IE920401A1 - Pharmaceutical product for the treatment of virus diseases - Google Patents

Abstract

The description relates to a pharmaceutical product for treating viral diseases, especially those affecting the skin. The pharmaceutical product has at least one virucidal agent encapsulated in a multilamellar liposome system.

Description

Pharmaceutical product for the treatment of virus diseases The present Invention relates to a pharmaceutical product for the treatment of virus diseases with the characteristics of the general description in claim 1.

In order to treat virus diseases, particularly virus-dependent skin diseases, such as, for example, herpes simplex, herpes labialia, herpes genitalis, herpes analls, herpes gestationls, herpes facialis, herpes febrilis, herpes menstrualis or herpes zoster, it is customary to apply an ointment-like or cream-like product to the areas of skin affected by the disease. So, for example, a cream frequently employed for the therapeutic treatment of the aforementioned diseases contains 50 mg acyclovir as active ingredient together with conventional additives such aa, for example, propylene glycol, poloxamer and cetylstearyl alcohol.

However, the known creams and ointments suffer from the disadvantage that they must be applied regularly and at short intervals, for example every 2 to 4 hours, since healing or relief cannot otherwise be guaranteed. However, this treatment is not always carried out conscientiously by all patients, so that the desired success frequently does not occur. Furthermore, treatment with the known pharmaceutical products is limited to a few days, for example to 5 or a maximum of 10 days.

The purpose of the present invention is to make available a pharmaceutical product of the aforementioned type that can be applied safely and without side effects over a longer period of time.

According to the invention this purpose is fulfilled by a pharmaceutical product with the characteristic attributes of

Claims (8)

