Silicone gel composition of walnut extract

Abstract

The present invention provides a new silicone gel composition suitable for preparing anti-herpes virus preparations of natural origin.The new composition has the ability to penetrate into the target epidermal side of the skin.The new composition has the ability to be retained on the target epidermal side of the skin for a certain period of time.The present invention also relates to the external use of the silicone gel composition for the treatment of herpes virus in a posology regime.

Description

[Technical field]

[0001] The present invention is in the field of topical emollient gel compositions containing silicone and a natural extract of walnut fruit suitable for preparing an anti-herpes virus product.

[0002] The present invention also relates to an emollient gel composition for topical use in the treatment of herpes viruses in a posology regime. [Background technology]

[0003] Recently, there has been a need for the development of natural preparations with improved efficacy for the treatment of herpes viruses.

[0004] However, the therapeutic efficacy of topical preparations is greatly influenced by the ability of each drug to penetrate the skin.

[0005] Silicones are well known in the art for external preparations. Silicones are very diverse and are mostly used for cosmetic formulations. In addition to being vegan-friendly, hypoallergenic, colorless, and odorless, they also have sensory properties.

[0006] However, the low penetration of silicones when applied topically onto human skin is well known in the art, see for example MB Reddy, RJ Looney, MJ Utell, KP Plotzke, ME Andersen in "Modeling of Human Dermal Absorption of Octamethylcyclotetrasiloxane (D4) and Decamethylcyclopentasiloxane (D5)", Toxicological Sciences, 2007; 99 (2), 422-431.

[0007] On the other hand, US Patent No. 9,511,034, directed to "Method of Applying Skin Treatment," discloses a skin treatment for managing skin conditions ranging from scars to burns and wrinkles. The skin treatment may comprise several components or layers: a cleansing solution component, a silicone elastomer component, and a mineral powder component. In an exemplary embodiment, three layers or components are used to treat and camouflage scars, namely a solution for cleansing the skin, a silicone elastomer for treating the cleansed skin, and a mineral powder for further protecting and camouflaging the treated skin compartment. A long list of additional additives is mentioned, including walnut extract (Juglans nigra). However, the walnut extract is as a source of browning.

[0008] European Patent No. 2,811,986 directed to "Silicone Emulsions for Delivery of Health Care Actives" discloses compositions comprising i) an aqueous silicone emulsion comprising A) 0.5% to 95% by weight of a silicone gum, resin, or pressure sensitive adhesive (PSA), B) 0.1 to 90% by weight of an ethylene oxide / propylene oxide block copolymer, and a sufficient amount of water to bring the total of all components of the silicone gum emulsion to 100 percent by weight, ii) a health care active, and iii) an optional enhancer. Certain silicone gum, resin, or pressure sensitive adhesive (PSA) emulsions are described for preparing dermal formulations for delivery of health care actives. The active can be a protein, such as an enzyme. The active can also be one or more plant extracts from a long list, including walnut extract. However, these compositions are formulated to treat fungal infections rather than viruses, and their purpose is to promote an enhanced rate of penetration for the effectiveness of these actives.

[0009] Similarly, EP 2,385,819 describes a silicone paste composition. EP 2,385,819 deals with the problem of making the composition sufficiently compatible so that it is stable when formulated as a personal or health care product. The composition combines a silicone organic elastomer gel with water or a hydrophilic solvent that may further contain a personal or health care active agent. However, EP 2,385,819 is in the field of fungal infections rather than viral infections.

[0010] On the other hand, juglone, also known as 5-hydroxy-1,4-naphthalenedione (IUPAC), has the molecular formula C 10 It is an organic compound with H6O3. Juglone can be found naturally in walnut trees, which contain gall and catechin tannins, juglone, juglandine, carotene, inositol, pyrogallol, vitamin C and other substances in the bark, leaves or fruit. The antimicrobial, antiviral and antibacterial properties of natural juglone are known, for example from European Patent No. 2,040,727 of the same applicant.

[0011] US Patent No. 6,296,838 refers to a topical composition containing juglone extract. In particular, US Patent No. 6,296,838 discloses that the extract with synergistic effect should contain a mixture of 20-30% ground roots of Nardostachys jatamansi or Vetiveria zizanioides or Catharanthus roseus with 10-15% juglone extract from walnut shell, because the extract of juglone only shows very little efficiency in fungal toxicity effect even in long-term healing treatment. US Patent No. 6,296,838 is in the field of treatment and prevention of fungal infection of human nails. Viruses are neither suggested nor disclosed.

