WO2023086839A1 - Compositions d'écran solaire comprenant des analogues d'imine d'un écran solaire comprenant une cétone - Google Patents

Compositions d'écran solaire comprenant des analogues d'imine d'un écran solaire comprenant une cétone Download PDF

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WO2023086839A1
WO2023086839A1 PCT/US2022/079573 US2022079573W WO2023086839A1 WO 2023086839 A1 WO2023086839 A1 WO 2023086839A1 US 2022079573 W US2022079573 W US 2022079573W WO 2023086839 A1 WO2023086839 A1 WO 2023086839A1
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Prior art keywords
imine
sunscreen
filter
ketone
oxybenzone
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PCT/US2022/079573
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English (en)
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Erika M. Milczek
William Shindel
Zsolt SZABADOS
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Curie Co. Inc.
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Priority claimed from US17/524,222 external-priority patent/US20220160601A1/en
Application filed by Curie Co. Inc. filed Critical Curie Co. Inc.
Publication of WO2023086839A1 publication Critical patent/WO2023086839A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/41—Amines
    • A61K8/415—Aminophenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A61K8/466—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur containing sulfonic acid derivatives; Salts

Definitions

  • the field concerns sunscreen compositions comprising an imine analog of a ketone- containing UV filter that has at least one property selected from the group consisting of a) is capable of extending UV protection into a visible region equal to or greater than 400 nm, b) is water resistant, and/or c) prevents or decreases skin penetration.
  • UV filters are compounds, mixtures, or materials that block or absorb UV light.
  • One of the major applications of UV filters is their use as sunscreens to protect skin from sunbum and other sun/UV-related damage. Since excessive UV radiation can cause sunbum, photoaging and skin cancer, care products such as sunscreen usually include a classification for the specific wavelengths they filter. UV classifications include UVA (320- 400 nm), UVB (290-320 nm) and UVC (200-280 nm). Broad spectrum sunscreens protect against both UVA and UVB rays.
  • UV-absorbing compounds are used not only in sunscreen, but also in other personal care products, such as lipstick, shampoo, hair spray, body wash, and insect repellant.
  • Chemical filters protect against UV radiation by absorbing, reflecting or scattering it. Reflection and scattering are accomplished by inorganic UV filters, such as titanium dioxide and zinc oxide. Absorption, mainly of UVB, is done by organic UV filters.
  • the European Union determines broad spectmm protection by the ratio of UVA to UVB protection, requiring one third of the sun protection factor (SPF) number to be UVA protection.
  • SPF sun protection factor
  • EU-approved UVA filters There are eight EU-approved UVA filters currently being used in European sunscreens. Some of the EU-approved UVA filters are triazine-containing UV filters. They also provide some UVB protection. Unfortunately, such compounds are still not FDA- approved for use in the United States, and it is not clear when such approval might be forthcoming
  • a sunscreen composition comprising at least one ketone-containing UV filter and at least one primary or secondary amine wherein the ketone-containing UV filter and the at least one primary or secondary amine react to form an imine analog of the ketone-containing UV filter wherein said imine analog has at least one property selected from the group consisting of a) is capable of extending UV protection into a visible region equal to or greater than 400 nm, b) is water resistant, and/or c) prevents or decreases skin penetration.
  • the ketone-containing UV filter is selected from the group consisting of avobenzone, diethylamino hydroxybenzoyl hexyl benzoate, sulisobenzone, and oxybenzone.
  • the imine analog form of the ketone-containing UV filter may be further modified to provide a substrate capable of reacting with transglutaminase or any variant thereof and/or a lysyl oxidase to bind the sunscreen composition to a target of interest.
  • a sunscreen active ingredient comprising at least one ketone-containing UV filter and at least one primary or secondary amine wherein the ketone-containing UV filter and the at least one primary or secondary amine react to form an imine analog of the ketone-containing UV filter wherein said imine analog has at least one property selected from the group consisting of a) is capable of extending UV protection into a visible region equal to or greater than 400 nm, b) is water resistant, and/or c) prevents or decreases skin penetration.
  • the ketone-containing UV filter is selected from the group consisting of avobenzone, diethylamino hydroxybenzoyl hexyl benzoate, sulisobenzone, and oxybenzone.
  • the imine analog form of the ketone-containing UV filter of the sunscreen active ingredient is further modified to provide a substrate capable of reacting with transglutaminase or any variant thereof and/or a lysyl oxidase to bind said sunscreen active ingredient to a target of interest.
  • a cosmetic or pharmaceutical preparation comprising at least one of the sunscreen compositions or sunscreen active ingredient described herein and a cosmetically or pharmaceutically acceptable carrier.
  • Figure 1 depicts the UV/Vis spectral properties of Imine-1, Imine-2, and Imine-3 compared to oxybenzone in acetonitrile.
  • Figure 2 depicts the UV/Vis spectral properties of Carbamate- 1 compared to oxybenzone in acetonitrile.
  • Figure 3 depicts the UV/Vis spectral properties of Imine-4, Imine-5, andN-Boc- Imine-6 compared to oxybenzone in acetonitrile.
  • Figure 4 depicts the UV/Vis spectral properties of N-Boc-Imine-6 in ethanol.
  • Figure 5 depicts the UV/Vis spectral properties of Imine-7 and N-Boc-Imine-7 compared to avobenzone in acetonitrile.
  • Figure 6 depicts the UV/Vis spectral properties of N-Boc-Imine-8 and Imine-8 compared to sulisobenzone in ethanol at about equal concentration.
  • Figure 7 depicts the UV/Vis spectral properties of Imine-10 in ethanol.
  • Figure 8 depicts the structures of avobenzone, oxybenzone, sulisobenzone, DHHB, and the imines described in the Examples below along with their estimated LogP values as determined by ChemDraw.
