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WO2013091056A1 - Compositions pharmaceutiques comprenant un extrait d'arrabidaea chica dans des systèmes à libération contrôlée, procédé de fabrication et utilisation de ceux-ci - Google Patents

Compositions pharmaceutiques comprenant un extrait d'arrabidaea chica dans des systèmes à libération contrôlée, procédé de fabrication et utilisation de ceux-ci Download PDF

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Publication number
WO2013091056A1
WO2013091056A1 PCT/BR2012/000532 BR2012000532W WO2013091056A1 WO 2013091056 A1 WO2013091056 A1 WO 2013091056A1 BR 2012000532 W BR2012000532 W BR 2012000532W WO 2013091056 A1 WO2013091056 A1 WO 2013091056A1
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Prior art keywords
extract
chica
controlled release
arrabidaea
release system
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English (en)
Portuguese (pt)
Inventor
Mary Ann FOGLIO
João Ernesto de CARVALHO
Ana lucia tasca Góis RUIZ
Michelle Pedroza JORGE
Leila SERVAT
Patricia Maria Wiziack ZAGO
Marcos Nogueira EBERLIN
Elaine Cristina Cabral POLCELLI
Maria Helena Andrade SANTANA
Viviane Ferre de SOUZA
Glyn Mara FIGUEIRA
Ilza Maria OLIVEIRA
Rodney Alexandre Ferreira RODRIGUES
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Universidade Estadual de Campinas UNICAMP
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Universidade Estadual de Campinas UNICAMP
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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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to stable pharmaceutical compositions comprising Arrabidaea chica extract in controlled release systems, in the form of liposomes, micro- or nanoparticles having as release control material natural and / or modified or synthetic polymers, as well as the respective procurement processes.
  • compositions of the present invention comprise polymeric micro and nanoparticulate systems or liposomes which guarantee the protection and stability of the crude extract of A. chica, said systems being comprised in a pharmaceutically acceptable carrier, thus resulting in compositions with greater stability relative to the compositions. containing the free extract.
  • the present invention also describes processes for the manufacture of polymeric micro and nanoparticulate systems or liposomes comprising A. chica extract. BACKGROUND OF THE INVENTION
  • the genus Arrabidaea is a source of anthocyanins, flavonoids and tannins. Species of this genus are used in folk medicine for wound asepsis and treatment of intestinal disorders.
  • Arrabidaea chica is a member of the Bignoniaceae family, and is present in tropical America from southern Mexico to central Brazil.
  • A. chica is used for the treatment of skin diseases (mycoses, herpes, psoriasis, wounds and ulcers), intestinal cramps, disinfection of women's intimate parts, diarrhea, leukorrhea, anemia and leukemia.
  • skin diseases mycoses, herpes, psoriasis, wounds and ulcers
  • intestinal cramps disinfection of women's intimate parts
  • diarrhea leukorrhea
  • anemia and leukemia anemia and leukemia.
  • efficacy of A. chica as anti-inflammatory and antifungal and for the treatment of oral cancer, uterus and leukemia.
  • Plant extracts have been used as a coloring material in cosmetic formulations (US20040076650, WO00241855, EP1339376).
  • a second stage consists of the knowledge of the aspects of the biological activity of the vegetable for the transformation of the medicinal plant in herbal medicine. At this stage several tests are performed to evaluate the activity of the extract, studies to identify and isolate major components of the extracts that may be considered important, and in some cases the need for isolation of compounds. Once proven the effectiveness of the extract, the next step is the production of a herbal medicine, ie development of the pharmaceutical composition containing the extract or isolated compounds.
  • the present invention aims to provide stable pharmaceutical compositions comprising (i) Arrabidaea chica extract conveyed in sustained release system, said system being in the form of microparticles, nanoparticles or liposomes; and (ii) pharmaceutically acceptable excipient for topical application, the active components present in the extract of A. chica being released in a therapeutically effective amount in tissue healing.
  • the Arrabidaea chica (A. chica) extract controlled release system comprises micro- or nanoparticles, using as matrices or wall material a natural polymer selected from the group consisting of maltodextrin, gum arabic and gum. cashew nuts or mixtures thereof.
  • the Arrabidaea chica extract controlled release system comprises micro- or nanoparticles, employing as a matrix a biopolymer selected from the group consisting of chitosan and hyaluronic acid.
  • the controlled release system of Arrabidaea chica extract comprises liposomes.
  • Another object of the present invention is to provide a process for producing the composition of the invention comprising the steps of: (a) forming the controlled release carrier system of Arrabidaea chica extract, (b) incorporating the Arrabidaea chica extract into said carrier system. in such a way as to maintain the physical, chemical and pharmacological properties of the A. chica extract components and (c) adding the controlled release A. chica extract to a pharmaceutically acceptable excipient so that the active components present in the A. chica extract are released. in therapeutically effective amount in tissue healing.
  • the controlled release system of A. chica extract is in the form of microparticles, nanoparticles or liposomes.
  • Figure 1 shows the flowchart of obtaining the crude extract of A. chica and the microparticles produced by spray drying.
  • Figure 2 shows the crude extract of A. chica after extraction (A) and after 15 days stability test at 40 ° C and 75% unit (B).
  • Figure 3 shows a graph comparing the average diameter of conventional and empty pegylated liposomes and in the presence of A. chica extract.
  • Figure 4 shows a graph comparing the polydispersity of conventional and empty pegylated liposomes and in the presence of A. chica extract.
  • Figure 5 shows a graph comparing the zeta potential of conventional and empty pegylated liposomes and in the presence of A. chica extract.
  • Figure 6 shows a graph comparing the electrical conductivity of conventional and empty pegylated liposomes and in the presence of A. chica extract.
  • Figure 7 shows a graph comparing the concentration of extract present in conventional and pegylated liposomes after disruption.
  • Figure 8 shows the flow curve of coventional liposomes (LC) and pegylated liposomes (LP).
  • Figure 9 shows a graph representing the mean LC diameter after elasticity test.
