WO2016066864A1 - Nanoparticles for the controlled release of active ingredients - Google Patents
Nanoparticles for the controlled release of active ingredients Download PDFInfo
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- WO2016066864A1 WO2016066864A1 PCT/ES2014/070814 ES2014070814W WO2016066864A1 WO 2016066864 A1 WO2016066864 A1 WO 2016066864A1 ES 2014070814 W ES2014070814 W ES 2014070814W WO 2016066864 A1 WO2016066864 A1 WO 2016066864A1
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- nanoparticles
- chitosan
- collagen
- hyaluronic acid
- active ingredient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
Definitions
- the invention relates to nanoparticles with active ingredients for the controlled release of these and their use in pharmacy and cosmetics.
- the nanoparticles object of the present invention are manufactured from colloidal systems that allow the incorporation of active ingredients and that result in nanoparticles with the characteristics suitable for the administration of the active ingredient.
- Vehicular systems are currently under development. In this sense, it is a priority objective to develop a transport system that allows the active ingredients to be selectively released and reduce their dose, avoiding adverse effects that occur in conventional therapies.
- Release is defined as the process in which the active ingredient reaches the appropriate site of action at the appropriate concentration (minimum effective concentration but low enough to avoid toxicity) for the correct period of time (sufficient time to allow the ingredient active do your job).
- the size can vary from nanometer to millimeter allowing to differentiate two groups whose vehicle possibilities are completely different. For sizes smaller than the micrometer, the insertion of the vehicle systems between the corneal cells can occur.
- the encapsulation of active principles in nanoparticulate systems have many advantages, such as: they protect the active principle from biodegradation, control the release of the latter through the matrix in which it is encapsulated and allow it to be selectively released at the appropriate site for exercise your function
- Document ES2226567 discloses a process for obtaining nanoparticles for the administration of an active ingredient comprising an acid salt hyaluronic and a cationic polymer of the chitosan, collagen or gelatin type.
- the process consists of a preparation of an aqueous solution of the hyaluronic acid salt, adding it to another aqueous solution of the cationic polymer and mixing it by stirring, obtaining the nanoparticles spontaneously.
- the active ingredient is dissolved in one of the initial solutions or in the suspension of the nanoparticles subsequently obtained, becoming absorbed by them.
- nanoparticles are of a pharmaceutical composition for administration on mucous, topical or parenteral.
- a system for the treatment of migraine which consists of a needle and a carrier of the drug that also controls its release over a period of more than four hours.
- the system can come in the form of nanoparticle, colloid, suspension, emulsion, or gel among others and is composed of hyaluronic acid, collagen and / or chitosan.
- Some of the active substances disclosed and transported in the nanoparticles are triptan, sumatriptan, almotriptan, eletriptan, rizatriptan, and zomitriptan.
- WO2007135164 a system for the release of biologically active substances composed of nanoparticles of hyaluronic acid and chitosan is described.
- the active molecule disclosed is of the oligonucleotide, siRNA, or polynucleotide type.
- the estimated release time is one hour, after adding specific enzymes for the degradation of the polymers that constitute the polymer matrix.
- EP1891943 describes nanoparticles for the release of biologically active molecules composed of at least 40% chitosan and less than 60% cyclodextrin or one of its derivatives.
- the administration of the medication can be topically.
- the estimated release time is approximately 5h and is released between 30-55% active ingredient.
- a composition is described which includes each and every one of the following ingredients: at least 2 or more polyanions, among which is collagen; 1 or more polycations, among which is the low molecular weight chitosan; 1 or more cations (sodium, potassium or calcium); 1 or more proteins, among which is hyaluronic acid; and that can be made in the form of a film, microcapsules or nanoparticles.
- certain compounds used in the vehiculization systems are capable of altering the barrier properties of the skin, thereby promoting the penetration of the encapsulated agent through the stratum corneum.
- the particle size of these systems determines the degree of contact with the skin and, therefore, the amount of active ingredient that will reach the site of action.
- the size can vary from nanometer to millimeter allowing to differentiate two groups whose vehicle possibilities are completely different. For sizes smaller than the micrometer, the insertion of the vehicular systems between the corneal cells can occur, characteristic of great applicability in the field of cosmetics.
- a small particle size ensures a closer contact with the stratum corneum, so nanoparticulate systems are the most suitable for this application.
- nanoparticulate systems encounters the viscosity of the formulation is very high thus preventing the passage of said systems through the skin.
- the nanoparticulate system must pass through the first layer of the epidermis: The stratum corneum (lipophilic layer that constitutes the first barrier to the passage of most of the active ingredients). Once the nanoparticulate system is in that layer, it is carried by diffusion at the end of it and then diffused through the following layers that make up the epidermis and are polar.
- the present invention relates to nanoparticles comprising a matrix of natural composition to which active ingredients can be added in a controlled manner, for application both for the manufacture of pharmaceutical formulations as cosmetics
- the present invention relates to nanoparticles comprising chitosan, hyaluronic acid and collagen (from now on, we will refer to them as nanoparticles of the invention) and also comprise an active ingredient, which is selected from a drug, vitamins, peptides, proteins, an oxidizing agent or any combination thereof.
- nanoparticles in the present invention those particles with a size less than 1000 nm, preferably with a size between 150 and 700 nm.
- the antioxidant agent is selected from the list comprising antioxidants from olive leaf extract, alperujo, yerba mate, thistle oil, tea, vitamin C, vitamin E, retinoids, idebenone, coenzyme Q10, lipoic acid, Picnogenol or any of its combinations.
- the antioxidant agent is selected from olive leaf extract, mate, cake and thistle oil or alperujo.
- the nanoparticles of the invention due to collagen and chitosan, have high biocompatibility, biodegradation control and excellent mechanical properties.
- a second aspect of the present invention relates to the use of the nanoparticles of the invention for the manufacture of a pharmaceutical composition or cosmetic composition.
- nanoparticulate systems Being nanoparticulate systems, it is easy to penetrate through epithelial barriers and protects them from being degraded. The ability of nanoparticulate systems to cross these barriers depends on their size and composition.
- composition in the present invention a compound that contains at least one high purity chemical used in the prevention of a disease, or to prevent the occurrence of an unwanted physiological process.
- cosmetic composition in the present invention a product used for body hygiene or for the purpose of improving beauty, especially of the face, body and lips.
