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WO2025027578A1 - Formulation de produits nanotechnologiques sous forme liposomale à base d'huile d'olive extra vierge, d'un extrait alcoolique de tronc d'olivier et de feuille d'olivier et de minéraux à l'état de trace de la mer de cortés - Google Patents

Formulation de produits nanotechnologiques sous forme liposomale à base d'huile d'olive extra vierge, d'un extrait alcoolique de tronc d'olivier et de feuille d'olivier et de minéraux à l'état de trace de la mer de cortés Download PDF

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Publication number
WO2025027578A1
WO2025027578A1 PCT/IB2024/057479 IB2024057479W WO2025027578A1 WO 2025027578 A1 WO2025027578 A1 WO 2025027578A1 IB 2024057479 W IB2024057479 W IB 2024057479W WO 2025027578 A1 WO2025027578 A1 WO 2025027578A1
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vitamin
approximately
process according
minutes
olive
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Ricardo Eduardo CAZARES GARCÍA
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • A23P10/35—Encapsulation of particles, e.g. foodstuff additives with oils, lipids, monoglycerides or diglycerides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • 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
    • 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)
    • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
    • 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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • 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
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to the field of health and nutrition, since lately technological advances have been developed in food supplements such as liposomes, which give advantage in the absorption in the body of nutritional components and / or medications, through the use of nanotechnology, that is why the present invention combines these elements in addition to being based on components of natural origin, unexpectedly solving the absorption of components such as, for example, vitamin C, since to date there is no presentation of the same that allows to assimilate doses beyond 30% of current pharmaceutical compositions, and as this technological advance for this composition is detailed below, we will be able to see that this technology is viable to be applied to other products, since the way of obtaining the liposomes of the present invention, makes them highly efficient carriers, for any other vitamin, nutrient or medication ensuring the quality of the manufactured products; since the invention corresponds to an intelligent drug administration system, based on nanoscale particles.
  • Nanotechnology has been defined as “concerned with materials and systems whose structures and components exhibit significantly improved physical, chemical, and biological properties, as well as phenomena and processes, due to their nanoscale size” (National Nanotechnology Initiative, 2000).
  • Nanomedicine the application of nanotechnology in the delivery of bioactive agents (drugs) [2]
  • nanomedicine involves the development of nanoscale devices ( ⁇ 100 nm in diameter), referred to as “nano vectors”.
  • the liquid dosage forms may comprise inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
  • the oral compositions may comprise inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
  • compositions are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and/or combinations thereof.
  • solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers and/or combinations thereof.
  • Patents CN104127326A, WO2021072139A1 , CN104146883A mention the use of emulsifying agents, such as the liquid dosage form for oral administration includes, but is not limited to pharmaceutically acceptable lotion, micro emulsion, solution, suspension, syrup and elixir. Except active component (i.e. particle, nanoparticle, liposome, micelle, polynucleotides/lipid complex) Outside, the liquid dosage form may also contain inert diluent common in the fields, such as water or other solvents, solubilising and emulsifying.
  • active component i.e. particle, nanoparticle, liposome, micelle, polynucleotides/lipid complex
  • the liquid dosage form may also contain inert diluent common in the fields, such as water or other solvents, solubilising and emulsifying.
  • Agent such as ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-BDO, two Methylformamide, oil (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame oil), glycerol, Tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan fatty acid esters and their mixture.
  • the orally administered composition may also include an adjuvant, such as a wetting agent, emulsifier and suspending agent, sweetener, flavouring agent and aromatic. But none of these backgrounds make any reference to polysorbate (60 or 80).
  • Patents CN104127326A and CN104146883A refer to the use of inorganic salts in a proportion of 0.02 to 1%, but are only limited to Sodium Chloride, Potassium Chloride or Calcium Chloride, our process provides more essential minerals than those indicated in said patents.
  • Patent KR 10-2020-0032092 mentions the use of saline solution, but does not specify the formulation. In our process, the use of trace minerals from the Sea of Cortez is defined, which is detailed later in the description of the invention.
