MICROCAPULE UNDERSTANDING SUN PROTECTION AGENTS, COMPOSITION, MICROCAPULE PREPARATION PROCESS CONTAI

专利摘要:
"microcapsules comprising sunscreen agents" means microcapsules composed of a core, comprising one or more sunscreen agent (s) and a shell of a polymeric wall-forming material, which are not breakable when rubbing or pressing on the skin, and their preparation processes are disclosed; topical formulations, comprising microcapsules, which can be, for example, sun protection formulations and skin care formulations, are also provided
公开号:BR112015020889B1
申请号:R112015020889-4
申请日:2014-02-27
公开日:2020-10-06
发明作者:Danny Goldstein；Olga Privalova；Lior BEN-ALTABET；Yaniv MENACHEM；Hanan HAJ
申请人:Tagra Biotechnologies Ltd.；
IPC主号:

专利说明:

[001] The present patent application, in some respective applications, relates to microcapsules suitable for use in topical compositions and, more particularly, but not exclusively, to microcapsules comprising sunscreen agents and topical formulations comprising them, which can be used, for example, in cosmetic formulations, such as sunscreen and skin care formulations.
[002] The harmful effects of exposure to UV rays from the sun have been well described in the literature. Both exposure to acute and chronic UV rays can lead to sunburn, photocarcinogenesis, photoimmunosuppression and photoaging. While the photoprotective benefits of inorganic UV filters TiO2 and ZnO have been known for decades, these previous generations of inorganic filters, comprised of large particles, produce an opaque, white appearance on the skin. In addition to the cosmetic disadvantages, the wide application of previous formulations containing TiO2 or ZnO was also hampered by its poor dispersive properties that resulted in granular and occlusive qualities. Considerable effort has been made to overcome the cosmetic deficiencies of these inorganic UV filters by gradually minimizing their particle size to the nano range (less than 100 nm).
[003] Nanoparticles are known to exhibit different mechanical, electrical and optical properties of standard sized particles. Recently, it has been reported, based on in vitro cell experiments, that pure TiO2 or ZnO nanoparticles can induce free radical formation in the presence of light and that this can damage with them applied. Therefore, the incorporation of TiO2 and ZnO nanoparticles in sunscreens has raised interesting questions regarding dermal penetration, systemic absorption and subsequent toxicity of these nanoparticles. Currently, there is no in vivo evidence to indicate possible toxicity of nanoparticulate TiO2 or ZnO in humans using sunscreen products. So far, the current weight of evidence indicates that the particles remain on the skin's surface and in the outer dead layer (stratum corneum) of the skin. Thus, an analysis of the available evidence fails to demonstrate toxicity of these products after skin application to healthy, intact skin. Nevertheless, comprehensive and extensive studies are being sponsored by health authorities in different countries to assess the adverse effects of TIO2 or ZnO nanoparticles on the biological properties of cells and their consequent negative health implications.
[004] Oxybenzone (benzophenone-3) is a widely used molecular lipophilic molecular sunscreen agent that effectively absorbs rays of ultraviolet B light (UVB; 290 to 320 nm), some ultraviolet A (UVA; 320 to 360 nm ) and some ultraviolet C (250 to 290 nm). However, oxybenzone is the most common cause of photoallergic contact dermatitis. In fact, many sun protection molecules penetrate the skin causing photoallergies, phototoxic reactions and skin irritation (Marcato et al., 2011: "Nanostructured polymer and lipid carriers for sunscreen. Biological effects and skin permeation", J. Nanoscience and Nanotechnology, 11, 1880-1886). In addition, systemic absorption of oxybenzone after its topical application to the skin has been reported (Burnett and Wang, 2011: "Current sunscreen controversies: a critical review", Photodermatology, Photoimmunology & Photomedicine, vol. 27, pages 58-67). In addition to its photoallergic potential, the main concerns in relation to its systemic absorption profile have generated heated debates about the global safety of this molecule.
[005] Avobenzone, a derivative of dibenzoylmethane (butyl methoxydibenzoylmethane; trade names Parsol® 1789, Eusolex® 9020, Escalol® 517 and others) is an oil-soluble ingredient used in sun protection products to absorb the full spectrum of UV rays -THE. Its ability to absorb ultraviolet light over a wider range of UVA wavelengths than many organic sunscreen agents has led to its use in many commercial preparations marketed as "broad spectrum" sunscreens. Avobenzone, as an active sunscreen, has become photo-unstable and tends to degrade chemically after prolonged exposure to ultraviolet radiation (UVR | ultraviolet radiation). The chemical degradation of avobenzone eliminates its ability to absorb UVR and thus protect the skin from damage from UV rays when used as an active sunscreen in sun protection products.
[006] Some of the sun protection compositions known to date contain more than one type of UV filter. Such compositions are often characterized by the fact that UV filters tend to interact, leading to a situation where the UV filter activity of one or more of the UV filters in the composition is reduced during storage or after being applied to the skin.
[007] European Patent No. 1899015 discloses a topical composition containing at least two different types of protection agents, in which at least one type of sun protection agent is encapsulated in microcapsules having an average particle size between 3 pm and 8 pm. Microcapsules smaller than 3 pm were released to leak. The microcapsules are obtainable by an emulsion polymerization process or by a sol-gel process, in which the encapsulating agent is a tetra-alkoxysilane. Sol-gel microcapsules that comprise sun protection agents are disclosed in U.S. Patent No. 6,303,149. These microcapsules were designed to permanently encapsulate sunscreen agents, but a significant amount of leakage of sunscreen agents through the microcapsules was observed when the microcapsules were incorporated into the usual sunscreen compositions, particularly when the microcapsules were smaller in size 3 pm.
[008] Marcato et al., 2011 disclose benzophenone-3 (BZ3) solid polymeric and lipid nanoparticles, with the aim of improving the safety of sun protection products by decreasing the penetration into the skin of BZ3 and decreasing the concentration of BZ3 in the formulation of sunscreen. BZ3 is encapsulated in poly (ε-caprolactone) nanoparticles (PCL | poly (ε-caprolactone) by the nanoprecipitation method and in solid lipid nanoparticles (SLN | solid lipid nanoparticles) by the high pressure hot homogenization method. stable for 40 days, after which time the encapsulated BZ3 was released.
[009] US Patents No. 6,932,984 and 7,838,037, by the present applicant, describe a method for microencapsulating substances through the solvent removal method using non-chlorinated solvents. The method is based on physical processes that do not cause any change in original physical and / or chemical properties, biological activity and safety of raw materials during the process. This method provides physical stability of the microcapsules, high ability to trap the active agents, protection of the active agents within the microcapsules and prevention of the diffusion of micro-encapsulated active agents to the external water phase in a water-based preparation. In U.S. Patent No. 7,838,037, the resulting microcapsules are double layer and / or triple layer microcapsules, designed to break through a slight mechanical action such as rubbing or pressing on the skin and thus immediately release its contents encapsulated. WO 2009/138978, by the present applicant, describes cosmetic compositions, including sunscreen compositions, comprising violatable double layer microcapsules containing one or more microencapsulated dyes, inter alia, titanium oxide. WO 2009/138978 discloses a sunscreen 45 SPF, color changing composition comprising encapsulated sunscreens, such as TiO2 and zinc oxide. SUMMARY
[0010] There is an unmet need for safer sun protection products, which are able to increase the sun protection factor (SPF | sun protection factor), while eliminating cosmetic disadvantages related to the appearance of the sunscreen formulation on the skin and beyond in addition, it reduces harmful effects such as skin penetration, photodegradation, systemic absorption and toxicity of UV filters such as TiO2, oxybenzone, avobenzone and other UV filters as currently used.
[0011] For example, it is highly desirable to decrease the concentration of oxybenzone in a sunscreen formulation, to photostabilize avobenzone and / or overcome incompatibilities between different UV filters.
[0012] According to an aspect of some applications of the present patent application, a microcapsule is provided comprising a core comprising at least one sun protection agent and a shell surrounding the core, the shell comprising a material
[0017] According to some applications of the present patent application, the sun protection agent is a water insoluble or water immiscible sun protection agent, as described here.
[0018] According to some applications of the present patent application, the microcapsule has a size within a selected range of about 1 pm to about 100 pm, from about 1 pm to about 90 pm, from about from 1 pm to about 80 pm, about 1 pm to about 70 pm, 1 pm to about 60 pm, about 1 pm to about 50 pm, about 1 pm to about 40 pm, about from 1 pm to about 30 pm, about 1 pm to about 20 pm, about 1 pm to about 10 pm, or about 2 pm to about 10 pm or about 2 pm to about 15 pm.
[0019] According to some applications of the present patent application, the sunscreen agent is a mixture of TiCh and one or more of avobenzone, p-aminobenzoic acid, cinoxate, dioxibenzone, ecamsule, homosalate, menthol anthranylate, octocrylene, octyl salicylate, octyl-methoxycinnamate, oxybenzone, trolamine salicylate or ZnO.
[0020] According to any of the applications of the present application, the polymeric wall-forming material comprises a polymer or copolymer selected from the group consisting of a polyacrylate, a polymethacrylate, a cellulose ether, cellulose or any combination thereof.
[0021] According to some applications of the present patent application, the polymeric wall-forming material comprises poly (methyl methacrylate) which exhibits PM within the range of 15,000 Daltons to 120,000 Daltons, type B ammonium methacrylate copolymer, ethyl cellulose ether, ethyl cellulose ester or any combination thereof.
[0022] According to any of the applications of the present application, the amount of the polymeric wall forming material is within a selected range of about 20% to about 70%, about 20% about 50%, about 20% to about 40%, or about 20% to about 30%, or about 20% or 50%, by weight.
[0023] According to some of any of the applications of the present patent application, the microcapsule further comprises a photostabilizer.
[0024] According to some applications of the present patent application, the amount of the photostabilizer in the microcapsule is within a selected range of about 5% to about 50%, from about 5% to about 40%, from about 5% to about 30% or from about 10% to about 25% or about 10% by weight.
[0025] According to any of the applications of the present patent application, the microcapsule is transparent.
[0026] According to an aspect of some applications of the present patent application, a composition is provided that comprises a plurality of microcapsules, at least a portion of the microcapsules comprising a plurality of microcapsules containing the sunscreen agent as described in any of the respective applications.
[0027] According to some applications of the present patent application, microcapsules in the plurality of microcapsules containing sunscreen are the same or different.
[0028] According to some applications of the present patent application, the plurality of microcapsules have an average size within a selected range of about 1 to about 100 pm, from about 1 to about 90 pm, from about 1 to about 80 pm, about 1 to about 70 pm, 1 about to about 60 pm, about 1 to about 50 pm, about 1 to about 40 pm, about 1 to about from 30 pm, about 1 to about 20 pm, about 1 to about 10 pm, or about 2 to about 10 pm or about 2 to about 15 pm.
[0029] According to some applications of the present patent application, the composition further comprises a photo-stabilizer.
[0030] According to some applications of the present patent application, at least a portion of microcapsules in the plurality of microcapsules containing sunscreen agent still comprises a photostabilizer.
[0031] According to an aspect of some applications of the present patent application, a process for preparing microcapsules containing sunscreening agent is provided, the process comprising: a) mixing a solution, comprising the sunscreening agent , a polymeric wall-forming material and an organic solvent, to obtain a homogeneous solution; b) mixing a homogeneous solution with an aqueous solution containing an emulsifier, under high shear stirring, to form an emulsion; and c) adding to the emulsion formed an amount of water that initiates the extraction of the organic solvent from the emulsion, thus obtaining the microcapsules.
[0032] According to some applications of the present patent application, the process further comprises isolating the microcapsules.
[0033] According to some applications of the present patent application, microcapsules containing sunscreen are as defined in any one of claims 1 to 22.
[0034] According to some applications of the present patent application, the plurality of microcapsules containing sunscreen agent in the composition as defined herein is prepared according to the process of any one of claims 29 to 31.
[0035] In accordance with an aspect of some applications of the present patent application, a cosmetic or cosmeceutical formulation comprising a sun protection composition according to any of the respective applications described herein is provided.
[0036] Unless otherwise stated, all technical and / or scientific terms used here have the same meaning as commonly understood by a technician in the subject to which the present application for a patent belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the applications of the present patent application, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. BRIEF DESCRIPTION OF THE DRAWINGS
[0037] Some applications of the present patent application are described here, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is emphasized that the characteristics shown are, by way of example and for purposes of illustrative discussion of the applications of the present application for an invention patent. In this regard, the description taken with the drawings makes it apparent to those skilled in the art how applications of the present patent application can be practiced. In the drawings:
[0038] Figures 1A-1B present images of scanning electron microscope (SEM | scanning electron microscope) of microcapsules, comprising poly (methyl methacrylate) (PMMA | poly (methyl methacrylate)) and TÍO2 encapsulated in xlOOO and x5000 magnification, respectively .
[0039] Figure 2 shows SEM images of microcapsules containing avobenzone, comprising PMMA as the wall forming polymer, magnified x5000.
[0040] Figure 3 is a graph showing the monochromatic protection factor (MPF | monochromatic protection factor) of a sun protection formulation, comprising 15% microencapsulated TiO2 as a wavelength function, for 9 scans taken from 9 different locations of a Transpore® tape substrate area covered with the formulation.
[0041] Figure 4 is a graph showing the monochrome protection factor of a sun protection formulation comprising 7.5% microencapsulated avobenzone as a function of wavelength, for 9 scans taken from 9 different locations in an area of Transpore® tape substrate covered with the formulation.
[0042] Figures 5A-5B are bar graphs that show the photostability test of a sun protection formulation containing non-encapsulated (crude) avobenzone and of a body lotion sun protection formulation containing microcapsules comprising 40% avobenzone and 10% octocrylene. The final concentration of avobenzone in both formulations is about 3%. The bars in figures 5A and 5B show% avobenzone in each formulation before and after 4 hours of exposure to the sun on two different dates. DETAILED DESCRIPTION
[0043] The present application for a patent, in some applications thereof, relates to microcapsules suitable for use in topical compositions and, more particularly, but not exclusively, in microcapsules comprising sun protection agents and topical formulations comprising same, which can be used, for example, in cosmetic formulations, such as sunscreen and skin care formulations.
[0044] Before explaining at least one application of the present invention patent application in detail, it should be understood that the present invention patent application is not necessarily limited in its application to the details set out in the description below or exemplified by the Examples.
[0045] In view of the recognized need for safer sunscreen products that deceive and even eliminate the cosmetic disadvantages and health risks associated with known sunscreen products and in view of another need to provide sunscreen products that exhibit an increased sun protection factor (SPF), efforts were made to design sun protection formulations that would have the benefits of an efficient UV filtering ability of UV filters such as TiÜ2r oxybenzone, avobenzone and other UV filters as currently used, low concentrations of such sunscreen agents in formulations, chemistry and photostability of sunscreen agents during prolonged storage and, especially, during application to the skin, and, at the same time, minimal harmful and harmful effects to the user.
[0046] The present inventors used the microencapsulation technique to encapsulate sun protection agents within firm, non-violable microcapsules that, on the one hand, protect the encapsulated sun protection agent from destabilizing the effects of light / sun, high temperatures and incompatible components in the formulation and, on the other hand, protect the user from the harmful and risky effects associated with direct contact of the sunscreen agent with the skin and with systemic absorption thereof.
[0047] The present inventors have designed to use the solvent removal method using non-chlorinated solvents to encapsulate the sunscreen agent. The solvent removal method is based on physical processes that do not cause any change in original physical and / or chemical properties, biological activity and safety of raw materials during the process. This method provides physical stability of the microcapsules, high ability to trap the active agents, protection of the active agents within the microcapsules and prevention of the diffusion of the microencapsulated active agents to the external water phase in a water-based preparation.
[0048] Thus, the present inventors have successfully designed and practiced a new methodology to obtain stable and safe sunscreen formulations for use, which exhibits exceptional performance even at low concentrations of sunscreen agents and which is useful, inter alia, in formulations containing sunscreen agents that are known to either have undesirable effects on the skin such as irritation, toxicity and systemic absorption, and / or as being chemically unstable.
[0049] For example, the present inventors have demonstrated that microencapsulation sunscreen agents that use the methodology as described here, allow formulating sunscreen agents such as avobenzone and TiO2 in concentrations lower than commonly practiced, can photo-stabilize photodegradable agents such as avobenzone and / or overcome incompatibilities between different UV filters and other components of the formulation, while maintaining and even improving the SPF of the formulation.
[0050] The microcapsules provided by the present application are available in powder form and consist of particles (for example, generally spherical particles), which are generally closed structures containing an encapsulated (entrapped) substance, which comprises or consists of , according to preferred applications, a sun protection agent or a mixture of sun protection agents. The particle generally has the structural characteristic of the core shell, that is, it consists of a polymeric shell and a core that comprises the sunscreen agent or can be made up of the sunscreen agent, surrounded by the shell. The polymeric shell is often applied as a wall forming material and serves as a membrane for the encapsulated substance. The microcapsule wall-forming material containing sunscreen provided by the present patent application does not contain a plasticizer and the microcapsules are non-violable by rubbing or pressing on the skin. In some applications, the shell of microcapsules containing sunscreen is transparent.
[0051] The microcapsules of the present patent application, among other uses, are intended for topical applications, for example, cosmetic, cosmeceutical and pharmaceutical (for example, dermatological). While applied to the skin, the microcapsules are able to sustain shear forces such as rubbing and pressing on the skin and remain intact in order to keep the UV filters encapsulated inside, secreted and separated from the other components of the formulation. The microcapsules are hard enough to prevent the destruction of the shell and the realization of the contents during the technological process by isolation, drying, sieving, etc. THE MICROCapsules
[0052] According to an aspect of some applications of the present patent application, a microcapsule is provided which comprises a core comprising at least one sun protection agent and a shell comprised of a polymeric wall-forming material involving the core. Such microcapsules are also referred to here as microcapsules containing sunscreen.
[0053] According to some applications of the present patent application, a microcapsule, as described here, is non-violable or non-breakable when applied to the skin; that is, a microcapsule, as described here, remains intact when applied to the skin, for example, it sustains its structure and shape, when subjected to shear forces that are applied when a microcapsule is rubbed or pressed on the skin.
[0054] The non-breakability of the microcapsules of the present patent application can be determined by the ability of the microcapsules to remain intact, for example, to keep the particle size and shape unchanged, following an ultrasonication for 1 minute or homogenization at 2000 rpm for 10 minutes.
[0055] In an exemplary test to determine the non-breakability of the microcapsules as described here, the microcapsules are incorporated into a basic formulation, such as a body lotion and subjected to ultrasonication (15 W, 28 kHz) for 1 minute.
[0056] In another exemplary test to determine the non-breakability of the microcapsules as described here, the microcapsules are incorporated into a base formulation and subjected to a low shear mixture and a high shear mixture (homogenizer) at 2000 rpm for 10 minutes.
[0057] In each of these tests, the microcapsules are then observed by light microscopy and a change in shape or size is determined, compared to a size and shape of the microcapsules previously subjected to an assay as described here. A change of less than 10% in the size of the microcapsule is indicative of the non-breakability of the microcapsules.
[0058] In some applications, microcapsules are subjected to one or both tests, as described here, and a change in microcapsule size is seen in less than 10% of microcapsules.
[0059] In some applications, microcapsules that contain the sunscreen agent, as described here, are prepared by the solvent removal method, as described in more detail here below.
[0060] In some applications, a microcapsule size, as described here, is within a selected range of about 1 to about 100 pm, about 1 to about 90 pm, about 1 to about 80 pm pm, from about 1 to about 70 pm, from about 1 to about 60 pm, from about 1 to about 50 pm, from about 1 to about 40 pm, from about 1 to about 30 pm, from about 1 to about 20 pm, from about 1 to about 10 pm, or from about 2 to about 10 pm, preferably about 2 to about 15 pm, including any sub-ranges and any intermediate values between them. WALL FORMING POLYMER
[0061] The term "wall-forming polymer", which is also referred to herein as "wall-forming polymeric material" refers to a polymeric material (for example, a polymer or copolymer) or a combination of two or more different polymeric materials, as defined here, that form a component of the outer wall or layer or shell of the microcapsules. The term "polymer shell" refers to a polymeric layer comprised of the wall-forming polymer (s).
[0062] In some applications, the wall-forming polymer is selected in order to sustain the shear forces used when the microcapsule is applied (for example, rubbed or pressed) on the skin.
[0063] In some applications, the polymeric wall-forming material comprises a polymer that has a relatively low molecular weight, containing a sufficient amount of functional groups that are capable of forming hydrogen bonds.
[0064] Without being bound by any particular theory, it is assumed that the polymeric material capable of forming strong hydrogen bonds is capable of forming a stabilized shell layer that represents the microcapsule's non-breakable characteristic.
[0065] In some applications, the polymeric material comprises functional groups of hydrogen bond formation having from 4 to 40% by weight of the total weight of the polymer.
[0066] Hydrogen bond forming functional groups include, among others, functional groups that comprise one or more electron donor atoms such as oxygen, sulfur and / or nitrogen.
Exemplary hydrogen bonding groups include, but are not limited to, hydroxyalkylal acid, thiol, amine, amide, amidoalkyl alkoxy alkanoyloxy, alkylcarbonylalkyl, thiohydroxy and thioalkoxy and any combination thereof.
[0068] In some applications, hydrogen bond forming groups include carboxylic acid, carboxylate, hydroxy or any combination thereof.
[0069] In some applications, the polymeric wall-forming material comprises a polyacrylate, a polymethacrylate, a cellulose ether or ester or any combination thereof.
[0070] In some of any of the applications of the present patent application, the polymeric wall-forming material comprises a polyacrylate or a polymethacrylate and / or comprises one or more polymers or copolymers that can be collectively represented as comprising the general structure Next:
characterized by: n representing the number of chemical structure units in the polymer or copolymer that presents the general structure above, R is alkyl and X is selected from the group consisting of hydrogen, alkyl, cycloalkyl and ammonium.
[0071] When X is ammonium, a counterion such as, for example, halide, is included.
[0072] Polymers or copolymers useful in the polymeric material of applications of the present patent application preferably contain the units of chemical structure described here in an amount of about 10% to about 40% of the total number of units of chemical structure in the polymer or copolymer.
[0073] In some applications, the polymer is a copolymer comprising a mixture of chemical structure units that have the above structure, so the units differ from each other by the type of R and / or the type of X.
[0074] In some applications, the polymer or copolymer comprises chemical structure units that have the general structure above, in which R is methyl and X is methyl, thus including the PMMA chemical structure units.
[0075] In some applications, the polymeric material comprises a copolymer comprising units of PMMA and units of additional chemical structure independently having the above structure.
[0076] In some applications, in some of the additional chemical structure units, X is ethyl.
[0077] In some applications, in some of the additional chemical structure units, X is ammonium, for example, trimethyl ammonium chloride.
[0078] In some applications, the polymeric wall-forming material comprises ammonium methacrylate copolymer type B (poly (ethyl acrylate) -co- (methyl methacrylate) -co- (trimethylammonium chloride-ethyl methacrylate), also known as Eudragit RSPO® or EuRSPO®).
[0079] Any combination of polymers and copolymers as described here is contemplated for the wall forming material.
[0080] In some other applications, the polymeric material comprises a cellulose ether or ester such as, but not limited to, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, cellulose acetate, cellulose acetate phthalate or hydroxypropyl methyl cellulose acetate. When cellulose or cellulose derivatives are used in the polymeric material, they preferably contain about 4 to 20% free hydroxyl groups to form hydrogen bonds.
