WO2021055273A1 - Composition de phospholipide polaire anionique et procédés associés pour le traitement d'affections des muqueuses - Google Patents

Composition de phospholipide polaire anionique et procédés associés pour le traitement d'affections des muqueuses Download PDF

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Publication number
WO2021055273A1
WO2021055273A1 PCT/US2020/050659 US2020050659W WO2021055273A1 WO 2021055273 A1 WO2021055273 A1 WO 2021055273A1 US 2020050659 W US2020050659 W US 2020050659W WO 2021055273 A1 WO2021055273 A1 WO 2021055273A1
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composition
app
mucous membranes
introducing
acid
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PCT/US2020/050659
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English (en)
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Thomas Glonek
Jack Greiner
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Essential Lipid Technologies, LLC
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Publication of WO2021055273A1 publication Critical patent/WO2021055273A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • 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
    • A61K47/26—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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents

Definitions

  • the principal function of the mucous membranes is to provide a barrier against microorganisms and physical and chemical trauma.
  • the epithelial cell membranes of the mucous membranes are comprised of large amounts of lipids, phospholipids, and water that form lipid bilayers. Disruption of these bilayers compromises both the barrier function and the hydration status of the mucus membranes potentially resulting in a range of disorders including, but not limited to, drying, inflammation, infection, impaired wound healing and discomfort. Disruption and damage to mucous membranes may be result from various causes such as high energy radiation associated with cancer treatments.
  • An anionic polar phospholipid (APP) composition includes at least one anionic phospholipid component and at least one carrier.
  • the APP composition further includes at least one viscosity modifier, at least one emulsifier, at least one antioxidant, at least one vitamin, at least one solvent, or any combination thereof.
  • the APP composition formulation is formulated as an aqueous solution, powder, lotion, hydrogel, oil, emulsion, paste, polish, injectable, salve, spray or cream.
  • the carrier is water.
  • at least one polar anionic phospholipid component includes one or more of lysophosphatidic acid, lysodiphosphatidylglycerol, phosphatidylglycerol, lysophosphatidylethanolamine, phosphatidic acid, diphosphatidylglycerol, ethanolamine plasmalogen, phosphatidylethanolamine, phosphatidylserine, dimethylphosphatidylethanolamine, lysophosphatidylcholine, phosphatidylinositol, and phosphatidylcholine.
  • the anionic phospholipid (zwitterionic and uncharged phospholipid) ratio is greater than or equal to 20 mole percent.
  • a method of moisturizing mucous membranes includes the step of introducing a composition as provided herein to one or more mucous membranes of subjects or individuals in need of treatment.
  • the step of introducing the APP composition includes applying the composition to contact and coat all exposed surfaces of the mucous membranes.
  • the step of introducing the composition includes injecting the composition into one or more layers of the mucous membranes.
  • the step of introducing the APP composition includes applying a transmucosal delivery system (such as a mucoadhesive), the transmucosal delivery system containing the APP composition.
  • a method of treating a mucous membrane disorder includes the step of introducing an APP composition as provided herein to the mucous membranes of a subjects or individuals in need of treatment.
  • the step of introducing the APP composition includes applying the composition to contact and coat all exposed surfaces of the mucous membranes.
  • the step of introducing the APP composition includes injecting the composition into one or more layers of the mucous membranes.
  • the step of introducing the APP composition includes applying transmucosal delivery system (such as a mucoadhesive), the transmucosal delivery system containing the APP composition.
  • the mucous membrane disorder includes damage from cancer cells, radiation, chemotherapy, burn, scrape, cut, fissure, ulcer or other surface irregularity.
  • the burn is on or within mucous membranes located in or on a vaginal mucosa, nasal mucosa, pharyngeal mucosa, respiratory mucosa, gastrointestinal mucosa, cervical mucosa, uterine mucosa, ano-rectal mucosa, or exposed mucosa of a tracheostomy, gastrostomy, duodenostomy, jejunostomy, ileostomy, or colostomy or any other exposed mucosa.
  • the burn may be caused by solar radiation, external beam ionizing radiation, thermal or chemical where the chemical burn may dry the mucous membranes.
  • the step of introducing the APP composition includes spraying the APP composition.
  • the step of introducing the APP composition includes administering the APP composition endoscopically.
  • the APP composition is administered during a diagnostic procedure (e.g., evaluations or treatments).
  • a method of preparing an APP composition includes the steps of preparing an aqueous phase, preparing an oil phase, mixing the oil phase and aqueous phase to form an emulsion, and introducing at least one anionic phospholipid component.
  • the APP composition is formulated as a cream, salve or spray.
  • the method further includes the step of suspending the APP composition in an aerosol to form a spray formulation.
  • phospholipid may refer to any variety of lipids containing a phosphate group. Particular embodiments include glycerol derivatives in which one of its hydroxyl groups is esterified with phosphoric acid and the other two hydroxyls are esterified with long-chain fatty acids, which may be equal or different from each other. A saturated phospholipid will be that whose fatty acids only have single (not multiple) carbon-carbon links.
