阅读说明：本技术 防晒制剂 (Sunscreen formulations ) 是由 孙益民 于 2019-09-10 设计创作，主要内容包括：本发明涉及新型防晒剂的合成,这些防晒剂用于制备旨在减少防晒剂的皮肤渗透的防晒制剂的用途。本发明的全部目的是通过我们新颖的防晒材料和配制技术来提高防晒产品的生物安全性,以减少或消除防晒剂的皮肤渗透。本发明的技术可以应用于化妆品,药品或驱虫剂产品。(The present invention relates to the synthesis of novel sunscreens, the use of these sunscreens for the preparation of sunscreen formulations intended to reduce skin penetration of the sunscreens. It is an overall object of the present invention to improve the biosafety of sunscreen products by our novel sunscreen materials and formulation techniques to reduce or eliminate skin penetration of sunscreens. The technology of the present invention can be applied to cosmetics, pharmaceuticals or insect repellent products.)

1. A sunscreen formulation comprising:

(1) compound a bound to excipient B by a covalent bond; and

(2) a carrier for topical administration, preferably, an aqueous based carrier,

the covalent bond is an ester bond or an amide bond, preferably an amide bond;

the compound A is a sunscreen compound with or derived from at least one hydroxyl, carboxyl or amine group;

said excipient B is selected from polymers and oligomers, preferably water-soluble polymers and oligomers; wherein the molecular weight of each of the polymer and oligomer is preferably 500-.

When said compound a is derivatised with a hydroxyl or amine group, said excipient B is derivatised with a carboxyl functional group;

when said compound a bears or is derivatised with a carboxyl group, said excipient B bears or is derivatised with a hydroxyl or amine functional group; and

the formulation does not contain an effective amount of compound a in free form.

2. Sunscreen preparation according to claim 1, characterized in that the preparation is heterogeneous or homogeneous, preferably homogeneous transparent, more preferably an ointment or a viscous solution.

3. A sunscreen formulation as claimed in claim 1 wherein said sunscreen compound having or to be derivatized with at least one hydroxyl, carboxyl or amine group is selected from avobenzone, cinoxate, dioxobenone, homosalate, amidobenzoate, octocryl, octyl methoxycinnamate, octyl salicylate, oxybenzone, octyl dimethylaminobenzoate, sulisobenzone, triethanolamine salicylate or combinations thereof.

4. Sunscreen preparation according to claim 1, characterized in that excipient B is selected from polyacrylic acid, polyvinyl alcohol, polyethyleneimine, polyallylamine and polyvinylamine, and combinations thereof, preferably polyacrylic acid and polyethyleneimine.

5. The sunscreen formulation according to claim 1, comprising a molar equivalent of compound a in free form of less than 20%, preferably less than 10%, more preferably less than 5%, particularly preferably less than 1%, relative to the molar amount of compound a covalently bound to the excipient B.

6. Sunscreen formulation according to claim 1, characterized in that the sunscreen compound to be derivatized by carboxyl groups is selected from avobenzone, cinoxate, dioxobenone, homosalate, aminobenzamide, octocrynine, octyl methoxycinnamate, octyl salicylate, oxybenzone, octyl dimethylaminobenzoate, sulfoisobenzone, triethanolamine salicylate or combinations thereof and the derivatized sunscreen compound has the following formula (I):

n is 0 to 18, preferably 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl of formula (II)]-phenoxy } -butyric acid:

or 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -phenoxy } -butyric acid of formula (III) below:

7. a sunscreen formulation as claimed in claim 1 wherein said amine-derived sunscreen compound is selected from the group consisting of avobenzone, cinoxate, dioxobenone, homosalate, aminobenzamide, octocrynine, octyl methoxycinnamate, octyl salicylate, oxybenzone, octyl dicarbamate, sulisobenzone, triethanolamine salicylate, or combinations thereof and the derived sunscreen compound may have the following formula (IV):

n-0-18, preferably 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl of formula (V) below]-3- (4-tert-butyl-phenyl) propane-1, 3-dione:

or (4-aminomethoxy-2-hydroxy-phenyl) phenyl-methanone of formula (VI):

8. sunscreen preparation according to claim 1, characterized in that excipient B is a partially esterified polyacrylic acid, preferably partially esterified with at least one of C1-C6 lower alcohols, more preferably methanol and/or propanol, in a molar amount of less than 95%, preferably 5-80%, more preferably 20-50% of the carboxylic acid groups of the polyacrylic acid to be esterified.

9. The sunscreen formulation of claim 1 wherein said covalent bond is an ester bond and compound a covalently bound to excipient B is

The excipient B is a random copolymer of three monomers, m, n and p in the formula VII are respectively the mole numbers of corresponding monomer units, m/(m + n + p) is preferably 20-50%, n/(m + n + p) is preferably 2-30%, more preferably 5-20%, and p/(m + n + p) is preferably 40-70%, or

Wherein the excipient B is a random copolymer of four monomers, m, n, o and p in formula VIII are respectively the number of moles of the corresponding monomer unit, wherein m/(m + n + o + p) is preferably 10% to 25%, n/(m + n + o + p) is preferably 2% to 30%, most preferably 5% to 20%, o/(m + n + o + p) is preferably 40% to 70%, and p/(m + n + o + p) is preferably 10% to 25%.

10. Sunscreen formulation according to claim 1, characterized in that the covalent bond is an amide bond and compound a, which is covalently bound to excipient B, is selected from at least one of the following compounds:

wherein the excipient B is a random copolymer of four monomers, m, n, o and p are each the number of moles of the corresponding monomer unit, m/(m + n + o + p) is preferably 10% to 25%, n/(m + n + o + p) is preferably 2% to 30%, most preferably 5% to 20%, o/(m + n + o + p) is preferably 40% to 70%, and p/(m + n + o + p) is preferably 10% to 25%,

11. a method of protecting skin from ultraviolet radiation comprising applying the formulation of claim 1 to skin in need thereof.

12. A method of making the formulation of claim 1, comprising: heating no more than, preferably 5-60% (w/w), more preferably 10-50% (w/w), most preferably 15-40% (w/w) of compound a based on the total weight of compound a and excipient B to react with excipient B at a temperature ranging from ambient temperature to 80 ℃ for 5 to 12 hours to obtain compound a covalently bound to excipient B; and

compound a covalently bound to excipient B is formulated with a carrier.

13. The method of claim 12, further comprising mixing compound a covalently bound to excipient B with an amount of excipient B polymer that is not covalently bound to compound a.

14. A sunscreen compound having a covalent amide or ester linkage having one of the following formulas:

wherein the polymer units in each formula are random copolymer units of three or four monomers, m, n, o and p are each the molar number of the corresponding monomer unit, m/(m + n + o + p) is preferably 10% to 25%, n/(m + n + o + p) is preferably 2% to 30%, most preferably 5% to 20%, o/(m + n + o + p) is preferably 40% to 70%, and p/(m + n + o + p) is preferably 10% to 25%

Wherein the molecular weight of each of the polymers and oligomers in the above formula is preferably 500-.

1. Field of the invention

The present invention relates to the synthesis of UV blockers and UV blocker sunscreen formulation materials that make sunscreen formulations that minimize skin penetration of UV blockers used to protect human skin from the sun's UV radiation.

2. Description of the Prior Art

Since the 30 s of the 20 th century, sunscreens have been used to prevent diseases caused by the sun. Electricity emitted by the sunThere are several types of magnetic radiation. Ultraviolet (UV) radiation is one type. Based on the characteristics of ultraviolet light interacting with human skin, it is divided into three bands based on wavelength: UVA radiation (320-400nm), UVB radiation (290-320nm) and UVC radiation (100-290 nm). UVA radiation constitutes 95% of all ultraviolet radiation emitted by the sun and reaching the earth's surface. UVA exposure is generally kept constant throughout the day and four seasons, whereas UVB exposure occurs more at noon and summer and UVC is almost completely replaced by O₃Absorb without ever reaching the earth's surface. UVA penetrates deeper into the human skin and causes damage and cancer under the skin, while UVB causes pigmentation, sunburn, and carcinogenesis. Currently, two sunscreens (UV filters) are used in sunblocks in order to minimize these adverse effects: 1. organic (chemical) filters, such as avobenzone, oxybenzone (benzophenone-3, bp-3) or octocrynine, etc.; 2. inorganic (physical) filtering agent, zinc oxide (ZnO) and titanium dioxide (TiO)₂). The organic filter absorbs ultraviolet rays, while the inorganic filter scatters/reflects ultraviolet rays to prevent ultraviolet rays from contacting. To cover the entire UV radiation band UVA and UVB, sunscreens are generally composed of two or more of these UV filters: organic, inorganic, or a combination of the two types to provide broad spectrum protection. In addition to their controversial efficacy, problems have been raised in recent years with respect to the main components of different sunscreen agents, in particular with respect to the incidence of the potential toxicity of these components to human health.