[0081] In some of any of the other applications of the present patent application, the polymeric wall-forming material comprises a combination of the polymers mentioned above such as, among others, combinations of Eudragit RSPO® with PMMA or ethyl cellulose (EC) .
[0082] In some of any of the applications in this application, the shell of the microcapsules comprises one or more polymers or copolymers (for example, as described here), having a molecular weight (MW) in the range of 5,000 Daltons to 300,000 Daltons.
[0083] In applications where PMMA is the polymer comprised in the shell, it is preferably a polymer that has a molecular weight within the range of 15,000 Daltons to 120,000 Daltons.
[0084] Without being bound by any particular theory, it is assumed that the relatively low PM of the polymers or copolymers comprising the polymeric wall-forming material and therefore relatively short polymeric chains, considered the non-breakability of the shell.
[0085] The amount (weight / weight) of the polymeric wall-forming material of the total weight of the microcapsule can be within a selected range of about 20% to about 70%, from about 20% to about 50% , from about 20% to about 40%, from about 20% to about 30%, preferably about 20% or 50%, by weight, including any sub-ranges and any intermediate values between them.
[0086] The shell of the microcapsules can be transparent, semi-transparent or non-transparent and is preferably transparent. "Transparency", as used here, means more than 70% light transmission. Thus, transparent polymers will transmit from 70% to 100% of light, while semitransparent ones will transmit up to 50% of light. In some exemplary applications, the microcapsules of the present patent application comprise a shell comprised of PMMA, as described here, and a core containing a sun protection agent with or without the photostabilizer, as described here.
[0087] An additional technical characteristic of the microcapsules containing sunscreen of the present application, which still considers their ability to sustain shear forces and remain non-breakable upon application, is that they comprise a wall forming material that does not contain a plasticizer.
[0088] Thus, the microcapsules containing sunscreen provided by some applications of the present patent application are essentially devoid of a plasticizer.
[0089] In some applications, the shell of the microcapsules is devoid of a plasticizer.
[0090] As used here in the context of the shell, "devoid of a plasticizer" means that the amount of plasticizer is less than 5%, less than 3%, less than 1%, less than 0.5%, less than 0, 1%, less than 0.05% and even 0% by weight of the peel. SUN PROTECTION AGENT
[0091] The terms "sun protection agents", "sunscreens", "UV filters", "active sunscreens" and "sunscreens" are used here interchangeably and refer to compounds that partially block or protect from UVA radiation by absorbing UV radiation (such as oxybenzone) or reflecting UV rays (such as titanium dioxide, zinc oxide) or a combination thereof. The above terms are intended to cover all groups of sunscreens, including, among others, UVA sunscreens, which block UV radiation in the wavelength range of about 320 to 400 nm, UVB sunscreens, which block radiation in the range from 290 to 320 nm and the broad spectrum agents that block all bands.
[0092] In some of any of the applications described here, sunscreen agents are sunscreen agents insoluble in water or immiscible in water.
[0093] In some of any of the applications described here, sun protection agents are water-dispersible or oil-soluble sun protection agents.
[0094] Non-limiting examples of such agents include TiC> 2, avobenzone, p-aminobenzoic acid, bemotrizinol, benzophenone-9, bexophenoma-3, bisoctrizol, 3- , dioxibenzone, drometrizole trisiloxane, ecamsule, ethylhexyl triazone, homosallation, menthyl anthranilate, octocrylene, octyl salicylate, iscotrizinol, isopentenyl-4-methoxycinnamate, octyl-dimethyl-p-aminobenzoic acid, octyl-dimethyl-p-aminobenzoic acid, -15, trolamine salicylate, ZnO and any combination thereof.
[0095] In some of any of the applications in this invention application, the sun protection agent is a UV filter approved by the United States Food and Drug Administration (FDA | Food and Drug Administration). Non-limiting examples of FDA-approved water-insoluble agents include THO2, avobenzone, p-aminobenzoic acid, cinoxate, dioxibenzone, ecamsule, homosalate, menthyl anthranilate, octocrylene, octyl salicylate, octyl-methoxycinate, oxybenzone, triacinate, zololinate .
[0096] In exemplary applications, the UV filter is Avobenzone.
[0097] Each of the sunscreen agents described here can be used in any combination and with each of the applications described here for microcapsules and / or the formulation / composition containing them.
[0098] According to some applications, a microcapsule can be loaded with a mixture of sunscreen agents, for example, with a mixture of two or more of THIO2, avobenzone, p-aminobenzoic acid, bemotrizinol, benzophenone-9, bexophenoma -3, bisoctrizol, 3- isopentenyl-4-methoxycinnamate, octyl-dimethyl-p-aminobenzoic acid, octyl-methoxycinnamate, oxybenzone, polysilicone-15, trolamine salicylate and ZnO.
[0099] In some of any of the applications in this application, the UV filter is a mixture of UV filters approved by the EDA, such as THO2, avobenzone, p-aminobenzoic acid, cinoxate, dioxibenzone, ecamsule, homosalate, anthranilate menthol, octocrylene, octyl salicylate, octyl-methoxycinnamate, oxybenzone, trolamine salicylate or ZnO.
[00100] In some applications, a microcapsule is loaded with a mixture of TiO2 and one or more of the UV filters approved by the EDA.
[00101] In some applications, sun protection agents that exhibit different properties, for example, UVA block, block or UVB reflection, are mixed.
[00102] In some of any of the applications described here, the amount of the sunscreen agent in a microcapsule ranges from about 20% to about 90% by weight, referring to the total weight of each microcapsule. For example, the amount can be about 20 to about 80%, about 40 to about 80%, preferably about 40% or 80%, by weight, including any sub-ranges and any intermediate values between them.
[00103] According to any of the applications of the present patent application, the microencapsulated sunscreen agent in the microcapsule is TIO2. In certain characteristics of these applications, the amount of TiO2 in the microcapsule is within a selected range of about 25 to about 95%, about 30 to about 90%, about 40 to about 90%, about from 50 to about 90%, from about 60 to about 90%, from about 70 to about 90%, from about 80 to about 90%, preferably about 80%, of the total weight of each microcapsule, including any sub-ranges and any intermediate values between them.
[00104] In some of any of the applications of the present patent application, the sun protection agent that is microencapsulated in the microcapsule is avobenzone. According to certain characteristics of these applications, the amount of avobenzone in the microcapsules is within a selected range of about 30 to about 90%, about 35 to about 90%, about 40 to about 90%, from about 50 to about 90%, from about 60 to about 90%, from about 70 to about 90%, from about 80 to about 90%, preferably about 40% by weight, including any sub-ranges and any intermediate values between them. SUN PROTECTION COMPOSITION
[00105] According to an aspect of some applications of the present application, a composition is provided that comprises a plurality of microcapsules, at least a portion of the microcapsules are microcapsules that comprise a core comprising at least one sunscreen agent and a shell comprised of a polymeric wall-forming material that surrounds the core, as described in any of the applications described here. Such a composition is also referred to here as a sunscreen composition.
[00106] In some applications, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90 %, at least 95%, at least 98% or at least 99% of the plurality of microcapsules in the composition are microcapsules containing sunscreen as described in any of the applications described here.
[00107] "Composition", as used herein, refers to a plurality of microcapsules, which may be the same or may have a plurality or variety of characteristics. According to the present patent application, at least a portion of the plurality of microcapsules exhibits all the technical characteristics that characterize a microcapsule of the present patent application, according to any of its applications, for example, having a core-shell structure, encapsulating a sun protection agent, which is non-breakable when rubbing on the skin, which is transparent and does not contain a plasticizer.
[00108] The term "at least one portion" means at least 20%, at least 50%, at least 70%, at least 60%, at least 80%, at least 90%, at least 95%, at least 98 %, at least 99% or all microcapsules that are non-breakable core-shell microcapsules containing sunscreen, as described in any of the respective applications.
[00109] In some applications, the microcapsules containing sunscreen, as described here in the composition, may be the same or may differ from each other by the sunscreen agent encapsulated here and / or by the polymeric wall-forming material comprising the shell .
[00110] In at least part or portion of the plurality of the microcapsules of the composition provided by the present patent application, the sun protection agent can be the same or different, and / or the microcapsules can encapsulate a mixture of core sunscreens .
[00111] In some applications related to the composition of the present patent application, particularly that portion of the plurality of microcapsules in the composition that exhibits the combination of technical characteristics that characterize a microcapsule of the present patent application, each microcapsule may contain one of a mixture of two or more agents, preferably a mixture of at least one UVA blocker with at least one UVB blocker. In some other applications, microcapsules that contain an agent can be mixed with microcapsules that contain another agent or mixture of agents, within the sunscreen composition.
[00112] In exemplary applications, the combination of UVA and UVB blockers include aminobenzoic acid (a UVB filter) and avobenzone (a UVA filter) or avobenzone and TIO2 (UVA and UVB filter) or octocrylene (UVB) and avobenzone or cinoxate (UVB ) and TiO2 or avobenzone and octocrylene and meradimata (menthyl anthranilate) (UVA).
[00113] In some applications, the composition, as described here, still comprises one or more additives. Exemplary additives include, among others, a photo-stabilizer and a non-water-soluble antioxidant.
[00114] In some applications, the composition still comprises a photostabilizer. The photostabilizer can be included in one or more of the microcapsules in the composition, optionally in combination with a sun protection agent as described here.
[00115] In some applications, at least a portion of the microcapsules containing sunscreen of the present patent application still comprises a photostabilizer, for example, in the core.
[00116] Photostabilizers are organic compounds that help prevent UV filters from losing their effectiveness in sunlight. Certain photo-stabilizers help to stabilize UV filter molecules structurally and geometrically through electrostatic and van der Waals interactions, which makes them less likely to participate in chemical reactions. Other photo-stabilizers protect sunscreens by helping to dissipate UV energy more quickly, thereby reducing or even eliminating the possibility of a chemical reaction. This process is called energy transfer and can occur when the sun protection agent and molecules of the photostabilizer exchange electrons. In this way, sunscreen agents are fully active in protecting the skin by absorbing harmful rays, while photostabilizers discard energy.
[00117] Non-limiting examples of photostabilizers include diethylhexyl-2,6-naphthalate (Corapan® TQ), octocrylene or 4-methylbenzylidene camphor (MBC).
[00118] In some of any of the applications of the present patent application, the amount of the photostabilizer in the microcapsules is within a selected range of about 5% to about 50%, from about 5% to about 40% , from about 5% to about 30% or from about 10% to about 25%, preferably about 10%, by weight, including any sub-ranges and any intermediate values between them.
[00119] Each of the microcapsules, as described here, can be used in any combination and with each of the applications described here for the formulation / composition containing them.
[00120] In some applications, an average size of microcapsules containing sunscreen in the sunscreen composition as described here is within a selected range of about 1 to about 100 pm, from about 1 to about 90 pm, from about 1 to about 80 pm, about 1 to about 70 pm, about 1 to about 60 pm, about 1 to about 50 pm, about 1 to about 40 pm, about 1 to about 30 pm, about 1 to about 20 pm, about 1 to about 10 pm, or about 2 to about 10 pm, preferably about 2 to about 15 pm, including any sub-bands and any intermediate values between them. EXEMPLARY SUN PROTECTION COMPOSITIONS
[00121] In some exemplary applications, at least a portion of a plurality of microcapsules comprising the composition of the present patent application comprises TiOz as the sun protection agent in an amount of about 80% by weight and the forming material wall cover comprises poly (methyl methacrylate) in an amount of about 20% by weight.
[00122] Example 1 here describes microcapsules that contain TiO2 as the sunscreen agent in an amount of about 80% by weight and PMMA in an amount of about 20% by weight.
[00123] Example 2 here describes microcapsules containing avobenzone that still contains the octocrylene photostabilizer. These microcapsules contain about 40% by weight of avobenzone, about 50% by weight of PMMA and about 10% by weight of octocrylene. It is shown in Example 8 here that sunscreen formulations comprising such avobenzone-octocrylene microcapsules exhibited higher photostability.
[00124] In other exemplary applications, the sun protection agent is homosalate and the microcapsules according to those applications contain about 40% by weight of homosalate and about 60% by weight of PMMA or the sun protection agent is octy methoxycinnamate and the microcapsules contain about 30% by weight of octyl methoxycinnamate, about 70% by weight of PMMA and about 2% by weight of the stabilizer BHT (Butylated Hydroxy Toluene | Butylated Hydroxytoluene). In other applications, the sunscreen agent is octissalate and the microcapsules contain about 40% by weight of octysalate and about 60% by weight of PMMA.
[00125] In other exemplary applications, the sun protection agent is avobenzone in an amount of about 40% by weight, the wall forming material is poly (methyl methacrylate) in an amount of about 50% by weight and a photo-stabilizer which is octocrylene is also included in the composition, in an amount of about 10% by weight.
[00126] The microcapsules containing sunscreen provided here have several advantages. When administered to the skin in a sunscreen formulation, they retain sunscreen in the surface layers of the skin; maintain or improve the safety and photoprotection ability of the sunscreen agent against the harmful effects of UV radiation; reduce systemic absorption of the sunscreen agent; and increase the photostability of the active sunscreen.
[00127] Furthermore, microcapsules containing TiO2 reduce the agglomeration of TiO2 aggregates which allows formulators to create a product that can offer high SPF efficacy, low whitening effect and better tactile properties. PROCESS
[00128] The process used for the preparation of the microcapsules of the present patent application as described here is based on the microencapsulation solvent removal method disclosed, for example, in US Patent Nos. 6,932,984 and 7,838,037 and WO 2012/156965, which are incorporated by reference as if fully established herein. According to this technology, the active ingredient is found in the nucleus of the microcapsule. This technique seals the micro-capped ingredient from chemical and cross-linked reactions, degradation, color change and loss of potency during production and for extended periods in storage.
[00129] For example, in certain applications, microcapsules according to the present patent application can be prepared by the solvent removal method, comprising the following steps: a) mixing a solution, comprising the protective agent solar, a polymeric wall-forming material and an organic solvent, to obtain a homogeneous solution; b) mixing the homogeneous solution with an aqueous solution containing an emulsifier, in high-shear stirring, to form an emulsion; and c) adding to the emulsion formed an amount of water that initiates the extraction of the organic solvent from the emulsion, thus obtaining the microcapsules. These steps are also detailed as follows:
[00130] The homogeneous solution prepared in step (a) is obtained by preparing an organic solution of the UV filter with a polymeric wall-forming material selected from an acrylate, a polymethacrylate, a cellulose ether, a cellulose ester or a combination thereof, in an organic solvent that is partially water miscible and is capable of dissolving or dispersing the wall-forming polymer, optionally with one or more additives such as photo-stabilizing agents and mixing / stirring to a homogeneous, optionally transparent solution , be obtained.
[00131] In step (b), the solution prepared in (a) is mixed with an aqueous solution containing an emulsifier, in high-shear stirring, to form an emulsion, which is added in step (c) to an excess amount of water to start extracting the organic solvent from the emulsion, thus obtaining the microcapsules.
[00132] In the additional steps, the emulsion is (c) left for a sufficient time to allow the microcapsules to settle; and (d) the microcapsules are isolated by centrifugation / filtration, subsequently washed with water or with water optionally comprising a substance that stabilizes the microcapsules during production, such as 0.1% EDTA. Then, the wet microcapsules are dried and sieved, resulting in a free flowing powder form.
[00133] In some applications, the drying stage can be done using different techniques such as fluidized bed, spray drying or lyophilization. In alternative applications, the emulsion obtained in (b) is spray dried.
[00134] In the context of the applications of the present patent application, the term "high shear agitation" refers to a mixture of about 1000 to 8000 rpm, preferably about 1000 to 3000 rpm, which provides smaller microcapsules . For example, an average particle size of TiO2 microcapsules obtained under agitation at 2500 rpm, ranges from 2 to 15 pm, as shown in Example 1 (step 1.2) and Figures 1A-1B. For avobenzone microcapsules, the average particle size obtained by shaking at 2500 rpm varies from 2 to 15 pm, as shown in Example 2 (step 2.2) and Figure 2. TOPICAL FORMULATIONS
[00135] In certain applications, the composition provided here is used in cosmetic, cosmeceutical or pharmaceutical formulations such as sunscreens and skin care or dermatological formulations or other topical pharmaceutical formulations, comprising microcapsules as described here (for example, a sun protection composition, as described here). The formulation can optionally and preferably further comprise a carrier and optionally active agents and / or additional additives.
[00136] As used herein, a "formulation" refers to a preparation comprising sunscreen compositions, as described here, with other chemical components such as cosmetic, cosmeceutical or pharmaceutical agents (e.g., drugs), physiologically carriers and excipients acceptable.
[00137] As used here, the term "physiologically acceptable" means approved by a regulatory agency of the federal or state government or listed in the North American Pharmacopoeia or another pharmacopoeia generally recognized for use in animals and more particularly in humans.
[00138] Here, the term "physiologically suitable carrier" refers to an approved carrier or a diluent that does not cause significant irritation to an organism and does not revoke the biological activity and properties of the administered conjugate.
[00139] Here, the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate the processes and administration of the active ingredients.
[00140] Protectors are important skin care products used to prevent photoaging and skin cancer. Sunscreen compositions that contain mixtures of active sunscreens like UVA and UVB can provide an SPF (sun protection factor) of 2 to 50.
[00141] In some application of the present patent application, the cosmetic or cosmeceutical formulation is formulated in the form suitable for topical application in the applied area.
[00142] By selecting the appropriate carrier and optionally other ingredients that may be included in the composition, as is detailed here below, the compositions of the present application can be formulated in any form typically employed for topical application.
[00143] The formulations can be water-based, oil-based or silicon-based.
[00144] In some applications, a formulation as described is in the form of a cream, an ointment, a paste, a gel, a lotion, a milk, an oil, a suspension, a solution, an aerosol, a spray, a foam or a mousse.
[00145] Ointments are semi-solid preparations, typically based on petroleum jelly or petroleum derivatives. The specific base of the ointment to be used is one that provides ideal distribution for the active agent chosen for a given formulation, and, preferably, also provides other desired characteristics (for example, emollience). As with other carriers or vehicles, an ointment base must be inert, stable, non-irritating and non-sensitive. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa .: Mack Publishing Co. (1995), pp. 1399-1404, the bases of the ointment can be grouped into four classes: oil bases; emulsifiable bases; emulsion bases; and water-soluble bases. The oil bases of the ointment include, for example, vegetable oils, fats obtained from animals and solid hydrocarbons obtained from petroleum. The emulsifiable bases of the ointment, also known as absorbent bases of the ointment, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petroleum jelly. The ointment emulsion bases are water-in-oil (W / O | water-in-oil) or oil-in-water (O / W | oil-in-water) emulsions and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight.
[00146] Lotions are preparations that must be applied to the skin surface without rubbing. Lotions are typically liquid or semi-liquid preparations in which solid particles, including microcapsules containing sunscreen, are present in a water or alcohol base. Lotions are typically preferred to cover / protect large areas of the body, due to the ease of applying a more fluid composition. Lotions are typically suspensions of solids and often comprise oil-in-water liquid oily emulsion. It is generally necessary for the insoluble material in a lotion to be finely divided. Lotions typically contain suspending agents to produce better dispersions, as well as compounds useful for locating and maintaining the active agent in contact with the skin, such as methyl cellulose, sodium carboxymethyl cellulose and the like.
[00147] Creams are viscous liquids or semi-solid emulsions, be it oil-in-water or water-in-oil. The cream bases are typically water washable and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the "internal" phase, is generally comprised of petroleum jelly and / or fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase typically, although not necessarily, exceeds the oil phase by volume and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. Reference can be made to Remington: The Science and Practice of Pharmacy, supra, for more information.
[00148] Pastes are semi-solid dosage forms in which the bioactive agent is suspended on an appropriate basis. Depending on the nature of the base, the pastes are divided between fatty pastes or those made from a single-phase aqueous gel. The base in a grease paste is usually petroleum jelly, hydrophilic petroleum jelly and the like. Pastes made of aqueous single-phase gels generally incorporate carboxymethylcellulose or the like as a base. Additional reference can be made to Remington: The Science and Practice of Pharmacy, for more information.
[00149] Gel formulations are semi-solid, suspension type systems. Single-phase gels contain organic macromolecules uniformly distributed throughout the carrier liquid, which is typically aqueous, but also preferably contains an alcohol and, optionally, an oil. Preferred organic macromolecules, i.e., gelling agents, are polymers of cross-linked acrylic acid such as the family of carbomer polymers, for example, carboxypolyalkylenes which can be obtained commercially under the trademark Carbopol ™. Other types of polymers preferred in the context are hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added or the gelling agent can be dispersed by grinding, mechanical mixing or stirring or combinations thereof.
[00150] Sprays generally provide the active agent in an aqueous and / or alcoholic solution that can be mixed solution on the skin for distribution. Such sprays include those formulated to provide concentration of the active agent solution at the administration site after delivery, for example, the spray solution may be primarily composed of alcohol or other volatile liquid in which the active agent can be dissolved. Upon delivery to the skin, the carrier evaporates, leaving the active agent concentrated at the injection site.
[00151] Foam compositions are typically formulated in a single or multiple phase form and housed in a suitable container, optionally together with a propellant that facilitates the expulsion of the composition from the container, thus transforming it into a foam upon application. Other foaming techniques include, for example, the "Bag in a can" formulation technique. The compositions so formulated typically contain a low-boiling hydrocarbon, for example, isopropane. The application of such a composition at body temperature causes the isopropane to vaporize and generate the foam, in a manner similar to a pressurized aerosol forming system. Foams can be water-based or hydroalcoholic, but are typically formulated with a high alcohol content that, upon application to a user's skin, evaporates quickly, triggering the active ingredient through the upper layers of the skin at the treatment site.
[00152] In some applications, the composition comprising a plurality of microcapsules, at least a portion of which encapsulates the sunscreens, is a lotion as shown in Example 3 or a base cream as shown in Example 4.
[00153] The preparation of the formulation can be carried out by mixing and homogenizing all ingredients except for the sunscreen microcapsules and adding the sunscreen microcapsules at the end, by mixing the mixture (as exemplified in Example 4). Alternatively, in some cases, the preparation of the formulation can be carried out by mixing microcapsules of the sunscreens with the other ingredients of the formulation and homogenizing the mixture, in which the other ingredients of the formulation can optionally be heated to obtain a homogeneous solution and cooled before adding the UV filter microcapsules (as exemplified in Example 3).
[00154] The microcapsules of the present patent application can be used in pharmaceutical compositions for topical application, which include, for example, pharmaceutically active agents for dermatological or transdermal applications.
[00155] In any of the formulations described here, additional agents and / or additives may be included. These agents and / or additives can be encapsulated or non-encapsulated.
[00156] In some applications, one or more of these agents and / or additives are encapsulated.
[00157] In some of these applications, agents and / or additives are encapsulated using microcapsules as described in any of US Patent Nos. 6,932,984 and 7,838,037 and WO 2009/138978.
[00158] Some representative non-limiting examples of additives and / or agents include humectants, deodorants, antiperspirants, tanning agents, hair conditioning agents, pH adjusting agents, chelating agents, preservatives, emulsifiers, occlusive agents, emollients, thickeners , solubilizing agents, penetration enhancers, anti-irritants, colorants, propellants and surfactants.
[00159] Representative examples of humectants include, without limitation, guanidine, glycolic acid and glycolate salts (eg ammonium salt and quaternary alkyl ammonium salt), aloe vera in any of its variety of forms (eg gel aloe vera), alatoin, urazol, polyhydroxy alcohols such as sorbitol, glycerol, hexanotriol, propylene glycol, butylene glycol, hexylene glycol and the like, polyethylene glycols, sugars and starches, sugar and starch derivatives (for example, alkoxylated glucose) , hyaluronic acid, monoethanolamine lactamide, monoethanolamine acetamide and any combination thereof.
