WO2017112993A1

WO2017112993A1 - Method for producing a thin-film nanostructure composed of a polymeric amphiphilic blend with a high concentration of the organic core as a u.v. protection filter

Info

Publication number: WO2017112993A1
Application number: PCT/BR2016/050353
Authority: WO
Inventors: Juliana Flor; Marcos Rogério SPINA; Natália NETO PEREIRA CERIZE; Adriano Marim De Oliveira; Kleber LANIGRA GUIMARÃES; Maria Helena AMBRASIO ZANIN; Thais ARAGÃO HOROIWA; Tatiana SANTANA BALOGH; Priscila CAROLLO MONCAYO; Simone Andrea EMIDIO; Karina MORETTI DA SILVA
Original assignee: Natura Cosméticos S.A.; Instituto De Pesquisas Tecnológicas Do Estado De São Paulo S.A. - Ipt
Priority date: 2015-12-29
Filing date: 2016-12-27
Publication date: 2017-07-06
Also published as: WO2017112993A8; AR107236A1; BR102015032897B1; BR102015032897A2

Abstract

The present invention relates to a method for producing a thin-film nanostructure composed of a polymeric amphiphilic blend with a high concentration of the organic core for use against ultraviolet radiation, belonging to the field of cosmetics and pharmaceutical preparations of active substances characterised by special physical forms, involving three phases: an organic phase, an aqueous phase and an aqueous dilution phase, wherein in the organic phase an organic solvent such as ketones, esters and alcohols is used, or a combination of two or more of these substances, wherein the hydrophobic polymer, the organic chemical agents against U.V. radiation, the hydrophilic copolymer and a non-ionic surfactant are added individually; the aqueous phase is prepared with distilled water and a surfactant such as lauryl ether sodium sulphate or cocoamidopropyl betaine or coconut fatty acid diethanolamide or sorbitan laurate 80 EO, or cetyl phosphate; and the dilution phase is prepared with distilled water and surfactants, such as lauryl ether sodium sulphate or cocoamidopropyl betaine or coconut fatty acid diethanolamide or sorbitan laurate 80 EO.

Description

PROCESS FOR PRODUCTION OF POLYMERIC AMPHIPHYLIC SLENDER FILM NANOSTRUCTURE WITH HIGH CONCENTRATION OF ORGANIC CORE AS FILTER

ULTRAVIOLET RADIATION FIELD

[001] The invention, which pertains to the cosmetics and pharmaceutical preparations sector of actives characterized by special physical forms, relates to the process of producing nanostructured nanoparticles acting as an ultraviolet radiation filter formed by a thin film of amphiphilic blend. high concentration polymeric encapsulated organic core as ultraviolet radiation filter. Due to their size scale, composition and morphology, these nanoparticles can be applied in cosmetic formulations for sunscreen preparation, or in any other formulation that has an interest in protection against solar radiation.

TECHNICAL STATE

Topical sunscreens are recommended to protect human skin against the acute and chronic adverse effects of solar radiation. The main reported effects of solar radiation are acute sunburn, many forms of photoallergy, premature photoaging, skin neoplasia, and pre-neoplastic melanoma and non-melanoma disorders.

[003] A modern sunscreen with a broad spectrum of UVB and UVA protection and a long-lasting effect should prevent erythema and skin inflammation (mediated by ROS species). Sunscreen preparations are usually applied to large areas of the skin and should remain on its surface and penetrate it as little as possible. Sunscreens usually need a long residence time on the skin to perform their function to absorb or reflect UV radiation, however. Both the risk of systemic distribution should be considered as they may lead to toxicological problems such as estrogenic and antiandrogenic activities, as well as carcinogenic effects, as well as being photosensitizing, photoirritating and photoallergenic. The most commonly used sunscreens are cinnamates such as octyl methoxycinnamate (WTO), which absorbs radiation in the region of 290 - 320 nm, and benzophenones, such as benzophenone-3 (BZ-3) which absorbs in the region of 320 - 340 nm.