Contact with sunscreen has begun since the first day of sunscreen use in the 30's of the 20 th century. Initially, the range and frequency of use of sunscreens in the human population was very limited. Thus, the level of uv filters found in human samples is generally low. However, over the past 20 years, the situation has changed dramatically. In an epidemiological study conducted in 2003-2004, 2517 urine samples from the general population in the United States were analyzed for the presence of oxybenzone (benzophenone-3, bp-3) as part of the National Health and nutrition test Survey in 2003-2004 [ A.M.Calafat, L.Y.Wong, X.YE, J.A.Reidy, L.L.Needham, Concentrations of the Sunscreant benzophenone-3in resistances of the United States: National Health and nutrition evaluation Survey 2003-2004, environ.health Perpect, 116(2008)893-897 ]. Oxybenzone was detected in 97% of the samples at an average concentration of 22.9ng/mL and a 95 th percentile concentration of 1040 ng/mL. As the data show, the range of sunscreen agents that occur is broad. Another study was subsequently conducted with an emphasis on the correlation between the gender ratios of uretophenone-type UV filters and their progeny among Couples, bp-3 being the most prominent of the study population, and the average concentration of these UV absorber compounds ranged from 0.05ng/ml to 8.65ng/ml (samples collected 2005-2009 in Michigan and Texas) [ J.Bae, S.Kim, K.Kannan, G.M.Buck Louis, coupling's url concentration of benzophenone-type ultraviolet filters and the second data set ratio, Sci.total environ.543(2016)28-36 ]. In 2007-2009, a study conducted on female subjects in california showed a very surprising finding. The level of oxybenzophenone found in urine samples collected from women in california in 2009 in 2007-2009 was about 9-fold higher (up to 13000ng/ml, with an average of about 200ng/ml), a result that may be a result of specific demographics [ c.philippiat, d.bennett, a.m.calcium, i.h.piciotto, Exposure to selected dyes and phenols through use of personal care products of amongg california additives and childern, environ.res.140(2015) -376 ]. The average oxybenzophenone concentration in the urine samples increased by more than 9-fold from 22.9ng/mL to 200ng/mL compared to the 2003-2004 study. This is a surprising development.

Experimental studies confirm the extensive absorption and distribution of organic filters, while inorganic filters appear to minimally penetrate human skin. A sunscreen preparation containing 10% oxybenzone, 4-methylbenzylidene camphor (4-MBC) and Octyl Methoxycinnamate (OMC) is used daily for one week (2 mg/cm) by adult²) The mean urine concentrations of these components are 60, 5ng/mL for women, 140, 7, 8ng/mL for men [19N.R.Janjua, B.Mogensen, A.M.Andersson, J.H.Petersen, M.Henriksen, N.E.Skakeback, H.C.Wulf, systematic Absorption of the Sunscreens Benzophenone-3, Octyl-Methoxycinnamate, and 3- (4-Met-toluene-3, respectivelyhyl-Benzylidene)Camphor After Whole-Body Topical Application and Reproductive Hormone Levels in Humans,J.Invest.Dermatol.,123(2004)57-61]. At the same time, the maximum plasma concentrations of these components were reached 3-4 hours after administration, 200, 20, 10ng/mL for women and 300, 20, 2ng/mL for men, respectively. Similar findings were reported after 4 days of exposure to these components, which were detectable in the plasma of human males and females only 2 hours after administration [20n.r.janjua, b.kongshoj, a.m.andersson, h.c.wulf, Sunscreens in human plasma and urea after treated human-body topical application, j.eur.Dermatol.Venererol.22(2008)456 461-]. More data on human skin penetration and distribution of organic and inorganic uv filters can be found in recent reviews. [21J.Rodriguez, H.I.Maibach, Percutaneous specificity and pharmacodynamics: Wash-in and Wash-off of sucrose and extract, J.Dermatolog.treatment,27(2016) 11-18; 22, B.Gulson, M.J.Mccall, D.M.Bowman, T.Pinheiro, A review of critical factors for assessing the need for metal oxide nanoparticles applied to humans, and a research strand to address current defects arm. Toxicol.89(2015)1909 and 1930; 15, H.Gonzalez, Percutaneous adsorption with emophilis on succinreens, Photochem.Photobiol.Sci.,9(2010)482-488]。

Importantly, some uv filters were also found in human milk samples. In a cohort study from 2004 to 2006, 54 human milk samples were analyzed. Uv filters were detected in 46 samples at levels that correlated positively with the reported usage of uv filter products [23m.schlumpf, k.kypke, m.wittastek, j.anger, h.masscher, d.masscher, C.M.Birchler，W.Lichtensteiger，Exposure patterns of UV filters,fragrances,parabens,phthalates,organochlor pesticides,PBDEs,and PCBs in human milk:Correlation of UV filters with use of cosmetics,Chemosphere,8(2010)1171-1183]。

In other studies, bp-3 levels in maternal urine samples taken at 6-30 weeks gestation positively correlated with the overall weight and head circumference of the infant [24c. philippipat, m. mortamais, c. chevrier, c. petit, AMCalafat, YEX, MJSilva, c. brambilla, i.pin, machares, s.cordier, r.slama, Exposure to metals and phenols during prediction and printing size at birthday, environ. health Persport, 120(2012)464- ]. These reports raise concerns about the potential prenatal exposure and developmental toxicity of uv filters.

While all of the data show that exposure to sunscreen by use of sunscreen products is very common and is a very common situation, there has been little research in improving the biosafety of sunscreen products by reducing or completely eliminating such exposure, as is the case with prior formulation technology.

Our prior PCT patent application PCT/CN2018/11181 has reviewed the development of sunscreen products and has made comprehensive comments on the wide range of biohazards that sunscreens pose to humans and the environment. PCT/CN2018/11181 reports a separate study aimed at minimizing the biohazard caused by sunscreens by reducing their skin penetration through formulation technology. The preparation technology can reduce the skin penetration of the sunscreen preparation by 5 times on average and 9 times optimally through a specific preparation.

09/05/2019, CNN reported that drug evaluation and research center, as a branch of the united states drug and food administration (FDA), initiated experimental studies related to the biological safety of existing sunscreen products in the market. The study found that it was startling and triggered a government safety survey. It has been found that several common sunscreen ingredients can be administered into the blood only one day, at levels high enough to be FDA critical. A study published in JAMA, a medical journal, 05 and 06, 2019, also found that the blood concentrations of the three components increased continuously with daily use and were present in the body for at least 24 hours after the sunscreen application was finished.

Background

Disclosure of Invention

A first aspect of the present application is a sunscreen formulation comprising:

(1) compound a bound to excipient B by a covalent bond; and

(2) a carrier for topical administration, preferably an aqueous based carrier.

The covalent bond is an ester bond or an amide bond, preferably an amide bond. Compound a is a sunscreen compound with or derivatized with at least one hydroxyl, carboxyl, or amine group. The excipient B is selected from polymers and oligomers, preferably water-soluble polymers and oligomers. The molecular weight of each of the polymer and oligomer is preferably 500-. When said compound a is derivatised with a hydroxyl or amine group, said excipient B is derivatised with a carboxyl functional group. When said compound a bears or is derivatised with a carboxyl group, said excipient B bears or is derivatised with a hydroxyl or amine functional group. The formulation does not contain an effective amount of compound a in free form. One excipient molecule may be bonded to multiple sunscreen molecules (of the same type or different types that block different UV bands) through multiple ester or amide covalent bonds.

The formulations may be heterogeneous or homogeneous, preferably homogeneous transparent, more preferably ointments or viscous solutions. The formulation may be aqueous or non-aqueous, preferably aqueous. In some cases, non-aqueous formulations may be advantageous when the formulation needs to be water resistant.

