Topical application dosage forms of pentacyclic triterpenes

Abstract

The present invention relates to systems or compositions for topical delivery and / or release of pentacyclic triterpenes or olive fruit extracts titrated with maslinic acid and / or oleanolic acid. The delivery and release system may be included in cosmetic compositions for skin, scalp, eyelashes, eyebrows, and nails.

Description

Technical Field

[0001] The present invention relates to topical dosage forms of pentacyclic triterpenes.

[0002] The invention originates from the field of systems for delivering and releasing active substances by topical route, in particular in the cosmetic or pharmaceutical fields.

[0003] In particular, the present invention relates to a release system suitable for delivering plant extracts and / or biologically active substances contained in said extracts through the skin, scalp and its appendages. Background Art

[0004] Topical administration requires that the substance to be administered be incorporated or delivered in a suitable dosage form.

[0005] Systems for the topical release of active substances are formulated in such a way that they deliver the active substances to the epidermis and regulate the release rate of these active substances.

[0006] These effects make it possible to increase the concentration of the active ingredient in the area of ​​the body to which the topical composition containing the release system is applied, thereby reducing the frequency of treatment, the amount of composition applied and the side effects associated with repeated applications.

[0007] The technology used to incorporate active substances and mixtures containing active substances into topical dosage forms has an impact on many aspects, including the compatibility between the carrier and the active substance to be incorporated, the stability of the formulation and the efficacy of the resulting topical formulation.

[0008] The preparation of topical formulations intended for the delivery of active substances through the skin requires consideration of the chemical-physical properties of the substance to be delivered.

[0009] In the preparation technology of topical preparations, special attention should be paid to some chemical-physical properties of the active substances to be incorporated. Among them, chemical structure, physical state, presence of functional groups, molecular weight, melting point or dropping point, n-octanol / water partition coefficient (Log P ow ), solubility or miscibility with the carrier is very important.

[0010] In some cases, the active substance to be delivered is incorporated into an intermediate system (usually called a release system) which affects the bioavailability by promoting skin absorption of the target substance.

[0011] Examples of these intermediate systems are those that make use of amphiphilic substances, such as liposomes and niosomes, or those based on the use of hollow structures, such as cyclodextrins.

[0012] Cyclodextrins are a family of dextrins composed of cyclic oligosaccharides of D-(+) glucopyranose linked by α,1-4 glycosidic bonds and closed to form a hydrophobic core. The number of monomers determines the size of the cavity.

[0013] Currently conventional cyclodextrins are described as: α, β and γ, with 6, 7 and 8 glycosidic units respectively.

[0014] Cyclodextrins are able to form solid inclusion complexes (host-guest complexes) with host compounds through molecular complexation. In these complexes, the guest molecule is located in the cavity of the cyclodextrin host. The size of the complex is the ratio between the host cavity and the guest molecule.

[0015] Liposomal systems consist of one or more layers of phospholipids forming vesicles, making them similar to cell membranes. These systems can be unilamellar (unilamellar vesicles) or multilamellar (multilamellar vesicles).

[0016] Since the structure of liposomes is similar to the fluid mosaic model of cell membranes, liposomes show high affinity for stratum corneum and intercellular cementum of epidermis.

[0017] Nonionic vesicular systems, or simply liposomes (nonionic liposomes), consist of bilayers formed by nonionic surfactants and cholesterol. They are not susceptible to oxidation like the phospholipids of liposomes and are used as storage systems for functional substances in cosmetic preparations.

[0018] However, the disadvantage of liposomes and niosomes is that they are unstable in some traditional cosmetic carriers. "Instability" refers to both changes in the three-dimensional structure of the vesicles (e.g., conversion of a lipid bilayer into a micellar monolayer) and chemical-physical changes (e.g., changes leading to phase separation, precipitation or creaming).

[0019] Another reason for the instability of liposomes and nonionic vesicle systems is the presence of some protic polar solvents in the formulation (such as ethanol, for example, at a concentration of 15%-20% v / v), or other solvents that may cause the amphiphilic bilayers to fuse and undergo coalescence and separation.

[0020] These drawbacks limit the use of liposomes and non-ionic vesicular systems in the preparation of topical compositions containing ethanol, such as lotions for the hair and scalp.

[0021] Similarly, the presence of amphiphilic substances in formulations containing liposomes or niosomes can affect the structural integrity of these vesicles and induce different reorganizations of different structures, such as the transition from lipid bilayer to monolayer. Typical examples are:

[0022] Systems containing large amounts of surfactants, such as cleaning products, typically shampoos, bath foams, body washes, and shower gels;

[0023] Systems containing large amounts of solubilizers, such as micellar water;

[0024] Systems containing large amounts of emulsifiers, e.g. emulsions.

[0025] Furthermore, due to the presence of double bonds in the two fatty chains of phospholipids, liposomal systems are susceptible to oxidation phenomena in the presence of oxygen and transition metals (impurities). This susceptibility has an impact on the organoleptic properties, shelf life, efficacy and safety of the preparations containing them.

[0026] In preparing a formulation or composition for topical use, the solubility of the active substance in the carrier is very important.

[0027] Many lipophilic bioactive substances, such as terpenes, have low solubility in carriers commonly used to prepare topical formulations.

[0028] In these cases, the addition of a solubilizer is used, for example, to facilitate the incorporation of a lipophilic substance into an aqueous or hydroalcoholic vehicle. These molecules typically have a hydrophile-lipophile balance closer to the upper end of the hydrophile-lipophile balance (HLB) range, which ranges from 0 (for soluble substances) to 20 (for substances that are dispersible in water).

[0029] It can be seen that the HLB value of oil-in-water emulsifiers is usually about 4-6; the HLB value of water-in-oil emulsifiers is usually about 8-15, the surfactant is usually about 13-16, and the solubilizer is usually about 15-18. Generally speaking, substances with an HLB value lower than 10 have lipophilic properties, substances with an HLB value higher than 10 have hydrophilic properties, and an HLB value of 10 represents a completely balanced state.

[0030] Thus, the solubility of significantly lipophilic substances, such as terpenoids, in aqueous or hydroalcoholic vehicles may be increased by the use of appropriate solubilizing agents.