  • Figure 10 shows a graph representing the mean diameter of LP after elasticity test.
  • Figure 11 shows a scanning microscopy of the structures obtained in the preparation of HA particles containing the active Arrabidaea chica.
  • A condition of 1500 and 200 rpm
  • B condition of 1500 and 1000 rpm.
  • Increase in negative 5000x.
  • Figure 12 shows a scanning microscopy to evaluate the Active (A. chica): AH ratio.
  • Molar relations of preparations A and B: 1: 1; C and D: 0.75: 1; E and F: 0.5: 1; G and H: 1.25: 1; A, C, E and G. were prepared under the conditions of 1,500 and 1,000 rpm, and B, D, F and H under the preparation conditions of 1,500 and 200 rpm.
  • Figure 13 shows a graph representing the results of the healing trial, the percentage of wound contraction after 10 days of treatment.
  • Figure 14 shows a graph demonstrating quantification of Arrabidaea chica anthocyanins by HPLC-DAD.
  • Pig 1 6,7,7 ', 4 ' - tetrahydroxy-5-methoxy-flavylium
  • Pig. 2 6,7,3'-trihydroxy-5-methoxyflavylium
  • Pig 3 Crajurine - 6,7-dihydroxy-5''-dimethoxyflavilium.
  • FAC extract without microencapsular
  • MAC microencapsulated extract.
  • Figure 15 shows a graph representing the assessment of chorioallantoid membrane (CAM) angiogenesis activity.
  • the vertical bars represent the standard deviation of the mean.
  • Figure 16 shows photographs of the healing assay. Visual observations after ten days of treatment with: A) Saline (negative control), B) Raw A. chica lg / mL extract, and C) Microencapsulated extract of A. chica 1g / ml.
  • Figure 17 shows photograph of the stability test comparing crude extract of A. chica after extraction (A) and microencapsulated extract with arabic gum (B) after 15 days in stability test at 40 ° C and 75% unit.
  • the present invention relates to stable pharmaceutical compositions comprising (i) controlled release system of Arrabidaea chica extract, in the form of micro-nanoparticles, or liposomes and (ii) a pharmaceutically acceptable excipient for topical administration.
  • the components present in Arrabidaea chica extract are released in a therapeutically sufficient amount for tissue healing.
  • the invention also relates to a process for the production of controlled release systems of A. chica extract in the form of oncapulated micro- or nanoparticles or liposomes.
  • the present invention also focuses on the use of stable pharmaceutical compositions comprising A. chica extract in controlled release systems for the treatment of healing wound lesions.
  • chica extracts have been employed in cosmetic or pharmaceutical formulations as components of sunscreens or skin care products, and as anti-inflammatory agents (WO200152809, WO0152809).
  • A. chica extract is also used together with extracts from other plants in skin treatment, anti aging, hair treatment and oral cavity (JP2001122763-A, 2001).
  • A. chica extract contains chemical compounds effective in healing skin lesions, with angiogenic properties and inducing fibroblast proliferation and collagen synthesis.
  • the most important biologically active chemical compounds found in Arrabidaea chica extract are pigment 1, pigment 2, and carajurine, which have the following chemical structures:
  • the inventors submitted the extracts of the plant A. chica to different methodologies for formation of particulate systems seeking the protection of their active compounds, and consequently the increased stability of the extract.
  • the first step of the present invention is related to obtaining the extract, since improper handling / processing of a plant, including A. chica, can cause loss of the active compounds present in the extract, resulting in the loss of the desired pharmacological activity.
  • the process of extracting the extracts of A. chica leaves follows the flow chart described in Figure 1.
  • the process of obtaining the extract consists of the steps of: (a) collecting the leaves; (b) extraction; (c) extract concentration; and (d) neutralization of the crude extract.
  • Leaf Collection Step The leaves collected they are dried in a ventilated oven at 40 ° C for 48 hours and ground in a 40 mesh sieve hammer mill. The dried and ground plant material can be used for extraction or vacuum packed for storage and further extraction.
  • the crude extract obtained by the above process is dried, preferably employing the spray drying technique, under specific conditions as listed in Table 1.
  • drying process must take place in an oxygen free environment, for example in an inert gas environment such as nitrogen or argon.
  • the raw extract was used by the inventors in the elaboration of compositions and efficacy tests, however, the researchers observed that the raw extract was very unstable and in only 15 days it no longer had its physical characteristics (Figure 2), and therefore has life. Useful too short.
  • Encapsulation and controlled release modify the pharmacokinetics and pharmacodynamics of bioactives, so that the formulation containing the encapsulated bioactive constitutes a new drug in relation to its free form.
  • the present invention is based on the preparation of (I) liposomal, (II) microparticulate and nanoparticulate release systems comprising A. chica extract, and further incorporation of these systems into pharmaceutical formulations under conditions which ensure controlled release of the active components of A. chica in a therapeutically effective amount in the treatment of tissue healing.
  • the object of the present invention comprises not only the development of controlled release systems of Arrabidaea chica extract, for example in the form of liposomes or micro- or nanoparticles, but also a pharmacologically acceptable excipient which ensures controlled release of the active components. of A. chica in therapeutically effective amount in the treatment of tissue healing.
  • the controlled release systems in the form of micro- or nanoparticle matrices employed in the present invention are polymeric compounds selected from the group consisting of: maltodextrin, gum arabic and cashew gum or mixtures thereof, chitosan, hyaluronic acid or other polymers. pharmaceutically acceptable.
  • One embodiment of the present invention is the preparation of pharmaceutical compositions comprising: (i) A. chica extract conveyed in liposomal delivery systems and
  • liposomes are spherical vesicles formed by concentric phospholipid bilayers that spontaneously organize in aqueous medium. Liposomes are classified with respect to their size and number of coverslips, as well as their interaction with the biological environment.
  • A. chica extracts may be carried on any type of liposome. Particularly, the liposome is formed by a lipoprotein.