The sunscreen compound with or to be derivatized by at least one hydroxyl, carboxyl or amine group may be selected from avobenzone, cinoxate, dioxobenzoate, homosalate, amidoamine aminobenzoate, oxclinine, octyl methoxycinnamate, octyl salicylate, oxybenzone, octyl dimethylaminobenzoate (padimate O), sulisobenzone, triethanolamine salicylate, or combinations thereof.

The excipient B may be selected from polyacrylic acid, polyvinyl alcohol, polyethyleneimine, polyallylamine and polyvinylamine, and combinations thereof, preferably polyacrylic acid and polyethyleneimine.

The sunscreen formulation comprises a molar equivalent of compound a in free form of less than 20%, preferably less than 10%, more preferably less than 5%, and especially preferably less than 1%, relative to the molar amount of compound a covalently bound to said excipient B.

The sunscreen compound to be derivatized by carboxyl groups may be selected from avobenzone, cinoxate, dioxobenone, homosalate, amidobenzoate, oxclinine, octyl methoxycinnamate, octyl salicylate, oxybenzone, octyl dimethylaminobenzoate, sulisobenzone, triethanolamine salicylate, or combinations thereof, and the derivatized sunscreen compound has the following formula (I):

n is 0 to 18, preferably 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl of formula (II)]-phenoxy } -butyric acid:

or 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -phenoxy } -butyric acid of formula (III) below:

the amine-derived sunscreen compound may be selected from the group consisting of avobenzone, cinoxate, dioxobenone, homosalate, aminobenzamide, oxkrine, octyl methoxycinnamate, octyl salicylate, oxybenzone, octyl dimethylaminobenzoate (padimate O), sulisobenzone, triethanolamine salicylate, or combinations thereof, and the derived sunscreen compound may have the following structure of formula (IV):

n-0-18, preferably 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl of formula (V) below]-3- (4-tert-butyl-phenyl) propane-1, 3-dione:

or (4-aminomethoxy-2-hydroxy-phenyl) phenyl methanone of formula (VI):

the excipient B may be a partially esterified polyacrylic acid, preferably partially esterified with at least one C1-C6 lower alcohol, more preferably methanol and/or propanol, in a molar amount of less than 95%, preferably 5-80%, more preferably 20-50% of the carboxylic acid groups of the polyacrylic acid to be esterified.

The covalent bond may be an ester bond, and the compound A covalently bound to excipient B is

Excipient B may be a random copolymer of three monomers, m, n and p in formula VII are respectively the number of moles of the corresponding monomer unit, m/(m + n + p) is preferably 20% to 50%, n/(m + n + p) is preferably 2% to 30%, more preferably 5% to 20%, p/(m + n + p) is preferably 40% to 70%, or

Wherein excipient B is a random copolymer of four monomers, m, n, o and p in formula VIII are respectively the mole numbers of the corresponding monomer units, wherein m/(m + n + o + p) is preferably 10% to 25%, n/(m + n + o + p) is preferably 2% to 30%, most preferably 5% to 20%, o/(m + n + o + p) is preferably 40% to 70%, and p/(m + n + o + p) is preferably 10% to 25%.

The covalent bond may be an amide bond, and compound a covalently bound to excipient B may be selected from at least one of the following compounds:

wherein excipient B is a random copolymer of four monomers, m, n, o and p are each the number of moles of the corresponding monomer unit, m/(m + n + o + p) is preferably 10% to 25%, n/(m + n + o + p) is preferably 2% to 30%, most preferably 5% to 20%, o/(m + n + o + p) is preferably 40% to 70%, and p/(m + n + o + p) is preferably 10% to 25%,

a second aspect of the present application is a method of protecting skin from ultraviolet radiation comprising applying the above formulation to the skin in need thereof.

A third aspect of the present application is a method of preparing the above formulation, comprising: heating no more than (i.e., equal to or less than), preferably 5% -60% (w/w), more preferably 10% -50% (w/w), most preferably 15% -40% (w/w) of compound a to excipient B at a temperature ranging from ambient temperature to (e.g., 20-25 ℃) to 80 ℃ for 5 to 12 hours to react with excipient B, based on the total weight of compound a and excipient B, to give compound a covalently bound to excipient B; compound a covalently bound to excipient B is formulated with a carrier. Preferably, the method comprises the steps of: compound a, covalently bound to excipient B, is mixed with an amount of excipient B polymer that is not covalently bound to compound a. For example, the amount of excipient B polymer not covalently bound to Compound A may be from 5% to 50% (w/w), preferably from 5% to 20% (w/w), relative to the weight of the material of excipient B covalently bound to Compound A. Alternatively, the sunscreen agent is first bound to the corresponding monomer, and then the monomer bound to the sunscreen agent is copolymerized with the underivatized monomer to yield compound a covalently bound to excipient B.

A fourth aspect of the present application is a sunscreen compound having a covalent amide or ester linkage having one of the following formulas:

wherein the polymer units in each formula are random copolymer units of three or four monomers, m, n, o and p are each the molar number of the corresponding monomer unit, m/(m + n + o + p) is preferably 10% to 25%, n/(m + n + o + p) is preferably 2% to 30%, most preferably 5% to 20%, o/(m + n + o + p) is preferably 40% to 70%, and p/(m + n + o + p) is preferably 10% to 25%

Wherein the molecular weight of each of the polymers and oligomers in the above formula is preferably 500-.

Drawings

FIG. 1 shows the results of skin permeation tests of oxybenzone-PAA-OMe (50) mice of example 22.

Figure 2 shows the results of the mouse skin penetration test of the oxybenzophenone suberate formulation of example 23.

FIG. 3 shows the results of skin permeation tests of mice with the [4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid-PEI preparation of example 24.

FIG. 4 shows an HPLC chromatogram of [4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid Std (0.5mg/mL) of example 24.

FIG. 5 shows an HPLC chromatogram of a test sample of the [4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid-PEI preparation of example 24.

FIG. 6 shows an HPLC chromatogram of (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone API Std (0.5mg/mL) of example 25. NW 1701-163.

Figure 7 shows an HPLC chromatogram of a plasma blank of example 25. NW 1701-163.

FIG. 8 shows an HPLC chromatogram of a test sample (10mg/mL) of the (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40) formulation of example 25. NW1701-163

FIG. 9 shows an HPLC chromatogram of a test sample (20mg/mL) + plasma of the (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40) formulation of example 25. NW1701-163

FIG. 10 shows an HPLC chromatogram of a plasma sample of the (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40) formulation of example 25 at 5 min. NW1701-163

FIG. 11 shows an HPLC chromatogram of a plasma sample of the (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40) formulation of example 25 at 15 min. NW1701-163

FIG. 12 shows an HPLC chromatogram of a plasma sample of the (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40) formulation of example 25 at 30 min. NW1701-163

FIG. 13 shows an HPLC chromatogram of a plasma sample of the (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40) formulation of example 25 at 60 min. NW1701-163

FIG. 14 shows an HPLC chromatogram of a plasma sample of the (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40) formulation of example 25 at 90 min. NW1701-163

FIG. 15 shows an HPLC chromatogram of a plasma sample of the (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40) formulation of example 25 at 120 min. NW1701-163

Figure 16 shows an HPLC chromatogram of a plasma blank of example 26. NW1701-164

FIG. 17 shows an HPLC chromatogram of 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) propane-1, 3-dione API Std (0.5mg/mL) of example 26. In (1). NW1701-164

FIG. 18 shows an HPLC chromatogram of 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) propane-1, 3-dione API Std (0.5mg/mL) + plasma of example 26. NW1701-164

FIG. 19 shows an HPLC chromatogram of a test sample (10mg/mL) of the 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione-PAA-OMe-OPr (40) formulation of example 26. NW1701-164

FIG. 20 shows an HPLC chromatogram of a test sample (10mg/mL) + plasma of 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione-PAA-OMe-OPr (40) formulation of example 26. NW1701-164

FIG. 21 shows an HPLC chromatogram of a plasma sample of the 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione-PAA-OMe-OPr (40) formulation of example 26 at 5 min. NW1701-164

FIG. 22 shows an HPLC chromatogram of a plasma sample of the 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione-PAA-OMe-OPr (40) formulation of example 26 at 15 min. NW1701-164

FIG. 23 shows an HPLC chromatogram of a plasma sample of the 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione-PAA-OMe-OPr (40) formulation of example 26 at 30 min. NW1701-164

FIG. 24 shows an HPLC chromatogram of a plasma sample of the 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione-PAA-OMe-OPr (40) formulation of example 26 at 60 min. NW1701-164

