Technical field

This invention relates to compositions that increase the solubility and skin permeation of catechin polyphenols, such as epigallocatechin-3-gallate (EGCG) and incorporate EGCG in an anhydrous carrier system which maintains it completely stable. The anhydrous compositions can be mixed water or with a moisturizing skin cream or lotion prepared with standard procedures, are easily emulsified, and impart all of the known beneficial effects of EGCG in a

cosmetically elegant formulation.

Background of the invention

Accumulating evidence from cellular, animal and epidemiological studies has supported the diverse health benefits of green tea polyphenols and its major constituent epigallocatechin-3-gallate (EGCG). Due to its wide range of biological effects like anti-oxidant, photo protective, anti-aging, anti-inflammatory, immune modulatory, anticancer (prostate, breast, lung, skin, pancreatic, colon, and head and neck cancers), diabetes, neuroprotective, cardio protective, antiviral and antibacterial effects, it has captured a lot of research interest. Paradoxically, the clinical application of EGCG is very rare and the beneficial effects of EGCG have hitherto been limited by its poor stability, absorption and bioavailability. As regards oral delivery the metabolic biotransformation of EGCG affects its absorption, distribution, excretion and toxicity, as well as overall efficiency in disease prevention and therapy. EGCG is a hydrophilic molecule, however sensitive to water, oxygen and UV- radiation, making the molecule unstable in usual topical formulations like lotions, creams and gels containing water. Therefore, it is a challenge to design a topical formulation capable of admitting EGCG to effectively and sufficiently exert its activity in the skin while supporting the solubility and stability in a cosmetically acceptable pharmaceutical composition Skin delivery of EGCG is further complicated by the size of the EGCG-moiecule (458.375 g/mol) which may require a skin penetration enhancer for transdermal delivery. US Patent Application 2007/0243271 describes the use of catechin polyphenols, such as EGCG for treatment of various skin conditions in water based formulations illustrated as creams and serums. However, EGCG is notoriously labile in aqueous environments and risk to lose its beneficial activity throughout handling and storage. The present invention intends to provide such solubilizing, stabilizing and skin penetration enhancing systems specially designed for EGCG.

Description of the invention

The present invention generally relates to new stable compositions comprising catechin polyphenols that are specially designed to administer or make use of such very liable compounds topically, for example by administration to the skin for cosmetic or pharmaceutical therapy. For this purpose, the present invention provides a carrier system essentially free from water and with a combination of agents that both assist to solubilize the catechin polyphenols and to enhance their penetration, while still further have complementary characteristics to provide a carrier system that is cosmetically acceptable by having an excellent compliance and a high aesthetic appearance. The objective of the presently invented compositions is providing stability to the catechin polyphenols, sufficient solubilization of the cathecin polyphenols and to enhance their uptake and skin penetration.

In general terms, the present invention is directed to anhydrous acidic topical compositions for cosmetic or pharmaceutical use, comprising at least one catechin polyphenol, phloretin and a non-aqueous cosmetically or pharmaceutically acceptable carrier system, wherein the carrier system comprises at least one polar component; a pH reducing agent; and an oil component comprising a source of oleic acid and/or linoleic acid and at least one co-solvent. In the present context, anhydrous has the meaning of essentially water free so that a small amount may or may not be present in the system or the composition, for example less than a few percent, such as 0.1 to 3 % (wt) of water in the

composition. The catechin polyphenol is selected from epigallocatechin gallate (EGCG), epigallocatechin (EGC), epigallocathechin 3-gallate (ECG) and

epicatechin (EC) and can be of natural origin or synthetically prepared, preferably, the catechin polyphenol is epigallocatechin gallate (EGCG).

Phloretin (CAS Registry Number: 60-82-2) is a natural polyphenolic compound derivable from apples and the bark of apple trees, and has been suggested to enhance penetration of certain agents in transdermal systems (most likely by modifying the membrane dipole potential or ion channel activity). It is also widely used as antioxidant and a component in skin-care products.

