BR102012031954A2 - ACTIVE SUBSTANCE NANOFIBERS FOR COSMETIC APPLICATION OF CONTROLLED RELEASE OBTAINED BY ELECTROPHIATION AND PROCESS - Google Patents

Abstract

NANOFIBERS WITH ACTIVE SUBSTANCE FOR COSMETIC APPLICATION OF CONTROLLED RELEASE OBTAINED BY ELECTROPHIATION AND PROCESS refers to cosmetic product, characterized by the special physical form and composition containing nitrogenous organic compounds of the xanthines group, obtained by electrophilization of polymeric solutions in the presence of the active targeting. its encapsulation for later controlled release in the dermis region, preferably to combat cellulite (gyno hydrolipodystrophy - HDLG). Ginoid hydrolipodystrophy (HDLG), more commonly known as cellulitis, is an organic dysfunction characterized by the onset of depressions and elevations caused by the accumulation of fat in various body regions such as legs, thighs, hips and buttocks. causes of its appearance. From puberty, estrogen is produced in greater quantity, leading to greater volume gain in the buttocks and thighs, by increased fluid retention and increased fat concentration in these regions. The formulations currently used with caffeine are generally found in cosmetic gel and emulsion form. One of the barriers found in topical use is related to the absorption of active principles by the epidermis (mainly by the horny extract), which is a limiting factor of its action in the case of HLDG, where the active principle must reach the patient's dermis. In addition to this difficulty, there is product loss due to the formulation's contact with external objects such as clothing and bedding. The incorporation of caffeine to skin-acting nanofilms is an alternative to increase the efficiency of this treatment, constantly providing the active ingredient to the skin, as well as occlusion at the application site, raising the skin temperature and promoting permeation. and the penetration of caffeine through the skin. Thus, we seek to increase the effectiveness of caffeine lipolytic action in reducing HLDG.

Description

"NANOFIBRAS WITH ACTIVE SUBSTANCE FOR COSMETIC APPLICATION OF CONTROLLED RELEASE OBTAINED BY ELECTROPHIATION AND PROCESS" The invention belongs to the cosmetic products and aesthetic applications sector (domestic or professional use); skincare, personal care and medicated preparations containing cosmetic / therapeutic active ingredients characterized by special non-woven nanostructured physical forms (nanofibers) containing active ingredients encapsulated within them, these ingredients being nitrogenous organic compounds from the xanthine group which are released in a controlled manner, providing greater stability to the active component, modulating its release to the skin over time and conferring greater efficacy in the intended action with lower risk of adverse effects.

Due to the diameter of the fibers that make up the nanofibers, their composition and morphology, the nanofibres prepared herein can be applied topically to human or animal skin products and / or as a transdermal system for the delivery of active components. The nanofiber presented here is obtained by the electrofinning process, using polymeric materials as encapsulating matrix and an active ingredient of the group of xanthines for cosmetic, pharmaceutical, veterinary and personal hygiene applications.

TECHNICAL STATE

Electro-spinning process The process known as electro-spinning is an old technique and its first descriptions date from the early 20th century. In 1969, Geoffrey Ingram Taylor contributed his work to the electrophony technique by developing a mathematical model that describes the cone formed by the drop of fluid under the influence of an electric field, known to this day as the Taylor cone [ 1]. In the beginning, this technique was known as electrostatic spray or electrostatic wiring, and later in the 1990s, it was renamed electropathing.

Preparation of nanofibers by electrofinning technology Nanofibers can be obtained by different technological pathways, each with its own advantages and disadvantages. However, the electrofinning technique has been outstanding in recent years due to its versatility for laboratory adaptation and industrial scale processes. and for the use of different polymer families. The nanofilm electrofinning process involves applying a large potential difference between a polymer solution and a collecting surface. As this difference increases, the drop of solution elongates into a cone, known as the Taylor cone. When the force of electric attraction exceeds the surface tension of the droplet, a solution jet forms that travels between the needle and the collector. In this path, the solvent is volatilized and only the polymer settles on the collecting surface, forming a film with nanometric dimensions.

More thoroughly, the process occurs when a drop of polymeric solution hangs on the tip of the syringe, which becomes electrified inducing charge accumulation on the droplet surface, and this droplet deforms into a cone (Taylor's cone). Such deformation is attributed to two reasons: a) electrostatic repulsion between the droplet surface charges, and b) the Coulomb force exerted by the applied external electric field. The movements of polymeric solutions in the form of a jet directed to the collector are accompanied by the simultaneous evaporation of solvent molecules, leading to the deposition of a nanofiber mat on the collector surface. This system is known as a single or monaxial nozzle because it uses only one capillary that contains the polymer solution to be electrophysed. There are newer wiring configurations, for example, the coaxial configuration. In this case, the process design involves two capillaries in a coaxial position that allow simultaneous electroporation of two polymer solutions in a structured nanofiber core-shell system. In this configuration, there are two separate polymer solutions that are pumped into different capillaries, which are coaxial with one capillary within a smaller larger capillary. In addition to this, there are other wiring configurations, such as multiple wiring, core-shell wiring, or solution blow wiring.

