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WO2025177181A1 - Microémulsions à auto-assemblage portant des produits nutraceutiques et leurs procédés d'utilisation - Google Patents

Microémulsions à auto-assemblage portant des produits nutraceutiques et leurs procédés d'utilisation

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Publication number
WO2025177181A1
WO2025177181A1 PCT/IB2025/051799 IB2025051799W WO2025177181A1 WO 2025177181 A1 WO2025177181 A1 WO 2025177181A1 IB 2025051799 W IB2025051799 W IB 2025051799W WO 2025177181 A1 WO2025177181 A1 WO 2025177181A1
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Prior art keywords
smeids
polyglyceryl
self
surfactant
composition
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Inventor
Petro Pawlo CZUPIEL
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Nanoprime Labs Corp
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Nanoprime Labs Corp
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Publication of WO2025177181A1 publication Critical patent/WO2025177181A1/fr
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    • 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
    • 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
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/10—Foods or foodstuffs containing additives; Preparation or treatment thereof containing emulsifiers
    • 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
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    • 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
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    • 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
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    • 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
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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    • A61K9/0085—Brain, e.g. brain implants; Spinal cord
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the present invention relates to microemulsions and more specifically to cationic microemulsions carrying nutraceuticals.
  • Ingredient Delivery Systems are designed to augment the water solubility of active ingredients characterized by poor water solubility, thereby enhancing the bioavailability of the active ingredient.
  • Emulsions, nanoemulsions and microemulsions typically consist of surfactants, stabilizers, antioxidants, preservatives, and solvents, with water being the predominant ingredient.
  • Self-Microemulsifying Ingredient Delivery Systems SMEIDS are water-free microemulsion preconcentrates that exhibit properties akin to microemulsions upon dilution and self-assemble in aqueous environments.
  • a SMEIDS composition including a water-insoluble active ingredient, a polyglyceryl containing (POGylated) surfactant, a polyol, a preservative and and antioxidant, the SMEIDS being devoid of water, PEG and lecithin.
  • PEG polyglyceryl containing
  • a method of preparing a SMEIDS composition includes a water-insoluble active ingredient, a POGylated surfactant, a polyol, a preservative and an antioxidant.
  • a method of using a SMEIDS composition including administering the composition by targeting systemic, parenteral, oral, intrathecal, intraarticular, nasal, ophthalmic and/or topical means.
  • the terms “approximately” “about” mean to be nearly the same as a referenced number or value. As used herein, the terms “approximately” and “about” should be generally understood to encompass ⁇ 20%, or alternatively ⁇ 15%, or alternatively ⁇ 10%, or alternatively ⁇ 5%, or alternatively ⁇ 2% of a specified amount, frequency, value, or other numerical designation.
  • compositions and methods shall mean excluding other elements of any essential significance to the combination for the intended use.
  • a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate-buffered saline, preservatives and the like.
  • Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure.
  • IDS inredient delivery system
  • IDS has various applications in multiple industries that are packaged in softgels, capsules, dissolvable strips, edibles, beverages, cosmetics, and others.
  • active ingredient is meant to refer to any ingredient that provides a biologically active or other direct effect in the diagnosis, mitigation, prevention, treatment or cure of a disease or affects the structure or any function of the body of humans or animals.
  • emulsions is meant to refer to mixtures of two or more immiscible liquids with droplet sizes or emulsion diameters exceeding 1,000 nm.
  • nanoemulsions are meant to refer to mixtures of two or more immiscible liquids characterized by thermodynamic instability and kinetic stability.
  • microemulsions is meant to refer to mixtures of two or more immiscible liquids characterized by thermodynamic stable isotropic liquids.
  • Typical microemulsions used in the food and pharmaceutical industry focus on oil-in-water microemulsions that consist of nanometer-sized spheroid particles comprised of oil and surfactants dispersed in water.
  • Microemulsions are formulated with active ingredients through low-energy processes that include, but are not limited to, mixing, dilution, or heating and cooling techniques in aqueous environments.
  • the principal constituent within microemulsions is water with other constituents such as surfactants, carrier oils, sugars, polyols, preservatives, and antioxidants.