Suitable pH adjusting agents include, for example, one or more of adipic acids, glycines, citric acids, calcium hydroxides, magnesium aluminum metasilicate, buffers or any combination thereof.
[00161] Representative examples of deodorant agents include, without limitation, quaternary ammonium compounds such as cetyl trimethylammonium bromide, cetyl pyridinium chloride, benzethonium chloride, diisobutyl phenoxy ethoxy ethyl dimethyl benzyl ammonium, N-lauryl sodium sarcosine, sodium N-palmityl sarcosine, lauroyl sarcosine, N-myristoyl glycine, potassium N-lauryl sarcosine, stearyl, trimethyl ammonium chloride, sodium chlorohydroxy aluminum lactate, tricethylmethyl ammonium chloride, ether of 2, 4,4'-trichloro-2'-hydroxy diphenyl, diaminoalkyl amides such as L-lysine hexadecyl amide, heavy metal citrate salts, salicylate and pyroctosis, especially zinc salts and acids thereof, heavy metal pyrithione salts, especially zinc pyrithione and zinc phenosulfate. Other deodorant agents include, without limitation, odor-absorbing materials such as carbonate and bicarbonate salts, for example, such as alkali metal carbonates and bicarbonates, ammonium and tetraalkylammonium carbonates and bicarbonates, especially sodium salts and potassium or any combination of the above.
[00162] Antiperspirant agents can be incorporated into the compositions of the present patent application, whether in a solubilized or particulate form and include, for example, astringent salts or aluminum or zirconium complexes.
[00163] Representative examples of tanning agents include, without limitation, dihydroxyacetone, glyceraldehyde, indoles and their derivatives. Tanning agents can be used in combination with sun protection agents.
[00164] Chelating agents are optionally added to the formulations in order to improve the preservative or preservation system. Preferred chelating agents are mild agents, such as, for example, ethylenediaminetetraacetic acid (EDTA), EDTA derivatives or any combination thereof.
[00165] Suitable preservatives include, without limitation, one or more alkanols, disodium EDTA (ethylenediamine tetraacetate), EDTA salts, EDTA fatty acid conjugates, isothiazolinone, parabens such as methylparaben and propylparaben, propylene glycols, sorbates, urea derivatives such as diazolindinyl urea or any combinations thereof.
Suitable emulsifiers include, for example, one or more sorbitans, alkoxylated fatty alcohols, alkyl polyglycosides, soaps, alkyl sulfates, monoalkyl and dialkyl phosphates, alkyl sulfonates, acyl isothionates or any combination thereof.
[00167] Suitable occlusive agents include, for example, petroleum jelly, mineral oil, beeswax, silicone oil, lanolin and oil-soluble lanolin derivatives, saturated and unsaturated fatty alcohols, such as beyl alcohol, hydrocarbons such as squalane and various animal and vegetable oils such as almond oil, peanut oil, wheat germ oil, flaxseed oil, jojoba oil, apricot kernel oil, nuts, palm seeds, pistachios, sesame seeds, rapeseed, Cade oil, corn oil, peach kernel oil, poppy seed oil, pine cone oil, castor oil, soybean oil, avocado oil, safflower oil, coconut oil, hazelnut oil, olive, grape seed oil and sunflower seed oil.
[00168] Suitable emollients include, for example, dodecane, squalane, cholesterol, that-hexadecane, isononyl isononanoate, PPG ethers, petroleum jelly, lanolin, saffron oil, castor oil, coconut oil, cotton seed oil , palm kernel oil, peanut oil, soybean oil, polyol carboxylic acid esters, derivatives thereof and mixtures thereof.
[00169] Suitable thickeners include, for example, non-ionic water-soluble polymers, such as hydroxyethylcellulose (commercially available under the Registered Mark Natrosol ™ 250 or 350), cationic water-soluble polymers such as Polyquat 37 (commercially available under the Mark Registered Synthalen ™, CN), fatty alcohols, fatty acids and their alkaline salts and mixtures thereof.
[00170] Representative examples of solubilizing agents that are usable in this context of the present patent application include, without limitation, complex forming solubilizers such as citric acid, ethylenediamine-tetraacetate, sodium metaphosphate, succinic acid, urea, cyclodextrin, polyvinylpyrrolidone, diethylammonium-ortho-benzoate and micelle forming solubilizers such as TWEENS and spans, for example TWEEN 80. Other solubilizers that are usable for the compositions of the present application are, for example, ester of polyoxyethylene sorbitan fatty acid, polyoxyethylene n-alkyl esters, n-alkyl amine n-oxides, poloxamers, organic solvents, phospholipids and cyclodextrins.
[00171] Suitable penetration enhancers include, but are not limited to, dimethyl sulfoxide (DMSO [dimethylsulfoxide), dimethyl formamide (DMF | dimethyl formamide), allantoin, urazol, N, N-dimethylacetamide (DMA | dimethylacetamide), decylmethylsulfoxide (Cio MSO IO ), polyethylene glycol monolaurate (PEGML I polyethylene glycol monolaurate), propylene glycol (PG I propyleneglycol), propylene glycol monolaurate (PGML I propyleneglycol monolaurate), glycerol monolaurate (GML | glycerol monolaurate), lecithin, azecine, lecithin 1- substituted, particularly 1-n-dodecylcyclazacycloheptan-2-one (available under the trademark AzoneR ™ from Whitby Research Incorporated, Richmond, Va.), Alcohols and the like. The permeation enhancer can also be a vegetable oil. Such oils include, for example, safflower oil, cottonseed oil and corn oil.
[00172] Suitable anti-irritants include, for example, steroidal and non-steroidal anti-inflammatory agents or other materials such as aloe vera, chamomile, alpha-bisabolol, nitric cola extract, green tea extract, tree oil tea, licorice extract, allantoin, caffeine or other xanthines, glycyrrhizic acid and its derivatives.
[00173] Exemplary additional active agents in accordance with that application of the present patent application include, without limitation, one or more or any combination of an antibiotic agent, an antimicrobial agent, an anti-acne agent, an anti-aging agent, an anti-aging agent wrinkle reduction, a skin lightening agent, a sebum-reducing agent, an antibacterial agent, an antifungal agent, an antiviral agent, a steroidal anti-inflammatory agent, a non-steroidal anti-inflammatory agent, an anesthetic agent, an antipruritic agent, an antiprotozoal agent, an antioxidant, an antineoplastic agent, an immunomodulator, an interferon, an antidepressant, an antihistamine, a vitamin, a hormone and an anti-dandruff agent.
[00174] Examples of these include alpha-hydroxy acid and esters, beta-hydroxy acids and esters, polyhydroxy acid and esters, kojic acid and esters, ferulic acid and ferulate derivatives, vanillic acid and esters, dioic acids (such as acids sebacids and azoleics) and esters, retinol, retinal, retinyl esters, hydroquinone, t-butyl hydroquinone, mulberry extract, licorice extract and resorcinol derivatives.
[00175] Anti-acne agents suitable for use in this context of the present patent application include, without limitation, keratolytics, such as salicylic acid, sulfur, glycolic acid, puruvic acid, resorcinol and N-acetylcysteine and retinoids such as retinoic acid and its derivatives (for example, cis and trans, esters).
[00176] Antibiotics suitable for use in this context of the present patent application include, without limitation, benzoyl peroxide, octopirox, erythromycin, zinc, tetracycline, triclosan, azelaic acid and its derivatives, phenoxy ethanol and phenoxy proponol, ethyl acetate, clindamycin and meclocycline; sebostats such as flavinoids; alpha and beta hydroxy acids; and bile salts such as scymnol sulfate and its derivatives, deoxycholate and cholate.
[00177] Representative examples of non-steroidal anti-inflammatory agents that are usable in this context of the present patent application include, without limitation, oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam and CP-14,304; salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal and fendosal; acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, thiopinac, zidomethacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac and ketorolac; phenamates, such as mefenamic, meclofenamic, flufenamic, niflumic and tolfenamic acids; propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenprofen, fenbufen, indoprofen, pyrprofen, carprofen, oxaprozin, pranoprofen, myroprofen, tioxaprofen, suprofen, alminoprofen and thiaprofen; pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone and trimetazone. Mixtures of these non-steroidal anti-inflammatory agents can also be used, as well as the dermatologically acceptable salts and esters of these agents. For example, etophenamate, a derivative of flufenamic acid, is particularly useful for topical application.
[00178] Representative examples of steroidal anti-inflammatory drugs include, without limitation, corticosteroids such as hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone phosphate, beclomethasone dipropionates, clobetasol valerate, desonide, deoxymethoxazone, deoxymethoxoneone, deoxymethoxamethasone. , dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumetasone pivalate, fluosinolone acetonide, fluocinonide, flucortin butyl esters, fluocortolone, fluoridone, fluoridone, fluoride and fluoride hydrocortisone, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone, fludrocortisone, diflurosone diacetate, fluradrenolone acetonide, ammonium, ammonium, ammonium, ammonium, ammonium and ammonium ednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, diflurprednate, flucloronide, flunisolide, fluorometalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydroportone, predionone, hydrocortone, cyclopentylpropionate, hydrochloride, predone, hydrocortone, themselves.
[00179] Suitable antipruritic agents include, without limitation, methylazine and trimeprazine pharmaceutically acceptable exits.
[00180] Non-limiting examples of anesthetic drugs that are suitable for use in the context of the present patent application include pharmaceutically acceptable salts of lidocaine, bupivacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine, diclonine, hexylcaine, procaine, cocaine, ketamine, pramoxin and phenol.
[00181] Suitable antimicrobial agents, including antibacterial, antifungal, antiprotozoal and antiviral agents for use in the context of the present patent application include, without limitation, beta-lactam drugs, quinolone drugs, ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin , triclosan, doxycycline, capreomycin, chlorhexidine, chlortetracycline, oxytetracycline, clindamycin, ethambutol, metronidazole, pentamidine, gentamycin, kanamycin, lineomycin, metacycline, methenamine, minocycline, neomycin, netylmycin, streptomycin and mycotin, heminomycin and streptomycin. Also included are tetracycline hydrochloride, farnesol, erythromycin stolate, erythromycin stearate (salt), amikacin sulfate, doxycycline hydrochloride, chlorhexidine hydrochloride, chlorhexidine hydrochloride, oxytetracycline hydrochloride hydrochloride, hydrochloride hydrochloride, hydrochloride hydrochloride, hydrochloride hydrochloride, , metronidazole hydrochloride, pentamidine hydrochloride, gentamicin sulfate, kanamycin sulfate, lineomycin hydrochloride, metacycline hydrochloride, methenamine hypurate, methenamine mandelate, minocycline hydrochloride, neomycin sulfate, netomycin sulfate, paromycin sulphate streptomycin, tobramycin sulfate, miconazole hydrochloride, amanfadine hydrochloride, amanfadine sulfate, triclosan, octopirox parachloromethane xylenol, nystatin, tolnaftate and clotrimazole and mixtures thereof.
[00182] Non-limiting examples of antioxidants that are usable in the context of the present application include ascorbic acid (vitamin C) and its salts, ascorbyl fatty acid esters, ascorbic acid derivatives (e.g. magnesium ascorbyl phosphate , sodium ascorbyl phosphate, ascorbyl sorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherol acetate other tocopherol esters, butylated hydroxy benzoic acids and their salts, 6-hydroxy-2,5,7,8- tetramethylchroman-2-carboxylic acid (commercially available under the trade name TroloxR), gallic acid and its alkyl esters, especially propyl gamma, uric acid and its alkyl salts and esters, sorbic acid and its salts, lipoic acid, amines (for example, N, N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (eg glutathione), fumaric dihydroxy acid and its salts, licin pidolate, arginine pilolate, nordihidroguaiarético acid, bioflavonoides, curcumin, lysine, methionine, proline, dismutasa superoxide, silymarin, tea extracts, grape / seed skin extracts, melanin and rosemary extracts.
[00183] Non-limiting examples of antineoplastic agents usable in the context of the present application include daunorubicin, doxorubicin, idarubicin, amrubicin, pirarubicin, epirubicin, teniposide, vincristine, mitomycin C, 5-FU, paclitaxel, docetaxel, actinomycin colchicine, topotecan, irinotecan, gemcitabine cyclosporine, verapamil, valspodor, probenecid, MK571, GF120918, LY335979, biricodar, terfenadine, quinidine, pervilein A and XR9576.
[00184] Non-limiting examples of antidepressants usable in the context of the present application include norepinephrine reabsorption inhibitors ("NRIs | norepinephrine-reuptake inhibitors"), selective serotonin reabsorption inhibitors (SSRIs | selective-serotonin-reuptake inhibitors ), monoamine oxidase inhibitors (MAOIs | monoamine-oxidase inhibitors), serotonin and noradrenaline reabsorption inhibitors ("SNFIs I serotonin-and-noradrenaline-reuptake inhibitors), corticotropin releasing factor antagonists (CRF | corticotropin-releasing factor), α-adrenoreceptor antagonists, NK1 receptor antagonists, 5-HTIA receptor agonist, partial antagonists and atypical antidepressants, as well as norepinephrine reabsorption inhibitors such as, but not limited to, amitriptyline, demethylamitriptyline, clomipramine, doxepine, doxyl imipramine, imipramine oxide, trimipramine; adinazolam, amyltriptylinoxide, amoxapine, desipramine, maprotiline, n ortriptyline, protriptyline, amineptine, butriptyline, demexiptyline, dibenzepine, dimethacrine, dotiepine, fluacizine, iprindol, lofepramine, melitracen, metapramine, norclolipramine, noxiptyline, opipramol, perinamine, propinine, reizine, pizotiline, pizotiline such as, but not limited to, binedaline, m-chloropiperzine, citalopram, duloxetine, etoperidone, femoxetine, fluoxetine, fluvoxamine, indalpine, indeloxazine, milnacipran, nefazodone, oxaflazone, paroxetine, prolintan, ritanserphine, sertraline, tetrine, sertraline, tetrine, sertraline, tetrine and sertraline, ventral.
[00185] Exemplary anti-dandruff agents include, without limitation, zinc pyrithione, shale oil and derivatives thereof such as sulfonated shale oil, selenium sulfide, sulfur; salicylic acid, coal tar, povidone-iodine, imidazoles such as ketoconazole, dichlorophenyl imidazolodioxalane, clotrimazole, itraconazole, miconazole, climbazol, thioconazole, sulconazole, butoconazole, fluconazole, and any such monomeric derivatives, and mono-isomeric and mono-derivatives (Octopirox), selenium sulfide and cyclopyrox olamine and mixtures thereof.
[00186] Non-limiting examples of vitamins include vitamin A and its analogs and derivatives: retinol, retinal, retinyl palmitate, retinoic acid, tretinoin, isotretinoin (collectively known as retinoids), vitamin E (tocopherol and its derivatives), vitamin C ( L-ascorbic acid and its esters and other derivatives), vitamin B3 (niacinamide and its derivatives), alpha hydroxy acids (such as glycolic acid, lactic acid, tartaric acid, malic acid, citric acid, etc.) and beta hydroxy acids ( such as salicylic acid and the like).
[00187] Non-limiting examples of dermatological active ingredients usable in the context of the present application for a patent include jojoba oil and aromatic oils such as methyl salicylate, gualtéria, peppermint oil, bay oil, eucalyptus oil and oils citrates, as well as ammonium phenolsulfonate, bismuth subgalate, zinc phenolsulfonate and zinc salicylate. Non-limiting examples of antifungal agents include miconazole, clotrimazole, butoconazole, fenticonasol, tioconazole, terconazole, sulconazole, fluconazole, haloprogine, ketonazole, ketoconazole, oxinazole, econazole, itraconazole, terbinafine, nystatin and gristatin and gristatin and nystatin and gratin.
[00188] Non-limiting examples of antihistamines usable in the context of the present application include chlorpheniramine, brompheniramine, dexchlorpheniramine, tripolidine, clemastine, diphenhydramine, promethazine, piperazines, piperidines, astemizole, loratadine and terfenadine.
[00189] It is expected that, during the life of a patent expiring from that patent application, many relevant sunscreen agents and wall forming materials will be developed and the scope of the term "sunscreen agent" and " wall forming polymer "is intended to include all these new technologies a priori.
[00190] Throughout this patent application, several applications of this invention patent application can be presented in a banner format. It should be understood that the description in the strip format is merely for convenience and brevity and not interpreted as an inflexible limitation on the scope of the present application for a patent. Consequently, the description of a range must be considered to have all possible sub-ranges specifically disclosed, as well as individual numerical values within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5 and 6. This applies regardless of the width of the range.
[00191] Whenever a numerical range is indicated here, it means including any quoted numeral (fractional or integral) within the indicated range. The expressions "varying / varies between" a first indication number and a second indication number and "varying / varies from" a first indication number "to" a second indication number are used interchangeably here and are intended to include the first and second numbers indicated and all fractional and integral numerals between them.
[00192] The dimensions and values disclosed here should not be understood as being strictly limited to the exact numerical values cited. Instead, unless otherwise stated, each dimension is intended to mean both the quoted value and a functionally equivalent range around that value. For example, a dimension reported as "10 pm" is intended to mean "about 10 pm".
[00193] As used here, numerical ranges preceded by the term "about" should not be considered limited to the range cited. Rather, the numerical ranges preceded by the term "about" are to be understood as including a range accepted by those skilled in the art for any given element in the microcapsules or formulations in accordance with the present patent application.
[00194] The term "about" as used here means within an acceptable error range for a particular value as determined by a person skilled in the art, which will depend, in part, on how the value is measured or determined, that is, the limitations of the measurement system. For example, "about" can mean a range of up to 10%, more preferably up to 5% and even more preferably up to 1% of a given value. Where particular values are described in the patent application and claims, unless otherwise stated, the meaning of the term "about" is within an acceptable error range for the particular value.
[00195] The terms "comprises", "comprising", "includes", "including", "bearing" and their conjugates mean "including, among others".
[00196] The term "consisting of" means "including and limited to".
[00197] The term "consisting essentially of" means that the composition, method or microcapsules may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts have not materially changed the basic and new characteristics of the claimed composition, method or structure.
[00198] As used here, the singular form "um", "uma" and "o / a" includes plural references, unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" can include a plurality of compounds, including mixtures thereof.
[00199] As used herein, the term "method" refers to the manner, means, techniques and procedures for carrying out a particular task including, among others, those ways, means, techniques and procedures known to or readily developed in ways, means , techniques and procedures known to practitioners of chemical, pharmacological, biological, biochemical and medical techniques.
[00200] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms. Whenever a numerical range, for example, "1 to 20", is mentioned here, this implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 20 carbon atoms. More preferably, the alkyl is a medium-sized alkyl having 1 to 10 carbon atoms. More preferably, unless otherwise indicated, alkyl is a lower alkyl having 1 to 5 carbon atoms. The alkyl group can be substituted or unsubstituted. When substituted, the substituting group can be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfinate, sulfonate, sulfonate cyano, nitro, sulfonamide, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, carboxy, thiocarbon, carbamate, thiocarbamate, starch, sulfonamido and amino, as defined herein.
[00201] As used herein, the term "hydroxyalkyl" refers to an alkyl, as that term is defined here, replaced by a hydroxy group, as defined here and includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxy-n -butyl.
[00202] As used here, the term "halogen", which is also referred to here interchangeably as "a halogen atom" or "halo", includes chlorine (Cl), bromine (Br), iodine (I) and fluorine (F ).
[00203] The term "alkanoyloxy" refers to a carbonyl group, as defined herein and includes, for example, acetyl, propionyl, butanoyl and the like.
[00204] The term "carboxyalkyl" refers to an alkyl, as that term is defined here, replaced by a carboxy group, as defined here and includes, for example, carboxymethyl, carboxyethyl, ethylene carbonoxy and the like.
[00205] The term "alkylcarbonylalkyl" refers to an alkyl, as that term is defined here, replaced by a carbonyl group, as defined here and includes, for example, methanoylmethyl, ethaneethyl and the like.
[00206] The term "amidoalkyl" refers to an alkyl, as defined herein, replaced by an amide group, as defined herein and includes, for example, -CH2CONH2; -CH2CH2CONH2; -CH2CH2CH2CONH2 and similar.
[00207] A "hydroxy" group refers to an -OH group.
[00208] An "alkoxy" group refers to both the -O-alkyl and -O-cycloalkyl groups, as defined here.
[00209] A "thiohydroxy" group refers to a -SH group.
[00210] A "thioalkoxy" group refers to both the -S-alkyl and -S-cycloalkyl groups, as defined here.
[00211] A "carbonyl" group refers to a -C (= O) -R 'group, where R' is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through ring carbon) or heteroalicyclic ( (linked via ring carbon) as defined here.
[00212] A "thiocarbonyl" group refers to a -C (= S) -R 'group, where R'is as defined here by R'.
[00213] A "carboxy" group refers to a - C (= O) -O-R 'where R' is as defined here.
[00214] An "amino" group refers to a group -NR'R''where R'e R''s are as defined here.
[00215] A "starch" group refers to a -C (= 0) -NR'R''or a R'C (= 0) -NR '' group, where R 'and R''s conform defined here.
[00216] It is appreciated that certain features of the present patent application, which are, for clarity, described in the context of separate applications, can also be provided in combination in a single application. On the other hand, various features of the present invention application, which are, for brevity, described in the context of a single application, can also be provided separately or in any suitable subcombination or as appropriate in any other application described in the present application. invention patent. Certain characteristics described in the context of various applications are not to be considered essential characteristics of those applications, unless the application is inoperative without those elements.
[00217] Various applications and aspects of the present invention patent application, as outlined here above and as claimed in the claims section below, find experimental support in the following examples. EXAMPLES
[00218] Reference is now made to the following examples, which together with the above descriptions illustrate some applications of the present patent application in a non-limiting manner. EXAMPLE 1 Preparation of microcapsules containing TiO2 1.1 Preparation of organic phase / standard mixture (MB / master batch).
[00219] An organic phase (here referred to indistinctly as the standard mixture (MB)) was prepared by the gradual addition of 20 grams of the polymethyl methacrylate wall-forming polymer (PMMA) while stirring (5 minutes), in 233.3 grams of ethyl acetate, heating to 50 ° C and stirring well until the mixture is homogeneous and transparent (about 20 minutes). The polymer solution obtained was cooled to 25 ° C. TiO2 was added to the stirring solution for about 5 minutes and then the mixture was homogenized for about 8 minutes. The components of the MB are shown in Table 1. Table 1. Constituents of the standard mixture
1.2 Preparation of the emulsion
[00220] An aqueous solution of 0.4% polyvinyl alcohol (PVA) was prepared by mixing water (810 grams) with 4% PVA solution (90 grams). Ethyl acetate (100 grams) was added to the water phase and then the standard mixture from step 1.1 above (333.3 grams) was gradually added to the high-shear stirring ethyl acetate / water emulsion at about 2500 RPM for 2 minutes. The ratio between the standard mixture and the emulsion (w / w) was 1: 3. The components of the emulsion are shown in Table 2. Table 2. Constituents of the emulsion
1.3 Extraction of organic solvent
[00221] The extraction fluid was composed of a mixture of 6,745 grams of water and 355 grams of 4% PVA solution (final concentration of PVA in the extraction fluid of 0.20% PVA). The emulsion from step 1.2 above (1333.3 grams) was gradually added to the extraction fluid in a 10 L bucket while stirring at 150 RPM using a hand pump and was further stirred for another 15 minutes. The resulting mixture was allowed to settle for about 24 hours at 25 ° C, thus obtaining microcapsules that comprise about 80% by weight of TIO 2 and about 20% by weight of PMMA. The components of the extraction medium are shown in Table 3. Table 3. Constituents of the extraction medium
1.4 Washing, drying and sieving of microcapsules
[00222] The TiO2 microcapsules obtained in step 1.3 above were separated by centrifugation or vacuum filtration. In the centrifugation procedure, the upper liquid phase of the bucket was decanted and the remaining suspension was stirred and divided into 50 ml tubes and then centrifuged at 2000 RPM for 2 minutes. The upper liquid phase in each tube was removed, the pellet was suspended in 5 ml of water and the suspension was transferred to a drying flask and stored at -20 ° C for freezing the sample. In the filtration procedure, the liquid from the upper phase was decanted from the bucket, the remaining suspension was stirred and then filtered and the sediment was rinsed in the filter with 400 ml of water. The suspension was transferred to a drying bottle and the microcapsules were stored at -20 ° C for freezing the sample. In the drying stage, the microcapsules were freeze-dried (lyophilized) for 48 hours.
[00223] In the screening stage, the dried microcapsules were sieved using an automatic "Ari j-Levy" sifter, Sifter MIC. 100. The sieved microcapsules were stored in an appropriate container in a refrigerator.
[00224] Scanning electron microscopy (SEM) images of TiOz microcapsules prepared as described above were taken using Zeiss Ultra Gemini® (Zeiss, Germany). SEM images of the microcapsules are shown in figures 1A-1B and show that the microcapsules are round in shape. The size of the TiO2 microcapsules ranges from 2.5 to 10 pm (Figure 1B). EXAMPLE 2 Preparation of microcapsules containing avobenzone 2.1 Preparation of standard mixture (MB)
[00225] A standard mixture was prepared under light protection conditions by gradually adding 50 grams of the PMMA wall-forming polymer, while stirring (5 minutes), into 300 grams of ethyl acetate in a flask, heating to 50 ° C and dissolving PMMA with stirring (about 20 minutes) in a homogeneous and transparent solution. The polymeric solution was then cooled to 25 ° C and octocrylene (10 grams) was added to the polymeric solution while stirring for about 3 minutes. 1- (4-methoxyphenyl) -3- (4-tert-butylphenyl) propane-1,3-dione (avobenzone; 40 grams) was then added to the mixture while stirring for 5 minutes. The components of the MB are shown in Table 4. Table 4. Constituents of MB
2.2 Preparation of the emulsion
[00226] An aqueous solution was prepared by mixing water (1,012.5 grams) with 0.1% EDTA (1.08 grams) and PVA (4%, 67.5 grams) so that the water phase consisted of in 0.25% PVA. Ethyl acetate (120 grams) was added to the water phase and then the standard mixture from step 2.1 above (400 grams) was gradually added to the high-shear ethyl acetate / water emulsion at 2500 RPM for about 2 minutes . The components of the emulsion are shown in Table 5. Table 5. Constituents of the emulsion