The Polymers Used in the Electro Spinning Process The raw materials commonly used in the industrial production of conventional woven and non-woven fibers are naturally occurring polymers first and synthetic polymers second. Reasons identified by various industries for this preference for polymeric materials are feasibility, moldability, flexibility, lightness, durability, and chemical and physicochemical stability. In this context, considering the possibility of obtaining nanoscale fibers, the polymers were chosen as the main candidates for the development of nanofibers, in line with the historical evolution, highlighting that the polymeric materials are the most exploited for the production of nanofibers today. in day. The selection of the type of electrophilic polymer depends on the material properties and must be considered as a function of the desired application for nanofiber, and the electrophilization process can be modified to obtain fibers with the desired morphology. For example, in applications such as wound healing support, polymer selection is limited to the biocompatibility of the material with the skin 121 and the polymer may be dissolved in a suitable solvent and subsequently electrophilized, or may be directly electrophilized from a mass. fused. In this case, the presence of the organic solvent is eliminated. However, polymer melting requires processing at a high temperature, whereas the polymer solution can be electrophilized at room temperature 13]. The family of polymers used in nanofiber production includes homopolymers and copolymers of natural and synthetic polymers, as well as mixtures of both polymers. The natural polymer based electrophilization process has been used to generate nonwoven webs for biomedical applications due to biocompatibility and low immunogenicity compared to synthetic polymers. However, these raw materials may have a limitation on properties that vary from batch to batch. The most commonly used natural polymers are chitosan, collagen, gelatin, casein, hyaluronic acid, cellulose acetate, silk protein, chitin and fibrinogen.

Synthetic polymers can be adapted to the desired properties of the application, and also allow for good uniformity in the spinning process. The most commonly used synthetic polymer in biomedical applications, and extended for drug delivery applications, include biodegradable hydrophobic polyesters such as poly (lactic acid-glycolic acid) (PLGA), poly (lactic acid) (PLA) and poly (D-caprolactone) (PCL). In addition, other biodegradable hydrophilic polymers such as polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA) and polyethylene oxide (PEO) have been used in biomedical applications.

Some applications require a structure with properties of two or more polymers, which can be obtained by polymerizing two different polymers (such as PLGA copolymer, a random glycolic (G) and lactic (L) copolymer), representing a polymer that is classic and well studied, described in the literature, lactide and ε-caprolactone (PLLA-CL), poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), and poly (p-dioxanone-co-lactide) - poly (ethylene glycol) block (PPDO / PLLA-b-PEG) or by physically mixing two or more polymers (blends). The mixtures allow the combination of different polymer families such as natural and synthetic polymers without a chemical reaction between these materials.

Nanotechnology in Controlled Release Systems (SLC) There is currently a great interest in selective drug release, and carrier systems have been extensively studied to improve the selectivity and efficiency of formulations. Modified release systems are a response to this trend as they are designed to provide or near optimal levels for extended periods, favoring treatment. In this context, biodegradable polymers in the form of colloidal particles have been studied with promising possibilities for success for future applications in injectable, topical and ophthalmic antimicrobial, anticancer and anti-inflammatory chemotherapy.

An example of successful use of nanotechnology in a very important subject for pharmaceutical development is the control of the physicochemical properties of bioactive agents. In the past, the development of one drug was abandoned or replaced by another when it encountered a molecule with low water solubility, consequently poor bioavailability. Currently, the use of nanocrystallization techniques (top-down or bottom-up nanocrystals generation) could minimize this bioavailability limitation of hydrophobic molecules. In addition, the use of bottom-up nanofabrication techniques requires the ability to predict the type of aggregate structure obtained and to synthesize molecules in a controlled manner that interact with biological surfaces at the nanoscale. This strategy results in the creation of technological platforms for the mimicization of biological systems that could be employed in encapsulation and controlled drug release processes. A limitation of Controlled Release Systems is the circulation time in the carrier's bloodstream, which in some cases is insufficient for complete drug release. This circulation time can be considerably increased with the use of nanocarriers. For example, nanocarriers with string-like morphology can increase the circulation time in the bloodstream by ten times compared to one in spherical shape. This type of information may suggest that in controlled release processes other factors may influence its success, including the type of nanoparticle morphology [4].

Nanoencapsulation The concept of microcapsule arose from the idealization of the cellular model. In this concept, the membrane that surrounds and protects the cytoplasm and other components simultaneously performs other functions, such as controlling the input and output of cell material. Similarly, the microcapsule generally consists of a polymer layer that acts as a protective film, isolating the active substance and avoiding the effects of its inadequate exposure. This membrane breaks down upon specific stimuli, releasing the substance at specific locations or at the rate most appropriate to treatment. Another possibility of encapsulation, besides capsules, is the formation of microspheres. In this second case, the active material is dispersed in a solid polymer matrix [5].

The first pharmaceutical research by the University of Wisconsin (United States) dates back to the 1950s. Microcapsules are mainly used to increase the stability of a drug, to modify or delay its release at specific sites of action. Anti-inflammatory substances, for example, may have their working time in blood plasma increased by microencapsulation, prolonging their effect on the body [5].

