cases.
Lineare Polyanionen greifen nicht nur direkt Tumorzellen an (Landsberger A. : Die Wirkung von Heparinoiden auf den Ehrlich- Ascites-Tumor bei Mäusen; Med. Welt 22, 1963, Seite 1222 bis 1233), sondern verstärken die gleichgerichtete Wirkung anderer Substanzen. Entsprechende therapeutische Zubereitungen, enthaltend anionische Linearpolymere und zytostatische Chemotherapeutica, wurden bereits patentiert (DE 3220326C2 und 3249658C2, US-A-4 , 710 , 493 und 4,738,955; CDN-B-1227427 ; EP 0176769B1) und befinden sich derzeit in der klinischen Erprobung (Landsberger A. , M. Landsberger: Tumorselektive Einschleusung zytostatischer Chemotherapeutica durch sulfatierte Glykosaminoglykane; TW. Gyn. , k. 2, 5, 1989, Seite 307 bis 314) . Zu den vielfältigen, experimentell gesicherten Wirkungen anionischer Linearpolymere gehören: die Hemmung der Vermehrung bestimmter Viren (Baba M. et al . : Sulfated Polysaccharides are Potent and Selective Inhibitors of Various Enveloped Viruses, Including Herpex Simplex Virus, Cytomegalovirus, Vesicular Stomatitis Virus, and Human Immunodeficiency Virus; Antimicrobial Agents and Chemoth. 32, 11, 1988, Seite 1742 bis 1745; Museteanu C, H. Voss: Sulfatierte Glykosaminoglykane als Virusinhibitoren, 3. Mitteilung: zur Ermittlung der Grundlagen einer Therapie von Viruskrankheiten mit Glykosaminoglykanpolysulfaten im Tierversuch; Zbl . Bakt . Hyg., I. Abt. Orig . A231, 1975, Seite 375 bis 388) , die Verstärkung der Wirkung von Wachstumsfaktoren (Nagasaki T., M. A. Lieberman: Heparin Potentiates the Action of Plasma Membrane-Associated Growth Stimulatory Activity; J. of Cellular Phys . 133, 1987, Seite 365 bis 371) und die Blockierung von Enzymen, die zur Entzündungs- und Geschwulstausbreitung durch den Abbau von Bestandteilen der Grundsubstanz des Bindegewebes beitragen (Greiling H., M. Kaneko: Die Hemmung lysosomaler Enzyme durch ein Glykosaminoglykanpolysulfat ; Arzneim. Forsch. (Drug Res . ) 23, 593, Seite 597 bis 1973) .Linear polyanions not only attack tumor cells directly (Landsberger A.: The effect of heparinoids on the Ehrlich ascites tumor in mice; Med. Welt 22, 1963, pages 1222 to 1233), but also enhance the rectified effect of other substances. Appropriate therapeutic preparations containing anionic linear polymers and cytostatic chemotherapeutics have already been patented (DE 3220326C2 and 3249658C2, US-A-4, 710, 493 and 4,738,955; CDN-B-1227427; EP 0176769B1) and are currently in clinical pharmacology h en testing (Landsberger A., M. Landsberger.:. Selective tumor infiltration of cytostatic chemotherapeutic agents by sulfated glycosaminoglycans; TW Gyn, k 2, 5, 1989, pages 307-314).. The diverse, experimentally proven effects of anionic linear polymers include: inhibiting the multiplication of certain viruses (Baba M. et al.: Sulfated Polysaccharides are Potent and Selective Inhibitors of Various Enveloped Viruses, Including Herpex Simplex Virus, Cytomegalovirus, Vesicular Stomatitis Virus, and Human Immunodeficiency Virus; Antimicrobial Agents and Chemoth. 32, 11, 1988, pages 1742 to 1745; Museteanu C, H. Voss: Sulfated glycosaminoglycans as virus inhibitors, 3rd communication: to determine the basics of a therapy for viral diseases with glycosaminoglycan polysulfates in animal experiments; Zbl. Bakt. Hyg., I. Dept. Orig. A231, 1975, pages 375 to 388), enhancing the effect of growth factors (Nagasaki T., MA Lieberman: Heparin Potentiates the Action of Plasma Membrane-Associated Growth Stimulatory Activity; J. of Cellular Phys. 133, 1987, pages 365 to 371) and the blocking of enzymes which spread to the inflammation and tumor contribute by breaking down constituents of the basic substance of the connective tissue (Greiling H., M. Kaneko: The inhibition of lysosomal enzymes by a glycosaminoglycan polysulfate; Pharm. Forsch. (Drug Res.) 23, 593, pages 597 to 1973).