  • lipoproteins suitable for liposome production are selected from the group consisting of: egg phosphatidylcholine, dioleylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine
  • DMPC Dipalmitoylphosphatidylcholine
  • DPPC Dipalmitoylphosphatidylcholine
  • DOPE Dioleylphosphatidylethanolamine
  • DMPG Dimyristoylphosphatidylglycerol
  • DPPG Dipalmitoylphosphatidylglycerol
  • DSPS Diestearoylphosphatidylserine
  • the Lipoprotein of major interest is egg phosphatidylcholine.
  • the liposomes of the present invention may be contacted with polyethylene glycol (PEG) to be pegylated.
  • PEG polyethylene glycol
  • liposomes are divided into three categories, namely: (a) multilamellar vesicles (MLV), liposomal forms formed by aqueous compartment-interspersed concentric phospholipid bilayers whose diameter ranges from 400 to 3500 nm; (b) large unilamellar vesicles (LUV), liposomal forms consisting of only one phospholipid bilayer but with a large aqueous cavity and diameter ranging from 200 to 1000 nm; and (c) small unilamellar vesicles (SUV), liposomal forms consisting of only one phospholipid bilayer and a small aqueous compartment whose diameter ranges from 20 to 50 nm (SCARPA, MV, OLIVEIRA, AG AND CUCCOVIA, IM. liposome chemicals (Infarma, 7, (1/2), 4-7, 1998).
  • MLV multilamellar vesicles
  • LUV large unilamellar vesicles
  • SUV small un
  • liposomes can be classified as cationic, anionic and neutral.
  • Another embodiment of the present invention relates to the process of producing liposomes. comprising extract of A. chica, such process comprising the steps:
  • the incubation is in the phospholipid: PEG 10:90 to 90:10 molar ratio, more preferably from 80:20 to 20:80, and even more preferably from 40:60 to 60:40.
  • the organic solvent is selected from the group consisting of: methanol, ethanol, methyl ether, ethyl ether, acetone, formol, dichloromethane, chloroform, tetrachloromethane or mixtures thereof.
  • the organic solvent is chloroform-methanol solution in the ratio 9: 1 (v / v).
  • the preferred buffer solution is 10mM HEPES buffer at pH 7.4, and the resting time is preferably 2 hours at a temperature of about 4 ° C.
  • Another step of the process consists of the production of the liposome system containing the extract of A. chica.
  • the extract is added to the hydration solution together with the buffer used in the preparation phase of the lipid film.
  • the liposomes underwent an ultrafiltration process for separation of the unencapsulated active.
  • Another embodiment of the present invention is the preparation of controlled release systems of A. chica extract conveyed in micro or nanoparticulate release systems.
  • a preferred embodiment of the present invention is the preparation of controlled release systems of A. chica extract comprising a polymeric matrix or wall material for the formation of micro or nanoparticles.
  • the matrix or wall material is selected from the group consisting of: maltodextrin, gum arabic, cashew gum and mixtures thereof.
  • the polymeric matrix is a biopolymer selected from the group consisting of chitosan, hyaluronic acid or a mixture thereof.
  • Micro or nanoparticle controlled release systems in accordance with the present invention may be obtained by various methods, including but not limited to physical methods such as spray drying, thermal bath spraying, fluidized bed, multiple orifice centrifugal extrusion, crystallization, lyophilization; chemical methods such as molecular inclusion and interfacial polymerization; and physicochemical methods, such as coacervation, organic phase separation and crosslinking agent spraying.
  • physical methods such as spray drying, thermal bath spraying, fluidized bed, multiple orifice centrifugal extrusion, crystallization, lyophilization
  • chemical methods such as molecular inclusion and interfacial polymerization
  • physicochemical methods such as coacervation, organic phase separation and crosslinking agent spraying.
  • the spray drying atomization method is used.
  • Spray drying may be defined as the transformation of a fluid material (solution, dispersion or paste) into dry particles in powder form and is widely known in the art.
  • the process is continuous and basically involves the following steps: formation of an emulsion or suspension of the matrix material and the active ingredient, atomization in a drying chamber containing air or a circulating hot inert gas and evaporation of the solvent, with consequent drying of the droplets.
  • atomized JACKSON LS, LEE K.
  • the selection of the material to be used as a polymeric matrix or wall material depends on a number of factors, including non-reactivity with the material to be incorporated into the matrix, the physicochemical properties of the material (such as molar mass, solubility and diffusibility). ), the process used to manufacture the microparticles and their final application.
  • the microparticulate system comprising Arrabidaea chica extract is composed of dies or specific wall material selected from the group consisting of maltodextrin, gum arabic, cashew gum or mixtures thereof.
  • Maltodextrin is, by definition, a modified starch, also defined as a complex carbohydrate, obtained from the conversion of starch, whose main characteristics are: excellent protection against volatile oxidation. encapsulated, lack of emulsifying capacity and low volatile retention (INGLETT, GE; GELBMAN, P.; REINECCIUS, GA Encapsulation of orange oil. Use of modified amylase starches of maize, rice, cassava and potato. Chapter 4. In: RISH, SJ; REINECCIUS, GA Flavor Encapsulation (ACS Symposium Series 370. American Chemical Society, 29-36, 1988).
  • Maltodextrin is usually marketed as a white powder, and can be defined as a glucose polymer.
  • the advantage of using maltodextrin as a matrix is its relatively low cost, neutral aroma and taste, low viscosity at high solids concentrations, and good protection against oxidation.
  • the major problem of this material as a matrix or wall material is its low emulsification capacity. Therefore, due to the low emulsification capacity of maltodexrin it is desirable to use it in combination with other biopolymers such as gum arabic or cashew gum.
  • Arabica gum is a natural resin composed of polysaccharides and glycoproteins often used as a thickener and stabilizer in the industrial sector. In the pharmaceutical industry, gum arabic is widely used as a thickener for syrups, creams, etc. It is also used to make capsules and coatings. as a binder and dispersant medium of active ingredients.