Colloidal nanocarriers, such as microemulsions, naemulsions and polymeric nanocapsules, are proposed as an alternative to improve topical administration based on their ability to encapsulate pharmaceutical and cosmetic actives when compared to usual topical compositions such as emulsions. and gels. The sunscreen encapsulation strategy enables an improvement in photostability and efficacy compared to unencapsulated sunscreen, thereby reducing toxicological effects, as shown in the papers by GK Borghetti (BORGHETTI GK) O / W lotions containing sunscreens, "Braz. J. Pharm. Sci., Vol. 42, pp. 531-537, 2006) and M. Burnett and S. Wang (Burnett, M. and WANG S." Current sun-screen controversies: a critical review, "Photomed., Photodermatol. Photoimmunol., vol. 27, pp. 58-67, 201 1).

In this context, some attempts have been made to increase the stability and effectiveness of sunscreen products and decrease their local intolerance using new formulation strategies such as microparticles, nanoparticles, cyclodextrins or liposomes (JIMENEZ , M.; PELLETIER, JB AND MARTINI, M. "Influence of encapsulation on the in vitro percutaneous absorption of octyl methoxycinnamate", Int. J. Pharm., Vol. 272, pp. 45-55, 2004.; OLVERA - MARTÍNEZ, B. et al, "Preparation of polymeric nanocapsules containing octyl methoxycinnamate by the emulsification-diffusion technique: penetration across the stratum corneum, "J. Pharm. Sci., vol. 94, pp. 1552-1559, 2005.; RAMON, E. et al." Liposomes as alternative vehicles for sun filter formulations, "Drug Delivery. , vol. 12, pp. 83-88, 2005.; MOLINARI, A. et al. "Influence of complexation with cyclodextrins on photo-induced free radical production by the common sun-screen agents octyl-dimethylaminobenzoate and octyl-methoxycinnamate "Pharmazie, vol. 61, pp. 41-45, 2006.; TURSILLI, R., et al." Solid lipid microparticles containing the sunscreen agent, octyl-dimethylaminobenzoate: effect of the vehicle ", Eur. J. Pharm. Bi - opharm .. vol. 66, pp. 483-487, 2007) Also, encapsulation has been shown as an effective way to prevent octylmethoxycinnamate (WTO) photodegradation in formulations and to reduce its penetration into the skin leading to an increase FPS (PERUGINI, P. et al "Effect of nanoparticle encapsulation on photostability of the suncreen agent, 2-ethylhexyl-p-methoxycinnamate", Int. J. Pharm., Vol. 246, pp. 37-45, 2002.; ANUMANSIRIKUL N. et al, "Chitosan UV-screening nanocontainers: increasing the photostability of encapsulated materials and controlled release", Nanotechnology, vol. 19, pp. 19, 2008.; WEISS-ANGELI VOL. et al, "Nanocapsules of octyl methoxycinnamate containing quercetin delayed the photodegradation of both components under ultraviolet A radiation", J. Biomed. Nanotechnol, Vol. 4, pp. 80-89, 2008) and decreased systemic absorption (ALVARZ-ROMÁN, R. et al. "Biodegradable polymer nanocapsules containing a sunscreen agent: preparation and photoprotection". Eur. J. Pharm. Biopharm., Vol. 52, 191 -195, 2001; KLINUBOL, P. et al., "Transdermal Penetration of UV Filters." Skin Pharmacol. Physiol., vol. 21, pp. 23-29, 2008.; VETTOR, M. et al. "Poly (D, L-lactide) nanoencapsulation to reduce photoinactivation of a sunscreen agent." Int. J. Cosmet. Sci., Vol. 30, pp. 21 9-227, 2008).

Studies have demonstrated the feasibility of developing of new products based on encapsulated sunscreens as disclosed in WO 2004069216 ("Aqueous suspension of nanocapsules encapsulating sunscreen agents") and WO 201 1 1 13129 ("Nanostructured sun protection agent and process"), where WO 2004069216 discloses a stabilized composition of the cinnamic ester sunscreen, relating to a method of increasing the photostability of an encapsulated cinnamate derivative in a topical sunscreen, and WO 201 1112129 discloses a nanostructured sunscreen agent and its synthesis process comprising core-shell nanoparticles, consisting of a wall formed of oxide nanoparticles and a core of broad spectrum solar radiation protection polymers from UVA to UVB.