- the usefulness of the nanoparticles of the invention in the field of pharmacy and cosmetics is due to the fact that active ingredients can be introduced into the pores thereof, which can be released in a controlled manner, thus acting the nanoparticles of the invention as a controlled release system of active ingredients.
- controlled release system of active ingredients in the present invention, it is understood a way of administering the active ingredient, as may be by way of example but not limited to the invention pharmaceutical and / or cosmetic compositions, which They are administered locally.
- the active ingredient is specifically released for a period of time in the place where it has been incorporated, acting effectively and precisely to promote bioactivity and without the need to be applied systemically.
- the active ingredient is incorporated in a necessary quantity to the nanoparticles, depending on the use that is desired to give them, the matrix nanoparticles acting.
- the pharmaceutical or cosmetic composition is topically or dermatologically administered; optionally, in the form of cream, mousse, serum, emulsion, spray, patch or film.
- Topical administration is of superficial application form on the dermis, and can be formulated, by way of example and without limitation, such as lotions, oils, ointments, creams, gels, powders, ointments, aerosols, microemulsions, pastes, poultices or solutions .
- the cosmetic composition in addition to the nanoparticles of the invention, to promote topical or dermatological administration may comprise at least one cosmetically acceptable excipient that is selected from the group consisting of emulsifiers, solubilizers, dispersants, humectants, co-emulsifiers, emollients, surfactants, thickeners, agents to increase viscosity, lipid components to increase the consistency of the emulsion, preservatives, pH adjusting agents, flavoring agents and perfumes, or any of their mixtures; said cosmetically acceptable excipients, liquid or solid, being both aqueous, lipidic or organic in nature.
- the present invention relates to a process for obtaining the nanoparticles of the invention, which comprises the steps:
- solution A comprises hyaluronic acid
- solution B comprises a crosslinking agent
- step (b) mixing the product obtained in step (a) with a solution C and D, where solution C comprises chitosan and solution D comprises collagen.
- step (a) of the process of the invention further comprises the addition of the active ingredient.
- the active ingredient is added in a weight percentage of between 5 and 80%.
- the crosslinking agent is selected from sodium tripolyphosphate, genipin, polyethylene glycol or any combination thereof.
- the mass ratio between chitosan / hyaluronic acid / collagen is between 1: 1: 2 and 9: 3: 9. In a more preferred embodiment, the mass ratio between chitosan / hyaluronic acid / collagen is between 2: 1: 9 and 9: 1: 2.
- Figure 1 Transmission electron microscopy images of nanoparticles comprising chitosan, hyaluronic acid and collagen, corresponding to formulations a) and b) prepared respectively according to mass ratios of 2: 1: 9 and 9: 1: 2.
- Figure 2 Transmission electron microscopy images of nanoparticles comprising chitosan, hyaluronic acid and collagen, with 20% encapsulated bovine serum albumin, corresponding to formulations a) and b) prepared respectively according to 2: 1 mass ratios: 9 and 9: 1: 2.
- Figure 3 Transmission electron microscopy images of nanoparticles comprising chitosan, hyaluronic acid and collagen, with 20% encapsulated olive leaf extract, corresponding to formulations a) and b) prepared respectively according to mass ratios of 2: 1 : 9 and 9: 1: 2.
- Figure 4 Size distribution of nanoparticles (nm) comprising chitosan, hyaluronic acid and collagen, according to a mass ratio of 9: 1: 2, corresponding to formulations a) empty or free of active ingredient, and b) with a % of encapsulated olive leaf extract, prepared at a pH of 4.5.
- Figure 5 Chart of% antioxidant release vs.
- BSA Bovine serum albumin
- Chitosan hydrochloride, hyaluronic acid and collagen nanoparticles were prepared, using sodium tripolyphosphate as a crosslinking agent.
- the solution of hyaluronic acid (3 mg / ml) and sodium tripolyphosphate (0.1%) was added to the solution containing chitosan hydrochloride (0.15%), under constant stirring and for 10 minutes, allowing the stabilization of the generated nanoparticles.
- the centrifugation of these was carried out in order to eliminate the possible unreacted chitosan and hyaluronic acid residues and the resulting pellet is resuspended in a collagen solution (5 mg / ml) for 2 hours, under constant stirring.
- Nanoparticles of chitosan hydrochloride, hyaluronic acid, collagen and sodium tripolyphosphate were prepared as crosslinking agent.
- Bovine serum albumin (BSA) was incorporated. It was incorporated into the chitosan solution due to its easy solubility in it. A theoretical load of 20% was established with respect to the weight of the polymers. Its average diameter was measured, as well as its surface electric charge and its morphology was studied by transmission electron microscopy.
- Table 3 and Figure 2 show the values that take the parameters mentioned according to the proportion of HCS, HA and Col used and the morphology of the nanoparticles obtained.
- Nanoparticles of chitosan hydrochloride, hyaluronic acid, collagen and tripol phosphate sodium were prepared as crosslinking agent.
- a set of antioxidants was incorporated, selecting for this purpose an olive leaf extract (OLE). It was incorporated into the solution of sodium tripolyphosphate, due to its hydrophilic character and easy solubility in it.
- a theoretical load of 20% was established with respect to the weight of the polymers. Its average diameter was measured, as well as its surface electric charge and its morphology was studied by transmission electron microscopy.
- Table 4 and Figures 3 and 4 show the values that take the parameters mentioned, depending on the proportion of HCS, HA and Col used.
- the encapsulation efficiency was determined by evaluating the amount of free polyphenols, using the Folin-Ciocalteu method. In-vitro release studies were carried out, at 37 ° C in aqueous medium, at pH: 5.5 for a period of 24h. The amount of active ingredient released was determined by visible ultraviolet spectrophotometry. In the graph of Figure 5,% release of polyphenols vs. time (hours), different lines are represented: one with squares, for the formulation d); one with triangles, for the formulation b); one with circles, for formulation c) and one without geometric elements, for formulation a).
Abstract
The invention relates to nanoparticles for the controlled release of active ingredients, comprising chitosan, hyaluronic acid and collagen and also containing an active ingredient. The invention also relates to a method for producing said nanoparticles, which involves the transformation of a liquid phase containing the polymers in a solid phase, which, in turn, contains the active ingredient in the form required for administration with a controlled-release profile, and allows the direct incorporation of the active ingredient, preserving the integrity or therapeutic action thereof. The invention further relates to the use of the nanoparticles for producing pharmaceutical or cosmetic compositions.