Initially, microparticles were produced with sizes ranging from 5 pm to 2 mm, however since 1980 a second generation of smaller sized microparticulate systems has been developed. These systems include nanoparticles (10-1000 nm in diameter) and microparticles (1-10 pm in diameter). Other systems capable of encapsulating active substances are liposomes and microemulsions. Microencapsulation was used as a model for the development of more sophisticated techniques, now in nanometer scale, allowing the manufacture of nanoparticulate systems. The discovery of liposomes in the 1960s increased the range of tools for the development of pharmaceutical nanotechnology with lipid systems for drug vectorization. In the 1990s, more sophisticated nanosystems emerged coated with hydrophilic polymers, called stealth systems, which allow a longer circulation time in the body. In addition to stealth systems, systems containing signaling molecules on nanoparticle surfaces, called site-specific, were developed for the purpose of targeting drugs specifically to target cells [6].

Letchford and Burt [7] present a generic classification of nanoparticle types employed in controlled drug release, later adapted by Oliveira [8].

Nanostructured carrier systems have been extensively studied for oral and parenteral administration and may also be used to release various substances through the skin. Polymeric nanoparticles are carrier systems that have diameters of less than 1pm and differ according to their composition and structural organization [9] [101. Nanoparticles may consist of a polymeric matrix, where the active substance may be retained, molecularly dispersed or adsorbed, with no oil in its composition (nanospheres). On the other hand, nanocapsules are constituted by a polymeric shell, containing an oily reservoir system, and the drug may be dissolved or retained in this nucleus and / or adsorbed to the polymeric wall. [10] [11] Nanoemulsions consist of a hydrophilic phase, a lipophilic phase and surfactants without the presence of the polymer. These systems are also made up of very small particles in the nanometer range. Drug delivery systems may also be comprised of lipids organized into a solid lipid matrix, which are termed solid lipid nanoparticles [12].

Nanofiber-based controlled release systems Polymeric nanofibers appear as a new drug delivery controlled release system, which can be manufactured by different methods, including the above-mentioned electrophony technique.

Polymeric nanofibers, whether obtained by electrophony or other techniques such as solution blow spinning, provide the development of a wide range of materials for diverse applications, either as biocompatible substrates or as controlled drug delivery devices. Several types of polymers (synthetic or natural, biodegradable), in the form of blends and / or composites, can be employed in the development of nanofiber blankets. With these products, one can control whether drug release occurs by diffusion mechanisms or by diffusion / degradation of the incorporation matrix. The use of fibrous matrices in the release of antibiotics, anticancer drugs and proteins has recently been evaluated, since one of the main purposes of drug incorporation in polymeric matrices is to treat infections and inflammatory processes that may lead to implant rejection. The electrophony technique for obtaining nanofibers has attracted the attention of many researchers due to the characteristics of the fabricated film, especially in relation to the high area / volume and length / diameter ratio, as well as its ability to incorporate elements such as cells, proteins and drugs. and / or controlled release active components and may be a potentially applicable process in the production of filters and optical devices in the biomedical area of tissue engineering and injury recovery I13].

The polymers employed to control active component release may or may not be biodegradable. Due to this great flexibility in the selection of materials to electrophyte, there are different families of active components that apply to this system as a vehicle for its release, such as antibiotics, antineoplastic, anti-inflammatory, contraceptives, among others 114].

Electrofinning nanofibers have the advantage of enhancing / enhancing the release of the active component when compared to the films obtained via casting (cast / cast), as a function of the amount of active ingredient released / area / time of skin contact. The application of nanofibers as a controlled drug release system may be an alternative for topical administration, that is, administration of substances to the skin, aiming at a local or even transdermal action. It is suggested that parameters such as occlusion of the application region as a function of nanometer fiber blanket overlap may be enhanced implying a more intense dermal absorption. HDLG, Pathophysiology and Treatment Gynoid hydrolipodystrophy (HDLG), more commonly and popularly known as cellulitis, is an organic dysfunction characterized by the onset of depressions and elevations caused by fat accumulation in various body regions such as legs, thighs, hips and buttocks.

Published studies suggest that approximately 85% of women have some post-adolescent HDLG degree. In men, this condition is very rare due to differences in connective tissues. HDLG generally results from localized adipose deposits and edema that occur within subcutaneous tissue. In women, connective tissue fibers are oriented longitudinally from the deep fascia to the dermis.

Connective tissue cells are fibroblasts or fibrocytes, and connective tissue fibers may be collagen fibers, reticular fibers, or elastic fibers, which form the framework of the supporting tissues. These fibers form fibrous septa that secrete fat into channels, and as the fat layer expands it is projected superficially, creating a wrinkled skin appearance. The cross-fiber pattern of male connective tissue in the thigh and buttock region, which holds the fat layer, prevents the projection of adipose tissue on the skin surface. Hormonal oscillation is a major cause of the onset of HDLG. From puberty, estrogen is produced in larger quantities, leading to greater volume gain in the buttocks and thighs because it increases fluid retention and causes increased fat concentration in these regions. Topical treatment of cellulite has been employed through different therapies, which can be divided into four categories based on the mechanism of action, namely increased microcirculation flow; lipogenesis reduction and lipolysis induction; restoration of the normal structure of the dermis and subcutaneous tissue and prevention of free radical formation.