FIG. 25 shows an HPLC chromatogram of a plasma sample of the 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione-PAA-OMe-OPr (40) formulation of example 26 at 90 min. NW1701-164

FIG. 26 shows an HPLC chromatogram of a plasma sample of the 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione-PAA-OMe-OPr (40) formulation of example 26 at 120 min. NW1701-164

Figure 27 shows an HPLC chromatogram of a plasma blank of example 27. NW1701-147

FIG. 28 shows an HPLC chromatogram of (4-benzoyl-3-hydroxy-phenoxy) -acetic acid API Std (0.5mg/mL) of example 27. NW1701-147

FIG. 29 shows an HPLC chromatogram of a test sample (10mg/mL) of the (4-benzoyl-3-hydroxy-phenoxy) -acetic acid PEI preparation of example 27. NW1701-147

FIG. 30 shows an HPLC chromatogram of a test sample (10mg/mL) + plasma of (4-benzoyl-3-hydroxy-phenoxy) -acetic acid PEI preparation of example 27. NW1701-147

FIG. 31 shows an HPLC chromatogram of a sample of plasma of the (4-benzoyl-3-hydroxy-phenoxy) -acetic acid PEI preparation of example 27 at 5 min. NW1701-147

FIG. 32 shows an HPLC chromatogram of a plasma sample of the (4-benzoyl-3-hydroxy-phenoxy) -acetic acid PEI preparation of example 27 at 15 min. NW1701-147

FIG. 33 shows an HPLC chromatogram of a sample of plasma of the (4-benzoyl-3-hydroxy-phenoxy) -acetic acid PEI preparation of example 27 at 30 min. NW1701-147

FIG. 34 shows an HPLC chromatogram of a plasma sample of the (4-benzoyl-3-hydroxy-phenoxy) -acetic acid PEI preparation of example 27 at 60 min. NW1701-147

FIG. 35 shows an HPLC chromatogram of a sample of plasma of the (4-benzoyl-3-hydroxy-phenoxy) -acetic acid PEI preparation of example 27 at 90 min. NW1701-147

FIG. 36 shows an HPLC chromatogram of a plasma sample of the (4-benzoyl-3-hydroxy-phenoxy) -acetic acid PEI preparation of example 27 at 120 min. NW1701-147

Figure 37 shows an HPLC chromatogram of a plasma blank of example 28. NW1701-161

FIG. 38 shows an HPLC chromatogram of {4- [3- (4-tert-butyl-phenyl) -3-oxopropanoyl ] -3-hydroxy-phenoxy } -butyric acid API Std (0.5mg/mL) of example 28. NW1701-161

FIG. 39 shows an HPLC chromatogram of {4- [3- (4-tert-butyl-phenyl) -3-oxopropanoyl ] -3-hydroxy-phenoxy } -butyric acid API Std (0.5mg/mL) + plasma of example 28. NW1701-161

FIG. 40 shows an HPLC chromatogram of a test sample of {4- [3- (4-tert-butyl-phenyl) -3-oxopropanoyl ] -3-hydroxy-phenoxy } -butyric acid-PEI (10mg/mL) preparation of example 28. NW1701-161

FIG. 41 shows an HPLC chromatogram of test sample + plasma of {4- [3- (4-tert-butyl-phenyl) -3-oxopropanoyl ] -3-hydroxy-phenoxy } -butyric acid-PEI (20mg/mL) formulation of example 28. NW1701-161

FIG. 42 shows an HPLC chromatogram of a plasma sample of {4- [3- (4-tert-butyl-phenyl) -3-oxopropanoyl ] -3-hydroxy-phenoxy } -butyric acid-PEI formulation of example 28 at 5 min. NW1701-161

FIG. 43 shows an HPLC chromatogram of a plasma sample of {4- [3- (4-tert-butyl-phenyl) -3-oxopropanoyl ] -3-hydroxy-phenoxy } -butyric acid-PEI formulation of example 28 at 15 min. NW1701-161

FIG. 44 shows an HPLC chromatogram of a plasma sample of {4- [3- (4-tert-butyl-phenyl) -3-oxopropanoyl ] -3-hydroxy-phenoxy } -butyric acid-PEI formulation of example 28 at 30 min. NW1701-161

FIG. 45 shows an HPLC chromatogram of a plasma sample of {4- [3- (4-tert-butyl-phenyl) -3-oxopropanoyl ] -3-hydroxy-phenoxy } -butyric acid-PEI formulation of example 28 at 60 min. NW1701-161

FIG. 46 shows an HPLC chromatogram of a plasma sample of {4- [3- (4-tert-butyl-phenyl) -3-oxopropanoyl ] -3-hydroxy-phenoxy } -butyric acid-PEI formulation of example 28 at 90 min. NW1701-161

FIG. 47 shows an HPLC chromatogram of a plasma sample of {4- [3- (4-tert-butyl-phenyl) -3-oxopropanoyl ] -3-hydroxy-phenoxy } -butyric acid-PEI formulation of example 28 at 120 min. NW1701-161

Detailed Description

The following examples are intended to illustrate the invention without limiting it.

Novel organic sunscreens with specifically designed functions were synthesized for formulation purposes.

New sunscreen agents or existing sunscreen agents having specific functional groups are reacted with cosmetic excipients, particularly oligomers, polymers and organic molecules, to form chemical covalent bonds between the sunscreen agent and the excipient molecules.

Reacting a sunscreen agent having-OH groups with a cosmetic vehicle, particularly an oligomer, a polymer bearing carboxyl groups and an organic molecule bearing carboxyl groups to form covalent ester linkages between the sunscreen agent and vehicle molecules.

Reacting a sunscreen agent having a carboxyl group with a cosmetic vehicle, in particular an oligomer, a polymer bearing-OH groups and an organic molecule bearing-OH groups to form covalent ester linkages between the sunscreen agent and the vehicle molecule.

Reacting a sunscreen agent having COOH groups with a cosmetic vehicle, in particular oligomers and polymers having primary/secondary amine groups and organic molecules having primary/secondary amine groups, to form covalent amide bonds between the sunscreen agent and vehicle molecules.

The sunscreen agents having amine groups are reacted with cosmetic excipients, in particular oligomers and polymers having COOH groups and organic molecules having COOH groups, to form covalent amide bonds between the sunscreen agent and the excipient molecules.

Formulation protocols have been developed using materials prepared from excipients as simple organic compounds, oligomers or polymers covalently bonded to sunscreen agents. Covalent bonds are designed to include ester or amide bonds, intended to reduce/eliminate skin penetration of the sunscreen.

The present invention relates to the preparation and novel formulation techniques of sunscreen materials that reduce the skin penetration of sunscreens to enhance the biosafety of sunscreen products or completely block the skin penetration of sunscreens to render sunscreen products completely biosafety.

The present inventors have conducted intensive studies to develop new active sunscreens with specifically designed functional groups to prepare sunscreen materials with excipients covalently bound to the sunscreen, and formulations for these sunscreen materials that will reduce or preferably eliminate the skin penetration of the sunscreen to ultimately improve the biosafety of the sunscreen product.

It was therefore an object of the present invention to provide a synthesis of sunscreens having a carboxyl function-COOH, which is specifically designed for the preparation of materials for sunscreen preparations.

It is therefore an object of the present invention to provide a process for the synthesis of-NH-bearing amine functions₂The sunscreen agent of (1), which is specifically designed for preparing a sunscreen preparation material.

It is another object of the present invention to provide a sunscreen formulation material that synthesizes an excipient wherein an excipient having a carboxyl functional group is covalently bonded via an ester linkage to a sunscreen having a hydroxyl functional group-OH.

Another object of the present invention is to provide a sunscreen preparation material for the synthesis of an excipient wherein an excipient having an-OH functional group is covalently bonded via an ester bond to a sunscreen agent having a carboxyl functional group-COOH.

In one aspect of the invention, sunscreen formulation materials are provided that synthesize an excipient having a carboxyl functional group with an amine functional group-NH₂The sunscreen agent is bonded through amido bonds, the final aim is to improve the biological safety of the sunscreen product, and the skin penetration of the sunscreen agent is reduced or prevented.

In another aspect of the invention, sunscreen formulation materials are provided which synthesize an excipient having primary/secondary amine functional groups-NH₂the/NH excipient is covalently bound to the sunscreen agent having a carboxyl function-COOH via an amide bond, with the ultimate goal of increasing the biosafety of the sunscreen product, reducing or preventing skin penetration of the sunscreen agent.