[0012] Thus, there is currently no topical preparation in the art for topically treating herpes viruses with enhanced efficacy.

[0013] Indeed, the current state of the art does not address the issue of efficacy versus skin penetration of topical compositions, but focuses on the rate of penetration for active agent efficacy as discussed above in EP 2,811,986.

[0014] Therefore, it remains desirable to provide a natural composition that has the ability to penetrate active agents at target sites in the skin where the virus resides in order to improve efficacy and reduce healing time. Achieving this goal may result in improved efficacy of treatment.

[0015] Additionally, retention of the composition at the target site on the skin for a certain period of time is also required for the efficacy and relief of topical silicone compositions.

[0016] Therefore, it also remains desirable to provide silicone compositions for topical use in the symptomatic relief of herpes viruses that are highly effective.

[0017] It is also desirable to provide a natural silicone composition that is stable on storage, and in particular to provide excellent stability despite the known poor stability of the natural components contained in walnut extract. Summary of the Invention

[0018] The present invention has been made in consideration of the above-mentioned prior art.The present invention provides a silicone gel composition comprising walnut extract for preparing anti-herpes virus preparation with improved efficacy.In particular, the present invention relates to an anti-herpes virus external gel composition comprising a combination of three types of silicone that can make walnut extract penetrate into the target site of skin in depth range to deliver natural naphthoquinone contained therein.The silicone gel composition of the present invention has the ability to penetrate into the target site of epidermis.

[0019] The silicone gel composition includes a natural extract of unripe walnut fruit (Juglans Regia L.) which contains natural naphthoquinone components.

[0020] Advantageously, the composition of the first aspect provides good permeability of walnut extract components in skin.In particular, the silicone gel composition of the present invention provides good natural naphthoquinone component permeation in the target site of epidermis, thereby providing systemic therapeutic safety since it is not absorbed or penetrated in the dermis site.

[0021] The authors of the present invention have found that the silicone gel composition of the first embodiment is not absorbed or penetrated at the dermal depth, but is capable of penetrating target sites in the epidermal depth range.

[0022] Advantageously, the silicone gel composition of the present invention has penetration in the epidermal zone in the depth range of about 30 to about 120 μm.

[0023] Additionally, the silicone gel composition of the first embodiment exhibits improved retention of the composition at target sites in the epidermal area, and over a period of time, thus even further improving efficacy.

[0024] Surprisingly, after topical application of the silicone gel composition of the present invention in the posology regime defined in the second aspect of the present invention, the silicone gel composition of the present invention is administered at a concentration of 500 to 800 ng / cm 2Concentrations of natural naphthoquinone components (especially juglone) were found in the epidermal depth range for at least 16 hours.

[0025] Thus, a second aspect of the present invention provides a silicone gel composition of the first aspect for topical use in the treatment of herpes viruses in a dosage regime of 125-175 mg administered at intervals of 3-5 hours, up to a total amount of 500-600 mg. [Brief description of the drawings]

[0026] [Figure 1] Figure 1 shows human skin layers and the range of thicknesses of each of the layers. The epidermal layer is in the range of 30-120 μm. The silicone gel composition of the present invention is intended to treat the epidermal area. [Diagram 2] Figure 2.1 shows the calibration line of juglone standard solutions from 100 ng / mL to 5000 ng / mL in 80:20 v / v methanol / water, and Figure 2.2 shows the spectral information obtained by HPLC MS / MS for the presence of 5 ppm juglone standard. [Diagram 3] FIG. 3 shows spectral information obtained by HPLC MS / MS of the penetration of natural naphthoquinone components (specifically juglone) through human skin into a collector solution after treatment with 600 mg of a silicone gel composition of the present invention. [Figure 4] FIG. 4 shows spectral information obtained by HPLC MS / MS of natural naphthoquinone components (particularly juglone) retained in human skin upon extraction of the natural naphthoquinone components (particularly juglone) from 2.54 cm2 of skin (400 μm thick) treated with 600 mg of the silicone gel composition of the present invention. Description of the Invention

[0027] Therefore, a first aspect of the present invention provides a silicone gel composition comprising a walnut extract suitable for the topical treatment of herpes viruses and having the ability to deliver natural naphthoquinone components at target sites in the epidermal area.