Description
NANOPARTÍCULAS PARA LA LIBERACIÓN CONTROLADA DE INGREDIENTES ACTIVOS NANOPARTICLES FOR THE CONTROLLED RELEASE OF ACTIVE INGREDIENTS
Descripción Description
Objeto de la invención Object of the invention
La invención se refiere a nanopartículas con ingredientes activos para la liberación controlada de éstos y su uso en farmacia y cosmética. En particular las nanopartículas objeto de la presente invención están fabricadas a partir de sistemas coloidales que permiten la incorporación de ingredientes activos y que producen como resultado unas nanopartículas con las características adecuadas para la administración del ingrediente activo. The invention relates to nanoparticles with active ingredients for the controlled release of these and their use in pharmacy and cosmetics. In particular, the nanoparticles object of the present invention are manufactured from colloidal systems that allow the incorporation of active ingredients and that result in nanoparticles with the characteristics suitable for the administration of the active ingredient.
Antecedentes de la técnica Prior art
Los sistemas vehiculares se encuentran actualmente en fase de desarrollo. En este sentido, es un objetivo prioritario el desarrollo de un sistema transportador que permita liberar selectivamente los principios activos y reducir la dosis de éstos, evitando efectos adversos que se producen en las terapias convencionales. Vehicular systems are currently under development. In this sense, it is a priority objective to develop a transport system that allows the active ingredients to be selectively released and reduce their dose, avoiding adverse effects that occur in conventional therapies.
La liberación se define como el proceso en el que el ingrediente activo llega al sitio de acción adecuado a la concentración adecuada (mínima concentración efectiva pero lo suficientemente baja para evitar toxicidad) por el periodo correcto de tiempo (el tiempo suficiente para permitir que el ingrediente activo haga su trabajo). Release is defined as the process in which the active ingredient reaches the appropriate site of action at the appropriate concentration (minimum effective concentration but low enough to avoid toxicity) for the correct period of time (sufficient time to allow the ingredient active do your job).
El tamaño puede variar del nanómetro al milímetro permitiendo diferenciar dos grupos cuyas posibilidades vehiculares son completamente diferentes. Para tamaños inferiores al micrómetro se puede producir la inserción de los sistemas vehiculares entre las células córneas. Así, la encapsulación de principios activos en sistemas nanoparticulados presentan muchas ventajas, tales como: protegen al principio activo de la biodegradación, controlan la liberación de éste a través de la matriz en la que se encuentra encapsulado y permiten liberarlo selectivamente en el sitio adecuado para ejercer su función. The size can vary from nanometer to millimeter allowing to differentiate two groups whose vehicle possibilities are completely different. For sizes smaller than the micrometer, the insertion of the vehicle systems between the corneal cells can occur. Thus, the encapsulation of active principles in nanoparticulate systems have many advantages, such as: they protect the active principle from biodegradation, control the release of the latter through the matrix in which it is encapsulated and allow it to be selectively released at the appropriate site for exercise your function
Las referencias donde se citan quitosano y/o ácido hialurónico y/o colágeno son las siguientes: El documento ES2226567 divulga un procedimiento de obtención de nanopartículas para la administración de un ingrediente activo que comprende una sal de ácido
hialurónico y un polímero catiónico de tipo quitosano, colágeno o gelatina. El procedimiento consta de una preparación de una disolución acuosa de la sal del ácido hialurónico, adicionarla a otra disolución acuosa del polímero catiónico y mezclarla mediante agitación obteniéndose espontáneamente las nanopartículas. El ingrediente activo es disuelto en una de las disoluciones iniciales o en la suspensión de las nanopartículas obtenidas posteriormente, pasando a ser absorbido por éstas. El uso divulgado de estas nanopartículas es de una composición farmacéutica para la administración sobre mucosas, tópica o parenteral. En la solicitud de patente WO2009134336 se describe un sistema para el tratamiento de la migraña que consta de una aguja y un transportador del medicamento que además controla su liberación en un periodo de más de cuatro horas. El sistema puede venir en forma de nanopartícula, coloide, suspensión, emulsión, o gel entre otros y está compuesto de ácido hialurónico, colágeno y/o quitosano. Algunas de las sustancias activas divulgadas y transportadas en las nanopartículas son triptan, sumatriptan, almotriptan, eletriptan, rizatriptan, y zomitriptan. References citing chitosan and / or hyaluronic acid and / or collagen are as follows: Document ES2226567 discloses a process for obtaining nanoparticles for the administration of an active ingredient comprising an acid salt hyaluronic and a cationic polymer of the chitosan, collagen or gelatin type. The process consists of a preparation of an aqueous solution of the hyaluronic acid salt, adding it to another aqueous solution of the cationic polymer and mixing it by stirring, obtaining the nanoparticles spontaneously. The active ingredient is dissolved in one of the initial solutions or in the suspension of the nanoparticles subsequently obtained, becoming absorbed by them. The disclosed use of these nanoparticles is of a pharmaceutical composition for administration on mucous, topical or parenteral. In patent application WO2009134336 a system for the treatment of migraine is described, which consists of a needle and a carrier of the drug that also controls its release over a period of more than four hours. The system can come in the form of nanoparticle, colloid, suspension, emulsion, or gel among others and is composed of hyaluronic acid, collagen and / or chitosan. Some of the active substances disclosed and transported in the nanoparticles are triptan, sumatriptan, almotriptan, eletriptan, rizatriptan, and zomitriptan.
En la solicitud de patente EP1977739 se describen nanopartículas formadas por una composición reticulada de sulfato de chondroitin y quitosano. El quitosano actúa como agente de liberación del medicamento y se encuentra en una proporción de entre el 50 al 90% respecto al medicamento que transporta. Este medicamento está indicado para tratamiento de problemas óseos o de piel. In the patent application EP1977739 nanoparticles formed by a cross-linked composition of chondroitin sulfate and chitosan are described. Chitosan acts as a drug release agent and is in a proportion between 50 and 90% of the medicine it carries. This medicine is indicated for the treatment of bone or skin problems.