  • SEQ ID NO: 1 corresponds to the amino acid sequence of wild-type transglutaminase (Tgase) sequence of Streptomyces mobaraensis.
  • SEQ ID NO:2 corresponds to a variant of the sequence of SEQ ID NO: 1 wherein this variant has a triple mutation (N282E, H289I, and S299K) relative to SEQ ID NO: 1.
  • SEQ ID NO:3 corresponds to a variant of SEQ ID NO: 1 wherein this variant has a quadruple mutation (N282K, G283A, S284P, and S299V) relative to SEQ ID NO:1.
  • SEQ ID NO:4 corresponds to a variant of SEQ ID NO: 1 wherein this variant has a double mutation (S199A and S299A) relative to SEQ ID NO:1.
  • SEQ ID NO:5 corresponds to a variant of SEQ ID NO: 1 wherein this variant has a double mutation (S199A and S299V) relative to SEQ ID NO:1.
  • SEQ ID NO:6 corresponds to a variant of SEQ ID NO: 1 wherein this variant has a triple mutation (S2P, S199G and S299V) relative to SEQ ID NO:1.
  • SEQ ID NO:7 corresponds to a variant of SEQ ID NO: 1 wherein this variant has a single mutation (S2P) relative to SEQ ID NO:1.
  • SEQ ID NO: 8 corresponds to SEQ ID NO: 1 with a polyhistidine tag, i.e., wild-type Tgase with a polyhistidine tag.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • the terms “a,” “an,” “the,” “one or more,” and “at least one,” for example, can be used interchangeably herein.
  • the term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range.
  • amino acid refers to the basic chemical structural unit of a protein, peptide, or polypeptide.
  • the following abbreviations used herein to identify specific amino acids can be found in Table 1.
  • avobenzone refers to a chemical compound C20H22O3 (CAS Registry Number 70356-09-1) that absorbs UVA radiation and is used as an ingredient in sunscreens.
  • UVA radiation is the type of UV light that contributes to skin cancer and aging of the skin.
  • avobenzone degrades in sunlight so it usually is combined with other ingredients to be effective. It is approved by the FDA in concentrations up to 3%.
  • Avobenzone is marketed under the trademark Parsol®.
  • composition refers to a combination of two or more substance or compounds.
  • corresponding to or “corresponds to” or “correspond to” or “corresponds” refers to an amino acid residue at the enumerated position in a protein or peptide, or an amino acid residue that is analogous, homologous, or equivalent to an enumerated residue in a protein or peptide.
  • corresponding region generally refers to an analogous position in a related protein or a reference protein.
  • cosmetic refers to most personal care, skin care, make-up and cosmetics.
  • a cosmetic is any substance or preparation intended to be placed in contact with any part of the human body, with a view to altering body odors, changing its appearance, cleansing it, maintaining it in good condition, perfuming it, and/or protecting it.
  • Cosmetics include, but are not limited to soap, shampoo and conditioner, moisturizer, bath bombs, hair dye, perfume, lipstick, mascara, nail polish, deodorant and many other products.
  • a “cosmetic preparation” is in ready -to use-form.
  • DHHB refers to diethylamino hydroxybenzoyl hexyl benzoate having molecular formula C24H31NO4 (CAS Registry Number 302776-68-7). DHHB is a UV filter with high absorption in the UV-A range. It was approved in Europe in 2005.
  • derived from encompasses the terms “originated from,” “obtained from,” “obtainable from,” “isolated from,” “purified from,” and “created from,” and generally indicates that one specified material finds its origin in another specified material or has features that can be described with reference to another specified material.
  • isolated refers to a material (e.g., a protein, nucleic acid, or cell) that is removed from at least one component with which it is naturally associated.
  • these terms may refer to a material which is substantially or essentially free from components which normally accompany it as found in its native state, such as, for example, an intact biological system.
  • An isolated nucleic acid molecule includes a nucleic acid molecule contained in cells that ordinarily express the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.
  • lysyl oxidase also known as protein-lysine 6-oxidase
  • LOX copper-dependent enzymes that catalyze formation of aldehydes from lysine residues in collagen and elastin precursors. These aldehydes are highly reactive and undergo spontaneous chemical reactions with other lysyl oxidase-derived aldehyde residues, or with unmodified lysine residues. This results in cross-linking collagen and elastin.
  • LOX proteins have been identified in animals, other eukaryotes, and in bacteria and archaea (reviewed in Grau-Bove, et al. (2015) Scientific Reports 5: Article number: 10568).
  • mutation refers to a change introduced into a parental sequence, including, but not limited to, substitutions, insertions, and deletions (including truncations), thereby producing a “mutant.”
  • the consequences of a mutation include, but are not limited to, the creation of a new character, property, function, phenotype or trait not found in the protein encoded by the parental sequence.
  • oxybenzone refers to a chemical organic compound having molecular formula C14H12O3 (CAS Registry Number 131-57-7). It is a benzophenone derivative used as a sunscreen agent. It is approved by the FDA in concentrations up to 6%. It absorbs UVB radiation and some UVA radiation.
  • peptides are used interchangeably herein and refer to a polymer of amino acids joined together by peptide bonds.
  • a “protein” or “polypeptide” comprises a polymeric sequence of amino acid residues.
  • the single and 3- letter code for amino acids as defined in conformity with the IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN) is used throughout this disclosure.
  • the single letter X refers to any of the twenty amino acids. It is also understood that a polypeptide may be coded for by more than one nucleotide sequence due to the degeneracy of the genetic code.
  • Mutations can be named by the one letter code for the parent amino acid, followed by a position number and then the one letter code for the variant amino acid.
  • mutating glycine (G) at position 87 to serine (S) is represented as "G087S” or "G87S”.