Desweiteren sind lineare Polyanionen aus Disaccharideinheiten selbst ein wesentlicher Bestandteil der Grundsubstanz. Im Bindegewebe des Menschen finden sie sich alsFurthermore, linear polyanions from disaccharide units are themselves an essential component of the basic substance. They are found in the connective tissue of humans as
Glykosaminoglykane, vor allem Chondroitinsulfat , überwiegend an Eiweißkörper zu Proteoglykanen bzw. Glykoproteinen gebunden. Sie beeinflussen den gesamten Stoffaustausch zwischen den versorgenden Blutgefäßen und den Zellen, bestimmen mit den Wassergehalt, die Ionen- und Metabolitenkonzentration, wirken als selektiver Filter und haben Abwehrfunktion. Sie fördern den Zusammenhalt der Fasern der Grundsubstanz und sind wahrscheinlich auch an der Bildung der Kollagenfasern aus Mikrofibrillen beteiligt (Bucher 0., H. Wartenberg: Cytologie, Histologie und mikroskopische Anatomie des Menschen; Seite 146 bis 163, Verlag Hans Huber, Bern, Stuttgart, Toronto 1989; Junqueira, L. C, J. Carneiro: Histologie. Zytologie, Histologie und mikroskopischen Anatomie des Menschen; Seite 151 bis 171, Springer Verlag, Berlin, Heidelberg, New York, Tokyo 1991) .Glycosaminoglycans, especially chondroitin sulfate, predominantly bound to protein bodies to form proteoglycans or glycoproteins. They influence the entire mass exchange between the supplying blood vessels and the cells, determine with the water content, the ion and metabolite concentration, act as a selective filter and have a defense function. They promote the cohesion of the fibers of the basic substance and are probably also involved in the formation of collagen fibers from microfibrils (Bucher 0., H. Wartenberg: Cytology, Histology and Microscopic Anatomy of Humans; pages 146 to 163, publisher Hans Huber, Bern, Stuttgart, Toronto 1989; Junqueira, L. C, J. Carneiro: Histology, cytology, histology and microscopic human anatomy; pages 151 to 171, Springer Verlag, Berlin, Heidelberg, New York, Tokyo 1991).
Aus der Gruppe der anionischen Linearpolymere werden bei der Vorbeugung und Behandlung von Krankheiten vor allem das Heparin und heparinähnliche Substanzen (z. B. Pentosanpolysulfat) genutzt. Injiziert werden die Substanzen zur Thrombose- und Embolieprophylaxe, zur Behandlung von frischen Gefäßverschlüssen, zur Gerinnungshemmung bei operativen Eingriffen mit extrakorporalem Kreislauf, bei Verbrauchskoagulopathie, bei Durchblutungsstörungen und Hyperlipidämie; lokal verabreicht man sie bei oberflächlichen Venenveränderungen, auch entzündlicher Natur, Durchblutungsstörungen, stumpfen Traumata, Frostschäden, Hämorrhoiden, Sehnenscheidenentzündungen, Insektenstichen und bei Herpes simplex labialis, besonders in der frühen Ausprägungsphase. Als Arzneimittel zugelassen sind auch fixe Kombinationen, z. B. mit Zinksulfat oder antientzündlichen Pflanzenextrakten (Bundesverband der Pharmazeutischen Industrie e. V. (Hrsg.): Rote Liste 1996; ECV, Editio Cantor, Aulendorf/Württ. 1996).From the group of anionic linear polymers, heparin and heparin-like substances (e.g. pentosan polysulfate) are mainly used in the prevention and treatment of diseases. The substances are injected for prophylaxis against thrombosis and embolism, for the treatment of fresh vascular occlusions, for coagulation inhibition during operations with extracorporeal circulation, for consumption coagulopathy, for circulatory disorders and hyperlipidemia; They are administered locally for superficial vein changes, including inflammatory in nature, circulatory disorders, blunt trauma, frost damage, hemorrhoids, tendonitis, insect bites and for herpes simplex labialis, especially in the early stage of development. Fixed combinations, e.g. B. with zinc sulfate or anti-inflammatory plant extracts (Federal Association of the Pharmaceutical Industry (ed.): Red List 1996; ECV, Editio Cantor, Aulendorf / Württ. 1996).