[0031] The same approach is used for the solubilization of fragrances in alcoholic or hydroalcoholic carriers. The solubilizer or pair of solubilizers is selected taking into account the composition of the continuous phase and the phase to be dissolved.

[0032] Obtaining a transparent composition indicates that the phase to be dissolved is effectively dissolved. The presence of turbidity or oily droplets on the surface and the appearance of creaming after centrifugation indicate that the phase is not dissolved.

[0033] However, in some cases, it is not possible to dissolve or solubilize one or more substances in the composition in a desired amount, thus making it difficult to prepare the composition.

[0034] Sometimes this obstacle can be overcome by implementing a decentralized system.

[0035] As applied to dispersed systems, Stokes' law is useful if one wishes to stabilize a formulation containing components that are not well soluble in the vehicle.

[0036] This law expresses the sedimentation rate of particles in a heterogeneous mixture. According to this law, the diameter d of the particle (the larger the diameter or radius of the particle, the higher the sedimentation rate); in the case of an emulsion, the density difference Δρ between the particle and the continuous or external phase (the larger the density difference, the higher the sedimentation rate); and the dynamic viscosity η of the formulation (the lower the viscosity, the higher the sedimentation rate) are parameters that can be varied, thereby affecting the physical stability of the product and slowing down the separation of the components (sedimentation, floating surface, sedimentation and creaming).

[0037]

[0038] However, in some cases, due to the nature of the formulation, it is not possible to stabilize the formulation by changing the variables in Stokes' Law.

[0039] This is the case, for example, with highly fluid or ultrafluid emulsions and hydroalcoholic lotions for the hair and scalp.

[0040] In both cases, low viscosity is ideal, consistent with the intended application of the product itself and compatible with the type of primary container being used.

[0041] Typical examples include lotions in bag-on-valve containers, or hair lotions in vials, which necessarily do not have the typical high viscosity of gels, or oil-in-water emulsions, which by their nature usually have a lipophilic internal phase of significantly lower density than the external aqueous phase.

[0042] Furthermore, in the case of hair lotions, factors such as sensory properties and the residue left on the hair are relevant as they weigh the hair down, affecting the manageability of the hair and the aesthetics of the hairstyle.

[0043] These formulation issues are more pronounced for some bioactive molecules that are poorly soluble in aqueous and hydroalcoholic systems.

[0044] A general object of the present invention is to overcome the problems encountered in preparing and incorporating poorly water-soluble biologically active substances or plant extracts containing them into topical formulations.

[0045] Another problem of the present invention is to prepare dosage forms for the topical administration and local controlled release of pentacyclic triterpenes.

[0046] Another technical problem of the present invention is to provide a composition for delivering and releasing a stable form of a topical composition or formulation containing pentacyclic triterpenes as biologically active components through the skin. Summary of the invention

[0047] The present invention arises from the technical field of formulation of systems for the delivery and release of active ingredients and provides technical solutions to the obstacles and technical problems encountered in the formulation and delivery of biologically active substances that are poorly soluble in aqueous and hydroalcoholic systems, such as pentacyclic triterpenes and organic mixtures containing pentacyclic triterpenes.

[0048] In a general aspect, the present invention provides a composition for the topical delivery and release of pentacyclic triterpenes and biological mixtures (eg, plant extracts) containing pentacyclic triterpenes.

[0049] In the scope of research activities in the field of the present invention, the inventors unexpectedly found that by combining poly-n-glyceryl-sorbityl enoxolone with highly branched cyclodextrins, a system suitable for delivering and releasing poorly water-soluble biologically active substances (such as pentacyclic triterpenes or plant extracts containing pentacyclic triterpenes) through the epidermis is obtained.

[0050] Therefore, an object of the present invention is a composition for the local delivery and / or release of a mixture of biologically active components of pentacyclic triterpenes or pentacyclic triterpenes, characterized in that the composition comprises poly-n-glyceryl-sorbitan glycyrrhetinate having the following formula (I):

[0051]

[0052] Where "n" is an integer from 1 to 3,

[0053] "Sorb" represents a sorbitol residue, and

[0054] "Polygly" means a glycerol or polyglycerol residue having a degree of polymerization of 1.5 to 10,

[0055] The composition also includes highly branched cyclodextrin.

[0056] In some embodiments, the pentacyclic triterpenes are contained in a plant extract, specifically a plant extract obtained from olive fruit.

[0057] Applicants have unexpectedly discovered that the combination of poly-n-glyceryl-sorbitan glycyrrhetinate and highly branched cyclodextrins, as described herein, form an effective topical transport and delivery system for pentacyclic triterpenes or mixtures or plant extracts containing pentacyclic triterpenes as biologically active components.

[0058] The compositions of the present invention may be absorbed into a delivery and / or release system that facilitates the delivery of a functional compound through the skin, such as a pentacyclic triterpene or a mixture of biologically active substances, preferably with a higher content of pentacyclic triterpene than the other biologically active components forming the mixture.

[0059] Typically, the compositions of the present invention are in topical dosage form.

[0060] The inventors have observed that compositions for topical delivery and / or release of bioactive substances are compatible and matched with the chemical-physical properties of pentacyclic triterpenes and bioactive substance mixtures containing pentacyclic triterpenes, such as some plant extracts.

[0061] The composition for delivering and / or releasing a bioactive substance of the present invention delivers pentacyclic triterpenes and mixtures containing pentacyclic triterpenes (eg, plant extracts) through the skin and appendages, thereby increasing the bioavailability of triterpenoids in the skin area after application.

[0062] The composition of the present invention is effective in regulating the release of pentacyclic triterpenes and mixtures of biologically active substances containing pentacyclic triterpenes or having pentacyclic triterpenes dispersed therein (eg, some plant extracts).

[0063] Preferably, the composition for delivering and / or releasing a biologically active substance as described herein is suitable for delivering the triterpenoid component present in a plant extract, in particular an olive fruit extract.

[0064] For the purposes of the present invention, the topical delivery and / or release of maslinic acid and / or oleanolic acid from the compositions or delivery systems described herein is particularly important.

