WO1992013524A1 - Produit pharmaceutique de traitement de maladies virales - Google Patents

Produit pharmaceutique de traitement de maladies virales Download PDF

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Publication number
WO1992013524A1
WO1992013524A1 PCT/DE1992/000078 DE9200078W WO9213524A1 WO 1992013524 A1 WO1992013524 A1 WO 1992013524A1 DE 9200078 W DE9200078 W DE 9200078W WO 9213524 A1 WO9213524 A1 WO 9213524A1
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WO
WIPO (PCT)
Prior art keywords
weight
product according
active ingredient
alcohol
phospholipids
Prior art date
Application number
PCT/DE1992/000078
Other languages
German (de)
English (en)
Inventor
Joachim Röding
Ursula Meusel
Original Assignee
A. Nattermann & Cie. Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by A. Nattermann & Cie. Gmbh filed Critical A. Nattermann & Cie. Gmbh
Priority to CA002079868A priority Critical patent/CA2079868A1/fr
Priority to JP92503906A priority patent/JPH05506671A/ja
Publication of WO1992013524A1 publication Critical patent/WO1992013524A1/fr

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to a pharmaceutical product for the treatment of viral diseases with the features of the preamble of claim 1.
  • virus-related skin diseases such as herpes simplex, herpes labialis, herpes genitalis, herpes analis, herpes gestationis, herpes facialis, herpes febrilis, herpes enstrualis or herpes zoster
  • ointment-like or cream-like products are usually used applied to the affected areas.
  • a cream frequently used for the therapeutic treatment of the aforementioned diseases has 50 mg of acyclovir as active ingredient in addition to conventional auxiliaries, such as, for example, propylene glycol, poloxamer and cetylstearyl alcohol.
  • the known creams or ointments have the disadvantage that they have to be applied regularly within short periods of time, for example between 2 and 4 hours, since otherwise a cure or relief is not ensured. However, this application is not consistently followed by all patients, so that the desired success often does not occur. In addition, the duration of treatment in the known pharmaceutical products is limited to a few days, for example 5 to a maximum of 10 days.
  • the present invention has for its object to provide a pharmaceutical product of the type specified, which can be safely used over a longer period of time without side effects.
  • the invention thus proposes a pharmaceutical product for the topical treatment of viral diseases, in particular viral diseases of the skin, in which at least one virucidally active substance is encapsulated in a multilamellar liposome system.
  • liposomes means spheres (vesicles) which are delimited by lipid double membranes and which contain an aqueous phase in which the at least one virucidal active ingredient is dissolved, dispersed or emulsified.
  • the pharmaceutical product according to the invention has
  • E RSAT Z BL ATT added a number of advantages.
  • the preparation according to the invention has to be applied to the diseased areas much less frequently than the known agents within a predetermined period of time, for example one day.
  • the pharmaceutical product according to the invention has a depot effect, since the active substance is encapsulated in the liposomes and is slowly and uniformly released therefrom.
  • the therapeutic product according to the invention has better bioavailability, since the liposomes are stored in the skin, and in particular in the cornea, so that it is not necessary to overcome the corneal barrier. This in turn means that deeper layers of the skin in the dermis are also reached, so that the viruses in these deeper layers of the skin are also killed.
  • the pharmaceutical preparation according to the invention has a high storage stability, since, as already explained above, the at least one active ingredient is encapsulated in the liposomes and is therefore optimally protected against external influences, for example oxidation.
  • a particularly suitable embodiment of the pharmaceutical product according to the invention has at least one polyanion, preferably dextran sulfate and / or a derivative thereof, as the virucidal active ingredient.
  • This is preferably a sulfuric acid ester of dextran, where dextran is a glucose polymer.
  • the dextran sulfate is used in the form of its salts, preferably its sodium or potassium salts.