En la solicitud de patente WO2007135164 se describe un sistema de liberación de sustancias biológicamente activas compuesto de nanopartículas de ácido hialurónico y quitosano. La molécula activa divulgada es del tipo oligonucleótido, siRNA, o polinucleótido. El tiempo de liberación estimado es de una hora, después de añadir enzimas específicas para la degradación de los polímeros que constituyen la matriz polimérica. In patent application WO2007135164 a system for the release of biologically active substances composed of nanoparticles of hyaluronic acid and chitosan is described. The active molecule disclosed is of the oligonucleotide, siRNA, or polynucleotide type. The estimated release time is one hour, after adding specific enzymes for the degradation of the polymers that constitute the polymer matrix.
En la solicitud de patente EP1891943 se describen unas nanopartículas para la liberación de moléculas biológicamente activas compuestas de al menos un 40% de quitosano y menos de un 60% de ciclodextrina o uno de sus derivados. La administración del medicamento puede ser por via tópica. El tiempo de liberación estimado es aproximadamente 5h y se libera entre un 30-55% de ingrediente activo.
En la solicitud de patente WO0064954 se describe una composición que incluye todos y cada uno de los siguientes ingredientes: al menos 2 ó más polianiones, entre los que se encuentra el colágeno; 1 ó más policationes, entre los que se encuentra el quitosano de bajo peso molecular; 1 ó más cationes (sodio, potasio o calcio); 1 ó más proteínas, entre las que se encuentra el ácido hialurónico; y que puede elaborarse en forma de película, microcápsulas o nanopartículas. EP1891943 describes nanoparticles for the release of biologically active molecules composed of at least 40% chitosan and less than 60% cyclodextrin or one of its derivatives. The administration of the medication can be topically. The estimated release time is approximately 5h and is released between 30-55% active ingredient. In patent application WO0064954 a composition is described which includes each and every one of the following ingredients: at least 2 or more polyanions, among which is collagen; 1 or more polycations, among which is the low molecular weight chitosan; 1 or more cations (sodium, potassium or calcium); 1 or more proteins, among which is hyaluronic acid; and that can be made in the form of a film, microcapsules or nanoparticles.
En cosmética, ciertos compuestos utilizados en los sistemas de vehiculización son capaces de alterar las propiedades de barrera de la piel, promoviendo de esta forma la penetración del agente encapsulado a través del estrato córneo. El tamaño de partícula de estos sistemas determina el grado de contacto con la piel y, por tanto, la cantidad de ingrediente activo que llegará al sitio de acción. El tamaño puede variar del nanómetro al milímetro permitiendo diferenciar dos grupos cuyas posibilidades vehiculares son completamente diferentes. Para tamaños inferiores al micrómetro se puede producir la inserción de los sistemas vehiculares entre las células córneas, característica de gran aplicabilidad en el campo de la cosmética. Un tamaño de partícula pequeño asegura un contacto más estrecho con el estrato córneo, por lo que los sistemas nanoparticulados son los más adecuados para esta aplicación. Uno de los principales problemas que los sistemas nanoparticulados encuentran es que la viscosidad de la formulación sea muy alta impidiendo así el paso de dichos sistemas a través de la piel. Una vez superado este obstáculo, el sistema nanoparticulado debe atravesar la primera capa de la epidermis: El estrato córneo (capa lipofílica que constituye la primera barrera para el paso de la mayoría de los ingredientes activos). Una vez que el sistema nanoparticulado se encuentra en dicha capa, es llevado mediante difusión al final de ella y luego es difundido a través de las siguientes capas que componen la epidermis y que son polares. In cosmetics, certain compounds used in the vehiculization systems are capable of altering the barrier properties of the skin, thereby promoting the penetration of the encapsulated agent through the stratum corneum. The particle size of these systems determines the degree of contact with the skin and, therefore, the amount of active ingredient that will reach the site of action. The size can vary from nanometer to millimeter allowing to differentiate two groups whose vehicle possibilities are completely different. For sizes smaller than the micrometer, the insertion of the vehicular systems between the corneal cells can occur, characteristic of great applicability in the field of cosmetics. A small particle size ensures a closer contact with the stratum corneum, so nanoparticulate systems are the most suitable for this application. One of the main problems that nanoparticulate systems encounter is that the viscosity of the formulation is very high thus preventing the passage of said systems through the skin. Once this obstacle has been overcome, the nanoparticulate system must pass through the first layer of the epidermis: The stratum corneum (lipophilic layer that constitutes the first barrier to the passage of most of the active ingredients). Once the nanoparticulate system is in that layer, it is carried by diffusion at the end of it and then diffused through the following layers that make up the epidermis and are polar.
Es por ello que estas desventajas encontradas en el estado de la técnica hacen la necesidad de crear un sistema de liberación controlada de ingredientes activos de adecuado tamaño nanométrico. That is why these disadvantages found in the state of the art make it necessary to create a controlled release system of active ingredients of suitable nanometric size.
Descripción de la invención Description of the invention
La presente invención se refiere a unas nanopartículas que comprenden una matriz de composición natural a la cual se le pueden añadir de forma controlada ingredientes activos, para su aplicación tanto para la fabricación de formulaciones farmacéuticas
como cosméticas. The present invention relates to nanoparticles comprising a matrix of natural composition to which active ingredients can be added in a controlled manner, for application both for the manufacture of pharmaceutical formulations as cosmetics
En un primer aspecto, la presente invención se refiere a nanopartículas que comprenden quitosano, ácido hialurónico y colágeno (a partir de ahora, nos referiremos a ellas como nanopartículas de la invención) y además comprenden un ingrediente activo, el cual se selecciona de entre un fármaco, vitaminas, péptidos, proteínas, un agente oxidante o cualquiera de sus combinaciones. In a first aspect, the present invention relates to nanoparticles comprising chitosan, hyaluronic acid and collagen (from now on, we will refer to them as nanoparticles of the invention) and also comprise an active ingredient, which is selected from a drug, vitamins, peptides, proteins, an oxidizing agent or any combination thereof.
Por "nanopartículas" se entiende en la presente invención por aquellas partículas con un tamaño inferior a 1000 nm, preferiblemente con un tamaño de entre 150 y 700 nm. By "nanoparticles" is meant in the present invention those particles with a size less than 1000 nm, preferably with a size between 150 and 700 nm.