Neben seiner Funktion als prosthetische Gruppe lichtempflindlicher Pigmente (Auge) greift das Vitamin A regulierend in die Vermehrung oberflächlicher Gewebe (Epithelien) und Bindegewebszellen ein und unterstützt die regelgerechte Ausdifferenzierung der Zellorganellen. Vitamin A ist außerdem ein wesentlicher Bestandteil der Zellmembran und hat Einfluß auf die Bildung schleimsezernierender Zellen. Diese Zellen produzieren Glykoproteine, deren Zuckeranteil sich vor allem aus Glykosaminoglykanen (früher als Mucopolysaccharide bezeichnet) zusammensetzt. Möglicherweise wird der für die Biosynthese anionischer Linearpolymere erforderliche Schwefel durch Vitamin A aktiviert (Sailer S.: Verdauung, Vitamine; in: Funktionelle Pathologie; Hrsg.: Wick G. et al . , Seite 578, Gustav Fischer Verlag, Stuttgart 1989; Strohmeyer G.: Vitaminstoffwechsel; in: Siegenthaler W. (Hrsg.): Klinische Pathophysiologie; Seite 221, Georg Thieme Verlag, Stuttgart, New York 1994) .In addition to its function as a prosthetic group of light-sensitive pigments (eye), vitamin A regulates the growth of superficial tissues (epithelia) and connective tissue cells and supports the regular differentiation of the cell organelles. Vitamin A is also an essential component of the cell membrane and influences the formation of mucus-secreting cells. These cells produce glycoproteins, the sugar content of which is mainly derived from glycosaminoglycans (formerly known as mucopolysaccharides referred to). The sulfur required for the biosynthesis of anionic linear polymers may be activated by vitamin A (Sailer S .: Digestion, Vitamins; in: Functional Pathology; Ed .: Wick G. et al., Page 578, Gustav Fischer Verlag, Stuttgart 1989; Strohmeyer G .: Vitamin metabolism; in: Siegenthaler W. (ed.): Clinical Pathophysiology; page 221, Georg Thieme Verlag, Stuttgart, New York 1994).
Vitamin-A-Mangelsymptome sind Nachtblindheit, übermäßige Verhornung der Hautoberflächen, Austrocknung der Binde- und Hornhaut des Auges, Eintrübung und Erweichung der Hornhaut, Infektion, Erblindung, Wachstumsstörungen, Zeugungsunfähigkeit, Mißbildungen. Demgegenüber kann aber auch die Überdosierung von Vitamin A zu Störungen führen, wie beispielsweise Kopfschmerzen, Übelkeit, Brechreiz, Juckreiz, Ablösung von Haut und Schleimhaut und Mißbildungen (Wolfram G. : Körper und Umwelt, Ernährung; in: Hierholzer K. , R. F. Schmidt (Hrsg.): Pathophysiologie des Menschen; Seite 38.1 bis 14, Ed. Medizin, VCH Verlagsgesellschaft, Weinheim, Basel, Cambridge, New York 1991) .Vitamin A deficiency symptoms include night blindness, excessive cornification of the skin surfaces, drying out of the conjunctiva and cornea of the eye, clouding and softening of the cornea, infection, blindness, growth disorders, inability to conceive, malformations. On the other hand, overdosing of vitamin A can also lead to disorders such as headache, nausea, nausea, itching, detachment of the skin and mucous membranes and malformations (Wolfram G.: body and environment, nutrition; in: Hierholzer K., RF Schmidt ( Ed.): Pathophysiology of humans; pages 38.1 to 14, Ed.Medicine, VCH publishing company, Weinheim, Basel, Cambridge, New York 1991).