  • self-microemulsifying ingredient delivery systems SMEIDS
  • SMEIDS self-microemulsifying ingredient delivery systems
  • the principal constituent is a surfactant or a combination of surfactants with other constituents such as active ingredients, carrier oils, sugars, polyols, preservatives, and antioxidants.
  • stable SMEIDS is meant to refer to SMEIDS formulations that are self-assembled in aqueous environments and maintain a single-phase microemulsion that has insignificant or is devoid of crystalization, precipitation, or liquid phase separation.
  • Aqueous environments include, but are not limited to water, gastric, intestinal or colonic fluid in fasted or fed states or a simulated form of any of the previously stated fluids.
  • FaSSGF fasted-state simulated gastric fluid
  • Compositions of FaSSGF include a pH of 1.6, taurocholate (0.08 millimole [mM]), phospholipids (0.02 mM), sodium (34 mM), and chloride (59 mM).
  • FaSSIF fasted-state simulated intestinal fluid
  • Compositions of FaSSIF include a pH of 6.5, taurocholate (3 mM), phospholipids (0.75 mM), sodium (148 mM), chloride (106 mM), and phosphate (29 mM).
  • cationic is meant to refer to a positive electrostatic charged microemulsion relative to a conventional microemulsion.
  • a conventional microemulsion exhibits a surface charge of -20 millivolts (mV)
  • a cationic microemulsion would exhibit a surface charge that is more positive than -20 mV, such as -19, -18, -17-, -16, -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, -1, 0, positive values, and fractions within the range, for example, but not limited to, 10.25, 16.72, 18.5, and 19.95 using millivolt (mV) units.
  • polyethylene gly col-containing or “PEGylated” is meant to refer to a surfactant, polymer, microemulsion, nanoemulsion, or SMEIDS that contains poly(ethylene) glycol.
  • polyethylene glycol-free or “PEG-free” is meant to refer to formulations that do not contain PEGylated ingredients.
  • lecithin-free is meant to refer to formulations that are essentially free of lecithin, lysolecithin, mono- and di-alkyl phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols and phosphatidylglycerols that can be obtained through chemical synthesis or animal or vegetable sources.
  • cationic surfactant is meant to refer to surfactants that exhibit a net positive charge. The positive charge is commonly offered through the incorporated nitrogen in different variations that include, but are not limited to, primary, secondary, and tertiary amines.
  • polyglceryl-containing or “POGylated” is meant to refer to a surfactant, polymer, microemulsion, nanoemulsion, or SMEIDS that contain glyceryl polymers with a degree of polymerization of n that is greater than 2.
  • the polyglyceryl polymer is commonly chemically attached to a fatty acid, multiple fatty acids, or other hydrophobic molecules or polymers through an ester or ether bond.
  • POGylated surfactants also exist as a monoester that has one fatty acid attached or multiesters where multiple fatty acids are attached to the polyglyceryl.
  • the fatty acid chain consists essentially of carbon chains that range from 6 to 18 carbons.
  • reducing agent or “antioxidant” is meant to refer to ingredients that act as a reducing agent with antioxidant.
  • polyols is meant to refer to small-chain carbohydrates that contain multiple hydroxyl groups that include but are not limited to glycerol or triol and propylene glycol or diol. ii. Examples
  • Example 1 Curcumin SMEIDS with one surfactant
  • Example 2 Curcumin SMEIDS with two or more surfactants and carrier oil or co-solvent
  • Example 3 SMEIDS Dispersion in Fasted-State Simulated Gastric Fluid
  • Example 4. SMEIDS Dispersion in Fasted-State Simulated Intestinal Fluid
  • Example 6 SMEIDS Incorporating either Resveratrol or Coenzyme Q10 and Dispersion Analysis in Boiling water, Fasted State Simulated Gastric Fluid, or Fasted State Simulated Intestinal Fluid.
  • Example 8 SMEIDS mixing and encapsulating in softgels at industrial scale
  • Curcumin SMEIDS with one surfactant can be sourced, but not limited to, BulkSupplements.com (Sku: curc25).
  • Exemplary polyglyceryl-3 monooleate (Caprol 3GO, 3GO) can be sourced, but not limited to, Abitech (Lot no. 230925-9).
  • Exemplary polyglyeryl-10 mono- and dioleate (Caprol PGE 860) can be sourced, but not limited to, Abitech (Lot no. 231004-9).
