Patent Application
20140227212
UV radiation penetrates the ozone layer over two wavelength regimes, UVB (290-320 nm) and UVA (320-400 nm). UVB acts directly on biological molecules, causing the familiar delayed sunburn that arises 12-24 hours after exposure, skin aging, skin cancer (melanoma), and eye photokeratities. UVA acts indirectly with the skin by forming reactive oxygen species, causing “immediate” sunburn that diminishes within 2 hours after exposure. UVA potentially plays a role in delayed sunburn and skin cancer. Although less energetic,
UVA, which accounts for about 5.6% of sunlight, penetrates the skin more deeply, even into the dermis, than does UVB radiation, which is about 0.5% of sunlight and, generally, is limited to the epidermis.
Melanoma has experienced the most rapid increase in the number of cases of all forms of cancer, with more than 51,000 cases reported in America each year. As most cases have been attributed to sun exposure, the market for sunscreens presently exceeds $1 billion a year. Sunscreens are substances used to protect the skin by absorbing, reflecting and/or scattering damaging ultraviolet (UV) radiation. Sunscreens are typically used as a component in a cream or lotion. Sunscreen formulations are an article intended for the prevention of a disease and are regulated as an over-the counter (OTC) drug.
In a Final Monograph of May 21, 1999, entitled “Sunscreen Drug Products for Over-The-Counter Human Use” by the U.S. Food and Drug Administration (FDA), conditions were established under which OTC sunscreen drug products are generally recognized as safe and effective and not misbranded as part of FDA's ongoing review of OTC drug products. The monograph established that an active ingredient of sunscreen products consists of any of the following (within the concentration specified for each ingredient when the finished product provides a minimum SPF value of not less than 2 as measured by a testing procedures established in the monograph): Aminobenzoic acid (PABA) (15%); Avobenzone (3%); Cinoxate (3%); Dioxybenzone (3%); Homosalate (15%); Menthyl anthranilate (5%); Octocrylene (10%); Octyl methoxycinnamate (7.5%); Octyl salicylate (5%); Oxybenzone (6%); Padimate O (8%); Phenylbenzimidazole sulfonic acid (4%); Sulisobenzone (10%); Titanium dioxide (25%); Trolamine salicylate (12%); and Zinc oxide (25%). Since 1999
Ecamsule (10%) and Phenylbenzimidazole sulfonic acid (4%) have been approved for use as sunscreens. Also approved for use in Europe are: 4-Methylbenzylidene camphor (4%); Bisoctrizole (10%); Bemotrizinol (10%); Bisdisulizole disodium (10%); Drometrizole trisiloxane (15%); Benzophenone-9 (10%); Ethylhexyl triazone (5%); Diethylamino hydroxybenzoyl hexyl benzoate (10%); Iscotrizinol (10%); Polysilicone-15 (10%); and Isoamyl p-Methoxycinnamate (10%).
Of these sunscreens, only Polysilicone-15 is a silicon based polymeric sunscreen with the IUPAC name α-(trimethylsilyl)-ω-(trimethylsilyloxy)poly[oxy(dimethyl)silylene]-co-[oxy-(methyl)(2-{4-[2,2-bis(ethoxycarbonyl)vinyl]phenoxy}-1-methyleneethyl)silylene]-co-[oxy-(methyl)(2-(4-[2,2-bis(ethoxycarbonyl)vinyl]phenoxy)prop-1-enyl)silylene] with about oxy(dimethyl)silylene units, about 4 oxy(methyl)(2-{4-[2,2-bis(ethoxycarbonyl) vinyl]phenoxy}-1-methyleneethyl) silylene units and about 1 oxy(methyl)(2-(4-[2,2-bis(ethoxycarbonyl) vinyl]phenoxy)prop-1-enyesilylene units on average with an average molecular weight of 6,070. Statistically, the random copolymer should have more than one percent of the chains that have no UV absorbing chromophores. An equivalent polymer of about 1,000 molecular weight would have less than half of the chains containing any UV absorbing chromophores. Polymeric sunscreens have the potential to provide a simple mode of distribution of the sunscreen in a vehicle, and to reduce or eliminate absorption of the sunscreen by the skin to which it is applied. Many examples of polymeric sunscreens have been disclosed in the patent literature.