[007] Documents were identified that reveal a UV filter system, as well as its route of obtaining by emulsifying the organic phase in the aqueous phase, however no documents were identified that revealed a process contemplating emulsification and solvent diffusion using distillation technique, or a nanostructure composed of a thin film of polymeric amphiphilic blend with a high core concentration of an organic character.

WO2015022471 ("Aqueous suspension of nanocapsules encapsulating sunscreen agents") relates to an aqueous nanocapsule suspension comprising at least one UV filter (avobenzone [butyl methoxydibenzoylmethane] and ethylhexyl salicylate obtained by a method employing two The addition of the organic phase is added to the aqueous phase. In "production process of polymeric amphiphilic slender film nanostructure with high concentration of organic core for application against ultraviolet radiation" 3 phases are used, one phase added to the aqueous and a second aqueous phase added to the first emulsion, initiating the controlled diffusion process, the latter being the formed structure comprises a core filter blend without oil or other additives; furthermore, the polymeric capsule contains a blend of hydrophobic polymers, PCL, and Plurnic hydrophilic copolymer, and not just a polymer like the above invention, giving a superior and unexpected technical effect of future colloidal stability as well as photoprotective effect. and superior sensory due to the inclusion of the other UV filters (diethylamino hydroxybenzoyl hexylbenzoate, homosalate and octocrene) in the formulation when compared to the formulation disclosed in WO 2015022471.

In WO2014132261 ("Microcapsules including sunscreen agents'), microcapsules composed of a core with one or more sunscreen agents and a cover of a wall-forming polymer are disclosed which do not break by rubbing or pressing on the shell. The product generated in a "high-concentration polymeric amphiphilic blend thin-film nanostructure of an organic core for application against ultraviolet radiation", as it has a superior photoprotective and sensory effect due to the nanometric scale, the amphiphilic character of the skin. The polymeric thin film and the organic content of the UV filter is not an obvious derivative of the disclosure, and WO2014132261 also uses a method of emulsification and solvent evaporation, which does not allow nanocapsules to be generated, but only microparticles. case of "blef thin film nanostructure production process "The high-concentration polymeric amphiphilic organic core for application against ultraviolet radiation", the process involves one emulsification step and one solvent diffusion step to produce the nanostructures. The mechanisms governing particle formation are different, as in the case of solvent extraction it is necessary to employ a non-soluble solvent in the external phase of the emulsion, while in the case of solvent diffusion employed. a solvent in the partially soluble organic phase is added to the aqueous phase so that it can diffuse which determines the physicochemical process of generating the nanostructure. Another point to be highlighted is the use of a mixed polymer blend.

WO2014074555 ("Composition containing a cellulose derived capsule with a sunscreen") describes sunscreen formulations with one or more sunscreen agents (homosalate, butyl methoxydibenzoylmethane, Uvinul A Plus (diethylamino hydroxybenzoyl hexyl). benzoate), octocrylene and ethylhexyl salicylate encapsulated in a cellulose-derived capsule, preferably in the range 400 - 700 nm, and one or more additional agents, which differs from that disclosed herein by the process of obtaining, as for the composition and morphology of the nanostructure obtained.

SUMMARY OF THE INVENTION

[001 1] "Production Process of Polymer Amphiphilic Slender Film Nanostructure with High Organic Core Concentration as Ultraviolet Radiation Filter" generates a product that is obtained by emulsification and solvent diffusion, and at least one hydrophobic polymer combined with a hydrophilic block copolymer, organic interior and mixed composition of UV radiation filters, forming core-shell nanoparticles, where the shell is comprised of a thin amphiphilic film and the core by at least one. chemical agent for protection from solar radiation, and the nanostructures provide sun protection over a wide spectral range, ranging from UVA to UVB. The nanostructure with a thin amphiphilic combination film containing high concentration of encapsulated sunscreen agents is novel and inventive in the concept of performance in the Sunscreen Factor (SPF) and sensory effect when applied to the skin, corroborated by the fact that this sunscreen concentrates on the core organic sunscreens in a range of 50 to 90 wt% UV filter relative to the nanocapsule, making it possible to encapsulate high filter contents in a very thin / thin polymer blend structure. Furthermore, it is possible to work with higher concentrations of the chemical agent in sunscreen formulations, maintaining a sensory and cosmetic elegance, since the sunscreens protected by the amphilic thin film do not cause skin irritation or irritability because they are nanoencapsulated. and maintain the protective effect of UV radiation even when acting on the core. DESCRIPTION OF THE FIGURES

[0012] Figure 1 - Electron microscopy photo of the polymer nanoparticles of Example 1, with photo 1A increasing by 5,000X and 1B increasing by 10,000X.