  • the microparticle controlled release system employed in the invention comprises as matrix a mixture of maltodextrin and gum arabic, a mixture of maltodextrin and cashew gum or a mixture of arabic gum and cashew gum, with the mixtures being can be in a ratio of 2: 8 to 8: 2.
  • A. chica extract and the microparticulate release system matrix are present in the microparticle formulation in a ratio of 2: 8 to Another embodiment of the present invention relates to the process of producing the controlled release system of A. chica extract in the form of micro or nanoparticles.
  • the microparticle formation process using the spray drying atomization drying technique comprises the steps of: (a) dissolving the matrix polymer in water; (b) dissolving the crude A. chica extract in the solution containing said matrix polymer; (c) drying the solution in a drying chamber under specified conditions; and (d) forming the controlled release system in the form of microparticles containing A. chica extract.
  • Steps (a) and (b) are simple and simply consist of adding and dissolving the matrix and extract in the selected medium.
  • incorporation of the A. chica extract is effected by mixing different proportions of the plant extract with the matrix material or mixture, or the mixture of materials. Mixing ratios between matrix materials may vary in the range of ratios from 80:20 to 20:80. In Table 2 some of these appropriate mixtures are described.
  • Table 2 Matrices and possibility of proportions used between two different matrix materials for the composition of the microparticle forming material.
  • the concentrated A.chica crude extract is mixed with the solution containing the matrix material under stirring and homogenized for approximately 3 minutes at 14000 rpm rotation.
  • the different ratios used to incorporate the extract into the matrix material are described in Table 3.
  • Table 3 Ratio of ratios used between the raw A.chica extract and the matrix material used.
  • step (c) the solution containing the matrix material and the extract is introduced by means of a pump peristaltic in a drying chamber.
  • the drying chamber is composed of three pipes with different functions: (1) entrance of the polymer solution and the active principle into the drying chamber; (2) supply of compressed air or inert gas, eg Nitrogen, which promotes solution passage through the atomizer; and (3) providing hot inert gas to effect solvent evaporation of the A. chica matrix solution and extract. After removal of the solvent, the dried material passes through the atomizer and the microspheres are formed and precipitated in the cyclone.
  • a B-290 mini-spray drying with B-295 inert loop manufactured by Buchi, Switzerland was employed.
  • Table 4 Conditions for processing microparticle formation by spray drying the matrix material mixture and Arrabidaea chica extract.
  • the controlled release system of Arrabidaea chica extract in the form of micro- or nanoparticles, is composed of biopolymer matrices.
  • biopolymers refers to high molecular weight chemical compounds consisting of smaller structural units (monomers), which are chain repeating and are produced by living beings.
  • examples of biopolymers useful for the present invention are carbohydrates, proteins, glycoproteins, lipoproteins and lipids, particularly alginic acid, alginate, chitin, chitosan, hyaluronic acid, cellulose, collagen, keratin, gelatin, cutin, suberine, among others.
  • Preferably being used in the present invention are the chitosan and / or hyaluronic acid biopolymers. Shown below are the chemical structures of chitosan (I), chitosan with sodium tripolyphosphate (II) and hyaluronic acid (III).
  • Chitosan is a biopolymer obtained from the deacetylation of chitin. Chitin is the second most abundant polymer in nature after cellulose, and is the main exoskeleton component of crustaceans, chitosan production. therefore economically viable (PEDRO AS, CABRAL- ALBUQUERQUE E, FERREIRA D, SARMENTO B. Chitosan: An option for development of essential oil delivery systems for oral cavity care? Carbohydrate Polymers, 76: 501-508, 2009).
  • Ionotropic gelation consists of ionic cross-linking of chitosan with multivalent counterions.
  • Electrostatic interaction refers to the interaction that occurs between opposite electrostatic charges, that is, the positive charges of chitosan interact with the negative charges of the crosslinking agent, promoting its ionic crosslinking. This process mainly aims to reduce their solubility in the environment to which they are exposed.
  • the crosslinking agent interacts with chitosan, reducing the pores of its matrix. As a result, the particles become stiffer, less swelling, and prolong the release time of the encapsulated bioactive.
  • TPP sodium tripolyphosphate
  • PIFFERI G PIFFERI G
  • SEGHIZZI R CAMERONI R. Swelling behavior of gelatin crosslinked with D, L-glyceraldehyde. Pharmacy and Pharmacology Letters, 5: 116-119, 1995).
  • Particles are formed by the addition of one solution to another under magnetic or mechanical stirring (Shu & Zhu, 2000).
  • the drug or bioactive to be delivered to the system may be added to the chitosan solution or the TPP solution.
  • Hyaluronic acid is a naturally occurring linear polysaccharide composed of repetitive disaccharide units formed by ⁇ -1,4-D-glucuronic acid ( ⁇ -1,3) N-acetyl-D-glycosamine bonds.
  • the primary structure of HA consists of these repeats, with more than five hydrogen bridges between every two neighboring disaccharides.
  • the secondary structure is formed as a double-stranded propeller by a 180 ° rotation of each disaccharide unit compared to those at the front and rear of the chain.
  • the ⁇ -sheet tertiary structure is energetically stabilized by the presence of intermolecular hydrogen. Hydrophobic interactions and hydrogen bridges, in partnership with counter electrostatic repulsion, enable a large number of molecules to aggregate forming AH arrays (BROWN MB, JONES S A. Hyaluronic acid: a unique topical vehicle for the delivery of drugs to the skin J Eur Acad Dermatol Venereol, 19: 308-318, 2005).
  • Soluble HA has been used in clinical applications including eye surgery, visco-supplementation for arthritis and wound healing. However, its poor mechanical properties, rapid degradation and in vivo clearance limit its direct clinical application.
  • HA can be chemically modified by covalent crosslinking making it less soluble.
  • Typical chemical modification of HA involves carboxylic acid groups and / or main chain alcohol groups. The carboxylic acid group may be modified by esterification and cross-linking with dihydrazide.