  • Chinese patent application, CN113116824A describes the method of preparing a nano emulsion by means of stirring, heating, incubation and ultrasonic dispersion.
  • the method for obtaining the nano emulsion is through micronization, which allows the nano emulsions to remain stable for up to 18 months (studies on particle size distribution and z potential in accelerated stability studies are attached, as mentioned in the NOM-073-SSA1-2015 standard, Stability of drugs and medications, as well as herbal remedies).
  • Patent application US20230023038A1 establishes a method for obtaining liposomes by a pressurized mixture that uses supercritical carbon dioxide as a base.
  • the method for obtaining the nano emulsion is by means of micronization.
  • the invention is based on the use of liposomes of extra virgin olive oil (including the stem and leaves) since the principle of the benefits of fats was considered, which among others are:
  • ⁇ Decreases adrenocorticotropic hormones (ACTH) and cortisol responses.
  • Dietary fats are emulsified by bile salts to form micelles.
  • Triglycerides combine with proteins within the Golgi apparatus to form Chylomicrons.
  • Chylomicrons enter the lacteal and are transported to the subclavian vein.
  • Olive oil is a functional food since apart from its high oleic acid content it contains many highly bioactive compounds. Only present in 1-2% of olive oil, it includes more than 230 compounds:
  • Polyphenols particularly hydroxytryosol and tryrosol, have been shown to have potent anti-inflammatory effects and may also influence cell proliferation, cell cycle progression, apoptosis, and arachidonic acid metabolism in cancer cells.
  • Oleic acid has the ability to alter the expression of certain oncogenes (Her-2/neu) associated with aggressive breast cancer tumors. (Source: Visioli F & Bernardini E. 2011. Extra virgin olive oil polyphenols: biological activities. Curr Pharm Des 17, 786-804)
  • the trapped nutrients acquire the pharmacokinetic characteristics of the carrier.
  • Bioavailability is understood as the percentage of a nutrient that is detected in the circulation after a certain time of having been administered, this is given by the following factors: Chemical nature.
  • Figure 1 is a representative Finished Product (FP) HPLC Chromatogram of COENZYME Q10. Where your QUANTITATIVE ANALYSIS OF COENZYME Q10 reports:
  • Peak width > 0.1 min (2 s response time) (2.5 Hz)
  • Figure 2 is an HPLC representation of Curcumin, showing 3 peaks, representing each of the curcuminoids (Bis-Demethoxy Curcumin (BDMC), Demethoxy Curcumin (DMC) and Curcumin), which provide the desired effect in the body.
  • Figure 3 corresponds to HPLC Chromatogram of EXTRACT OF
  • Peak width > 0.1 min (2 s response time) (2.5 Hz)
  • Figure 5 Corresponds to the HPLC Chromatogram of Standard D -
  • Figure 6 Corresponds to: Representative HPLC Chromatogram of Curcumin (BAS-NA LIPOSOMAL:1004-19) TR (min) 2,604 Area 980. 9348 BDMC, TR (min) 2,950 Area 1319.6872 DMC, TR (min) 3,353 Area 6829.0605; Dilution factor 20:50
  • Method information Last saved as: C: ⁇ CDSProjects ⁇ IQK ⁇ Methods ⁇ CURCUMINA LUIS.amx Modified: 2019-12-28 14:39:57-08:00 Modifier: RICARDO CAZARES Created: 2019-07-13 09:40:19-07:00 Creator: RICARDO CAZARES Description: CURCUMINA LUIS
  • Figure 8 refers to the analysis of vitamin C and states the following:
  • Figures 9, 10 and 11 refer to the analysis of particle size B of the complex with nanoliposomal iron, carried out by the Mexican National Technological Institute of Tijuana, where it is reported:
  • Figures 12 and 13 refer to the particle size analysis of liposomal colostrum, prepared by the Technological Institute of Mexico, with good quality results, reporting the following:
  • the sample was diluted in distilled water and measured after 24 h and 48 h. Measurement temperature: 25 °C. The analysis was performed in triplicate.