[0065] Typically, controlled release and / or topical administration systems of pentacyclic triterpenes are used for cosmetic or pharmaceutical purposes.

[0066] In another aspect, the present invention relates to the use of a composition as defined herein for delivering and / or releasing a pentacyclic triterpene, in particular maslinic acid and / or oleanolic acid, from a topical composition.

[0067] One advantage of the compositions or delivery systems described herein is their broad versatility, as they can be applied to complex mixtures of pentacyclic triterpenes and bioactive substances containing pentacyclic triterpenes without requiring the use of more complex or different equipment than is typically available in dosage form manufacturing laboratories or by raw material manufacturers in the pharmaceutical or cosmetic industries.

[0068] In another aspect, a cosmetic composition is provided comprising a composition for topical delivery or release of a pentacyclic triterpene as defined herein and a pentacyclic triterpene, in particular maslinic acid and / or oleanolic acid, or an olive fruit extract, and further comprising a cosmetically acceptable carrier.

[0069] In another aspect, the present invention relates to the use of a cosmetic composition comprising a system for topical delivery and / or release of pentacyclic triterpenes or olive fruit extract for improving the appearance of the skin or nails or stimulating the physiological growth of hair, eyelashes or eyebrows, mucous membranes, nail epithelium / periungual epidermis.

[0070] Several aspects of the invention will become more apparent from the following description of the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 A graphical representation of the absorption spectrum of a product containing 10% olive (Olea europaea) fruit dry extract (75%-80% total pentacyclic triterpenes by HPLC titration, of which 60%-68% is maslinic acid and 12%-15% is oleanolic acid) in 0.08% ethanol solution is shown;

[0072] Figure 2 shows a graphical representation of the absorption spectrum of the formulation of Example 15, which is based on aerosolized pentacyclic terpenoids containing highly branched cyclodextrins in water;

[0073] Figure 3 shows a graphical representation of the absorption spectrum of the formulation of Example 16, which contains a pentacyclic terpene delivery system of highly branched cyclodextrin and polyglycerol-sorbitan glycyrrhetinate in water according to one embodiment of the present invention;

[0074] Figure 4 shows a graphical representation of the absorption spectrum of the formulation of Example 17, which is based on aerosolized pentacyclic terpenoids containing highly branched cyclodextrins in a hydroalcoholic solution;

[0075] Figure 5 A graphical representation showing the absorption spectrum of the formulation of Example 18, which relates to a pentacyclic terpene delivery system containing highly branched cyclodextrin and polyglycerol-sorbitan glycyrrhetinate in a hydroalcoholic solution, according to one embodiment of the present invention;

[0076] Figure 6 shows a graphical representation of the absorption spectrum of the formulation of Example 19, which involves dissolving an olive fruit extract titrated with maslinic acid and oleanolic acid using polyoxyethylene (40) hydrogenated castor oil in water;

[0077] Figure 7 A graphical representation of the absorption spectrum of the formulation of Example 20 is shown, which relates to a pentacyclic terpene delivery system containing highly branched cyclodextrin and polyglycerol-sorbitan glycyrrhetinate and polyoxyethylene (40) hydrogenated castor oil in water according to one embodiment of the present invention. DETAILED DESCRIPTION

[0078] One of the purposes of the compositions or delivery systems described herein is to improve the bioavailability of bioactive substances that are difficult to prepare as topical compositions and / or are poorly soluble in aqueous and hydroalcoholic systems, such as triterpenoids, in particular pentacyclic triterpenes. These molecules can be traced back to the skeletons of ursane, oleanane, lupane and suberane, and have high biological value, but due to their poor solubility, no desirable topical applications have been found. Therefore, according to certain aspects, the present invention arises from the need to create systems that facilitate both the inclusion of these substances in topical preparations or compositions and their delivery through the epidermis.

[0079] To achieve these objectives, the inventors have prepared a composition or delivery system having two components or carriers in which pentacyclic triterpenes or complex mixtures of bioactive substances containing pentacyclic triterpenes are dissolved or solubilized.

[0080] The two essential components or carriers of the compositions of the present invention are suitable for topical application and are pharmaceutically or cosmetically acceptable.

[0081] According to a first aspect, the present invention provides a composition for local delivery and / or release of a bioactive substance, the composition comprising poly-n-glyceryl-sorbitan glycyrrhetinate as defined herein and at least one highly branched cyclic dextrin, wherein the bioactive substance is a pentacyclic triterpene or a mixture of bioactive components containing pentacyclic triterpenes, preferably a plant extract, in particular a plant extract from olive tree fruit.

[0082] In some preferred embodiments, the mixture of bioactive components containing pentacyclic triterpenes is an olive tree fruit extract titrated with maslinic acid and / or oleanolic acid.

[0083] One of the components or carriers of the topical compositions described herein is poly-n-glyceryl-sorbitan glycyrrhetinate, which has the following formula (I):

[0084]

[0085] Where "n" is an integer from 1 to 3,

[0086] "Sorb" represents a sorbitol residue, and

[0087] "Polygly" means a glycerol or polyglycerol residue having a degree of polymerization of 1.5 to 10.

[0088] In some embodiments, Polygly in poly-n-glyceryl-sorbitan glycyrrhetinate represents a polyglycerol residue with a degree of polymerization of 1.5 to 10, preferably 3 to 5.

[0089] According to certain embodiments, in formula (I) the ester is 1.

[0090] Another component or carrier of the composition of the present invention is highly branched cyclodextrin.

[0091] For the purposes of the present invention, the term highly branched cyclodextrin or cyclodextrin (highly branched cyclodextrin) refers to a dextrin with a cyclic structure produced starting from a substance made of or containing amylopectin (e.g. corn starch), which is obtained by a cyclization reaction carried out by an enzyme, separating two highly branched clusters or regions (regions of the amylopectin molecule in which branches with 1 to 6 bonds are present) by hydrolysis of the chains (1→4), thereby producing fragments of highly branched cyclic amylopectin polysaccharide.

[0092]

[0093] Advantageously, no alpha, beta or gamma cyclodextrins are used within the scope of the present invention. These conventional cyclodextrins are different from the highly branched cyclodextrins contained in the compositions or delivery systems described herein.