  • a preferred embodiment relates to the process of producing controlled release system of A. chica extract in the form of micro- or nanoparticles comprising as chitosan biopolymer as matrix material.
  • the process for producing chitosan micro or nanoparticles comprises the steps of: (a) Chitosan purification; (b) Preparation of the chitosone solution for crosslinking; (c) Chitosan particle production.
  • Chitosan was initially suspended in half the total water volume along with acetic acid to facilitate chitosan dissolution. Mixing was performed under mechanical stirring for a period of approximately 24 hours and at room temperature. Then the volume was made up with the remaining water and stirred for a further approximately 24 hours. During the stirring process, the container was covered with plastic wrap to prevent solvent evaporation.
  • the solution was boiled for a period of approximately 15 minutes for precipitation of the contaminants followed by centrifugation.
  • the supernatant was filtered through a porous plate funnel with filter paper.
  • the pH of the solution was corrected to pH 9 using 1 N sodium hydroxide.
  • the mixture was centrifuged and the precipitate redispersed and pelleted again by centrifugation twice using pH 9 water as the dispersing medium. The procedure was repeated with water until the pH reached pure water values.
  • the sample was lyophilized and stored at 4 ° C.
  • a 0.25% (w / v) solution of purified chitosan obtained in the previous step was prepared together with 0.375% (v / v) acetic acid under constant stirring for about 48 hours.
  • the solution was stored in a refrigerator (5 ° C) to prevent the proliferation of microorganisms.
  • the ionotropic gelation technique which consists of the ionic cross-linking of chitosan with multivalent counterions, employing a specific gelling agent, and preferably sodium tripolyphosphate (TPP) as a gelling or crosslinking agent.
  • TPP sodium tripolyphosphate
  • TPP is gradually added under mechanical agitation using a toothed rotor approximately 1000 rpm, in beakers with baffles.
  • aliquots of ImL were removed from the reaction medium to measure diameter and zeta potential using the ZetaSizer® Malvern Instruments-Nano-ZS equipment.
  • the present invention for the production of the particles containing the A. chica extract, it is incorporated into the chitosan solution and / or the gelling agent solution during the particle production step.
  • the present invention relates to the process for producing the controlled release system of A. chica extract in the form of micro- or nanoparticles using hyaluronic acid as a matrix material.
  • the polymeric micro- and nano-particles employing hilauronic acid were obtained by the A / O (water / oil) emulsion method.
  • Hyaluronic acid polymer (HA) was chemically cross-linked with adipic acid dihydrazide (ADH), according to the protocol of Yun and colleagues (YUN YH, GOETZ DJ, YELLEN P, CHEN. , 25: 147-157, 2004) with adaptations.
  • This process comprises the steps of: (a) cross-linking hyaluronic acid; (b) phase separation and second crosslinking reaction; (c) obtaining the particles; and (d) obtaining the particles containing the A. chica extract.
  • the hyaluronic acid cross-linking step began with the addition of mineral oil and emulsifying agent Spam 80 to a baffle beaker under constant stirring on an automatic stirrer. After stirring has commenced, an amount of the crosslinker dissolved in 0.5% hyaluronic acid is added to the container. After approximately 30 minutes, an emulsion of another crosslinking agent dissolved in water and hydrochloric acid is added to the medium. The mixture is kept under constant agitation for the reaction to occur.
  • the first crosslinking agent is adipic dihydrazide (ADH).
  • the second crosslinking agent is 1-ethyl-3- (3-dimethylamino-propyl) carbodiimide (EDCI).
  • the first crosslinking reaction takes place under constant agitation for 12 to 24 hours.
  • the particles are resuspended in a solution of crosslinking agents or distilled water.
  • the crosslinking agents are selected from adipic dihydrazide 1-ethyl-3- (3-dimethylamino-propyl) carbodiimide.
  • IPA isopropyl alcohol
  • the emulsion was washed with isopropyl alcohol (IPA) under agitation and the visual phase separation occurred. Physical separation of the phases (water / oil) was performed with separation funnel. The aqueous portion containing the particles was then centrifuged and the supernatant discarded. Resuspension of the particles was performed with the crosslinking agents ADH and EDCI dissolved in 90% isopropyl alcohol under stirring.
  • hydrochloric acid was added, and constant stirring was maintained for approximately 24 hours.
  • the particle collection step was performed by centrifugation and addition of 90% isopropyl alcohol, repeating the process three times. After removal of isopropyl alcohol, the material was then resuspended in distilled water and centrifuged. The supernatant containing the nanoparticles was separated from the pellet containing the microparticles. The particles were frozen in liquid nitrogen (N2) and lyophilized.
  • N2 liquid nitrogen
  • Another specific embodiment of the present invention relates to stable pharmaceutical compositions comprising controlled release A. chica extract in the form of microparticles, nanoparticles or liposomes, and one or more pharmaceutically acceptable excipients, vehicles, preservatives and adjuvants.
  • the microparticles or nanoparticles are produced using a matrix material selected from the group consisting of maltodextrin, gum arabic and cashew gum and mixtures thereof.
  • the micro- or nanocapsules are produced using a biopolymer matrix, preferably chitosan or hyaluronic acid.
  • A. chica extract is carried in liposomal systems.
  • “Pharmaceutically acceptable excipients, carriers, preservatives and adjuvants” means any substances commonly used in the formulation of topical pharmaceutical compositions, including, but not limited to, water, beeswax, mineral oil, inorganic salts, Lanette N ®.
  • the pharmaceutical composition may be in the form of cream, ointment, gel, hydrogel or lotion.
  • the pharmaceutical composition of the invention is in the form of cream, gel or hydrogel.
  • the process of the present invention for the preparation of the pharmaceutical composition of the invention comprises the steps of: (a) forming the controlled release carrier system of Arrabidaea chica extract, (b) incorporating the Arrabidaea chica extract into said carrier system under controlled conditions. to maintain the physical, chemical and pharmacological properties of the components of the A. chica extract and (c) to add the controlled release A. chica extract to a pharmaceutically acceptable excipient such that the active components present in the A extract chica are released in a therapeutically effective amount in tissue healing.