  • the Dh (% number) is 75.05 nm (99.2%) having unimodal distribution. Quality of the results: The polydispersity value of this sample is large.
  • Sample preparation The sample was diluted in distilled water and measured after 24 h and 48 h.
  • Sample preparation The sample was diluted in distilled water and measured after 24 h. Measurement temperature: 25 °C. The analysis was performed in triplicate. The analysis result shows a zeta potential of -39.9 mV (100 %).
  • the figure shows the unimodal distribution peak of the analyzed sample. Quality of the result: good
  • Sample preparation The sample wax diluted in distilled wter and measured after 24 h..
  • Th® analysis was carried out in triplicate.
  • Figures 14 and 15 refer to the Proanselin particle size, produced by the Tijuana Institute of Technology, reporting that it was produced under the following conditions, and considering the product to be of good quality:
  • DLS dynamic light scattering
  • Sample preparation ; The sampr? or a-, PJ 4 b ⁇ ' ⁇ a .h' ⁇ k ⁇ ? v.jk'j .mt >v?jmred after 24 h.
  • Sample preparation The sample was diluted m distilled dressing and measured after 24 fa.
  • Tire imalysis was carried mt ia tri plicate.
  • the result of tire analysis stows a zeta potential Tire ⁇ giirs stews the great tolkridsl stability of the analyzed saEtiple.
  • Figures 16 to 22 refer to an analysis carried out by the National Technological Institute of Mexico in Tijuana which reports the following:
  • DLS Dynamic light scattering studies of the following nanoliposome samples are presented below: ANTIOXIDANT 10, CURCUFLEX, VITA C PLUS, POWER PEA PROTEIN, VITA+MINS, IRON B COMPLEX, HEALTHY FISH MEAL LIPOSOMAL.
  • the analyses performed were hydrodynamic diameter (Dh) and zeta potential.
  • the equipment used is a Nano-ZS Nanosizer from Malvern Instruments (ZEN 3690). The instrument is equipped with a helium neon laser (633 nm) with a size detection range of 0.6 nm-5 Dm. DLS experiments were performed at a scattering angle of 90o and equilibrated for 2 minutes prior to data collection. An individual report for each sample is attached.
  • Figure 16 refers to SAMPLE: VITA+MINS LIPOSOMAL A ⁇ ialysis: Hydrt ⁇ dyssniii' diameter (1K)
  • Sample preparation The sample was diluted in distilled water and measured after 24 h.
  • Figure 17 corresponds to: SAMPLE: HEALTHY LIPOSOMAL FISH MEAL.
  • the D Si (% uante) is 130 nm (100 %) having uniform distribution. Result quality; gmxL
  • Figure 19 corresponds to: SAMPLE: CURCUFLEX LIPOSOMAL
  • Sample preparaiter The sample was -diluted in distilled water and measured after 24 h. Measurement temperature: 25 ®C. The analysis was carried out in triplicate.
  • Figure 20 corresponds to: SAMPLE: B COMPLEX WITH IRON
  • Sample preparation The sample was diluted in distilled water and mwamd after 24 h.
  • Figure 21 corresponds to: SAMPLE: VITA C PLUS LIPOSOMAL Analysis: Itydr&dynsmle ditunefer (ESfc)
  • Figure 22 corresponds to: SAMPLE: POWER PEA PROTEIN
  • Figures 23 to 28 refer to another analysis carried out by the Technological Institute of Mexico Campus Tijuana, in reference to the DLS analysis of particle size, where this report presents the results carried out on our liposomal OME-NA and liposomal SEL-NA. Indicating that hydrodynamic diameter (Dh) and zeta potential analyses were carried out on the liposomal OME-NA and liposomal SEL-NA samples.
  • the dynamic light scattering (DLS) equipment was where the measurements were made and has the following characteristics: Instruments Malvern Nano-ZS Nanosizer (ZEN 3690). The instrument is equipped with a helium-neon laser (633 nm) with a detection range of 0.6 nm -5 pm. DLS experiments were carried out with a scattering angle of 90° and equilibrated for 10 min prior to each data collection.