The polar component of the inventive carrier system can be regarded as a non- aqueous organic solvent base and may include agents or mixtures of agents with both high polarity and slight polarity. In one aspect, the polar component comprises a polyol solvent composition, preferably selected from at least one of 1 ,3-propanediol, propylene glycol, glycerol and a polyethylene glycol. One suitable polyol solvent in the system comprises 1.3-propanediol and glycerol in about 30 to 55% (wt) of the inventive compositions. In another aspect the polar component can further comprise an extract from pine bark, comprising 1 -hexanol and alpha- terpineol. A suitable pine bark extract has the trade name Extvolat, as supplied by PineAqua. In this aspect, the polar component comprises a mixture of pine bark extract and polyol in order to solubilize and stabilize both EGCG and phloretin. Preferably accord to this aspect, the pine bark extract is present as a polar component, so the resulting composition comprises 20 to 75% (wt) of and the polyol component, such as 1 ,3-propanediol is present as a polar component so it so the resulting composition comprises 1 to 10% 1 ,3-propanediol .

The polar component can further comprise a pH reducing agent, preferably a pH reducing amount of ascorbic acid or citric acid or mixtures thereof. Preferably, the pH of the system is less than 5. The oil component of the carrier system, preferably comprises a source of oleic acid or linoleic acid, which may be free oleic acid or linoleic, or an oil rich in oleic acid, such as avocado oil or sunflower oil. The oil component can further be combined with waxes, such as Kahlwax 6290 and hydrophobic agents such as hemisqualane. The oil component is selected so as to solubilize the catechin polyphenol and can further comprise one or several co-solvents. The co-solvents are preferably selected to contribute to solubilize the catechin polyphenol and to enhance permeation, but also to contribute to the quality of the composition by acting as at least one of an emollient, spreading agent, emulsifier, skin

conditioning agent, humectant, demulcent coupling agent, antioxidant, moisturizer, and/or viscosity modifier in order to improve the compliance and aesthetical value for the user. In one aspect, the co-solvent is selected from at least one of mixtures of cetearyl alcohol and polyethylene glycol ether of cetearyl alcohol (ceteareth 20); mixtures of C13-C16 isoparaffin and heptyl undecylenate; cyclomethicone; Rhus vernicifua peel wax; Rhus succedanea fruit wax; and polypropylene glycol (PPG)-2 myristyl ether propionate.

The compositions of the invention can further comprise a surfactant, preferably a non-ionic amphiphilic surfactant, such as dodecyl p--D-glucopyranoside or sodium lauryl sulfate. The surfactant can be a part of the oil component pf the carrier system.

The compositions of the invention can further comprise additional agents that further enhances the compositions usefulness in therapy and/or cosmetology:

Such additional agents are elected from skin conditioning agents, emollients, humectants, demulcents, moisturizers, colorants, fragrances, anti-oxidants and viscosity modifying agents.

The anhydrous compositions can comprise microcrystalline cellulose and/or lactobionic acid. Preferably, the microcrystalline cellulose has a particle size of 70 to 700 pm, examples of suitable brands are Vivapur® and/or Vitacel ®. In one aspect, the compositions according to the invention comprises 0.5 to 20% (wt) epigallocatechin gallate (EGCG), 0.05 to 20% (wt) phloretin, ascorbic acid,

1 ,3-propanediol or propylene glycol, glycerol, a source of oleic acid or linoleic acid and at least one co-solvent selected as previously outlined.

In one embodiment, the anhydrous compositions of invention comprise 0.5 to 20% (wt) of each of epigallocatechin gallate (EGCG) and phloretin, at least 40% (wt)

1 ,3 propanediol or propylene glycol; 1 to 20% % (wt) ascorbic acid; 5 to 10% (wt) glycerol; 15 to 20% (wt) of a source of oleic acid or linoleic acid, preferably avocado oil or sunflower oil or mixtures thereof; and 10 to 20% (wt) of at least one co-solvent. The anhydrous compositions can be mixed water or with a moisturizing skin cream or lotion prepared with standard procedures, and are easily emulsified, and impart all of the known beneficial effects of EGCG in a cosmetically elegant formulation. Alternatively, the anhydrous compositions can be combined with a water based composition of microcrystalline cellulose optionally also comprising lactobionic acid when applied to the skin of a patient in order to accomplish a peeling or exfoliating effect.