  • the derivatives of dextrin sulfate are, in particular, the esters, preferably the methyl, ethyl, propyl, butyl
  • E RSATZB LATT esters in question, the ester formation can take place both via SO3OH groups and via hydroxyl groups.
  • the molecular weight of the polyanion, in particular the dextran sulfate, the corresponding salts and / or derivatives is preferably between 5000 and 15000, in particular between 7000 and 12000.
  • the concentration of the virucidal active ingredient or the mixture of the virucidal active ingredients in the pharmaceutical product according to the invention depends on the type of virucidal compounds used, the areas of the body to be treated and the degree of the disease. In general, the concentration of the virucidal active ingredient in the product according to the invention varies between 0.001% by weight and 5% by weight, in each case based on the mass of the liposome system into which the active ingredient is encapsulated. In the case of minor diseases and for use in the area of the mucous membrane, such embodiments of the product according to the invention are used whose active substance concentration varies between 0.001% by weight and 0.1% by weight.
  • products are preferably used whose concentration of active substance varies between 0.1% by weight and 2% by weight. If, on the other hand, the depot effect brought about by the encapsulation of the active ingredient or the active ingredient mixture into the liposome system is to be fully utilized, the active ingredient concentration in the product according to the invention can be increased to 2% by weight to 5% by weight, in which case such an amount Product must be applied in correspondingly extended periods, in particular in a rhythm of 24 hours.
  • the concentration data given above relate to the mass of the liposome system which encapsulates the active ingredient or the active ingredient mixture.
  • those liposome systems are preferably selected whose liposomes have an average diameter between 100 nm and 500 nm. Liposome systems in which the average liposome diameter varies between approximately 150 nm and approximately 300 nm have proven particularly advantageous.
  • a product according to the invention which is in the form of a gel-like liposome dispersion which, in addition to the active substance or mixture of active substances, comprises 8 to 22% by weight of soy phospholipids and water and / or alcohol.
  • phosphatidylcholine By weight of phosphatidylcholine, and from 2% by weight to 40% by weight of further phospholipids, such as, in particular, phosphatidylethanolamine, phosphatidic acid and / or phosphatidylinositol.
  • RA TZB L ATT A further improvement of the effectiveness, simplex particularly against herpes is achieved in the inventive product, that one uses a Liposo ensystem, which is of special soya phospholipids be ⁇ , said special soya phospholipids 76 ⁇ 3 wt.% Phosphatidyl choline and from 0 to 6% by weight of lysophosphatidylcholine. Furthermore, these soy phospholipids can also have the aforementioned further phospholipids, in particular about 5% by weight of phosphatidylethanolamine, about 8% by weight of phosphatidic acid and / or traces of phosphatidylinositol.
  • Such a liposome system is particularly suitable for encapsulating active ingredients based on polyanions, in particular based on dextran sulfate, derivatives and / or salts of dextran sulfate, and releasing these active ingredients evenly over a correspondingly long period of time after the liposomes have penetrated the skin. so that such an embodiment of the product according to the invention has an excellent depot effect and thus an excellent long-term effect.
  • a particularly suitable embodiment of the product according to the invention has high-purity soy phospholipids which contain 93 ⁇ 3% by weight % Contain phosphatidylcholine and 0-6% by weight lysophosphatidylcholine.
  • soy phospholipids the previously mentioned further phospholipids, the detection limit of which is approximately 0.5% by weight, can no longer be detected or can only be detected in traces.
  • the product according to the invention in addition to the liposome system and the active ingredient, has between about 12% by weight and about 20% by weight, preferably about 16% by weight.
  • Alcohol in addition to the liposome system and the active ingredient, has between about 12% by weight and about 20% by weight, preferably about 16% by weight.