  • Figure 23 refers to the SAMPLE: LIPOSOMAL OME-NA, reporting:
  • Figure 25 corresponds to SAMPLE: OME-NA and reports: Analysis: Pderód
  • Measuring temperature 25 ®C.
  • the ;. ⁇ SU& ⁇ 5 was carried out by tópUcsde.
  • Figure 26 corresponds to the SEL-NA SAMPLE generating the following information:
  • the Dti (H in number) is 79.B8 nm>(W0 %) and the distribution is observed wmt ⁇ K ⁇ aL Ltisge, the .LE (H in Irs tosidad) is passed d cus ⁇ is ds 22115 n ⁇ a (M.é %X
  • Figure 27 also corresponds to the SEL-NA SAMPLE reporting:
  • Figure 28 corresponds to: a SAMPLE: SEL-NA LIPOSOMAL giving the following data:
  • Figures 29 and 30 refer to SAMPLE: VITAMIN C WITH NANO LIPOSOMAL ZINC LOT NO. 509-20, made by the National Technological Institute of Mexico, Tijuana campus, which presents:
  • Sample preparation The sample was diluted in distilled water and measured after 24 h.
  • Measuring temperature 25 °C.
  • the Dh (% number) is 18.29 nm (100%) having a unimodal distribution.
  • the Dh (% intensity) is 236.3 nm (81.7%) and 27.65 nm (18.3%) showing a bimodal distribution.
  • Quality of results See quality report.
  • Figure 31 refers to:
  • Figure 32 represents the PARTICLE SIZE of Cardio Liposomal Support which reports:
  • Figure 33 refers to the PARTICLE SIZE of Cardio Liposomal Support which reports: 90% measures between 10 nm - 62 nm
  • Figure 34 represents the Cardio PARTICLE SIZE
  • Figures 35 to 38 are very representative because the long-term result of Proanseline A (stability) shows what was mentioned about the particle size and z potential in stability studies.
  • DLS Dynamic light scattering studies for the following nanoliposomal samples are: reported below: PROANSELIN (PROANSELIN) (long term stability and accelerated stability) LIPOSOMAL. The analysis performed was hydrodynamic diameter (Dh) and zeta potential. The equipment used is a Nano-ZS Nanosizer from Malvern Instruments (ZEN 3690). The instrument is equipped with a helium neon laser (633 nm) with a size detection range of 0.6 nm-5 pm. DLS experiments were performed at the scattering angle of 90° and equilibrated for 2 min before data collection. An individual report is attached for each sample.
  • Sample preparation The sample was diluted in distilled water and measured after 24 h. Measurement temperature: 25 °C. The analysis was performed in triplicate.
  • the Dh (number in %) is 36.64 nm (100 %) with unimodal distribution. Result quality: good. that ⁇ qsrn ty ⁇ >
  • Sample preparation The sample was diluted in distilled water and measured after 24 h. Measuring temperature: 25 °C.
  • the analysis was performed in triplicate.
  • the analysis result shows a zeta potential of -41.7 mV (100%).
  • the figure shows the high colloidal stability of the analyzed sample.
  • Sample preparation The sample was diluted in distilled water and measured after 24 h. Measurement temperature: 25 °C. The analysis was performed in triplicate.
  • the Dh (% number) is 46 nm (100%) having a unimodal distribution. Quality of the result: good
  • Sample preparation The sample was diluted in distilled water and measured after 24 h. Measuring temperature: 25 °C.
  • the analysis result shows a zeta potential of -46.6 mV (100%).
  • the figure shows the high colloidal stability of the analyzed sample.
  • Figure 39 corresponds to the intestinal permeability test obtained by ingesting the formulation of the present invention containing iron, in which it is shown that the absorption of said trace metal is increased. That is, according to the results obtained, it is demonstrated that the amount of permeated iron compared to other pharmaceutical formulations is highly acceptable (85.39%).
