WO2015164657A1 - Incorporation de composant(s) soluble(s) dans l'eau dans des formulations anhydres - Google Patents

Incorporation de composant(s) soluble(s) dans l'eau dans des formulations anhydres Download PDF

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WO2015164657A1
WO2015164657A1 PCT/US2015/027371 US2015027371W WO2015164657A1 WO 2015164657 A1 WO2015164657 A1 WO 2015164657A1 US 2015027371 W US2015027371 W US 2015027371W WO 2015164657 A1 WO2015164657 A1 WO 2015164657A1
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extract
hydrolyzed
butylene glycol
peg
compound
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PCT/US2015/027371
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Chantal Burnison
Christopher R. Stahl
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Bcs Business Consulting Services Pte Ltd
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    • 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
    • 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)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • 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
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine

Definitions

  • compositions for topical administration generally (e.g., pharmaceutics or cosmetics), and more particularly to a composition for incorporating a water soluble component (or water soluble components) into a relatively hydrophobic and/or anhydrous formulation and associated methods of making and using the composition.
  • Green tea polyphenols may help prevent skin cancer with direct (topical) application to the skin. See, e.g., Katiyar et al. "Green tea and skin,” Arch Dermatol. 136:989-994 (2000). Evidence also exists that green tea constituents help protecting the skin from sun damage. See, e.g., Katiyar et al. "Polyphenolic antioxidant (-)-epigallocatechin-3-gallate from green tea reduces UVB-induced inflammatory responses and infiltration of leukocytes in human skin," Photochem Photobiol. 69: 148-153 (1999); Katiyar et al.
  • Green tea itself though is a complex composition of polyphenols.
  • Green tea extract is derived from green tea leaves ⁇ Camellia sinensis), and contains various antioxidant ingredients - mainly green tea catechins (GTC).
  • GTC itself comprises four major epicatechin derivatives; i.e., epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and EGCG (or EGCg).
  • EGCg green tea catechins
  • Other components of green tea include flavonoids, such as kaempferol, quercetin, and myricetin.
  • polyphenol has been defined differently.
  • WBSSH White-Bate-Smith-Swain-Haslam
  • polyphenols are generally moderately water-soluble compounds, typically with molecular weights of 500-4000 Da, having, e.g., more than 12 phenolic hydroxyl groups and 5-7 aromatic rings per 1000 Da.
  • WBSSH White-Bate-Smith-Swain-Haslam
  • polyphenols are generally moderately water-soluble compounds, typically with molecular weights of 500-4000 Da, having, e.g., more than 12 phenolic hydroxyl groups and 5-7 aromatic rings per 1000 Da.
  • [t]he term 'polyphenol' should be used to define compounds exclusively derived from the shikimate/phenylpropanoid and/or the polyketide pathway, featuring more than one phenolic unit and deprived of nitrogen- based functions.”
  • the term "polyphenol” is to be used inclusively.
  • polyphenols For use by topical skin application (e.g., as is the case in cosmetic and pharmaceutical applications), one issue with polyphenols is their generally moderately water-solubility, which relative hydrophilicity hinders their use in hydrophobic anhydrous formulations.
  • the formulations may be produced by dispersing polyphenols in a hydrophobic and/or anhydrous vehicle.
  • such formulations often have poor stability and tend to phase separate, resulting in poor shelf stability and inconsistent performance.
  • relatively hydrophobic vehicles e.g., gels and ointments
  • a relatively hydrophilic compound such as polyphenol(s)
  • the emulsifying agent is chosen to form, e.g., reverse micelles, and/or liposomes and preferably forms a water-in-oil system.
  • an emulsified polyphenol green tea for incorporation into a hydrophobic and/or anhydrous formulation containing a relatively hydrophobic vehicle and other ingredients.
  • the resulting hydrophobic and/or anhydrous formulation contains at least 0.1% (preferably greater than 1%) green tea content.