  • a position followed by amino acids listed in parentheses indicates a list of substitutions at that position by any of the listed amino acids.
  • 6(L, I) means position 6 can be substituted with a leucine or isoleucine.
  • a slash (/) is used to define substitutions, e.g., F/V, indicates that the position may have a phenylalanine or valine at that position.
  • pharmaceutical preparation refers to a drug intended for human or veterinary use, presented in its finished dosage form, i.e., ready to use.
  • primary amine refers to organic derivatives of ammonia in which one of the hydrogen atoms has been replaced, for example, including but not limited to, by an unsubstituted or substituted alkyl, a cyclic alkyl or an aromatic/heteroaromatic group.
  • secondary amine refers organic derivatives of ammonia in which two of the hydrogen atoms are replaced, for example, including but not limited to, by unsubstituted or substituted alkyl and/or aromatic/heteroaromatic groups.
  • sulisobenzone refers to 5-benzoyl-4-hydroxy-2- methoxybenzenesulfonic acid having molecular formula C 14 H 12 O 6 S ( CAS Registry Number 4065-45-6). It is approved by the FDA in concentrations up to 10%. It works to filter out UVA and UVB rays. It is used as a UV -filter ingredient in sunscreens and other personal care products.
  • “sunscreen” and “sunscreen composition” are used interchangeably herein and refer to any compound, substance, mixtures, or material that is capable of blocking or absorbing UV radiation. It can be regarded as a photoprotective topical agent.
  • the term “sunscreen active ingredient” refers to that part of a compound or substance that produces the desired chemical or biological effect which in this case involves the blocking, reflection or absorption of UVA and UVB radiation.
  • target of interest refers to any exogenous protein or peptide such as a dermatologically relevant protein, or any part of a human body or animal body, suitable for binding to an imine form of any ketone-containing UV filter that has been modified to serve as a substrate for a Tgase or any variant thereof.
  • the Tgase or any variant thereof then catalyzes a reaction whereby the modified imine is conjugated/linked to the relevant part of the human body, i.e., the target of interest.
  • the target of interest may include, but is not limited to, glutamine-glycine, collagen, keratin and/or elastin.
  • transglutaminase (Tgase EC 2.3.2.13) refers to enzymes capable of catalyzing an acyl transfer reaction in which a ⁇ -carboxy-amide group of a peptide-bound glutamine residue is the acyl donor.
  • Primary amino groups in a variety of compounds may function as acyl acceptors with the subsequent formation of monosubstituted ⁇ -amides of peptide bound glutamine.
  • the ⁇ -amino group of a lysine residue in a peptide chain serves as the acyl acceptor, the Tgases form intramolecular or intermolecular ⁇ -glutamyl- ⁇ - lysyl crosslinks.
  • the catalytic reaction proceeds via glutamine deamination and formation of a protein-glutamyl-thioester at the active site of the enzyme.
  • Nucleophilic attack by a lysyl 8- amino group of a second protein at the carbonyl moiety of the thioester intermediate generates isopeptide-crosslinked proteins that are largely resistant to proteolysis by common peptidases (Mariniello, et al. (2007) J Agr Food Chem. 55:4717-4721).
  • Tgase bonds formed by a Tgase exhibit high resistance to proteolytic degradation (proteolysis). Tgases from microbial origin are calcium-independent, which represents a major advantage for their practical use. Tgase has found many applications in biotechnology and in the food processing industry, where it has earned the moniker “meat glue.” The peptide crosslinking activity has been shown to be useful for a variety of industrial purposes ranging from food processing, biotechnology, pharmaceuticals, medical devices, personal and household goods, and leather and textile treatment. The most commonly used Tgase is microbial transglutaminase from Streptomyces mobaraensis, having the amino acid sequence depicted in SEQ ID NO:1 and referred to hereinafter as Tgase.
  • UV filter refers to any compounds, mixture, substances, or materials that block, reflect, or absorb UV light.
  • UV light refers to a form of electromagnetic radiation with a wavelength from 10 nm to 400 nm which falls in range of the electromagnetic spectrum between visible light and X-rays.
  • UVA has a wavelength in the range of 320-400nm. It is not absorbed by the ozone layer. UVA rays are further classified into UVA1 and UVA 2. UVA1 is between 340 and 400 nm whereas UVA2 is between 320 and 340 nm in wavelength.
  • UVB has a wavelength in the range 290-320 nm. It is mostly absorbed by the ozone layer, but some does reach the surface of earth.
  • UVC has a wavelength in the range 100-290 nm. It is completely absorbed by the ozone layer and the earth’s atmosphere.
  • variant proteins differ from another (i.e., parental) protein and/or from one another by a small number of amino acid residues.
  • a variant may include one or more amino acid mutations (e.g., amino acid deletion, insertion or substitution) as compared to the parental protein from which it is derived.
  • variants may have a specified degree of sequence identity with a reference protein or nucleic acid, e.g., as determined using a sequence alignment tool, such as BLAST, ALIGN, and CLUSTAL.
  • variant proteins or nucleic acid may have at least about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or even 99.5% amino acid sequence identity with a reference sequence and integer percentage therebetween.
  • visible light refers to a form of electromagnetic radiation that is perceived by the human eye with a wavelength from 400 nm to 700 nm which falls in the range of the electromagnetic spectrum between UV light and infrared light.
  • high energy visible light HEVL with a wavelength from 400 nm to 450 nm is particularly important for causing oxidative stress, free radical generation and dermal cellular damage to the skin.
  • visible light filter refers to any compounds, mixture, substances, or materials that block, reflect, or absorb UV light.
  • wild-type in reference to an amino acid sequence or nucleic acid sequence indicates that the amino acid sequence or nucleic acid sequence is a native or naturally occurring sequence.