[0013] Figure 2 - SEM photo of the polymeric nanoparticles of Example 2 containing potassium cetyl phosphate in the aqueous phase and dilution, photo 2A increasing by 5,000X and 2B increasing by 10,000X.

[0014] Figure 3 - Analysis results from Sample 3, where 3A Particle Size Distribution Chart, 3B Zeta Potential Distribution Profile, 3C1 SEM SEM micrograph with 20,000X magnification, 3C2 SEM SEM micrograph with 50,000X magnification, Figure 3D Thermography Curve Graph of the dry sample, 3E Differential Exploratory Calorimetry Profile Chart of the dry sample and 3F Physical Stability Profile Chart of the nanocapers suspension.

[0015] Figure 4 - Results of analysis of Sample 4, being 4A Particle Size Distribution Chart and 4B 23 h Turbidimetry Physical Stability Profile Chart.

[0016] Figure 5 - Representative non-scaled photographs of tests performed on the sample of Example 3, where 5A Photo of the sample layout on automated skin permeation system, 5B featuring Tape-stripping procedure and 5C showing shredded skins mixed with acetone for filter extraction.

DETAIL OF THE INVENTION

[0017] The "Organic Core High Concentration Polymeric Amphiphilic Slender Film Nanostructure Production Process for Application Against Ultraviolet Radiation" generates a peel-to-core nanoparticle conjugation product, where the shell is composed of a thin polymeric film comprising a blend of a hydrophobic polymer, which may be of the type polyester, polycarbonate, acrylate, methacrylate, acrylate derivatives, polyhydroxybutyrate, vinyl, styrenic, acrylamide, methacrylamide, preferably polycaprolactone, and polymer may also be used. of different molecular weights, such as 10 kDa, 45 kDa, 90 kDa, mixed with a hydrophilic copolymer, which may be of the polyether, polyacid, polyol type, preferably polyoxyethylene or polyoxypropylene copolymers, and the core by a character phase comprising the combination of chemical radiation protection agents the ultraviolet, salicylates, cinnamates, benzophenones, anthranilates, dibenzoylmethanes, camphor derivatives, triazones and PABA derivatives (or p-aminobenzoates) preferably the combination of at least two of these comprising a liquid physical mixture at a temperature of 22 ° C. 25 ^Q C.

The synthesis of the nanostructures involves three phases: organic, aqueous and aqueous dilution phase. In the organic phase, organic solvents such as ketones, esters and alcohols are used, or a combination of two or more of them, preferably ethyl acetate, where the hydrophobic polymer, the organic content of chemical agents against UV radiation, is added individually. hydrophilic copolymer polyoxyethylene polyoxypropylene copolymer, and a nonionic surfactant, preferably sorbitan laurate 80 EO. The aqueous phase is prepared with distilled water and surfactant type sodium lauryl ether sulfate or cocoamidopropyl betaine or coconut fatty acid diethanolamide or sorbitan 80 EO laurate, preferably cetyl phosphate. The dilution phase is prepared with distilled water and surfactants such as sodium lauryl ether sulfate or cocoamidopropyl betaine or coconut fatty acid diethanolamide or sorbitan 80 EO laurate.

The organic phase is prepared under magnetic or mechanical stirring from 10 to 700 rpm, preferably 200 rpm, and a temperature of 15 to 65 ° C, preferably 50 ° C until total dissolution of the components. The aqueous and dilution phases are prepared under mechanical agitation at 10 to 700 rpm, preferably at 200 rpm, and at a temperature of 15 to 65, preferably 25, until complete solubilization of the surfactants. Emulsion is formed by adding the organic phase to the aqueous phase directly with vigorous mechanical stirring from 1,000 to 23,000 rpm, preferably 7,000 rpm. The emulsion formed is transferred to the reactor under mechanical agitation at 150 to 1000 rpm, preferably at 400 rpm, and the dilution phase is added directly to the reactor. The system should remain under a vacuum of 1 to 600 mmHg, preferably 200 mmHg, at a temperature of 35 to 75, preferably 50, with mechanical stirring of 150 to 1000 rpm, preferably 400 rpm, for a time period of 15 to 180 minutes. preferably 40 minutes for extraction of the organic solvent.

