WO1992013524A1 - Pharmaceutical for treating viral diseases - Google Patents

Pharmaceutical for treating viral diseases 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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Prior art keywords
weight
product according
active ingredient
alcohol
phospholipids
Prior art date
Application number
PCT/DE1992/000078
Other languages
German (de)
French (fr)
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.)
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Publication date
Application filed by A. Nattermann & Cie. Gmbh filed Critical A. Nattermann & Cie. Gmbh
Priority to CA002079868A priority Critical patent/CA2079868A1/en
Priority to JP92503906A priority patent/JPH05506671A/en
Publication of WO1992013524A1 publication Critical patent/WO1992013524A1/en

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    • 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.

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Abstract

A pharmaceutical for treating viral diseases, in particular skin viral diseases, contains at least one virucidal active substance encapsulated in a multilamellar liposome system.

Description

Pharmazeutisches Produkt zur Behandlung von Viruserkrankungen Pharmaceutical product for the treatment of viral diseases
Die vorliegende Erfindung betrifft ein pharmazeutisches Produkt zur Behandlung von Viruserkrankungen mit den Merk¬ malen des Oberbegriffs des Patentanspruchs 1.The present invention relates to a pharmaceutical product for the treatment of viral diseases with the features of the preamble of claim 1.
^ Um Viruserkrankungen, insbesondere virusbedingte Hauter¬ krankungen, wie beispielsweise Herpes simplex, Herpes labialis, Herpes genitalis, Herpes analis, Herpes gestationis, Herpes facialis, Herpes febrilis, Herpes enstrualis oder Herpes zoster, zu behandeln, werden ° üblicherweise salbenartige bzw. σremeartige Produkte auf die jeweils erkrankten Bereiche aufgebracht. So weist beispiels¬ weise eine häufig für die therapeutische Behandlung der zuvor genannten Erkrankungen angewendete Creme als Wirkstoff 50 mg Aciclovir neben üblichen Hilfsstoffen, wie beispiels- 5 weise Propylenglykol, Poloxamer und Cetylstearylalkohol, auf.^ In order to treat viral diseases, in particular 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. For example, 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.
ERSATZBLATT Die bekannten Cremes oder Salben weisen jedoch den Nachteil auf, daß sie regelmäßig innerhalb von kurzen Zeiträumen, beispielsweise zwischen 2 und 4 Stunden, aufgetragen werden müssen, da ansonsten eine Heilung oder Linderung nicht sichergestellt ist. Diese Anwendung wird jedoch nicht von allen Patienten konsequent eingehalten, so daß häufig der erwünschte Erfolg nicht eintritt. Darüber hinaus ist die Behandlungsdauer bei den bekannten pharmazeutischen Pro¬ dukten auf wenige Tage eingeschränkt, so z.B. auf 5 bis maximal 10 Tage.REPLACEMENT LEAF However, 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.
Der vorliegenden Erfindung liegt die Aufgabe zugrunde, ein pharmazeutisches Produkt der angegebenen Art zur Verfügung zu stellen, das auch über einen längeren Zeitraum ohne Ne¬ benwirkungen unbedenklich angewendet werden kann.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.
Diese Aufgabe wird erfindungsgemäß durch ein pharmazeu¬ tisches Produkt mit dem kennzeichnenden Merkmal des Patentanspruchs 1 gelöst.This object is achieved according to the invention by a pharmaceutical product with the characterizing feature of patent claim 1.
Erfindungsgemäß wird somit ein pharmazeutisches Produkt zur topischen Behandlung von Viruserkrankungen, insbesondere von Viruserkrankungen der Haut vorgeschlagen, bei dem mindestens ein virucider Wirkstoff in einem multilamellaren Liposomen- syste eingekapselt ist.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.
Hierbei werden in der vorliegenden Anmeldung unter dem Be¬ griff Liposomen Kugeln (Vesikel) verstanden, die durch Lipiddoppelmembranen begrenzt sind und die in ihrem Inneren eine wäßrige Phase enthalten, in der der mindestens eine virucide Wirkstoff gelöst, dispergiert oder emulgiert ist.In the present application, the term 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.
Das erfindungsgemäße pharmazeutische Produkt weist im Ver¬ gleich zu den bekannten salbenartigen bzw. cremeartigen Pro-In comparison to the known ointment-like or cream-like products, the pharmaceutical product according to the invention has