Therapeutisch eingesetzt werden Vitamin A und seine Derivate neben der Substitution bei Mangelerscheinungen vor allem bei Veränderungen von äußeren und inneren Hautoberflächen, z. B. Akne, Seborr oe, Hyperkeratosen und Dyskeratosen, Verletzungen der Hornhaut des Auges und zur Förderung der Wundheilung. Versucht wird auch, die Empfindlichkeit bösartiger Tumore gegenüber ionisierenden Strahlen und Zytostatika durch Vitamin A zu erhöhen. Verabreicht wird Vitamin A sowohl systemisch (oral) als auch topisch (Tropfen, Öle, Salben) . Verbreitet sind fixe Kombinationen, z. B. mit anderen Vitaminen, wie beispielsweise Vitamin E (Bundesverband der Pharmazeutischen Industrie e. V. (Hrsg.): Rote Liste 1996; ECV, Editio Cantor, Aulendorf/Württ. 1996; Merck AG (Hrsg.): Vitamine in der ärztlichen Praxis; Darmstadt 1962). Die erfindungsgemäße Zusammensetzung wird vorzugsweise kutan, d. h. äußerlich durch Auftragen auf die Haut, insbesondere in Form einer dermatologischen Zubereitung, verabreicht. Dermatologische Zubereitungen umfassen beispielsweise Umschläge und Pasten, vorzugsweise aber Salben, Gele, Lotionen oder Puder, gegebenenfalls mit zusätzlichen Hilfsstoffen. Bei topischer Applikation solcher Zubereitungen werden die Wirkstoffe in einer Konzentration durch die Hornhaut resorbiert, die ausreicht, um zum Beispiel eine übermäßige Verhornung auf ein Normalmaß zu senken.In addition to substitution in the event of deficiency symptoms, vitamin A and its derivatives are used therapeutically, especially when there are changes in the outer and inner skin surfaces, e.g. B. acne, seborr oe, hyperkeratosis and dyskeratosis, injuries to the cornea of the eye and to promote wound healing. Attempts are also being made to increase the sensitivity of malignant tumors to ionizing radiation and cytostatics through vitamin A. Vitamin A is administered both systemically (orally) and topically (drops, oils, ointments). Fixed combinations are common, e.g. B. with other vitamins, such as vitamin E (Federal Association of the Pharmaceutical Industry (ed.): Red List 1996; ECV, Editio Cantor, Aulendorf / Württ. 1996; Merck AG (ed.): Vitamins in the medical Practice; Darmstadt 1962). The composition according to the invention is preferably administered cutaneously, ie externally by application to the skin, in particular in the form of a dermatological preparation. Dermatological preparations include, for example, envelopes and pastes, but preferably ointments, gels, lotions or powders, optionally with additional auxiliaries. When such preparations are applied topically, the active ingredients are absorbed by the cornea in a concentration which is sufficient, for example, to reduce excessive cornification to a normal level.
Die benötigte Dosierung der Wirkstoffe wird in Abhängigkeit von üblichen Faktoren, wie der Natur und Schwere der Erkrankung, vom Arzt festgelegt. Vorzugsweise enthält die erfindungsgemäße Zusammensetzung 10 bis 15000 mg, insbesondere 50 bis 1000 mg, ganz besonders bevorzugt 100 bis 300 mg Polyanion pro 250000 I.E. bis 10 Mio. I.E. Vitamin A.The required dosage of the active ingredients is determined by the doctor depending on common factors, such as the nature and severity of the disease. The composition according to the invention preferably contains 10 to 15000 mg, in particular 50 to 1000 mg, very particularly preferably 100 to 300 mg polyanion per 250,000 I.U. up to 10 million IU Vitamin A.