  • an extract of polyphenol from green tea is encapsulated into appropriate liposomes or reverse micelles to incorporate the water soluble green tea polyphenols at 0.1% green tea polyphenol content into the hydrophobic and/or anhydrous formulation.
  • reverse micelles are discrete nanoscale particles composed of a water core surrounded by surfactant
  • reverse micelles are relatively easy to be detected for, e.g., counterfeit detection measures.
  • At least a portion of the encapsulated hydrophilic component (e.g., polyphenol(s)) contained in the, e.g., reverse micelles disassociates from the reverse micelles upon contact with the skin so that the skin benefits from the effect of the hydrophilic component.
  • the encapsulated hydrophilic component e.g., polyphenol(s)
  • At least a portion of the encapsulated hydrophilic component (e.g., green tea polyphenol(s)) contained in the, e.g., reverse micelles leaves the reverse micelles after contact and transport through a portion of the skin so that the layer under the skin benefits from the effect of the hydrophilic component.
  • the encapsulated hydrophilic component e.g., green tea polyphenol(s)
  • At least a portion of the encapsulated hydrophilic component (e.g., green tea polyphenol(s)) contained in the, e.g., reverse micelles leaves the reverse micelles after transport through skin for systemic delivery of the hydrophilic component.
  • the encapsulated hydrophilic component e.g., green tea polyphenol(s)
  • Also described is a method of detecting a counterfeit of a brand hydrophobic formulation comprising: incorporating reverse micelles or liposomes into the brand hydrophobic formulation, and analyzing a suspect counterfeit product for the presence of the reverse micelles or liposomes.
  • Methods of making the composition and associated formulation are also described herein.
  • FIG. 1 depicts a schematic of reverse micelles in a hydrophobic and/or anhydrous formulation according to one embodiment
  • FIG. 2 depicts a schematic of liposomes in a hydrophobic and/or anhydrous formulation according to one embodiment.
  • a delivery system that includes a hydrophobic and/or anhydrous (e.g., liquid) formulation for application to a surface (e.g., a biological surface such as skin, endothelial tissue, mucous membranes of the eye, vulva, anus, and nose, the inside of the mouth or other orifice, etc.); a hydrophilic compound or compounds for delivery by the system, and an emulsifying agent, wherein the emulsifying agent encapsulates the hydrophilic compound forming reverse micelles and/or liposomes for incorporation into the hydrophobic and/or anhydrous (e.g., liquid) formulation for distribution of the hydrophilic compound or compounds to the surface through the system.
  • a hydrophobic and/or anhydrous (e.g., liquid) formulation for application to a surface
  • a surface e.g., a biological surface such as skin, endothelial tissue, mucous membranes of the eye, vulva, anus, and nose, the inside
  • a method of incorporating a relatively hydrophilic compound into a relatively hydrophobic vehicle includes utilizing an emulsifying agent to emulsify a desired amount of the hydrophilic compound into the hydrophobic vehicle. Also described is a method of detecting a counterfeit of a brand hydrophobic formulation includes incorporating reverse micelles or liposomes into the brand hydrophobic formulation, and analyzing a suspect counterfeit product for the presence of the reverse micelles or liposomes.
  • a delivery system includes a hydrophobic and/or anhydrous (e.g., liquid) formulation for application to a surface; a hydrophilic compound or compounds for delivery by the system, and an emulsifying agent.
  • the hydrophobic and/or anhydrous liquid formulation comprises a relatively hydrophobic vehicle (i.e., the vehicle is more hydrophobic than the compound or compounds for delivery by the system).
  • the emulsifying agent encapsulates the hydrophilic compound forming reverse micelles and/or liposomes for incorporation into the hydrophobic and/or anhydrous (e.g., liquid) formulation for distribution of the hydrophilic compound or compounds to the surface through the system
  • a delivery system 100 includes a hydrophobic and/or anhydrous (e.g., liquid) formulation 101 for application to a surface; a hydrophilic compound or compounds 102 for delivery by the system, and an emulsifying agent 103.