Methylxanthines such as caffeine, aminophylline, theophylline and theobromine are classified as β-agonists, being the main well-described category in the treatment of HDLG. The most widely used and safe methylxanthine is caffeine, usually employed at concentrations of 1 to 2% that acts directly on adipose cells, promoting lipolysis by inhibiting phosphodiesterase and increasing intracellular cyclic adenosine monophosphate (AMP) concentration. This action activates the lipase enzyme, resulting in the breakdown of triglycerides in free fatty acids and glycerol helping lipolysis, which leads to an improvement in HDLG status. In addition, caffeine also has a stimulating effect on skin microcirculation.

There are studies that relate the topical use of caffeine to the anticellulitic action [15] and there are products on the market that use this substance for this same purpose.

The formulations currently used with caffeine are generally found in cosmetic gel and emulsion form. One of the main barriers encountered in topical use is the absorption of active principles by the epidermis, especially by the horny extract, which is a limiting factor of its action in the case of HLDG, where the active principle must reach the patient's dermis. In addition to this difficulty, there is also product loss due to contact of the gel or emulsion with external objects such as clothing and bedding.

Nanofiber-based controlled release systems for HDLG treatment

Some patented inventions have used electrophilic polymeric nanofibers for controlled release application of different actives, for example, in document KR 20100092545 I16], where a hydrophobic polymeric nanofiber is electrofinance for the delivery and controlled release of an anticancer peptide. This composition contains poly (D-caprolactone) (PCL ^ a hydrophilic portion containing ethylene polyoxide (PEO) and the drug. The surface porosity of nanofiber is greater than 99% and the weight average molecular weight of PCL employed is 75,000 to Although this invention indicates the use of nanofibers for the conveyance of an asset, in this case the conveyed asset is an anticancer of specific use for this purpose, whereas “ACTIVE SUBSTANCE NANOFIBERS FOR CONTROLLED COSMETIC APPLICATION OBTAINED BY ELECTROPHIATION AND PROCESS” ”Deals with the use of nanofibers for encapsulation and delivery of assets applied to the treatment of cellulite.

Other works that report the application of caffeine are cited here in order to align the state of the art of application, however they all deal with topical applications employing particulate systems such as nanolipids, emulsions and creams. FR2921270-A1 [17] discloses the use of an active ingredient capable of stimulating and / or elevating the expression of adipose triglyceric lipase (ATGL) and / or identification of comparative gene 58 (CGI-58) in skin cells for preparation dermopharmaceutical cosmetic composition for cellulite reduction; FR2944442-A1 1181 discloses corilagin extract for use in the preparation of cosmetic compositions as an anticellulitic agent, drainage agent, angiogenesis inhibitor and / or extracellular matrix regulator, and DE102009028996-A11191 discloses a formulation employing different active ingredients, among them, caffeine via a lipid carrier in the form of a lipid vesicle, which is administered in the form of a gel, cream or lotion. In none of these cases was a controlled release formulation simultaneously delivered through nanofibers, which is new in relation to the state of the art.

Similarly, another document describing electrofinishing nanofibers (W02005025630) 1201 requires the use of this product for filtration devices, medical prosthetics, controlled release of assets, cosmetic masks and protective clothing. Despite the possibility of using this nanofiber for a controlled release system, it is based on a composite that combines the polymeric material of the polyphosphazene group with inorganic or organometallic polymers and also hydroxyapatite nanometric particles, which constitutes a fundamental difference in composition. and structuring the nanofibers in relation to the product object of this patent.

A work that presents aspects similar to the object of this patent deals with polymeric nanofibers obtained by electrofinning for controlled release application of different actives, described in the document W02009133059 [211, however this work reports the obtaining of nanofiber polymer matrix containing a suspended active ingredient or externally impregnated in the fibers formed by electrophilization, which constitutes a determining difference in the release mechanism of the active mat obtained in relation to “NANOFIBRAS WITH ACTIVE SUBSTANCE FOR CONTROLLED COSMETIC APPLICATION OBTAINED BY ELECTROPHIATION AND PROCESS”, where the asset is not suspended or impregnated or dispersed on the fibers, thereby contrasting the release mechanism and featuring a controlled release mechanism quite distinct from that described in the document. The system object of this patent is an encapsulant non-woven blanket (in non-woven or “woven” form), and the asset is encapsulated within the nanofiber that forms it, where for the release of this asset to occur. contact with a liquid medium and the swelling or degradation of the encapsulating structure (polymeric matrix), resulting in a sophisticated controlled release mechanism On the other hand, in the work W02009133059í21] the active is suspended or impregnated in the fibers, ie free in the nanofiber blanket, requiring no degradation, erosion or even swelling process for its release to the medium.