  • Exemplary polyglyceryl-3 monooleate blended with polyglyeryl-10 mono- and di-oleate can be sourced, but not limited to, Abitech (Lot no. 230215-9).
  • Exemplary polyglyeryl-10 laurate (Polyaldo 10-1-L, 10-1-L) can be sourced from, but not limited to, Lonza or Arxada (Product code 192646).
  • Exemplary polyglyeryl-10 oleate (Polyaldo 10-1-0, 10-1-0) can be sourced from, but not limited to, Lonza or Arxada (Product code 1007182).
  • Exemplary polyglyeryl-10 caprate/caprylate (Polyaldo 10-1-CC, 10-1-CC) can be sourced from, but not limited to, Lonza or Arxada (Product code 177445).
  • SMEIDS formulations were prepared according to the compositions listed in Tables 1-6.
  • the surfactants (3 GO, PGE 860, MPGO, 10-1-L, 10-1-0, 10-1-CC) were individually warmed in a water bath with water set at 85-95 °C for at least 15 minutes. Curcumin was carefully added into scintillation vials followed by the surfactant listed in tables 1 -6 using an appropriate analytical scale with readability down to 1 mg.
  • the scintillation vials were placed on a hotplate to increase the temperature of the SMEIDS liquid ranging from 60-130 °C for 30 minutes with intermittent shaking of the scintillation vials.
  • the SMEIDS were verified for homogeneous mixing by testing if light can transmit through the SMLEDS.
  • SMEIDS and the self-assembled microemulsions prepared with curcumin at compositions less than 2.5 w/w% yielded more favourable results for the prepared SMEIDS and the microemulsions self-assembled in boiling water.
  • SMEIDS containing 3GO, PGE 860, MPGO, and 10-1-CC prepared translucent or transparent SMEIDS that were flowable at room temperature (SMEIDS 1.6, 2.4, 3.4, 6.6).
  • SMEIDS containing 10-1-L and 10-1-0 were not flowable at room temperature (SMEIDS 4.4, 5.6).
  • SMEIDS and self-assembled microemulsions were investigated using combinations of polyglyceryl- 10 caprate/caprylate (Polyaldo 10-1-CC, 10-1-CC), polyglyceryl-3 monooleate and polyglyceryl- 10 monooleate (Caprol MPGO, MPGO), polyglyceryl- 10 mono- and dioleate (Caprol PGE 860), sunflower oil (SO) and propylene glycol (PG) with curcumin ranging from 2.0-4.9 w/w% as shown in Table 10. Observations of the prepared SMEIDS and the stability of their respective self-assembled microemulsions in boiling water and stored at room temperature for up to 14 days are shown in Table 11.
  • SMEIDS and the self-assembled microemulsions were investigated using Polyglyceryl- 10 caprate/caprylate (Polyaldo 10-1-CC, [10-1-CC]), polyglyceryl- 10 monolaurate (Polyaldo [10-1-L], 10-1-L) and polygly eery 1-10 monooleate (Polyaldo 10-1-0, [10-1-0]) either alone or with propylene glycol (PG) and ethyl lauroyl arginate (eLA) as shown in Table 12. Observations of the prepared SMEIDS and the stability of self-assembled SMEIDS in boiling water and stored at room temperature for up to 14 days are shown in Table 13.
  • SMEIDS 12.1-12.4 were not flowable when cooled to room temperature but SMEIDS 12.5 was flowable due to the presence of PG at 17.2 w/w%. Nearly all of the SMEIDS self-assembled into translucent or transparent microemulsions when in boiling water but SMEIDS 12.1-12.4 crystalized the next day. Only SMEIDS 12.5 unexpectedly self-assembled into stable and translucent microemulsions for up to 14 days after self-assembly when stored at room temperature. This provides insight into the stable compositions of eLA with 10-1-CC, 10-1-L, and 10-1-0 that self-assemble into stable microemulsions in boiling water.
  • the hydrophobic component of eLA, lauric ester may anchor into the self-assembled microemulsion oil core while the positive charge from the guanidine group aids in the stability of the microemulsion. Therefore, 10-1-CC, 10-1-L, 10-1-0, eLA, and blends produce stable and flowable SMEIDS that produce translucent microemulsions that are stable 14 days after self-assembly. SMEIDS 12.5 warrants further investigation in simulated gastric and intestinal fluids.