1. 20 Thus, according to the invention, a pharmaceutical product is proposed for the topical treatment of virus diseases, particularly of virus diseases of the skin, with at least one virucidal active ingredient encapsulated in a multilamellar liposome system. Whereby in the present application the term liposomes is understood to refer to spheres (vesicles) that are bounded by lipid double membranes and contain within them an aqueous phase in which at least one virucidal active ingredient is 30 dissolved, dispersed or emulsified. The pharmaceutical product according to the invention exhibits a number of advantages over the known ointment-like or cream-like preparations. Firstly, it has become apparent that, in contrast to the known agents, the preparation according to the invention has to be applied to the diseased areas appreciably leas frequently over a period of time, for example one day. This is attributed to the pharmaceutical product according to the invention possessing a depot effect 5 since the active ingredient is encapsulated ln the liposomes and is slowly and evenly released from these. Furthermore, the therapeutic product according to the invention possesses a better bioavailability, since the liposomes are stored in the skin and particularly in the stratum corneum, so that it 10 Is not necessary to cross the barrier of the horny layer. This again leads to the deeper skin layers in the dermis being reached so that the viruses to be found in these deeper skin layers are killed. Furthermore, the pharmaceutical preparation according to the invention possesses a 15 high storage stability, since as stated previously, the minimum of one active ingredient is encapsulated in the liposomes and, hence, is optimally protected against external influences, for example oxidation. 20 At least one polyanion, preferably dextran sulphate and/or a derivative thereof as virucidal agent has been found to be a particularly suitable method of realizing the pharmaceutical product according to the invention. Hereby this is preferably a sulfuric acid ester of dextran, whereby dextran is a 25 glucose polymer. Particularly dextran sulphate is employed in the form of a salt, preferably its sodium or potassium salt. 30 The derivatives of dextran sulphate that come into question are particularly the esters, preferably the methyl, ethyl, propyl, butyl esters, whereby esterification can involve both the SOs OH groups and the hydroxy groups. The molecular weight of the polyanion, particularly of the dextran sulphate, of the corresponding salt and/or derivative lies preferably between 5000 and 15000, particularly between 7000 and 12000. The concentration of the virucidal active ingredient or of the mixture of virucidal active ingredients in the pharmaceutical product according to the invention is adjusted according to the nature of the virucidal compounds employed, 10 the regions of the body to be treated and the severity of the disease. In general the concentration of virucidal active ingredient in the product according to the invention ranges from 0.001% by weight to 5% by weight of the mass of the liposome system in which the active ingredient is encap15 sulated. In the case of mild disorders and for application to the mucosa application forms of the product according to the invention are employed whose active ingredient concentration lies between 0.001% by weight and 0.1% by weight. In the case of severe disorders and particularly of those 20 disorders where the virus infection does not extend to the mucous membranes, products are preferably used whose active ingredient concentration lies between 0.1% by weight and 2% by weight. However, if it is desired to exploit the depot effect brought about by encapsulation of the active ingre25 dient or active ingredient mixture in the liposome system the active ingredient concentration In the product according to the invention can be raised to 2% by weight to 5% by weight, whereby such a product must be applied at correspondingly extended intervals, particularly in a 24 hour rhythm. 30 The aforementioned concentration ranges are in each case with respect to the mass of the liposome system that encapsulates the active ingredient or the active ingredient mixture. In order to improve the deposition of the product in the skin and particularly in the stratum corneum, in the case of the product according to the invention such liposome systems are preferably chosen whose liposomes have a mean diameter 5 between 100 nm and 500 nm. Here liposome systems with a mean liposome diameter of about 150 nm to about 300 nm have shown themselves to be particularly advantageous. It has also been established to be advantageous, that such 10 liposome systems that exhibit a negative surface charge penetrate the skin particularly rapidly and well and, hence, possess high effectivity. With respect to the liposome system encapsulating the active 15 ingredient or mixture of active ingredients in the pharmaceutical product according to the invention, it may be stated in general that any suitable liposome system may be used that fulfils the aforementioned conditions concerning mean diameter and surface charge and forms multilamellar 20 vesicles. However, the product according to the invention is preferably used in which the liposomes are present in the form of a gel-like dispersion, that contains 8 to 22¾ by weight soya phospholipids together with water and/or alcohol in addition to the active ingredient or active ingredient 25 mixture. A particularly high efficacy, expressed in the form of a good depot effect, and a particularly good bioavailability of the active ingredient or of the active Ingredient mixture 30 are exhibited by forms of realization of the pharmaceutical product according to the invention where the soya phospholipids contain a high concentration of phosphatidylcholine, particularly from 60¾ by weight to 98¾ by weight phosphatidylcholine and 2¾ by weight to 40¾ by weight of other phospholipids, such as, in particular, phosphatidylethanolamine, phosphatidic acid and/or phosphatidylinositol. A further improvement in efficacy, particularly with respect to herpes simplex, is achieved for the product according to 5 the invention where a liposome system is used which is made up of specific soya phospholipids, whereby these specific soya phospholipids contain 76 ± 3% by weight phosphatidylcholine and 0 to 6* by weight lysophosphatidyleholine. Moreover, these soya phospholipids can also contain the afore10 mentioned other phospholipids particularly ca. 5* by weight phosphatidylethanolamine, ca. 8* by weight phosphatidic acid and/or traces of phosphatidylinositol. In particular such a liposome system is excellently suitable for the encapsulation of active ingredients based on polyanions, particularly 15 based on dextran sulphate, derivatives and/or salts of dextran sulphate, and for the release of these evenly over an appropriately extended period of time after penetration of the liposomes into the skin, so that such a mode of execution of the product according to the invention possesses an 20 excellent depot effect and, hence, an excellent long-term effect. A form of realization of the product according to the invention characterized by high purity soya phospholipids con25 tainlng 93 ± 3¾ by weight phosphatidylcholine and 0-6¾ by weight lysophosphatidyleholine was found to be particularly suitable for the complete avoidance of undesired but harmless side effects, such as, for example, the occurrence of skin reddening in especially sensitive patients, and for 30 further improvement of the aforementioned advantages. These soya phospholipids do not contain or contain only traces of the aforementioned other phospholipids, whose detection limit is ca. 0.5¾ by weight. In order to ensure that the product according to the invention has a long storage life and in particular to ensure good liposome stability, the product according to the invention contains, in addition to the liposome system and the active ingredient, between ca. 12* by weight and ca. 20* 5 by weight, preferably ca. 16* by weight alcohol, particularly ethanol and/or 2-propanol, as well as between ca. 80* by weight and about 58* by weight water. In this context it has been established that, in addition to exhibiting excellent storage properties over several years, such a product ia 10 also topically applicable with outstanding effectivity and without the occurrence of skin irritation. The present invention also refers to a method for the preparation of the pharmaceutical product described above, that 15 contains soya phospholipids of the aforementioned type as the liposome system. According to the invention such a product is prepared by dissolving a phospholipid mixture in alcohol, preferably 20 ethanol and/or 2-propanol, and thereafter adding sufficient water to produce a gel and then mixing the gel, for example by stirring, with at least one active ingredient. Unexpectedly it could be established that the aforementioned 25 method resulted in the formation of liposomes, that encapsulate the aforementioned added active ingredient, whereby these liposomes display a defined and constant particle size between ca. 150 nm and ca. 300 nm, preferably ca. 230 nm. Furthermore, it could also be established that, as a result 30 of the addition of water and/or further dilution with water, free liposomes with several bilayers were formed in the pharmaceutical product. Furthermore, in the method according to the invention it is not necessary to carry out additional, energy-consuming steps involving, for example, the raising of the temperature, the application of ultrasound or excessive stirring in order to prepare the liposomes that encapsulate the active ingredient or mixture of active ingredients. It is sufficient here if the above-mentioned components are stirred together for 2 to 8 minutes with a 5 laboratory stirrer of conventional construction. Furthermore, it was also possible to establish that the product according to the invention has an extremely low microbiological count of less than 100 organlsms/g, thus fulfilling the USP 21 and DAB 9 standards. A further mode of execution of the method according to the invention proposes that the phospholipid mixture be dissolved in only a part of the required quantity of alcohol and that the remaining part of the alcohol be added during 15 and/or after stirring the gel with the active ingredient and then the necessary amount of water be added in order to adjust the viscosity to that desired for the pharmaceutical product. Here it has been found to be particularly suitable when the phospholipid mixture is first dissolved in 10¾ by 20 weight to 30¾ by weight of the required amount of alcohol and then the remaining alcohol, i.e. 70¾ by weight to 90¾ by weight, is added during and/or after stirring the gel with the active ingredient. 25 Advantageous developments of the pharmaceutical product according to the invention are mentioned in later claims. The pharmaceutical product according to the invention will be further explained with the aid of two execution examples. Example 1 20 g of a phospholipid mixture comprising 82.5 ± 3.5* by weight phosphatidylcholine (3-Sn-PC), not more than 10¾ by weight phosphatidylethanolamine IE 920401 ___ 0 - 6% by weight lysophosphatidyIcholine and no t more than 10% by weight other lipids with a peroxide value of not more than 5 and a total microbiological count of not more than 100 organisms/g was 5 dissolved in 3.6 g ethanol. Then 47 g demineralized water was added to this solution and the solution was homogenized for 3 minutes with a rapidly operating laboratory stirrer. A transparent gel was produced thereby. This gel was stirred with 12.4 g ethanol and differing quantities of dextran 10 sulphate (Table 1), that took the form of a sodium salt and had a molecular weight of ca. 8000 (rapidly operating laboratory stirrer, 2 minutes). Then the batch was made up to 100 g finished product by the addition of demineralized water followed by a final stirring with a rapidly operating labor15 atory stirrer for 2 minutes. The products so produced were designated products 1-4. In addition a product range 5-8 was also prepared in parall20 el, whereby the same starting materials were used in identical amounts as for products 1-4. However, this time the corresponding amounts of dextran sulphate were not added until the last water had been added and the dextran sulphate and the liposome system were mixed manually in a convention25 al mortar. A product 9 was also prepared in parallel, whereby product 9 contained the same components as products 1-8 except that dextran sulphate was omitted from product 9. Table 1 Product Concentration of dextran sulphate In 100 g 5 completed product Example 1 Example 2 1 or 1 1.6 g 2 or 2 1 0.16 g 10 3 or 3* 0.016 g 4 or 4’ 0.0016 g 5 or 5' 1.6 g 6 or 6’ 0.16 g 7 or 7 ' 0.016 g 15 8 or 8’ 0.0016 g 9 or 9* o g The afore mentioned products 1 to 9 were tested on a group of 30 randomly chosen patients all suffering from herpes elm20 piex. For this purpose products 1 to 9 were applied locally to the diseased areas of skin and briefly rubbed in twice daily at 12 hourly intervals. Only three days after the beginning of the treatment there 25 was an appreciable improvement in the disease in patients treated with products 1 to 8. After 6 days of application of products 1, 2, 5 and 6 50% of the patients treated no longer exhibited herpes simplex. 30 After 6 days of treatment with products 3, 4, 7 and 8 40% of the patients treated no longer exhibited 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 exhibited herpes simplex, while the patients treated with products 3, 4, 7 and 8 required a total treatment period of 14 days before the herpes simplex disappeared completely. All patients treated with product 9 exhibited unchanged 5 herpes simplex even after treatment for a period of 14 days. Example 2 20 g of a phospholipid mixture (soya phospholipid), 10 comprising 95% by weight phosphatidylcholine, 3% by weight lysophosphatidylcholine and