  • LA TT in particular ethanol and / or propanol 2, and between about 80% by weight and about 58% by weight of water. It was found here that, in addition to excellent storage stability of several years and excellent effectiveness, such a product can be applied topically without the occurrence of skin irritation.
  • the present invention further relates to a method for producing the pharmaceutical product described above which contains soy phospholipids of the type described above as the liposome system.
  • such a product is produced by dissolving a phospholipid mixture in alcohol, preferably ethanol and / or propanol 2, then adding enough water until a gel forms and then the gel with the at least one active ingredient, for example mixed by stirring.
  • liposomes are formed in the previously described process which encapsulate the added and previously described active ingredient, these liposomes being characterized by a defined and constant particle size between approximately 150 nm and approximately 300 nm, preferably at approximately 230 nm , mark. Furthermore, it was found that due to the addition of water and / or by further dilution with water in the pharmaceutical product, free liposomes are formed with several bilayers. In addition, it is not necessary in the process according to the invention to use additional energy-consuming steps, such as temperature increases, ultrasound or excessive stirring, in the production of the liposomes that encapsulate the active ingredient or the active ingredient mixture.
  • TZB L ATT A further embodiment of the process according to the invention provides that the phospholipid is only dissolved in part of the required amount of alcohol, and during and / or after the gel has been mixed with the active ingredient, the remaining amount of alcohol is added and then the required amount of water feeds, so as to set the desired viscosity of the pharmaceutical product.
  • the phospholipid mixture is first dissolved in 10% by weight to 30% by weight of the required amount of alcohol and then during and / or after the gel has been stirred with the active ingredient, the missing amount of alcohol, ie thus 70% by weight to 90% by weight.
  • products 1-4 The products created in this way were referred to as products 1-4.
  • the previously described products 1 to 9 were tested on a group of 30 randomly selected patients, all of whom had herpes simplex. For this purpose, the products 1 to 9 were applied twice daily to the diseased skin areas at a time interval of 12 hours and briefly rubbed in there.
  • a phospholipid mixture (soy phospholipid) consisting of 95% by weight of phosphatidylcholine, 3% by weight of lysophosphatidylcholine and 2% by weight of unidentified other phospholipids were dissolved in 3.6 g of ethanol. Then 47 g of demineralized water were added to this solution and the solution was homogenized for three minutes using a high-speed laboratory stirrer. A transparent gel formed during this. This gel was stirred with 12.4 g of ethanol and the previously stated different amounts of dextran sulfate (Table 1), which was in the form of a sodium salt and had a molecular weight of about 8,000 (laboratory stirrer running for two minutes). This was followed by filling with demineralized water to 100 g of finished product and stirring again with a high-speed laboratory stirrer for two minutes.
  • Table 1 dextran sulfate
  • product 1 '- 4' The product created in this way was designated as product 1 '- 4'.
  • the previously described products V to 9 ' were tested on a group of 30 selected patients who had pronounced skin sensitivity when using other products and who were all suffering from herpes simplex.
  • the products 1 1 to 9 1 were applied twice daily at intervals of 12 hours to the diseased skin areas and the adjacent healthy skin areas and briefly rubbed in there.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un produit pharmaceutique de traitement de maladies virales, notamment de maladies virales de la peau, contient au moins une substance active virucide encapsulée dans un système de liposomes multilamellaires.
PCT/DE1992/000078 1991-02-07 1992-02-03 Produit pharmaceutique de traitement de maladies virales WO1992013524A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA002079868A CA2079868A1 (fr) 1991-02-07 1992-02-03 Preparation pharmaceutique pour le traitement d'affections virales
JP92503906A JPH05506671A (ja) 1991-02-07 1992-02-03 ウイルス性疾患を治療するための薬剤

