阅读说明：本技术 防晒制剂 (Sunscreen formulations ) 是由 孙益民 于 2018-10-25 设计创作，主要内容包括：本发明涉及新类型防晒剂的合成,该防晒剂在旨在减少防晒剂皮肤渗透的防晒配方中的用途,以及使用现有防晒剂但减少防晒剂皮肤渗透的配方技术,因此提高了防晒产品的生物安全性。(The present invention relates to the synthesis of a new class of sunscreen agents, their use in sunscreen formulations aimed at reducing the skin penetration of sunscreen agents, and formulation techniques using existing sunscreen agents but reducing the skin penetration of sunscreen agents, thus improving the biological safety of sunscreen products.)

1. A sunscreen formulation comprising:

(1) an ionic complex formed between compound a and excipient B; and

(2) a water-based carrier for topical administration of a drug,

wherein the compound A is in the enol form, or has an active acidic proton, or is derived from- [ CH ]₂]_nCOOH or- [ CH₂]_nNH₂Wherein n is 0 to 18;

when the sunscreen compound A is in the enol form, or has an active acidic proton, or is derived from- [ CH ]₂]_nCOOH, excipient B contains an amine function and sunscreen compound A is derived from- [ CH ]₂]_nNH₂When excipient B contains a carboxyl functional group;

the formulation is substantially free of compound a in free form; and is

The sunscreen formulation is preferably homogeneous and transparent, more preferably an ointment or viscous solution.

2. The formulation according to claim 1, comprising less than 20%, preferably 10%, most preferably less than 5% mol equivalent of compound a in free form relative to the molar amount of ionic complex.

3. The formulation of claim 1, which is free of compounds that are substantially detrimental to the formation or presence of ionic complexes or the stability of the formulation.

4. The formulation according to claim 3, wherein the compound substantially detrimental to the formation or presence of an ionic complex or formulation stability is another ionic compound not listed in claim 1.

5. The formulation of claim 3, wherein the compound that is substantially detrimental to the formation or presence of an ionic complex or the stability of the formulation is an ionic surfactant.

6. The formulation according to claim 1, wherein is derived from [ CH₂]_nThe COOH sunscreen compound is selected from avobenzone, cinoxate, dioxybenzone, homosalate, oxybutynin, octyl methoxycinnamate, octyl salicylate, oxybenzone, or combinations thereof, and the derived sunscreen compound has the following structure:

preferred are (4-benzoyl-3-hydroxy-phenoxy) -acetic acids of the formula:

7. the formulation according to claim 1, wherein is derived from- [ CH₂]_nNH₂The sunscreen compound of (a) is selected from avobenzone, cinoxate, dioxybenzone, homosalate, octocrynine, octyl methoxycinnamate, octyl salicylate, oxybenzone, or combinations thereof, and the derived sunscreen compound has the following structure:

preferred are (4-aminomethoxy-2-hydroxy-phenyl) phenyl-methanones of the formula:

8. the formulation according to claim 1, wherein the amine functional group containing excipient B is selected from spermidine, spermine, tris- (2-aminoethyl) amine, 1,1, 1-tris (aminomethyl) ethane, macrocyclic polyamines, polyvinylamines, polyallylamines, polyethyleneimines, chitosan or combinations thereof, preferably branched polyethyleneimines with a molecular weight of 1000-50000.

9. The formulation according to claim 1, wherein excipient B containing carboxyl functions is selected from oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, citric acid, isocitric acid, propane-1, 2, 3-tricarboxylic acid, carboxymethylcellulose, polyacrylic acid, hyaluronic acid, or combinations thereof, preferably glutaric acid or polyacrylic acid with a molecular weight of 1000-50000.

10. The formulation according to claim 1, wherein the enol form of the sunscreen compound is avobenzone.

11. The formulation of claim 1, wherein the sunscreen compound having an active acidic proton is selected from oxybenzone, hexyl diethylaminohydroxybenzoyl benzoate, homosalate, dihydroxybenzone, 2-ethylhexyl salicylate, sulfoisobenzone, or combinations thereof.