[0094] Unlike amylopectin which is insoluble in cold water, highly branched cyclodextrin is very soluble in water, and the solution obtained therefrom has little effect on the osmotic pressure and shows almost no tendency to deterioration.

[0095] Since all bonds are alpha type, the structure of both the starting polysaccharide and the fragments is a coiled alpha-helix with approximately 3.5 monomer molecules. Due to their structure, highly branched cyclodextrins have inclusion areas for "guest" molecules, such as the pentacyclic triterpenes described herein.

[0096] Advantageously, both components of the composition act as carrier and solubilizer for pentacyclic triterpenes or biologically active mixtures containing pentacyclic triterpenes, such as maslinic acid and oleanolic acid, in particular extracts from plant parts, such as extracts from olive fruit.

[0097] The one or more biologically active substances delivered by the compositions or delivery systems described herein are triterpenoids, specifically lipid-soluble pentacyclic triterpenoids that are poorly soluble in polar protic solvents such as water, ethanol, and mixtures thereof.

[0098] Pentacyclic triterpenes are active phytochemicals that possess a wide range of biological activities of human interest, such as anti-inflammatory, hepatoprotective, antihypertensive, anti-ulcer, and anticancer activities.

[0099] Suitable examples of pentacyclic triterpenes are compounds containing the ursane, oleanane, lupane and suberane skeletons, which have the following structural formula:

[0100]

[0101] According to some embodiments, the pentacyclic triterpene is a derivative of ursane, oleanane, lupane, suberane and mixtures thereof, specifically selected from the following:

[0102] Lupane derivatives: Lupeol; 3α,27-Dihydroxylup-20(29)-en-28-oic acid methyl ester; Betulin; Betulinic acid; Pulsatillic acid; Ochraceolide D; Ochraceolide A; Ochraceolide B.

[0103] Ursolic Acid: α-Amyrin; Ursolic Acid; Regelin; Quinovic Acid; Corosolic Acid; Pomolicacid; Euscaphic Acid; β-Boswellic Acid, Acetyl-β-Boswellic Acid; 11-Keto-β-Boswellic Acid; Acetyl-11-Keto-β-Boswellic Acid; 3-O-Acetyl-11-Keto-β-Boswellic Acid;

[0104] Oleanane derivatives: Oleanolic acid; epi-Oleanolic acid; Moronic acid; Maslinic acid; Maytenfolicacid; Acetyl-α-boswellic acid; α-boswellic acid; Acetyl-α-boswellic acid; Hydroxyamyrins; Remangilone A; Remangilone C; Oleanolic acid 3-trans-caffeate; Oleanolic acid 3-trans-cumarate; Oleanolic acid 3-cis-caffeate; Oleanolic acid 3-trans-caffeate; Oleanolic acid 3-trans-caffeate; β-amyrin;

[0105] Corkane derivatives: Friedelin, Celastrol, 3-Oxo-friedelan-29-oic acid); 3-Oxo-friedelan-28-oicacid; 28-29-Dihydroxyfriedelan-3-one; Maytenfolone-A; Tingenone; Pristimerin; Tripterygium wilfordii; Iguesterin; Isoiguesterin; 22β-Hydroxytingenone; 20-Hydroxy-20-epi-tingenone; Netzahualcoyondiol; Netzahualcoyon e; 15α-Hydroxypristimerin; 17-(Methoxycarbonyl)-28-nor-isoiguesterin; Amazoquinone; Netzahualcoyonol; Scutione; 6-Oxotingenol; 7,8-Dihydro-6-oxo-tingenol; 3-Methyl-6-oxotingenol; 6-Oxopristimerol; Demethylzeylasteral.

[0106] In the context of the present invention, particular interest is given to the pentacyclic triterpenes maslinic acid and oleanolic acid, which can be obtained from the processing of the fruits of the olive tree (Olea europaea).

[0107] According to some embodiments, the pentacyclic triterpenes to be delivered are maslinic acid and / or oleanolic acid and plant extracts containing them obtained from olive fruit.

[0108] Maslinic acid [CAS 4373-41-5] and oleanolic acid [CAS 508-02-1] may be present in the composition as plant extracts, in particular as individual molecules or as a mixture.

[0109] According to certain embodiments, the composition or delivery system described herein comprises a plant extract, in particular a plant extract from olive fruit, preferably with a pentacyclic triterpene content greater than or equal to 75% by weight.

[0110] Within the scope of the present invention, suitable plant extracts can be obtained from olive fruits, in particular from the Olea europaea plant.For the use according to the invention, the extract is preferably obtained from olive tree fruits (olives).

[0111] Plant extracts can be obtained from olives by extraction using a physiologically acceptable solvent as extraction medium.

[0112] The term "physiologically acceptable solvent" means a solvent that does not produce significant adverse reactions when introduced into or applied to the human body. Suitable solvents for obtaining plant extracts are physiologically acceptable liquids in which the biologically active components of the selected plant are soluble and in which they do not undergo changes that lose their activity.

[0113] In some embodiments, the physiologically acceptable solvent is selected from protic polar solvents such as water, acetic acid, ethanol, n-butanol, ethyl acetate, isopropanol, n-propanol, and mixtures thereof.

[0114] Preferably, the extraction solvent is a protic polar solvent selected from water, ethanol, ethyl acetate and a mixture thereof, more preferably the extraction solvent is a mixture of water and ethyl acetate.

[0115] To obtain plant extracts, solid-liquid extraction techniques may be used to separate / extract one or more bioactive components from plant tissues of plants.

[0116] In certain embodiments, one or more bioactive components are extracted by extracting a portion of the olive or plant matrix in a suitable solvent.

[0117] According to a preferred embodiment, the process for producing a suitable extract from olive fruit comprises the following steps: a) extraction from olives using a protic polar solvent, preferably a protic polar solvent based on a mixture of water and ethyl acetate, b) drying and removal of the solvent. Advantageously, a purification step of the olive extract product is provided between the two steps a) and b).

