WO2014117236A1 - Nanoémulsion huile dans l'eau et son procédé de production - Google Patents

Nanoémulsion huile dans l'eau et son procédé de production Download PDF

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WO2014117236A1
WO2014117236A1 PCT/BR2014/000023 BR2014000023W WO2014117236A1 WO 2014117236 A1 WO2014117236 A1 WO 2014117236A1 BR 2014000023 W BR2014000023 W BR 2014000023W WO 2014117236 A1 WO2014117236 A1 WO 2014117236A1
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oil
nanoemulsion
production process
water
mass
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PCT/BR2014/000023
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English (en)
Portuguese (pt)
Inventor
Claudia Regina ELIAS MANSUR
Eduardo RICCI JÚNIOR
Vânia Emerich BUCCO DE CAMPOS
Juliana PERDIZ SENNA
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Universidade Federal Do Rio De Janeiro - Ufrj
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Publication of WO2014117236A1 publication Critical patent/WO2014117236A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A61P33/12—Schistosomicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention belongs to the field of nanotechnology, specifically to the field of manufacture or treatment of nanostructures, more specifically to the field of nanostructures for the release of hydrophobic compounds.
  • Nanotechnology has been experiencing rapid growth with several innovative applications in the pharmaceutical, cosmetic, food, chemical, materials science and polymer industry.
  • nanostructured systems such as nanoparticles, liposomes, nanoemulsion and dendrimers have emerged in recent decades as carrier systems of hydrophobic compounds.
  • hydrophobic compounds may be administered as emulsions, wherein the substance is dissolved in an organic solvent, which is dispersed in an aqueous phase as droplets and stabilized with a surfactant, the colloidal stability of these formulations being controlled by the chemical structure of the formulation. interface.
  • nanoemulsions have been studied and the interest in their application owes to the ability of these systems to increase the solubility and hence the bioavailability of hydrophobic assets; the ability to incorporate hydrophilic and hydrophobic actives at the same time and improving their stability.
  • Nanostructured systems have a size range from 1 to 999 nm. However, as compound release systems, the nano effect is only evident for systems in the range of 20 to 200 nm where high permeability of these systems in biological membranes and cells is achieved.
  • nanoemulsions can be administered intravenously as well as intramuscularly and subcutaneously, thereby minimizing health risks.
  • parenterally administered drugs directly affect the systemic circulation, preventing the first-pass effect caused by hepatic metabolism.
  • a drug such as praziquantel in nanoemulsions
  • This drug belongs to the broad spectrum anthelmintics class and is of first choice for the treatment of schistosomiasis.
  • Zinc Phthalocyanine (PhyZn) and Chloro-Aluminum Phthalocyanine (PhyAl) to improve the bioavailability of these drugs.
  • Phthalocyanines are second generation photosensitizing drugs that are currently used in photodynamic therapy (PDT) in cancer treatment.
  • fat-soluble vitamins in nanoemulsified systems such as vitamin E may be of particular interest to the cosmetic industry.
  • the present invention relates to a nanoemulsion containing at least one surfactant, an oil and optionally a solvent.
  • the invention also relates to the process of producing a nanoemulsion containing at least one hydrophobic compound, at least one surfactant, an oil and optionally a solvent.
  • FIGURE 1 shows the droplet size chart of the nanoemulsion containing 5% of clove essential oil, relative to preparation time.
  • FIGURE 2 shows the droplet size chart of the nanoemulsion containing the clove essential oil and praziquantel drug relative to preparation time.
  • FIGURE 3 shows the droplet size graphs of nanoemulsion containing clove essential oil, ZN and Cl-Al phthalocyanine, relative to preparation time.
  • Figure 4 shows the droplet size chart of nanoemulsion containing clove essential oil and vitamin E, relative to preparation time.
  • Figure 5 shows the graph of the nanoemulsion toxicological profile, containing clove essential oil and praziquantel drug, on viability of Caco-2 cells after 5 and 24h incubation.
  • Figure 6 shows the different systems tested in the transport study through Caco-2 cells.