  • SMEIDS and their self-assembled microemulsions were investigated using Polyglyceryl- 10 caprate/caprylate (Polyaldo 10-1-CC, 10-1-CC), polygly ceryl- 10 monooleate (Polyaldo 10-1- O, 10-1-0), and polygly eery 1-3 monooleate (Caprol 3GO, 3GO) either alone or with propylene glycol (PG), sunflower oil (SO) and ethyl lauroyl arginate (eLA) as shown in Table 14.
  • PG propylene glycol
  • SO sunflower oil
  • eLA ethyl lauroyl arginate
  • SMEIDS incorporated curcumin at 13.2 and 5.0 w/w%, respectively, indicating that the total surfactants to oil (tS/O) mass ratio of 6.6 and 16.9 is not sufficient to maintain stable microemulsions.
  • Most of the self-assembled SMEIDS of series A self-assembled into translucent or transparent microemulsions in boiling water.
  • four SMEIDS maintained the stability of the formed microemulsions up to 14 days after self-assembly (SMEIDS 14.1-14.4).
  • Curcumin compositions were lower than 2.0 w/w% and the tS/O mass ratio was above 43.4 indicating that these parameters are predictors of self-assembled microemulsion stability.
  • Four of the Series A formulations were stable for up to 14 days and will be investigated further in simulated gastric and intestinal fluids.
  • SMEIDS 14.13-14.18 that focus on the mixture of 10-1-CC with 10-1-0 at various 10-1 -CC/10-1-0 mass ratios ranging from 2.0-3.7 and curcumin compositions ranging from 2.1-9.6 w/w%. All of the prepared SMEIDS were not flowable liquids when cooled to room temperature, but were able to self-assemble into translucent or transparent microemulsions in boiling water, excluding SMEIDS 14.13. The opaque microemulsion self-assembled by SMEIDS 14.13 is due to the higher composition of curcumin at 9.6 w/w%.
  • Stable microemulsions were either translucent or transparent up to 7 days after self-assembly (SMEIDS 14.14-14.17). Notably, transparent microemulsions are self-assembled when the 10-1-CC/10-1-0 mass ratio is above 3.6 (SMEIDS 14.16, 14.17) indicating that the mass ratio should be targeted at or above this mass ratio. All of the formulations were destabilized 14 days after self-assembly. This provides insight that nonfl owable SMEIDS can be self-assembled into transparent microemulsions using the preferred 10- 1-CC to 10-1-0 mass ratio at or above 3.6 while a mass ratio ranging from 2.0-3.4 selfassembles into translucent microemulsions.
  • the 10-1-CC/10-1-0 mass ratio ranged from 2.2-4.0 with the tS/O mass ratio above 35.4. However, these microemulsions destabilized by 14 days after selfassembly. Therefore, incorporating curcumin at less than 2 w/w% with the addition of PG to blends that contain 10-1-CC to 10-1-0 mass ratios of 2.2-4.0 provides flowable SMEIDS that self-assembled into translucent or transparent microemulsions while maintaining stability up to 7 days after self-assembly.
  • microemulsions are indications that the diameters of the microemulsions are less than 150 nm, whereas translucent microemulsions would indicate that the microemulsion diameter is larger than 150 nm.
  • a select number of unstable SMEIDS along with the stable SMEIDS will proceed to the investigation of self-assembly in simulated gastric and intestinal fluids.
  • Exemplary fasted state simulated gastric fluid includes, but is not limited to, dissolution medium containing taurocholate (0.08 millimole [mM]), phospholipids (0.02 mM), sodium (34 mM), chloride (59 mM), and pH 1.6. It is noted that an academic publication investigated resting volumes of gastric components in fasted and fed states. 1 Gastric fluids in a fed state introduce complex factors such as the variable food that may be consumed coupled with variable gastric volumes.
  • the SMEIDS would be diluted 353-fold. Therefore, the selected SMEIDS were diluted 353-fold in FaSSGF with temperatures maintained at 37 ⁇ 2 °C and the self-assembled microemulsion was monitored for up to six hours.
  • SMEIDS 14.22-14.24 Self-assembly of the two surfactant systems with PG in FaSSGF at 37 °C resulted in translucent microemulsions that were destabilized by sedimentation in the range of 0.75-3.50 hours.