U.S. Pat. Nos. 7,291,322, 6,376,679, 6,312,673, 6,251,373, 6,221,343, 6,214,324, 6,200,557, 6,159,456, and 5,753,209, and U.S. Patent Application Publications 2007/0020204, 2004/0213746, 2002/0054860, and 2001/0026789 are directed to silicone based polymeric sunscreens that are random copolymers similar to Polysilicone-15 with various UV absorbing chromophores. Another form of polymeric sunscreens is random acrylic copolymers, as disclosed in U.S. Pat. Nos. 5,741,924, 5,487,885, 5,099,027 and 4,524,061 (which also discloses the polymers from a cyclic lactams). Substantive polymers that are prepared by random vinyl copolymerization are disclosed in U.S. Pat. No. 7,087,692 and U.S. Patent Application Publication 2004/0101498. Substantive polymers that are prepared by random condensation copolymerization are disclosed in U.S. Pat. Nos. 4,004,074 and 3,864,473. Water dispersible polymeric sunscreens have been prepared by a random condensation copolymerization with polyethylene glycol monomers, as disclosed in U.S. Pat. Nos. 5,250,652, 5,243,021, and 5,134,223. An acrylamide homopolymer having UV active chromophores at every repeating unit is disclosed in U.S. Pat. No. 4,233,430. U.S. Patent Application Publication 2005/0186152 discloses a polyanhydride modified by the addition of nucleophilic UV active chromophores to place the chromophores on every repeating unit of the polymer chain with the formation of an equal amount of carboxylic acid groups on the polymer chain. U.S. Pat. Nos. 6,962,692, 6,926,887, 6,919,473, 6,899,866, 6,890,521, 6,800,274, and 5,993,789, disclose a homo-polyester sunscreen where UV active chromophores are on every repeating unit of the polymer.
As disclosed, polymeric sunscreens have very high levels of UV absorbing chromophores that can result in a non-uniform distribution of the chromophores in the vehicles, as can occur with homopolymer where every repeating unit has the chromophore, or with random copolymers where molecular weights or UV absorbing chromophores are limited to those having high molecular weights or high levels of UV absorbing units. A method of making uniform molecular weight homopolymers or copolymers having similar quantities of chromophores on every chain would be advantageous for the preparation of a sunscreen product that has enhanced chromophore stability and that is resistant to skin penetration.
Embodiments of the invention are directed to soluble polymeric sunscreens where the polymer has a narrow molecular weight distribution and has one or more repeating units that comprise a chromophore unit that is an effective sunscreen for UVA and/or UVB. The UV absorbing chromophores can be equivalents to and derived from the conjugated group of the approved sunscreens: Aminobenzoic acid; Avobenzone; Cinoxate; Dioxybenzone; Homosalate; Menthyl anthranilate; Octocrylene; Octyl methoxycinnamate; Octyl salicylate; Oxybenzone; Padimate O; Phenylbenzimidazole sulfonic acid; Sulisobenzone; Trolamine salicylate; Ecamsule; Phenylbenzimidazole sulfonic acid; 4-Methylbenzylidene camphor; Bisoctrizole; Bemotrizinol; Bisdisulizole disodium; Drometrizole trisiloxane; Benzophenone-9; Ethylhexyl triazone; Diethylamino hydroxybenzoyl hexyl benzoate; Iscotrizinol; or Isoamyl p-Methoxycinnamate. The polymer is substituted with the chromophores, which can occur because the chromophores are attached to a monomer before polymerization to the polymeric sunscreen, or it can be formed on a prepolymer that has a reactive functionality on at least one repeating unit, where the chromophore is attached by reaction of a complementary functionality with the reactive functionality on the repeating unit(s) of the prepolymer. Once prepared the UVA and/or UVB absorbing chromophore-comprising polymer can be transformed to a second UVA and/or UVB absorbing chromophore-comprising polymer by reaction with the polymer, for example, reaction with the alkene groups in the chain that result from a ring-opening metathesis polymerization (ROMP)
Embodiments of the invention are directed to monomers for the preparation of the above UVA and/or UVB absorbing chromophore-comprising polymer. The monomers comprise a cycloalkane, which polymerizes by a (ROMP) mechanism and one or more UV absorbing chromophores that absorb light in the UVA and/or UVB regions of the electromagnetic spectrum. In an embodiment of the invention, the cycloalkane ring undergoes an exothermic ring-opening during ROMP and the polymerization is “living” in nature, where the polymerization occurs to a large extent with little or no chain-transfer to a polymer chain to yield a narrow molecular weight distribution and high, often quantitative, conversion of the monomer. In embodiments of the invention, the UV absorbing chromophore or chromophores are attached to the monomer ring such that polymerization yields a polymer that is not high symmetric and is amorphous, such that it has a high solubility in at least one solvent that is useful in a personal care formulation. In another embodiment of the invention, a copolymer is produced between two or more cycloalkane- comprising monomers such that an amorphous copolymer is formed. The copolymer can comprise one or more monomers comprising one or more UV absorbing chromophores and can comprise other cycloalkane-comprising monomers that lack a chromophore, but may include other units to promote solubility or other properties, such as those desired for a pleasant feel and appearance on a skin surface.