En una realización preferida, el agente antioxidante se selecciona de la lista que comprende antioxidantes de extracto de hojas de olivo, alperujo, yerba mate, aceite de cardo, té, vitamina C, vitamina E, retinoides, idebenona, coenzima Q10, ácido lipoico, picnogenol o cualquiera de sus combinaciones. En una realización más preferida, el agente antioxidante se selecciona de entre extracto de hojas de olivo, yerba mate, torta y aceite de cardo o alperujo. In a preferred embodiment, the antioxidant agent is selected from the list comprising antioxidants from olive leaf extract, alperujo, yerba mate, thistle oil, tea, vitamin C, vitamin E, retinoids, idebenone, coenzyme Q10, lipoic acid, Picnogenol or any of its combinations. In a more preferred embodiment, the antioxidant agent is selected from olive leaf extract, mate, cake and thistle oil or alperujo.
Las nanopartículas de la invención, debido al colágeno y quitosano, presentan una elevada biocompatibilidad, un control de la biodegradación y excelentes propiedades mecánicas. The nanoparticles of the invention, due to collagen and chitosan, have high biocompatibility, biodegradation control and excellent mechanical properties.
Un segundo aspecto de la presente invención se refiere al uso de las nanopartículas de la invención para la fabricación de una composición farmacéutica o composición cosmética. A second aspect of the present invention relates to the use of the nanoparticles of the invention for the manufacture of a pharmaceutical composition or cosmetic composition.
Al ser sistemas nanoparticulados, es fácil su penetración a través de las barreras epiteliales y las protege de ser degradadas. La capacidad de sistemas nanoparticulados para atravesar dichas barreras depende de su tamaño y composición. Being nanoparticulate systems, it is easy to penetrate through epithelial barriers and protects them from being degraded. The ability of nanoparticulate systems to cross these barriers depends on their size and composition.
Por "composición farmacéutica" se entiende en la presente invención a un compuesto que contenga al menos una sustancia química de alta pureza utilizada en la prevención de una enfermedad, o para evitar la aparición de un proceso fisiológico no deseado.
Por "composición cosmética" se entiende en la presente invención a un producto utilizado para la higiene corporal o con la finalidad de mejorar la belleza, especialmente del rostro, cuerpo y labios. By "pharmaceutical composition" is meant in the present invention a compound that contains at least one high purity chemical used in the prevention of a disease, or to prevent the occurrence of an unwanted physiological process. By "cosmetic composition" is meant in the present invention a product used for body hygiene or for the purpose of improving beauty, especially of the face, body and lips.
La utilidad de las nanopartículas de la invención en el campo de la farmacia y de la cosmética se debe a que en los poros de las mismas se pueden introducir ingredientes activos, los cuales pueden liberarse de forma controlada, actuando por tanto las nanopartículas de la invención como un sistema de liberación controlada de ingredientes activos. The usefulness of the nanoparticles of the invention in the field of pharmacy and cosmetics is due to the fact that active ingredients can be introduced into the pores thereof, which can be released in a controlled manner, thus acting the nanoparticles of the invention as a controlled release system of active ingredients.
Por "sistema de liberación controlada de ingredientes activos", en la presente invención, se entiende a una forma de administrar el ingrediente activo, como pueden ser a modo de ejemplo pero sin carácter limitante de la invención composiciones farmacéuticas y/o cosméticas, las cuales se administran localmente. El ingrediente activo se libera específicamente durante un periodo de tiempo en el lugar donde ha sido incorporado, actuando de modo efectivo y preciso para favorecer la bioactividad y sin necesidad de aplicarse de forma sistémica. El ingrediente activo se incorpora en una cantidad necesaria a las nanopartículas, dependiendo del uso que se las desee dar, actuando las nanopartículas de matriz. By "controlled release system of active ingredients", in the present invention, it is understood a way of administering the active ingredient, as may be by way of example but not limited to the invention pharmaceutical and / or cosmetic compositions, which They are administered locally. The active ingredient is specifically released for a period of time in the place where it has been incorporated, acting effectively and precisely to promote bioactivity and without the need to be applied systemically. The active ingredient is incorporated in a necessary quantity to the nanoparticles, depending on the use that is desired to give them, the matrix nanoparticles acting.
Preferiblemente, la composición farmacéutica o cosmética es de administración tópica o dermatológica; opcionalmente, en forma de crema, mousse, sérum, emulsión, aerosol, parche o film. Preferably, the pharmaceutical or cosmetic composition is topically or dermatologically administered; optionally, in the form of cream, mousse, serum, emulsion, spray, patch or film.
La administración tópica es de forma de aplicación superficial sobre la dermis, y puede formularse, a modo de ejemplo y sin carácter limitante, como lociones, aceites, ungüentos, cremas, geles, polvos, pomadas, aerosoles, microemulsiones, pastas, cataplasmas o disoluciones. Topical administration is of superficial application form on the dermis, and can be formulated, by way of example and without limitation, such as lotions, oils, ointments, creams, gels, powders, ointments, aerosols, microemulsions, pastes, poultices or solutions .
La composición cosmética además de las nanopartículas de la invención, para favorecer la administración tópica o dermatológica, puede comprender al menos un excipiente cosméticamente aceptable que se selecciona de entre el grupo formado por emulsionantes, solubilizantes, dispersantes, humectantes, co-emulsionantes, emolientes, tensioactivos, espesantes, agentes para incrementar la viscosidad,
componentes lipidíeos para aumentar la consistencia de la emulsión, conservantes, agentes para ajustar el pH, agentes aromatizantes y perfumes, o cualquiera de sus mezclas; pudiendo ser dichos excipientes cosméticamente aceptables, líquidos o sólidos, tanto de naturaleza acuosa, lipídica u orgánica. The cosmetic composition in addition to the nanoparticles of the invention, to promote topical or dermatological administration, may comprise at least one cosmetically acceptable excipient that is selected from the group consisting of emulsifiers, solubilizers, dispersants, humectants, co-emulsifiers, emollients, surfactants, thickeners, agents to increase viscosity, lipid components to increase the consistency of the emulsion, preservatives, pH adjusting agents, flavoring agents and perfumes, or any of their mixtures; said cosmetically acceptable excipients, liquid or solid, being both aqueous, lipidic or organic in nature.
En un tercer aspecto, la presente invención se refiere a un procedimiento de obtención de las nanopartículas de la invención, que comprende las etapas: In a third aspect, the present invention relates to a process for obtaining the nanoparticles of the invention, which comprises the steps:
a) mezclar al menos dos disoluciones A y B, donde la disolución A comprende ácido hialurónico y la disolución B comprende un agente entrecruzante, a) mixing at least two solutions A and B, where solution A comprises hyaluronic acid and solution B comprises a crosslinking agent,
b) mezclar el producto obtenido en la etapa (a) con una disolución C y D, donde la disolución C comprende quitosano y la disolución D comprende colágeno. b) mixing the product obtained in step (a) with a solution C and D, where solution C comprises chitosan and solution D comprises collagen.