ERSATZBLATT dukten eine Reihe von Vorteilen auf. So ist zunächst heraus¬ zustellen, daß die erfindungsgemäße Zubereitung im Vergleich zu den bekannten Mitteln innerhalb eines vorgegebenen Zeit¬ raumes, beispielsweise eines Tages, wesentlich weniger häu¬ figer auf die jeweils erkrankten Bereiche aufgetragen werden muß. Dies wird darauf zurückgeführt, daß das erfindungs¬ gemäße pharmazeutische Produkt eine Depotwirkung besitzt, da der Wirkstoff in den Liposomen eingekapselt ist und hieraus langsam und gleichmäßig freigesetzt wird. Weiterhin besitzt das erfindungsgemäße therapeutische Produkt eine bessere Bioverfügbarkeit, da die Liposomen in der Haut, und insbe¬ sondere in der Hornhaut, eingelagert werden, so daß eine Überwindung der Hornhautbarriere nicht erforderlich ist. Dies wiederum führt dazu, daß auch tiefere Hautschichten in der Dermis erreicht werden, so daß auch die sich in diesen tieferen Hautschichten befindlichen Viren abgetötet werden. Darüber hinaus besitzt das erfindungsgemäße pharmazeutische Präparat eine hohe LagerStabilität, da, wie bereits vor¬ stehend dargelegt, der mindestens eine Wirkstoff in den Liposomen eingekapselt und somit gegen äußere Einflüsse, beispielsweise Oxidation, optimal geschützt ist.E RSAT Z BL ATT added a number of advantages. First of all, it should be pointed out that 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. This is attributed to the fact that 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. Furthermore, 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. In addition, 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.
Eine besonders geeignete Ausführungsform des erfindungs¬ gemäßen pharmazeutischen Produktes weist als viruciden Wirkstoff mindestens ein Polyanion, vorzugsweise Dextran- sulfat und/oder ein Derivat davon, auf. Hierbei handelt es sich vorzugsweise um einen Schwefelsäureester des Dextrans, wobei Dextran ein Glucosepolymerisat ist.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.
Insbesondere wird das Dextransulfat in Form seiner Salze, vorzugsweise seiner Natrium- oder Kaliumsalze, eingesetzt.In particular, the dextran sulfate is used in the form of its salts, preferably its sodium or potassium salts.
Als Derivate des Dextrinsulfates kommen insbesondere die Ester, vorzugsweise die Methyl-, Ethyl, -Propyl-, Butyl-The derivatives of dextrin sulfate are, in particular, the esters, preferably the methyl, ethyl, propyl, butyl
ERSATZBLATT ester, in Frage, wobei die Esterbildung sowohl über SO3OH- Gruppen als auch über Hydroxy-Gruppen erfolgen kann.E RSATZB LATT esters, in question, the ester formation can take place both via SO3OH groups and via hydroxyl groups.
Vorzugsweise liegt das Molekulargewicht des Polyanions, insbesondere des Dextransulfates, der entsprechenden Salze und/oder Derivate zwischen 5000 und 15000, insbesondere zwischen 7000 und 12000.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.
Die Konzentration des viruciden Wirkstoffes bzw. des Gemisches der viruciden Wirkstoffe richtet sich bei dem erfindungsgemäßen pharmazeutischen Produkt nach der Art der eingesetzten viruciden Verbindungen, der zu behandelnden Körperbereiche sowie dem Grad der Erkrankung. Allgemein variiert in dem erfindungsgemäßen Produkt die Konzentration des viruciden Wirkstoffes zwischen 0,001 Gew.% und 5 Gew.%, jeweils bezogen auf die Masse des Liposomensystems, in die der Wirkstoff eingekapselt ist. Bei leichteren Erkrankungen und für die Anwendung im Schleimhautbereich werden solche Ausführungsformen des erfindungsgemäßerr^Produktes einge¬ setzt, deren Wirkstoffkonzentration zwischen 0,001 Gew.% und 0,1 Gew.% variiert. Bei schwereren Erkrankungen und insbe¬ sondere bei solchen Erkrankungen, bei denen sich die Virus¬ infektion nicht auf Schleimhäute erstreckt, gelangen vor¬ zugsweise Produkte zur Anwendung, deren Wirkstoffkonzen¬ tration zwischen 0,1 Gew.% und 2 Gew.% variiert. Soll hin¬ gegen die durch die Einkapselung des Wirkstoffes bzw. des Wirkstoffgemisches in das Liposomensystem herbeigeführte Depotwirkung voll ausgenutzt werden, so kann die Wirkstoff- konzentration in dem erfindungsgemäßen Produkt auf 2 Gew.% bis 5 Gew.% heraufgesetzt werden, wobei dann ein derartiges Produkt in entsprechend verlängerten Zeiträumen, insbeson¬ dere in einem Rhythmus von 24 Stunden, aufgetragen werden muß. Die zuvor wiedergegebenen Konzentrationsangaben be¬ ziehen sich jeweils auf die Masse des Liposomensystems, das den Wirkstoff bzw. das Wirkstoffgemisch einkapselt. Um bei dem erfindungsgemäßen Produkt die Einlagerung des Produktes in der Haut, insbesondere in der Hornhaut, zu verbessern, werden vorzugsweise solche Liposomensysteme ausgewählt, deren Liposome einen mittleren Durchmesser zwischen 100 nm und 500 nm aufweisen. Besonders vorteil¬ haft haben sich hierbei Liposomensysteme gezeigt, bei denen der mittlere Liposomen-Durchmesser zwischen etwa 150 nm und etwa 300 nm variiert.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. In the case of more severe diseases and in particular in those diseases in which the virus infection does not extend to mucous membranes, 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. In order to improve the storage of the product in the skin, in particular in the cornea, in the product according to the invention, 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.