Other embodiments of the invention are directed to a method of preparing a polymeric sunscreen, where one or more of the cycloalkane-comprising monomers are polymerized in the presence of a catalyst to promote ROMP and where the degree of polymerization can be controlled. Olefin metathesis catalysts that can be used include Schrock's catalyst or Grub's catalyst.
Other embodiments of the invention are directed to sunscreen lotions where the polymeric sunscreens are included with a fluid vehicle. The fluid vehicle can include a solvent for the polymeric sunscreen or can include any combination of solvents, non-solvents, and/or dispersing agents to emulsify or suspend the polymeric sunscreen in a non-solvent vehicle.
Another embodiment of the invention is a method to prevent sunburn by providing a polymeric sunscreen that is applied to skin. The polymeric sunscreen can be delivered to the skin as a component of a fluid that is a solution, emulsion, and/or dispersion.
Embodiments of the invention are directed to polymeric sunscreens that comprise a polymeric backbone that has a narrow distribution of repeating units where at least one of the repeating units of the chain comprises one or more UVA and/or UVB absorbing chromophores. Sunscreen molecules that comprise a single UVA and/or UVB absorbing chromophores of relatively low molecular weight are often absorbable by the skin. Skin absorption can allow radical/oxidative damage to the skin or can be toxic or carcinogenic to the sunscreen user. A photolytically and hydrolytically stable polymeric structure prohibits the skin absorption of the individual UV absorbing chromophores that function as the sunscreen. The polymeric sunscreen is soluble in at least one solvent that is useful as a fluid vehicle in a personal care formulation. In embodiments of the invention, the polymeric sunscreen comprises a polymer or copolymer of low symmetry such that crystallization is inhibited and solubility is achievable in a desirable solvent to provide a sunscreen lotion useful for application to skin for protection against sunburn.
In one embodiment of the invention, the polymeric sunscreen is a polymer that can be formed by a ring-opening metathesis polymerization (ROMP) of a cycloalkane-comprising monomer, where the resulting polymer has at least one repeating unit to which one or more UVA and/or UVB absorbing chromophores are attached. The chromophore can be attached to a monomer before polymerization, or can be attached by a reaction with the polymer after polymerization. In an embodiment of the invention, the cycloalkane-comprising monomer undergoes an exothermic ring-opening, such that chain-transfer to polymer or chain-chain redistribution is low, often absent, relative to the ring-opening polymerization process, which promotes a narrow molecular weight distribution and very high, often quantitative, conversion of the monomers. In an embodiment of the invention, because the polymerization process results in a Poisson distribution of repeating units rather than a normal or broader distribution, a relatively low molecular weight polymeric sunscreen, an oligomeric sunscreen, can be formed that lacks a significant fraction of the distribution that is monomeric, often free of a monomeric species. According to an embodiment of the invention, the ratio of the weight average to number average degree of polymerization, the molecular weight distribution, can be less than 1.5, for example, 1.4, 1.35, 1.3, 1.25, 1.2, 1.15, 1.1, 1.05 or 1.01. Such an oligomeric sunscreen can display a heightened miscibility with a fluid vehicle for a sunscreen lotion and permit a relatively high concentration of UVA and/or UVB absorbing chromophores in a lotion that would otherwise display an undesirably high viscosity because polymeric sunscreens from other routes require a higher degree of polymerization to assure almost no monomeric components in the sunscreen, which may be absorbable by the skin. The average degree of polymerization can be three or more, for example, about 3, 3.5, 4, 5, 6, 10, 20, 30, 40, 50, 100, 500, 1,000, or more.
In one embodiment of the invention, the polymer comprises a multiplicity of repeating units that have alkene units that reside at both ends of the repeating unit, and where at least one repeating unit comprises one or more UVA and/or UVB absorbing chromophores. In one embodiment of the invention, the polymeric sunscreen consists of a homopolymer from a single chromophore-comprising repeating unit or the polymeric sunscreen consists of a copolymer having two or more different chromophore-comprising repeating units, but where all repeating units comprise at least one UVA and/or UVB absorbing chromophore. In another embodiment of the invention, the polymeric sunscreen is a copolymer consisting of a multiplicity of repeating units, where at least one repeating unit comprises one or more INA and/or UVB absorbing chromophores and at least one repeating unit that lacks any UVA and/or UVB absorbing chromophores. A portion of the repeating units lacking any UVA and/or UVB absorbing chromophores can be an unsubstituted repeating unit and a portion of the repeating units lacking any UVA and/or UVB absorbing chromophores can be substituted to impart a desired property to the sunscreen lotion formed from the polymeric sunscreen. For example, one or more of the substituted repeating units lacking any UVA and/or UVB absorbing chromophores can include substituents to impart solubility in a desired solvent or to impart desired properties to the sunscreen lotion, such as, a color or a tactile sensation, as might be identified by a sensory panel during the development of a sunscreen lotions formulation.