  • ⁇ ethanol-soluble praziquantel dispersed in N- (2-hydroxyethyl) piperazine- '- (2-ethanesulfonic acid) (HEPES) at the concentration of ⁇ ;
  • HEPES piperazine- '- (2-ethanesulfonic acid
  • ⁇ Orange oil nanoemulsion containing praziquantel, 1.25mg / mL in HBSS;
  • A Clove oil nanoemulsion containing praziquantel, 5 mg / mL in HBSS;
  • PRAZIQUANTEL-containing PLGA nanoparticles 0.1 mg / mL in HBSS.
  • the present invention is an oil in water nanoemulsion consisting of at least one surfactant, at least one oil and optionally one or more solvents.
  • the nanoemulsion contains from 5 to 40% mass / mass (w / w) of a nonionic surfactant known to those skilled in the pharmaceutical field, such as surfactants in the group consisting of: poly (ethylene oxide) block copolymers ) -poly (propylene oxide) (PEO-PPO) or ethoxylated alcohols or a mixture thereof.
  • a nonionic surfactant known to those skilled in the pharmaceutical field, such as surfactants in the group consisting of: poly (ethylene oxide) block copolymers ) -poly (propylene oxide) (PEO-PPO) or ethoxylated alcohols or a mixture thereof.
  • the nanoemulsion comprises from 7 to 25% w / w of a nonionic surfactant or mixtures of nonionic surfactants.
  • the oil phase consists of from 1 to 50% w / w of a vegetable oil, which may be a crude oil and / or an essential oil.
  • the essential oils that may be used in this invention are, for example, the essential oil of: lemongrass (Cymbopogon citratus), orange (Citrus sinensis), clove (Eugenia caryophyllus), lime ⁇ Citrus. aurantifolia), lemon balm (Melissa off ⁇ cinalis), passion fruit (Passiflora spp), mint (Mentha spp) and / or a mixture of these essential oils.
  • Crude oils which may be used in this invention are, for example, oils belonging to the group consisting of: avocado (Persea gratissima), fennel (Foeniculum vulgare), rapeseed (Brassica napus), buriti (Mauritia flexuosa), almond ( Prunus dulcis), grape seed (Vitis spp), and / or a mixture of these crude oils.
  • avocado Persea gratissima
  • fennel Feeniculum vulgare
  • rapeseed Brassitia flexuosa
  • almond Prunus dulcis
  • grape seed Vitis spp
  • a mixture between an essential oil and a crude oil may also be used.
  • the oil is the essential orange (Citrus sinensis) and / or clove.
  • the nanoemulsion further contains one or more hydrophobic compounds in the ratio of 0.5: 1 to 1/20 m / m.
  • Hydrophobic compounds are those that have little or no water solubility, and the solubilization of these compounds enables the production of liquid formulations for use, for example, topical, oral or parenteral.
  • hydrophobic compounds may be poorly soluble or water-insoluble drugs such as carbamazepine, dapsone, griseofulvin, ibuprofen, nifedipine, nitrofurantoin, phenytoin, sulfamethoxazole, trimethoprim, acid.
  • valproic acid iopanoic acid, nalidixic acid, nevirappine, rifampicin, amitriptyline, aluminum hydroxide, furosemide, indinavir, nelfinavir, ritonavir, saquinavir, acetazolamide, azathioprine, albendazole, lumetfantrine, artemether, chlorpromazine, chlorpromazine, chlorpromazine, , glibenclamide, haloperidol, ivermectin, lopinavir, mebendazole, mefloquine, niclosamide, pyrantel, pyrimethamine, spironolactone, sulfadiazine, sulfasalazine, triclabendazole, zinc phthalocyanine and chloroaluminum phthalocyanine.
  • fat-soluble vitamins such as retinol, beta-carotene, tretinoin, alfacarotene, ergocalciferol, cholecalciferol, didrotaquisterol, calcitriol, calcidiol, tocopherol, tocotrienol, naphthoquinone, phylloquinone and menatetrenone.
  • cosmetics such as, for example, octyl methoxycinnamate (MCO) and also fat soluble food products.
  • MCO octyl methoxycinnamate
  • the hydrophobic compound is: praziquantel, zinc phthalocyanine, chloroaluminum phthalocyanine, tocopherol or tocotriene.