Als weiterhin vorteilhaft konnte festgestellt werden, daß solche Liposomensysteme, die eine negative Oberflächenladung aufweisen, besonders gut und schnell in die Haut penetrieren und damit eine hohe Wirksamkeit besitzen.It was also found to be advantageous that such liposome systems which have a negative surface charge penetrate particularly well and quickly into the skin and are therefore highly effective.
Bezüglich des Liposomensystems, das bei dem erfindungs¬ gemäßen pharmazeutischen Produkt den Wirkstoff bzw. das Wirkstoffgemisch einkapselt, ist allgemein festzuhalten, daß hier jedes geeignete Liposomensystem verwendbar ist, das die vorstehend genannten Bedingungen bezüglich der mittleren Durchmesser und der Oberflächenladung erfüllt und das multi- lamellare Vesikel bildet. Vorzugsweise wird jedoch ein er- findungsgemäßes Produkt verwendet, das als gelartige Lipo- somendispersion vorliegt, die neben dem Wirkstoff bzw. dem Wirkstoffgemisch 8 bis 22 Gew.% Sojaphospholipide sowie Wasser und/ oder Alkohol umfaßt.With regard to the liposome system which encapsulates the active ingredient or the active ingredient mixture in the pharmaceutical product according to the invention, it should generally be stated that any suitable liposome system can be used here which fulfills the above-mentioned conditions with regard to the mean diameter and the surface charge and which is multi-lamellar Vesicle forms. However, a product according to the invention is preferably used 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.
Eine besonders hohe Wirksamkeit, die sich durch eine gute Depotwirkung und eine besonders gute Bioverfügbarkeit des Wirkstoffes bzw. Wirkstoffgemisches ausdrückt, weisen solche Ausführungsformen des erfindungsgemäßen pharmazeutischen Produktes auf, bei denen die Sojaphospholipide eine hohe Konzentration an Phosphatidylcholin, insbesondere zwischen 60 Gew.% bis 98 Gew.% Phosphatidylcholin,sowie 2 Gew.% bis 40 Gew.% weitere Phospholipide, wie insbesondere Phosphatidylethanolamin, Phosphatidsäure und/oder Phosphatidylinosit, enthalten.Those embodiments of the pharmaceutical product according to the invention in which the soy phospholipids have a high concentration of phosphatidylcholine, in particular between 60% by weight and 98%, have a particularly high effectiveness, which is expressed by a good depot effect and a particularly good bioavailability of the active ingredient or active ingredient mixture % 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.
R ATZBLATT Eine weitere Verbesserung der Wirksamkeit, insbesondere gegenüber Herpes simplex, wird bei dem erfindungsgemäßen Produkt dadurch erreicht, daß man ein Liposo ensystem einsetzt, das aus speziellen Sojaphospholipiden be¬ steht, wobei diese speziellen Sojaphospholipide 76 ± 3 Gew.% Phosphatidyl- cholin und 0 bis 6 Gew.% Lyso-Phosphatidylcholin enthalten. Weiterhin können diese Sojaphospholipide noch die zuvor genannten weiteren Phospho- lipide, insbesondere etwa 5 Gew.% Phosphatidylethanolamin, etwa 8 Gew.% Phosphatidsäure und/oder Spuren von Phosphatidylinosit aufweisen. Ein der¬ artiges Liposomensystem ist insbesondere hervorragend geeignet, Wirkstoffe auf Basis von Polyanionen, insbesondere auf Basis von Dextransulfat, Derivaten und/oder Salzen des Dextransulfates, einzukapseln und diese Wirkstoffe nach der Penetration der Liposomen in die Haut über einen entsprechend langen Zeitraum gleichmäßig abzugeben, so daß eine derartige Ausführungsform des erfindungsgemäßen Produktes eine hervorragende Depotwirkung und damit eine ausgezeichnete Langzeitwirkung besitzt. 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.
Um unerwünschte jedoch unbedenkliche Nebenwirkungen restlos auszu¬ schließen, wie beispielsweise das Auftreten von Hautrötungen bei beson¬ ders empfindlichen Patienten, und um die zuvor beschriebenen Vorteile weiter zu verbessern, weist eine besonders geeignete Ausführungsform des erfindungsgemäßen Produktes hochreine Sojaphospholipide auf, die 93 ± 3 Gew.% Phosphatidylcholin und 0 - 6 Gew.% Lyso-Phosphatidylcholin ent¬ halten. In diesen Sojaphospholipiden sind dann die zuvor angesprochenen weiteren Phospholipiden, deren Nachweisgrenze bei etwa 0,5 Gew.% liegt, nicht mehr oder nur in Spuren nachweisbar.In order to completely rule out undesirable but harmless side effects, such as the occurrence of skin reddening in particularly sensitive patients, and to further improve the advantages described above, 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. In these 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.