[00227] The extraction, washing, drying and screening procedures are identical to the extraction, washing, drying and screening procedures described above in steps 1.3 and 1.4 of Example 1. The content of the extraction solution is as detailed in Table 6 below and the water used to suspend the sediment or rinse the sediment in the filter additionally comprised 0.1% EDTA. The microcapsules, comprised of PMMA (about 50% by weight) and containing about 40% by weight and about 10% by weight of octocrylene, were obtained as a white to light yellow powder. Table 6. Extraction medium constituents

[00228] Scanning electron microscopy (SEM) images of avobenzone microcapsules prepared as described above were taken using Zeiss Ultra Gemini® (Zeiss, Germany). The SEM image is described in figure 2 and shows that the microcapsules have a round shape and their size varies from 2.5 to 10 pm. EXAMPLE 3 Preparation of body lotion sunscreen formulation
[00229] Sunscreen formulations of body lotion comprising microcapsules containing sunscreens from some applications of the present patent application and the ingredients listed in Table 7 below were prepared by combining 4 phases prepared separately, as follows:
[00230] Phase 1 was obtained by thoroughly mixing the ingredients listed in Table 7 and heating to 70 ° C.
[00231] Phase 2, the stabilization gel was prepared by mixing glycerin in water, followed by the slow addition of the gelling emulsifying agent Ecogel ™ in order to increase viscosity and avoid agglutination. The mixture was heated to 70 ° C in mixture and still mixing while maintaining that temperature for another 20 minutes.
[00232] Phase 3, the dispersion of the sunscreen agent was prepared by adding microcapsules containing sunscreen agent according to some applications of the present patent application, for example, microcapsules containing TIO2, in the dispersion agent Crodasperse ™ (particularly useful in inorganic pigments such as titanium oxide) using an efficient mixer paddle at an appropriate speed (depending on the mixer used) to completely and uniformly disperse the UV filter microcapsules. The dispersion was then set aside.
[00233] Phase 4, the cosmetic additive solution was prepared by adding Geogard ™ Ultra multifunctional cosmetic additives to water (at 100 mL) in a suitable flask and heating the mixture to 70 ° C. Cosmetic and personal care additives such as Geogard ™ Ultra are naturally derived products with broad spectrum protection that improve the skin's moisture content and have an exceptional toxicity profile.
[00234] The final product, sun protection formulation, was prepared by adding to Phase 4 (aqueous solution of cosmetic additives), the mixture of Phase 1 in a high shear mixture at 70 ° C. The stabilization gel prepared in Step 2 was then added and the resulting mixture was mixed and homogenized for several minutes until uniformity was obtained. The pH was measured and adjusted, when necessary, to pH 5-6 with lactic acid. A mixture was allowed to cool. Sepiplus ™ 400, a multifunctional polymer that serves as a thickening agent, was added to the mixture in a strong mixture. The mixture was homogenized and cooled to 30 ° C. The Phase 3 UV filter dispersion was remixed again and added to the main flask containing Phases 1 + 2 + 4 in paddle mixture until the microcapsules containing UV filter were uniformly mixed in the product. The final product was homogenized for 2 to 3 minutes and cooled to room temperature. Table 7. Body lotion formulation ingredients
EXAMPLE 4 Preparation of a UV-based cream
[00235] For the preparation of a UV-based cream containing microcapsules containing sun protection agent from some applications of the present patent application, a base cream formulation was first prepared from the ingredients listed in Table 8. Three separately prepared phases were combined to give the final product as follows:
[00236] Phase 1 was obtained by thoroughly mixing all the ingredients listed in Table 8 and heating to 70 ° C. phase 2 was prepared by mixing water and glycerin, heating to 70 ° C in mixture and then adding Phase 2 to Phase 1. Phase 3, comprising the preservative Euxyl PE 9010, was added to the combined phases 1 + 2, followed by by mixing and homogenizing for several minutes until uniformity is achieved. The resulting mixture was cooled to 30 ° C in a gentle mixture, homogenized for 2 to 3 minutes and cooled to room temperature. Table 8. Ingredients for the base cream

