Formulations containing esculoside and the use thereof in the pharmaceutical and cosmetic fields

Abstract: The present invention relates to the use of esculoside alone or in combination with adenylate cyclase stimulators, such as forskolin or Salvia miltiorrhiza diterpenes and/or with phosphodiesterase inhibitors, such as apigenine-skeleton dimeric flavones, in topical formulations for the treatment of peripheral vasculopathies related to an impaired peripheral microcirculation, cellulitis or unesthetisms connected with a deposit of superfluous fat. For the reduction of the deposits of superfluous fat of any origin, the above mentioned products are advantageously also combined with caffeine, theophylline and derivatives thereof.

Description: The present invention relates to formulations containing esculoside alone or in combination with adenylate cyclase stimulators, such as forskolin or Salvia miltiorrhiza diterpenes and/or phosphodiesterase inhibitors such as apigenin-skeleton dimeric flavones, for the topical use in the treatment of cellulitis or unesthetisms connected with the deposit of superfluous fat. The above mentioned products can be added with caffeine, theophylline, pentoxifylline. The invention also relates to the use of esculoside alone or in combination with adenylate cyclase stimulators, such as forskolin or Salvia miltiorrhiza diterpenes and/or phosphodiesterase inhibitors such as apigenin-skeleton dimeric flavones for the preparation of the above cited formulations. FR-A-2583640 and DE-A-1939008 disclose pharmaceutical compositions for the oral or parenteral administration comprising Aesculus hippocastanum extracts combined with Gingko biloba extracts and the thophylline respectively. Said compositions are useful for the treatment of Central Nervous System diseases. GB-20922445 discloses topical compositions for the treatment of cellulitis comprising a saponin containing extracts, an extract of Arnica montana and extract of Kola nuts. E. Bombardelli, Fitoterapia, vol LXVII, n 6, 1996, pages 483-511 reviews the use of esculoside, mostly by the oral route, for the treatment of venous peripheral diseases. Esculoside is a glucosidated coumarin extracted from the fruit pericarp and from the bark of Aesculus hippocastanum , and such a product has been used for a long time in the treatment of pathological conditions connected with an impaired permeability and capillary fragility and it is still used for the topical or systemic administration in the treatment of venous stasis vasculopathies, hemorrhoids and as a decongestionant in ophthalmology. It has surprisingly been found that, when formulations containing esculoside alone or in combination with compounds having adenylate cyclase stimulating activity or antiphosphodiesterase activity, and optionally also other lipolytic agents such as caffeine, theophylline, pentoxifylline, are administered to area affected with disorders due to chronic venous deficiency, such as cellulitis, or on deposits of superfluous fat such as the unesthetisms following a forced diet, a marked decrease in the pathology occurs thanks to the improvement of district microcirculation due to esculoside and to the lipolytic effect of the other components. The administrations are performed for times ranging from a few days to some months, usually three months, depending on the severity of the pathology or the unesthetism. esculoside alone or in combination with antiphosphodiesterase agents or adenylate cyclase stimulating agents can be used in treating skin early ageing, particularly face and neck skin, cellulitis-like derm-hypoderm panniculopathies and stretch marks (striae distensae); moreover the higher blood supply acts favourably also on not-glabrous skin, such as scalp, and is useful in the treatment of the primitive and secondary alopecias. In the cosmetic fields, the main uses of the products object of invention relate the ageing of the skin and cellulitis, which affects a high percentage of population in the industrialized Countries. In thigh cellulitis due to chronic venous insufficiency, a 20 subjects group was treated from the throcanterian area to the ankle for three months with a formulation containing 1.5% esculoside, 0.3% of Salvia miltiorrhiza extract (this extract containing 15% tanshinone A2), 0.4% Ginkgo biloba dimeric flavones (prepared according to Indena Patent EP 0360556) and 0.2% theophylline. In these subjects, the observed parameters dramatically changed, as it is evidenced by the data reported in Figure 1. In another test, a group of 20 subjects affected with fibrosclerotic panniculopathy of the trochanterian area with a deposit of superfluous fat was treated for 2 months with a formulation containing 1.5% esculoside, 0.3% Salvia miltiorrhiza extracts of and 1% pentoxifylline. The main control parameter was the reduction of the deposit of superfluous fat, therefore the diameter of the trochanterian area was measured; said diameter surprisingly decreased of 2.6 ± 0.2 cm. A number of other tests were carried out changing the composition and the components ratios or the nature of the components, for the treatment of the above cited pathologies and unesthetisms. The formulations according to the invention contain, besides the above mentioned active principles, the conventional carriers, additives, preservatives and the like known in pharmaceutical technique, such as those reported in the following non-limiting examples. Example I - Gel containing esculoside, Salvia miltiorrhiza extract and Ginkgo biloba dimeric flavones. 100 g of gel contain: Salvia miltiorrhiza extract 0.30 g Esculoside 1.50 g Ginkgo biloba dimeric flavones 0.50 g Hydrogenated castor oil 40(OE) (Cremophor RH40 - BASF) 1.00 g Propylene glycol 1.50 g Preservatives 0.10 g Hydroxyethyl cellulose (Natrosol 250 HHX - Aqualon) 3.00 g Purified water q.s. to. 100 g Example II - Alcoholic fluid gel containing Salvia miltiorrhiza extract and caffeine. 100 g of gel contain : Salvia miltiorrhiza extract 0.25 g Esculoside 1.50 g Caffeine 0.50 g Hydrogenated castor oil 40(OE) (Cremophor RH40 - BASF) 5.00 g Propylene glycol 3.00 g Carbomer 940 (Carbopol 980 - Goodrich) 1.00 g Ethanol 45.00 g Phosphatidylcholine (Phospholipon 90-Natterman) 0.70 g Gliceryl 6(OE)Caprilate/Caprinate (Softigen 767) 15.00 g Preservatives 0.40 g Butylhydroxytoluene 0.05 g α-Tocopherol 0.20 g Ascorbic acid 0.30 g Dimethicone copolyol (SF 1188 - General Electric) 2.00 g 10% Triethanolamine sol. 5.00 g Depurated water q.s. to. 100 g Example III - Cream containing esculoside, Salvia miltiorrhiza extract and extract of Cola nut titrated in caffeine-like alkaloids. 100 g of cream contain: Salvia miltiorrhiza extract 0.25 g Esculoside 1.50 g Cola nut dry extract (14% total alkaloids) 0.50 g Hydrogenated castor oil 40(OE) (Cremophor RH40 - BASF) 2.00 g Propylene glycol 2.00 g Carbomer 934 (Carbopol 934 P - Goodrich) 0.50 g Acrylates/Alkyl C 10-30 -Acrylate crosspolymer (Carbopol 1382 - Goodrich) 0.50 g Ethanol 15.0 g Preservatives 0.40 g Cetyl Palmitate (Cutina CP - Henkel) 8.00 g Polyisoprene (Syntesqual - Vevy) 5.00 g Polysorbate 80 (Tween 80 - ICI Americans) 2.00 g α-Tocopherol 0.20 g Ascorbyl palmitate 0.10 g Hydrogenated lanolin (Lanocerina - Esperis) 5.00 g Dimethicone 350 cps (Tegiloxan 350 - Tego) 0.50 g 10% NaOH sol. 2.40 g Depurated water q.s. to. 100 g Example IV - Lotion containing esculoside and theophylline. 100 ml of lotion contain: Esculoside 1.00 g Theophylline 0.50 g Butylhydroxytoluene 0.10 g Ethyl alcohol 50° q.s. to 100 ml Example V - gelified emulsion containing esculoside. 100 g of gelified emulsion contain: Esculoside 1.00 g Isopropyl myristate 5.00 g Preservatives 0.40 g Perfume 0.10 g Polyacrylamide, C 13-14 Isoparaffin and lauric alcohol 7(OE) (Sepigel 305 - Seppic) 3.00 g Depurated water q.s. to 100 g