Eine weitere bevorzugte Ausführungsform betrifft parenteral verabreichbare Zusammensetzungen, wie Lösungen, die zur Injektion geeignet sind und die erfindungsgemäße Zusammensetzung enthalten. Beispielsweise können solche Lösungen durch intravenöse Infusion in den Körper eingebracht werden. Diese Art der Verabreichung ist insbesondere auch zur Behandlung von Krebs angezeigt.A further preferred embodiment relates to compositions which can be administered parenterally, such as solutions which are suitable for injection and which contain the composition according to the invention. For example, such solutions can be introduced into the body by intravenous infusion. This type of administration is particularly indicated for the treatment of cancer.
Wirksame Dosierungen für beispielsweise Patienten mit fortgeschrittenen epithelialen und esenchymalen Geschwülsten lagen in dem Bereich von 50.000 bis 2.000.000 IE Vitamin A, vorzugsweise 150.000 bis 1.200.000 IE Vitamin A, in öliger Lösung zur intramuskulären Injektion, wobei weiterhin 50 bis 1000 mg, vorzugsweise 200 bis 600 mg, Pentosanpolysulfat in der Infusionslösung vorliegen. Dabei kann die vitaminhaltige Lösung und die pentosanpolysulfathaltige Lösung auch getrennt voneinander verabreicht werden. Bei der getrennten Verabreichung der Vitamin A Lösung und der Pentosanpolysulfatlösung wird letztere beispielsweise in 250 ml 5%ige Glucose oder 250 ml isotonische Kochsalzlösung infundiert. Bei einer bevorzugten Ausführungsform wird die Vitamin A-haltige Lösung intramuskulär verabreicht während die Pentosanpolysulfatlösung intravenös verabreicht wird. Die Anzahl der Wiederholungen der Injektionen hängt vom Krankheitszustand des Patienten ab, jedoch hat sich ein Schema mit einer Verabreichung von 1 bis 2 mal pro Woche über 4 bis 12 Wochen als erfolgreich erwiesen. In Einzelfällen sind Behandlungen über einen längeren Zeitraum erforderlich.Effective dosages for, for example, patients with advanced epithelial and esenchymal tumors ranged from 50,000 to 2,000,000 IU of vitamin A, preferably 150,000 to 1,200,000 IU of vitamin A, in an oily solution for intramuscular injection, still 50 to 1000 mg, preferably 200 to 600 mg of pentosan polysulfate are present in the infusion solution. The vitamin-containing solution and the pentosan polysulfate-containing solution can also be administered separately from one another. When the vitamin A solution and the pentosan polysulfate solution are administered separately, the latter is, for example, in 250 ml 5% glucose or 250 ml isotonic saline infused. In a preferred embodiment, the vitamin A-containing solution is administered intramuscularly while the pentosan polysulfate solution is administered intravenously. The number of repetitions of the injections depends on the patient's condition, but a regimen with administration 1 to 2 times a week for 4 to 12 weeks has proven successful. In individual cases, treatments over a longer period are required.
Die folgenden Beispiele erläutern die Erfindung:The following examples illustrate the invention:
Es wurden Verabreichungen bei Venenentzündungen und überschießender Narbenbildung mit folgender Zusammensetzung durchgeführt :Administration of phlebitis and excessive scarring was carried out with the following composition:
400 mg PPS (Pentosanpolysulfat), 3 Mio. I. E. Retinopaimitat auf 100 g Basiscreme.400 mg PPS (pentosan polysulfate), 3 million I.U. retinopaimitat on 100 g base cream.