  • SMEIDS 14.22 incorporated curcumin at 5.0 w/w% with PG at 29.4 w/w% and the self-assembled microemulsions destabilized within 0.75 hours in FaSSGF at 37 °C.
  • SMEIDS 14.23 and 14.24 incorporated PG at 19.4 and 9.5 w/w% and destabilized within 3.0 and 3.5 hours, respectively.
  • the tS/O mass ratios of the previously mentioned SMEIDS ranged from 13.1 to 18.3, but destabilization occurred within 3.5 hours.
  • an unexpected stability enhancement was observed as seen in the stability results of SMEIDS 14.36-14.38 in FaSSGF at 37 °C. While the tS/O mass ratios are similar between SMEIDS 14.22-14.24 and 14.36-14.38, the addition of the third surfactant, eLA, in SMEIDS 14.36-14.38 enhances the stability of self-assembled microemulsions which are translucent for up to 6 hours in FaSSGF at 37 °C.
  • SMEIDS 14.22 and 14.36 which included PG at around 28 w/w%
  • SMEIDS 14.36 demonstrated stability for up to 6 hours mainly due to the eLA present at 3.0 w/w%.
  • Identical interpretations are made with the SMEIDS containing around 20% PG (SMEIDS 14.23, 14.37) and 10% PG (SMEIDS 14.24, 14.38).
  • SMEIDS 14.35 destabilized after 3 hours as the tS/O mass ratio was reduced to below 12.4 with 35.6 w/w% PG and 4.0 w/w% eLA.
  • Exemplary fasted state simulated intestinal fluid can be sourced from, but is not limited to, Biorelevent.com Ltd. that prepares dissolution medium containing taurocholate (3 mM), phospholipids (0.75 mM), sodium (148 mM), chloride (106 mM), phosphate (29 mM), and pH 6.5. It is noted that an academic publication investigated resting volumes of intestinal components in fasted and fed states. 1 The intestinal fluid in a fed state is variable and dependent on the food that may be consumed which also varies the intestinal fluid volume.
  • Enteric capsules or softgel shells comprise polymers that do not disintegrate in the acidic gastric fluid and delay the disintegration by targeting intestinal fluid conditions such as a neutral pH of 6.5. Once the enteric capsule or softgel that carries 0.68 g of SMEIDS expectedly disintegrates in the intestine, the SMEIDS would be diluted 113-fold in intestinal fluid.
  • the selected SMEIDS were diluted 113-fold in FaSSIF with temperatures maintained at 37 ⁇ 2 °C and the self-assembled microemulsion was monitored for up to six hours.
  • Table 18 The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 16 incubated in fasted state simulated intestinal fluid (FaSSIF) for up to six hours at 37 °C. The visual scores are described in paragraph 0089.
  • SMEIDS 14.35 self-assembled into microemulsions that destabilized within 3.5 hours in FaSSGF at 37 °C.
  • An unexpected stability enhancement is observed again when directly comparing the microemulsions with eLA absent, SMEIDS 14.22- 14.24, to eLA present, SMEIDS 14.36-14.38. Therefore, SMEIDS 14.36-14.38 may be filled in conventional capsules or softgels that disintegrate in gastric fluid or enteric capsules or softgels that disintegrate in intestinal fluid showing similar self-assembled microemulsion stability. From the perspective of the stability of the active ingredient, curcumin, it would be a conservative decision to bypass the gastric conditions and self-assemble the microemulsion in intestinal fluids.
  • SMEIDS 14.4 self-assembled into unstable microemulsions in FaSSGF similar to FaSSIF conditions which may be due to the 10-1-CC to the combination of 10-1-0, 3GO mass ratio of 2.8. It is noted that transparent microemulsions are indications that the diameters of the microemulsions are less than 150 nm, whereas translucent microemulsions would indicate that the microemulsion diameter is larger than 150 nm. As most of these formulations were stable in FaSSIF for up to 6 hours, it was not possible to capture the stability benefits of eLA with SMEIDS incorporating curcumin at compositions lower than 3.4 w/w%. These SMEIDS are both free of PEG and lecithin. Antioxidants and preservatives will be required to be added in the concentration range of 10-1,000 parts per million in order to preserve the chemical stability of the active ingredient.