  • the quantity of trace minerals varies in composition and concentration depending on the time of collection, since sea evaporation is greater in summer and the contribution of minerals is greater during the rainy season, mainly due to the rainfall discharges of the Colorado River, which passes through 4 states of the American Union and empties into the port of San Felipe in the Sea of Cortez, where the Baja California peninsula begins.
  • Minerals make up 5% of the normal human diet, but are essential for health and optimal functioning of the body. Minerals can be classified into different groups. Macrominerals: minerals that adults need in amounts greater than 100 mg/day or that constitute ⁇ 1% of total body weight. Trace minerals or trace elements: minerals that adults require in amounts of 1 to 100 mg/day or that constitute less than 0.01% of total body weight. Ultra trace minerals: those mineral elements that are required in amounts less than 1 g/day.
  • Nanotechnology is the understanding and control of matter at the nanoscale, with dimensions between 1 and 100 um. It is used to create and use structures, devices and systems that have new properties and functions due to their size.
  • a Liposome are nano-bubbles based on natural oils that have the ability to transport bioactive substances (vitamins, minerals, amino acids, etc.) inside or in their membrane. They have a Excellent tolerance thanks to its composition, identical to that of our cell membranes, and to the low concentration of active ingredients. They allow a controlled release of the active ingredients contained, enhancing the bioavailability of the product (release extended over time). Its particle size, less than 100 nanometres, means that they are quickly absorbed by the intestinal wall, thus considerably increasing the bioavailability of nutrients. Its structure, almost identical to the cell wall, allows for more efficient fusion and delivery and absorption up to 9 times greater than tablets or capsules with similar formulas, which increases the beneficial effect of the supplement to a higher percentage.
  • Nanocarriers are capable of directing active substances to the site where they are required, with the aim of maintaining and controlling the delivery of the drug in time and space.
  • First generation nanocarriers They comprise a passive delivery system that is located within the target site where the content is released.
  • An example of this are nanoparticles or liposomes, which when administered with the intention of reaching a tumor as a target tissue, are forced to accumulate at the site of action due to a “promoted permeation and retention” effect or EPR. This effect occurs given the fact that tumors present fenestrations or interruptions in the cell line of the epithelia adjacent to the vascularization.
  • step 6 Concentrate the volume of the solution obtained in step 5 on a rotary evaporator until it reaches approximately 20 to 30% of the initial volume. 7. Take a sample portion and analyze according to the Oleuropein analysis method, to verify that the solution obtained in step 6 contains between 30 to 35% v/v of said component.
  • step 7 If it is below the specification mentioned in step 7, proceed with the evaporation in relation to the % of the component until reaching the required 30 to 35% v/v.
  • step 6 Heat the mixture resulting from step 6 to a temperature ranging from approximately 55°C to approximately 60°C (boiling and distillation temperature) in order to evaporate the alcohol present in the mixture.
  • step 8 Filter the aqueous solution from step 7 containing the trace minerals through a fiberglass filter.
  • steps 10 and subsequent steps correspond to a standard quality control and that they are not part of the invention, but are listed herein. request, since they are elements that demonstrate the quality that we seek to preserve and obtain in our products.
  • the method for obtaining the nanoemulsion is by means of micronization, which allows the nanoemulsions to remain stable for up to 18 months (studies of particle size distribution and z potential in accelerated stability studies are attached (see figures and their description, especially figures 35 to 38), as mentioned in the NOM-073-SSA1 -2015 standard, Stability of drugs and medications, as well as herbal remedies).
  • the method for obtaining the nanoemulsion is by means of immersion micronization with a head, formed by a rotor and a toothed stator made of 316 L stainless steel (pharmaceutical grade), which, driven by a 3.0 horsepower (HP) explosion-proof motor, our equipment reaches up to 20,000 revolutions per minute (RPM), regulated by an Ultra Turrax type central gearbox.
  • a head formed by a rotor and a toothed stator made of 316 L stainless steel (pharmaceutical grade)
  • HP 3.0 horsepower
  • RPM revolutions per minute
  • the liposome preparation process consists of the following steps:
  • Dissolution phase i.