[00237] UV base cream formulations were prepared by adding microcapsules containing UV filters from some applications of the present patent application, for example, TiO2 containing microcapsules, to the formulation of the above base cream, followed by homogenization. EXAMPLE 5 In vitro SPF measurements of a sunscreen formulation comprising microencapsulated TiO2.
[00238] The sun protection factor (SPF) of a sun protection formulation (UV based cream) comprising 18.5% microencapsulated TIO2 (final concentration of 15% TiO ) Was measured using an SPF-290S Analyzer, WinSPF software (Optometries, UK) and the US EDA standard protocol. In general, a 1 ml syringe was used to dispense 100 or more strokes of a sample over an area of Transpore® tape substrate (70.7 x 70.7 mm) at a rate of 2 pl / cm2, as specified in EDA from the USA. The results were determined by averaging the results of 9 sample scans at different locations on the Transpore® tape substrate. Each scan covered a transmittance measurement over an increase of 1 nm wavelength starting from 290 to 400 nm. These measurements were compared to a reference scan at the same wavelength to compute the transmittance of the sample. The SPF-290S 'WinSPF software converted measurements of the monochrome protection factor (MPF) to the SPF values using well-known calculation methods. Figure 3 shows curves of the MPF values as a function of the wavelength of a sunscreen formulation of the present patent application comprising 18.75% of the microencapsulated TIO2. The calculated SPF value was 32.19, while the UVA / UVB ratio was 0.67. These values clearly indicate that TiOz microcapsules can serve as a UVB filter, which absorbs UV light from 280 to 320 nm. EXAMPLE 6 In vitro SPF measurements of a sunscreen formulation comprising microencapsulated avobenzone.
[00239] The SPF of the sun protection formulation (UV based cream) comprising 7.5% microencapsulated avobenzone (final avobenzone concentration was 3%) was measured using the SPF-290S Analyzer, the WinSPF software (Optometries, UK ) and the standard FDA protocol, as described in Example 5. Figure 4 shows the MPF of the sunscreen formulation as a function of the wavelength for 9 scans taken from 9 different locations of an area of the covered Transpore® tape substrate with the formulation. The SPF value was 7.84, while the UVA / UVB ratio was 1.202. These values clearly indicate that avobenzone microcapsules can serve as a UVA filter, which absorbs UV light from 320 to 400 nm. EXAMPLE 7 In vivo SPF measurements of a sunscreen formulation comprising microencapsulated avobenzone.
[00240] The SPF of a sun protection formulation (UV based cream) comprising 7.5% microencapsulated avobenzone (final concentration of 3% avobenzone) was measured and analyzed according to the FDA's 2011 final rules. In the in vivo test, the sun protection formulation of the present invention patent application (Test Product) was applied to 6 individuals and the degree of protection provided, SPF, was measured and compared to that obtained from a standard formulation (Standard P2 , a reference formulation used as a methodological control to verify the test procedure). The average SPF in the standard is 16.3 with a standard deviation of 3.43.
[00241] The test areas on the subjects' backs were coated with the test product. Between the application of the product and irradiation, a waiting time of 15 minutes was performed. The irradiation was carried out in 6 different doses. The resulting erythema was used to determine the minimum erythema dose (MED | minimal erythema dose). The minimum dose of erythema is defined as the lowest dose of UV that produces the first unmistakable, clear erythema with defined margins that appear in most of the UV exposure field. MED was evaluated visually 20 ± 4 hours after exposure with uniform controlled lighting in a blinded manner.
[00242] The individual sun protection factor (SPF) was determined from the proportion of MEDu (MED of untreated skin) and MEDp (MED of protected skin) of the area treated with the Test Product. An SPF result was expressed as the arithmetic mean of the individual SPF values obtained from the total number of individuals used.
[00243] Individuals who participated in this test were selected on the basis of the Fitzpatrick skin type table or based on the typing of skin color by colorimetric measurements, respectively (ITA °> 28 '). They corresponded to most users as far as their skin sensitivity rating is concerned. Subjects with a skin phototype called Type I had very light skin and individuals with Type II skin color had a light skin color.
[00244] The Test Product formulation of these applications of the present invention patent application and Standard P2, was applied in average amounts of 73.2 (± 1.0) mg and 72.7 (± 1.2) mg, respectively, in an area of the skin of 36.0 cm2 (application amounts of 2.03 (+0.027) and 2.02 (± 0.034) mg / cm2 for Test Product and P2, respectively). The irradiation was performed by 6 different doses. The results are shown in Table 9. Table 9. SPF measurements in vivo for a formulation containing microencapsulated avobenzone