SUMMARY OF THE INVENTION

Considering the context of this state of the art, the work strategy was to develop a nanostructured system for drug delivery and active ingredients that would allow controlled release during the application period for topical administration and result in a modified skin permeation of these active agents into the skin. It can be used to treat HDLG. The incorporation of caffeine to nanofilms, forming non-woven blankets, which act as skin adhesives is an alternative to increase the efficiency of this treatment, constantly providing the active principle to the skin, besides causing occlusion at the application site, avoiding loss of active contact, increasing skin temperature and promoting the permeation and penetration of caffeine through the skin, thereby increasing the effectiveness of caffeine lipolytic action in reducing HLDG. “ACTIVE SUBSTANCE NANOFIBERS FOR COSMETIC APPLICATION OF CONTROLLED RELEASE OBTAINED BY ELECTROPHIATION AND PROCESS” also considers polymer materials with characteristics especially suitable for encapsulation and controlled release of caffeine, allowing a solution of them to be electrophilized, forming nonwoven webs of nanofibers. that allow the caffeine to be encapsulated, protecting it from chemical and physical degradation and thus preserving its stability, releasing it in a controlled manner and modulating its action in the environment, such as improving its skin permeation when compared with the free active.

Thus, “NANOFIBERS WITH ACTIVE SUBSTANCE FOR COSMETIC APPLICATION OF CONTROLLED RELEASE OBTAINED BY ELECTROPHIATION AND PROCESS” is a product consisting of a caffeine-carrier polymeric film or blanket formed of polysaccharides, animal or vegetable protein, chitosan, gum arabic, xanthan gum, guar gum, carrageenan gum, cashew gum, tara gum, tragacanth gum, karaya gum, gati), cellulose derivatives (carboxymethyl cellulose, carboxyethyl cellulose, etc.), polyvinylpyrrolidone (PVP), poly (meta) acrylates (PM), poly (meta) acrylamides, polyesters, polyvinylcaprolactans, polyamides, polyvinyl alcohol (PVA) or blends of these polymers with nanometric dimensions, ie diameters from 50 to over 1000 nm (moving to microfiber category ) obtained by the electrophilization process, aiming at the formation of a system of cosmetic use that promotes the controlled release of this active ingredient (caffeine) in the dermis to the fight against cellulite, and the variables of the electropower process that generate this product. The novelty and inventive activity of the invention disclosed herein consists of a non-woven nanofiber blanket, the active being encapsulated within the nanofiber, and the release mechanism of this active relying on the swelling, degradation or erosion of the polymeric matrix, implying a sophisticated mechanism of controlled release, and also the variables of the process of electrophony generation of this product. Moreover, the application of these nanofibers for topical caffeine administration and HDLG treatment increases the skin's permeation of the active compared to the free active, with a new technical result.

DESCRIPTION OF THE FIGURES

Figure 1. Microphotograph of electrophilized PVA nanofibers with a flow rate of 2 mL / h and 22 kV voltage, obtained by 3500x magnification Scanning Electron Microscopy Figure 2. Microphotograph of electrophilized PVA nanofibers with a flow rate of 1mL / h 18 kV, obtained by Scanning Electron Microscopy at 5000x magnification.

Figure 3. Microphotograph of electroplated PVP / PM nanofibers with a flow rate of 1 mL / hr and 18 kV voltage obtained by Scanning Electron Microscopy at 75,000x magnification.

Figure 4. Microphotograph of caffeine-containing PVP / PM nanofibers obtained by Scanning Electron Microscopy at 5000x magnification.

Figure 5. Microphotograph of caffeine-containing PVP / PM nanofibers obtained by Scanning Electron Microscopy at 25000x magnification.

Figure 6. Chart of DSC Profiles. (a) caffeine; (b) PM polymer; (c) PVP polymer; (d) Caffeine free nanofiber and (e) Caffeine nanofiber.

Figure 7. Graph of FTI IR Profiles of (a) Caffeine; (b) PM polymer; (c) PVP polymer; (d) Caffeine free nanofiber and (e) Caffeine nanofiber.

Figure 8. Controlled release (LC) graph of caffeine in two distinct buffered solutions employing pH 5.5 and pH 7.4 buffer solution. Figure 9. Graph of caffeine permeation by pigskin skin area performed on Vertical Cell Diffusion

DETAILED DESCRIPTION OF THE INVENTION "ACTIVE SUBSTANCE NANOFIBERS FOR COSMETIC CONTROLLED RELEASE APPLICATION OBTAINED BY ELECTROPHIATION AND PROCESS" consists of a nanostructured active ingredient delivery system produced by the electrophony process that can be easily applied topically and / or transdermally. The incorporation of diverse actives in the nanofibres confers application versatility, controlled release of the incorporated active ingredient and stability of this component in the action medium, inhibiting degradation reactions by esterases present in the skin, promoting effective skin permeation.

