Compositions comprising an isothiazole derivative and a peat-derived bioactive product

Abstract: A bioactive composition comprises an isothiazole compound of the general formula I wherein R₁ is halophenyl, R₂ is phenyl and R₃ is lower alkyl - and a peat-derived product containing not more than 70%, preferably not more than 60%, by weight, of inorganic salts, especially of sodium chloride, based on dry solids.

Description: The present invention relates to bioactive compositions and to pharmaceutical preparations containing same. It is known that certain isothiazole derivatives, particularly amides of 5-aminoisothiazole-4-carboxylic acid, have anti-inflammatory activity comparable with the activity of non-steroidal anti-inflammatory drugs, such as indomethacin. These compounds are also known to possess antiviral, antibacterial and antimycotic activities. A typical representative of these isothiazole derivatives is the p-chlorophenylamide of 3-methyl-5-benzoyl-aminoisothiazole-4-carboxylic acid, also known as Vratizolin (R) (Arch. Immunol. et Ther. Exp. 1973, 21, 891). On the other hand, peat extracts obtained by various methods using various extraction media are known to contain bioactive ingredients, which render such extracts useful for cosmetic and pharmaceutical purposes. (Chemical Abstracts 101(10), 78854e). It has now been found that the combination of the above thiazole derivatives with certain peat extracts (peat-derived products) results in an antiviral and anti-inflammatory drug with increased therapeutic potential. Thus, the present invention relates to a bioactive composition which is characterized in that it comprises a) an isothiazole compound of the general formula I wherein R 1 is halophenyl, R 2 is phenyl and R 3 is lower alkyl, and b) a peat-derived product containing not more than 70%, preferably not more than 60%, by weight, of inorganic salts, especially of sodium chloride, based on dry solids. Preferred compositions according to the present invention are characterized in that the isothiazole compound a) is a compound of formula I, wherein R 1 is chlorophenyl, preferably p-chlorophenyl. With respect to the substituent R 3 of the isothiazole compounds a), those compounds are preferred, wherein R 3 is methyl. The most preferred isothiazole compound a) is a compound of formula I, wherein R 1 is p-chlorophenyl, R 2 is phenyl and R 3 is methyl, i.e. the compound 3-methyl-5-benzoylamino-isothiazole-4-carboxy-p-chloro-phenylamide, also designated as Vratizolin (R) . This compound has the formula II Vratizolin (R) is a registered trade mark in Poland. Further preferred compositions according to the present invention are characterized in that the peat-derived product is obtainable by a process wherein a highly concentrated solution of inorganic salts, especially of sodium chloride, containing peat-derived bioactive ingredients, is diluted with demineralized water and subjected to reverse osmosis in order to desalinate the solution, inorganic salts being removed, and wherein the resulting solution is concentrated and clarified, and, preferably, sterilized and/or spray-dried. Peat-derived products of this type as well as their production are described in PCT Application No. PCT/EP92/00491 of 4th March, 1992. A particularly preferred peat-derived product is the product TTP (R) as specified in the above PCT Application and available from Torf Corporation, Wroclaw, ul. Mydlana 2, Poland. It is a spray-dried powder which is easily processable in forming pharmaceutical preparations. TTP (R) stands for "TOLPA (R) Torf Preparation", TOLPA (R) being a registered trade mark in Poland. The weight ratio of compound a) to compound b) in the compositions according to the present invention is about 30:1, preferably 30:2, more preferably 30:3. The compositions according to the present invention are useful for producing pharmaceutical preparations according to conventional methods by mixing these compositions with pharmaceutically acceptable carriers. Accordingly, the present invention also relates to pharmaceutical preparations comprising a combination of an isothiazole compound as described above and a peat-derived product as described above, together with a pharmaceutically acceptable carrier material. Such preparations may contain the active ingredient (i.e. the combination of peat-derived product and isothiazole compound) in a quantity of 3.1%, preferably 3.2%, more preferably 3.3% by weight. A preferred pharmaceutical preparation is one which contains Vratizolin (R) and TTP (R) . Vratizolin (R) and related isothiazoles are not inducers of cytokines, such as interferons (IFN) and