12. The formulation of claim 1, wherein the aqueous-based carrier is selected from the group consisting of aqueous-based chitosan, aqueous-based hyaluronic acid, aqueous-based PEG200, aqueous-based PEG400, aqueous-based PEG1500, or a combination thereof.

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

14. A method of preparing the formulation according to claim 1, comprising:

dissolving said compound a in said carrier, reacting with not less than, preferably more than 20% of the stoichiometric amount of said excipient B, and blending at a temperature in the range of 20 ℃ to 50 ℃ to form a homogeneous transparent composition, preferably an ointment or viscous solution.

15. The method of claim 14, prior to the blending step, comprising blending the blend by a blend derived from a monomer having- [ CH ]₂]_nCOOH or- [ CH₂]_nNH₂Wherein n is 0-18, to prepare compound a.

16. (4-aminomethoxy-2-hydroxy-phenyl) phenyl-methanone of the formula:

1. Field of the invention

The present invention relates to the synthesis of uv blockers and uv blocker sunscreen formulations which can 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. There are several types of electromagnetic radiation emitted by the sun. Ultraviolet (UV) radiation is one type. Based on the characteristics of ultraviolet rays interacting with human skin, and based on wavelengthIs divided into three wave bands: 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 there are two sunscreens (UV filters) used as sunscreens 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 one 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 potential toxicity of these components to human health.

Since the first day of use of sunscreens in the 30's of the 20 th century, exposure to sunscreens has begun. 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 Sunscreen _ Genumbenzophenone-3 in resistances of the United States: National Health and nutrition Examdition Surveiy 2003-2004, environ.health Perfect 116 (893-2008). Oxybenzone was detected in 97% of all 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 urooxybenzone-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, Couples' urinearyconcentrations of benzophenone-type virolter and the second data xratio, 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 oxybenzone found in urine samples collected from women in california in 2007-2009 was about 9-fold higher (up to 13000ng/ml, with an average of about 200ng/ml), which may be a result of specific demographics [ c.philippiat, d.bennett, a.m.calafat, i.h.piciotto, Exposure to selected dyes and phenols through use of personal care products, amy calcium additives and the childern, environ.res.140(2015) -376 ]. The average concentration of oxybenzone in urine samples increased by more than 9-fold from 22.9ng/mL to 200ng/mL compared to the 2003-2004 study. This is an alarming 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) for adults²) In this case, the mean urine concentrations of these constituents 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.Skakakakak, H.C.Wulf, systematic adsorption of the Sunscreen Benzophenone-3, Octyl-Methoxylinamate, and 3- (4-Methyl-Benzylene) Camphorafter wheel-Body inductive Application and reproduction of Hormone chains informans, J.Dermatol, 123(2004)57-61, 57-61 ng/mL, respectively]. 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. (21 J.Rodriguez, H.I.Maibach, Percutaneous specificity and pharmacodynmics: Wash-in and Wash-off of sucrose and extract repeat, J.Dermatolog.Tree, 27(2016) 11-18; 22, B.Gulson, M.J.Mccall, D.M.Bowman, T.Pinheiro, A review of critical factors for the analysis of the negative absorbance of metal oxide nanoparticles from secreted to humans, and a research strand to address current discovery arm. Toxicol.89(2015) 1909-; 15, H.Gonzalez, Percutaneous absorbance with a simple on succincreens, 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 ofUV filters,fragrances,parabens,phthalates,organochlor pesticides,PBDEs,andPCBs 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. philipapat, m. mortamais, c. chevrier, c. petit, AMCalafat, YEX, MJSilva, c. brambilla, i.pin, machares, s.cordier, r. slama, Exposure to temperature and phenol during prediction and printing size at birthday, environ. Healthperspect,120(2012)464- ]. These reports raise concerns about potential prenatal exposure and developmental toxicity of uv filters.

While all of the data show widespread exposure to sunscreen by use of sunscreen products, little research has been reported into improving the biosafety of sunscreen products by reducing or completely eliminating such exposure.