  • solvents may be used to compose the oil phase and increase the solubility of hydrophobic compounds.
  • the solvents that may be used are alcohols, such as ethanol and glycerol.
  • the nanoemulsion of this invention has an average diameter of 1 to 200 nm, preferably 5 to 100 nm.
  • the invention further relates to the process of producing an oil-in-water nanoemulsion comprising the steps of:
  • Step (a) begins by adding from 5 to 40% mass / mass (w / w) of a nonionic surfactant in water.
  • the surfactants employed in this invention belong to the group consisting of poly (ethylene oxide) -poly (propylene oxide) block copolymers (PEO-PPO); ethoxylated alcohols; or a mixture thereof. Then the surfactant solution in water is allowed to stand at room temperature. 5 ° C for a period of 12 hours for complete solubilization.
  • the nanoemulsion comprises from 7 to 25% w / w of a nonionic surfactant or mixtures of nonionic surfactants.
  • the oil phase (b) consists of a vegetable oil, which may be a crude oil and / or an essential oil.
  • the essential oils that can be used in this invention are, for example, the essential oils of: lemongrass (Cymbopogon citratus), orange (Citrus sinensis), clove (Eugenia caryophyllus), lime (Citrus aurantifolia), lemon balm ⁇ Melissa officinalis), passion fruit (Passiflora spp), mint (Mentha spp) and / or a mixture of these essential oils.
  • Crude oils which may be used in this invention are, for example, the oils of: avocado (Persea gratissima), fennel (Foeniculum vulgare), rapeseed (Brassica napus), buriti (Mauritia flexuosa), almond (Prunus dulcis), grape seed (Vitis spp), and / or a mixture of these crude oils.
  • the essential oil of orange (Citrus sinensis), clove (Eugenia caryophyllus), lime (Citrus. Aurantifolia), and / or lemon balm (Melissa officinalis) is used.
  • the oil is the essential orange (Citrus sinensis) and / or clove.
  • one or more hydrophobic compounds in the ratio of 0.5: 1 to 1/20 m / m are added under stirring over a period of up to 10 minutes.
  • Hydrophobic compounds have little or no water solubility. These compounds are also known as hydrophobic or supportive, lipophilic or fat soluble. Moreover, their solubilization enables the production of liquid formulations for use, for example, topical, oral or parenteral.
  • Hydrophobic compounds may be poorly soluble or water-insoluble drugs, such as carbamazepine, dapsone, griseofulvin, ibuprofen, nifedipine, nitrofurantoin, phenytoin, sulfamethoxazole, trimethoprim, valproic acid, iopanoic acid, nalidixin, rifipin, hydriphoxine, rifampine, aluminum, furosemide, indinavir, nelfinavir, ritonavir, saquinavir, acetazolamide, azathioprine, albendazole, lumetfantrine, artemether, chlorpromazine, ciprofloxacin, clofazimine, efavirenz, diloxanide, folic acid, glibenclamide, meoperidine, haloperidine pyrimethamine, spironolactone, s
  • fat-soluble vitamins such as retinol, beta-carotene, tretinoin, alfacarotene, ergocalciferol, cholecalciferol, didrotaquisterol, calcitriol, calcidiol, tocopherol, tocotrienol, naphthoquinone, phylloquinone and menatetrenone.
  • cosmetics such as, for example, octyl methoxycinnamate (MCO) and also fat soluble food products.
  • MCO octyl methoxycinnamate
  • the hydrophobic compound employed is praziquantel, zinc phthalocyanine, chloroaluminum phthalocyanine, tocopherol or tocotriene.
  • one or more solvents may be used to compose the oil phase and increase the solubility of hydrophobic compounds.
  • the solvents that may be used are alcohols, such as ethanol and glycerol.
  • the oil phase composed of an oil or mixtures of oils, hydrophobic compounds and optionally one or more solvents is mixed with the aqueous phase in the oil phase proportions between 0.5 / 1 (0.5%) to 1/5 ( 20%) v / v.
  • After mixing the two phases it is homogenized in high energy equipment for vigorous homogenization for 1 to 15 minutes; between 5 and 35 ° C; can occur at positive pressure up to 125 MPa, so that an O / W nanoemulsion in the form of droplets is obtained.