  • the emulsifying agent 103 encapsulates the hydrophilic compound 102, forming reverse micelles 104 for incorporation into the hydrophobic and/or anhydrous (e.g., liquid) formulation 101 for distribution of the hydrophilic compound or compounds 102 to the surface through the system.
  • the hydrophobic and/or anhydrous liquid formulation 101 comprises a relatively hydrophobic vehicle 105 (i.e., the vehicle 105 is more hydrophobic than the compound or compounds 102 for delivery by the system 100).
  • the reverse micelles 104 are shown in FIG. 1 as spherical reverse micelles, it is understood that the reverse micelles may have other structures, such as non-spherical reverse micelles or cylindrical reverse micelles, etc.
  • a delivery system 200 includes a hydrophobic and/or anhydrous (e.g., liquid) formulation 201 for application to a surface; a hydrophilic compound or compounds 202 for delivery by the system, and an emulsifying agent 203.
  • the emulsifying agent 203 encapsulates the hydrophilic compound 202 forming liposomes 204 for incorporation into the hydrophobic and/or anhydrous (e.g., liquid) formulation 201 for distribution of the hydrophilic compound or compounds 202 to the surface through the system.
  • the liposomes 104 are shown in FIG. 2 as spherical liposomes, it is understood that other structures of liposomes may be formed in the delivery system, such as non- spherical liposomes.
  • the hydrophobic and/or anhydrous (e.g., liquid) formulation includes a relatively hydrophobic vehicle suitable for topical administration.
  • Suitable relatively hydrophobic vehicles may include oleaginous ointment bases, absorption ointment bases, water/oil emulsion ointment bases, oil/water emulsion ointment bases, and water-miscible ointment bases such as white petrolatum, white ointment, hydrophilic petrolatum, anhydrous lanolin, AquabaseTM, Aquaphor®, Polysorb®, cold cream type, hydrous lanolin, rose water ointment, HydrocreamTM, Eucerin®, Nivea®, hydrophilic ointment, DermabaseTM, Velvachol®, Unibase®, PEG ointment, and PolybaseTM.
  • the hydrophobic anhydrous vehicle may be serum/gel that includes cyclopentasiloxane, squalene, dimethiconol, ethoxyheptyl bicyclooctanone (ETHOCYN ® ), ubiquinone, various extracts, tetrahexyldecyl ascorbate, safflower seed oil, Oenothera Biennis (evening primrose) oil, tocopherol linoleate/oleate, octyldodecyl citrate crosspolymer, tocopherol acetate, polydecene, caprylic/capric triglyceride, dimethicone, and corn oil.
  • cyclopentasiloxane cyclopentasiloxane
  • squalene dimethiconol
  • ETHOCYN ® ethoxyheptyl bicyclooctanone
  • ubiquinone various extract
  • the hydrophilic compound or compounds for delivery by the system may include polyphenol, e.g., green tea polyphenols.
  • polyphenol compounds may include epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin (EC), epicatechin gallate (ECG), and catechin.
  • a composition comprises (a) from about 0.1% to about 5% of a hydrophilic compound comprising EGCg, (b) from about 20% to about 25%o of glycol solvent, (c) from about 20%> to about 30%> of PEG-20 sorbitan monooleate, and (d) from about 41% to about 61% sorbitan oleate, wherein the percentages are by weight based upon total weight of the composition and wherein the composition is clear and uniform.
  • glycol solvent may be propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, or polyethylene glycols such as PEG-4, PEG-8, PEG- 16, and PEG-32.
  • a composition comprises (a) from 0.5% to 4% of a hydrophilic compound comprising EGCg, (b) from 21% to 24% of propylene glycol, (c) from 22% to 28% of PEG-20 sorbitan monooleate, and (d) from 45% to 56% sorbitan oleate, wherein the percentages are by weight based upon total weight of the composition and wherein the composition is clear and uniform.