Um bei dem erfindungsgemäßen Produkt eine lange Haltbarkeit und insbe¬ sondere eine gute Liposomenstabilität sicherzustellen, weist das erfin¬ dungsgemäße Produkt neben dem Liposomensystem und dem Wirkstoff zwischen etwa 12 Gew."' und etwa 20 Gew.%, vorzugsweise etwa 16 Gew.%, Alkohol,In order to ensure a long shelf life and in particular good liposome stability in the product according to the invention, 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,
LATT insbesondere Ethanol und/oder Propanol 2, sowie zwischen etwa 80 Gew.% und etwa 58 Gew.% Wasser auf. Hier konnte festgestellt werden, daß ein derartiges Produkt neben einer ausgezeichneten Lagerstabilität von mehreren Jahren und einer hervorragenden Wirksamkeit topisch ohne Auftreten von Hautreizungen anwendbar ist. 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.
Die vorliegende Erfindung betrifft ferner ein Verfahren zur Herstellung des zuvor beschriebenen pharmazeutischen Pro¬ duktes, das als Liposomensystem Sojaphospholipide der vor¬ stehend beschriebenen Art enthält.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.
Erfindungsgemäß wird ein derartiges Produkt dadurch herge¬ stellt, daß man ein Phospholipidgemisch in Alkohol, vorzugs¬ weise Ethanol und/oder Propanol 2 löst, hiernach soviel Was- ser zugibt, bis sich ein Gel ausbildet und anschließend das Gel mit dem mindestens einen Wirkstoff beispielsweise durch Verrühren vermischt.According to the invention, 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.
Überraschend konnte festgestellt werden, daß sich bei dem zuvor beschriebenen Verfahren Liposome ausbilden, die den zugesetzten und vorstehend beschriebenen Wirkstoff einkap¬ seln, wobei sich diese Liposomen durch eine definierte und konstante Teilchengröße zwischen etwa 150 nm und etwa 300 nm, vorzugsweise bei etwa 230 nm, auszeichnen. Weiter- hin konnte festgestellt werden, daß infolge der Zugabe von Wasser und/oder durch weitere Verdünnung mit Wasser in dem pharmazeutischen Produkt frei vorliegende Liposome mit mehreren Bilayren ausgebildet werden. Darüber hinaus ist es bei dem erfindungsgemäßen Verfahren nicht erforderlich, bei der Herstellung der Liposomen, die den Wirkstoff bzw. das Wirkstoffgemisch einkapseln, zusätzliche energieaufwendige Schritte, wie beispielsweise Temperaturerhöhungen, Ultra¬ schall oder ein exzessives Verrühren, anzuwenden. Hier reicht es aus, wenn die zuvor genannten Komponenten mit einem Laborrührer üblicher Bauart während 2 bis 8 Minuten verrührt werden. Ferner konnte festgestellt werden, daß das erfindungsgemäße Produkt eine extrem niedrige Keimzahl be¬ sitzt, insbesondere eine Keimzahl unter 100 Keime/g, wo¬ durch somit die USP 21- und DAB 9-Normen erfüllt sind. TZBLATT Eine weitere Ausführungsform des erfindungsgemäßen Ver¬ fahrens sieht vor, daß man das Phospholipidge isch nur in einem Teil der benötigten Alkoholmenge löst, und während und/oder nach dem Verrühren des Gels mit dem Wirkstoff die restliche Alkoholmenge zugibt und anschließend die erfor¬ derliche Menge Wasser zuführt, um so die gewünschte Viskosität des pharmazeutischen Produktes einzustellen. Hierbei hat es sich als besonders geeignet herausgestellt, wenn man das Phospholipidgemisch zunächst in 10 Gew.% bis 30 Gew.% der erforderlichen Alkoholmenge löst und an¬ schließend während und/oder nach dem Verrühren des Gels mit dem Wirkstoff die fehlende Akoholmenge, d.h. somit 70 Gew.% bis 90 Gew.%, zugibt.Surprisingly, it was found that 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. It is sufficient here if the aforementioned components are stirred with a laboratory stirrer of the usual type for 2 to 8 minutes. It was also found that the product according to the invention has an extremely low bacterial count, in particular a bacterial count below 100 germs / g, which means that the USP 21 and DAB 9 standards are thus met. 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. It has proven to be particularly suitable here if 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.
Vorteilhafte Weiterbildungen des erfindungsgemäßen pharma¬ zeutischen Produktes sind in den Unteransprüchen angegeben.Advantageous further developments of the pharmaceutical product according to the invention are specified in the subclaims.
Das erfindungsgemäße pharmazeutische Produkt wird nach¬ folgend anhand von zwei Ausführungsbeispielen näher erläutert.The pharmaceutical product according to the invention is explained in more detail below using two exemplary embodiments.