2. % by weight other not identified phospholipids was dissolved in

3.6 g ethanol. Then 47 g demineralized 15 water was added to this solution and the solution was homogenized for three minutes with a rapidly operating laboratory stirrer. A transparent gel was produced thereby. This gel was stirred with 12.

4. G ethanol and the aforementioned differing quantities of dextran sulphate (Table 1), that 20 took the form of a sodium salt and had a molecular weight of ca. 8000 (rapidly operating laboratory stirrer, 2 minutes). Then the batch was made up to 100 g finished product by the addition of demineralized water followed by a final stirring with a rapidly operating laboratory stirrer for 2 minutes. The products so prepared were designated products 1' - 4'. Products 5' - 8' were also prepared in parallel, whereby the same starting materials were used in identical amounts as 30 for products l*-4'. However, this time the corresponding quantities of dextran sulphate were not added until the last water had been added and the dextran sulphate and the liposome system were mixed manually in a conventional mortar. A further product 9’ was also prepared in parallel, whereby product 9 contained the same components as products 1’ - 8’ except that dextran sulphate was omitted from product 9’.

5. The aforementioned products 1' to 9 ’ were tested on a group of 30 chosen patients all suffering from herpes simplex who all complained of skin irritation after the application of other preparations. For this purpose products 1' to 9’ were applied locally to the diseased areas of skin and to the

6. 10 neighbouring healthy areas of skin and briefly rubbed in twice daily at 12 hourly intervals. With respect to the treatment of herpes simplex the results were basically the same as those obtained in example 1,

7. 15 whereby the impression was obtained that the total treatment times tended to be shortened by about 1 to 2 days. However, it was worthy of note that none of the patients suffered skin irritation.

8. 20 This treatment investigation was naturally also confirmed by the fact that all the patients treated with product 9* exhibited unchanged herpes simplex even after treatment for a period of 14 days.