Debido a los elevados pesos moleculares de las moléculas que comprenden las nanopartículas de la invención, anteriormente no se han podido obtener sistemas nanoparticulados que comprendan quitosano, colágeno y ácido hialurónico. Sin embargo, gracias al procedimiento de la presente invención se han conseguido tamaños que permiten a las nanopartículas penetrar a través de la piel ejerciendo su función desde el interior. En una realización preferida, la etapa (a) del procedimiento de la invención además comprende la adición del ingrediente activo. En una realización más preferida el ingrediente activo se adiciona en un porcentaje en peso de entre 5 y 80%. Due to the high molecular weights of the molecules comprising the nanoparticles of the invention, previously it has not been possible to obtain nanoparticulate systems comprising chitosan, collagen and hyaluronic acid. However, thanks to the process of the present invention, sizes have been achieved that allow the nanoparticles to penetrate through the skin exerting their function from the inside. In a preferred embodiment, step (a) of the process of the invention further comprises the addition of the active ingredient. In a more preferred embodiment the active ingredient is added in a weight percentage of between 5 and 80%.
Preferiblemente, el agente entrecruzante se selecciona de entre tripolifosfato sódico, genipina, polietilenglicol o cualquiera de sus combinaciones. Preferably, the crosslinking agent is selected from sodium tripolyphosphate, genipin, polyethylene glycol or any combination thereof.
En una realización preferida, la relación en masa entre el quitosano/ácido hialurónico/colágeno es de entre 1 :1 :2 y 9:3:9. En una realización más preferida, la relación en masa entre el quitosano/ácido hialurónico/colágeno es de entre 2:1 :9 y 9:1 :2. In a preferred embodiment, the mass ratio between chitosan / hyaluronic acid / collagen is between 1: 1: 2 and 9: 3: 9. In a more preferred embodiment, the mass ratio between chitosan / hyaluronic acid / collagen is between 2: 1: 9 and 9: 1: 2.
A lo largo de la descripción y las reivindicaciones, la palabra "comprende" y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la
invención. Los siguientes ejemplos y dibujos se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención. Los signos numéricos relativos a los dibujos y colocados entre paréntesis en una reivindicación, son solamente para intentar aumentar la comprensión de la reivindicación, y no deben ser interpretados como limitantes del alcance de la protección de la reivindicación. Además, la presente invención cubre todas las posibles combinaciones de realizaciones particulares y preferidas aquí indicadas. Throughout the description and the claims, the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention. The numerical signs relating to the drawings and placed in parentheses in a claim are only intended to increase the understanding of the claim, and should not be construed as limiting the scope of protection of the claim. In addition, the present invention covers all possible combinations of particular and preferred embodiments indicated herein.
Descripción de las figuras Description of the figures
Figura 1 : Imágenes de microscopía electrónica de transmisión de nanopartículas que comprenden quitosano, ácido hialurónico y colágeno, que corresponden a unas formulaciones a) y b) preparadas respectivamente según relaciones en masa de 2:1 :9 y 9:1 :2. Figura 2: Imágenes de microscopía electrónica de transmisión de nanopartículas que comprenden quitosano, ácido hialurónico y colágeno, con un 20% de albúmina de suero bovino encapsulado, que corresponden a formulaciones a) y b) preparadas respectivamente según relaciones en masa de 2:1 :9 y 9:1 :2. Figura 3: Imágenes de microscopía electrónica de transmisión de nanopartículas que comprenden quitosano, ácido hialurónico y colágeno, con un 20% de extracto de hojas de olivo encapsulado, que corresponden a formulaciones a) y b) preparadas respectivamente según relaciones en masa de 2:1 :9 y 9:1 :2. Figura 4: Distribución de tamaño de nanopartículas (nm) que comprenden quitosano, ácido hialurónico y colágeno, según una relación en masa de 9:1 :2, que corresponden a formulaciones a) vacías o exentas de ingrediente activo, y b) con un 20% de extracto de hojas de olivo encapsulado, preparadas a un pH de 4,5. Figura 5: Gráfico de % de liberación de antioxidantes vs. tiempo (horas), a partir de nanopartículas que comprenden quitosano, ácido hialurónico y colágeno con un 20% de extracto de hojas de olivo encapsulado, según unas formulaciones a), b), c) y d), que corresponden respectivamente a relaciones en masa de 9:1 :2, 2:1 :9, 1 :1 :2 y 2:3:6. EJEMPLOS
En los ejemplos de la presente invención se emplean las siguientes abreviaturas: HCS: Hidrocloruro de quitosano Figure 1: Transmission electron microscopy images of nanoparticles comprising chitosan, hyaluronic acid and collagen, corresponding to formulations a) and b) prepared respectively according to mass ratios of 2: 1: 9 and 9: 1: 2. Figure 2: Transmission electron microscopy images of nanoparticles comprising chitosan, hyaluronic acid and collagen, with 20% encapsulated bovine serum albumin, corresponding to formulations a) and b) prepared respectively according to 2: 1 mass ratios: 9 and 9: 1: 2. Figure 3: Transmission electron microscopy images of nanoparticles comprising chitosan, hyaluronic acid and collagen, with 20% encapsulated olive leaf extract, corresponding to formulations a) and b) prepared respectively according to mass ratios of 2: 1 : 9 and 9: 1: 2. Figure 4: Size distribution of nanoparticles (nm) comprising chitosan, hyaluronic acid and collagen, according to a mass ratio of 9: 1: 2, corresponding to formulations a) empty or free of active ingredient, and b) with a % of encapsulated olive leaf extract, prepared at a pH of 4.5. Figure 5: Chart of% antioxidant release vs. time (hours), from nanoparticles comprising chitosan, hyaluronic acid and collagen with 20% encapsulated olive leaf extract, according to formulations a), b), c) and d), which correspond respectively to mass ratios of 9: 1: 2, 2: 1: 9, 1: 1: 2 and 2: 3: 6. EXAMPLES The following abbreviations are used in the examples of the present invention: HCS: Chitosan Hydrochloride