  • curcumin solubility in SGF using six commercially available supplements containing curcumin that sold on Amazon.com and carried at least 6,000 customer reviews at the time of purchase was directly compared.
  • turmeric powder purchased from a grocery store was inserted into a capsule.
  • the ingredients of the six commercially available curcumin supplements are listed in Table 19 along with our two optimized SMEIDS that incorporated eLA or not.
  • One capsule or softgel was placed in a beaker that contained 250 mL of SGF containing 0.2 weight/volume% sodium chloride and 0.7 volume/volume% hydrogen chloride with a pH of 1.2. Each of these beakers was placed in an incubator shaker that was set to 37 °C.
  • curcumin mass solubilized per 250 mL is quantified by HPLC analysis and then extrapolated to the 250 mL volume of SGF used in the incubation period.
  • the commercially available curcumin supplements demonstrated insignificant enhancement of the solubility of curcumin when compared to turmeric powder purchased from a grocery store.
  • Piper nigrum which is included in C1-C3 competitors, coconut oil, included in the C4 competitor, and ginseng extract and ginger root, included in the C5 competitor, did not enhance the solubility of curcumin in SGF.
  • curcumin solubility in SGF is most likely due to lower pH and salt.
  • ingesting turmeric powder purchased from a grocery store is as efficient as ingesting the mentioned curcumin supplements in terms of solubilizing curcumin in SGF.
  • the optimized SMEIDS, with eLA absent or present, discussed in this patent performed as expected in a third-party laboratory.
  • the SMEIDS OS1 and OS2 included around 6.4 mg of curcumin per capsule. Once these capsules disintegrated in the SGF, the self-assembled microemulsions were sufficiently stable for the 3 -hour incubation period. After filtering through a 0.45 nylon syringe filter and extrapolating to the SGF volume of 250 mL, 5.438 mg and 5.490 mg of curcumin were unexpectedly quantified to be solubilized in SGF for SMEIDS OS1 and OS2, respectively. Interestingly.
  • SMEIDS OS2 contained eLA that unexpectedly resulted in 0,053 mg more curcumin solubilized in SGF relative to SMEIDS OS1. This is an extension of the microemulsion stability enhancement that was visually observed in FaSSGF in Table 17 (SMEIDS 14.23 and 14.37).
  • the missing 0.0530 mg in using SMEIDS OS1 formulation may have precipitated and captured in the centrifuge pellet or the microemulsions grew in size to be filtered out when using the 0.45 nylon syringe filter.
  • Example 6 SMEIDS Incorporating either Resveratrol or Coenzyme Q10 and Dispersion Analysis in Boiling water, Fasted State Simulated Gastric Fluid, or Fasted State Simulated Intestinal Fluid.
  • Table 21 SMEIDS compositions with either resveratrol (Resv.) or Coenzyme Q10 (COQ10), and Polylado 10-1-CC (10-1-CC), Polyaldo 10-1-0 (10-1-0), propylene glycol (PG), and ethyl lauroyl arginate (eLA) along with the 10-1-CC/10-1-0 and total surfactant (10-1-CC, 10-1-0, eLA) to oil phase (Resv. or COQIO) [tS/O] mass ratios. boiling water the day of as well as 7 and 14 days after self-assembly.
  • Resv. resveratrol
  • COQ10 Coenzyme Q10
  • composition of coenzyme Q10 lower than 5.1 w/w% in SMEIDS aids in the self-assembly of transparent microemulsions that are expected to be less than 150 nanometers in diameter. Similar to the SMEIDs containing resveratrol, all of the SMEIDs containing coenzyme Q10 destabilized within 7 days after self-assembly. The microemulsion stability test in FaSSGF and FaSSIF would be more appropriate to gauge the suitability of the SMEIDS systems.
  • Table 23 The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 21 incubated in Fasted State Simulated Gastric Fluid (FASSGF) for up to six hours at 37 °C. The visual scores are described in paragraph 0089.
  • FASSGF Fasted State Simulated Gastric Fluid
  • Table 24 The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 21 incubated in Fasted State Simulated Intestinal Fluid (FaSSIF) for up to six hours at 37 °C. The visual scores are described in paragraph 0089.