In an embodiment of the invention, the repeating unit can be one that is derived from a cycloalkene, non-conjugated cycloalkadiene, bicycloalkene, or bicycloalkadiene having a ring that comprises at least three carbon atoms, and wherein the alkene has a “ring strain” and will polymerize exothermically. For example, a cycloalkane or cycloalkadiene from which the repeating unit is derived can have the structure:
to yield repeating groups
where x is 1 to 6, y is 1 or 2, and R and R′ are independently H, a substituent comprising a UVA and/or UVB absorbing chromophore, or any stable monovalent substituent, where any pair of R and R′ on the same carbon or different carbons of the cycloalkene or cycloalkadiene can be connected by a divalent substituent to form a second ring comprising three to twelve atoms forming a bicycloalkene or bicycloalkadiene, and where one or more of the sp3 hybridized carbons can be a replaced with a heteroatom, such as O, N, or Si. For example, the bicycloalkene with a heteroatom can be derived from 7-oxo-norbornene, norbornene-2,3-dicarboxylic anhydride, or any norbornene-2,3-dicarboxylic imide. In a specific embodiment of the invention, the repeating unit is derived from norbornene:
that upon ROMP results in the repeating unit:
Where the polymeric sunscreen is a copolymer of two or more repeating units, the repeating units can be distributed randomly throughout the copolymer, or can be formed in a block or gradient manner where one or more of the repeating units dominate an initial end of the copolymer and one or more of the repeating units dominate the terminal end of the copolymer. For example the polymerization can be carried out with a continuous feed of the comonomers, where monomer addition to the active center is rapid relative to termination of the active center and the comonomer feed is controlled and changing during polymerization, or where the comonomers are of sufficiently different reactivity that one or more comonomers undergo addition to the active center at a significantly higher rate than do one or more other comonomers. For example, where addition is not diffusion controlled and the ring strain is significantly different for two or more comonomers, promoting the polymerization of one comonomer can be followed by polymerization of a second monomer or one or more additional comonomers in the initial comonomer mixture to form a block copolymer.
In exemplary embodiments of the invention, bicyclo[2.2.1]hept-5-ene-2-carboxylic acid can be converted into one or more UVA and/or UVB absorbing chromophore-comprising monomers, as illustrated by the reaction schemes in
In other embodiments of the invention, the UVA and/or UVB absorbing chromophore-comprising monomers can be copolymerized with one or more monomers that do not provide a UVA and/or UVB absorbing chromophore, as illustrated in
In addition to polymerization and copolymerization of UVA and/or UVB absorbing chromophore-comprising monomers, monomers free of UVA and/or UVB absorbing chromophore can be polymerized by ROMP to a polymer that can subsequently be converted into a soluble UVA and/or UVB absorbing chromophore-comprising polymer, according to embodiments of the invention. For example, a silyl ester of bicyclo[2.2.1]hept-5-ene-2-carboxylic acid can be polymerized or copolymerized, deprotected, and subsequently transformed into a UVA and/or UVB absorbing chromophore-comprising polymer, as indicated in
The types of UVA and/or UVB absorbing chromophores can be, but are not limited to, those that have equivalent conjugated structures to the compounds approved for use by the
FDA or other worldwide regulatory agencies. Those approved chromophores are: Aminobenzoic acid; Avobenzone; Cinoxate; Dioxybenzone; Homosalate; Menthyl anthranilate; Octocrylene; Octyl methoxycinnamate; Octyl salicylate; Oxybenzone; Padimate O; Phenylbenzimidazole sulfonic acid; Sulisobenzone; Trolamine salicylate; Ecamsule; Phenylbenzimidazole sulfonic acid; 4-Methylbenzylidene camphor; Bisoctrizole; Bemotrizinol; Bisdisulizole disodium; Drometrizole trisiloxane; Benzophenone-9; Ethylhexyl triazone; Diethylamino hydroxybenzoyl hexyl benzoate; Iscotrizinol; Isoamyl p-Methoxycinnamate; and those attached to Polysilicone-15. Other UV absorbing chromophores can be used including those equivalent to UV absorbing conjugated systems disclosed in: U.S. Pat. Nos. 7,291,322; 7,087,692; 6,962,692; 6,926,887; 6,919,473; 6,899,866; 6,890,521; 6,800,274; 6,376,679; 6,312,673; 6,251,373; 6,221,343; 6,214,324; 6,200,557; 6,159,456; 5,993,789; 5,753,209; 5,741,924; 5,487,885; 5,250,652; 5,243,021; 5,134,223; 