[0028] The silicone gel composition comprising a walnut extract comprises: - a silicone mixture consisting of a silicone elastomer gel, a silicone fluid base, and a silicone emulsifier; and - Walnut extract containing natural naphthoquinones comprising Silicone elastomer gel in an amount of 60-75%, silicone fluid base in an amount of 12-25%, silicone emulsifier in an amount of 2-6%, and walnut extract in an amount of 5-15%, and Percentages are expressed by weight relative to the weight of the composition, provided that the sum of all components does not exceed 100%. It is characterized in that

[0029] Advantageously, the silicone gel composition of the present invention is capable of penetrating the epidermis area at targeted sites.

[0030] The present invention additionally relates to a silicone gel composition capable of maintaining the concentration of walnut extract in the target area of ​​the epidermis for a period of time, thus further improving the effectiveness of the composition while ensuring the retention of the walnut extract in the target area of ​​the epidermis.

[0031] In one embodiment, the silicone gel composition of the present invention may optionally further comprise one or more external use excipients.

[0032] The silicone gel composition has the appearance of a semi-solid gel.

[0033] Selection of the silicone elastomer gel, silicone fluid base, and silicone emulsifier within the ranges described herein in combination with the walnut extract containing natural ingredients provides the advantages described herein.

[0034] Advantageously, the silicone gel compositions of the present invention demonstrate low or no penetration into the dermis above the vascular plexus, conferring systemic therapeutic safety.

[0035] Furthermore, the silicone gel composition of the present invention has excellent storage stability.

[0036] A preferred silicone elastomer gel contains decamethylcyclopentasiloxane (D5) in a network backbone of polydimethylsiloxane (PDMS), also known as cyclomethicone dimethicone crosspolymer.

[0037] In one embodiment, the silicone elastomer gel comprises decamethylcyclopentasiloxane (D5) in an amount of about 85% by weight and a crosslinked polymer of greater than 5,000 average molecular weight in an amount of about 12% by weight.

[0038] A preferred silicone fluid base comprises a cyclopentasiloxane compound.

[0039] In one embodiment, the cyclopentasiloxane compound comprises greater than about 95% by weight of decamethylcyclopentasiloxane (D5).

[0040] Preferred silicone emulsifiers include alkylmethylsilicone polyether copolymers.

[0041] As mentioned above, the silicone mixture is comprised of a mixture of silicone elastomer gel, silicone fluid base, and silicone emulsifier. The components of the silicone mixture are described in detail below.

[0042] - Silicone elastomer gel - Silicone elastomer gel is a non-polar material that is incompatible with hydrophilic materials.

[0043] Its physical form at 25° C. is a paste (gel). Its color is clear to slightly translucent. It may also have a slight yellow or brown color.

[0044] As mentioned above, the preferred silicone elastomer gel comprises decamethylcyclopentasiloxane (D5) in a network backbone of polydimethylsiloxane (PDMS). In the network, the polydimethylsiloxane chains are crosslinked by shorter polydimethylsiloxane chains and hexyl chains. The network is expanded in the presence of decamethylcyclopentasiloxane (D5).

[0045] In one embodiment, the silicone elastomer gel comprises high molecular weight crosslinked polymers (about 12% w.) in decamethylcyclopentasiloxane (D5) (about 85% w.). High molecular weight crosslinked polymers include crosslinked polymers having an average molecular weight greater than 5,000.

[0046] Commercially available steels range from 350,000 to 490,000 cSt (centistokes [cSt] = 1 mm 2 It can be found as "ST-Elastomer-10®" sold by Down Corning Corporation (also named cyclomethicone-dimethicone crosspolymer) with a viscosity of 1000000000000 / s. High molecular weight silicone elastomer (about 12%) and decamethylcyclopentasiloxane (D5) (about 85%) are the major components. Impurities are octamethylcyclotetrasiloxane and other cyclomethylsiloxanes, as well as residual short vinyl polymers (dimethylvinylsiloxy-terminated dimethylsiloxane). "ST-Elastomer-10®" is a silicone elastomer particle dispersed and expanded in a volatile silicone solvent, decamethylcyclopentasiloxane (also known as cyclomethicone 5 or D5). The elastomeric silicone particles are made from crosslinked polymers of MW>5,000 obtained by hydrosilylation reaction between the SiH groups of a high MW SiH silicone polymer (trimethylsiloxy-terminated dimethylmethylhydrogensiloxane) and the vinyl groups of 1,5-hexadiene in the presence of a platinum catalyst and decamethylcyclopentasiloxane.