Beispiel 1example 1
20 g eines Phospholipidgemisches, bestehend aus 82,5 ± 3,5 Gew.% Phosphatidylcholin (3-SN-PC), maximal 10 Gew.% Phosphatidylethanolamin,20 g of a phospholipid mixture consisting of 82.5 ± 3.5% by weight phosphatidylcholine (3-SN-PC), maximum 10% by weight phosphatidylethanolamine,
0 - 6 Gew.% Lyso-Phosphatidylcholin und maximal 10 Gew.% sonstigen Lipiden mit einer Peroxidzahl von maximal 5 und einer Gesamtkeimzahl von maximal 100 Keimen/g wurden in 3,6 g Ethanol gelöst. An¬ schließend wurden zu dieser Lösung 47 g ent ineralisiertes Wasser zugegeben und die Lösung mit einem schnell laufenden Laborrührer während 3 Minuten homogenisiert. Hierbei bildete sich ein transparentes Gel aus. Dieses Gel wurde mit 12,4 g Ethanol und unterschiedlichen Mengen Dextransulfat (Tabelle 1) , das in Form eines Natriumsalzes vorlag und ein Moleku- largewicht von etwa 8000 aufwies, verrührt (schnell laufen¬ der Laborrührer, 2 Minuten) . Anschließend erfolgte die Auffüllung mit entmineralisiertem Wasser auf 100 g Fertig¬ produkt und das nochmalige Verrühren mit einem schnell lau¬ fenden Laborrührer während 2 Minuten.0 - 6% by weight of lysophosphatidylcholine and a maximum of 10% by weight of other lipids with a maximum peroxide number of 5 and a maximum number of 100 bacteria / g 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 3 minutes using a high-speed laboratory stirrer. A transparent gel formed during this. This gel was treated with 12.4 g of ethanol and different amounts of dextran sulfate (Table 1), which was in the form of a sodium salt and one molecule had a weight of about 8000, stirred (fast running laboratory stirrer, 2 minutes). The mixture was then made up to 100 g of finished product with demineralized water and mixed again with a fast-running laboratory stirrer for 2 minutes.
Die so erstellten Produkte wurden als Produkte 1-4 be¬ zeichnet.The products created in this way were referred to as products 1-4.
Parallel hierzu wurde eine Produktreihe 5-8 hergestellt, wobei dieselben Ausgangssubstanzen in den selben Mengen eingesetzt wurden wie bei den Produkten 1-4. Abweichend hiervon wurden jedoch die entsprechenden Dextransulfat¬ mengen erst nach der letzten Wasserzugabe zugesetzt, wobei die Vermischung des Liposomensystems mit dem Dextransulfat im normalen Mörser per Hand erfolgte.At the same time, a product range 5-8 was produced, using the same starting substances in the same quantities as for products 1-4. Deviating from this, however, the corresponding amounts of dextran sulfate were only added after the last addition of water, the liposome system being mixed with the dextran sulfate in a normal mortar by hand.
Parallel hierzu wurde ein Produkt 9 erstellt, wobei das Produkt 9 die selben Bestandteile aufwies wie die Produkte 1-8, jedoch mit der Abweichung, daß das Produkt 9 kein Dextransulfat enthielt.In parallel to this, a product 9 was produced, the product 9 having the same constituents as the products 1-8, but with the difference that the product 9 did not contain any dextran sulfate.
Tabelle 1Table 1
Produkt Konzentration vonProduct concentration of
Dextransulfat in 100 gDextran sulfate in 100 g
Fertigprodukt Beispiel 1 ΕeVspιe'1 2Finished product Example 1 ΕeVspιe ' 1 2
Figure imgf000011_0001
Figure imgf000011_0001
TT
Figure imgf000012_0001
TT
Figure imgf000012_0001
An einer Gruppe von 30 willkürlich ausgewählten Patienten, die alle an Herpes simplex erkrankt waren, wurden die zuvor beschriebenen Produkte 1 bis 9 erprobt. Hierzu wurden die Produkte 1 bis 9 zweimal täglich in einem Zeitabstand von 12 Stunden lokal auf die erkrankten Hautbereiche aufgetra¬ gen und dort kurz eingerieben.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.
Bereits nach 3 Tagen nach dem Beginn der Behandlung konnte bei den Patienten, die mit den Produkten 1 bis 8 behandelt wurden, eine deutliche Besserung der Erkrankung festgestellt werden. Nach 6 Tagen Anwendung der Produkte 1, 2 sowie 5 und 6 wiesen 50% der behandelten Patienten keinen Herpes simplex auf.Already after 3 days after the start of treatment, the patients who were treated with products 1 to 8 showed a clear improvement in the disease. After 6 days of using products 1, 2 and 5 and 6, 50% of the treated patients showed no herpes simplex.
Nach 6 Tagen Anwendung der Produkte 3 und 4 sowie 7 und 8 zeigten 40% der behandelten Patienten keinen Herpes simplex mehr.After 6 days of using products 3 and 4 and 7 and 8, 40% of the treated patients no longer showed herpes simplex.