In yet another aspect of the invention, a formulation scheme is provided which uses sunscreen formulation materials of the excipient wherein the excipient is covalently bonded to the sunscreen via an ester or amide linkage to reduce or prevent skin penetration of the sunscreen with the ultimate goal of increasing the biosafety of the sunscreen product.

Examples

The invention is illustrated herein by experiments described in the following examples, which should not be construed as limiting. Those skilled in the art will appreciate that the present invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will fully convey the invention to those skilled in the art. Many modifications and other embodiments of the invention will come to mind to one skilled in the art to which this invention pertains having the benefit of the teachings presented in the foregoing descriptions. Although specific terms are employed, they are used as is in the art unless otherwise indicated.

Example 1

Synthesis of 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -phenoxy } -butyric acid

Synthetic schemes

Synthesis of intermediate Compound 1

Avobenzone (5.0g) was dissolved in acetic acid (50 mL). To the solution was added 48% HBr solution (20 mL). The mixture was stirred and refluxed for 16 hours under nitrogen. After the reaction solution was concentrated, saturated brine (100mL) was added to quench the reaction. The product was extracted with ethyl acetate (EtAc) (30mL X3). With Na₂SO₄The ethyl acetate extract was dried. Na was filtered off₂SO₄And the solution was concentrated. Using a mixture of hexane: column purification was performed with ethyl acetate (5:1) as eluent to give compound 1(13.0g) as a colorless solid. The yield was 62.9%

Synthesis of intermediate Compound 2

Compound 1(2.0g) and ethyl 4-bromobutyrate (1.34g) were dissolved in DMF (15 mL). Adding K₂CO₃(1.4g) and the mixture was stirred under N₂Stirred at 60 ℃ for 5 hours. The reaction was quenched by addition of water (50 mL). The solid was filtered and collected. The solid was purified using the eluent hexane ethyl acetate (10: 1). Compound 2 was obtained in 87% yield as a colorless solid (2.4 g).

Synthesis of 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -3-hydroxy-phenoxy } -butyric acid

Compound 2(2.0g) was dissolved in ethanol (20 mL). NaOH (0.39g) and water (12mL) were added. The mixture was stirred at ambient temperature for 12 hours. The reaction mixture is concentrated by removing the organic volatile solvent. The pH was adjusted to 4-5 by addition of 2N HCl. A large amount of solids is produced. Filter and wash the solid with water. After drying, the product was obtained as a pale yellow solid (1.8g) with a yield of 97%.

Example 2

Synthesis of 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione

Synthetic schemes

Synthesis of intermediate Compound 3

Reacting 4- {4- [3- [4- (tert-butyl-phenyl) -3-oxo-propionyl]-phenoxy } -butyric acid (1.0g) was dissolved in^tBuOH (10 mL). TEA (0.53g) and DPPA (1.4g) were added. The mixture was stirred and refluxed for 5 hours. The reaction mixture was concentrated and purified by column chromatography with hexane: ethyl acetate (5: 1). A pale yellow oily substance (1.1g) was obtained in a yield of 93%.

Synthesis of 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione

Compound 3(1.0g) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (5mL) was added to the solution. The mixture was stirred at ambient temperature for 12 hours. After the reaction solution was concentrated, saturated Na was added₂CO₃To adjust the pHThe pitch is about 8. The product was extracted with ethyl acetate and Na₂SO₄The ethyl acetate extract solution was dried. Na was filtered off₂SO₄And concentrating the filtrate. Column purification gave the product as a pale yellow solid (0.6 g). The yield was 77%.

Example 3

Synthesis of 4- {4- [4, 6-bis- (4-methoxy-phenyl) - [1,3,5] triazin-2-yl ] -phenoxy } -butyric acid

The synthesis scheme is as follows:

4- {4- [4, 6-bis- (4-methoxy-phenyl) - [1,3,5] triazin-2-yl ] -phenoxy } -butyric acid

Synthesis of intermediate Compound 4

4-Hydroxybenzonitrile (2.0g) was dissolved in dichloromethane (20 mL). Cooling it to below 0 ℃ and keeping it at N₂Under drop CF₃SO₃H (7.5 g). CF after addition₃SO₃After H, heat to ambient temperature and stir the mixture for 12 hours. The solvent was removed and then ice water (50mL) was added. Many colorless solids were produced. By NH₄OH adjusts the pH between 4 and 5 and the solid is filtered off. The solid was washed with copious amounts of water. After drying, a colorless solid (1.92g) was obtained, intermediate compound 4, in 96% yield.

Synthesis of intermediate Compound 5

The compound ethyl 4, 4-bromobutyrate (0.864g) and K were reacted₂CO₃Dissolved in DMF (20 mL). The mixture was stirred at 40 ℃ for 8 hours. The reaction mixture was poured into water (50 mL). The product was extracted with a large amount of ethyl acetate. The ethyl acetate solution was washed with Na₂SO₄And (5) drying. Filtering and concentrating the extract. Column purification yielded a yellow solid, intermediate compound 5, in 48% yield.

Synthesis of intermediate Compound 6

Mixing Compound 5(1.0g), K₂CO₃(1.2g) was dissolved in acetone (10 mL). Addition of Me with stirring at ambient temperature₂SO₄(1.07 g). After the addition was complete, the reaction mixture was refluxed at 60 ℃ and stirred for 8 hours. The reaction mixture was poured into water (50 mL). The product was extracted with ethyl acetate (30mL X2). With Na₂SO₄Dry, filter and concentrate the filtrate. Column purification afforded compound 6(0.8g) as a pale yellow solid in 75% yield.

Synthesis of 4- {4- [4, 6-bis- (4-methoxy-phenyl) - [1,3,5] triazin-2-yl ] -phenoxy } -butyric acid

Compound 6(0.72g) was dissolved in ethanol (10 mL). NaOH (0.115g) and water (7mL) were added. The mixture was stirred at ambient temperature for 8 hours. The reaction mixture is concentrated by removing the organic volatile solvent. The pH was adjusted to 4-5 by addition of 3N HCl. A large amount of solids is produced. Filter and wash the solid with water. After drying, the product was obtained as a pale yellow solid (0.680g) with a yield of 100%.

Example 4

Preparation of oxybenzone-PAA-OMe (50) material

Note: (oxybenzophenone-PAA-OMe (50) ═ 50 means that 50% of the-COOH groups of PAA are randomly terminated by-OMe)

With 50% methyl ester [ PAA-OMe (50)]Synthesis of modified polyacrylic acid (PAA): PAA solid 4.42g (-COOH mole number 4.42/72 ═ 61.30mmol) was taken, MeOH-80 mL was added, and completely dissolved. At 0 deg.C, 2.25mL SOCl was added₂(0.0613x50％x118.97/1.63＝224mL) and 4 drops of DMF. Stirring was carried out at 0 ℃ for 30 minutes. Heat to ambient temperature and stir for 12 hours. Excess MeOH was removed in vacuo to yield 5.35g of a solid. PAA-OMe (50) was extracted with 50mL of ethyl acetate. The precipitate (0.36g) was separated and part of the solvent was removed to give a concentrated PAA-OMe (50) viscous solution.

Preparation of PAA-OMe (50) -COCl: an aliquot of PAA-OMe (5) EtAc solution was taken and all volatile solvents were removed. A concentrated viscous material (2.03g) (-COOH mole: 2.03/72 × 0.50 ═ 14.1mmol) was obtained. Adding CH₂Cl₂PAA-OMe (50) was dissolved (10 mL). At ambient temperature, adding SOCl₂(4.89g, 41.10mmoles, 3mL) CH added to PAA-OMe (50)₂Cl₂To the solution, 3 drops of DMF were added. Stirring was carried out at ambient temperature for half an hour, then the temperature was raised to-80 ℃ for 9 hours. The solvent and excess SOCl were removed under vacuum at 80 deg.C₂To give a thick viscous material.

Oxybenzone (0.65g, 2.85mmol, 0.65/228.47) was added at ambient temperature. The mixture was stirred and NEt was added slowly₃To neutralize the HCl produced, thereby maintaining the pH of the reaction mixture at 8-9. Stir at ambient temperature for 12 hours. Obtaining crude oxybenzone-PAA-OMe (50) material. .