EXAMPLES OF CARRYING OUT THE INVENTION

EXAMPLE 1: Obtaining high-concentration polymeric amphiphilic blend thin-film nanostructure of an organic character for application against ultraviolet radiation with addition of dilution phase in the reactor The organic phase was prepared with 50.0 g of ethyl acetate, 1.0 g of polycaprolactone (MW: 10 KDa), 1.0 g of polyoxyethylene polyoxypropylene block copolymers, 2.5 g of Ethoxylated Sorbitan Monolaurate 80 EO and 18.0 g of the mixture of butyl methoxydibenzoylmethane, diethylamino hydroxybenzoyl hexylbenzoate, ethylhexyl salicylate, homo-salate and octocrylene in 13.64% butyl methoxydibenzoyl methane, 4, 54% diethylamino hydroxybenzoyl hexylbenzoate, 18.18% ethylhexyl salicylate, 22.73% homosalate and 40.91% octocrylene. The aqueous phase was prepared with 22.5 g of distilled water and 2.5 g of sodium lauryl ether sulfate surfactant. The dilution phase was prepared with 45.0 g of distilled water, 2.5 g of sodium lauryl ether sulfate and 2.5 g of 80 EO ethoxylated sorbitan monolaurate. The organic phase was prepared under magnetic stirring at 100 rpm and heating to 50 ^Q C until complete dissolution of the components, yielding a translú- acidic solution. The aqueous and dilution phases were prepared by mechanical stirring at 250 rpm at room temperature until complete solubilization of the surfactants.

After solubilization of all components, the organic phase was poured onto the aqueous phase slowly with mechanical stirring of 7,000 rpm for 1 minute. Then the emulsion formed was inserted into the reactor under mechanical stirring at 400 rpm and the dilution phase added directly into the reactor. The system remained under vacuum (300 mmHg) at 50 ° C and mechanical stirring at 400 rpm for 40 minutes for ethyl acetate extraction.

The morphology of the nanocapsulated suspensions was evaluated and particle size, polydispersion index (IP) and pH were determined, and the results are presented in Table 1. Figure 1 presents the electron microscopy (SEM) images of the obtained sample.

Table 1: Results obtained with the product produced from according to the experimental conditions of Example 1.

EXAMPLE 2: Obtaining thin film nanostructure of polymeric amphiphilic blend with high organic core concentration with addition of potassium cetylphosphate as a dilution and aqueous phase

The production of polymeric amphiphilic slender thin film nanostructures containing sunscreen involved the preparation of three phases: organic, aqueous and dilution. In the organic phase, prepared with 50.0 g ethyl acetate, 1.0 g polycaprolactone (PM: 10 KDa), 1.0 g polyoxyethylene polyoxypropylene block copolymers, 2.5 g ethoxylated sorbitan monolaurate 80 EO and 18.0 g of a mixture of butyl methoxydibenzoylmethane, diethylamino hydroxybenzoyl hexylbenzoate, ethylhexyl salicylate, homosalate and octocrylene (13.64% diethylamino hydroxybenzoylhexylbenzoate, 18.18% ethylene salt) 22.73% homosalate and 40.91% octocrylene The aqueous phase was prepared with 22.5 g of distilled water and 2.7 g of potassium cetyl phosphate The dilution phase was prepared with 45.0 g of water distilled, 0.675 g of potassium cetyl and 2.5 g of sorbitan monolaurate 80 EO ethoxylate. the organic phase was prepared under magnetic stirring of 400 rpm and heating at 50 ^Q C until complete dissolution of the components obtaining a clear solution The aqueous and dilution phases were prepared mechanically stirred at 400 rpm at room temperature until complete solubilization of the surfactants.