These nanofibers can carry other hydrophilic or partially hydrophilic actives at the dermis absorption site and promote controlled release at the desired absorption site within the groups: anti-aging, anti-acne, dye, emollient, sunscreen, exfoliating, antioxidant, humectant , nutrient, anti-inflammatory and anticellulitic. The caffeine nanofiber disclosed herein is obtained through the electrophony process, which can be conducted in a mono or coaxial system. The polymeric solution containing the caffeine to be electrophilized and solubilized in acetone / ethanol solution should be in the mass ratio of 0.01% to 60% (w / w), preferably 10% (w / w) relative to the solution. of acetone / ethanol (50:50% vo). The voltage used in the electroplating process is from 10 to 30 kV, preferably 18 kV, and at a temperature of 5 to 40 ° C, preferably room temperature. The distance between the tip of the needle and the collector surface may vary from 5 to 30 cm, preferably 10 cm and the flow rate of the pump that feeds the electrophony system may vary from 0.01 to 10 mL / hr, preferably with a flow rate. 2 mL / h at the pump and the pickup cylinder rotation may range from 1 to 300 rpm, preferably 30 rpm. The incorporated active content may range from 0.1 to 50% relative to the polymer mass, preferably 8% (w / w). The polymeric solution may be composed of different polymers such as polysaccharides, animal or vegetable protein, chitosan, gums (gum arabic, xanthan gum, guar gum, carrageenan gum, cashew gum, tara gum, tragacanth gum, karaya gum, gati gum ), cellulose derivatives (carboxymethyl cellulose, carboxyethyl cellulose, etc.), polyvinylpyrrolidone (PVP), poly (meta) acrylates (PM), poly (meta) acrylamides, polyesters, polyvinylcaprolactams, polyamides, polyvinyl alcohol (PVA) or blends of these polymers .

Nanofibers were characterized for morphology, thermal properties, crystallography, chemical composition, encapsulation efficiency and active substance release kinetics and in vitro skin permeation.

The nanofibers and their diameters were characterized by scanning electron microscopy and the caffeine encapsulation efficiency consisted in quantifying the active principle incorporated in the nanofiber compared to the amount of caffeine initially added in the process, and the caffeine content contained in the nanofiber film. done by High Performance Liquid Chromatography (HPLC) on the same day, and one month after product production. The release rate of nanofiber caffeine, since it should penetrate and permeate the skin, extending several layers to the dermis and hypodermis, where the cellulite region is located, was characterized by the Franz Cell Release Test, with cellulose acetate membranes, and to quantify caffeine released from the nanometer film to the Franz Cell collecting solution, High Performance Liquid Chromatography (HPLC) was used.

The nanofibers produced in this invention had size ranging from 50 to 2000 nm and encapsulation efficiency close to 100%. EXAMPLE 01: Obtaining polyvinyl alcohol (PVA) nanofiber through the electrofinning process.

About 7 mL of a 10% w / w PVA dispersion in water was dispensed into a syringe and ejected through an infusion pump connected to a high voltage source. A rotating, grounded, parchment-covered cylinder served as the collector for the polymer film. The prepared solution was characterized by conductivity, viscosity and surface tension and Table 1 presents the results of these characterizations.

Table. 1. Characterization of the PVA solution The electrophiliation process was conducted employing a distance of 10 cm between the needle tip and the collector surface, 2 mL / h flow rate at the pump, 22 kV at the high voltage source and 30 ° C rotation. rpm in the collecting cylinder for a period of 150 min. The nanofiber obtained was characterized by scanning electron microscopy (SEM) and the image obtained is identified in Figure 1. EXAMPLE 02: Obtaining polyvinylpyrrolidine (PVP) nanofiber and ethyl-co-methyl acrylate poly (methacrylate) -ammonium methacrylate) (PM) through the electrofinning process.

Initially a 1: 1 (w / w) PVP / PM polymer mixture was solubilized in ethyl alcohol / acetone (1: 1 v / v) with magnetic stirring until complete solubilization. The prepared solubilization was characterized by conductivity, viscosity and surface tension, as shown in Table 2.

Table 2. Characterization of PVP / PM polymer solution before being electrophilized.

After the PVP / PM solution was prepared, the nanofibers were prepared through the electrofinning process using 1.0 mL / h of polymeric solution flow, 18 KV voltage and 30 rpm collector rotation for a period of 60 min. The nanofiber produced was characterized by SEM morphology, as shown in Figures 2 and 3, where it can be observed that the obtained fibers presented a homogeneous size distribution in nanometer scale. The product had a final PVP: PM composition of 1: 1 (w / w). EXAMPLE 03: Caffeine encapsulation employing polyvinylpyrrolidine nanofiber (PVP) and poN (ammonium methyl co-acrylate methyl methacrylate) (PM). The caffeine encapsulation process was performed using a 1: 1 (w / w) PVP / PM solution solubilized in ethyl alcohol / acetone (1: 1 v / v) containing 8% (w / w) active (caffeine) . The prepared solution was characterized for conductivity, viscosity and surface tension, as shown in Table 3.

Table. 3. Characterization of the polymeric solutions The electrophony process was conducted at a flow rate of 1.0 ml / h of the polymeric solution, 18 kV voltage and 30 rpm collector rotation for a period of 120 min. The caffeine-containing nanofiber produced was characterized by SEM morphology, as shown in Figures 4 and 5, and encapsulation efficiency by quantifying the caffeine content in HPLC by HPLC.

In this encapsulation example, the encapsulation efficiency was 99% and, as can be seen from the SEM images, the product is nanoscale. After one month of production, the caffeine content of the nanofiber film was still 99%, indicating that nanofiber can protect the asset from degradation by the encapsulation principle.