Bei oberflächlicher Ausbildung von Geschwülsten (Hautabsiedelungen bei Organkrebs) sind dagegen erheblich höhere Konzentrationen erforderlich:In contrast, with superficial development of tumors (skin deposits in organ cancer) considerably higher concentrations are required:
1500 bis 15000 mg PPS, 5 bis 8 Mio. I.E. Retinolpalmitat auf 100 g Basiscreme.1500 to 15000 mg PPS, 5 to 8 million IU Retinol palmitate on 100 g base cream.
Klinische Beobachtungen zeigten, daß bei einigen Patienten mit oberflächlichen Absiedelungen von Organkrebsen eine zumindest teilweise Rückbildung mit anschließender normaler Hautneubildung zu erreichen ist. Bei Patienten mit ausgedehnten Entzündungen oberflächlicher Venen, ausgelöst durch zytostatische Chemotherapeutika, klangen die Symptome nach ungewöhnlich kurzer Zeit ab. Bei einer Patientin mit der seltenen fortschreitenden generalisierten Sklerodermie wurden bereits verhärtete Hautstellen wieder geschmeidig. Darüber hinaus wurden günstige Effekte bei mehreren Patienten und Patientinnen beobachtet, bei denen oberflächliche Entzündungen (Furunkel) , Herpex simplex labialis, schlecht heilende Hautrisse (Rhagaden) , überschießende Verhornung oder bislang erfolglos behandelte Hautpilzerkrankungen vorlagen.Clinical observations showed that in some patients with superficial colonization of organ cancers an at least partial regression with subsequent normal new skin formation can be achieved. In patients with extensive inflammation of superficial veins caused by cytostatic chemotherapy drugs, the symptoms subsided after an unusually short time. In one patient with the rare progressive generalized scleroderma, already hardened skin areas became supple again. In addition, beneficial effects have been observed in several patients with superficial inflammation (Boils), Herpex simplex labialis, poorly healing skin cracks (Rhagaden), excessive cornification or previously unsuccessful skin fungal diseases were present.
Bisher wurden ca. 40 Patienten mit Injektionslösungen enthaltend die erfindungsgemäße Zusammensetzung behandelt, wobei die Vitamin A-haltige Lösung jeweils intramuskulär verabreicht wurde, während die Pentosanpolysulfatlösung intravenös verabreicht wurde. Es wurden in praktisch allen Fällen Verbesserungen des Krankheitsbildes beobachtet . So gelang es bei Patienten mit weit fortgeschrittenen Krebserkrankungen und reduziertem Allgemeinzustand eine deutliche Verbesserung des Befindes zu erreichen. Darüberhinaus wurden Hinweise erhalten, daß neben der Befindungsverbesserung auch eine meßbare Tumorverkleinerung einherging. Schließlich wurde bei einigen Patienten, die neben ihrer Krebserkrankung auch unter Beschwerden des rheumatischen Formenkreises litten ein Rückgang auch der rheumatischen Beschwerden beobachtet.So far, approximately 40 patients have been treated with injection solutions containing the composition according to the invention, the vitamin A-containing solution being administered intramuscularly, while the pentosan polysulfate solution was administered intravenously. Improvements in the clinical picture were observed in practically all cases. So it was possible to achieve a significant improvement in the condition of patients with advanced cancer and reduced general condition. In addition, indications were obtained that, in addition to improving the condition, there was also a measurable reduction in tumor size. Finally, a decrease in rheumatic complaints was also observed in some patients who suffered from rheumatic diseases in addition to their cancer.
Unerwünschte Nebenwirkungen traten nur selten auf und beschränkten sich in der Regel auf Hauterscheinungen, wie Jucken oder Schuppung, Anstieg der Leberenzyme, GOT, GPT und γGT, sowie mäßige Schmerzsymtomatik, die über etwa 1 bis 2 Tage anhielt . Alle unerwünschten Nebenwirkungen waren voll reversibel . Adverse effects were rare and were usually limited to skin symptoms such as itching or scaling, increased liver enzymes, GOT, GPT and γGT, and moderate pain symptoms that persisted for about 1 to 2 days. All undesirable side effects were fully reversible.