  • the O / W nanoemulsion thus obtained occurs as gauge droplets, the mean diameter of which according to the above steps is from 1 to 200 nm, preferably from 5 to 10.0 nm.
  • the homogenization equipment used in this step is state of the art and may, for example, be high pressure (PAH) or ultrasound (US) equipment.
  • PAH high pressure
  • US ultrasound
  • Nanoemulsion objects of this invention allow an increase in the therapeutic index of hydrophobic compounds, as well as minor side effects and prolonged therapeutic effect, since the compound is solubilized in an oil phase, which in turn is dispersed in water in the form of nanogoticles.
  • Nanoemulsions may be used for the delivery of other hydrophobic compounds, such as fat-soluble vitamins, antioxidants used by the cosmetic, food and pharmaceutical industries.
  • Example 1 Nanoemulsion containing praziquantel drug (solubility study):
  • Praziquantel was subjected to solubility tests on different oils at concentrations of 1-30% w / v.
  • the following oils were used: almonds, grape seed, avocado, sweet fennel, almond, lipo S, buriti, isopropyl myristate, octyl palmitate and essential oils such as cloves, lime, mint, passion fruit, lemongrass, Lemon balm and orange.
  • the choice of the oil phase for the preparation of nanoemulsions was made by visual observation using a qualitative criterion based on the United States Pharmacopoeia (USP) in the chapter entitled “Description and Relative Solubility" (USP, 1995).
  • Example 2 Preparation of Nanoemulsions containing (or not) the praziquantel drug in orange or clove essential oil.
  • Oil-in-water nanoemulsions were prepared by the high energy method, in ultrasound (US) or in high pressure homogenizer.
  • the oily phase consisted (or not) of praziquantel dissolved in the orange or clove essential oil at a concentration of 5% w / w of the formulation.
  • a commercial ethoxylated alcohol based or PEO-PPO block copolymer surfactant was used, which were employed at a concentration of 12% w / w.
  • Nanoemulsions prepared (whether or not containing) the drug showed good stability and droplet sizes below 100 nm.
  • Example 3 Nanoemulsion containing phthalocyanine-based drugs (solubility study).
  • Zinc phthalocyanine was dissolved in several types of essential oils, measuring the volume of oil needed to solubilize 1mg of the drug. Every 1 mL of After the oil was added, the sample was ultrasounded and then evaluated for the presence of insoluble particles in the sample. This procedure was repeated until the solution was clear, no trace of unsubstituted drug, or 10mL of oil was spent. In addition to the oils, the test was also performed with DMSO in order to prove PhyZn solubility in it. The results obtained are described in Table 1.
  • Table 1 Solubility of zinc phthalocyanine in different types of oils.
  • UV spectrometry analyzes were performed, observing between 600 - 750nm the characteristic peak of phthalocyanine.
  • Example 4 Preparation of Nanoemulsions containing (or not) phthalocyanine-based drugs in clove essential oil (whether or not containing solvents).
  • PhyZn clove oil Clove Oil with PhyAl
  • Clove Oil with PhyAl and Ethanol Three oil phases proved to be good candidates for the development of phthalokinan-containing nanoemulsion: PhyZn clove oil; Clove Oil with PhyAl and Clove Oil with PhyAl and Ethanol.
  • a PEO-PPO block copolymer was used in the Nanoemulsion preparation. These were prepared in a high pressure homogenizer (PAH) using surfactant amounts of 10 and 12% and 5, 7, 10 and 15% of each of the oil phases. The obtained nanoemulsions were clear and with small droplet size. In addition, formulations containing ethanol in the oil phase showed even better results, achieving Nanoemulsion with up to 10% oil phase, suggesting that ethanol acts as a co-surfactant in the formulation.
  • PAH high pressure homogenizer
  • This evaluation was performed by initially analyzing the size distribution of the emulsion dispersed particles at time zero. Then, the emulsion was allowed to stand and further analyzes were performed from time to time until the phase separation of these systems was observed.
  • Table 2 shows some of the Nanoemulsions obtained with the aid of US equipment.
  • Table 3 shows some of the Nanoemulsions obtained with the aid of HAP equipment.