Nach weiteren 4 Tagen der Behandlung zeigten die verblei¬ benden 50% der mit den Produkten 1, 2, 5 und 6 behandelten Patienten keinen Herpes simplex mehr, während die mit denAfter a further 4 days of treatment, the remaining 50% of the patients treated with products 1, 2, 5 and 6 no longer showed herpes simplex, while those with the
Produkten 3, 4, 7 und 8 behandelten Patienten eine Gesamtbe- handlungszeit von 14 Tagen erforderten, bis der Herpes simplex vollständig beseitigt war.Products 3, 4, 7 and 8 treated patients required a total treatment time of 14 days until the herpes simplex was completely eliminated.
Alle Patienten, die mit dem Produkt 9 behandelt wurden, zeigten selbst nach einer Behandlungszeit von 14 Tagen un¬ verändert den Herpes simplex. Beispiel 2All patients who were treated with product 9 showed the herpes simplex unchanged even after a treatment time of 14 days. Example 2
20 g eines Phospholipidgemisches (Sojaphospholipid) , bestehend aus 95 Gew.% Phosphatidylcholin, 3 Gew.% Lyso-Phosphatidylcholin und 2 Gew.% nicht identifizierter sonstiger Phospholipide wurden in 3,6 g Ethanol gelöst. Anschließend wurde zu dieser Lösung 47 g entmineralisiertes Wasser zugegeben und die Lösung mit einem schnell- laufenden Laborrührer während drei Minuten homogenisiert. Hierbei bildete sich ein transparentes Gel aus. Dieses Gel wurde mit 12,4 g Ethanol und den zuvor angegebenen unterschiedlichen Mengen Dextransulfat (Tabelle 1), das in Form eines Natriumsalzes vorlag und ein Molekular¬ gewicht von etwa 8.000 aufwies, verrührt (schneilaufender Laborrührer, zwei Minuten). Anschließend erfolgte die Auffüllung mit entminerali- sierten Wasser auf 100 g Fertigprodukt und das nochmalige Verrühren mit einem schnellaufenden Laborrührer während zwei Minuten.20 g of 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.
Das so erstellte Produkt wurde als Produkt 1' - 4' bezeichnet.The product created in this way was designated as product 1 '- 4'.
Parallel hierzu wurde ein Produkt 5' - 81 hergestellt, wobei die selben Ausgangssubstanzen in den selben Mengen eingesetzt wurden wie bei den Produkten 1' - 4'. Abweichend hiervon wurde jedoch bei der Produktreihe 5' - 8' die entsprechenden Dextransulfatmengen erst nach der letzten Wasserzugabe zugesetzt, wobei die Vermischung des Liposomensystems mit dem Dextransulfat im normalen Mörser per Hand erfolgte.In parallel to this, a product 5 '- 8 1 was produced, the same starting substances being used in the same amounts as for products 1' - 4 '. Deviating from this, however, the corresponding amounts of dextran sulfate were only added to the product series 5 '- 8' after the last addition of water, the liposome system being mixed with the dextran sulfate in a normal mortar by hand.
T Parallel hierzu wurde ein weiteres Produkt 9' erstellt, wobei das Produkt 91 die selben Bestandteile aufwies wie die Produkte T - 8', jedoch mit der Abweichung, daß das Produkt 9' kein Dextransulfat enthielt.T In parallel to this, a further product 9 'was created, the product 9 1 having the same constituents as the products T-8', but with the difference that the product 9 'did not contain any dextran sulfate.
An einer Gruppe von 30 ausgwählten Patienten, die sich durch eine aus¬ gesprochene Hautempfindlichkeit bei der Anwendung von anderen Produkten auszeichneten und die alle an Herpes simplex erkrankt waren, wurden die zuvor beschriebenen Produkte V bis 9' erprobt. Hierzu wurden die Produkte l1 bis 91 zweimal täglich in einem Zeitabstand von 12 Stunden lokal auf die erkrankten Hautbereiche sowie die hierzu benachbarten gesunden Hautbereiche aufgetragen und dort kurz eingerieben.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. For this purpose, 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.
Die Ergebnisse in bezug auf die Behandlung des Herpes simplex entsprachen im wesentlichen den zuvor bei Beispiel 1 wiedergegebenen Ergebnissen, wobei der Eindruck entstand, daß sich eine Tendenz zur Verkürzung der Gesamtbehandlungszeiten um etwa 1 bis 2 Tagen abzeichnete. Auffallend war jedoch, daß bei keinem der Patienten Hautreizungen auftraten.The results relating to the treatment of herpes simplex essentially corresponded to the results given previously in Example 1, giving the impression that there was a tendency to shorten the total treatment times by about 1 to 2 days. It was striking, however, that none of the patients experienced skin irritation.
Selbstverständlich belegte auch dieser Behandlungsversuch, daß alle die Patienten, die mit dem Produkt 91 behandelt wurden, selbst nach einer Behandlungszeit von 14 Tagen unverändert den Herpes simplex zeigten. Of course, this treatment attempt also demonstrated that all the patients who were treated with the product 9 1 showed the herpes simplex unchanged even after a treatment time of 14 days.