  • FaSSIF Fasted State Simulated Intestinal Fluid
  • SMEIDS incorporating resveratrol was found to be stable in both FaSSGF and FaSSIF.
  • SMEIDS incorporating resveratrol at 2.6 or 4.9 w/w% demonstrated unexpected stability in both FaSSIF and FaSSGF for up to 6 hours at 37 °C (SMEIDS 21.1, 21.2).
  • the tS/O mass ratio in SMEIDS 21.2 was 15.6 indicating that this is the minimum tS/O mass ratio to ensure stability of the selfassembled microemulsions encapsulating resveratrol in both FaSSGF and FaSSIF for up to 6 hours at 37 °C.
  • SMEIDS are both free of PEG and lecithin.
  • the stable SMEIDS 21.1 and 21.2 are suitable candidates that can either self-assemble in gastric or intestinal conditions. However, from the perspective of the active ingredient stability, it is preferred to release the self-assembled microemulsion containing resveratrol in the intestinal fluid to bypass the harsh gastric conditions.
  • SMEIDS 21.6 incorporated coenzyme Q10 at 5.1 w/w% and self-assembled into transparent microemulsions that crystalized in FaSSGF within 3.0 hours and in FaSSIF within 2.5 hours at 37 °C. Both of these time points are passed the expected residency time of the microemulsions in gastric and intestinal conditions and this result is determined to be stable.
  • SMEIDS 21.7 and 21.8 incorporated coenzyme Q10 at 7.3 and 9.4 w/w% and self-assembled into transparent or translucent microemulsions that quickly and similarly crystallized at 0.75 and 1.25 hours in FaSSGF and FaSSIF, respectively. If required, antioxidants and preservatives can be added to minimize the degradation and oxidation of the active ingredient, resveratrol.
  • SMEIDS 21.5 is a suitable formulation for coenzyme QI 0 that can be dispersed in either gastric or intestinal conditions. However, from the perspective of the stability of the active ingredient, coenzyme Q10, it is preferred to release the SMEIDS in the intestinal fluid to bypass the harsh gastric conditions.
  • Table 42 indicates the compositions of the liquified SMEIDS that are converted to plated powders using the compositions stated in the table.
  • the main result of the plated powder is it produces free-flowing powders that can be easily incorporated into food products, gel products, and pellets.
  • the solids produced by the encapsulation process yielded flowable powders with resting angles near 30°, and particles ranging from 2 to 10 microns that make the powders amenable to integration into solid products to be incorporated into capsules.
  • the plating agent includes, but is not limited to, cellulose, microfine cellulose, microcrystalline cellulose, dicalciumphosphate dihydrate, zein powder, magnesium carbonate, dextrin, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, hyalonic acid, silica dioxide, fiber, citrus fiber, oligofrustose, rice bran powder, Dehydol OD5, alpha-lactose monohydrate, anhydrous lactose, spray dried alpha-lactose monohydrate, granulated alpha-lactose monohydrate, and combinations thereof.
  • the plated SMEIDS can be processed further to blend with other powders conventionally used to fill powders into capsules to fine-tune the compressibility, flowability, tensile strength.
  • Table 25 Master stock composition breakdown of SMEIDS used to blend with a plating agent to be processed further or filled into capsules.
  • Table 26 Master stock composition breakdown of SMEIDS containing curcumin and Polyalso 10-1-CC used to blend with a plating agent to be processed further or filled into capsules.
  • Polyaldo 10-1-L used to blend with a plating agent to be processed further or filled into capsules.
  • Polyaldo 10-1-P used to blend with a plating agent to be processed further or filled into capsules.
  • Table 30 Master stock composition breakdown of SMEIDS containing curcumin and Caprol MPGO used to blend with a plating agent to be processed further or filled into capsules.
  • Caprol PGE860 used to blend with a plating agent to be processed further or filled into capsules.
  • Table 32 Master stock composition breakdown of SMEIDS containing curcumin and Caprol 3 GO used to blend with a plating agent to be processed further or filled into capsules.
  • Table 33 Master stock composition breakdown of SMEIDS containing curcumin, ethyl lauroyl, arginate and Polyaldo 10-1-CC used to blend with a plating agent to be processed further or filled into capsules.
  • Polyaldo 10-1-0 used to blend with a plating agent to be processed further or filled into capsules.