  • naturally-occurring refers to anything (e.g., proteins, amino acids, or nucleic acid sequences) that is found in nature.
  • non-naturally occurring refers to anything that is not found in nature e.g., recombinant/ engineered nucleic acids and protein sequences produced in the laboratory or modification of the wild-type sequence).
  • ultraviolet filters also referred to as sunscreens or sun protectants, are the elements present in photo-protector formulas that interfere directly with the incident solar radiation through absorption, reflection or dispersion of energy. They are classified into two categories based on their mechanism of action: chemical or organic sunscreens and mineral-based or organic sunscreens.
  • sunscreen products are classified as over-the-counter (OTC) drugs. This means that they are strictly regulated and require pre-market registration with the U.S. Food and Drug Administration (FDA). Regulation on sunscreens includes Sunscreen Drug Products for Over-The-Counter Human Use Monograph (21 CFR 352) and the Sunscreen Innovation Act.
  • FDA Food and Drug Administration
  • the U.S. FDA in February 2019 issued a proposed rule that would alter the regulations associated with the manufacturing and selling of sunscreen, as well as other sun-care related products. This proposed rule is aimed at bringing nonprescription, OTC sunscreens that are marketed without FDA-approved application, together with the latest science to better ensure that consumers have access to safe and effective preventative sun care options.
  • a sunscreen composition comprising at least one ketone- containing UV filter and at least one primary or secondary amine wherein the ketone- containing UV filter react to form an imine analog of the ketone-containing UV filter wherein said imine analog
  • [78] has at least one property selected from the group consisting of a) is capable of extending UV protection into a visible region equal to or greater than 400 nm, b) is water resistant, and/or c) prevents or decreases skin penetration.
  • the sunscreen compositions disclosed herein comprising at least one ketone- containing UV filter and at least one primary or secondary amine wherein the ketone- containing UV filter react to form an imine analog of the ketone-containing UV filter wherein said imine analog has at least one property selected from the group consisting of a) is used as a UV filter and visible light filter, b) is water resistant, and/or c) prevents or decreases skin penetration.
  • the sunscreen compositions described herein can be manufactured more easily than a multicomponent system, suitably at a lower cost. Furthermore, in contrast to use the use of two ingredients as a UV filter and visible light filter respectively, each having its own absorbance profile, the sunscreen compositions disclosed herein provide continuous photoprotection extended from UV light to visible light range.
  • sunscreen compositions are free of, or substantially free of, other visible light filters.
  • pigments such as iron oxide.
  • the visible light filter of the sunscreen compositions described herein preferably block or absorb visible light of a wavelength from 400 nm to 450 nm.
  • ketone-containing UV filters include, but are not limited to, avobenzone, oxybenzone, sulisobenzone, enzacamene, diethylamino hydroxybenzoyl hexyl benzoate and ecamsule.
  • Preferred ketone-containing UV filters are avobenzone, diethylamino hydroxybenzoyl hexyl benzoate (DHHB), sulisobenzone, and oxybenzone.
  • the imine analog also has at least one property selected from the group consisting of a) is capable of extending absorbance into the UVA-1, UVA-2, and/or UVB regions as well as into the visible region equal to or greater than 400 nm, b) is water resistant, and/or c) prevents or decreases skin penetration.
  • Such useful amines include, but are not limited to, amino acids, cadaverine, putrescine, hydrazine, adipic acid dihydrazide, sebacic dihydrazide, ethylenediamine, hexamethylenediamine, benzyl amine, aniline, amodimethicone, tromethamine, polyethylenimine, polylysine, dimethylaminopropylamine, aminomethyl propanol, etc.
  • the at least one ketone-containing UV filter and the at least one primary or secondary amine are added to a reactor, they are capable of reacting to form an imine analog of the ketone-containing UV filter.
  • the imine analog is selected from one or more of imine-1, imine-2, imine-4, imine-5, imine-6, imine-7, imine-8, imine-9, N-Boc-Imine 7, N- Boc-Imine 8, N-Boc-Imine 9, and/or imine-10 as shown in Figure 8 along with their estimate Log P values as calculated by ChemDraw.
  • the resulting imine analog may dimerize, for example, Dimer-Imine 6 as shown in Figure 8.
  • the resulting imine analog may be regarded as a reaction product of a ketone-containing UV filter and a primary or secondary amine.
  • the imine analog of the present embodiments functions simultaneously as a UV filter and a visible light filter and/or is water resistant and/or decreases skin penetration.
  • this imine analog of the ketone-containing UV filter has at least one property selected from the group consisting of a) is capable of extending absorbance into the UVA-1, UVA-2, and/or UVB regions as well as into the visible region equal to or greater than 400 nm, b) is water resistant, and/or c) prevents or decreases skin penetration. It is believed that this is the first imine-containing sunscreen composition or sunscreen ingredient to have at least one of these properties as discussed herein. This is shown in greater detail below in the Examples and in the Figures provided herein.
  • sunscreen compositions disclosed herein comprising an imine analog of a ketone-containing UV filter as a visible light filter, wherein said imine analog is a reaction product of a ketone-containing UV filter and a primary or secondary amine.
  • UV-filters are required to remain on the surface, for example, of skin, to maintain their photoprotective character. Skin penetration of UV -filters in sunscreen products should be avoided. In addition to reduction of UV-protection due to skin penetration, photosensitivity reactions may also occur.
  • the success of topical delivery depends on the ability to overcome biological barriers such as the skin. When it comes to sunscreen safety, the goal is to limit skin penetration of chemicals from the topical formulations to avoid toxicity.
  • the 500 Dalton rule postulates that the molecular weight (MW) of a compound should be under 500 Dalton to allow skin absorption. (Bos et al., Exp Dermatol 2000: 9: 165-169).