[0118] For example, a suitable extract can be obtained by soaking or immersing a portion of olives in a mixture of water and ethyl acetate for a period of time suitable for enriching the solvent with one or more biologically active components. Under these conditions, the extraction of biologically active components from the plant tissue of the selected plant is essentially carried out by diffusion and / or osmosis. The immersion time of the plant part in the solvent is variable, for example from 1 to 48 hours. The material obtained from the extraction is purified and then dried.

[0119] According to certain embodiments, the preparation of a suitable olive extract comprises the following steps:

[0120] - Shred the olives or peel,

[0121] - adding an extraction solvent, such as a water-ethyl acetate mixture, to obtain a drug / hydroalcoholic solvent ratio of about 1:10 w / w to about 1:50 w / w,

[0122] - Impregnation,

[0123] - Extraction of bioactive components,

[0124] -filter,

[0125] - concentrating the filtrate, for example by evaporating the hydroalcoholic solvent under reduced pressure,

[0126] - Dry extract.

[0127] According to another embodiment, the olive extraction method comprises the following steps:

[0128] - Shred the olives,

[0129] - transfer the obtained powder into a suitable percolator,

[0130] - diafiltration, e.g. with an amount of extraction solvent to obtain a product / solvent ratio of about 1:20 w / w to about 1:100 w / w,

[0131] - recirculate part of the leachate until the material to be extracted is exhausted,

[0132] - Pressing the extracted plant bed to recover all the extraction solvent,

[0133] - filtration of the leachate,

[0134] - Concentrating the filtrate, for example by evaporating the solvent under reduced pressure.

[0135] According to some embodiments, in a final step of removing the solvent by evaporation, a solid support, such as starch or maltodextrin, is added to obtain the extract in the form of a dry powder.

[0136] The extract obtained from olives can be liquid, moist or dry.

[0137] Olive extracts of varying polarity can be prepared.

[0138] In certain embodiments, the extraction is accomplished using a solvent to plant matrix weight ratio of 1:10 to 10:1.

[0139] Preferably, the extract obtained from olive tree fruit comprises maslinic acid and / or oleanolic acid; more preferably, the total amount of maslinic acid in the extract is between 10% and 80%, between 30% and 80%, even more preferably between 75% and 80%.

[0140] According to certain embodiments, the olive fruit extract comprises 75%-80% of total pentacyclic triterpenes, of which 60%-68% are maslinic acid and 12%-15% are oleanolic acid, by HPLC titration.

[0141] Maslinic acid, (2α,3β)-2,3-dihydroxyolean-12-ene-28-oic acid (IUPAC), CAS No. 4373-41-5, belongs to the pentacyclic triterpenoids called oleanane. This compound can be derived from the wax present in the olive skin, which is a byproduct of the extraction of olive oil from the fruit of the plant.

[0142] Oleanolic acid, CAS 508-02-1, is a pentacyclic triterpene with the following structural formula, which occurs naturally in olive oil and its extracts,

[0143]

[0144] According to certain embodiments, the compositions or delivery systems described herein may also be applied to systems containing surfactants, in particular systems containing no more than 20% detergent actives, advantageously when turbidity or opalescence is present, which is an indicator of a poor ability of the carrier to incorporate the biologically active substance.

[0145] According to certain embodiments, the compositions described herein may comprise or be included in an oil-in-water (O / W) emulsion. According to these embodiments, the incorporation of the composition or system is carried out in a hot / hot or cold / hot emulsion, preferably by stirring, when the temperature of the system is below 40° C. The same incorporation conditions apply to water-in-oil emulsions.

[0146] The composition or delivery system of the present invention can be incorporated into a pharmaceutical or cosmetic composition.

[0147] According to another aspect, the present invention relates to a cosmetic or pharmaceutical composition for topical use comprising a composition or a delivery system according to the embodiments described herein, a pharmaceutically or cosmetically active substance and a pharmaceutically and / or cosmetically acceptable carrier.

[0148] Cosmetically or pharmaceutically acceptable carriers suitable for use in the compositions of the present invention may include ingredients belonging to the following categories: rheology modifiers, plasticizers, emulsifiers, surfactants, humectants, superfatting agents, solubilizers, colorants, lubricants, stabilizers, conditioners, fragrances, essential oils, adsorbents, preservatives, buffers, antimicrobial agents, antioxidants, antisebum agents, antistatic agents, absorbents, chemical or physical sunscreens, astringents, chelating agents, skin conditioning agents, covering agents, denaturing agents, depigmenting agents, emollients, emulsifiers, film formers, humectants or moisturizing substances, hydrotropes, soothing agents, emollients, opacifiers or pearlescent agents, skin protectants, reducing agents, fresheners, sebum restoration agents, solvents, emulsion stabilizers, toners, humectants, colorants, texturizers, and mixtures thereof.

[0149] According to some embodiments, the compositions / delivery and dispersion systems described herein are incorporated into the composition in an amount of 0.01 wt% to 20 wt%, preferably 0.05 wt% to 5 wt%, relative to the total weight of the composition.

[0150] The cosmetic / pharmaceutical compositions of the present invention may be in any form suitable for topical or external application.

[0151] Advantageously, the composition is a topical composition intended for use on the skin, appendages and scalp.

[0152] In certain embodiments, the compositions of the present invention are in the form of a liquid, such as an aqueous lotion containing one or more carriers and / or excipients suitable for cosmetic applications.

[0153] Other embodiments of compositions in liquid form include solutions, suspensions, shampoos, lotions, or solid or semisolid or liquid forms such as balms, serums, ointments or creams.

[0154] In liquid form, the composition may typically contain about 1% to 99.9% by weight of water. In some embodiments, water is present in an amount of 5% to 95% by weight. In other embodiments, water is present in an amount of 10% to 90% by weight.

[0155] In some embodiments of the present invention, the cosmetic or pharmaceutical composition is anhydrous or contains less than 10% by weight of water.

[0156] In other embodiments of the present invention, the cosmetically acceptable carrier is anhydrous or contains water in an amount less than 2% by weight, confined within a soft gelatin capsule.

[0157] In some embodiments, the carrier of the composition of the present invention is a base formulation for cosmetic formulations, preferably for preparing a liquid formulation suitable for skin application.