tumor necrosis factor (TNF). However, in the presence of IFN and TNF inducers they may stimulate the synthesis of such cytokines and prolong their action. It was found that the above isothiazole derivatives, such as Vratizolin (R) , administered together with the above peat-derived products, such as TTP (R) , in human peripheral blood leukocyte cultures potentiate the activity of the peat-derived product in the production of IFN and TNF. The combination of the two components a) and b) in the composition according to the present invention was found to be clearly synergistic. Pharmaceutical preparations according to the present invention, i.e. preparations comprising the components a) and b) are useful for the treatment of herpes virus infections of the skin or mucous membranes (e.g. H. simplex labialis, facialis, H. genitalis, H. zoster varicella, eczema herpetica, other viral infections of mucous membranes, and yarious inflammatory skin diseases. Pharmaceutical preparations according to the present invention i. e. preparations comprising the components a) and b) are particularly useful for the treatment of genital virus infections transmitted during sexual intercourse and also for the prophylaxis of HIV infections together with condoms. Examples of pharmaceutical preparations are: 1. Vratizolin (R) 0.10 TTP (R) 0.01 Vehiculum ad 10.00 The hydrophilic vehiculum for the treatment of mucous membrane infections is qualitatively composed e.g. of the following ingredients: polyethylene glycol 300, glycerin, polyethylene glycol 4000, and Tween® 80 or ORABASE® Plain of Colgate-Hoyt Labs., Div. of Colgate-Palmolive Comp., One Colgate Way, Canton, WA 02021 USA (ingredients: pectin, sodium carboxymethylcellulose, and plasticized hydrocarbon gel).The vehiculum for the treatment of skin infections is hydrophilic, with following ingredients: polyethylene glycol 300, glycerin, polyethylene glycol 4000, and Tween 80. 2. Vratizolin (R) 1.50 TTP (R) 0.05 Vehiculum ad 50.00 The vehiculum for the treatment and prevention of genital and oral virus infections is as quoted above.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, GR, IE, IT, LI, LU, MC, NL, PT, SE Bioactive composition, characterized in that it comprises a)an isothiazole compound of the general formula I wherein R 1 is halophenyl, R 2 is phenyl and R 3 is lower alkyl and b) a peat-derived bioactive product containing not more than 70%, preferably not more than 60%, by weight, of inorganic salts, especially of sodium chloride, based on dry solids. A composition as claimed in claim 1, wherein R 1 of compound a) is chlorophenyl, preferably p-chlorophenyl. A composition as claimed in claim 1 or 2, wherein R 3 of compound a) is methyl. A composition as claimed in any one of claims 1 to 3, wherein R 1 of compound a) is p-chlorophenyl, R 2 is phenyl and R 3 is methyl, the compound thus being 3-methyl-5-benzoylaminoisothiazole-4-carboxy-p-chloro-phenylamide (Vratizolin). A composition as claimed in anyone of claims 1 to 4, characterized in that the peat-derived product b) is a product obtainable by a process, wherein a highly concentrated aqueous solution of inorganic salts, especially of sodium chloride, containing peat-derived bioactive ingredients, is diluted with demineralized water and subjected to reverse osmosis in order to desalinate the solution, inorganic salts being removed, and wherein the resulting solution is concentrated and clarified, and, preferably, sterilized and/or spray-dried. A composition as claimed in any one of claims 1 to 5, characterized in that the peat-derived product b) is a bioactive peat extract, preferably in the form of a spray-dried powder. A composition as claimed in anyone of claims 1 to 6, characterized in that the weight ratio of compound a) and product b) is 30:1, preferably 30:2, more preferably 30:3. A composition according to any one of claims 1 to 7, characterized in that it further contains a pharmaceutically acceptable carrier material. A composition as claimed in any one of claims 1 to 8, characterized in that it contains 3-methyl-5-benzoylaminoisothiazole-4-carboxy-p-chloro-phenylamide (Vratizolin) and a bioactive peat extract as defined in claim 6. A composition as claimed in claim 8 or 9, characterized in that it contains compound a) and product b) in a total quantitiy of 3.1%, preferably 3.2%, more preferably 3.3% by weight. A composition according to any one of claims 1 to 10, for use as a medicament. Claims for the following Contracting State : ES Process for the preparation of a bioactive composition, wherein a peat derived bioactive product b) is obtained by a process, in which a highly