  • Table 2 Nanoemulsions prepared in PAH equipment.
  • Example 6 Study of the toxicological profile of formulations containing praziquantel in Caco-2 cells.
  • the cytotoxicity of two formulations presented in this work one containing orange oil and the other containing clove oil, praziquantel% and PEO- block copolymer PPO was evaluated by measuring the viability of Caco-2 cells in the presence and absence of formulations.
  • the method used in this study used the reagent 3- (4, 5-dihydro 'methylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium (MTS), which measures mitochondrial activity of cells.
  • Caco-2 cells were cultured in 96-well plates containing 250,000 cells / cm 2 for 72 hours. After this period, the culture medium was removed from each well.
  • the different formulations were diluted in culture medium and added to each well, cells were incubated in this medium for 5 and 24 hours at 37 ° C with 95% relative humidity and 5% CO ⁇ . After this incubation time, 20 ⁇ l of MTS solution (5 mg / ml) was added to each well and again incubated for 3 hours under the same conditions as above. The absorbance of each well was made by spectroscopic measurements at 530 nm. Cytotoxicity was expressed as a percentage of cell viability, which is calculated by the ratio between the number of cells treated (addition of different formulations) and control cells (culture medium only).
  • Figure 6 shows the different systems tested in the transport study through Caco-2 cells.
  • Toxicity and phototoxicity studies were performed for Nanoemulsions containing chloroaluminium photalocyanine using A549 lung adenocarcinoma cells. These trials aim to evaluate the toxic potential of formulations and their separate components. For this The study was divided into two stages: one in the dark (Toxicity Study) and one in the light (Phototoxicity Study). Initially, the cells are distributed in a plate containing 96 wells. It is incubated in an oven at 37 ° C for a period of 24 hours so that the cells can adhere to the bottom of the well. Then different solutions composed of: drug nanoemulsion, drugless nanoemulsion, ethanol drug control and saline only control are added to the wells separately.

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Abstract

La présente invention concerne une nanoémulsion huile dans l'eau comprenant entre 5 et 50% masse/masse (m/m) d'au moins un tensioactif, entre 1 et 50% m/m d'au moins une huile et, éventuellement, environ 30% d'un ou plusieurs solvants, son procédé de production ainsi que son utilisation pour véhiculer des composés hydrophobes, sous la forme d'un médicament, d'un produit cosmétique, d'une vitamine ou d'un composé alimentaire.
PCT/BR2014/000023 2013-01-30 2014-01-30 Nanoémulsion huile dans l'eau et son procédé de production WO2014117236A1 (fr)

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BR102013002259-4A BR102013002259B1 (pt) 2013-01-30 Nanoemulsão óleo em água e seu processo de produção
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CN113713093A (zh) * 2021-08-31 2021-11-30 中国人民解放军陆军军医大学 一种新型高效增强体液免疫应答和粘膜免疫应答的维甲酸纳米乳佐剂及其制备方法和应用
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CN104208023A (zh) * 2014-09-11 2014-12-17 中国科学院成都生物研究所 一种伊维菌素纳米乳抗寄生虫药物及其制备方法
CN104771360A (zh) * 2015-04-09 2015-07-15 中国农业科学院兰州畜牧与兽药研究所 一种蒿甲醚纳米乳药物组合物及其制备方法
CN104771360B (zh) * 2015-04-09 2018-12-04 中国农业科学院兰州畜牧与兽药研究所 一种蒿甲醚纳米乳药物组合物及其制备方法
US11529361B2 (en) 2015-05-29 2022-12-20 UNION therapeutics A/S Halogenated salicylanilides for treating Clostridium infections
CN109846821A (zh) * 2019-01-03 2019-06-07 昆药集团股份有限公司 一种蒿甲醚纳米制剂及其制备方法
CN109846821B (zh) * 2019-01-03 2021-07-06 昆药集团股份有限公司 一种蒿甲醚纳米制剂及其制备方法
CN113713093A (zh) * 2021-08-31 2021-11-30 中国人民解放军陆军军医大学 一种新型高效增强体液免疫应答和粘膜免疫应答的维甲酸纳米乳佐剂及其制备方法和应用

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