  • the UV-filter in a sunscreen composition should have a MW of at least 500 Dalton to reduce the likelihood of skin penetration.
  • the partition coefficient (P) is the ratio of concentrations of a compound in a mixture of two immiscible solvents at equilibrium. This ratio is therefore a comparison of the solubilities of the solute in these two liquids, specifically for un-ionized solutes.
  • the Log P value is a measure of lipophilicity or hydrophobicity.
  • Lipophilicity is a key determinant of permeability across tissue membranes.
  • a negative value for log P means the compound has a higher affinity for the aqueous phase, i.e., it is more hydrophilic.
  • a positive value for Log P denotes a higher concentration in the lipid phase, i.e., the compound is more lipophilic.
  • water-resistant or “very water-resistant” have replaced the term “waterproof’ with respect to sunscreen compositions.
  • water-resistant or “very water-resistant” can be used when the sun protection provided by a sunscreen product is reduced by less than 50% after a lukewarm bath lasting 40 minutes or 80 minutes, respectively. When sunscreen “sticks” to the skin, it is less likely to wash off in the water or when performing intense, sweat-inducing exercise.
  • oxybenzone is a ketone-containing filter that can be contacted with a primary or secondary amine to form an imine analog thereof. It is also possible to combine 2 equivalents of oxybenzone or a similar ketone-containing compound with one equivalent of a diamine, such as hexamethylene diamine, to dimerize the oxybenzone via an imine. This is depicted in Figure 8. The resulting dimer would have a MW above 500 Daltons and a Log P above the 1-3 range while retaining all the benefits afforded by expanding the range of UV protection into the visible range equal to or greater than 400 nm.
  • the sunscreen compositions of the embodiments suitably comprise water, emulsifier, humectant, emollient, thickener, preservative, chelating agent, and/or other conventional ingredients in appropriate amounts.
  • the sunscreen composition comprises 1.0-20% w/w% of the UV filters described herein.
  • the imine analogs of the ketone-containing UV filters disclosed herein may be further modified to provide a substrate capable of reacting with transglutaminase or any variant thereof and/or a lysyl oxidase to bind the sunscreen composition or sunscreen active ingredient to a target of interest.
  • Tgase enzymes that are variants of the Ca 2+ -independent microbial transglutaminase (Tgase) Streptomyces mobaraensis.
  • the wild-type enzyme from Streptomyces mobaraensis corresponds to the amino acid sequence set forth in SEQ ID NO:1.
  • Tgase variants of SEQ ID NO: 1 may be obtained by mutating at one or more amino acids in the polypeptide sequence of the wild type Tgase and observing transglutaminase transamidation activity between a glutamine amino acid residue and an amine (or hydroxylamine) acceptor.
  • Methods for recombinant expression of proteins with mutational substitutions have been described previously and are well known in the art, for example, Molecular Cloning. A Laboratory Manual 4th ed., Cold Spring Harbor Press (1989), Current Protocols in Molecular Biology. John Wiley & Sons (1987-1997) and the like.
  • Combinations of point mutations can be generated using a number of methods including error-prone PCR, gene shuffling, molecular breeding, and the like.
  • Tgase variants and wild-type Tgase may further comprise a polyhistidine peptide extension at their C-terminus, as exemplified with amino acid residues 334-339 of SEQ ID NO: 8.
  • the polyhistidine peptide is a useful tag for purification purposes and does not affect enzymatic activity.
  • the polyhistidine peptide is 6-8 residues long (SEQ ID NO: 9).
  • Tgase variants may further comprise a methionine residue at their N-terminus.
  • the mature wild-type Streptomyces mobaraensis Tgase enzyme lacks the N-terminal methionine residue encoded by the gene sequence that encodes the enzyme.
  • the Tgase variant is expressed as a variant of the mature Streptomyces mobaraensis Tgase without an N-terminal methionine residue.
  • the Tgase is expressed as the mature Tgase with an additional N-terminal methionine residue, which may be provided by an expression vector from which the Tgase is expressed.
  • Tgase variants of interest can be found in the amino acid sequences of SEQ ID NOs: 2, 3, 4, 5, 6, or 7.
  • the “target of interest” refers to any exogenous protein or peptide such as a dermatologically relevant protein, or any part of a human body or animal body, suitable for binding to an imine or enamine form of any ketone-containing UV filter that has been modified to serve as a substrate for a Tgase or any variant thereof.
  • the Tgase or any variant thereof then catalyzes a reaction whereby the modified imine or enamine is conjugated/linked to the relevant part of the human body, i.e., the target of interest.
  • the target of interest may include, but is not limited to, glutamineglycine, collagen, keratin and/or elastin.
  • cosmetic or pharmaceutical preparations comprising any of the sunscreen compositions or sunscreen active ingredients disclosed herein along with a cosmetically or pharmaceutically acceptable carrier.
  • any of the imine analogs of the ketone-containing UV filters disclosed herein may or may not be further modified to provide a substrate capable of reacting with transglutaminase or any variant thereof and/or a lysyl oxidase to bind the sunscreen composition or sunscreen active ingredient to a target of interest.
  • cosmetically acceptable carriers include, but are not limited to, water and/or water -soluble solvents, aqueous gels, alcoholic gels, ointments, oils, alcoholic or aqueous fluids, water in oil emulsions, water in silicone emulsions, etc.
  • Non-limiting examples of cosmetically acceptable carrier include glycerin, Cl -4 alcohols, organic solvents, fatty alcohols, fatty ethers, fatty esters, polyols, glycols, vegetable oils, mineral oils, liposomes, laminar lipid materials.