  • the controlled release system of A. chica extract is in the form of microparticles, nanoparticles or liposomes.
  • chica extract in the healing process of skin lesions has already been known from the state of the art, the problem of serious and rapid degradation of the active components present in the skin in the present process had not been resolved.
  • Degradation mainly caused by oxidation, occurs already in obtaining the extract from the raw plant material of A. chica.
  • specific conditions are employed to prevent such degradation, fundamentally with respect to reduction of extraction time, strict temperature control and storage of the extract under light as described above.
  • A. chica extract is incorporated into a controlled release system in the form of micro-, nanoparticles or liposomes under operating conditions that ensure the stability of the active components present in the drug.
  • A. chica extract are related to the use of inert gas environment, for example, in the drying step of the micro- or nanoparticles, and the choice of suitable material for liposome formation.
  • Another embodiment of the present invention relates to the use of the pharmaceutical composition of the invention in the manufacture of medicament for treating skin lesions with healing activity.
  • skin lesion is any abnormality of the skin or mucosa that is characterized by tissue loss and may be caused by hypoxia, physical agents, chemical agents (therapeutic or otherwise), infectious agents, immunological reactions, genetic disorders, nutritional disorders or others.
  • Healing is a complex and dynamic process that results in restoration of anatomical function and continuity. This process can be divided into three phases: inflammatory, proliferative and remodeling. Changes in one of these phases lead to a slow healing process or even its interruption.
  • diabetic neuropathy In conditions such as diabetes, the onset of diabetic neuropathy may lead to foot ulcers (diabetic foot) as a result of endothelial dysfunction that prevents effective action of inflammation mediators. This scar deficiency can, in many cases, contribute to the process leading to limb amputation.
  • A. chica A. chica crude extract was able to stimulate concentration-dependent fibroblast growth, increased collagen production, moderate antioxidant action, and topical healing activity demonstrated in trials using the crude extract.
  • the results obtained by the present inventors demonstrate the efficacy of A. chica extract in controlled release systems, in the form of micro- and nano-particles, in the healing of skin and mucosal lesions, and healing in 84% of treated wounds. with extract of A. chica in the form of microparticles.
  • Example 1 Process for obtaining A. chica crude extract
  • Leaf collection Leaves from the A. chica plant were collected, and the leaves were dried in a ventilated oven at 40 ° C for 48 hours and ground in a 40 mesh sieve hammer mill and then vacuum packed. .
  • the crude extract obtained by the above process is dried using the spray drying technique under specific conditions as listed in Table 1.
  • the egg phosphotidylcholine liposome is used.
  • Phospholipid was weighed to 1mM concentration (corresponding to 0.0494 g of phospholipid (80% purity) to 50 ml liposome suspension) in round bottom flask, followed by solubilization with chloroform-methanol solution at ratio 9 : 1 (v / v).
  • Example 3 Preparation of liposomal system containing A. chica extract.
  • step (a) The A. chica extract produced according to Example 1 is added to the HEPES buffer solution used in the liposome hydration step described in Example 2, step (a), as detailed below.
  • the HEPES buffer is prepared by solubilizing its salt in ultrapure water (MiliQ) (0.1191 g HEPES salt in 50 mL of MiliQ water, forming 10 mM HEPES buffer pH 7.4). Then the extract of A. chica powder is weighed and added to the ready buffer. The mixture is vortex solubilized. The concentrations and their respective extract masses used are described in the table below:
  • the liposomal dispersion is left to stand for about 2 hours under refrigeration (4 ° C) to accommodate the phospholipids in the bilayer.
  • the liposomal suspension collected in the extrusion process was characterized by hydrodynamic diameter, polydispersity, zeta potential and electrical conductivity. Subsequently, the ultrafiltration process was performed to separate the encapsulated A. chica extract (present in the ultrafiltration filtered liposomes) and the unencapsulated (retained in the ultrafiltration membrane) extract. The membrane is permeable to by weight of about 50,000 Da. Extrusion is performed at 40 Psi (2.72 atm) pressure using nitrogen gas as the inert gas.
  • Size reduction and homogenization were done by extrusion, employing a pressure of 15 atm, with cycles of 15 consecutive passes through two overlapping polycarbonate membranes of nominal diameter 100 nm employing stainless steel extruder (Model T001, Lipex Membranes Inc.) and nitrogen for pressurization. Liposomes were stored refrigerated (Tecnal Refrigerator TE-184) and protected from light.
  • A. chica extract incorporated into the liposomes was made by computer-coupled UV / VIS Spectrophotometer (Genesys 6 - Thermo Electron Corporation) using Vision Lite TM software, by constructing a calibration curve ( Absorbance versus Concentration). Initially, A. chica extract was diluted in HEPES buffer (10mM; pH 7.4) at a known concentration for scanning to determine the maximum absorption wavelength, ideal for spectroscopic reading of the extract. After determining the ideal wavelength (485 nm), dilutions were made for the construction of the calibration curve.
  • the amount of A. chica extract incorporated into the liposomes was determined by reading the concentrations of the five lipid film hydration solutions (0.5mM, 1mM, 2mM, 3nM and 5mM), called initial absorbances, and the absorbances of the filtrates obtained from ultrafiltration of all experimental groups, called final absorbances. The difference between the starting and ending values gives the amount of A. chica extract incorporated into the liposomes. This procedure was performed in triplicate for each sample.
  • Example 4 Production of the controlled release system in the form of micro- or nanoparticles.
  • the A. chica extract produced according to concentrated and neutral Example 1 was subjected to microencapsulation by the atomization method using the spray dryer.
  • Wall forming material As matrix or wall material, gum arabic, maltodextrin and cashew gum were employed or a mixture of these materials in the ratio of 80:20 to 20:80 as described in Table 2.