[0047] The silicone elastomer gel (after hydrosilylation reaction leading to an elastomeric network and formation of a gel) has a composition including decamethylcyclopentasiloxane (D5) (about 85% w.), reaction product of dimethylmethylhydrogensiloxane with 1,5-hexadiene (about 12% w.); octamethylcyclotetrasiloxane (D4) (up to 0.9% w.); dimethylvinylsiloxy-terminated dimethylsiloxane (about 0.6% w.); and dimethylcyclosiloxane (1% w.).

[0048] Preferably, the silicone elastomer gel may be present in the mixture in an amount of from 65 to 72% by weight, more preferably from 67 to 69% by weight, even more preferably about 68% by weight, based on the weight of the composition of the first aspect of the present invention.

[0049] - Silicone fluid base - Silicone fluid bases are volatile fluids that have significant vapor pressure at ambient temperature.

[0050] As noted above, the preferred silicone fluid base comprises a cyclopentasiloxane compound, which is a polydimethylcyclopentasiloxane composed primarily of decamethylcyclopentasiloxane (>95%).

[0051] [ka]

[0052] In one embodiment, the silicone fluid base comprises decamethylcyclopentasiloxane (D5) in an amount greater than 95% by weight of the silicone fluid base components.

[0053] Commercially available products on the market are around 3.8 mPa / s (4.0 mm 2 .s -1A typical example of such a silicone oil can be found as "ST-Cyclomethicone 5 NF®" sold by Down Corning Corporation, having a viscosity of 1000 g / l at 25° C. It may be used alone or blended with other silicone or organic excipients to provide a fluid base for a variety of formulations.

[0054] Preferably, the silicone fluid base may be present in the silicone mixture in an amount of from 17 to 19% by weight, more preferably from 14 to 20% by weight, even more preferably about 18% by weight, based on the weight of the composition of the first aspect of the present invention.

[0055] - Silicone emulsifier - Silicone emulsifier is liquid silicone that allows the formulation of cream and lotion at room temperature.The silicone emulsifier component in the composition of the first embodiment allows the formation of a very stable viscoelastic film when the composition is applied on human skin for external use.The film formation protects against and prevents the colonization of Herpesviridae viruses, and achieves the percutaneous penetration of naphthoquinone contained in walnut extract in the epidermal depth range without reaching the dermis, thus achieving safe use on the skin affected by viral infection.

[0056] As noted above, preferred silicone emulsifiers include (liquid) alkylmethyl silicone polyether copolymers, which lead to excellent stability of the silicone gel composition at high water concentrations and low emulsifier levels.

[0057] Commercially available oils range from 1,100 to 2,600 cSt (centistokes [cSt] = 1 mm 2One example is "Dowsil-5200 Formulation Aid®", Lauryl PEG / PPG - 18 / 18 Methicone, sold by Down Corning Corporation, which has a viscosity of 1000 s / s at 25° C. and a flash point of 92.5° C., with a low hydrophilic-lipophilic balance. Dowsil is effective in making water-oil emulsions or water-in-silicone emulsions with low to medium polarity oil phases and can be used alone or blended with other silicone or organic excipients to provide a fluid base for a variety of formulations.

[0058] Lauryl Methicone PEG / PPG-18 / 18 is an alkoxylated derivative of lauryl methicone containing an average of 18 moles of ethylene oxide and 18 moles of propylene oxide.

[0059] Preferably, the alkylmethylsilicone polyether copolymer component may be present in the silicone mixture in an amount of from 2 to 6% by weight, preferably from 3 to 5% by weight, more preferably about 4% by weight, based on the weight of the composition of the first aspect of the present invention.

[0060] - Walnut extract containing natural naphthoquinone components - The silicone gel composition according to the first aspect of the present invention further comprises a walnut extract in an amount of 5 to 15% by weight based on the weight of the composition.

[0061] As is known in the art, walnut extracts (Juglans Regia L.) contain natural naphthoquinones, particularly juglone, usually in amounts of 0.1-0.5% by weight.

[0062] As disclosed above, the walnut extract is present in an amount of 5-15% by weight, preferably 8-12% by weight, more preferably about 10% by weight relative to the weight of the composition of the first aspect of the present invention.