After solubilization of all components, the organic phase was poured into the aqueous phase for 2 minutes with vigorous mechanical stirring of 7,000 rpm using Ultraturrax. Then the emulsion formed was inserted into the reactor with mechanical stirring of 400 rpm and the dilution phase added directly to the reactor. The system remained under vacuum -480 mmHg at 50 ° C with mechanical stirring of 400 rpm for 40 minutes for extraction of ethyl acetate.

The morphology of the nanocapsulated suspensions was evaluated by high resolution scanning electron microscopy (SEM-FEG) and the particle size, polydispersion index (IP) and pH were determined. The results are shown in Table 2. Figure 2 shows the electron microscopy (SEM) images of the obtained sample.

Table 2: Results obtained with the product produced under the experimental conditions of Example 2.

EXAMPLE 3: Obtaining a high-concentration organic polymeric amphiphilic blend thin film nanostructure with phase warming, high shear homogenization, and 3 g polymer mass

The production of polymeric amphiphilic slender thin film nanostructures containing sunscreen involved the preparation of three phases: organic, aqueous and dilution. In the organic phase, prepared with 50.0 g ethyl acetate, 3.0 g polycaprolactone (PM: 10 KDa), 1.0 g polyoxyethylene polyoxypropylene block copolymers, 2.5 g ethoxylated sorbitan monolaurate 80 EO and 30.0 g of the mixture of butyl methoxydibenzoylmethane, diethylamino hydroxybenzoyl hexylbenzoate, ethylhexyl salicylate, homosalate and octocrene (13.64% butyl methoxydibenzoylmethane, 4.54% diethylamino hydroxybenzoylhexylbenzoate, 18.18% ethylene 22.73% homosalate and 40.91% octocrylene The aqueous phase was prepared with 22.5 g of distilled water, 2.5 g of 80 EO ethoxylated sorbitan monolaurate and 0.34 g of cetylphosphonate. Potassium fact. The dilution phase was prepared with 45.0 g of distilled water, 0.68 g of potassium cetyl phosphate, 2.5 g of 80 EO ethoxylated sorbitan monolaurate. The organic phase was prepared with magnetic stirring of 400 rpm under heating to 50 ^Q C until complete dissolution of the components to give a clear solution. The aqueous layers were diluted and prepared with magnetic stirring of 400 rpm under heating to 50 ^Q C until complete solubilization of the surfactants.

After solubilization of all components, the organic phase was poured slowly over the aqueous phase for 15 minutes with mechanical stirring of 7,000 rpm. Then, the dilution phase was poured onto the formed emulsion and the dispersion formed was allowed to stir for 3 minutes at 7,000 rpm. The particulate suspension was then added to the reactor, leaving the system under vacuum - 480 mmHg at 50 ° C with mechanical stirring of 400 rpm for 40 minutes for ethyl acetate extraction.

The morphology of the nanocapsulated suspensions was evaluated by high resolution scanning electron microscopy (SEM-FEG) and particle size, polydispersion index (IP) and pH were determined. Thermogravimetric analysis (TG), differential exploratory calorimetry profile (DSC) and physical stability of the suspension by turbidimetry were performed. The results obtained are shown in Table 3.

Figure 3A shows the electron microscopy (SEM) images of the sample obtained in the method.

Table 3 - Results of Sample Characterizations of Example 3

EXAMPLE 4: Obtaining nanostructured film nanostructure high concentration polymeric amphiphilic blend of an organic core for application against ultraviolet radiation with heating of the aqueous and dilution phases and use of high shear homogenization

[0037] The production of the organic core high concentration polymeric amphiphilic thin film nanostructure for application against ultraviolet radiation involved the preparation of three phases: organic, aqueous and dilution. In the organic phase, prepared with 150.0 g ethyl acetate, 12.0 g polycaprolactone (PM: 10 KDa), 6.0 g polyoxyethylene polyoxypropylene block copolymers, 7.6 g ethoxylated sorbitan monolaurate 80 EO and 90.0 g of the mixture of butyl methoxydibenzoylmethane, diethylamino hydroxybenzoyl hexylbenzoate, ethylhexyl salicylate, homosalate and octocrylene (13.64% diethylamino hydroxybenzoylhexylbenzoate, 18.18% ethylene salt) 22.73% homosalate and 40.91% octocrylene The aqueous phase was prepared with 67.6 g of distilled water, 1.0 g of potassium cetylphosphate and 7.5 g of 80 EO ethoxylated sorbitan monolaurate. The dilution phase was prepared with 135.7 g of distilled water, 2.0 g of potassium cetyl phosphate, 7.6 g of 80 EO ethoxylated sorbitan monolaurate.The organic phase was prepared with magnetic stirring at 400 rpm under 50 ° C heating. ^Q C until the total dissolution of the components obtaining a translucent solution. gone. The aqueous layers were diluted and prepared with magnetic stirring of 400 rpm under heating at 50 ^Q C until complete solubilization of the active tenso-.