The raw materials (caffeine active agent and PVP and PM polymer encapsulating agents) were characterized by differential scanning calorimetry (DSC) and infrared spectrometry (IR), as well as nanofibers with or without the drug. Figures 6 and 7. The product had a final PVP: PM: Caffeine composition 6: 6: 1 (w / w). EXAMPLE 04: In vitro caffeine release assay encapsulated in polyvinylpyrrolidine (PVP) nanofibers and polyethyl ammonium-co-methacrylate (PM) methyl methacrylate (PM).

In order to evaluate the caffeine release profile from inside the nanofibers, two films were produced, one with caffeine and the other without the active one. The caffeine release assay was conducted in a vertical Franz diffusion cell employing a pH 5.5 or pH 7.4 buffer solution as the receiving solution in the release process at 32 ° C and a synthetic cellulose acetate membrane as support for nanofiber support and separation of the receiving medium. The released caffeine was quantified by HPLC at different times in order to build a release profile. Figure 8 shows the graph showing the two caffeine release curves in both buffered solutions. It is possible to observe that caffeine was released faster in the pH 7.4 buffer solution. EXAMPLE 05: Caffeine skin permeation assay released by polyvinylpyrrolidine (PVP) nanofibers and polyethyl ammonium co-methacrylate methyl methacrylate (PM).

In order to evaluate the permeation profile of caffeine released from nanofiber in animal membrane, a skin permeation study was performed using pig ear skin as an animal membrane model. The caffeine permeation assay was conducted in a vertical diffusion cell employing pH 5.5 buffer solution as a receiving solution at 32 ° C and pig ear skin as a support for caffeine-containing nanofiber support and separation of the medium. receptor. The released caffeine was quantified by HPLC in different regions of the pig's ear skin and in the receiving phase. Table 4 shows the values of the amount of caffeine retained in different regions of pig's ear skin and the amount of caffeine that permeated the skin and was detected in the receptor phase. Figure 9 illustrates the permeation profile of caffeine released from nanofibre as a function of time in pig's ear skin.

Table 4. Quantity of caffeine in mass, by area and in percentage, for the average of quadruplicate samples retained in the horn extract, in the most dermal epidermis and caffeine permeated in the mass receiving solution. 63.355 + 11.92 pg 41.140 + 7.74 pg / cm2 3.402% + 0.68 7.857 + 2.25 pg 49.900 + 14.61 pg / cm2 0.41% + 0.12 111.010+ 33.20 pg 5, 92% + 1.67 REFERENCES [1] Taylor, Gl. Electrically Driven Jets. Proceedings of the Royal Society of London Series A: Mathematical and Physical Sciences 313: 453-475, 1969. [2] Smith, DJ; Reneker, DH; McManus, AT; Schreuder-Gibson, HL; Mello, C; Sennet, MS. US Patent 6,753,454, 2004. [3] Sill, TJ; Recum, HA. Electrospinning: Applications in drug delivery and tissue engineering. Biomater 29, p.1989-2006, 2008. [4] Youan, BBC. Impact of nanoscience and nanotechnology on controlled drug delivery, Nanomedicine, v. 3, p. 401-406, 2008. [5] RE, M1. Microencapsulation in search of smart products, Science Today, v. 27, p. 24-29, 2000. [6] Pimentel, LF; Tavares, AJJ; Furtado, WM .; Santos, NSM. Pharmaceutical nanotechnology applied to the treatment of malaria. Brazilian Journal of Pharmaceutical Sciences, v. 43, p.1-14, 2007. [7] Letchford, K .; Burt, H. A review of the formation and classification of amphiphilic block copolymers nanoparticulate structures: micelles, nanospheres, nanocapsules and polymersomes. European Journal of Pharmaceutics and Biopharmaceutics, v. 65, p. 259-269, 2007. [8] Oliveira, A M. Obtaining Temperature and pH Sensitive Nanoparticles from Core-Shell Block Copolymers Using Block Copolymers Consisting of Poly (Hydroxybutyrate-Co-Hydroxyvalerate) and Poly ( N-Isopropylacrylamide-Acrylic Co-Acid) Synthesized Via Raft, for Encapsulation Application and Controlled Release of Assets. 2008. 269 f. Doctorate - Lorraine School of Engineering - USP, 2008. [9] Soppimath, KS; Aminabhavi, TM .; Kulkarni, AR. Biodegradable polymeric nanoparticles as drug delivery devices .J. Control Release, v. 1, no. 70, p.1-20, 2001. [10] Schaffazick, SR., Guterres, SS; Freitas, LL; Pohlmann, AR. Characterization and physicochemical stability of nanoparticulate polymeric systems for drug administration. New Chemistry, 26, p. 726-737, 2003. [11] Allémann, E; Gurny, R; Doelker, E; Eur. J. Pharm. Biopharm 39, 173, 1993. [12] Muller, RH; Radtke, M; Wissing, SA. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations, Advanced Drug Delivery Reviews, v. 54, p. S131-S155, 2002. [13] Hellmann, CH; Belardi, J; Dersch R; Greiner, A; Wendorff, JH; Bahnmueller, S. High Precision Deposition Electrospinning of nanofibers and nanofiber Nonwovens. Polymer, v. 50, p. 1197-1205, 2009. [14] Sill, TJ; Recum, HA Electrospinning: Applications in drug delivery and tissue engineering. Biomater 29: 1989-2006, 2008. [15] Ciporkin, H; PASCHOAL, LH. Therapeutic and pathophysiological update of gynoid lipodystrophy. Sao Paulo: Santos, p. 1, 322, 357, 1992. [16] Kim, KH; Hyung; Y H. New drug delivery system using electrospinning of biodegradable polymers. Patent KR 20100092545, 2010. [17] Paufique, J. Use of an active ingredient capable of stimulating and / or increasing expression of adipose triglyceride lipase and / or comparative gene identification-58 in skin cells, to prepare cosmetic and / or dermopharmaceutical composition for slimming. Patent FR2921270-A, 2009. [18] Bezivin C .; Borel M .; Calmon E. Use of corilagin to prepare cosmetic composition, as slimming agent, anticellulite and inhibitor of angiogenesis and / or regulator of extracellular matrix. Paptent FR2944442-A, 2010. [19] Teichmueller, D. Cosmetic formulation, useful for reducing external appearance of cellulite or dimpled skin, comprising caffeine, L-carnitine, Centella asiatica extract, an extract of plants from Coleus or Plectranthus that contain forskolin and a carrier. Patent DE102009028996-A1, 2009. [20] Laurencin C. Polymeric nanofibers for tissue engineering and drug delivery. WO 2005/025630, 2005. [21] Seiler, M; Mchugh, M; Bernhardt S; Gloeckler B; Schneider, R; Marckmann H. Nanofiber matrices formed from electrospun hyperbranched polymers. Patent W0133059, 2009.