In one embodiment anhydrous compositions of invention comprise 0.5 to 20% (wt) of each of epigallocatechin gallate (EGCG) and phloretin; 1 to 10% (wt) of 1 ,3 propanediol; 20 to 75% (wt) of pine bark extract; 1 to 20 % (wt) of ascorbic acid and/or citric acid; 10 to 30% (wt) each of microcrystalline cellulose and lactobionic acid; and 10 to 30% (wt) of oil component as previously defined, preferably comprising a source of linoleic acid. In certain aspects of the invention, the compositions can be combined with a conventional, either mechanical or chemical, peeling therapy, of the skin in order to further support administration of the active agents, in particular EGCG, to a desired part skin.

In one aspect, the invention pertains to a method of preparing a composition according to invention, wherein a first step comprises admixing at least one of a catechin polyphenol and phloretin with the polar component; heating the resulting mixture to about 80°C; combining the mixture with the oil component, adding microcrystalline cellulose; and stirring the mixture while cooling. Preferably other components of the composition are added the polar component. Preferably according to the method EGCG and phloretin is added to 1 ,3-propendiol, then pine bark extract and other components are added, and the oil component is added at suitable high temperature admitting any wax component to melt, whereupon the microcrystalline cellulose is added.

The present invention further includes a multi-compartment kit for preparing a composition according to any previous claim comprising a first compartment comprising the oil component as described with at least one catechin polyphenol and phloretin dissolved in said oil component; a second compartment comprising the polar component as described with a pH reducing amount of ascorbic acid and/or citric acid and a means for admixing the oil component and the polar component into a cosmetically and/or pharmaceutically acceptable composition.

In one aspect of the kit, the oil component with the at least one catechin

polyphenol and phloretin is essentially free from oxygen. Accordingly, the first compartment is filled under controlled atmospheric conditions to safeguard oxygen free conditions, while the oil component may have undergone a process to remove oxygen in order to store oxidation labile active agents. For this purpose, the first compartment can be made impervious to air and/or UV-light using conventional such materials known to those skilled in pharmaceutical manufacturing and packaging.

The compositions, methods and the kit of the invention admit stable conditions for catechin polyphenol, such as EGCG, and the possibility to topically administer such compounds in compositions with high doses that support sufficient permeation. For these reasons, the inventive compositions will open possibilities to fully exploit the therapeutic promises of EGCG which so far have been

inaccessible due to the difficulties to find suitable formulations and poor

bioavailability. Description of embodiments

Example 1

Epigallocatechin + Phloretin 1.1 + 1.1 % 1 ,3-propanediol 42.9%

Avocado oil 16.1 %

Ascorbic acid 14.9%

Cetearyl Alcohol and Ceteareth-20 9.7%

Glycerol (99.5%) 8.7% PPG-2 Myristyl Ether Propionate 6.4%

All ingredients heated to ca. 80°C while stirring, homogenized for 20 s. Allowed to cool slowly without stirring, The appearance immediately after preparation was an homogenous cream-like formulation (after cooling). The appearance after storage at RT was unchanged after 6 days (and 3 months). The batch size was

approximately 60 g. All percentages are by weight.

Example 2

Epigallocatechin + Phloretin 1.2 + 1.1 %

1 ,3-propanediol 42.9%

Ascorbic acid 14.0 % Glycerol (99.5%) 8.6%

Avocado oil 16.1 %

Cetearyl Alcohol and Ceteareth-20 9.5% PPG-2 Myristyl Ether Propionate 6.5%

Oil phase with actives heated to ca. 85°C, polar phase to ca. 80°C. Combined while stirring, homogenized for 20 s. Allowed to cool slowly without stirring, The appearance immediately after preparation was an homogenous cream-like formulation (after cooling). The appearance after storage at RT was unchanged after 6 days (and 3 months). The batch size was approximately 60 g. All percentages are by weight.