After solubilization of all components, the organic phase was poured slowly over the aqueous phase over 15 minutes with mechanical stirring of 7,000 rpm. Then the dilution phase was poured over the formed emulsion and the dispersion formed was left to stir for 3 minutes at 7,000 rpm. The particle suspension was It is then added to the reactor, leaving the system under vacuum at 400 rpm at 50 ° C, with mechanical stirring at 400 rpm for 5 hours to extract ethyl acetate. To the suspension of the obtained nanoencapsulates was added 1.2% (w / w) mixture of phenoxyethanol with caprylyl glycol and 0.6% (w / w) dehydroacetic acid as preservative system. Particle size, polydispersion index (IP) and solids content as shown in Table 4 were determined, and the physical stability of the nanoparticle suspension was monitored by dynamic turbidity where the 23 hr profile is presented. in Figure 4B.

Table 4 - Sample Characterization Results from Example 4

Horn, stratum and dermis of Example 3

In the skin permeation assay, vertical diffusion cells (CVD) were used, employing animal membrane (pig's ear skin) as permeant membrane.

The assay was conducted at a temperature of 32 ± 0.5 and rotation of 300 rpm, with 0.4 g of sample formulation taken, evenly spread in duplicate over the permeant membrane, placed over the area of 1 µm. 77 cm ² available for diffusion cell permeation as depicted in Figure 5A using pH 7.2 phosphate buffer as the receptor solution.

For the determination of permeated sunscreen blend concentrations, 1.0 mL aliquots of the receiving solution were collected at predetermined time intervals (0, 1, 2, 4, 6, 8, 10, 12 and 24 hours), and the total duration of the experiment was 24 hours. Asset concentrations were quantified by high performance liquid chromatography (HPLC) using column chromatography. 150 x 4.6 mm and diode array detector (DAD). The concentrations of each component of the sunscreen blend were measured by the linear regression method using a calibration curve constructed with standards prepared by mixing the constituent chemicals of the sunscreen blend at the composition concentrations solubilized with ethanol PA.

At the end of the experiment, the membranes were subjected to tape stripping to measure the dye retained in the stratum corneum. For this, the membranes were removed from the CVDs, washed with water and gently dried, and the stratum corneum layers of the dye contact region were removed by adhesive tapes (16 strokes), as shown in Figure 5B. The strips were washed in 10 mL of acetone on a mechanical shaker at 2500 rpm for 1 minute, then ultrasound for 16 minutes. The supernatant was analyzed by HPLC according to the above methodology.

After stratum corneum removal, the membrane contact area was cut and ground in acetone, as shown in Figure 5C 3, and subjected to centrifugation separation at 5000 rpm for 5 minutes. The supernatant was assessed by HPLC under the conditions previously cited.

The results indicated that there was no permeation of the dye blend in the animal membrane, since the absorbance for the collected samples were close to zero and below the detection limit of the method, indicating that the nanostructure probably does not have systemic absorption.

The permeation assay indicated that the percentages for permeate were practically zero and below the detection limit of the method, indicating that there is no nanoencapsulated filter blend penetration.