[00245] The results presented in Table 9 show that the SPF obtained for in vivo application of the formulation containing the final concentration of 3% avobenzoa (7.5% encapsulated avobenzone) was 5 to 7 and in line with the results in obtained for this formulation (SPF 7.84). In addition, the SPF in vivo was higher than expected for tests conducted in vivo and clearly indicates that the formulation was absorbed into the skin and provided excellent protection against UV radiation at the maximum avobenzone concentration allowed by the FDA. EXAMPLE 8 Photostability of unencapsulated versus microencapsulated avobenzone after sun exposure.
[00246] Avobenzone is known to be unstable upon exposure to sunlight and tends to break down into unknown chemicals. In the present example, the photostability of avobenzone in a body lotion sunscreen formulation comprising unencapsulated avobenzone or microencapsulated avobenzone of the present patent application was measured.
[00247] Photostability was assessed by dispersing a known amount of body lotion sun protection formulation (40 ± 3 mg), containing free avobenzone (unencapsulated, raw material) or microcapsules containing about 40% avobenzone weight and 10% by weight of the octocrylene photo stabilizer obtained in Example 2 above, in a final concentration in the formulation of 3%, on the microscope slides at an application density of about 2 mg / cm2. After application, the glass slides were left for 4 hours at maximum exposure to the sun outdoors. The exposure period was established from 10:00 AM to 14:00 PM in Tel-Hai, Upper Galilee, Israel, on two different dates. The unexposed slides served as controls and were stored in the dark until extraction.
[00248] After exposure to the sun, the treated and untreated glass slides were placed in sterile polypropylene tubes (PP I polypropylene) of 50 ml. Dichloromethane (DCM, 25 ml) was added to each tube and the tubes were roughly shaken for two minutes for complete sunscreen extraction. After extraction, the samples were further diluted with 1:10 DCM and 3 ml of the final dilution were filtered with 0.45 micron Teflon filters. The UV absorbance of the DCM extracts was recorded from 280 to 400 nm using a spectrophotometer (Jasco V-53 UV / VIS Spectrophotometer). The loss in avobenzone was measured using a UV spectrophotometer at 358 nm. The absorbance corrected at 358 nm due to avobenzone alone was then used to obtain a calculated weight of avobenzone in the lotion of a standard curve prepared for each product.
[00249] Figures 5A and 5B show the results of the photostability test for crude avobenzone (left bars) versus microencapsulated avobenzone (right bars) in a body lotion sun protection formulation for some applications of the present patent application. As seen in the figures, there is a significant loss of the UV filter in the sun protection formulation comprising crude avobenzone (reduction of the UV filter concentration to 0.21% and 0.24% in two measurements), while the sun protection formulation with the microencapsulated avobenzone was more stable (reduction of the concentration of the UV filter only to 1.35% and to 1.24% in two measurements). The reduction in the lower concentration of avobenzone was not only due to its simple encapsulation, but instead due to octocrylene coencapsulation. However, the percentage of octocrylene was significantly lower when compared to formulations containing the non-encapsulated form of avobenzone. Normally, the octocrylene level is not less than half that of avobenzone. EXAMPLE 9 Determination of the breakability of microcapsules containing sunscreen.
[00250] In order to evaluate the durability of the microcapsule-containing sunscreen agent for shear forces, a sample of a base cream, such as body lotion prepared in Example 3, was subjected to a low shear mixture by a shovel mixer simple from 50 to 200 rpm and / or to the high shear mixture using the homogenizer from 1000 to 2000 rpm, both for 10 minutes.
[00251] Another sample of the base cream was submitted to ultrasonication (15 W, 28 kHz) for 1 minute.
[00252] Before homogenization and ultrasound, a sample of the base cream was observed under a microscope and the particle size distribution was evaluated (qualitatively). The samples of the homogenized and ultrasonic cream containing the microcapsules of the present patent application were viewed under a microscope and the particle size distribution was qualitatively evaluated again. A reduction in particle size of less than 10% compared to the sample that was not sonicated or homogenized indicated that the microcapsules sustained the shear force exerted by them and classified them as non-breakable microcapsules.
[00253] Although the present application for a patent has been described in conjunction with respective specific applications, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Consequently, it intends to encompass all these alternatives, modifications and variations that fall within the spirit and broad scope of the attached claims.
[00254] All publications, patents and patent applications mentioned in this specification are incorporated here in their entirety by reference in the specification, to the same extent as if each individual publication, patent and patent application were specifically and individually indicated as being incorporated. here by reference. In addition, the citation or identification of any reference in that patent application should not be interpreted as an admission that such reference is available as a prior art to the present invention patent application. Insofar as the section titles are used, they should not be interpreted as necessarily limiting.