[0063] The walnut extract may be obtained from any extraction method known in the art. However, a preferred walnut extract may be obtained according to the method described in granted European Patent No. 2,040,727, the entirety of which is incorporated herein by reference.

[0064] The general process of EP 2,040,727 comprises the following steps: i) collecting unripe walnut fruits as raw material; ii) preparing the raw material for extraction; iii) freezing the raw material prepared in the preceding steps; iv) drying; v) extracting within a time period shorter than 10 minutes, wherein the extraction step (v) comprises breaking the dry mass obtained in the drying step into small pieces and adding alcohol in a weight / volume ratio of 1 / 2 to 1 / 5 and carrying out the extraction for a time period shorter than 10 minutes; and vi) filtering.

[0065] In the freezing step (iii), it is preferred to keep the walnuts in a frozen chamber at a temperature of -18 to -20°C for 70 to 170 hours, and in the drying step (iv), it is preferred to first shell the frozen walnuts in a thin layer of 2 to 3 mm, and then dry them until a humidity of less than 10% is obtained.

[0066] In one embodiment, the silicone gel composition comprises: - 60-75% Cyclomethicone Dimethicone Crosspolymer, 10-25% cyclopentasiloxane, and 2-6% alkylmethylsilicone polyether copolymer A silicone mixture consisting of - Walnut extract in amounts of 5-15% comprising Percentages are expressed by weight relative to weight of composition provided that the total of all components does not exceed 100%. In another embodiment, the silicone gel composition comprises: - 67-69% Cyclomethicone Dimethicone Crosspolymer, 17-19% cyclopentasiloxane, 3-5% alkyl methyl silicone polyether copolymer A silicone mixture consisting of: - Walnut extract in an amount of 9-11% comprising Percentages are expressed by weight relative to weight of composition provided that the total of all components does not exceed 100%.

[0067] In a more preferred embodiment, the silicone gel composition comprises - 68% Cyclomethicone Dimethicone Crosspolymer as a Silicone Elastomer Gel; 18% cyclopentasiloxane compound as the silicone fluid base, and 4% alkylmethylsilicone polyether copolymer as a silicone emulsifier A silicone mixture consisting of - Walnut extract in an amount of approximately 10% comprising Percentages are expressed by weight relative to weight of composition provided that the total of all components does not exceed 100%.

[0068] In yet another preferred embodiment, the silicone gel composition comprises 10% walnut extract; 68% cyclomethicone and dimethicone crosspolymer as an elastomer; 18% cyclopentasiloxane compound as a base, and 4% alkylmethylsilicone polyether copolymer as an emulsifier, the percentages being expressed by weight out of the total weight of the composition, and the sum of all components not exceeding 100%.

[0069] The silicone gel composition of the first aspect has a semi-solid texture that facilitates topical application as compared to a liquid texture, hi one embodiment, the semi-solid texture is a semi-solid gel.

[0070] In a second aspect, the present invention relates to the topical use of the silicone gel composition of the first aspect of the invention for the treatment of herpes family viruses in a posology regime.

[0071] The silicone gel composition defined in the first aspect is suitable for topical use in the treatment of herpes viruses.

[0072] Use comprises a dosing regime of 125-175 mg administered at intervals of 3-5 hours up to a total dose in the range of 500-600 mg.

[0073] In one embodiment, the dosage regime is 125 to 175 mg administered at four hour intervals up to a total of 500 mg.

[0074] In another embodiment, the dosage regime is 150 mg administered at 4 hour intervals up to a total of 600 mg.

[0075] Advantageously, the silicone gel compositions of the first and second aspects of the present invention have naphthoquinone (especially juglone) penetration in the epidermal zone in the depth range of about 30 to about 120 μm.

[0076] Topical use of the silicone gel composition of the present invention exhibits improved retention of active ingredients at target sites in the epidermal area, and over a period of time, thus even further improving efficacy.

[0077] Surprisingly, in the above-mentioned posology regime, naphthoquinone provides a therapeutic effect in the epidermal depth range of 500-800 ng / cm for at least 16 hours. 2 is maintained at a concentration of

[0078] - Assay - The authors of the present invention carried out several studies to analyze the properties of the silicone gel compositions of the first and second aspects of the present invention.

[0079] The first study focused on the permeation rate of juglone (a natural naphthoquinone) through human skin.

[0080] The second study focused on extracting the amount of natural naphthoquinones retained in human skin.

