A STABLE PRODUCT OF ISOHEXYLNAPHTHAZARINS WITH PENTA- AND TETRA-CYCLIC TRITERPENES

Abstract: A stable pharmaceutical preparation comprising of isohexylnaphtharazins with penta- and tetra-cyclic terpenes which are the ingredients of plant oleoresins and gums. A stable pharmaceutical preparation that is the analogue of isohexylnaphtharazin that contains as active ingredients isohexylnaphtharazins and/or esters analogues from the chain alcohol hydroxyl groups of chemical formula (I), with the addition of penta- and tetra-cyclic triterpenes or better embedded in thawed oleoresins and gums of the resin-producing varieties of the genus <i>Pistacia</i>. The isohexylnaphtharazins and their analogues are useful wound-healing medicines but do present sensitivity to heat, oxygen and especially to light. A stable preparation of isohexylnaphtharazins is obtained after the dilution in olive oil and the addition of oleoresins and gums rich in penta- and tetra-cyclic triterpenes with euphane, oleanane, ursane, lanostane, lupane, and dammarane structure.

Description: A STABLE PRODUCT OF ISOHEXYLNAPHTHAZARINS WITH PENTA-AND TETRA-CYCLIC TRITERPENES The present invention is about the stable product of isohexylnaphtharazin (IEN) and/or its esters that are derived from the alcohol hydroxyl groups of the isohexyl chain. Furthermore, the invention involves a very useful medicinal product, and a method for the industrial manufacturing of the various pharmaceutical formulations of the product. Especially, the present invention is about a stable product that contains: (a) as active ingredients isohexylnaphtharazins substituted at the aromatic nucleus and/or their ester analogues that are derived from the alcohol hydroxyl groups of the isohexyl chain following the general chemical formula (I): (the R is an alkyl group: -CH(A)-CH2-CH2-C(R',R")B or CH(A)-CH=CH-C(R',R")B or -CH(A)-CH2CH=C(R',R"), A=B is a hydrogen or OX and the X is either a hydrogen or acyl derivative of carboxylic acid. The R ' and R" are alkyl groups), (b) Penta- and/or Tetra- cyclic triterpenes (PTCP) with euphane, oleanane. ursane, lanostane, lupane, and dammarane skeleton, that are components of various plant oleoresins and gums mainly from the genus Pistacia and especially the acidic fraction of Pistacia lentiscus var. Chia and Pistacia terebinthus. These molecules serve as stabilizing factors with synergistic pharmacological action and (c) virgin olive oil that serves as a stabilizing factor with antioxidant properties, as a solvent and an emulsifier of the above phases of the active ingredients IEN and the stabilizing and synergistic substances PTCP. IEN and its ester analogues from the alcohol hydroxyl groups that are represented from the chemical structure (I) possess antimicrobial, antiinflammatory and mainly wound- healing properties. IEN and its ester derivatives from the alcohol hydroxyl groups are substances sensitive against various physicochemical factors such as light, temperature, pH, the nature of the solvent or extracting agent and oxygen. However, they show specific sensitivity to light (UV- Visible) that renders them unstable because they undergo photoconversion (photooxidation, photopolymerism, photocyclization). Hence, when they are dissolved or extracted from a plant (e.g. the roots oϊAlkanna tinctoria) or when they are made with a standard method into a medicinal or cosmetic product or when they are applied externally as medicines (e.g. wound-healing ointment) as well as cosmetics, their disintegration or photoconversion occurs which results in the loss of their pharmacological properties. In order to stabilize the IEN unstable substances or their ester analogues, their preparation into pharmaceutical or cosmetic products should involve the following conditions: complete absence of light, air. temperature as well as the presence of water should be eliminated from the extracts (solutions) but also from the excipients. Specifically, the preparation of solutions or extracts of IEN requires the temperature of solvency or extraction not to exceed 40-50°C, the absence of oxygen and the presence of nitrogen and most importantly the absence of light. The application of this methodology requires specific instrumentation, which increases the cost of the producer. Furthermore, the use of these products by the consumer runs the danger of their photoconversion because of their exposure to the sunlight and thus the gradual but steady loss of their pharmaceutical properties. In addition, the fatty substances (mainly vegetable oils) that are utilized as solvents or extracting agents of IEN undergo serious alterations (tanginess) during their storage and that is due mainly to their oxidation. Hence, the addition of synthetic antioxidants is required which does not generally fall within the realm of the regulatory laws. Aim of the present invention is to provide with a pharmacologically active but also stable product of IEN or an ester analogue from an alcohol hydroxyl group. This aim has been achieved with the mixing of certain components such as PTCP with euphane, oleanane. ursane, lanostane, lupane. and dammarane skeleton, from which the most actives have been proven to be the isomeric acids masticadienonic, isomasticadienonic, ursolic and oleanolic mainly from plant oleoresins of the genus Pistacia. The use of the plant oleoresins instead of the pure PTCP is utilized because the cost for the production of the product is decreased remarkably. Virgin olive oil plays a significant role in the stabilization of the product because it contains natural antioxidant compounds (tocopherols). Thus, the present invention results in a remarkably effective and stable product of IEN and analogues but also a method for the industrial production of the above product in which one or more of the