[0158] The compositions described herein may be incorporated into topical preparations or compositions in solid form (e.g., creams, ointments, or salve), or in semisolid form (e.g., gel), or in liquid form (e.g., solutions, suspensions, slurries, or lotions).

[0159] Preferably, the composition can be added to hair or skin lotions, creams, micellar waters and hydroalcoholic preparations containing essential oils and / or odoriferous substances.

[0160] For the purposes of the present invention, lotion refers to a water-based solution or dispersion, which may contain ethanol. For example, the amount of ethanol may be 1% v / v to 50% v / v, 20% v / v to 30% v / v (volume / volume).

[0161] For purposes of this invention, a slurry refers to a topical formulation containing a higher than average concentration of one or more active ingredients, sometimes referred to as an elixir.

[0162] In certain embodiments, the compositions described herein may be added at 18% to 30% by weight.

[0163] For the purposes of the present invention, micellar water refers to a preparation commonly used for perfumery, cleansing the skin, and removing makeup, which usually contains amphiphilic substances with a high hydrophilic-lipophilic balance and can be classified as solubilizers or surfactants in most cases. An example of such a product is a makeup remover micellar water.

[0164] The compositions or delivery systems described herein allow the production of cosmetic preparations having organoleptic properties.

[0165] The compositions of the present invention may be applied in an effective amount directly to the area to be treated, typically the skin and its appendages, scalp, lips, eyelashes, eyebrows and nails.

[0166] The following examples are provided primarily to illustrate the present invention.

[0167] Example 1

[0168] Anti-hair loss lotion

[0169]

[0170] Prepare according to Example 7:

[0171]

[0172]

[0173] Example 2

[0174] Hemorrhoid gel

[0175] Prepare according to Example 7:

[0176] Example 3

[0177] Eyelash serum

[0178]

[0179] Prepare according to Example 7:

[0180] Example 4

[0181] Facial serum

[0182] Prepare according to Example 7:

[0183]

[0184]

[0185] Example 5

[0186] Anti-hair loss shampoo

[0187] Prepare according to Example 7:

[0188]

[0189]

[0190] Example 6

[0191] Nail and Cuticle Protective Gel

[0192]

[0193] Prepare according to Example 7:

[0194]

[0195] Example 7

[0196] Composition / pentacyclic terpene delivery system containing highly branched cyclodextrin and polyglycerol sorbitan glycyrrhetinate.

[0197] 1.5% Poly-3-glyceryl sorbitan glycyrrhetinate: IUPAC name: 3-Poly-(1,2,3)-trihydroxypropane-(2S,3R,4R,5R)-hexane-1,2,3,4,5-pentanol-6-oxa-(3β,20β)-3-hydroxy-11-oxo-olean-12-ene-29-ate.

[0198] 10% olive (Olea europaea) fruit dry extract (75%-80% total pentacyclic triterpenes by HPLC titration, of which 60%-68% is maslinic acid and 12%-15% is oleanolic acid).

[0199] 88.5% highly branched cyclodextrin (HBCD content>80%, glucose equivalent≤5%)

[0200] Example 8

[0201] A nebulized pentacyclic terpene product containing highly branched cyclodextrin.

[0202] 10% olive (Olea europaea) fruit dry extract (75%-80% total pentacyclic triterpenes by HPLC titration, of which 60%-68% is maslinic acid and 12%-15% is oleanolic acid).

[0203] 90% highly branched cyclodextrin (HBCD content>80%, glucose equivalent≤5%)

[0204] Example 9

[0205] A composition comprising aerosolized pentacyclic terpenes containing highly branched cyclodextrins in water.

[0206] Ingredient (INCI name) Amount w / w (%)

[0207] Prepare according to Example 8:

[0208] Dextrin, olive fruit extract 0.80%

[0209] Demineralized water: Water: 99.20%

[0210] Total: 100.00%

[0211] Method: Cold preparation. In a suitable container, add the atomized pentacyclic terpenes containing highly branched cyclodextrins to demineralized water; mix with a magnetic stirrer at 600 rpm for 10 minutes.

[0212] Example 10

[0213] A pentacyclic terpene delivery system containing highly branched cyclodextrins and polyglycerol sorbitan glycyrrhetinate in water.

[0214] Ingredient (INCI name) Amount w / w (%)

[0215] Preparation of Example 7:

[0216] Dextrin, olive fruit extract, poly-3-glyceryl sorbitan glycyrrhetinate: 0.80%

[0217] Demineralized water: Water 99.20%

[0218] Total 100.00%

[0219] Method: Cold preparation. In a suitable container, add the atomized pentacyclic terpenes containing highly branched cyclodextrin and polyglycerol sorbitan glycyrrhetinate to demineralized water; mix with a magnetic stirrer at 600 rpm for 10 minutes.

[0220] Embodiment 11

[0221] Aerosolized pentacyclic terpenes containing highly branched cyclodextrins in a hydroalcoholic solution.

[0222] Ingredient (INCI name) Amount w / w (%)

[0223] Preparation of Example 8:

[0224] Dextrin, olive fruit extract 0.80%

[0225] 16.5% w / w hydroalcoholic solution: water, denatured alcohol type C 99.20%

[0226] Total 100.00%

[0227] Method: Cold preparation. In a suitable container, add the atomized pentacyclic terpenes containing highly branched cyclodextrins to the hydroalcoholic solution; mix with a magnetic stirrer at 600 rpm for 10 minutes.

[0228] Example 12

[0229] A pentacyclic terpene delivery system containing highly branched cyclodextrins and polyglycerol sorbitan glycyrrhetinate in a hydroalcoholic solution.

[0230] Ingredient (INCI name) Amount w / w (%)

[0231] Prepare according to Example 7:

[0232] Dextrin, olive fruit extract, poly-3-glyceryl sorbitan glycyrrhetinate: 0.80%

[0233] 16.5% w / w hydroalcoholic solution: water, denatured alcohol type C 99.20%

[0234] Total 100.00%

[0235] Method: Cold preparation. In a suitable container, add the pentacyclic terpene delivery system containing highly branched cyclodextrin and polyglycerol sorbitan glycyrrhetinate to the hydroalcoholic solution; mix with a magnetic stirrer at 600 rpm for 10 minutes.