  • a charged or “polar” phospholipid may be one in which another phosphoric acid hydroxyl is esterified by an alcohol substituted by a polar group and whose net charge is negative.
  • anionic is meant to refer to the state of being net negatively charged.
  • the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression, substantially ameliorating clinical symptoms, repairing, or substantially preventing the appearance of various signs, including those associated with hyperproliferative disease.
  • carriers acceptable to mucosal tissue refers to a carrier or a diluent that does not cause significant irritation to the mucous membranes and does not abrogate the biological activity and properties of the applied active agent.
  • mucous membrane refers to the lining of body passages (respiratory, digestive, sexual, genitourinary, and alimentary tracts) or exposed ostomy sites or their associated canals or channels that include cells and associated glands that secrete mucus.
  • Mucous membranes include a surface layer of epithelial tissue covering a deeper layer of connective tissue and protects the underlying structure, secretes mucus, and absorbs water, salts, and other solutes.
  • the term “mucoadhesive delivery system” refers to an APP delivery system that permits or facilitates the achievement of prolonged therapeutic drug levels or a neutralizing agent or a facilitating agent by increasing residence time at the site of absorption via adhesive interactions between the delivery system and a mucosal membrane.
  • the present disclosure provides cosmetic and therapeutic APP compositions that includes at least one anionic polar phospholipid.
  • the APP composition is particularly useful for treatment of various cosmetic conditions as well as conditions or disorders associated with mucous membranes.
  • the present disclosure also provides a method of preparing an APP composition that includes at least one anionic polar phospholipid.
  • the APP compositions as provided herein seek to treat injured cells that are leaking because their membranes have been disrupted or injured.
  • the present APP compositions treat the flaws and repair the cells including the mucous membranes.
  • the phospholipid composition of the present disclosure also overcomes the deficiencies of existing formulations by the unique engineering of phospholipid bilayer components, where an anionic polar head group interacts with water and the hydrocarbon tails interact with oil.
  • the two interconnected units of each molecule thus act like a “zipper” to hold together the dissimilar oil and water, repairing the separated lipid bilayers of the lamellae system into a functional film and thus creating an environment conducive to the repair and restoration of compromised or damaged mucous membrane tissue.
  • the APP compositions as provided herein exhibit therapeutic properties.
  • the APP composition as provided herein includes a phospholipid component.
  • the phospholipid component includes at least one anionic polar phospholipid.
  • the at least one anionic polar phospholipids are chemically pure.
  • the anionic polar phospholipid is obtained from soy bean lecithin.
  • the anionic polar phospholipid is not obtained from any animal originated material (e.g., egg).
  • the anionic polar phospholipid is not neutrally charged.
  • At least one anionic polar phospholipid is lysophosphatidic acid, lysodiphosphatidylglycerol, phosphatidylglycerol, lysophosphatidylethanolamine, phosphatidic acid, diphosphatidylglycerol, ethanolamine plasmalogen, phosphatidylethanolamine, phosphatidylserine, dimethylphosphatidylethanolamine, lysophosphatidylcholine, phosphatidylinositol, phosphatidylcholine or any combination thereof.
  • the phospholipid component is not derived from unrefined lecithins that contain a sufficient amount of neutral zwitterionic phospholipids that interfere with the action of the APP compositions provided herein.
  • the APP compositions provided herein are anionic-enriched phospholipid preparations.
  • the phospholipid component is extracted and purified from a plant (such as soybean) and highly purified.
  • the phospholipid component is obtained from an anionic enriched commercial source.
  • the phospholipid component is present in the APP composition in a concentration suitable for the purpose or end use of the APP composition. Conditions and disorders that present more severe symptoms may require a higher concentration of the phospholipid component. According to one embodiment, the phospholipid component is present in the APP composition in a concentration of typically from about 0.05% to about 10%. According to one embodiment, the phospholipid component is present in the APP composition in a concentration of typically from about 1% to about 5%. According to one embodiment, the anionic phospholipid (zwitterionic and uncharged phospholipid) ratio is greater than or equal to 20 mole percent.
  • the APP compositions as provided herein may also include one or more emulsion stabilizer or rheology modifier, or viscosity modifier.
  • suitable modifiers include mineral oil, light mineral oil, natural oil (e.g., vegetable, corn, canola, sunflower, soybean, olive, coconut, cocoa, peanut, almond, cottonseed, persic, sesame, squalane, castor, cod liver, etc.) hydrogenated vegetable oil, partially hydrogenated oil, beeswax, polyethoxylated beeswax, paraffin, normal wax, medium chain monoglycerides, diglycerides and triglycerides, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, saturated or unsaturated fatty acids, hydrogenated fatty acids, fatty acid glycerides, polyoxyethylated oleic glycerides, monoglycerides and diglycerides, mono-, bi- or tri-substituted glycerides,
  • the APP compositions do not include a rheology modifier.
  • the APP compositions as provided herein may also include one or more emulsifiers.