Purification of oxybenzophenone-PAA-OMe (50): the crude oxybenzophenone-PAA-OMe (50) was loaded onto the column and eluted with a large amount of Hex: EtAc (5:1) until there was no free oxybenzophenone. By CH₂Cl₂MeOH (5:1) elutes the product oxybenzone-PAA-OMe (50).

Example 5

Preparation of oxybenzone-PAA-OMe-OPr (30) material.

Preparation of PAA-OMe-OPr (30): the PAA solid (1.72g) (-COOH mole 1.72/72 ═ 23.90mmol) was taken and dissolved in MeOH-10 mL. 10mL of n-propanol was added and mixed well. At ambient temperature, SOCl was added₂(0.52mL) (0.0239x 30% x118.97/1.63 — 0.52 mL). The solution became clear. 3 drops of DMF were added and the mixture was stirred for 5 hours. All solvents were removed under vacuum with a mechanical pump. A viscous solid PAA-OMe-OPr (30) was obtained.

Preparation of PAA-OMe-OPr (30) -COCl: adding CH₂Cl₂20mL to dissolve PAA-OMe-OPr (30%) as a viscous solid. Addition of SOCl at ambient temperature₂(2.0mL) and 3 drops of DMF were added. Stir at ambient temperature for one hour, then raise the temperature to 50-55 ℃. The mixture was stirred at 50-55 ℃ for 3 hours. Solvent and unconsumed SOCl were removed under vacuum with a mechanical pump₂. PAA-OMe-OPr (30) -COCl, a thick viscous material was obtained.

Addition of 10mL CH₂Cl₂To dissolve PAA-OMe-OPr (30) -COCl. Oxybenzone (1.02g) was added at ambient temperature. The mixture was stirred and NEt was added slowly₃To neutralize the HCl produced to maintain the pH of the reaction mixture at 8-9. Stirred for 5 hours and then the solvent was removed. The solid was washed several times with ethyl acetate until no free oxybenzone could be detected by TLC. By CH₂Cl₂Extracting the solid and filtering. After removal of the solvent, a pale beige solid (1.91g) was obtained.

Example 6

Preparation of oxybenzone suberate.

Suberic acid (0.39g) was added to CH₂Cl₂(10 mL). Adding SOCl₂(1mL) and 3 drops of DMF. The mixture was stirred until all solids dissolved. Solvent and excess SOCl were removed in vacuo₂. Adding anhydrous CH₂Cl₂(10mL) and oxybenzone (0.78 g). The mixture was stirred for 8 hours. The reaction was quenched with saturated brine. Saturated aqueous sodium bicarbonate was added to adjust the pH and extracted with ethyl acetate. The crude product is purified by column chromatography over silica gel and eluent Hex: EtAc (10:1)Purification until free oxybenzone is absent. The di-and mono-substituted products were eluted with Hex: EtAc (5: 1). The eluent is removed to yield a mixture of di-and mono-substituted oxybenzoates.

Example 7

Preparation of [4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid-polyethyleneimine material

Taking [4- (2, 4-dimethoxy-benzoyl) -phenyl]Acetic acid (0.50g), HBTU (0.76g) dissolved in DMSO (10 mL). DIPEA (0.32g) was added and stirred at ambient temperature for 30 minutes. Polyethyleneimine (PEI) (2.01g) was added and the reaction was stirred for 12 hours. The reaction was quenched with saturated brine (30mL) and extracted with ethyl acetate (EtAc). With Na₂SO₄And (5) drying. The ethyl acetate was removed in vacuo to give [4- (2, 4-dimethoxy-benzoyl) -phenyl ] -ethyl acetate]-acetic acid-PEI material (2.34 g). TLC confirmed the absence of free [4- (2, 4-dimethoxy-benzoyl) -phenyl]-acetic acid.

Example 8

Preparation of (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40) material

Preparation of PAA-OMe-OPr (40): MeOH (25mL) was added to dissolve PAA solids (5.52g) (-COOH mol ═ 5.52/72 ═ 76.7 mmol). 20mL of n-propanol was added and mixed well. At 0.0 deg.C, SOCl was added₂(2.24mL) (0.0767x 40% x118.97/1.63 — 2.24 mL). Add 3 drops of DMF and heat to ambient temperature. The mixture was stirred at ambient temperature for 3 hours. All solvents were removed under vacuum with a mechanical pump. A viscous solid of PAA-OMe-OPr (40) was obtained.

Preparation of PAA-OMe-OPr (40) -COCl: addition of CH₂Cl₂(15mL) to dissolve the viscous solid of PAA-OMe-OPr (40) (1.67 g). Adding SOCl at 0 deg.C₂(2.5mL) and 3 drops of DMF. The reaction was stirred at ambient temperature for one hour. The temperature was raised to 50-55 ℃ and the mixture was stirred for 5 hours. Solvent and unconsumed SOCl were removed under vacuum with a mechanical pump₂. A viscous product of PAA-OMe-OPr (40) -COCl was obtained.

12.5mL of CH was added₂Cl₂To dissolve the PAA-OMe-OPr (40) -COCl prepared above. At 0 deg.C, 5mL of CH was added₂Cl₂(4-Aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone (0.40 g). Slow addition of NEt₃To neutralize the HCl produced to maintain the pH of the reaction mixture at 8-9. The reaction was stirred at 0 ℃ for 1 hour and then at ambient temperature for 12 hours. An orange precipitate formed. Removal of CH₂Cl₂Adding H₂O (10mL) and adjusted the pH to 2-3 with 2N HCl. EtAc (20mL) was added to extract the product. The EtAc layer was treated with H₂O (20mL) wash. EtAc was removed to give a pale beige solid (1.44 g).

Example 9

Preparation of 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione-PAA-OMe-OPr (40) Material

Preparation of PAA-OMe-OPr (40): the procedure described in the preparation of PAA-OMe-OPr (40) of example 8 was followed.

Preparation of PAA-OMe-OPr (40) -COCl: adding CH₂Cl₂(15mL) to dissolve the viscous solid of PAA-OMe-OPr (40) (1.62 g). Adding SOCl at 0 deg.C₂(2.5mL) and 3 drops of DMF. Heat to ambient temperature and stir the reaction for one hour. The temperature was raised to 50 ℃ and the mixture was stirred for 5 hours. Solvent and unconsumed SOCl were removed under vacuum with a mechanical pump₂. A viscous product of PAA-OMe-OPr (40) -COCl was obtained.

Adding CH₂Cl₂(12mL) to dissolve PAA-OMe-OPr (40) -COCl prepared as above. 5mL of CH was added at 0 deg.C₂Cl₂1- [4- (3-amino-propoxy)-phenyl radical](iii) -3- (4-tert-butyl-phenyl) -propane-1, 3-dione (0.400g) and treatment with NEt₃The HCl produced was slowly neutralized to maintain the pH of the reaction mixture at 8-9. The reaction was stirred at 0 ℃ for 1 hour and then at ambient temperature for 12 hours. An orange precipitate formed. Removal of CH₂Cl₂. Addition of H₂O (10mL) and adjusted the pH to 2-3 with 2N HCl. EtAc (20mL) was added to extract the product. The EtAc layer was treated with H₂O (20mL) wash. EtAc was removed to give a pale beige solid (1.87 g).

Example 10

Preparation of (4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI material

(4-benzoyl-3-hydroxy-phenoxy) -acetic acid (0.50g), HBTU (0.84g) was dissolved in DMF (10 mL). A solution of DIPEA (0.356g) in DMF (5mL) was added and stirred at ambient temperature for 30 minutes. PEI (0.79g) was dissolved in a mixture of DMF (10mL) and DMSO (3 mL). The (4-benzoyl-3-hydroxy-phenoxy) -acetic acid/HBTU/DIPEA solution was added to the PEI solution. The reaction was stirred for 12 hours. The reaction was quenched with 2N HCl (20 mL). By CH₂Cl₂/MeOH (10:1)15mLX2 wash. By CH₂Cl₂the/MeOH (5:1)10mLX2 washes until no (4-benzoyl 3-hydroxy-phenoxy) -acetic acid could be detected by TLC. Removal of H by mechanical vacuum pump₂O to give (4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI material (4.52g) as a rubbery material.

Dialyzing (4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI material: NaOH (42mg) was weighed out to dissolve in H₂O (10 mL). Water was added to the (4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI material. To the aqueous solution of (4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI was added 3mL NaOH solution. Mixing uniformly and transferring to dialysis bag (100 pieces)Left) for dialysis. The (4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI aqueous solution was concentrated, then a second NaOH solution (3mL) was added and dialysis was continued until no Cl was detected in the dialyzed aqueous phase^-. Removal of H from aqueous (4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI solution₂O, to give an orange viscous material of (4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI.