concentrated aqueous solution of inorganic salts, especially of sodium chloride, containing peat-derived bioactive ingredients, is diluted with demineralized water and subjected to reverse osmosis in order to desalinate the solution, inorganic salts being removed, and wherein the resulting solution is concentrated and clarified, and preferably sterilized and/or spray-dried, characterized in that said peat derived bioactive product b) which contains not more than 70%, preferably not more than 60%, by weight, of inorganic salts, especially of sodium chloride, based on dry solids, is mixed with an isothiazole compound a) of the general formula I wherein R1 is halophenyl, preferably chlorophenyl, more preferably p-chlorophenyl, R2 is phenyl and R3 is lower alkyl to yield said bioactive composition. Process as claimed in claim 1, wherein R3 of compound a) is methyl. Process as claimed in claim 1 or 2, wherein R1 of compound a) is p-chlorophenyl, R2 is phenyl and R3 is methyl, the compound thus being 3-methyl-5-benzoylaminoisothiazole-4-carboxy-p-chloro-phenylamide (Vratizolin). Process as claimed in any one of claims 1 to 3, characterized in that a bioactive peat extract, preferably in the form of a spray-dried powder, is used as said peat-derived product. Process as claimed in any one of claims 1 to 4, characterized in that the weight ratio of compound a) and peat derived product b) is 30:1, preferably 30:2, more preferably 30:3. Process as claimed in any one of the preceding claims, characterized in that the bioactive composition is prepared by mixing 3-methyl-5-benzoylaminoisothiazole-4-carboxy-p-chloro-phenylamide (Vratizolin) and a bioactive peat extract obtainable by a process as defined in claim 4. Process as claimed in any one of claims 1 to 6, characterized in that compound a) and peat derived product b) are further mixed with a pharmaceutically acceptable carrier material. Process as claimed in claim 6 or 7, characterized in that the composition contains compound a) and product b) in a total quantity of 3,1%, preferably 3,2%, more preferably 3,3% by weight. Bioactive composition, characterized in that it comprises a)an isothiazole compound of the general formula I wherein R 1 is halophenyl, R 2 is phenyl and R 3 is lower alkyl and b) a peat-derived bioactive product containing not more than 70%, preferably not more than 60%, by weight, of inorganic salts, especially of sodium chloride, based on dry solids. A composition as claimed in claim 9, wherein R 1 of compound a) is chlorophenyl, preferably p-chlorophenyl. A composition as claimed in claim 9 or 10, wherein R 3 of compound a) is methyl. A composition as claimed in any one of claims 9 to 11, wherein R 1 of compound a) is p-chlorophenyl, R 2 is phenyl and R 3 is methyl, the compound thus being 3-methyl-5-benzoylaminoisothiazole-4-carboxy-p-chloro-phenylamide (Vratizolin). A composition as claimed in anyone of claims 9 to 12, characterized in that the peat-derived product b) is a product obtainable by a process, wherein a highly concentrated aqueous solution of inorganic salts, especially of sodium chloride, containing peat-derived bioactive ingredients, is diluted with demineralized water and subjected to reverse osmosis in order to desalinate the solution, inorganic salts being removed, and wherein the resulting solution is concentrated and clarified, and, preferably, sterilized and/or spray-dried. A composition as claimed in any one of claims 9 to 13, characterized in that the peat-derived product b) is a bioactive peat extract, preferably in the form of a spray-dried powder. A composition as claimed in anyone of claims 9 to 14, characterized in that the weight ratio of compound a) and product b) is 30:1, preferably 30:2, more preferably 30:3. A composition according to any one of claims 9 to 15, characterized in that it contains compound a) and product b) together with a pharmaceutically acceptable carrier material. A composition as claimed in any one of claims 9 to 16, characterized in that it contains 3-methyl-5-benzoylaminoisothiazole-4-carboxy-p-chloro-phenylamide (Vratizolin) and a bioactive peat extract as defined in claim 14. A composition as claimed in claim 16 or 17, characterized in that it contains compound a) and product b) in a total quantitiy of 3.1%, preferably 3.2%, more preferably 3.3% by weight. A composition according to any one of claims 9 to 18 or manufactured according to any one of claims 1 to 8, for use as a medicament.

Inventors: BLACH-OLSZEWSKA ZOFIA, INGLOT ANNA, DUBOWSKA INGLOT, ANNA, PROF.
Applicants: TORF ETS, TORF ESTABLISHMENT
Application year: 1992
Main classification: A61K35
IPC codes: A61K35