IEN substances have the following structure of the following three unknown till today substituted analogues that possess the general formula (I) and are represented with the formulae (II), (III), and (IV): IEN of the type (I) are produced synthetically or biotechnologicalh- (with the culture of plant tissues from the roots of species that belong to the family Boraginaceae, e.g. Alkanna tinctoria etc.) or in the simpler of cases they are taken from the roots of the medicinal plants Alkanna tinctoria or Lithospermum erythrorizon by extracting with cold virgin olive oil. The synthetically or biotechnologically produced IEN are dissolved in cold virgin olive oil of acidity that ranges from 0-1 and in proportion of 0.05-5% but preferably between 0.1-3%. Of similar concentration must be the Boraginaceae root extracts provided that the active substances IEN are indeed extracted. The above unstable IEN oily solutions or extracts become stable with the addition of PTCP or better fully incorporated into liquefied or melted or thawed oleoresins of the genus Pistacia of which more preferable is the Pistacia lentiscus var. Chia or Pistacia terebinthus which contain in great proportion in their acidic fraction the aforementioned PTCP. To choose either pure PTCP or plant resin or even the acidic fraction of the resin that is rich in the aforementioned triterpenes depends only on the cost but it is definitely preferable to use the plant resin. While the stabilizing ability of either the pure PTCP or the rich in PTCP plant oleoresins on the oil solutions of IEN was being studied, we observed that they possess an additional action which is the prevention of tanginess of olive oil. Specifically, the resin Pistacia lentiscus or Pistacia terbinthus or their acidic fraction when either one is added to the olive oil in concentration of 1 to 7% results in strong antioxidant action equivalent to equal amounts of known synthetic antioxidant compounds such as butyl hydroxyanisol (BHA) and butyl hydroxytoluene (BHT). Subsequent to the aforementioned treatment, the achieved stable oil solution (or extract) IEN without dependencies or need for prophylaxis from temperatures exceeding 50°C. absence of oxygen, absence of light, nitrogen atmosphere etc. is propagated with strong mixing into suitable excipients such as the preferable yellow beeswax and then is homogenized fully till it achieves room temperature. During the homogenization phase 1-3% pellets of zinc ricinoleate are added in order to deodorize the extract. The ideal proportion of the ingredients (i.e., weight fractions of the oil solutions (extracts) of IEN, oleoresin Pistacia and beeswax) of the product must be 76.5: 7.5: 16.0 (±10%) respectively. The diagrams of the industrial production of the stable product IEN with the method of extraction and dissolution are presented in Figures 1 and 2 respectively. The above stable product in various pharmaceuticals forms such as ointment, impregnated gauze, strips, spray, suspensions, emulsions and creams has been proven to be remarkably effective as a wound-healing agent in ulcerous conditions for dermatological or gastric ulcers in both human and veterinary use. More specifically, this pharmaceutical preparation is utilized for skin conditions (e.g. acne, eczema) or traumatic eruptions of the skin such as indolent ulcers of multiple etiology (venous stasis), decubitous ulcers, burns, skin openings and other skin wounds, gangrenous and leprous ulcers, gastric ulcers and duodenal ulcers. Example 1 0.1 g of IEN mixture of the type (I) is dissolved in 1 OOg of virgin olive oil of acidity 0- 1. In 76.5g of IEN oil extract, lg of a PTCP is added, preferably isomers of masticadienoic acids or oleanolic acid. Then the oil solution is heated with simultaneous stirring till the PCTP is completely dissolved. Subsequently, the warm stabilized oil solution of IEN is added to 16g of thawed yellow beeswax under strong stirring till complete homogenization is reached. Then, the stable homogenized product is dispersed in a suitable carrier (synthetic and elastic gauze) and thus it is converted into impregnated gauzes or strips. Example 2 O.lg of IEN mixture of type (I) is dissolved in lOOg of virgin olive oil of acidity 0-1. After, 76.5g of the oil extract of IEN is added to 7.5g of Pistacia lentiscus or Pistacia terebinthus resin. Then, the oil solution is heated with simultaneous stirring till all the resin is dissolved. Subsequently, the warm stabilized oily solution of IEN is added to 16g of thawed yellow beeswax under strong stirring till complete homogenization is achieved. Similarly to Example 1, besides being an ointment, the product could be in other pharmaceutical formulations such as impregnated gauzes or strips. Example 3 lOOg of pulverized root of the plant Alkanna tinctoria is extracted under normal temperature with simultaneous stirring till the absorption factor of 0.5% of the oil extract of IEN in CHC1 3 has a value of 0.450 in the visible region of the spectrum. The oil extract contains 0.1% of the mixture IEN of the type (I) and is added with stirring and heat to the thawed Pistacia lentiscus or Pistacia terebinthus resin till all the resin is dissolved. Subsequently, the warm stable oil extract IEN is added to 16g of thawed yellow beeswax to which lg of zinc ricinoleate has already been added to deodorize the mixture from the presence of the odor producing valerianic acid and continue with strong stirring till complete homogenization is reached. Example 4 The stable solution of Example 3 after the addition of deodorizers is placed in metal containers or pumps to be used as an aerosol (spray) with the help of propellants to treat extensive damage of the skin such as burns and decubitous ulcers. The product can also have veterinary applications as well.