Background

Disclosure of Invention

The present invention provides a formulation that reduces or minimizes or eliminates skin penetration of sunscreen agents, thereby improving the biosafety of the sunscreen product.

According to a first aspect of the application, a sunscreen formulation comprises:

(1) an ionic complex formed between compound a and excipient B; and

(2) aqueous-based vehicles for topical administration.

The compound A being in the enol form, or having an active acidic proton, or being derived from- [ CH ]₂]_nCOOH or- [ CH₂]_nNH₂Wherein n is 0 to 18.

When the sunscreen compound is in the enol form, or has an active acidic proton, or is derived from- [ CH ]₂]_nCOOH, excipient B contains an amine function and when sunscreen compound A is derived from- [ CH ]₂]_nNH₂In this case, excipient B contains a carboxyl functional group.

The formulation is substantially free of compound a in free form.

The sunscreen formulation is homogeneous and transparent, preferably in the form of an ointment or viscous solution.

The formulation preferably comprises less than 20%, more preferably 10%, most preferably less than 5% molar equivalents of compound a in free form relative to the molar amount of ionic complex.

The formulation preferably does not contain compounds that are substantially detrimental to the formation or presence of ionic complexes or formulation stability. A compound that is substantially detrimental to the formation or presence of an ionic complex or the stability of a formulation is another ionic compound not specifically described above. The compound that is substantially detrimental to the formation or presence of ionic complexes or the stability of the formulation may be an ionic surfactant.

Derived from [ CH₂]_nThe COOH sunscreen compound may be avobenzone, cinoxate, dioxobenone, homosalate, oxclinine, octyl methoxycinnamate, octyl salicylate, oxybenzone, or combinations thereof, and the derivatized sunscreen compound has the following structure:

preferred are (4-benzoyl-3-hydroxy-phenoxy) -acetic acids of the formula:

derived from- [ CH ]₂]_nNH₂The sunscreen compound of (a) may be avobenzone, cinoxate, dioxybenzone, homosalate, oxybutynin, octyl methoxycinnamate, octyl salicylate, oxybenzone, or combinations thereof, and the derived sunscreen compound has the following structure:

preferred are (4-aminomethoxy-2-hydroxy-phenyl) phenyl-methanones of the formula:

excipient B containing amine functionality may be spermidine, spermine, tris- (2-aminoethyl) amine, 1,1, 1-tris (aminomethyl) ethane, macrocyclic polyamine (cyclen), polyvinylamine, polyallylamine, polyethyleneimine, chitosan or combinations thereof, preferably a branched polyethyleneimine having a molecular weight of 1000-50000.

Excipient B containing carboxyl functional groups may be oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, citric acid, isocitric acid, propane-1, 2, 3-tricarboxylic acid, carboxymethylcellulose, polyacrylic acid, hyaluronic acid, or combinations thereof, preferably glutaric acid or polyacrylic acid having a molecular weight of 1000-50000.

The enol form of the sunscreen compound is preferably avobenzone.

The sunscreen compound having an active acidic proton is preferably oxybenzone, diethylamino hydroxybenzoyl hexyl benzoate, homosalate, dihydroxybenzone, 2-ethylhexyl salicylate, sulisobenzone, or combinations thereof.

The carrier can be water-based chitosan, water-based hyaluronic acid, water-based PEG200, water-based PEG400, water-based PEG1500, or a combination thereof.

According to a second aspect of the present application, a method for protecting skin from ultraviolet radiation comprises applying the above formulation to skin in need thereof.

According to a third aspect of the application, a method of preparing the formulation comprises:

compound a is dissolved in a carrier, reacted with not less than, preferably greater than 20% of stoichiometric excipient B, and blended at a temperature in the range of 20 ℃ to 50 ℃ to form a composition, preferably a homogeneous transparent composition, more preferably an ointment or viscous solution.

Prior to the blending step, the method may include a step of blending a copolymer derived from a monomer having- [ CH ]₂]_nCOOH or- [ CH₂]_nNH₂Wherein n is 0-18, to prepare compound a.