Example 11

Preparation of 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -3-hydroxy-phenoxy } -butyric acid-PEI material

Taking 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl]-3-hydroxy-phenoxy } -butyric acid (0.49g), HBTU (0.60g) was dissolved in DMF (10 mL). Stirred for 30 minutes. A solution of DIPEA (0.25g) in 2mL DMF was added and stirred at ambient temperature for 30 minutes. The above solution was added to a solution of PEI (0.77g) in DMF (11mL) and the reaction was stirred for 12 hours. The reaction was quenched with 2N HCl at 0 deg.C and the pH was adjusted to 2-3. Addition of H₂O (30mL) to give a clear solution. By CH₂Cl₂/MeOH (10:1)15mLX2 and CH₂Cl₂10mL of wash solution in/MeOH (5: 1).

4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl]-dialysis of 3-hydroxy-phenoxy } -butyric acid-PEI material: 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl]The solution of-3-hydroxy-phenoxy } -butyric acid-PEI was dialyzed against a dialysis bag (100 cut-off) until no Cl was detected in the dialysis water^-Until now. From 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl]Removal of H from aqueous solutions of (E) -3-hydroxy-phenoxy } -butyric acid-PEI₂O, an orange viscous material is obtained.

Example 12

Preparation of 4- {4- [4, 6-bis- (4-methoxy-phenyl) - [1,3,5] triazin-2-yl ] -phenoxy } -butyric acid-PEI material

Taking 4- {4- [4, 6-bis- (4-methoxy-phenyl) - [1,3,5]]Triazin-2-yl radical]Phenoxy } -butyric acid (0.52g), HBTU (0.51g) in DMF (DMF) (N.sub.X.)5 mL). Stirred for 15 minutes. A solution of DIPEA (0.22g) in DMF (2mL) was added and stirred at ambient temperature for 30 minutes. A colorless precipitate formed. The suspension was added to a solution of PEI (0.80g) in DMF (8mL) and the reaction was stirred for 12 hours. The colorless precipitate disappeared. The reaction was quenched with saturated brine at 0 ℃ and the pH was adjusted to 2-3 with 2N HCl. A clear solution was obtained. By CH₂Cl₂The solution was washed with MeOH (10:1)15mLX 2.

4- {4- [4, 6-bis- (4-methoxy-phenyl) - [1,3,5]]Triazin-2-yl radical]Dialysis of phenoxy } -butyric acid-PEI material: 4- {4- [4, 6-bis- (4-methoxy-phenyl) - [1,3,5]]Triazin-2-yl radical]The phenoxy } -butyric acid-PEI solution was dialyzed against a dialysis bag (100 cut-off). Dialyzing until no Cl was detected in the dialyzed water^-Until now. From 4- {4- [4, 6-bis- (4-methoxy-phenyl) - [1,3,5]]Triazin-2-yl radical]Removal of H from aqueous solutions of-phenoxy } -butyric acid-PEI₂O gives an orange viscous material.

Example 13

oxybenzone-PAA-OMe (50) formulations

Oxobenzophenone-PAA-OMe (50) formulation composition

Oxybenzone ketone	PEG200	PEG400	PEG15
				1.05g	0.59g	0.33g	1.13g

PEG 200 was added to oxybenzone-PAA-OMe (50). And (4) fully mixing. Add PEG 400 and mix well. PEG 1500 was added to the above homogeneous solution. Heat was gently applied to dissolve PEG 1500 until a homogeneous solution was obtained. The% oxybenzophenone content was determined to be 7.4% by calculation based on UV absorbance data.

Oxybenzone/[ 4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid control formulation

For comparison purposes, a control formulation of oxybenzone/[ 4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid was prepared. The lack of covalent interaction between oxybenzone/[ 4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid and the excipient base is the basis for a control standard. The following table lists the compositions.

Control formulation composition for oxybenzone-PAA-OMe (50) formulation

Weigh 2 amounts of each component, oxybenzone, [4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid, PEG 200, PEG 400 and PEG 1500 into a small beaker. The mixture was heated in an oven at 35 ℃ and mixed thoroughly until a clear solution was obtained. Cooling to room temperature produced an ointment.

Example 14

Suberic acid oxybenzophenone ester preparation

Suberic acid oxybenzophenone ester preparation composition

PEG 200 was added to oxybenzone suberate. Thoroughly mix under mild heating until all oxybenzophenone suberate ester is dissolved. PEG 400 and PEG 1500 were added and mixed well with gentle heating until all PEG 1500 dissolved. A homogeneous solution was obtained. The% oxybenzophenone content was determined to be 8.71% by calculation based on UV absorbance data.

Control formulation of oxybenzone/[ 4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid

Same as in example 13

Example 15

[4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid-PEI formulation

[4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid-PEI formulation composition

Sunscreen material	PAA(30％	PEG20
			1.33g (oxybenzone)	1.35g	0.59g

MeOH (5m2L3)8 was added to) [4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid-PEI material (1.33g) to dissolve completely. PEG 200(0.71g) was added and mixed well. MeOH was evaporated under vacuum. PEG 1500(0.34g) was added and mixed well with gentle heating. The% oxybenzophenone content was determined to be 10.0% by calculation based on UV absorbance data.

Control formulation of oxybenzone/[ 4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid

Same as in example 13

Example 16

(4-Aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40) formulations

(4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40) formulation composition

EtAc (2.80g) and acetic acid (0.43g) were added to (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40) material (1.40g) and mixed. PEG 200(0.21g) and PAA 30% solution (0.24g) were added and mixed thoroughly. PEG 200(1.03g) was added and mixed well. The volatile solvent was evaporated in an oven at 37 ℃. Finally, 3.04g of an ointment was obtained.

The% oxybenzophenone content was determined to be 6.18% by calculation based on UV absorbance data.

Control formulation of oxybenzone/[ 4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid

Same as in example 13

Example 17

1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione-PAA-OMe-OPr (40) formulation

1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) propane-1, 3-dione-PAA-OMe-OPr (40) formulation composition

Sunscreen material	PAA(30％)	PEG200
			1.81g (Avobenzone 213mg)	1.35g	0.59g

Ethyl acetate (2.50g) was added to the 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione-PAA-OMe-OPr (40) material (1.81g) to dissolve completely. Acetic acid (1.10g) was added and mixed well. EtAc was evaporated. Acetic acid (1.09g) was added and mixed well. The ethyl acetate was evaporated. Aqueous PAA (30%) (0.68g) was added and mixed well. More 0.67g of aqueous PAA (30%) was added and mixed thoroughly. The volatile solvent was evaporated in an oven at 37 ℃. PEG 200(0.59g) was added and mixed well. The% avobenzone content was determined to be 5.34% by calculation based on UV absorbance data.

Avobenzone control formulation

Avobenzone control formulation

PEG 200 and PEG 1500 were weighed into a beaker. The beaker was placed in an oven at 35 ℃. Mix until a clear solution is obtained. Avobenzone is weighed into a container containing PEG. Mix thoroughly. A clear solution was obtained.

Example 18

(4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI formulations

(4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI formulation composition

0.46g of PEI was added to the (4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI material (0.84g) and mixed well to dissolve completely. PEG 200(0.66g) was added and mixed well. PEG 1500(0.73g) was added and mixed well with gentle heating. The% oxybenzophenone content was 7.5% as determined by calculation based on UV absorbance data.

Oxybenzone/[ 4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid control formulation

Same as in example 13.

Example 19

4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -3-hydroxy-phenoxy } -butyric acid-PEI formulation

4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -3-hydroxy-phenoxy } -butyric acid-PEI formulation composition

PEI (0.63g) was added to 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -3-hydroxy-phenoxy } -butyric acid-PEI material (2.50g) and mixed well to dissolve completely. PEG 200(1.16g) was added and mixed well. The% avobenzone content was determined to be 4.82% by calculation based on UV absorbance data.

Avobenzone control formulation

Same as in example 17.