  • organic solvents include, but are not limited to, monoalcohols and polyols such as ethyl alcohol, isopropyl alcohol, propyl alcohol, benzyl alcohol, and phenylethyl alcohol, or glycols or glycol ethers, such as, monomethyl, monoethyl and monobutyl ethers or ethylene glycol, propylene glycol, butylene glycol, hexylene glycol, dipropylene glycol as well as alkyl ethers of diethylene glycol for example monoethyl ether or monobutyl ether of diethylene glycol.
  • organic solvents are ethylene glycol, propylene glycol, butylene glycol, hexylene, glycol, propane diol, and glycerin.
  • the organic solvents can be volatile or non-volatile compounds.
  • cosmetically acceptable carriers may comprise water, a mixture of water and at least one cosmetically acceptable organic solvent, or at least one cosmetically acceptable organic solvent. Additionally, cosmetically acceptable carriers may be or may include ethanol, a glycol ether, for example dipropylene glycol n-butyl ether, isodecane, mineral oil, propylene glycol, pentylene glycol, hexylene glycol, glycerol and mixtures thereof.
  • a pharmaceutical or drug carrier is any substrate used in the process of drug delivery which serves to improve the selectivity, effectiveness, and/or safety of drug administration.
  • Drug carriers can be used to control the release of a drug into systemic circulation.
  • Examples of pharmaceutically acceptable carriers include, but are not limited to, creams, emulsions, gels, liposomes, nanoparticles, microspheres, polymeric micelles, nanofibers, protein- drug complexes and/or ointments.
  • a sunscreen composition comprising at least one ketone-containing UV filter and at least one primary or secondary amine wherein the ketone-containing UV filter and the at least one primary or secondary amine react to form an imine analog of the ketone-containing UV filter wherein said imine analog has at least one property selected from the group consisting of a) is capable of extending UV protection into a visible region equal to or greater than 400 nm, b) is water resistant, and/or c) prevents or decreases skin penetration.
  • ketone-containing UV filter is selected from the group consisting of avobenzone, diethylamino hydroxybenzoyl hexyl benzoate (DHHB), sulisobenzone, and oxybenzone.
  • the sunscreen composition of embodiment 2 wherein the imine analog form of the ketone-containing UV filter is further modified to provide a substrate capable of reacting with transglutaminase or any variant thereof and/or a lysyl oxidase to bind said sunscreen composition to a target of interest.
  • a sunscreen active ingredient comprising at least one ketone-containing UV filter and at least one primary or secondary amine wherein the ketone-containing UV filter and the primary or secondary amine react to form an imine analog has at least one property selected from the group consisting of a) is capable of extending UV protection into a visible region equal to or greater than 400 nm, b) is water resistant, and/or c) prevents or decreases skin penetration.
  • ketone-containing UV filter is selected from the group consisting of avobenzone, diethylamino hydroxybenzoyl hexyl benzoate, sulisobenzone, and oxybenzone.
  • the sunscreen active ingredient of embodiment 4 or 5 wherein the imine analog form of the ketone-containing UV filter is further modified to provide a substrate capable of reacting with transglutaminase or any variant thereof and/or a lysyl oxidase to bind said sunscreen active ingredient to a target of interest.
  • a cosmetic or pharmaceutical preparation comprising the sunscreen composition of embodiment 1 or 2 or the sunscreen active ingredient of embodiment 4 or 5and a cosmetically or pharmaceutically acceptable carrier.
  • a cosmetic or pharmaceutical preparation comprising the sunscreen composition of embodiment 3 or the sunscreen active ingredient of embodiment 6 and a cosmetically or pharmaceutically acceptable carrier.
  • US 5490980A proposed a transglutaminase-compatible oxybenzone-derived- carbamate functionalized at the phenolic oxygen of oxybenzone with an alkyl-diamine.
  • Carbamate- 1 was prepared using methods known in the art. However, functionalization at the phenolic oxygen reduces the UV filter properties resulting in reduced UVA blocking.
  • Carbamate-1 first described in patent US 5490980A, was synthesized, purified, and isolated (see above). Carbamate-1 was dissolved in acetonitrile to a final concentration of 0.05 mM and analyzed by UV/Vis (Cary-50 Spectrophotomer). The spectral properties were compared to oxybenzone in acetonitrile at a final concentration of 0.05 mM. The results in Figure 2 demonstrate that Carbamate -1 (having functionalization at the phenolic oxygen) resulted in reducing the UV filter properties, more specifically, UVA blocking was reduced.
  • Example 3 Synthesis and analysis of oxybenzone series of imines, Tgase substrates, a. Synthesis of Imine-4.
  • the aqueous phase was lyophilized to afford the crude product, which was purified by reversed-phase HPLC (column: Xtimate C18 150 * 40 mm * 10 pm; mobile phase: [water(HCl)-ACN]; B%: 30%-60%,10 min).
  • the JV-Boc-Imine-4 (350 mg, 537 pmol, 41% yield) was isolated as green solid, confirmed by LCMS and J H NMR (CDC1 3 ).
  • Imine-4, Imine-5, and N-Boc- 1 mine-6 were synthesized, purified, and isolated (see above). All three compounds were separately dissolved in acetonitrile to a final concentration of 5 mM ( Figure 3) and analyzed by UV/Vis (Cary-50 Spectrophotomer). N-Boc-Imine-6 was diluted in acetonitrile to a final concentration of 0.05 mM ( Figure 3, inset) and analyzed by UV/Vis. The N-Boc-Imine-6 was utilized for this data, instead of Imine-6, due to poor solubility of Imine-6 in acetonitrile. Spectral properties were compared to oxybenzone in acetonitrile at the same concentration.
  • Figure 3 depicts the absorption spectra of the three imines derived from oxybenzone and shows that the three imines encompassed the UVA-1, UVA-2, and UVB regions as well as the visible region of the spectrum (greater than 400 nm).