According to a fourth aspect of the present application there is provided (4-aminomethoxy-2-hydroxy-phenyl) phenyl-methanone of the formula:

which can be used in the above formulations as a compound for derivatizing sunscreen compounds.

Drawings

Figure 1 shows the results of a mouse skin permeation test of benzoic acid in relation to a formulation based on example 3 of the present application.

Figure 2 shows the results of a mouse skin permeation test of 4-methoxy-benzylamine in relation to a formulation based on example 4 of the present application.

Figure 3 shows the results of a mouse skin permeation test of (4-benzoyl-3-hydroxy-phenoxy) -acetic acid in relation to a formulation based on example 5 of the present application.

Figure 4 shows the results of a mouse skin permeation test of (4-aminomethoxy-2-hydroxy-phenyl) -phenyl-methanone in relation to a formulation based on example 6 of the present application.

Figure 5 shows the results of a mouse skin permeation test of 2-hydroxy-4-methoxybenzophenone (oxybenzone) in relation to a formulation based on example 7 of the present application.

Figure 6 shows the results of a mouse skin permeation test of avobenzone formulations in relation to formulations based on example 8 of the present application.

Detailed description of the preferred embodiments of the invention

The following examples are provided to illustrate, but not to limit, the present invention.

Novel organic sunscreen agents with specifically designed functions are synthesized.

Formulations have been developed using sunscreens containing carboxyl groups coupled with simple organic compounds, oligomers or macromolecules containing amine groups. This combination results in an interaction between the carboxyl groups of the sunscreen agent and the amine groups of the excipient molecule to reduce/eliminate skin penetration of the sunscreen agent.

Formulations have been developed using sunscreens containing amine groups coupled to simple organic compounds, oligomers or macromolecules containing carboxyl groups. The ionic interaction between the amine groups of the sunscreen agent and the carboxyl groups of the excipient molecule will reduce, minimize or eliminate skin penetration of the sunscreen agent.

Using simple organic compounds, oligomers or macromolecules containing amino groups with the enol form of the sunscreen (avobenzone) or with the active acidic protons of the sunscreen (oxybenzone, diethylaminohydroxybenzoyl hexyl benzoate, homosalate, dibenzil)Oxybenzylketone, 2-ethylhexyl salicylate, sulfoisobenzone) to produce ionic interactions between simple organic compounds, oligomers or macromolecules containing amino groups and the sunscreen agent. The combination is by promoting NH of sunscreen agent and excipient₂The interaction between the groups minimizes, reduces or eliminates skin penetration of the sunscreen.

The present inventors have conducted intensive studies to develop novel active sunscreens having specifically designed functional groups and to develop formulation schemes that will reduce or minimize skin penetration of the sunscreen to ultimately improve the biosafety of the sunscreen product.

It is therefore an object of the present invention to provide a synthesis of sunscreen agents having carboxyl functionality specifically designed for formulation purposes.

It is another object of the present invention to provide a synthesis of sunscreen agents having amine functional groups specifically designed for formulation purposes.

In one aspect of the invention, a formulation scheme is provided which uses the active acidic protons of the enol form sunscreen or sunscreen with NH of simple organic compounds, oligomers or macromolecules₂The groups undergo chemical reactions to reduce or prevent skin penetration of the sunscreen, ultimately with the goal of increasing the biological safety of the sunscreen product.

In another aspect of the invention, a formulation scheme is provided which uses a sunscreen having a carboxyl functional group and an excipient consisting of an amine group to reduce or prevent skin penetration of the sunscreen with the ultimate goal of improving the biosafety of the sunscreen product.

In another aspect of the invention, a formulation is provided that uses a sunscreen having amine functional groups and an excipient consisting of a carboxyl group to reduce or prevent skin penetration of the sunscreen with the ultimate goal of improving the biosafety of the sunscreen product.

Examples

The invention is illustrated by the 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 in a generic and descriptive sense only and not for purposes of limitation.