Example 20

4- {4- [4, 6-bis- (4-methoxy-phenyl) - [1,3,5] triazin-2-yl ] -phenoxy } -butyric acid-PEI formulation

4- {4- [4, 6-bis- (4-methoxy-phenyl) - [1,3,5] triazin-2-yl ] -phenoxy } -butyric acid-PEI formulation composition

Sunscreen material	PEI	H2O
			1.64g (═ triazine 348.5mg)	0.69g	0.46g

PEI (0.69g) was added to 4- {4- [4, 6-bis- (4-methoxy-phenyl) - [1,3,5]]Triazin-2-yl radical]-phenoxy } -butyric acid-PEI material (1.64g) and H₂O (1.05g) was mixed well to dissolve completely. Evaporation of H₂O until a suitable viscosity is reached. An ointment (2.79g) was obtained. The% content was 12.5% as determined by calculation based on UV absorbance data.

Example 21

Animal test results:

mouse test procedure:

mouse preparation and blood sample collection: a group of 16 to 60 mice was fed with sufficient food and water for 3 days. Twelve hours prior to testing, food was removed and only water was fed. Typically 12 mice were randomly selected and 2 mice were assigned at each time point of 5, 15, 30, 60, 90, 120 minutes. Sometimes, 3 mice may be selected at certain sampling time points. Two hours prior to the test, mice were anesthetized and the hair on the back was removed (2.5-3.0 cm)²). After recovery from anesthesia, the mice will be applied with a sample of the test ointment. Exactly the same test procedure was performed using the control standard sample. Blood samples (1mL) were collected at 5, 15, 30, 60, 90, 120 minutes after eye removal.

Pretreatment of a blood sample: after the blood sample was collected, it was immediately centrifuged at 12000rpm for 10min to obtain a supernatant plasma layer, which was stored at-20 ℃ for later use.

Blood sample preparation: a150 μ L plasma sample was accurately transferred to a 1.5mL EP tube. Methanol and acetonitrile were added in 200. mu.L, respectively. Vertex mix (Vertex mix) for 1 minute, then centrifuge at 12000rpm for 10 minutes. The supernatant was accurately transferred to another tube. Nitrogen was purged at 40 ℃ until dry. To the remaining solid was added 150. mu.L of methanol and mixed on top for 1 minute. Centrifuge at 12000rpm for 10 minutes. The supernatant was used directly for HPLC analysis.

HPLC analysis:

oxybenzone-PAA-OMe (50): column: c18RP column (250X 4.6mm, 5 m); column temperature: at 25 ℃. Mobile phase：MeOH:H₂O75: 25; flow rate: 1.0 mL/min.

Wavelength: 290 nm; sample introduction amount: 20 μ L NW1701-125

Oxybenzophenone suberate ester: as described above.

(2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid-PEI: column: c18RP column (250X 4.6mm, 5 μm). Column temperature: 25 ℃; mobile phase: MeOH: 0.05% formic acid 60: 40; flow rate: 1.0 mL/min. Wavelength: 260nm, 290 nm; sample introduction amount: 20L;

oxybenzone and (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid control samples: as described above. NW1701-128

(4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone-PAA-OMe-OPr (40): column: c18RP chromatography column (250X 4.6mm, 5 μm); column temperature: at 25 ℃. Mobile phase: MeOH: 0.05% formic acid 70: 30; flow rate: 1.0 mL/min; wavelength: 310 nm; sample introduction amount: 20L;

1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) propane-1, 3-dione-PAA-OMe-OPr (40): column: c18RP column (250X 4.6mm, 5 m); column temperature: at 25 ℃. Mobile phase: MeOH: 0.05% formic acid 80: 20; flow rate: 1.0 mL/min; wavelength: 360 nm; sample introduction amount: 20 mu L of the solution;

(4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI: column: c18RP chromatography column (250X 4.6mm, 5 μm); column temperature: at 25 ℃. Mobile phase: MeOH: 0.05% formic acid 60: 40; flow rate: 1.0 mL/min. Wavelength: 260 nm; sample introduction amount: 20 mu L of the solution;

{4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -3-hydroxy-phenoxy } -butyric acid-PEI: column: c18RP column (250X 4.6mm, 5 μm); column temperature: at 25 ℃. Mobile phase: MeOH: 0.05% formic acid 80: 20; flow rate: 1.0 mL/min. Wavelength: 360 nm; sample introduction amount: 20 mu L of the solution;

4- {4- [4, 6-bis- (4-methoxy-phenyl) - [1,3,5] triazin-2-yl ] -phenoxy } -butyric acid-PEI: column: c18RP chromatography column (250X 4.6mm, 5 μm); column temperature: at 25 ℃. Mobile phase: MeOH: 0.05% formic acid 90: 10; flow rate: 1.0 mL/min. Wavelength: 310 nm; sample introduction amount: 20 mu L of the solution;

example 22

oxybenzone-PAA-OMe (50) material preparation mouse skin penetration test result

As shown in fig. 1, oxybenzophenone-PAA-OMe (50) material formulations did not completely block skin permeation of oxybenzophenone, but did result in a significant reduction in skin permeation of oxybenzophenone. Studies in the laboratory have shown that oxybenzone-PAA-OMe (50) materials can hydrolyze to produce free oxybenzone, which is responsible for deleterious skin penetration. The concentration of oxybenzone in the blood sample of the control formulation was significantly higher than the concentration of oxybenzone in the test formulation sample. The area under the curve (AUC) representing oxybenzone exposure for the control sample was 2.24 times the AUC for the test formulation.

Example 23

Mouse skin penetration test result of suberic acid oxybenzophenone ester preparation

No free oxybenzophenone was detected in the sunscreen preparation samples by HPLC. After 5 minutes, a large amount of oxybenzone was detected in the mouse blood sample, but no oxybenzone ester suberate was detected, indicating skin permeation of oxybenzone ester suberate and rapid hydrolysis of oxybenzone ester suberate in plasma. The oxybenzophenone concentration profile in blood of the suberate oxybenzophenone ester test sample was very similar to that of the free oxybenzophenone control sample.

Example 24

The retention time of [4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid was 6.462 minutes. HPLC data of test sample NW1701-126 indicated the presence of free [4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid in the sample at 6.559 minutes. Contamination was due to unsuccessful purification process. The results of the mouse skin permeation test showed that the skin permeation of [4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid was significantly reduced by 84%. Elimination of contaminating free [4- (2, 4-dimethoxy-benzoyl) -phenyl ] -acetic acid can result in zero skin permeability.

Example 25

HPLC data showed no peak at 8.661 min for (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone detected in all plasma samples, indicating complete elimination of skin permeation of (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone. Zero skin penetration was successfully achieved.

Example 26

HPLC data indicated a retention time of sunscreen 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione of 13.35 minutes. The combination of 164 test samples and plasma did produce a fraction that eluted at 13.408min, indicating that 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione-PAA-OMe-OPr (40) may be hydrolysed. However, 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) -propane-1, 3-dione was not detected in all plasma samples, indicating complete elimination of the skin permeation of 1- [4- (3-amino-propoxy) -2-hydroxy-phenyl ] -3- (4-tert-butyl-phenyl) propane-1, 3-dione. Zero skin penetration was successfully achieved.

Example 27

HPLC data showed the retention time of sunscreen (4-benzoyl-3-hydroxy-phenoxy) -acetic acid to be 8.307 minutes. The mixing of the NW1701-147 test sample and plasma did produce a fraction that eluted at 8.382min, indicating that hydrolysis of the (4-benzoyl-3-hydroxy-phenoxy) -acetic acid-PEI material was likely to occur. However, (4-benzoyl-3-hydroxy-phenoxy) -acetic acid was not detected in all plasma samples, indicating that the skin penetration of (4-benzoyl-3-hydroxy-phenoxy) -acetic acid was eliminated. Zero skin penetration was successfully achieved.

Example 28

HPLC data indicated the retention time of sunscreen 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -3-hydroxy-phenoxy } -butyric acid was 14.007 minutes. The mixing of the NW1701-161 test sample and plasma did not produce a component that eluted at 14.007min, indicating that the 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -3-hydroxy-phenoxy } -butyric acid-PEI material was not hydrolyzed. 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -3-hydroxy-phenoxy } -butyric acid was not detected in all plasma samples, indicating complete elimination of the skin permeation of 4- {4- [3- (4-tert-butyl-phenyl) -3-oxo-propionyl ] -3-hydroxy-phenoxy } -butyric acid. Zero skin penetration was successfully achieved.

The invention is not limited to the embodiments described above, which are given by way of example only, but can be modified in various ways within the scope of protection defined by the appended patent claims.