  • a composition comprises (a) from 1.0% to 3% of a hydrophilic compound comprising EGCg, (b) from 22% to 23% of propylene glycol, (c) from 24% to 26% of PEG-20 sorbitan monooleate, and (d) from 48% to 53% sorbitan oleate, wherein the percentages are by weight based upon total weight of the composition and wherein the composition is clear and uniform.
  • a composition comprises (a) 2.5% of a hydrophilic compound comprising EGCg, (b) from 22.5% propylene glycol, (c) 25% of PEG-20 sorbitan monooleate, and (d) from 50% sorbitan oleate, wherein the percentages are by weight based upon total weight of the composition and wherein the composition is clear and uniform.
  • ingredients that are relatively hydrophilic for delivery with the described system include (supplier in parenthesis): Alistin (DD Chemco), Chlorellagen DP (DD Chemco), Depollutine (Devereaux), Derm SRC (DD Chemco), Dragosine (Symrise), Ellagi-C (Devereaux), Hydro lite 5P (Symrise), IBR Dormins (Israeli Biotechnology Research, Ltd.), Kaden berry extracts (Symrise), Matrixyl synthe 6 (Croda), Matrixyl 3000 (Croda), Micromeral (BASF), Milk Peptide Complex (Devereaux), Mitostime L (DD Chemco), Minythis (DD Chemco) Muciliance fruit (Devereaux), Phytosan-K (Devereaux), Pholsine (DD Chemco), Pinoxide (DD Chemco), Quicklift (BASF), Scopariane BPC (DD Chemco), Seanerg
  • the hydrophilic compound or compounds for delivery by the system may include those compounds, available from, e.g., Silab S.A. of Saint Viance, France, such as those selected from the group consisting of Saccharomyces cerevisiae extract, Withania somnifera root extract, butylene glycol and hydrolyzed Coriandrum sativum fruit extract and Citrus aurantium dulcis (orange) fruit extract, Helianthus annuus (sunflower) seed extract, Taraxacum officinale (dandelion) extract, hydrolyzed Viola tricolor extract, Pyrus malus (apple) fruit extract (e.g., Bioprotectyl ® ), hydrolyzed Celosia cristata extract and hydrolyzed Prunella vulgaris extract, hydrolyzed Citrus aurantium dulcis fruit extract, hydrolyzed Candida saitoana extract (e.g., Celldetox ® ), Lindera strychnifolia root extract, Triticum vulgare (whe
  • the hydrophilic compound or compounds for delivery by the system may include a collagen increasing compound.
  • the collagen increasing compounds may include any of these compounds available from Silab S.A. of Saint Viance (France): Nutipeptides GR compound, RETILACTYL D® RC compound, ASTRESSYL® GR compound, p-REINYL® PX compound, or TELOSOMYL® compound; or any of these compounds available from Centerchem Inc. (Connecticut, USA): SYN®-TC compound, SYN®-Coll compound, PEPHA®- Tight compound, or HOMEOSTATINETM compound; or combinations of any thereof.
  • the hydrophilic compounds may include proteins, peptides, nucleic acids, and hydrophilic drugs (characterized chemically by having a relatively low octanol/water partition coefficient) such as vancomycin, phenobarbital, antibiotics such as ampicillin, streptomycin, aminoglycosides, and the penicillins, theophylline, polysaccharides, non-ADEK vitamins, digoxin, atenolol, paclitaxel, 5- fluorouracil, inulin, lithium, ara-C, gemcitabine, propranolol, tramadol, diltiazem, etc.