  • Table 35 Master stock composition breakdown of SMEIDS containing curcumin and Polyaldo 10-1-0 and Polyaldo 10-1-CC used to blend with a plating agent to be processed further or filled into capsules.
  • Table 36 Master stock composition breakdown of SMEIDS containing curcumin and Polyalso 10-1-L, Polyaldo 10-1-0 and Polyaldo 10-1-CC used to blend with a plating agent to be processed further or filled into capsules.
  • Table 37 Master stock composition breakdown of the plated powder blended with the SMEIDS indicated in Tables 26-36 with a plating agent to be processed further or filled into capsules.
  • Example 8 SMEIDS mixing and encapsulating in softgels at industrial scale
  • capsules may be processed further, for example, by enteric coating.
  • enteric coating An example of the homogeneous mixing of SMEIDS and then encapsulating in softgels is described below:

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Abstract

La présente invention concerne des compositions sous forme de pré-concentrés de microémulsions cationiques qui contiennent au moins un agent actif lipophile et insoluble dans l'eau, au moins un émulsifiant contenant du polyglycéryle, au moins un émulsifiant cationique, des huiles porteuses, des agents de solubilisation, des antioxydants et des conservateurs. Lorsqu'ils sont mis en contact avec un milieu aqueux ou un fluide gastrique ou intestinal, les pré-concentrés de microémulsions cationiques s'auto-assemblent en microémulsions cationiques qui sont stables dans des fluides gastriques et intestinaux. L'invention concerne également des procédés de fabrication et d'utilisation des pré-concentrés de microémulsions cationiques.
PCT/IB2025/051799 2024-02-19 2025-02-19 Microémulsions à auto-assemblage portant des produits nutraceutiques et leurs procédés d'utilisation Pending WO2025177181A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2547712A1 (fr) * 2004-01-06 2005-07-21 Doron Friedman Composition non aqueuse pour une administration orale d'agents bioactifs non solubles
US20100331356A1 (en) * 2006-12-27 2010-12-30 Lek Pharmaceuticals D.D. Self-microemulsifying drug delivery systems
CA2966619A1 (fr) * 2014-11-04 2016-05-12 Innopharmax, Inc. Administration orale de medicaments instables ou mal absorbes
WO2018219804A1 (fr) * 2017-06-02 2018-12-06 Bayer Pharma Aktiengesellschaft Systèmes d'administration de médicaments auto-émulsifiants
WO2019135225A1 (fr) * 2018-01-03 2019-07-11 Icdpharma Ltd. Compositions de cannabinoïdes auto-emulsifiantes solides
US20190247309A1 (en) * 2016-06-10 2019-08-15 Friulchem Self-emulsifying lipid compositions
WO2020225395A1 (fr) * 2019-05-07 2020-11-12 Bausch Health Ireland Limited Formulations posologiques orales liquides de méthylnaltrexone

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Publication number Priority date Publication date Assignee Title
CA2547712A1 (fr) * 2004-01-06 2005-07-21 Doron Friedman Composition non aqueuse pour une administration orale d'agents bioactifs non solubles
US20100331356A1 (en) * 2006-12-27 2010-12-30 Lek Pharmaceuticals D.D. Self-microemulsifying drug delivery systems
CA2966619A1 (fr) * 2014-11-04 2016-05-12 Innopharmax, Inc. Administration orale de medicaments instables ou mal absorbes
US20190247309A1 (en) * 2016-06-10 2019-08-15 Friulchem Self-emulsifying lipid compositions
WO2018219804A1 (fr) * 2017-06-02 2018-12-06 Bayer Pharma Aktiengesellschaft Systèmes d'administration de médicaments auto-émulsifiants
WO2019135225A1 (fr) * 2018-01-03 2019-07-11 Icdpharma Ltd. Compositions de cannabinoïdes auto-emulsifiantes solides
WO2020225395A1 (fr) * 2019-05-07 2020-11-12 Bausch Health Ireland Limited Formulations posologiques orales liquides de méthylnaltrexone

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SAIPIN SETTHACHEEWAKUL ET AL.: "Development and evaluation of self- microemulsifying liquid and pellet formulations of curcumin and absorption studies in rats", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 76, 2010, pages 475 - 485, XP027503476, DOI: 10.1016/j.ejpb.2010.07.011 *

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