  • Water-soluble active ingredients Dissolve the water-soluble ingredients in 50% of the total solvent of the formula, dividing 50% by the number of ingredients to carry out the dissolution independently. At the end, mix each of the solutions obtained, except for the dissolution of the flavorings.
  • Fat-soluble active ingredients Dissolve the fat-soluble ingredients in 7% of the extra virgin olive oil, dissolving the ingredients one by one.
  • the quantities will depend on the active ingredients to be dissolved, that is, if 70% of the active ingredients in the formulation are water-soluble, it means that the formulation will have 70% water and only 7% extra virgin olive oil, otherwise, the formulation will contain 8% extra virgin olive oil and 60% purified water.
  • Organoleptic tests taste, color, texture, appearance.
  • Physicochemical analysis pH, density, microscopy, HPLC titration of ingredients, particle size and Z potential.
  • Microbiological analysis aerobic mesophiles, fungi and yeasts, pathogens (E. Coli, Staphylococcus spp and Salmonella spp).
  • IDA Iron deficiency anemia
  • elemental iron is required in adults at doses of 180 mg/day divided into three doses, given that, it is related to the problems with current iron formulations, which are:
  • EDTA AS DISODIUM SALT [0107]
  • the reagent commonly used is its disodium salt, since in practice EDTA is usually partially ionized, forming less than six coordinate covalent bonds with metal cations.
  • Vitamin C has multiple health benefits, such as antioxidant, antitumor, anti-aging and helping collagen; Vitamin C can prevent, help and even cure various viral and bacterial diseases, since the action of vitamin C is dual since on the one hand it strengthens the immune system and on the other it limits the inflammatory damage, which begins when the defenses detect an infectious agent, so that the symptoms are milder, and the recovery faster, unfortunately, vitamin C has a low intestinal absorption and a rapid elimination through urine, reasons why it is a challenge to reach the doses that are required to obtain all its benefits.
  • nano carriers can be developed for various substances such as vitamin C, and more specifically thanks to the nano liposomes of the present invention, which are obtained from vegetable fats such as olive oil, and more specifically from olive oil from the leaves and stems thereof.
  • the nanoliposomes of the present invention directly penetrate the intestine, without requiring any carrier. specific, and its absorption is close to 100%; when the nano liposome measures less than 100 nm, it is not detected by the liver, passing directly into the bloodstream and organs, distributing itself throughout the body.
  • nano liposomes The surface of the nano liposomes is very similar to the cell membrane, and upon contact, it recognizes it and introduces it directly through a process called endocytosis.
  • the nano liposome opens, releasing the administered substance.
  • said substance is not only vitamin C, but any other substance such as vitamins, drugs or nutrients in general.
  • vitamin C we can say that practically 100% of the vitamin C administered by this route is absorbed, so one gram of liposomal vitamin C will have a much greater effect compared to any other conventional form of administration.
  • the formulation of our example with vitamin C shows that thanks to this form of administration with the formulation of the liposomes of the present invention, it is possible to reach the concentrations that are required to strengthen the immune system and maintain the protection of the individual against bacterial and viral diseases, such as influenza, flu and coronavirus, among others.
  • Nanoliposomes are not eliminated through urine, because they are not soluble in water, so they remain in the circulation for the necessary time to be used by the cells.
  • the nano liposomes of the present invention being made from olive oil, leaves and stems, and minerals from the Sea of Cortez, add the anti-inflammatory and antioxidant benefits of said substances.
  • a retention sample is taken for quality control for physical, chemical and microbiological analysis; once approved by quality control, it is conditioned.
  • the active ingredient called D-Mandelonithlo or Amygdalin is a water-soluble input, as defined above, which is strictly soluble in water.
  • the content of amygdalin is about 1 g per about 15 mL (dose). That is, for a batch of about 30 L, about 2 kg of raw material was weighed.