权利要求:
Claims (15)
[0001]
1. MICROCapsule, comprising a core comprising at least one water-insoluble sun protection agent and a shell surrounding the core, the shell being composed of a polymeric wall-forming material comprising at least one selected polymer or copolymer of the group consisting of a polyacrylate, a polymethacrylate, a cellulose ether, a cellulose ester or any respective combination, a concentration of plasticizer in said peel being less than 5% by weight, characterized by the fact that the amount of said polymeric material of wall formation in the microcapsule is within a range of 20% to 50% by weight and the amount of said sunscreen agent in the microcapsule is within a range of 40% to 80% by weight, the microcapsule being non-breakable when rubbed or pressed on the skin and being non-breakable when subjected to homogenization at 2000 rpm for 10 minutes and / or ultrasonication at 15 W and 28 kHz for 1 minute, and having a size within a selected range from 1 pm to 50 pm, where the sunscreen agent is selected from the group consisting of avobenzone, bemotrizinol, bisoctrizol, 3- (4-methylbenzylidene) camphor, cinoxate, diethylamino hydroxybenzoyl hexyl benzoate, dioxibenzone , drometrizole trisiloxane, ethylhexyl triazone, homosalate, menthyl anthranylate, octacrylene, octyl salicylate, iscotrizinol, isopentenyl-4-methoxycinnamate, octyl-dimethyl-p-aminobenzoic acid, octyl-methoxy-hydroxymethyl, any combination of polyethylene oxide and any other polyoxyamine.
[0002]
2. MICROCapsule, according to claim 1, characterized by the fact that the shell is transparent.
[0003]
3. MICROCapsule, according to claim 1 or 2, characterized by the fact that the sun protection agent is avobenzone.
[0004]
4. MICROCAPULE according to claim 1 or 2, characterized in that the sunscreen agent is selected from the group consisting of bemotrizinol, iscotrizinol, ethylhexyl triazone and diethylamino hydroxybenzoyl hexyl benzoate.
[0005]
5. MICROCapsule according to any one of claims 1 to 4, characterized in that the polymeric wall-forming material comprises poly (methyl methacrylate) which exhibits PM within the range of 15,000 Daltons to 120,000 Daltons, type B ammonium methacrylate copolymer , cellulose acetate or any combination thereof.
[0006]
6. MICROCapsule according to any one of claims 1 to 5, characterized by the fact that it also has a photo-stabilizer.
[0007]
7. COMPOSITION, characterized in that it comprises a plurality of microcapsules, at least a portion of the microcapsules comprising a plurality of microcapsules containing the sunscreen agent, according to any one of claims 1 to 6.
[0008]
8. COMPOSITION according to claim 7, characterized in that the microcapsules in the plurality of microcapsules containing the sun protection agent are the same or different.
[0009]
9. COMPOSITION according to claim 7, characterized by the fact that it also has a photo-stabilizer.
[0010]
10. COMPOSITION according to claims 7 or 9, characterized in that at least a portion of microcapsules in the plurality of microcapsules containing the sunscreen agent further comprises a photostabilizer.
[0011]
11. PROCESS OF PREPARING MICROCapsules CONTAINING THE SUN PROTECTION AGENT, as defined by any one of claims 1 to 6, the process characterized by the fact that it comprises: a) the mixture of a solution, comprising the said sun protection agent, a said wall-forming polymeric material and an organic solvent to thereby obtain a homogeneous solution; b) mixing the homogeneous solution with an aqueous solution, containing an emulsifier, in high-shear stirring to thus form an emulsion; and c) the addition to the emulsion formed of an amount of water that initiates the extraction of the organic solvent from the emulsion, thus obtaining the microcapsules.
[0012]
12. COSMETIC OR COSMECHANICAL FORMULATION, characterized by the fact that it has the composition according to any one of claims 7 to 10.
[0013]
13. COSMETIC OR COSMECHANICAL FORMULATION, according to claim 12, characterized by the fact that it also has a cosmetic or cosmeceutically acceptable carrier.
[0014]
14. MICROCapsule, characterized by the fact that it comprises a core comprising TIO2 and a transparent shell surrounding the core, the shell being composed of a polymeric wall-forming material comprising at least one polymer or copolymer selected from the group consisting of a polyacrylate , a polymethacrylate, a cellulose ether, a cellulose ester or any combination thereof, where a concentration of plasticizer in said peel is less than 5% by weight, the microcapsule being non-breakable when rubbed or pressed on the skin and having a size within a selected range from 1 pm to 30 pm, where an amount of TiO2 in the microcapsule is within the range of 70% to 90% by weight.
[0015]
15. COMPOSITION UNDERSTANDING A MICROCapsule PLURALITY characterized by the fact that at least a portion of microcapsules comprises a plurality of microcapsules containing the sunscreen agent according to claim 14.