Example 3 Epigallocatechin + Phloretin 1.0 + 1.0%

1 ,3 Propanediol 42.2%

Ascorbic acid 13.6%

Glycerol (99.5%) 8.4%

Colloidal silica M-SP 0.5% Avocado oil 15.7%

Cetearyl Alcohol and Ceteareth-20 9.5%

PPG-2 Myristyl Ether Propionate 6.3%

C13-C16 Isoparaffin and Heptyl Undecylenate 1.4%

Decyl glucoside 0.2% Oil phase (plus actives, but without silica) heated to ca. 91 °C to obtain clear solution, the silica was added. Polar phase heated to ca. 80°C, combined while stirring, homogenized for 30 s. Allowed to cool slowly without stirring, The appearance immediately after preparation was an homogenous cream-like formulation (after cooling). The appearance after storage at RT was unchanged after 2 days (and after 3 months). The batch size was approximately 60 g. All percentages are by weight.

Example 4 Epigallocatechin + Phloretin 12.3 + 1.1 % 1 ,3 propanediol 42.9% Ascorbic acid 5.0 % Glycerol (99.5%) 7.6%

Avocado oil 15.1 % Cetearyl Alcohol and Ceteareth-20 9.6% PPG-2 Myrisiyl Ether Propionate 6.5%

Oil phase with actives heated to ca. 85°C, polar phase to ca. 80°C. Combined while stirring, homogenized for 20 s. Allowed to cool slowly without stirring, The appearance immediately after preparation was an homogenous cream-like formulation (after cooling). The appearance after storage at RT was unchanged after 6 days (and after 3 months). The batch size was approximately 60 g. All percentages are by weight.

Example 5

Epigallocatechin + Phloretin 17.3 + 1.0% 1 ,3 Propanediol 37.2%

Ascorbic acid 3.0%

Glycerol (99.5%) 8.4%

Colloidal silica M-SP 0.5% Avocado oil 15.7%

Cetearyl Alcohol and Ceteareth-20 9.5%

PPG-2 Myrisiyl Ether Propionate 6.3%

C13-C16 Isoparaffin and Heptyl Undecylenate 1.4% Decyl glucoside 0.2%

Oil phase (plus actives, but without silica) heated to ca. 91 °C to obtain clear solution, the silica was added. Polar phase heated to ca. 80°C, combined while stirring, homogenized for 30 s. Allowed to cool slowly without stirring, The appearance immediately after preparation was an homogenous cream-like formulation (after cooling). The appearance after storage at RT was unchanged after 2 days (and after 3 months). The batch size was approximately 60 g. All percentages are by weight.

Example 6

Epigallocatechin + Phloretin 15.0 + 0.1 % 1 ,3 Propanediol 39,6%

Ascorbic acid 4.0%

Glycerol (99.5%) 8.4%

Colloidal silica 0.5%

Avocado oil 15.0% Rhus verniciflua peel cera 9.5%

PPG-2 Myristy! Ether Propionate 6.3%

C13-C16 Isoparaffin and Heptyl Undecylenate 1.4%

Decyl glucoside 0.2% Polar phase with actives heated to ca. 96°C to obtain clear solution. Oil phase heated to ca. 85°C combined while stirring, homogenized for several minutes, then silica was added and further homogenized. Allowed to cool slowly. The

appearance immediately after preparation was a slightly heterogeneous runny formulation (after cooling). The appearance after storage at RT, slightly more viscous, slightly grainy after 5 days. The batch size was approximately 60 g. All percentages are by weight.

Example 7 Epigallocatechin (98%) + Phloretin 1.0 + 0.2 %

Pine Extvolate 35.0%

Ascorbic acid 12.0 %

Lactobionic acid 10.0%

1 ,3-propanediol (Zemea®) 5% Microcrystalline cellulose 9.0%

Sunflower oil (HO) 12.0%

Kahlwax 6290 9.0%

Olivem 1000 4.0%

Hemisqualane 2.8% The active agents were mixed with the propanediol and heated to 40°C to obtain a clear solution, after which the other ingredients added and heated to 80°. The oil component was heated to melt wax (about 60°C) and added to the polar component while stirring, the microcrystalline cellulose was added and the mixture further stirred to smooth consistence while cooling. All percentages are by weight.