5,099,027; 4,524,061; 4,233,430; 4,004,074; and 3,864,473 and U.S. Patent Application Publications 2007/0020204; 2005/0186152; 2004/0213746; 2004/0101498; 2002/0054860; and 2001/0026789. Many other conjugated systems that absorb in the UVA and/or UVB spectral ranges can be used, even some that are known to be damaging to the skin or to other organs or systems of an individual using a sunscreen because the chromophores are irreversibly bound to a polymer chain that renders it passive to the system. The UV absorbing chromophores can be linked in the chromophore unit by any sufficiently stable bridging group. For example, where the conjugated UV absorbing chromophore unit contains a carboxylic acid group, the chromophore unit can have a hydroxy group and the UV absorbing chromophores can be attached via ester functionality. The bridging group can be a single bond or it can be a series of covalently bonded atoms, depending on what is required to link the chromophore to the cycloalkene or cycloalkadiene moiety. One skilled in the art can readily appreciate appropriate complimentary functionalities to form desirable bridges between the UV absorbing chromophores to polymerizable moieties of the monomers.
The formation of UVA and/or UVB absorbing chromophore-comprising polymer can be carried out by polymerization of the strained cycloakene, cycloalkadiene, bicycloalkene, or bicycloalkadiene comprising monomers using any known metathesis catalyst, for example Schrock's catalyst Mo(═CHCMe2Ph)(N-2,6-C6H3-i-Pr2)(OCMe(CF3)2)2 or Grubbs' catalyst RuC12(═CHPh)(PCy3)2, where the specific catalyst that is employed depends upon the structure of the monomers used, as taught in Trnka et al. Acc. Chem. Res. 2001, 34, 18-29, and Handbook of Metathesis, Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003 and can be appreciated by those skilled in the art. As needed, the UVA and/or UVB absorbing chromophore-comprising polymer can be isolated from the polymerization mixture by any method, including precipitation, extraction, or centrifugation.
The catalyst that is used to prepare the polymer depends upon the UVA and/or UVB absorbing chromophores that are present in the monomer. For example, the presence of a chromophore equivalent in structure to Octocrylene in a monomer, as shown in
Once in possession of UVA and/or UVB absorbing chromophore-comprising polymer in a desired isolated form, the polymer can be combined with one or more solvents, and, as needed or desired, a surfactant, emulsifier, fragrance, buffers, powder, or any other ingredient to form a lotion or other fluid vehicle for application to skin in need of sun protection. The proportions of the UVA and/or UVB absorbing chromophore-comprising polymer and other ingredients are chosen to give the desired degree of sun protection, for example a desired SPF number, to achieve a desired flow, and to provide other properties that are conducive with a mode of manufacture or to the desired sensory properties of the fluid when spread and maintained on the skin.
As indicated in
As indicated in
As indicated in
A mixture of 6 g hexanethiol (50.94 mmol, 1.7 eq.) and 50 mL anhydrous dimethyl formamide was cooled to 5° C. in a round bottom flask under nitrogen atmosphere. 5.4 g potassium t-butoxide (47.94 mmol, 1.6 eq.) was added in one lot and the reaction mixture was allowed to warm to room temperature. After stirring for 20 min, 9.3 g Avobenzone (29.96 mmol) was added in one lot and the solution was heated to 110° C. for 1 h. The mixture was cooled to room temperature, poured into 100 mL of ice water, and finally acidified to pH 1 with 1 M aq. HCl. The resultant mixture was transferred to a separatory funnel and extracted twice using 75 mL portions of ethyl acetate. The organic layer was evaporated to yield 1-(4-(tert-butyl)phenyl)-3-(4-hydroxyphenyl)propane-1,3-dione as a pale brown oil (8.0 g), which was used without further purification.
As indicated in
As indicated in
All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.
It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application.
The present application claims the benefit of U.S. Provisional Application Ser. No. 61/532,701, filed Sep. 9, 2011, which is hereby incorporated by reference herein in its entirety, including any figures, tables, or drawings.
The subject invention was made with government support under Contract No. DMR-0703261, awarded by the National Science Foundation. The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US12/54376 | 9/10/2012 | WO | 00 | 3/10/2014 |
| Number | Date | Country | |
|---|---|---|---|
| 61532701 | Sep 2011 | US |
