EP0527979A1

EP0527979A1 - Pharmaceutical for treating viral diseases

Info

Publication number: EP0527979A1
Application number: EP19920904330
Authority: EP
Inventors: Joachim Röding; Ursula Meusel
Original assignee: A Natterman und Cie GmbH
Current assignee: A Natterman und Cie GmbH
Priority date: 1991-02-07
Filing date: 1992-02-03
Publication date: 1993-02-24
Also published as: WO1992013524A1; JPH05506671A; DE4121389A1; IE920400A1; CA2079868A1

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

Description

Pharmaceutical product for the treatment of viral diseases

The present invention relates to a pharmaceutical product for the treatment of viral diseases with the features of the preamble of claim 1.

^ 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.

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.

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.

This object is achieved according to the invention by a pharmaceutical product with the characterizing feature of patent claim 1.

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.

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.

In comparison to the known ointment-like or cream-like products, the pharmaceutical product according to the invention has

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.

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.

In particular, 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. 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.

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.

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.

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.

_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.

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.

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,

_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.

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.

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.

Advantageous further developments of the pharmaceutical product according to the invention are specified in the subclaims.

The pharmaceutical product according to the invention is explained in more detail below using two exemplary embodiments.

example 1

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% 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.

The products created in this way were referred to as products 1-4.

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.

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.

Table 1

Product concentration of

Dextran sulfate in 100 g

Finished product Example 1 ΕeVspιe ^' 1 2

TT

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.

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.

After 6 days of using products 3 and 4 and 7 and 8, 40% of the treated patients no longer showed herpes simplex.

After 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

Products 3, 4, 7 and 8 treated patients required a total treatment time of 14 days until the herpes simplex was completely eliminated.

All patients who were treated with product 9 showed the herpes simplex unchanged even after a treatment time of 14 days. Example 2

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.

The product created in this way was designated as product 1 '- 4'.

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 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.

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.

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.

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

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. 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. 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. Product according to any one of claims 1 to 3, characterized in that it contains the virucidal active ingredient in one

_EBSA TZB _L Arr Concentration between 0.001 wt% and 5 wt%, based on the mass of the liposome system, contains.

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. 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. Product according to any one of the preceding claims, characterized in that it has a liposome system which has a negative surface charge.

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. Product according to claim 8, characterized in that the soy phospholipids

60 to 98% by weight of phosphatidylcholine and

Contain 2 to 40% by weight of other phospholipids.

10. Product according to claim 8 or 9, characterized in that the soy phospholipids

76 ± 3% by weight of phosphatidylcholine and

0 to 6% by weight of lysophosphatidylcholine.

11. Product according to claim 8 or 9, characterized in that the soy phospholipids

Contain 93 ± 3% by weight of phosphatidylcholine and 0-6% by weight of lysophosphatidylcholine.

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. 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. 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. 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.