  • hydrophilic drugs characterized chemically by having a relatively low octanol/water partition coefficient
  • Liposomes are also non-toxic, biodegradable and are readily prepared on a large scale. Liposomes are microscopic vesicles composed of one or more lipid bilayers arranged in concentric fashion enclosing an equal number of aqueous compartments. Various amphipathic molecules have been used to form the liposomes, and the method of preparation can be tailored to control their size and morphology. Drug molecules can either be encapsulated in the aqueous space or intercalated into the lipid bilayer; the exact location of a drug in the liposome will depend upon its physicochemical characteristics and the composition of the lipids.”
  • Liposomes in: R. Langer and M. Chassin (Eds.), Biodegradable polymers as drug delivery systems, Marcel Dekker, New York (1990), the contents of the entirety of each of which are incorporated herein by this reference]. Liposomes have shown great potential as a drug delivery system.”
  • amphiphilic molecules In a hydrophobic formulation, amphiphilic molecules (having both hydrophilic portion and hydrophobic portion) form aggregates called “reverse micelles.” Reverse micelles form only when the concentration of the amphiphilic molecules reaches a given concentration called critical micelle concentration ("CMC") and then act as emulsifiers. That condition may be monitored by the sudden change in the chemical and physical properties of the formulation. Below CMC, reverse micelles are completely absent. In reverse micelles, the hydrophilic portion (i.e., hydrophilic head) of amphiphilic molecule avoids contact with the hydrophobic vehicle in the hydrophobic formulation, pointing toward the aggregate interior, which lacks hydrophobic vehicle.
  • CMC critical micelle concentration
  • Hydrophobic portion i.e., hydrophobic tail
  • hydrophobic head points toward the interior of the aggregate to escape the contacts with the hydrophobic vehicle.
  • Reverse micelles are able to hold relatively large amounts of water in their interior.
  • hydrophobic vehicle In a hydrophobic vehicle, it is the exposure of the hydrophilic heads of amphiphilic molecules to the surrounding hydrophobic vehicle that is energetically unfavorable, giving rise to a water-in-oil system.
  • the hydrophilic heads are sequestered in the core and the hydrophobic tails extend away from the core.
  • These inverse micelles are proportionally less likely to form when the charges on hydrophilic heads increase, since hydrophilic sequestration would create highly unfavorable electrostatic interactions.
  • Hydrophobic compounds such as water soluble enzymes have been immobilized in microemulsion-based gels (G D Rees, Thesis, University of East Yale, (1990); G D Rees et al, Biochim Biophys Acta, 1073, 493 (1991); G D Rees & B H Robinson, Advanced Materials 5, 608 (1993); and G D Rees et al, Indian J Chem, 32B, 30 (1993), the contents of the entirety of each of which are incorporated herein by this reference).
  • microemulsions are of the water-in-oil type (w/o or "water in oil”) in which the enzyme is dissolved in water droplets surrounded by oil.
  • surfactant "AOT” a w/o type microemulsion of water, isooctane and a sodium l,4-bis(2-ethylhexyl)sulfosuccinate
  • AOT a w/o type microemulsion of water, isooctane and a sodium l,4-bis(2-ethylhexyl)sulfosuccinate
  • the hydrophilic component, the lipophilic component and the surfactant form, when examined on a macroscopic scale, a one-phase solution, and the lipophilic component is dispersed as colloidal droplets in the hydrophilic component, or the hydrophilic and the lipophilic components form a microemulsion with bicontinuous structure wherein the components form elongated intertwined channels, and the drug is dissolved in the dispersed component or in the hydrophilic or the lipophilic component of a microemulsion of bicontinuous structure.
  • the microemulsion is stabilized by means of the surfactant, wherein a gelatinizer and water are added to the microemulsion to bring the microemulsion into gel form.
  • methods for preparing a pharmaceutical composition are characterized in that a hydrophilic component, a lipophilic component and a non-toxic, pharmaceutically acceptable surfactant are mixed into a one -phase microemulsion, wherein the lipophilic component is dispersed as colloidal droplets in the hydrophilic component, or the hydrophilic and the lipophilic components form a microemulsion with bicontinuous structure wherein the components form elongated intertwined channels, and a (e.g., hydrophobic) drug is added to the microemulsion and a gelatinizer is dissolved in water at a raised temperature and the microemulsion containing the drug is added thereto.