  • the active ingredient was solubilized in approximately

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Abstract

La présente invention concerne une formulation de produits nanotechnologiques sous forme liposomale à base d'huile d'olive extra vierge, d'un extrait alcoolique de tronc d'olivier et de feuilles d'olivier et de minéraux à l'état de trace de la mer de Cortés, de telles formulations constituant des supports hautement efficaces pour une vitamine, un nutriment, un médicament ou un complément alimentaire quelconque, assurant la qualité des produits fabriqués, l'invention correspondant à un système d'administration intelligent d'agents pharmaceutiques, faisant intervenir des particules à l'échelle nanométrique. Ladite formulation est constituée par : une nanoémulsion orale d'huile d'olive extra vierge produite à partir des noyaux avec une teneur en oleuropéine comprise entre 35 % et 40 %, en tant qu'agent antioxydant ; des agents émulsionnants ; un extrait d'eau de mer de Cortés ; et éventuellement un édulcorant, un arôme et un agent de conservation.
PCT/IB2024/057479 2023-08-01 2024-08-01 Formulation de produits nanotechnologiques sous forme liposomale à base d'huile d'olive extra vierge, d'un extrait alcoolique de tronc d'olivier et de feuille d'olivier et de minéraux à l'état de trace de la mer de cortés Pending WO2025027578A1 (fr)

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MXMX/A2023/009065 2023-08-01
MX2023009065A MX2023009065A (es) 2023-08-01 2023-08-01 Formulacion de productos nanotecnologicos en forma liposomal a base de aceite de olivo extravirgen, extracto alcoholico del tallo y hojas de olivo y minerales traza del mar de cortes.

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5714150A (en) * 1997-01-08 1998-02-03 Nachman; Leslie Method for producing extract of olive leaves

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5714150A (en) * 1997-01-08 1998-02-03 Nachman; Leslie Method for producing extract of olive leaves

Non-Patent Citations (5)

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Title
GONZALEZ-ORTEGA, R. ET AL.: "Liposomal Encapsulation of Oleuropein and an Olive Leaf Extract: Molecular Interactions, Antioxidant Effects and Applications in Model Food Systems.", FOOD BIOPHYSICS, vol. 16, 2021, pages 84 - 97, XP037375953, DOI: 10.1007/s11483-020-09650-y *
K/\TSOULI, M. ET AL.: "Optimization of water in olive oil nano-emulsions composition with bioactive compounds by response surface methodology.", LWT-FOOD SCIENCE AND TECHNOLOGY, vol. 89, 2018, pages 740 - 748, XP085313226, DOI: 10.1016/4.1wt. 2017.11.04 6 *
PINGALE PRASHANT, KENDRE PRAKASH, PARDESHI KRUTIKA, RAJPUT AMARJITSING: "An emerging era in manufacturing of drug delivery systems: Nanofabrication techniques", HELIYON, ELSEVIER LTD, GB, vol. 9, no. 3, 1 March 2023 (2023-03-01), GB , pages e14247, XP093278323, ISSN: 2405-8440, DOI: 10.1016/j.heliyon.2023.e14247 *
PLAZA-OLIVER, M. ET AL.: "Current approaches in lipid-based nanocarriers for oral drug delivery.", DRUG DELIV TRANSL RES., vol. 11, no. 2, April 2021 (2021-04-01), pages 471 - 497, XP037393804, DOI: 10.1007/513346-021-00808-7 *
TAHIR MEHMOOD: "Optimisation of food grade mixed surfactant‐based l‐ascorbic acid nanoemulsions using response surface methodology", IET NANOBIOTECHNOLOGY, THE INSTITUTION OF ENGINEERING AND TECHNOLOGY, MICHAEL FARADAY HOUSE, SIX HILLS WAY, STEVENAGE, HERTS. SG1 2AY, UK, vol. 15, no. 3, 10 February 2021 (2021-02-10), Michael Faraday House, Six Hills Way, Stevenage, Herts. SG1 2AY, UK , pages 309 - 317, XP006109267, ISSN: 1751-8741, DOI: 10.1049/nbt2.12014 *

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