Claims (7)

1. “NANOFIBERS WITH ACTIVE SUBSTANCE FOR COSMETIC APPLICATION OF ELECTROPHIATION CONTROLLED RELEASE” consists of a nanostructured active ingredient delivery system, characterized by being produced by the electrophony process; be applied topically and / or transdermally; the active content incorporated into nanofiber ranges from 0.1 to 50% with respect to the encapsulating polymer mass; the polymeric solution containing the caffeine to be electrophilized and solubilized in acetone / ethanol solution (50:50% vol.) is in the weight ratio of 0.01% to 60% (w / w) relative to the acetone / ethanol solution ; the encapsulant-generating polymer solution is composed of polymers such as polysaccharides, animal or vegetable protein, chitosan, gums, cellulose derivatives, polyvinylpyrrolidone (PVP), poly (meta) acrylates (PM), poly (meta) acrylamides, polyesters, polyamides, polyvinylcaprolactams, polyvinyl alcohol (PVA) or blends of such polymers; and the nanofibers have minimum nanometric dimensions, ie diameters greater than 50 nm. 2. "NANOFIBERS WITH ACTIVE SUBSTANCE FOR COSMETIC APPLICATION OF ELECTROPHIATED CONTROLLED RELEASE" according to claim 1, characterized in that nanofibers carry hydrophilic or partially hydrophilic actives and promote controlled release of actives within the antiage groups; anti-acne, dye, emollient, sunscreen, exfoliating, antioxidant, humectant, nutrient, anti-inflammatory and anti-cellulite at the desired absorption site. 3. "NANOFIBERS WITH ACTIVE SUBSTANCE FOR COSMETIC APPLICATION OF CONTROLLED RELEASE OBTAINED BY ELECTROFIATION" according to claim 1, are gum arabic, xanthan gum, guar gum, carrageenan gum, cashew gum, tragacanth gum, Karaya gum, gati gum; and the cellulose derivatives are carboxymethyl cellulose, carboxyethyl cellulose. Active electron nanofibers for controlled electrode controlled cosmic release according to claims 1 and 2, characterized in that the nanofiber for the treatment of gynoid hydrolipodystrophy (HDLG) utilizes a polyvinylpyrrolidine (PVP) polymer solution ammonium methyl co-acrylate (PM) methyl methacrylate (PM) solubilized in acetone / ethanol solution (50:50% vol.) containing 8% (w / w) caffeine and the nanofibers are arranged under the form of a non woven blanket. Active electron nanofibers for controlled electrode controlled cosmic release according to claims 1 and 2, characterized in that the nanofiber for the treatment of gynoid hydrolipodystrophy (HDLG) uses PVA in water concentration solution 10% w / w, containing 8% (w / w) caffeine and the nanofibers arranged in the form of a non-woven blanket. 6. “ELECTROPHYING PROCESS”, consisting of a mono or coaxial electrofinning process, characterized in that the conditions of the nanofiber electrofinning process are voltage of 10 to 30 kV, at a temperature of 5 to 40 ° C, and the conditions of electrofinning of nanofibers for the treatment of gynoid hydrolipodystrophy (HDLG) are the use of a distance of 5 to 30 cm between the needle tip and the collector surface, with a flow rate of 0.01 to 10 mL / h at the pump, and rotation of 1 at 300 rpm in the pickup roller. "ELECTROPHYING PROCESS" according to claims 6 and 4 or 5, characterized in that the conditions of the electrode spinning process for the treatment of gynoid hydrolipodystrophy (HDLG) are the use of a distance of 10 cm between the tip of the the needle and the collector surface, with a flow rate of 2 mL / h at the pump and 30 rpm rotation in the collector cylinder, at room temperature and 18 kV voltage.