Claims: CLAIMS 1. A wound-healing preparation utilized for the treatment of skin conditions or traumatic eruptions of the skin such as skin ulcers of multiple etiology and for the treatment of traumatic eruptions of the epithelium such as in gastric and duodenal ulcers containing as an active ingredient isohexylnaphtharazins (IEN) of the following chemical formula: (the R is an alkyl group: -CH(A)-CH2-CH2-C(R',R")B or CH(A)-CH=CH-C(R\R")B or -CH(A)-CH2CH=C(R',R"), A=B is a hydrogen or OX and the X is either a hydrogen or acyl derivative of carboxylic acid. In this claim, the active ingredient can also be a mixture of compounds of the above formula type (I) that are embedded into a carrier with stabilizing factors. 2. As in claim 1, a preparation where one or more of the active substances have the chemical structure of the following types II, III. and IV: O OH (IV) O OH O-C— CH-CH-CH, I I I I O CH 3 CH 3 3. As in claim 1, a preparation where the carrier is olive oil. 4. As in claim 3, a preparation where the stabilizing factor is pentacyclic triterpenes, acids and/or esters with an oleanane structure. 5. As in claim 3, a preparation where the stabilizing factor is tetracyclic triterpenes, acids and/or esters with a lanostane structure. 6. As in claim 3, a preparation where the stabilizing factor is pentacyclic triterpenes, acids and/or esters with an ursane structure. 7. As in claim 3. a preparation where the stabilizing factor is the plant oleoresin secretions of the gum-producing plant species belonging to the genus of Pistacia and more specifically the Pistacia lentiscus var. Chia. 8. As in claim 3. a preparation where the stabilizing factor is the plant oleoresin and gum secretions of the gum-producing plant species belonging to the genus of Commiphora and more specifically the Commiphora myrrha (myrrh). 9. As in claim 3, a preparation where the stabilizing factor is the plant oleoresin and gum secretions of the gum-producing plant species belonging to the genus of Boswellia and more specifically the Boswellia serata (olibanum). 10. As in claim 7. a stable preparation in an aerosol (spray) formulation. 1 1. As in claim 7. a stable preparation in an impregnated gauze formulation. 12. As in claim 7. a stable preparation in an ointment formulation. 13. As in claims 10,11,12, a stable preparation in aerosol impregnated gauze and ointment formulations that are prepared under the industrial method of extraction of plant tissue. 14. As in claims 10,11,12, a stable preparation in aerosol impregnated gauze and ointment formulations that are prepared under the industrial method of dissolution of IEN in olive oil. 15. As in claim 7. a stable preparation as an oil suspension formulation. 16. As in claim 10, a preparation to be used topically for the wound-healing of traumatic eruptions of the skin such as indolent ulcers of multiple etiology (venous stasis), decubitous ulcers, gangrenous and leprous ulcers, and burns. 17. As in claim 1 1. a preparation to be used topically for the wound-healing of traumatic eruptions of the skin such as indolent ulcers of multiple etiology (venous stasis), decubitous ulcers, gangrenous and leprous ulcers, and burns. 18. As in claim 12, a preparation to be used topically for the wound-healing of traumatic eruptions of the skin such as indolent ulcers of multiple etiology (venous stasis), decubitous ulcers, gangrenous and leprous ulcers, and burns. 19. As in claim 15, a preparation utilized systemically for wound healing of the epithelium in gastric and duodenal ulcers.

Inventors: PAPAGEORGIOU VASSILIOS, PAPAGEORGIOU, VASSILIOS
Applicants: PAPAGEORGIOU VASSILIOS, PAPAGEORGIOU, VASSILIOS
Application year: 2000
Main classification: A61K47
IPC codes: A61K9, A61K31, A61K47, A61P1, A61P17