  • N- Boc-Imine-6 was prepared in ethanol in the presence of catalytic glacial acetic acid.
  • N-Boc-Imine-6 was stable over 24 hours at high temperature (70 °C) in ethanol without reversion to the starting ketone and amine (Figure 4). Additionally, the Boc-protecting group remained intact throughout the reaction and UV/Vis analysis. The results in Figure 4 show that absorption of N-Boc-Imine 6 encompasses the UVA and UVB regions as well as the visible region of the spectrum (greater than 400 nm).
  • UVA and UVB absorption properties are UVA and UVB absorption properties.
  • Imine-7 and N-Boc-Imine-7 were synthesized, purified, and isolated using preparative HPLC (see above). Imine-7 and N-Boc-Imine-7 were dissolved in acetonitrile to an estimated concentration of 5 mM ( Figure 5) and 0.05 mM ( Figure 5, inset). Both solutions were analyzed by UV/Vis (Cary-50 Spectrophotomer). The concentration of Imine-7 and N-Boc- Imine-7 (0.05 mM) is an estimation, and the absorbance signal is lower than would be expected. The low purity of the compounds is likely due to additional salt from HPLC purification and presence of residual t-butanol (confirmed by NMR). Spectral properties were compared to avobenzone in acetonitrile for qualitative purposes only as the extinction coefficient are likely equal to or greater than unfunctionalized avobenzone. The results are shown in Figure 5.
  • Example 5 Synthesis and analysis of sulisobenzone derived imine, Tgase substrate.
  • N-Boc-Imine-8 (0.32 pmol, 1 eq) in DCM (6 mL) is treated with HC1/dioxane (4 M, 737 uL, 5 eq) at 25 °C for 4 hrs. The mixture is concentrated, and Imine-8 is obtained.
  • Imine-8 was prepared directly by reaction of sulisobenzone (1 eq) with 1-6-hexamethylene diamine (1 eq) in refluxing ethanol. UVA and UVB absorption properties.
  • V-Boc-Imine-8 and Imine-8 was synthesized, purified, and isolated (see above). N- Boc-Imine-8 and Imine-8 were dissolved in ethanol to a final concentration of 0.032 mM and 8 mM, respectively ( Figure 6) and analyzed by UV/Vis. (Cary-50 Spectrophotomer).
  • Example 6 Synthesis and analysis of diethylamino hydroxy benzoyl hexyl benzoate derived imine, Tgase substrate.
  • N-Boc-Imine-9 (0.32 pmol, 1 eq) in DCM (6 mL) is treated with HCl/dioxane (4 M, 737 uL, 5 eq) at 25 °C for 4 hrs. The mixture is concentrated, and Imine-9 is obtained.
  • Imine-9 was prepared directly by reaction of DHHB (1 eq) with 1-6- hexamethylene diamine (leq) in refluxing ethanol. Both V-Boc-Imine-9 and Imine-9 result in a red shift of the absorbance spectra, which extends to the visible region (data not shown).
  • Example 7 Synthesis and analysis of oxybenzone imine on a high molecular weight polymer
  • the high molecular weight imine polymer described in this example has an increased absorbance in the UVA range as well as the visible range ( Figure 7) and avoids skin penetration due to its high molecular weight. It is believed that Imine-10 will have water resistant properties owing to the hydrophobic nature of the silicone backbone.
  • UVA and UVB absorption properties are UVA and UVB absorption properties.
  • Imine-10 was first dissolved in methyl tert-butyl ether and then diluted in ethanol to a final concentration of 5 mM and 0.04 mM ( Figure 7) and analyzed by UV/Vis. (Cary-50 Spectrophotomer). Spectral properties were compared to oxybenzone at similar concentration. The results in Figure 7 show that Imine-10 retains absorbance in the UVB region and extended absorbance into the UVA and visible region.
  • Example 8 Covalent addition of sunscreen-linker to peptide.
  • Cbz-Gln-Gly dipeptide 100 pL of 10 g/L stock solution dissolved in 90% acetonitrile in water
  • a solution of wild-type transglutaminase or a variant (SEQ ID NO: 2 and 7) in 0.1 M Tris-HCl pH 8.0, 1 mM EDTA (800 ⁇ L. 0.03 g/L final concentration).
  • To this solution was added the imine products described in Examples 3-6 dissolved in a suitable solvent (100 pL of 10 g/L stock solution dissolved in solvent identified in table 2). The suspensions were incubated at 37 °C overnight with constant agitation.
  • Transglutaminase wild-type or variant catalyzed, covalent addition of the dipeptide to the imine was confirmed by HPLC and LCMS. Conversion of starting material to product was calculated using peak areas. Relative reactivity is calculated by dividing all conversions by the data obtained for the least reactive imine. In the absence of transglutaminase, no covalent addition of the imine to the peptide was observed. Reactivity of the imine was dependent of the imine’s solubility upon addition to the aqueous reaction. The more water-soluble imines afford higher conversion to the imine-peptide product.
  • a sunscreen composition comprising any of the UV filters described herein may be formulated as set forth in Table 3.
  • the below described formulation is suitable for both oil-in-water emulsions and water-in-oil emulsions.
  • Vitro-Skin® N-19 (IMS, Inc.) are hydrated following the manufacturer’s recommendations (16-18 hours at 90-95% relative humidity at room temperature).
  • Vitro-Skin® simulates the properties of composition, wettability, pH, ionic strength, and surface topography of human skin.
  • a measured amount (6-7 mg) of formulation containing an imine or enamine as described herein is applied on pre-hydrated pieces of Vitro-Skin® (28x38 mm) that are mounted in 35 mm slide mounts. The emulsion is carefully spread using a rubber-gloved finger with initial circular and then linear motion for approximately one minute.