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同族专利:

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公开号 | 公开日

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CN105163706A|2015-12-16|

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JP2016510022A|2016-04-04|

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DK2961370T3|2021-03-15|

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US20200281827A1|2020-09-10|

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WO2014132261A2|2014-09-04|

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WO2014132261A3|2014-11-06|

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EP2961370B1|2020-12-23|

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AU2014222376B2|2018-09-13|

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EP2961370A2|2016-01-06|

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EP3721860A1|2020-10-14|

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CA2902476A1|2014-09-04|

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HK1215538A1|2016-09-02|

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AU2014222376A1|2015-10-08|

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BR112015020889A2|2017-07-18|

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PT2961370T|2021-03-29|

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KR20150121719A|2015-10-29|

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ES2863125T3|2021-10-08|

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US20160008237A1|2016-01-14|

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IL240892D0|2015-10-29|

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法律状态:
2018-02-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-07-23| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-04-07| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2020-08-04| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-08-04| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: A61K 8/29 , A61K 8/35 , A61K 8/73 , A61Q 17/04 , A61K 8/81 , A61K 8/02 Ipc: A61K 8/11 (2006.01), A61K 8/29 (2006.01), A61K 8/3 |

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2020-10-06| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/02/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201361770773P| true| 2013-02-28|2013-02-28|

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US61/770,773|2013-02-28|

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PCT/IL2014/050207|WO2014132261A2|2013-02-28|2014-02-27|Microcapsules comprising sunscreen agents|

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