  • a hydrophilic component is dispersed as colloidal droplets in the hydrophilic component, or the hydrophilic and the lipophilic components form a microemulsion with bicontinuous structure wherein the components form elongated intertwined channels, and a (e.g., hydrophobic) drug is added to the microemulsion and
  • surfactants for use herein include ionic and/or non-ionic surface active materials.
  • Particularly suitable surfactants are, e.g., phospholipids, especially naturally occurring egg and soya bean lecithins.
  • any other pharmaceutically acceptable surfactant can be used, such as: polyoxyethylene (PEG) sorbitan of fatty acid ester (i.e., polysorbate) known under the trade name TWEEN® surfactant from Croda Inc., polyethoxylaied castor oil known under the trade name CREMPOPHOR® surfactant from BASF Corporation, sorbitan sesquistearate known under the trade name NIK OL® surfactant from Nikkol Chemicals Co., Ltd., polyoxyethylene fatty acid ester known under the trade name MYRJ® surfactant from Croda Inc., sorbitan mono fatty acid ester known under the trade name SPAN® surfactant from Croda Inc., and fatty acid ester known under the trade name CETI
  • the polyoxyethylene (PEG) sorbitan of fatty acid ester may be PEG-20 sorbitan monolaurate (e.g., polysorbate 20, TWEEN® 20 surfactant from Croda Inc.), PEG-40 sorbitan monolaurate, PEG-60 sorbitan monolaurate, PEG-80 sorbitan monolaurate, PEG-20 sorbitan monopalmitate (e.g., polysorbate 40, TWEEN® 40 surfactant from Croda Inc.), PEG-40 sorbitan monopalmitate, PEG-60 sorbitan monopalmitate, PEG-80 sorbitan monopalmitate, PEG-20 sorbitan monostearate (e.g., polysorbate 60, TWEEN® 60 surfactant from Croda Inc.), PEG-40 sorbitan monostearate, PEG-60 sorbitan monostearate, PEG-80 sorbitan monostearate, PEG-20 sorbitan monostearate (e
  • Soya bean lecithins (phospholipids) for liposome preparation are available from American Lecithin Company of Oxford, CT. See, e.g.,
  • Reverse micelles and their formulation are known in the art and described in, e.g., Faeder J and Ladanyi B, "Molecular Dynamics Simulations of the Interior of Aqueous Reverse Micelles," A Chem Soc, 1984: 13-9 (1984); Keir et al. "Micellisation of metal alkanoates in non-aqueous media,” Coll. Surf. A 157-203 (1999); and Zingaretti et al., "Kinetics and mechanism for the reaction of 1-chloro- 2,4-dinitrobenzene with n-butylamine and piperidine in AOT/n-hexane/water reverse micelles," ARKIVOC 34: 189-200 (2003), the contents of each of which are incorporated herein by this reference.
  • Typical liposomal excipients used in the pharmaceutical industry include DMPC, DMPG, HSPC, cholesterol, DSPG, DOPC, DPPG, Lipova-E120, Leciva- S70, Leciva-S90, egg PG, MPEG-DSPE, soybean oil, polysorbate 80, and egg sphingomyelin.
  • the delivery system includes a lower alkyl- substituted bicycloalkane 6-(5-ethoxyhept-l-yl)bicyclo[3.3.0]octan-3-one (available under the trade name ETHOCYN® compound from BCS Business Consulting Services Pte Ltd of Singapore) or 6-(5-methoxyhept-l-yl)bicyclo[3.3.0]octan-3-one.