[0236] Embodiment 13

[0237] Olea europaea fruit extract titrated with maslinic acid and oleanolic acid was dissolved in water using polyoxyethylene (40) hydrogenated castor oil.

[0238]

[0239] Method: In a suitable container, add olive extract titrated with maslinic acid and oleanolic acid, then add polyoxyethylene (40) hydrogenated castor oil previously introduced into a hot chamber. Mix until homogeneous. Heat the phase to 85°C on a plate, then slowly add 1 / 10 of demineralized water while keeping the system under constant stirring. In another container of suitable size, add the remaining water, then drop in the phase containing the olive extract. Mix for 10 minutes at 600 rpm using a magnetic stirrer.

[0240] Embodiment 14

[0241] A pentacyclic terpene delivery system containing highly branched cyclodextrin and polyglycerol sorbitan glycyrrhetinate in water and containing polyoxyethylene (40) hydrogenated castor oil.

[0242] Ingredient (INCI name) Amount w / w (%)

[0243] Prepare according to Example 13:

[0244]

[0245] Method: Cold preparation. In a suitable container, add the pentacyclic terpene delivery system containing highly branched cyclodextrin and polyglycerol sorbitan glycyrrhetinate to the formulation water, and then add the polyoxyethylene (40) hydrogenated castor oil previously introduced into the hot chamber. Mix until homogeneous. Mix with a magnetic stirrer at 600 rpm for 10 minutes.

[0246] Embodiment 15

[0247] Aerosolized pentacyclic terpenes in water containing highly branched cyclodextrins.

[0248] Ingredient (INCI name) Amount w / w (%)

[0249] Prepare according to Example 14:

[0250] Dextrin, olive fruit extract 0.80%

[0251] Demineralized water: Water 99.20%

[0252] Total 100.00%

[0253] Method: Cold preparation. In a suitable container, add the atomized pentacyclic terpenes containing highly branched cyclodextrins to demineralized water; mix with a magnetic stirrer at 600 rpm for 10 minutes.

[0254] Embodiment 16:

[0255] Pentacyclic terpenoid delivery system with highly branched cyclodextrin and polyglycerol sorbitan glycyrrhetinate in water (invention).

[0256] Ingredient (INCI name) Amount w / w (%)

[0257] Prepare according to Example 1:

[0258] Dextrin, olive fruit extract, poly-3-glyceryl sorbitan glycyrrhetinate 0.80%

[0259] Demineralized water: aqueous solution 99.20%

[0260] Total 100.00%

[0261] Method: Cold preparation. In a suitable container, add the pentacyclic terpene delivery system containing highly branched cyclodextrin and polyglycerol sorbitan glycyrrhetinate to demineralized water; mix with a magnetic stirrer at 600 rpm for 10 minutes.

[0262] Embodiment 17

[0263] Aerosolized pentacyclic terpenes containing highly branched cyclodextrins in a hydroalcoholic solution.

[0264] Ingredient (INCI name) Amount w / w (%)

[0265] Preparation of Example 14:

[0266] Dextrin, olive fruit extract 0.80%

[0267] 16.5% w / w hydroalcoholic solution: water, denatured alcohol type C 99.20%

[0268] Total 100.00%

[0269] Method: Cold preparation. In a suitable container, add the atomized pentacyclic terpenes containing highly branched cyclodextrins to the hydroalcoholic solution; mix with a magnetic stirrer at 600 rpm for 10 minutes.

[0270] Embodiment 18

[0271] Pentacyclic terpene delivery system containing highly branched cyclodextrins and polyglycerol sorbitan glycyrrhetinate in a hydroalcoholic solution (invention).

[0272] Ingredient (INCI name) Amount w / w (%)

[0273] Prepared according to Example 13

[0274] Dextrin, olive fruit extract, poly-3-glyceryl sorbitan glycyrrhetinate: 0.80%

[0275] 16.5% w / w hydroalcoholic solution: water, denatured alcohol type C 99.20%

[0276] Total 100.00%

[0277] Method: Cold preparation. In a suitable container, add the pentacyclic terpene delivery system containing highly branched cyclodextrin and polyglycerol sorbitan glycyrrhetinate to the hydroalcoholic solution; mix with a magnetic stirrer at 600 rpm for 10 minutes.

[0278] Embodiment 19

[0279] Olea europaea fruit extract titrated with maslinic acid and oleanolic acid was dissolved in water using polyoxyethylene (40) hydrogenated castor oil.

[0280]

[0281] Method: In a suitable container, add olive extract titrated with maslinic acid and oleanolic acid, then add polyoxyethylene (40) hydrogenated castor oil previously introduced into a hot chamber. Mix until homogeneous. Heat the phase to 85°C on a plate, then drop 1 / 10 of demineralized water, keeping the system under constant stirring. In another container of suitable size, add the remaining water, then drop the phase containing the olive extract. Mix for 10 minutes at 600 rpm using a magnetic stirrer.

[0282] Embodiment 20

[0283] A pentacyclic terpene delivery system containing highly branched cyclodextrin and polyglycerol sorbitan glycyrrhetinate in water, containing polyoxyethylene (40) hydrogenated castor oil (invention).

[0284] Ingredient (INCI name) Amount w / w (%)

[0285] Prepared according to Example 13

[0286]

[0287]

[0288] Method: Cold preparation. In a suitable container, add the pentacyclic terpene delivery system containing highly branched cyclodextrin and polyglycerol sorbitan glycyrrhetinate to the formulation water, and then add the polyoxyethylene (40) hydrogenated castor oil previously introduced into the hot chamber. Mix until homogeneous. Mix with a magnetic stirrer at 600 rpm for 10 minutes.

[0289] Embodiment 21

[0290] 1. Purpose of experimental work

[0291] The purpose of the following experimental procedure was to develop a method suitable for validating the efficacy of a technology based on poly-n-glyceryl-sorbitan glycyrrhetinate (PG3GS) cyclodextrin.