  • the average size of the obtained microparticles is in the range of 10 to 800 ⁇ .
  • microparticles were produced by the atomization method using a Buchi B-290 spray dryer at operating temperatures of 150 ° C ⁇ 5 ° C of the inlet gas *, eg inert gas. , at approximately 90-110 ° C, and 5 ° C outlet temperature, 30% total solids, 1 bar (100 kPa) air pressure, 10 L / min air flow, 10 mL / min pump, 20% filling (extracts and isolated compound) to total solids.
  • wall forming material gum arabic, maltodextrin, cashew gum or mixtures thereof were employed as indicated in Table 2.
  • the processing conditions of the microparticles are shown in Table 4.
  • the volume was made up to 100 mL and stirred for a further 24h at room temperature (25 ° C). During the stirring process, the container was covered with plastic wrap to prevent solvent evaporation.
  • TPP Sodium tripolyphosphate gelling agent
  • Example 6 Preparation of the controlled release system of A. chica extract in the form of micro- and nanoparticles using chitosan matrix.
  • the A. chica extract produced according to Example 1 may be incorporated into the chitosan solution or the gelling agent solution during the cross-linking of particles.
  • emulsifying agent Span 80 sorbitan surfactant monooleate / SIGMA / St. Louis; USA
  • the emulsion is washed with 150 ml isopropyl alcohol (IPA) while stirring in orbital Shacker at 200 rpm for 20 min.
  • IPA isopropyl alcohol
  • Phase separation (water / oil) is performed with a separation funnel.
  • the aqueous portion containing the particles is then centrifuged for 5 minutes at 1500 rpm and the supernatant discarded.
  • ⁇ Particulate collection is performed by centrifugation for 5 minutes at 1,500 rpm and addition of 90% IPA, repeating the process three times.
  • the material is then resuspended in 10 mL of distilled water, centrifuged for a further 15 min at 5,000 rpm and the supernatant containing the nanoparticles separated from the pellet containing the microparticles.
  • Example 8 Production of hyaluronic acid particles containing A. chlca extract
  • the Arrabidaea chica extract comprising the active components is added after the formation of the A / 0 emulsion described in Example 7, and is given. following the methodology described in example 7.
  • Polydispersity analysis demonstrates the variability of liposome diameters in the sample and can be considered a tool to analyze vesicle polymorphism, therefore it has no unit of measurement.
  • the polydispersity results of conventional and elastic liposomes are presented in Table 6 and Figure 4.
  • Table 6 Polydispersity and standard deviation of LC and LP.
  • LCs have approximately constant polydispersity over the entire concentration range.
  • the characterization of the produced liposomes showed the following properties: the empty liposomes presented average diameter around 100nm (LC) and 60nm (LP), with low polydispersity (around 0.2). This result demonstrates the efficiency of extrusion in polycarbonate membranes as a process of size reduction and homogenization.
  • the smaller size of PEG-8L liposomes is due to their distribution between liposomes and their own micelles (smaller than liposomes), generating a smaller overall mean diameter than LC. In both cases, the average diameter of the liposomes is within the range considered appropriate for the intended percutaneous application.
  • polydispersity As for polydispersity, the results indicate that in both cases polydispersity can be considered low (less than 0.5), both in empty liposomes and in those containing the extract.
  • Zeta potential analysis determines the charge density in the layer adjacent to the surface of the particles. It can be used as a tool to determine the presence of the extract on the liposome surface, and the stability of the formulation.
  • the potential results The range of conventional and pegylated liposomes are shown in Table 7 and Figure 5.
  • Table 7 Zeta potential of LC and LP.
  • Table 8 LC and LP electrical conductivity.
  • A. chica extract in the LC does not change significantly up to 1mM, but reaches a maximum of 2mM, reducing to values close to the empty LP.
  • the low electrical conductivity is due to the zwiterionic character of lecithin phospholipids.
  • the conductivity of LP was higher due to the presence of PEG micelles in the dispersion, and due to the solvation layer generated by the hydrophilic tails of the PEG-8L polymer chain.
  • the presence of the extract increased the conductivity of the medium due to the presence of anthocyanin aggregates mainly at higher concentrations, which is shown more clearly in LC.
  • Table 9 presents the results of A. chica encapsulation in LC and LP.
  • the initial absorbance values for each extract concentration can be verified, besides the values of A. chica not incorporated after ultrafiltration.
  • the incorporation efficiency for the LC reaches its maximum value of approximately 15%, already in the first concentration of A. chica used (0.5mM).
  • the LP have the same pattern of incorporation efficiency, with a maximum value at the first concentration, followed by a decrease in efficiency at higher concentrations. It is observed that the loading percentage of the LC reaches its maximum at 0.5mM extract as well, while the LP reaches the maximum with 2mM. Seemingly low incorporation efficiency values are in the range of observed values for amphiphilic and charged compounds. Elasticity test
  • Liposome samples obtained with initial concentrations of A. chica of 0.5mM and 1mM of conventional and pegylated liposomes were selected for the elasticity test.
  • the particles were obtained with the addition of A. chica (active) under two agitation conditions: 1,500 rpm in the first crosslinking reaction and 200 / 1,000 rpm in the second crosslinking reaction. Initially an excess of active was adopted in the ratio of 2 parts of active to 1 part of polymer (2: 1).
  • nanoparticles obtained presented spherical geometry, mean diameter 295.3 nm in intensity and number, with polydispersity index of 0.108 and the microparticles presented mean diameter of 3 ⁇ and standard deviation of ⁇ 1 pm.
  • Figure 13 shows the results of the healing trial, using as a parameter the percentage of wound contraction after 10 days of treatment.
  • Example 14 Comparison between the content of active ingredients in crude extract and that incorporated in microparticles
  • Table 12 Relative content of the three antoclanidines in the EB (FAC) and EBM * samples.