Claims: Pharmaceutical and/or cosmetic formulations for the topical use, containing as the active principles esculoside combined with adenylate cyclase stimulators and/or phosphodiesterase inhibitors and/or lipolytic agents. Pharmaceutical and/or cosmetic formulations according to claim 1, containing forskolin or Salvia milthiorriza diterpenes or mixtures thereof as adenylate cyclase stimulators. Pharmaceutical and/or cosmetic formulations according to claims 1-2, containing apigenin-skeleton dimeric flavones as phosphodiesterase inhibitors. Pharmaceutical and/or cosmetic formulations according to claim 3, wherein the flavones are selected from Ginkgo biloba dimeric flavones and amentoflavone. Pharmaceutical and/or cosmetic formulations according to claims 1-4, containing caffeine, theophylline, pentoxifylline or mixtures thereof as the lipolytic agents. Pharmaceutical and/or cosmetic formulations according to claims 1-5, for the treatment of peripheral vasculopathies related to an impaired peripheral microcirculation, of cellulitis and of unesthetisms connected with a deposit of superfluous fat. The use of esculoside alone or in combination with adenylate cyclase stimulators and/or phosphodiesterase inhibitors and/or lipolytic agents for the manufacture of a medicament for the topical use, intended for the treatment of cellulitis and of unesthetisms connected with a deposit of superfluous fat.

Inventors: BOMBARDELLI EZIO, CRISTONI ALDO, MORAZZONI PAOLO, BOMBARDELLI, EZIO, CRISTONI, ALDO, MORAZZONI, PAOLO
Applicants: INDENA SPA, INDENA S.P.A.
Application year: 1995
Main classification: A61K31
IPC codes: A61P9, A61K8, A61K31, A61K36, C07H17, A61P17, A61P43, C07D311, A61Q19