HA: Ácido hialurónico HA: Hyaluronic Acid
Col: Colágeno Cabbage: Collagen
TPP: Tripolifosfato sódico TPP: Sodium Tripolyphosphate
BSA: Albúmina de suero bovino BSA: Bovine serum albumin
OLE: Extracto de hojas de olivo OLE: Olive Leaf Extract
NPs: Nanopartículas Ejemplo 1 NPs: Nanoparticles Example 1
Se prepararon nanopartículas de hidrocloruro de quitosano, ácido hialurónico y colágeno, utilizando tripolifosfato sódico como agente entrecruzante. Se adicionó la disolución de ácido hialurónico (3 mg/ml) y tripolifosfato sódico (0,1 %) sobre la disolución que contiene hidrocloruro de quitosano (0,15%), bajo agitación constante y durante 10 minutos, permitiendo la estabilización de las nanopartículas generadas. Se procedió a la centrifugación de éstas con objeto de eliminar los posibles residuos de quitosano y ácido hialurónico sin reaccionar y el pellet resultante se vuelve a suspender en una disolución de colágeno (5 mg/ml) durante 2 horas, en agitación constante. Posteriormente, se añadió una cantidad adecuada de tripolifosfato sódico y se deja reaccionar 30 minutos, permitiendo la completa evolución del sistema hasta la obtención de nanopartículas estables. Una vez preparadas, se midió su diámetro medio (nm), así como su carga eléctrica superficial y se estudió su morfología mediante microscopía electrónica de transmisión. En la tabla 1 , para todo el rango de concentraciones y en las figuras 1 y 4, para unas concentraciones determinadas, se muestran algunos de los valores que toman los parámetros citados en función de la proporción de HCS, HA, Col y TPP utilizados. Chitosan hydrochloride, hyaluronic acid and collagen nanoparticles were prepared, using sodium tripolyphosphate as a crosslinking agent. The solution of hyaluronic acid (3 mg / ml) and sodium tripolyphosphate (0.1%) was added to the solution containing chitosan hydrochloride (0.15%), under constant stirring and for 10 minutes, allowing the stabilization of the generated nanoparticles. The centrifugation of these was carried out in order to eliminate the possible unreacted chitosan and hyaluronic acid residues and the resulting pellet is resuspended in a collagen solution (5 mg / ml) for 2 hours, under constant stirring. Subsequently, an adequate amount of sodium tripolyphosphate was added and allowed to react for 30 minutes, allowing the complete evolution of the system until obtaining stable nanoparticles. Once prepared, its average diameter (nm) was measured, as well as its surface electric charge and its morphology was studied by transmission electron microscopy. In Table 1, for the entire range of concentrations and in Figures 1 and 4, for certain concentrations, some of the values taken by the parameters mentioned are shown according to the proportion of HCS, HA, Col and TPP used.
Tabla 1 Table 1
9:1 :2 214±3,2 26±0,8 9: 1: 2 214 ± 3.2 26 ± 0.8
9:3:9 459±8,7 16±1 ,8 9: 3: 9 459 ± 8.7 16 ± 1, 8
HCS/HA/Col (p/p) HCS/HA/Col (p/p) HCS/HA/Col (p/p) HCS / HA / Col (p / p) HCS / HA / Col (p / p) HCS / HA / Col (p / p)
Ejemplo 2 Example 2
Se usa la técnica descrita en el ejemplo 1 , pero se procedió a la incorporación de 20 μΙ de un agente estabilizante (glicerol) a la disolución obtenida después de adicionar ácido hialurónico y tripol ¡fosfato sódico sobre la disolución que contiene hidrocloruro de quitosano. Se midió su diámetro medio, así como su carga eléctrica superficial. En la Tabla 2 se muestran los valores que toman los parámetros citados en función de la proporción de HCS, HA y Col utilizados. Tabla 2 The technique described in example 1 is used, but 20 µΙ of a stabilizing agent (glycerol) was incorporated into the solution obtained after adding hyaluronic acid and tripol sodium phosphate on the solution containing chitosan hydrochloride. Its average diameter was measured, as well as its surface electric charge. Table 2 shows the values that take the parameters mentioned according to the proportion of HCS, HA and Col used. Table 2
Ejemplo 3 Example 3
Se prepararon nanopartículas de hidrocloruro de quitosano, ácido hialurónico, colágeno y tripolifosfato sódico como agente entrecruzante. Se procedió a la incorporación de albúmina de suero bovino (BSA). Se incorporó en la disolución de quitosano debido a su fácil solubilidad en éste. Se estableció una carga teórica de un 20% respecto al peso de los polímeros. Se midió su diámetro medio, así como su carga eléctrica superficial y se estudió su morfología mediante microscopía electrónica de transmisión. Nanoparticles of chitosan hydrochloride, hyaluronic acid, collagen and sodium tripolyphosphate were prepared as crosslinking agent. Bovine serum albumin (BSA) was incorporated. It was incorporated into the chitosan solution due to its easy solubility in it. A theoretical load of 20% was established with respect to the weight of the polymers. Its average diameter was measured, as well as its surface electric charge and its morphology was studied by transmission electron microscopy.