  • ETHOCYN® compound available under the trade name ETHOCYN® compound from BCS Business Consulting Services Pte Ltd of Singapore
  • 6-(5-methoxyhept-l-yl)bicyclo[3.3.0]octan-3-one available under the trade name ETHOCYN® compound from BCS Business Consulting Services Pte Ltd of Singapore
  • compositions comprising a lower alkyl-substituted bicycloalkane such as 6-(5-ethoxyhept-l-yl)bicyclo[3.3.0]octan-3- one (ETHOCYN® compound) or 6-(5-methoxyhept-l-yl)bicyclo[3.3.0]octan-3-one (CYOCTOLTM compound) are described in great detail in U.S. Patents 4,689,349, 4,689,345, and 4,855,322 (the contents of each of which are incorporated herein in their entirety by this reference).
  • the hydrophobic and/or anhydrous formulation contains at least about 0.1% (preferably greater than about 1%) of hydrophilic compound, e.g., green tea polyphenols.
  • the hydrophobic and/or anhydrous formulation may further include an additional biologically active ingredient, a pharmaceutically and/or cosmetically acceptable additive, or both.
  • the hydrophobic and/or anhydrous formulations may further include at least one of the following: adjuvants, excipients, solubilizers, thickeners, gelling agents, fillers, colorants, lubricants, binders, moisturizing agents, preservatives, fragrances, electrolytes, adsorption enhancers, skin penetration enhancers, UV blocking materials; antioxidants, neutralizing agents, buffering agents, and viscosity enhancers (e.g., bee wax).
  • the delivery system may be in various forms, e.g., as a cream, lotion, gel, ointment, or dermal adhesive patch, as known in the pharmaceutical art or cosmetic art.
  • the delivery system may be stable at room temperature, without agitation, for one week or more.
  • the delivery system may be used to treat a condition (e.g., to cure an abnormal condition, to prevent an undesirable condition, and/or to enhance a desirable condition) in a mammal, preferably human, in need thereof.
  • a condition e.g., to cure an abnormal condition, to prevent an undesirable condition, and/or to enhance a desirable condition
  • the method of treating such a condition may involve topically administering the delivery system to the subject in need of treatment.
  • the subject may be any animal, but preferably mammals, and most preferably humans.
  • the liquid formulation contained about 22.50% propylene glycol solvent, about 2.5% Camellia sinensis tea leaf extract SUNPHENON® EGCg, about 25% TWEEN® 80 surfactant, and about 50% SPAN® 80 surfactant (by weight) based on total weight of the liquid formulation.
  • a hydrophobic anhydrous formulation for topical administration was prepared that included the liquid formulation of Example I dissolved into a base formulation comprising cyclopentasiloxane, squalene, dimethiconol, ethoxyheptyl bicyclooctanone (ETHOCYN® compound), ubiquinone, various extracts, tetrahexyldecyl ascorbate, safflower seed oil, Oenothera Biennis (evening primrose) oil, tocopherol linoleate / oleate, octyldodecyl citrate crosspolymer, tocopherol acetate, polydecene, caprylic / capric triglyceride, dimethicone, and corn oil. Accelerated stability testing was conducted, and the hydrophobic anhydrous formulation was stable.
  • a base formulation comprising cyclopentasiloxane, squalene, dimethiconol
  • a Camellia sinensis tea leaf extract SUNPHENON® EGCG at 0.1% content (w/w) are incorporated into a base formulation comprising cyclopentasiloxane, squalene, dimethiconol, ethoxyheptyl bicyclooctanone (ETHOCYN® compound), ubiquinone, various extracts, tetrahexyldecyl ascorbate, safflower seed oil, Oenothera Biennis (evening primrose) oil, tocopherol linoleate / oleate, octyldodecyl citrate crosspolymer, tocopherol acetate, polydecene, caprylic / capric triglyceride, dimethicone, and corn oil, by utilizing poly(styrene)-b-poly(4-pyrrolidone) as an emulsifying agent to create reverse micelles.
  • a Camellia sinensis tea leaf extract SUNPHENON® EGCG at 0.1% content (w/w) are incorporated into the base formulation of EXAMPLE III by utilizing a soya phospholipid as an emulsifying agent to create reverse micelles.