  • the sample of EB after 90 days in the chamber, showed a reduction in content of approximately 77% of 6,7,7 ', 4'-tetrahydroxy-5-methoxyflavilium m / z 301, 75.5% of 6,7-trihydroxy -5-methoxyflavilium m / z 285 and 50% carajurin m / z 299. That is, there was a greater drop in the concentration of compounds m / z 301 and 285.
  • ED50 Effective dose required to reduce the ulcerative lesion index, ILU
  • EBM maintained the antiulcerogenic action at time 30 equivalent to time 0, being 8 times more effective than EB.
  • the maximum dose assessed (1,000 mg / kg) of EB was not able to reduce ulcerative lesions by 50%, while EBM needs to double the dose to achieve 50% reduction of ILU.
  • Table 13 shows the ED50 values obtained for the EB and EBM samples at times 0, 30 and 90 days.
  • Example 15 Chorioallantoid membrane (CAM) angiogenic activity test
  • CAM chorioallantoid membrane
  • the chicken eggs (Gallus domestlcus) Rhoss strain were incubated in an automatic greenhouse produced by Brasmatic Ind. And Com. LTDA, with temperature control (38 ° C) and humidity (65%), displaced laterally every 15 minutes during First 5 days of incubation. At the end of this period, the eggs were submitted to a circular opening (1.0 cm in diameter) in their largest base, where the air chamber is located, with the aid of a Dremel micro-grinder.
  • saline (0.9% w / v NaCl) was deposited to aid in the removal of the shell membrane, exposing the already vascularized MCA.
  • the opening was then sealed with masking tape and the egg incubated again, but without periodic agitation and with the perforated base facing upwards.
  • filter paper discs conveying 3 ⁇ . of the solution to be tested in each group (free HA, empty particles prepared by shaking condition 1500 and 200 * / 1000 **, A. chica 5, 10 and 25 mg / mL) and sterile saline (negative control) were deposited directly onto the membrane carefully and sterile.
  • the eggs were returned to incubation until day 16, when they were removed from the incubator. Then the CAMs were fixed in 10% formaldehyde solution for 5 min, removed from the embryo and photographed on a white background, size 640X480 pixels and 24 bit RGB format. The photographs were treated with Corel Photo Paint 11 software so that brightness and saturation allowed better visualization of blood vessels that were counted macroscopically.
  • a cream formulation was developed.
  • the cream was prepared by heating the components of the oily and aqueous phase (water) to 70 ° C, pouring the aqueous phase over the oily, with constant manual stirring until cooling. At 35 ° C, the extract was added, dissolved in propylene glycol, previously solubilized by ultrasound. The pH of the formulation was checked, and when necessary adjusted to pH 7 with triethanolamine.
  • Formulation 50% base cream with 50% free extract or incorporated into a controlled release system of the present invention 50% base cream with 50% free extract or incorporated into a controlled release system of the present invention.
  • a control was also obtained using the free extract of A. chica, that is, without being incorporated into the controlled release system of the invention.
  • Table 15 shows the composition of the formulation produced by heating all components except propylene glycol and extract until gelation. After cooling, propylene glycol was added with the solubilized extract with the aid of ultrasound. Check the pH and if necessary correct it with triethanolamine.

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Abstract

La présente invention concerne des compositions pharmaceutiques stables comprenant un extrait d'Arrabidaea chica dans des systèmes à libération contrôlée, sous forme de liposomes, de microparticules ou de nanoparticules, avec comme matière de contrôle de libération des matières de paroi naturelles et/ou polymères modifiées ou synthétiques, ainsi que les procédés d'obtention respectifs. L'invention concerne également l'utilisation d'une composition pharmaceutique dans la préparation d'un médicament pour le traitement de la cicatrisation tissulaire.
PCT/BR2012/000532 2011-12-20 2012-12-19 Compositions pharmaceutiques comprenant un extrait d'arrabidaea chica dans des systèmes à libération contrôlée, procédé de fabrication et utilisation de ceux-ci Ceased WO2013091056A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2014094085A1 (fr) * 2012-12-21 2014-06-26 Universidade Estadual De Campinas - Unicamp Procédé d'obtention de produits à base de chitosane et enrichis avec arrabidaea chica
WO2015085386A1 (fr) 2013-12-12 2015-06-18 Universidade Estadual Paulista "Julio De Mesquita Filho" - Unesp Utilisation de composés obtenus à partir d'extraits d'arrabidaea brachypoda comme anti-ulcérogène

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BR102016028506B1 (pt) * 2016-12-05 2021-10-13 Universidade Estadual De Campinas - Unicamp Processo para obtenção de membranas poliméricas por electrospinning, membranas poliméricas contendo extratos de pterodon pubescens benth e arrabidaea chica verlot e seus usos

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FR2803753A1 (fr) * 2000-01-19 2001-07-20 Serobiologiques Lab Sa Preparations cosmetiques et/ou pharmaceutiques comportant un extrait d'arrabidaea chica
WO2010146294A1 (fr) * 2009-06-17 2010-12-23 Ephyla Extrait de végétal pour la fabrication de composition de contrôle de la mélanogénèse, composition de contrôle obtenue et procédé de contrôle mettant en œuvre une telle composition

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FR2803753A1 (fr) * 2000-01-19 2001-07-20 Serobiologiques Lab Sa Preparations cosmetiques et/ou pharmaceutiques comportant un extrait d'arrabidaea chica
WO2010146294A1 (fr) * 2009-06-17 2010-12-23 Ephyla Extrait de végétal pour la fabrication de composition de contrôle de la mélanogénèse, composition de contrôle obtenue et procédé de contrôle mettant en œuvre une telle composition

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014094085A1 (fr) * 2012-12-21 2014-06-26 Universidade Estadual De Campinas - Unicamp Procédé d'obtention de produits à base de chitosane et enrichis avec arrabidaea chica
WO2015085386A1 (fr) 2013-12-12 2015-06-18 Universidade Estadual Paulista "Julio De Mesquita Filho" - Unesp Utilisation de composés obtenus à partir d'extraits d'arrabidaea brachypoda comme anti-ulcérogène

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