[0292] 2. Materials

[0293] 3.1. Test preparations

[0294] We then prepared the following formulation:

[0295] The formulations reported in the aforementioned Examples 15-20.

[0296] Experimental procedures

[0297] 1. For each preparation, prepare the supernatant by centrifugation at 2000 rpm, 20°C for 60

[0298] 2. Then take spectrophotometric readings using Jasco spectrophotometer v-530 mode;

[0299] The readings were taken using a quartz cuvette according to the following conditions: wavelength range 250nm-600nm, reading range 5nm;

[0300] Each reading was done in duplicate;

[0301] The same percentage (0.08%) of maslinic acid dissolved in ethanol present in the formulation was used as blank (negative control);

[0302] Data processing

[0303] 1. Compare the absorption spectra of the preparation and a negative control containing maslinic acid with each other;

[0304] 2. For each reading, select the maximum peak corresponding to the absorption of maslinic acid (identified at 315 nm);

[0305] 4. Results

[0306] like Figure 1It is clearly seen that the absorption peak of maslinic acid is recorded at 315 nm;

[0307] On the basis of this data, we then compared the absorption spectra of the formulations containing maslinic acid (as reported in point 3.1 herein).

[0308] Thus, using the described experimental procedure, the amount of maslinic acid dissolved by the release technique (expressed as a percentage of maslinic acid in the supernatant) could be clearly determined.

[0309] In Table 1 below, the data are presented as percentage increases for formulations 15 vs. 16, 17 vs. 18, and 19 vs. 20. The absorbance peaks were 34.38%, 44.02%, and 71% higher in formulations 16, 18, and 20, respectively. This percentage increase is directly proportional to the percentage dispersion of maslinic acid.

[0310] Table 1

[0311] preparation <![CDATA[A 315nm ]]> ％ Negative control 0.041 Formulation prepared according to Example 15 0.040 Formulation prepared according to Example 16 0.055 +34.38 Formulation prepared according to Example 17 0.046 Formulation prepared according to Example 18 0.081 +44.02 Formulation prepared according to Example 19 0.024 Formulation prepared according to Example 20 0.068 +70.83

Claims

1. A composition for topical delivery and / or release of pentacyclic triterpenes or a mixture of biologically active components containing pentacyclic triterpenes or a plant extract, characterized in that The composition comprises: Poly-n-glyceryl-sorbitan glycyrrhetinate having the following structural formula Where "n" is an integer from 1 to 3, "Sorb" represents a sorbitol residue, and "Polygly" means a glycerol or polyglycerol residue having a degree of polymerization of 1.5 to 10, The composition also comprises at least one highly branched cyclodextrin.

2. The composition according to claim 1, wherein the pentacyclic triterpenes are selected from: Lupane derivatives selected from lupeol; 3α,27-dihydroxylupine-20(29)-ene-28-methyl ester; betulin; betulic acid; pulsatilla acid; ochratolide D; ochratolide A; ochratolide B, and mixtures thereof; Ursane derivatives selected from α-amyrin; ursolic acid; melanin; quinoic acid; corosolic acid; styrax acid; β-boswellic acid, acetyl-β-boswellic acid; 11-keto-β-boswellic acid; acetyl-11-keto-β-boswellic acid; 3-O-acetyl-11-keto-β-boswellic acid, and mixtures thereof; Oleanolic acid derivatives selected from oleanolic acid; epioleanolic acid; moroconolic acid; maslinic acid; maytansinic acid; Acetyl-α-boswellic acid; α-boswellic acid; Acetyl-α-boswellic acid; Hydroxyamyl alcohol; Remangilone A; Remangilone C; Oleanolic acid 3-trans caffeate, and mixtures thereof; The corkane derivative is selected from corkone, tripterygium wilfordii, 3-oxo-29-acid; 3-oxo-28-acid; 28-29-dihydroxy-3-one; maytansinone A; dulcitone; stylosin; tripterygium wilfordii; igasterol; isoigasterol; 22β-hydroxydulcitone; 20-hydroxy-20-epigasterol; Netzahualcoyondiol; Netzahualcoyone; 15α-hydroxystylosin; 17-(methoxycarbonyl)-28-norisoigasterol; Amazonaquinone; Netzahualcoyonol; Scutione; 6-oxodulcitol; 7,8-dihydro-6-oxo-dulcitol; 3-methyl-6-oxodulcitol; 6-oxodulcitol; norzelamaldehyde, and mixtures thereof.

3. The composition according to claim 1 or 2, wherein the cyclic triterpene is maslinic acid, oleanolic acid and mixtures thereof.

4. The composition according to claim 3, wherein the maslinic acid and / or oleanolic acid is contained in or obtained from an olive tree fruit extract.

5. The composition according to any one of claims 1 to 4, wherein the plant extract containing pentacyclic triterpenes is an olive fruit extract.

6. Use of a composition as claimed in any one of claims 1 to 5 for delivering and / or releasing pentacyclic triterpenes, in particular maslinic acid and / or oleanolic acid, from a topical composition.

7. Use according to claim 6, wherein the topical composition is in solid form as a cream, ointment, or in semi-solid form as a gel, or in liquid form as a solution, suspension, slurry or lotion.

8. A cosmetic composition comprising: Poly-n-glyceryl-sorbitan glycyrrhetinate having the following structural formula Where "n" is an integer from 1 to 3, "Sorb" represents a sorbitol residue, and "Polygly" means a glycerol or polyglycerol residue having a degree of polymerization of 1.5 to 10; Highly branched cyclodextrins, and Pentacyclic triterpenes or a mixture of biologically active components or a plant extract containing pentacyclic triterpenes, A cosmetically acceptable carrier.

9. The cosmetic composition according to claim 8, wherein The pentacyclic triterpenes are selected from hawthorn acid, oleanolic acid and mixtures thereof, The plant extract containing pentacyclic triterpenes is an olive fruit extract.

10. Use of the cosmetic composition of claim 8 or 9 for improving the appearance of the skin or nails or stimulating the physiological growth of hair, eyelashes or eyebrows, mucous membranes, nail epithelium / periungual epidermis.

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