[0081] The amount retained in samples generated during the study and the depth reached in the skin were measured in the laboratory using a previously qualified and proven suitable liquid chromatography-mass spectrometry method as well as using confocal microscopy techniques.

[0082] - Confocal optical microscopy - Penetration in human skin was also studied by confocal microscopy, using the fluorescence of the juglone molecule, exciting it with 488 nm light and observing its fluorescence in the 510-702 nm window. For this penetration study, a Leica microscope, model SPE Confocal Microscope, with a 10x lens was used. The position of the juglone molecule in depth was established with this instrument (perpendicular to the skin surface). The accumulation of juglone at different depth levels causes the appearance of compartments with different fluorescence intensities and allows to directly observe where the molecule is retained. It must be noted that Caucasian skin was chosen to prevent interference of basal fluorescence and therefore to clearly observe the fluorescence of the juglone molecule.

[0083] - Penetration of juglone through human skin - The skin absorption study was performed according to the “Guidance document for the conduct of skin absorption studies”. OECD series on testing assessment. Number 28. ENV / JM / MONO (2004) 2.05-Mar-2004. 2A Franz-type cell with the surface of the skin was used. The permeation membrane used was human skin (0.400 mm thick) of a previously treated abdominal compartment from a repair operation. This thickness covers the epidermis and the dermis above the vascular plexus. The integrity of the used skin was checked by estimating the value of the parameter TEWL (transepidermal water loss). The study of juglone retention in the skin was carried out considering the epidermal compartment between the surface and a depth of 0.150 mm and the dermal compartment above the vascular plexus with a depth of 0.150-0.400 mm. For each study, human skin from a population sample (n=6) was used, so that the results were representative of the group providing inter-individual differences.

[0084] In the cell donor compartment, 600 mg of silicone gel composition containing 10% walnut extract and 0.04% w / w juglone content in the silicone gel composition was applied at 150 mg each in four applications at 0, 4, 8 and 14 hours, and the receiving solution was collected at 16 hours. It was applied by gentle rubbing onto the skin, simulating application with a fingertip. As receiving solution, a 90:10 v / v deionized water / ethanol solution was used, which allowed to keep sink conditions throughout the study; additionally, the cell was maintained at 32±1°C using a heating jacket. Sampling was performed from the receiving compartment at the following times: 4, 8, 14 and 16 hours. The sample volume collected was 0.3 mL.

[0085] Two studies were performed using the silicone gel composition of the present invention to study the juglone content across the skin and the amount retained in the skin. In both studies, the silicone gel composition contained 10% walnut extract (0.04% w / w juglone). In the first study, human skin was placed in five Franz cells as described above, with no other drive; the second study consisted of horizontally sectioning a skin sample placed in a sixth Franz cell, dividing it into two layers: one layer 0.150 mm thick (0 mm to 0.150 mm deep (epidermis)) and another layer 0.250 mm thick (0.150 mm to 0.400 mm deep (dermis above the vascular dermal plexus)). The first peeled layer on the one hand and the remaining layer on the other hand were sonicated with 80:20 v / v methanol / water, keeping the temperature constant at 25° C. and protecting it from light to allow approximating the compartment in which juglone was mainly fixed in the skin, since the epidermis is not delimited in a precisely defined thickness (FIG. 1) and shows invaginations that make it irregular both on the surface and in depth.

[0086] - Research on the extraction of retained juglone - The determination of juglone retained in human skin was performed after washing the outer surface of the skin with 0.1% sodium lauryl sulfate solution followed by rinsing with HPLC grade water, after which the approximate depth of juglone penetration in the skin was determined using confocal microscopy techniques after drying and weighing the skin.

[0087] The next step in the study was to submerge five of the six skins used as membranes in an 80:20 v / v methanol / water solution, with juglone harvested from the skin components treated with the silicone gel composition, corresponding to the extraction of juglone throughout the entire thickness of the skin (0.400 mm). The method used involved sonication for 20 minutes under bath temperature control (25° C.).

[0088] A study on the extraction of juglone retained in human skin was performed immediately after observation under confocal light microscopy of five of the six pieces. The skin discs were placed in glass vials, to which 1 ml of 80:20 v / v methanol / water was added, vortexed, sonicated for 20 min in an ultrasonic bath at 100 w power, and allowed to stand for 30 min. The extracts were transferred to two vials in an automated injector for chromatography for analysis by HPLC-MS / MS.