  • Example III The presence of the reverse micelles of Example III are detected utilizing the analysis described in the incorporated Vasquez et al., "Stability and comparative analysis of AOT/water/isooctane reverse micelle system using dynamic light scattering and molecular dynamics," J. Phys. Chem. B. 115(12):2979— 87 (March 31, 2011).
  • a suspected counterfeit composition is analyzed for the presence of reverse micelles utilizing the analysis described in the incorporated Vasquez et al., "Stability and comparative analysis of AOT/water/isooctane reverse micelle system using dynamic light scattering and molecular dynamics," J. Phys. Chem. B. 115(12):2979- 87 (March 31, 2011). No reverse micelles were identified, and the suspected counterfeit composition was confirmed to be counterfeit.

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Abstract

Système comprenant une formulation hydrophobe et/ou anhydre (par ex. liquide) pour application à une surface ; un ou des composés hydrophiles pour administration par le système, et un agent émulsifiant, l'agent émulsifiant encapsulant le composé hydrophile formant des micelles inverses pour l'incorporation dans la formulation hydrophobe et/ou anhydre (par ex. liquide) en vue de la distribution du ou des composés hydrophiles à la surface par l'intermédiaire du système.
PCT/US2015/027371 2014-04-23 2015-04-23 Incorporation de composant(s) soluble(s) dans l'eau dans des formulations anhydres WO2015164657A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018034988A1 (fr) * 2016-08-15 2018-02-22 Natura Cosmeticos Sa Procédés et compositions pour réduire le grisonnement des cheveux
WO2019000067A1 (fr) * 2017-06-30 2019-01-03 Natura Cosméticos S.A. Composition cosmétique de correction du teint de la peau, utilisation d'une composition cosmétique et procédé de correction du teint de la peau dans un environnement urbain
WO2022211632A1 (fr) * 2021-03-31 2022-10-06 Metselaar Amsterdam Beheer B.V. Formulations de produit de soins de la peau avec ingrédient actif hydrophile

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US6004580A (en) * 1994-05-24 1999-12-21 Leiras Oy Pharmaceutical compositions derived from microemulsion-based gels
WO2008030524A2 (fr) * 2006-09-08 2008-03-13 Merck & Co., Inc. Formulations pharmaceutiques liquides pour l'administration orale d'un antagoniste du cgrp

Patent Citations (2)

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US6004580A (en) * 1994-05-24 1999-12-21 Leiras Oy Pharmaceutical compositions derived from microemulsion-based gels
WO2008030524A2 (fr) * 2006-09-08 2008-03-13 Merck & Co., Inc. Formulations pharmaceutiques liquides pour l'administration orale d'un antagoniste du cgrp

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Title
VASQUEZ VR ET AL.: "Stability and comparative analysis of AOT/water/isooctane reverse micelle system using dynamic light scattering and molecular dynamics.", J PHVS CHEM B., vol. 115, no. 12, 31 March 2011 (2011-03-31), pages 2979 - 2987, XP055232588, ISSN: 1520-6106 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018034988A1 (fr) * 2016-08-15 2018-02-22 Natura Cosmeticos Sa Procédés et compositions pour réduire le grisonnement des cheveux
WO2019000067A1 (fr) * 2017-06-30 2019-01-03 Natura Cosméticos S.A. Composition cosmétique de correction du teint de la peau, utilisation d'une composition cosmétique et procédé de correction du teint de la peau dans un environnement urbain
WO2022211632A1 (fr) * 2021-03-31 2022-10-06 Metselaar Amsterdam Beheer B.V. Formulations de produit de soins de la peau avec ingrédient actif hydrophile
NL2027878B1 (en) * 2021-03-31 2022-10-17 Metselaar Amsterdam Beheer B V Skin care formulations with hydrophilic active ingredient

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