Claims

1 . Production process of polymeric amphiphilic slender film nanostructure with high concentration of organic core for application against ultraviolet radiation, characterized by involving three phases: organic, aqueous and aqueous dilution phase, where in the organic phase solvent is used. organic compounds such as ketones, esters and alcohols, or a combination of two or more of them, where the hydrophobic polymer, the organic content of chemical agents against UV radiation, the hydrophilic copolymer, and a nonionic surfactant are added individually; the aqueous phase is prepared with distilled water and surfactant of the sodium lauryl ether sulfate or cocoamidopropyl betaine or coconut fatty acid diethanolamide or sorbitan 80 EO laurate or cetyl phosphate type surfactant; and the dilution phase is prepared with distilled water and surfactants such as sodium lauryl ether sulfate or cocoamidopropyl betaine or coconut fatty acid diethanolamide or sorbitan laurate 80 EO;

Process for producing an organic core high concentration polymeric amphiphilic slender thin film nanostructure for application against ultraviolet radiation according to claim 1, characterized in that the organic phase is prepared under magnetic or mechanical stirring from 10 to 700 rpm, and a temperature of 15 to 65 ° C until total dissolution of the components; the aqueous and dilution phases are prepared under mechanical agitation at 10 to 700 rpm, and at a temperature of 15 to 65 ° C until complete surfactant solubilization; wherein the emulsion is formed by the addition of the organic phase to the aqueous phase directly with mechanical stirring from 1,000 to 23,000 rpm; the emulsion formed is transferred to the reactor under mechanical agitation at 150 to 1000 rpm and the dilution phase is added directly to the reactor; finally the system must remain under vacuum from 1 to 600 mm Hg under temperature from 35 to 75, with mechanical stirring of 150 to 1000 rpm for a time period of 15 to 180 minutes for extraction of the organic solvent.

Process for producing an organic core high concentration polymeric amphiphilic slender thin film nanostructure for application against ultraviolet radiation according to claims 1 and 2, characterized in that the organic phase is used as an organic solvent ethyl acetate wherein the polyoxyethylene polyoxypropylene hydrophilic copolymer and sorbitan laurate 80 EO are added individually as a nonionic surfactant; the aqueous phase is prepared with distilled water and cetyl phosphate as a surfactant, and the dilution phase is prepared with distilled water and surfactants such as sodium lauryl ether sulfate, or coco fatty acid diethylamide and coconut fatty acid sorbitan laurate. IT'S THE;

Process for the production of an organic high-density polymeric amphiphilic blend thin film nanostructure for application against ultraviolet radiation according to claims 1 and 2, characterized in that a core shell is used for constitution of the core shell. blend of a hydrophobic polymer of the polyester, polycarbonate, acrylate, methacrylate type, acrylate, polyhydroxybutyrate, vinyl, styrenic, acrylamide, methacrylamide derivatives, or polymers of different molecular weights of 10 kDa or 45 kDa or 90 kDa mixed to a hydrophilic copolymer of the polyether, polyacid, polyol, polyoxyethylene or polyoxypropylene type, and for the composition of the nucleus the combination of chemical ultraviolet radiation protection agents salicylates, cinnamates, benzophenones, anthranilates, benzoylmethanes, camphor derivatives, triazones and PABA derivatives (or p-aminobenzoates) comprising a physical mixture ca liquid temperature at 22 to 25 ^Q C.

5. Production process of high core concentration polymeric amphiphilic thin film nanostructure Organic material for application against ultraviolet radiation according to Claims 1 and 2, characterized in that the organic phase is prepared under magnetic or mechanical stirring at 200 rpm and at a temperature of 50 ° C until the total dissolution of the components; the aqueous and dilution phases are prepared under mechanical agitation of 200 rpm and 25 ° C until complete surfactant solubility; emulsion formation occurs by adding the organic phase to the aqueous phase directly with mechanical stirring of 7,000 rpm, the emulsion formed being transferred to the reactor under mechanical stirring at 400 rpm, and the dilution phase being added directly to the reactor; and the system remains under vacuum of 200 mmHg, at a temperature of 50 ° C, with mechanical stirring of 400 rpm for a time period of 40 minutes for extraction of the organic solvent.

Process for the production of a high-concentration polymeric amphiphilic blend thin-film nanostructure of an organic character for application against ultraviolet radiation according to claim 5, characterized in that a blend of the core shell is used for constitution of the core shell. polycaprolone hydrophobic polymer mixed with the polyoxyethylene or polyoxypropylene hydrophilic copolymers, and the combination of at least two ultraviolet radiation shielding chemicals to form the core.