[0089] The sixth skin sample was processed similarly but in two components. The first component was the superficial or epidermal component, cut with a Leica cryomicrotome at a depth of 0 mm to 0.150 mm. The second component was the remaining piece at a depth of 0.150 mm to 0.400 mm, corresponding to the upper dermal compartment of the vascular plexus. Each section of 1 square centimeter was used. The corresponding extraction solution, performed with 500 μL of 80:20 v / v methanol / water, was transferred to both vials of the automated injector for chromatography for analysis by HPLC-MS / MS.

[0090] Preparation of calibration standards and analytical samples was carried out as follows. Samples from juglone extraction absorbed into human skin with 1 mL of 80:20 v / v methanol / water were analyzed by HPLC-MS / MS. A stock solution (1000 ppm juglone standard in solution) was prepared containing 1.00 mg juglone standard (commercial standard Aldrich HA47003), 500 μL methanol, 400 μL acetone and 100 μL deionized water and filtered through a 0.22 μm pore Teflon membrane. From this, solutions of 100, 500, 1000, 2000, 3000, 4000 and 5000 μg / L juglone standard (ppb) were prepared to construct a calibration line. Samples were taken directly into the chromatograph autoinjector without any further preparation (Figure 2). The operating conditions for HPLC-MS / MS were as follows: HPLC (Agilent 1100 Series); Mass spectrometer (API3000-AB Sciex); Chromatography column: Luna 5 μm C18(2) 150X2mm; Flow rate: 0.80 mL / min; Injection volume: 10 μL; Mobile phase: A) 10 mM ammonium acetate in water (pH 6); B) acetonitrile. Elution gradient:

[0091] [Table 1]

[0092] result Confocal optical microscopy: Images corresponding to the juglone distribution in depth were generated and it was observed that the specific fluorescence of the juglone molecule was maintained in what could be called the epidermal region, below a depth of 120 μm, while the signal disappeared at greater depths.

[0093] Table 1 below shows the depth range in which fluorescence was observed due to the presence of juglone in 400 μm thick human abdominal skin sections, with the zero level corresponding to the surface of the epidermis.

[0094] [Table 2]

[0095] HPLC-MS / MS, results of the permeation study: Table 2 shows the ng / cm permeation rate at each time point tested after four sequential applications of 150 mg each (times = 0, 4, 8 and 14 hours, respectively). 2 Figure 3 shows the amount of juglone that penetrated 400 μm thick human skin for each donor (n=6) and silicone gel composition, expressed as σ. The median is given as the central tendency parameter since these are biological samples with high variability (Figure 3).

[0096] [Table 3]

[0097] Results of a study on the retention of juglone in human skin by HPLC-MS / MS: Table 3 shows that 2 of surface area in ng / cm 2 4 shows the amount of juglone, expressed in absolute amounts (ng), harvested from 0.400 mm thick human skin for the tested silicone gel compositions (n=5) and applications (FIG. 4).

[0098] [Table 4]

[0099] Table 4 below shows the percent of treated 2.54 cm ducts retained in the epidermis and dermis above the vascular plexus for the silicone gel compositions tested after application. 2 of surface area in nanograms and ng / cm 2 1 shows the amount of juglone taken from human skin in two horizontal sections, one from 0 mm to 0.150 mm thick (0.150 mm thick) and the other from 0.150 mm to 0.400 mm thick (0.250 mm thick), corresponding to the epidermis with a thickness of 0.150 mm and the dermis, respectively, expressed in , which correlates with a ratio of the two amounts that clearly favors the epidermis versus the dermis.

[0100] [Table 5]

[0101] conclusion The percutaneous permeation study demonstrates that the amount of juglone that permeated human skin (by accumulation) at the 16 hour time point of the study. Given these results, all skins exhibit a similar systemic safety profile.

[0102] Considering the amount of product retained in human skin, which is likely to have some effect "in situ", significant differences were found between the epidermis and dermis in the study. Since a silicone gel composition containing 10% wt. of walnut extract and 0.04% w / w juglone content remained on the skin for 16 hours after a total dose of 600 mg of silicone gel composition (4 applications of 150 mg each), the analytical technique used made it possible to find 3.74 times more juglone in the epidermal section than in the dermal section.

[0103] The amount of juglone harvested from five skin samples from different donors demonstrates that this silicone gel composition promotes retention of juglone at the site of application, which may translate to higher efficacy. Microscopy studies support the observations made by analytical chemistry routes.