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DEP4103732.4 1991-02-07
DE4103732 1991-02-07
DEP4121389.0 1991-06-28
DE4121389A DE4121389A1 (de) 1991-02-07 1991-06-28 Pharmazeutisches produkt zur behandlung von viruserkrankungen

Publications (1)

Publication Number Publication Date
WO1992013524A1 true WO1992013524A1 (fr) 1992-08-20

Family

ID=25900838

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE1992/000078 WO1992013524A1 (fr) 1991-02-07 1992-02-03 Produit pharmaceutique de traitement de maladies virales

Country Status (6)

Country Link
EP (1) EP0527979A1 (fr)
JP (1) JPH05506671A (fr)
CA (1) CA2079868A1 (fr)
DE (1) DE4121389A1 (fr)
IE (1) IE920400A1 (fr)
WO (1) WO1992013524A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07145081A (ja) * 1993-08-20 1995-06-06 Euro Celtique Sa 消毒剤及び／又は創傷治癒促進剤の外用製剤
WO1998000112A1 (fr) * 1996-07-02 1998-01-08 University College Dublin Systemes organises contenant des polyelectrolytes pieges et a charge negative
WO1998017284A2 (fr) * 1996-10-22 1998-04-30 Daniel Favre Inhibition de la synthese proteique independante de la coiffe au moyen de l'heparine ou de mimetiques de l'heparine
EP1534303A1 (fr) * 2002-08-13 2005-06-01 Monash University Polymeres charges d'agents antimicrobiens presentant une resistance a la degradation lysosomiale lors de la filtration et du passage renaux, compositions et procede d'utilisation

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2201358C (fr) * 1994-09-30 2004-06-08 Jurgen Regenold Composition pharmaceutique
ES2526264B1 (es) * 2013-06-05 2015-12-02 Consejo Superior De Investigaciones Cientificas (Csic) Secuencia de nucleótidos codificante de una enzima con actividad dextransacarasa, células que la expresan y su uso para la obtención de exopolisacáridos con actividad antiviral y composiciones que los contienen

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0066379A2 (fr) * 1981-05-15 1982-12-08 Riker Laboratories, Inc. Composition pour le traitement du virus herpès
EP0172007A2 (fr) * 1984-08-10 1986-02-19 Syntex (U.S.A.) Inc. Liposomes stables à médicaments hydrosolubles
WO1991001719A1 (fr) * 1989-08-01 1991-02-21 The University Of Michigan Administration topique de peptides/proteines enfermes dans des liposomes deshidrates/rehydrates

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0066379A2 (fr) * 1981-05-15 1982-12-08 Riker Laboratories, Inc. Composition pour le traitement du virus herpès
EP0172007A2 (fr) * 1984-08-10 1986-02-19 Syntex (U.S.A.) Inc. Liposomes stables à médicaments hydrosolubles
WO1991001719A1 (fr) * 1989-08-01 1991-02-21 The University Of Michigan Administration topique de peptides/proteines enfermes dans des liposomes deshidrates/rehydrates

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ARZNEIMITTEL-FORSCHUNG/DRUG RESEARCH Bd. 40(II, Nr. 12, Dezember 1990, AULENDORF (DE) Seiten 1365 - 1368; C.ARTMANN ET AL.: 'liposomes from soya phospholipids as percutaneous drug carriers' *
SEIFEN-öLE-FETTE-WACHSE Bd. 116, Nr. 14, 3. September 1990, AUGSBURG (DE) Seiten 509 - 515; J.RÖDING: 'natipide II: new easy liposome system' *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07145081A (ja) * 1993-08-20 1995-06-06 Euro Celtique Sa 消毒剤及び／又は創傷治癒促進剤の外用製剤
WO1998000112A1 (fr) * 1996-07-02 1998-01-08 University College Dublin Systemes organises contenant des polyelectrolytes pieges et a charge negative
WO1998017284A2 (fr) * 1996-10-22 1998-04-30 Daniel Favre Inhibition de la synthese proteique independante de la coiffe au moyen de l'heparine ou de mimetiques de l'heparine
WO1998017284A3 (fr) * 1996-10-22 1998-08-20 Daniel Favre Inhibition de la synthese proteique independante de la coiffe au moyen de l'heparine ou de mimetiques de l'heparine
EP1534303A1 (fr) * 2002-08-13 2005-06-01 Monash University Polymeres charges d'agents antimicrobiens presentant une resistance a la degradation lysosomiale lors de la filtration et du passage renaux, compositions et procede d'utilisation
EP1534303A4 (fr) * 2002-08-13 2008-03-19 Univ Monash Polymeres charges d'agents antimicrobiens presentant une resistance a la degradation lysosomiale lors de la filtration et du passage renaux, compositions et procede d'utilisation

Also Published As

Publication number Publication date
IE920400A1 (en) 1992-08-12
CA2079868A1 (fr) 1992-08-08
EP0527979A1 (fr) 1993-02-24
JPH05506671A (ja) 1993-09-30
DE4121389A1 (de) 1992-08-13

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