  • Samples are then placed in a humidity chamber (90-95% relative humidity at room temperature) for 20 minutes to allow for emulsion coalescence.
  • Four UV spectra are collected per sample in the wavelength range of 250-350 nm using a spectrophotometer. Each spectrum is collected after a 90° rotation of the sample giving four separate area scans for each sample.
  • Samples are scanned against the untreated reference sample in the reference beam of the two-beam spectrophotometer. Absorbance readings are taken at 310 and 291 nm and are labeled as the initial absorbance, Ai. Samples are then immersed in a temperature-controlled water bath (25 ⁇ 0.2°C) for 80 minutes with constant mixing using a paddle type impeller at 50 rpm.
  • the volume of the water bath is large enough (2000 ml) to prevent a high concentration of dispersed sunscreen and possibility of re-adsorption.
  • the samples are taken out of the water, lightly shaken to remove the largest water droplets and are hung in the air in a climate-controlled room at 50% relative humidity for 30 minutes. Afterward, the samples are placed back into the humidity chamber for 120 minutes.
  • Final absorbance readings, Af are taken in the same manner as the initial ones.
  • the percentage of water resistance is calculated as (Af / Al) x 100. Samples are run in quadruplicates giving 32 readings (4 samples x 4 orientations x 2 wavelengths) for each formulation that is tested.
  • each blank control sample (without sunscreen) is treated and is measured in exactly the same way.
  • the control sample is immersed in a separate water bath, to ensure no sunscreen transfer from formulation-treated samples.
  • E. coli BL21(DE3) cells harboring the Tgase expression plasmid were grown in shake flasks, lysed by homogenization, and the Tgase was isolated from the cell debris by centrifugation. The resulting semi-purified enzyme (clarified lysate) was further purified by affinity column on a Ni-IMAC resin prior to dialysis. Purified Tgase was stored at -80 °C.
  • Tgase specific activity was measured in the examples herein using a colorimetric hydroxamate activity assay (Folk and Cole (1965) J Biol Chemistry 240(7):2951-2960). Briefly, the hydroxamate assay uses N-carbobenzoxy-L-glutaminylglycine (Z-Gln-Gly or CBZ-Gln-Gly) as the amine acceptor substrate and hydroxylamine as an amine donor. In the presence of transglutaminase, the hydroxylamine is incorporated to form Z- glutamylhydroxamate-glycine, which develops a colored complex with iron (III), detectable at 525 nm after incubation at 37 °C for 5-60 minutes.
  • Z-Gln-Gly or CBZ-Gln-Gly N-carbobenzoxy-L-glutaminylglycine
  • hydroxylamine is incorporated to form Z- glutamylhydroxamate-glycine,
  • Tgase is defined as the amount of enzyme that catalyzes formation of Ipmol of the peptide derivative of ⁇ -glutamylhydroxylamine per minute.

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Abstract

L'invention concerne des compositions d'écran solaire et des ingrédients actifs d'écran solaire qui comprennent au moins un filtre UV contenant de la cétone et au moins une amine primaire ou secondaire, au moins un filtre UV contenant de la cétone et au moins une amine primaire ou secondaire réagissant pour former un analogue d'imine du filtre UV contenant de la cétone, l'analogue d'imine possédant au moins une propriété choisie dans le groupe constitué par a) est capable d'étendre la protection contre les UV dans une région visible égale ou supérieure à 400 nm, b) est résistant à l'eau, et/ou c) empêche ou diminue la pénétration dans la peau. Cet analogue d'imine peut être modifié avantage en vue de produire un substrat capable de réagir avec la transglutaminase ou toute variante de celle-ci et/ou une lysyl oxydase en vue de lier la composition d'écran solaire ou l'ingrédient actif d'écran solaire à une cible d'intérêt. L'invention concerne également des préparations cosmétiques ou pharmaceutiques comprenant l'une quelconque des compositions d'écran solaire ou des ingrédients d'écran solaire conjointement avec un vecteur cosmétiquement ou pharmaceutiquement acceptable.
PCT/US2022/079573 2021-11-11 2022-11-09 Compositions d'écran solaire comprenant des analogues d'imine d'un écran solaire comprenant une cétone WO2023086839A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0302529A2 (fr) * 1987-08-07 1989-02-08 Fuji Photo Film Co., Ltd. Matériel d'enregistrement contenant un leuco-colorant
US5490980A (en) 1994-09-28 1996-02-13 Chesebrough-Pond's Usa Co., Division Of Conopco, Inc. Covalent bonding of active agents to skin, hair or nails

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0302529A2 (fr) * 1987-08-07 1989-02-08 Fuji Photo Film Co., Ltd. Matériel d'enregistrement contenant un leuco-colorant
US5490980A (en) 1994-09-28 1996-02-13 Chesebrough-Pond's Usa Co., Division Of Conopco, Inc. Covalent bonding of active agents to skin, hair or nails

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"Molecular Cloning, A Laboratory Manual", 1989, COLD SPRING HARBOR PRESS
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CAS , no. 4065-45-6
FOLKCOLE, JBIOL CHEMISTRY, vol. 240, no. 7, 1965, pages 2951 - 2960
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STIEFEL CONSTANZE ET AL: "Reactions of cosmetic UV filters with skin proteins: model studies of ketones with primary amines", TRENDS IN PHOTOCHEMISTRY & PHOTOBIOLOGY, 1 January 2013 (2013-01-01), pages 63 - 75, XP093030554, Retrieved from the Internet <URL:http://www.researchtrends.net/tia/article_pdf.asp?in=0&vn=15&tid=15&aid=5032> [retrieved on 20230310] *

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