[0104] The amount of juglone that penetrated human skin after application of multiple doses was not detectable at the 16-hour time point of the study, which is within the limit of quantification of the technique (180 ng / cm in this study) at the 16-hour time point of the study in all donors studied. 2 ) under the test conditions. Therefore, the silicone gel composition has a non-percutaneous penetration profile of less than 180 ng / cm 2 The results show that juglone is not absorbed in the skin and penetrates but not penetrates in the epidermal depth range, and the product can be presumed to be safe and effective for topical use on human skin.

[0105] Silicone gel compositions of Composition A and Composition B were prepared. Example 1: Silicone gel composition "A" Components of the silicone gel composition include:

[0106] [Table 6]

[0107] Example 2: Silicone gel composition "B" In this example, the same components and percentages were used as in Example 1, except that juglone was present in a higher amount:

[0108] [Table 7]

[0109] Example 3: Preparation of Silicone Gel Composition (A or B) The ingredients were added to the central, anchor-stirred reactor cavity in the order shown in the scheme below. Processing was carried out at room temperature between 15-25° C. Once blending was complete, the product was packaged in 10 ml recipients.

[0110] [Table 8]

[0111] The same methodology was followed for the preparation of silicone gel compositions A and B described in Examples 1 and 2.

Claims

1. 1. A silicone gel composition comprising a walnut extract, said composition comprising: - a silicone mixture consisting of a silicone elastomer gel, a silicone fluid base, and a silicone emulsifier; and - Walnut extract containing natural naphthoquinone components comprising the silicone elastomer gel in an amount of 60-75%, the silicone fluid base in an amount of 12-25%, the silicone emulsifier in an amount of 2-6%, and the walnut extract in an amount of 5-15%, and the percentages are expressed by weight relative to the weight of the composition, provided that the sum of all components does not exceed 100%; The silicone gel composition.

2. 2. The silicone gel composition of claim 1, wherein the silicone elastomer gel comprises decamethylcyclopentasiloxane (D5) in a network backbone of polydimethylsiloxane (PDMS), the silicone fluid base comprises a cyclopentasiloxane compound, and the silicone emulsifier comprises an alkylmethylsilicone polyether copolymer compound.

3. 3. The silicone gel composition of claim 1 or 2, wherein the silicone elastomer gel comprises decamethylcyclopentasiloxane (D5) in an amount of about 85% by weight and a crosslinked polymer of greater than 5,000 average molecular weight in an amount of about 12% by weight.

4. 3. The silicone gel composition of claim 1 or 2, wherein the silicone fluid base comprises greater than about 95% by weight of decamethylcyclopentasiloxane (D5).

5. 3. The silicone gel composition of claim 1 or 2, wherein the silicone emulsifier comprises an alkylmethylsilicone polyether copolymer.

6. 6. The silicone gel composition of claim 1, wherein the silicone elastomer gel is in an amount of 67-69% by weight based on the weight of the composition.

7. The silicone gel composition of any one of claims 1 to 6, wherein the silicone fluid base is in an amount of from 17 to 19% by weight based on the weight of the composition.

8. 8. The silicone gel composition of claim 1, wherein the silicone emulsifier is present in an amount of from 3 to 5% by weight based on the weight of the composition.

9. 9. The silicone gel composition according to claim 1, wherein the walnut extract is present in an amount of 8 to 12% by weight based on the weight of the composition.

10. 10. The silicone gel composition according to claim 1, wherein the walnut extract contains juglone as a natural naphthoquinone component in an amount of 0.1 to 0.5% by weight based on the weight of the walnut extract.

11. A silicone gel composition comprising a walnut extract as defined in claims 1 to 10 for topical use in the treatment of herpes viruses.

12. The silicone gel composition of claim 11, wherein said use comprises a dosage regime of 125-175 mg administered at intervals of 3-5 hours up to a total of 500-600 mg.

13. 13. The silicone gel composition of claim 11 or 12, wherein the dosage regime is 125-175 mg administered at four hour intervals up to a total of 500 mg.

14. 13. The silicone gel composition of claim 11 or 12, wherein the dosage regime is 150 mg administered at four hour intervals up to a total of 600 mg.

15. The silicone gel composition of any one of claims 11 to 14, wherein the treatment is within a target skin depth range of about 30 μm to about 120 μm.

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