En la tabla 3 y figura 2 se muestran los valores que toman los parámetros citados en función de la proporción de HCS, HA y Col utilizados y la morfología de las nanopartículas obtenidas. Tabla 3
Table 3 and Figure 2 show the values that take the parameters mentioned according to the proportion of HCS, HA and Col used and the morphology of the nanoparticles obtained. Table 3
Ejemplo 4 Example 4
Se prepararon nanopartículas de hidrocloruro de quitosano, ácido hialurónico, colágeno y tripol ¡fosfato sódico como agente entrecruzante. Se procedió a la incorporación de un conjunto de antioxidantes, seleccionando para tal fin un extracto de hojas de olivo (OLE). Se incorporó en la disolución de tripolifosfato sódico, debido a su carácter hidrofílico y fácil solubilidad en éste. Se estableció una carga teórica de un 20% respecto al peso de los polímeros. Se midió su diámetro medio, así como su carga eléctrica superficial y se estudió su morfología mediante microscopía electrónica de transmisión. En la tabla 4 y las figuras 3 y 4 se muestran los valores que toman los parámetros citados, en función de la proporción de HCS, HA y Col utilizados. La eficacia de encapsulación se determinó evaluando la cantidad de polifenoles libres, usando el método de Folin-Ciocalteu. Se llevaron a cabo estudios de liberación in-vitro, a 37°C en medio acuoso, a pH: 5,5 durante un periodo de 24h. La cantidad de principio activo liberado se determinó por espectrofotometría de ultravioleta visible. En el gráfico de la figura 5, % de liberación de polifenoles vs. tiempo (horas), se representan diferentes líneas: una con cuadrados, para la formulación d); una con triángulos, para la formulación b); una con círculos, para la formulación c) y una sin elementos geométricos, para la formulación a). Nanoparticles of chitosan hydrochloride, hyaluronic acid, collagen and tripol phosphate sodium were prepared as crosslinking agent. A set of antioxidants was incorporated, selecting for this purpose an olive leaf extract (OLE). It was incorporated into the solution of sodium tripolyphosphate, due to its hydrophilic character and easy solubility in it. A theoretical load of 20% was established with respect to the weight of the polymers. Its average diameter was measured, as well as its surface electric charge and its morphology was studied by transmission electron microscopy. Table 4 and Figures 3 and 4 show the values that take the parameters mentioned, depending on the proportion of HCS, HA and Col used. The encapsulation efficiency was determined by evaluating the amount of free polyphenols, using the Folin-Ciocalteu method. In-vitro release studies were carried out, at 37 ° C in aqueous medium, at pH: 5.5 for a period of 24h. The amount of active ingredient released was determined by visible ultraviolet spectrophotometry. In the graph of Figure 5,% release of polyphenols vs. time (hours), different lines are represented: one with squares, for the formulation d); one with triangles, for the formulation b); one with circles, for formulation c) and one without geometric elements, for formulation a).
Tabla 4 Table 4
Claims
1 . Nanopartículas para la liberación controlada de ingredientes activos que comprenden quitosano, ácido hialurónico y colágeno, caracterizadas porque además comprenden un ingrediente activo, el cual se selecciona de entre un fármaco, vitaminas, péptidos, proteínas, un agente antioxidante o cualquiera de sus combinaciones. one . Nanoparticles for the controlled release of active ingredients comprising chitosan, hyaluronic acid and collagen, characterized in that they also comprise an active ingredient, which is selected from a drug, vitamins, peptides, proteins, an antioxidant or any combination thereof.
2. Nanopartículas según la reivindicación 1 , caracterizadas porque el agente antioxidante se selecciona de la lista que comprende antioxidantes de extracto de hojas de olivo, alperujo, yerba mate, torta, aceite de cardo, té, vitamina C, vitamina E, retinoides, idebenona, coenzima Q10, ácido lipoico, picnogenol o cualquiera de sus combinaciones. 2. Nanoparticles according to claim 1, characterized in that the antioxidant agent is selected from the list comprising antioxidants from olive leaf extract, alperujo, yerba mate, cake, thistle oil, tea, vitamin C, vitamin E, retinoids, idebenone , coenzyme Q10, lipoic acid, picnogenol or any combination thereof.
3. Nanopartículas según la reivindicación 2, caracterizadas porque el agente antioxidante se selecciona de entre extracto de hojas de olivo, yerba mate, torta y aceite de cardo o alperujo. 3. Nanoparticles according to claim 2, characterized in that the antioxidant agent is selected from olive leaf extract, mate, cake and thistle oil or alperujo.
4. Nanopartículas según cualquiera de las reivindicaciones 1 a 3, caracterizadas por tener un tamaño de partícula de entre 150 y 700 nm. 4. Nanoparticles according to any one of claims 1 to 3, characterized in that they have a particle size between 150 and 700 nm.
5. Uso de las nanopartículas según cualquiera de las reivindicaciones 1 a 4, para la fabricación de una composición farmacéutica o composición cosmética. 5. Use of the nanoparticles according to any of claims 1 to 4, for the manufacture of a pharmaceutical composition or cosmetic composition.
6. Uso según la reivindicación 5, caracterizado porque la composición farmacéutica o cosmética es de administración tópica. 6. Use according to claim 5, characterized in that the pharmaceutical or cosmetic composition is topically administered.
7. Procedimiento de obtención de las nanopartículas según cualquiera de las reivindicaciones 1 a 4, que comprende las siguientes etapas: 7. Method for obtaining the nanoparticles according to any of claims 1 to 4, comprising the following steps:
a) mezclar al menos dos disoluciones A y B, donde la disolución A comprende ácido hialurónico y la disolución B comprende un agente entrecruzante. a) mixing at least two solutions A and B, where solution A comprises hyaluronic acid and solution B comprises a crosslinking agent.
b) mezclar el producto obtenido en la etapa (a) con dos disoluciones C y D, donde la disolución C comprende quitosano y la disolución D comprende colágeno. b) mixing the product obtained in step (a) with two solutions C and D, where solution C comprises chitosan and solution D comprises collagen.
8. Procedimiento según la reivindicación 7, que además comprende la adición del ingrediente activo en la etapa (a). 8. The method according to claim 7, further comprising adding the active ingredient in step (a).
9. Procedimiento según la reivindicación 8, caracterizado porque el ingrediente activo se adiciona en un porcentaje en peso de entre 5 y 80%.
9. Method according to claim 8, characterized in that the active ingredient is added in a weight percentage of between 5 and 80%.
10. Procedimiento según cualquiera de las reivindicaciones 7 a 9, caracterizado porque el agente entrecruzante se selecciona de entre tripolifosfato sódico, genipina, polietilenglicol o cualquiera de sus combinaciones. Method according to any one of claims 7 to 9, characterized in that the crosslinking agent is selected from sodium tripolyphosphate, genipin, polyethylene glycol or any combination thereof.
1 1. Procedimiento según cualquiera de las reivindicaciones 7 a 10, caracterizado porque la relación en masa entre el quitosano/ácido hialurónico/colágeno es de entre 1. Method according to any of claims 7 to 10, characterized in that the mass ratio between chitosan / hyaluronic acid / collagen is between
1 :1 :2 y 9:3:9. 1: 1: 2 and 9: 3: 9.
12. Procedimiento según la reivindicación 1 1 , caracterizado porque la relación en masa entre el quitosano/ácido hialurónico/colágeno es de entre 2:1 :9 y 9:1 :2.
12. Method according to claim 1, characterized in that the mass ratio between chitosan / hyaluronic acid / collagen is between 2: 1: 9 and 9: 1: 2.
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