Claims

Patentansprüche Claims
1. Pharmazeutisches Produkt zur Behandlung von Viruser¬ krankungen, insbesondere Viruserkrankungen der Haut, mit mindestens einem viruciden Wirkstoff, dadurch gekenn¬ zeichnet, daß der Wirkstoff in einem multilamellaren Liposomensystem eingekapselt ist.1. Pharmaceutical product for the treatment of viral diseases, in particular viral diseases of the skin, with at least one virucidal active ingredient, characterized in that the active ingredient is encapsulated in a multilamellar liposome system.
2. Produkt nach Anspruch 1, dadurch gekennzeichnet, daß es als viruciden Wirkstoff mindestens ein Polyanion, vorzugs¬ weise Dextransulfat, ein Salz und/oder ein Derivat davon, enthält.2. Product according to claim 1, characterized in that it contains at least one polyanion, preferably dextran sulfate, a salt and / or a derivative thereof, as the virucidal active ingredient.
3. Produkt nach Anspruch 2, dadurch gekennzeichnet, daß das virucide Polyanion ein Molekulargewicht zwischen 5000 und 15000, vorzugsweise zwischen 7000 und 12000, aufweist.3. Product according to claim 2, characterized in that the virucide polyanion has a molecular weight between 5000 and 15000, preferably between 7000 and 12000.
4. Produkt nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß es den viruciden Wirkstoff in einer4. Product according to any one of claims 1 to 3, characterized in that it contains the virucidal active ingredient in one
EBSATZBLArr Konzentration zwischen 0,001 Gew.% und 5 Gew.%, bezogen auf die Masse des Liposomensystems, enthält. EBSA TZB L Arr Concentration between 0.001 wt% and 5 wt%, based on the mass of the liposome system, contains.
5. Produkt nach einem der vorangehenden Ansprüche, dadurc gekennzeichnet, daß es ein Liposomensystem enthält, dessen Liposome einen mittleren Durchmesser zwischen 100 nm und 500 nm aufweisen.5. Product according to any one of the preceding claims, characterized in that it contains a liposome system whose liposomes have an average diameter between 100 nm and 500 nm.
6. Produkt nach Anspruch 5, dadurch gekennzeichnet, daß die Liposome des Liposomensystems einen mittleren Durch¬ messer zwischen etwa 150 nm und 300 nm besitzen.6. Product according to claim 5, characterized in that the liposomes of the liposome system have an average diameter between approximately 150 nm and 300 nm.
7. Produkt nach einem der vorangehenden Ansprüche, dadurc gekennzeichnet, daß es ein Liposomensystem aufweist, das eine negative Oberflächenladung besitzt.7. Product according to any one of the preceding claims, characterized in that it has a liposome system which has a negative surface charge.
8. Produkt nach einem der vorangehenden Ansprüche, dadurc gekennzeichnet, daß das Liposomensystem eine gelartige Lipo somendispersion ist, die neben dem mindestens einen Wirk¬ stoff 8 bis 22 Gew.% Sojaphospholipide sowie Wasser und/ode Alkohol umfaßt.8. Product according to any one of the preceding claims, characterized in that the liposome system is a gel-like liposomal dispersion which, in addition to the at least one active ingredient, comprises 8 to 22% by weight of soybean phospholipids and water and / or alcohol.
9. Produkt nach Anspruch 8, dadurch gekennzeichnet, daß die Sojaphospholipide9. Product according to claim 8, characterized in that the soy phospholipids
60 bis 98 Gew.% Phosphatidylcholin sowie60 to 98% by weight of phosphatidylcholine and
2 bis 40 Gew.% sonstige Phospholipide enthalten.Contain 2 to 40% by weight of other phospholipids.
10. Produkt nach Anspruch 8 oder 9 , dadurch gekennzeichnet, daß die Sojaphospholipide10. Product according to claim 8 or 9, characterized in that the soy phospholipids
76 ± 3 Gew.% Phosphatidylcholin und76 ± 3% by weight of phosphatidylcholine and
0 bis 6 Gew. % Lyso-Phospatidylcholin, enthalten. 0 to 6% by weight of lysophosphatidylcholine.
11. Produkt nach Anspruch 8 oder 9, dadurch gekennzeichnet, daß die Sojaphospholipide11. Product according to claim 8 or 9, characterized in that the soy phospholipids
93 ± 3 Gew.% Phosphatidylcholin und 0 - 6 Gew.% Lyso-Phosphatidylcholin enthalten.Contain 93 ± 3% by weight of phosphatidylcholine and 0-6% by weight of lysophosphatidylcholine.
12 • Produkt nach einem der Ansprüche 5 bis 11 , dadurch gekennzeichnet, daß das Liposomensystem neben den Phospho- lipiden zwischen 12 Gew.% und 20 Gew.% Alkohol, insbeson¬ dere Ethanol und/oder Propanol 2, und zwischen 80 Gew.% und 58 Gew.% Wasser aufweist.12 • Product according to one of claims 5 to 11, characterized in that the liposome system in addition to the phospholipids between 12 wt.% And 20 wt.% Alcohol, in particular ethanol and / or propanol 2, and between 80 wt.% and 58% by weight of water.
13. Verfahren zur Herstellung des pharmazeutischen Produk¬ tes nach einem der Ansprüche 8 bis 12 , dadurch gekennzeich¬ net, daß man die Sojaphospholipide in Alkohol, vorzugsweise Ethanol oder Propanol 2, löst, hiernach soviel Wasser zu¬ gibt, bis sich ein Gel ausbildet und das Gel mit dem mindestens einen Wirkstoff vermischt.13. A process for the preparation of the pharmaceutical product according to one of claims 8 to 12, characterized in that the soy phospholipids are dissolved in alcohol, preferably ethanol or propanol 2, and then water is added until a gel is formed and the gel is mixed with the at least one active ingredient.
14. Verfahren nach Anspruch 13, dadurch gekennzeichnet, daß man die Sojaphospholipide nur in einem Teil der Alkoholmenge löst und während und/oder nach dem Vermischen des Gels mit dem Wirkstoff die restliche Alkoholmenge sowie Wasser zu¬ gibt.14. The method according to claim 13, characterized in that the soy phospholipids are only dissolved in part of the amount of alcohol and the remaining amount of alcohol and water are added during and / or after mixing the gel with the active ingredient.
15. Verfahren nach Anspruch 14, dadurch gekennzeichnet, daß der erste Teil der Alkoholmenge zwischen 10 und 30 Gew.% und der restliche Teil der Alkoholmenge zwischen 70 und 90 Gew.% liegt. 15. The method according to claim 14, characterized in that the first part of the amount of alcohol is between 10 and 30% by weight and the remaining part of the amount of alcohol is between 70 and 90% by weight.
PCT/DE1992/000078 1991-02-07 1992-02-03 Pharmaceutical for treating viral diseases WO1992013524A1 (en)