Claims

Patentansprüche claims
1. Zusammensetzung, enthaltend mindestens ein Polyanion, ein Vitamin A und/oder eine Vorstufe von Vitamin A.1. Composition containing at least one polyanion, a vitamin A and / or a precursor of vitamin A.
2. Zusammensetzung nach Anspruch 1, dadurch gekennzeichnet, daß das Polyanion ein lineares Polyanion ist .2. Composition according to claim 1, characterized in that the polyanion is a linear polyanion.
3. Zusammensetzung nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß der Grundbaustein des Polyanions ein Disaccharid ist.3. Composition according to claim 1 or 2, characterized in that the basic building block of the polyanion is a disaccharide.
4. Zusammensetzung nach Anspruch 3, dadurch gekennzeichnet, daß das Polyanion ein Glykosaminoglykanpolysulfat oder Derivat davon ist.4. Composition according to claim 3, characterized in that the polyanion is a glycosaminoglycan polysulfate or derivative thereof.
5. Zusammensetzung nach Anspruch 4, dadurch gekennzeichnet, daß das Polyanion ausgewählt wird aus Chondroitinpolysulfat , Dermatanpolysulfat und Pentosanpolysulfat.5. Composition according to claim 4, characterized in that the polyanion is selected from chondroitin polysulfate, dermatan polysulfate and pentosan polysulfate.
6. Zusammensetzung nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, daß das Vitamin A Retinolpalmitat ist.6. Composition according to one of claims 1 to 5, characterized in that the vitamin A is retinol palmitate.
7. Zusammensetzung nach einem der Ansprüche l bis 6, dadurch gekennzeichnet, daß die Vorstufe des Vitamin A Beta-Carotin ist.7. Composition according to one of claims 1 to 6, characterized in that the precursor of vitamin A is beta-carotene.
8. Zusammensetzung nach einem der Ansprüche l bis 7, dadurch gekennzeichnet, daß die Zusammensetzung ungefähr 10 mg bis ungefähr 15000 mg Polyanion pro 250000 I.E. bis 10 Mio. I.E. Vitamin A enthält .8. A composition according to any one of claims 1 to 7, characterized in that the composition is about 10 mg to about 15,000 mg polyanion per 250,000 IU. up to 10 million IU Contains vitamin A.
9. Zusammensetzung nach einem der Ansprüche 1 bis 8 als Salbe, Gel, Lotion, Puder, oder Lösung. 9. Composition according to one of claims 1 to 8 as an ointment, gel, lotion, powder, or solution.
10. Zusammensetzung nach einem der Ansprüche 1 bis 9 als Arzneimittel .10. Composition according to one of claims 1 to 9 as a medicament.
11. Zusammensetzung nach einem der Ansprüche 1 bis 9 als Kosmetikum.11. Composition according to one of claims 1 to 9 as a cosmetic.
12. Verwendung der Zusammensetzung nach einem der Ansprüche 1 bis 9 zur Behandlung überschießender Narbenbildung, Bindegewebsverhärtungen, Reizungen oberflächlicher Venen, Geschwüren, oberflächlicher Ausprägung von Geschwülsten, insbesondere Krebs, virusbedingten Hauterscheinungen und/oder Hautpilzerkrankungen.12. Use of the composition according to one of claims 1 to 9 for the treatment of excessive scarring, hardening of connective tissue, irritation of superficial veins, ulcers, superficial expression of tumors, in particular cancer, virus-related skin symptoms and / or skin fungus diseases.
1 . Verwendung der Zusammensetzung nach einem der Ansprüche 1 bis 9 zur Körperpflege.1 . Use of the composition according to any one of claims 1 to 9 for personal care.
1 . Verwendung der Zusammensetzung nach einem der Ansprüche l bis 9 zur intramuskulären/intravenösen Behandlung bösartiger Geschwülste 1 . Use of the composition according to any one of claims 1 to 9 for the intramuscular / intravenous treatment of malignant tumors
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