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DEP4103732.4 1991-02-07
DE4103732 1991-02-07
DEP4121389.0 1991-06-28
DE4121389A DE4121389A1 (en) 1991-02-07 1991-06-28 PHARMACEUTICAL PRODUCT FOR TREATING VIRUS DISEASES

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WO1992013524A1 true WO1992013524A1 (en) 1992-08-20

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CA (1) CA2079868A1 (en)
DE (1) DE4121389A1 (en)
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WO (1) WO1992013524A1 (en)

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JPH07145081A (en) * 1993-08-20 1995-06-06 Euro Celtique Sa Externally applied preparation of disinfectant and/or wound curing accelerator
WO1998000112A1 (en) * 1996-07-02 1998-01-08 University College Dublin Organised assemblies containing entrapped negatively charged polyelectrolytes
WO1998017284A2 (en) * 1996-10-22 1998-04-30 Daniel Favre Inhibition of cap-independent protein synthesis and hiv-tar translation by heparin or heparin mimetics, and methods for gene therapy
EP1534303A1 (en) * 2002-08-13 2005-06-01 Monash University Antimicrobial charged polymers that exhibit resistance to lysomal degradation during kidney filtration and renal passage, compositions and method of use thereof

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WO1996010389A1 (en) * 1994-09-30 1996-04-11 Mika Pharma Gesellschaft Für Die Entwicklung Und Vermarktung Pharmazeutischer Produkte Mbh Pharmaceutical composition
ES2526264B1 (en) * 2013-06-05 2015-12-02 Consejo Superior De Investigaciones Cientificas (Csic) SEQUENCE OF NUCLEOTID CODING OF AN ENZYME WITH DEXTRANSACARASA ACTIVITY, CELLS THAT EXPRESS IT AND ITS USE FOR THE OBTAINING OF EXOPOLISACARIDS WITH ANTIVIRAL ACTIVITY AND COMPOSITIONS CONTAINING THEM

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EP0066379A2 (en) * 1981-05-15 1982-12-08 Riker Laboratories, Inc. Composition for combating herpes virus
EP0172007A2 (en) * 1984-08-10 1986-02-19 Syntex (U.S.A.) Inc. Stable liposomes with aqueous-soluble medicaments and methods for their preparation
WO1991001719A1 (en) * 1989-08-01 1991-02-21 The University Of Michigan Topical delivery of peptides/proteins entrapped in dehydration/rehydration liposomes

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07145081A (en) * 1993-08-20 1995-06-06 Euro Celtique Sa Externally applied preparation of disinfectant and/or wound curing accelerator
WO1998000112A1 (en) * 1996-07-02 1998-01-08 University College Dublin Organised assemblies containing entrapped negatively charged polyelectrolytes
WO1998017284A2 (en) * 1996-10-22 1998-04-30 Daniel Favre Inhibition of cap-independent protein synthesis and hiv-tar translation by heparin or heparin mimetics, and methods for gene therapy
WO1998017284A3 (en) * 1996-10-22 1998-08-20 Daniel Favre Inhibition of cap-independent protein synthesis and hiv-tar translation by heparin or heparin mimetics, and methods for gene therapy
EP1534303A1 (en) * 2002-08-13 2005-06-01 Monash University Antimicrobial charged polymers that exhibit resistance to lysomal degradation during kidney filtration and renal passage, compositions and method of use thereof
EP1534303A4 (en) * 2002-08-13 2008-03-19 Univ Monash Antimicrobial charged polymers that exhibit resistance to lysomal degradation during kidney filtration and renal passage, compositions and method of use thereof

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DE4121389A1 (en) 1992-08-13
IE920400A1 (en) 1992-08-12
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CA2079868A1 (en) 1992-08-08
JPH05506671A (en) 1993-09-30

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