  • Suitable emulsifiers include sorbitan stearate, acacia, cholesterol, diethanolamine, glyceryl monostearate, glyceryl, stearate, lanolin alcohols, lecithin, mono- and di-glycerides, monoethanolamine, oleic acid, oleyl alcohol poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol diacetate, propylene glycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate
  • the APP compositions provided herein do not include an alcohol that would cause drying at the site of application. According to one embodiment, the APP compositions provided herein do not include an alcohol such as an alcohol including one to four carbons. According to one embodiment, the APP compositions provided herein include one or more of only high molecular weight alcohols known commonly as fats. According to one embodiment, the APP compositions provided herein do not include any protein.
  • the APP compositions as provided herein may also include one or more antioxidants.
  • Suitable antioxidants include tocopherols (e.g., alpha tocopherol, beta tocopherol, gamma tocopherol, or delta tocopherol), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), lecithin, citric acid, ascorbic acid, phenolic diterpenes (e.g., carnosic acid, carnosol, rosmanol, epirosmanol, isorosmanol, or methyl carnosate), rosmarinic acid, eugenol, eugenyl acetate, clove bud extract, methanolic extract, tea catechins (e.g., epigallocatechin gallate, epicatechin gallate, epigallocatechin, or epicatechin) or any combination thereof.
  • tocopherols e.g., alpha tocopherol, beta tocophe
  • the APP compositions as provided herein may also include one or more additives.
  • Suitable additives include, but are not limited to, non-ionic, anionic or cationic polymers, preservatives, oils, pH regulators, waxes, fragrances, anti-fatting agents, sequestrating agents, perfumes, dyes, cationic surfactants, proteins, silicones, surfactants, organic solvents and any other additive conventionally used in the cosmetics or therapeutics field.
  • Other suitable additional additives include, but are not limited to, solid emollients, emulsifiers, surface active agents, gum, humectant, thickener, powder diluent, dispersant, or carrier so as to facilitate the distribution of the APP composition when applied.
  • the APP compositions as provided herein may also include one or more solvents.
  • Suitable solvents include glycerol, glycols or glycol ethers such as the monobutyl ether of ethyleneglycol, propyleneglycol, or the monoethylether or the monomethylether of diethyleneglycol or any combination thereof.
  • the solvents are both cosmetically acceptable as well as therapeutically acceptable for treatment of mucous membranes.
  • the APP compositions as provided herein may also include one or more carriers acceptable to mucosal tissues.
  • the carriers as provided herein do not cause significant irritation to the mucous membranes and do not abrogate the biological activity and properties of the applied active agent.
  • Specific carriers include, but are not limited to, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrosylates, liquid alkylated protein hydrosylates, liquid lanolin and lanolin derivatives, and other like materials.
  • Exemplary carriers include, but are not limited to, water, alcohols inclusive of both monohydric and polyhydric alcohols (e.g.
  • a suitable carrier includes both alcohol and water.
  • the APP compositions as provided herein may also include one or more antioxidants.
  • Suitable antioxidants comprise tocopherols (e.g., alpha tocopherol, beta tocopherol, gamma tocopherol, or delta tocopherol), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), lecithin, citric acid, ascorbic acid, phenolic diterpenes (e.g., carnosic acid, carnosol, rosmanol, epirosmanol, isorosmanol, or methyl carnosate), rosmarinic acid, eugenol, eugenyl acetate, clove bud extract, methanolic extract, tea catechins (e.g., epigallocatechin gallate, epicatechin gallate, epigallocatechin, or epicatechin) or any combination thereof.
  • tocopherols e.g., alpha tocopherol, beta tocophe
  • the APP compositions as provided herein may also include one or more vitamins. Suitable vitamins include ascorbic acid, citric acid, vitamin D, vitamin E, vitamin K, niacin, pantothenic acid, choline, inositol, folic acid or any combination thereof.
  • the APP compositions as provided herein may also include one or more nutraceuticals.
  • suitable nutraceuticals include, but are not limited to, amino acids, terpenoids (e.g., carotenoid terpenoids and non-carotenoid terpenoids), herbal supplements, homeopathic supplements, glandular supplements, polyphenolics, flavonoid polyphenolics, phenolic acids, curcumin, resveratrol, lignans, glucosinolates, isothiocyanates, indoles, thiosulfinates, phytosterols, anthraquinones, capsaicin, piperine, chlorophyll, betaine, oxalic acid, acetyl-L-carnitine, allantoin, androstenediol, androstendione, betaine (trimethylglycine), caffeine, calcium pyruvate (pyruvic acid), carnitine, carnosine, carotene, carotenoid,
  • APP compositions as provided herein may also include one or more suitable film forming agents.
  • suitable film forming agents include, but are not limited to, liquid or solid emollient, emulsifiers, surface active agents, gums, humectants, thickeners, powders, protein solutions or any combination thereof.
  • the APP compositions as provided herein may also include one or more emollients.
  • Suitable emollients include mineral oil, fatty alcohols, alkyl esters, natural waxes (carnauba wax, bees wax, jojoba wax, etc.), silicones, silicone derivatives or any combination thereof.
  • the APP compositions as provided herein may also include one or more preservatives. Suitable preservatives include sodium benzoate, ascorbic acid, parabens, bronopol, methylisothiazolinone and their combinations.
  • the anti-oxidant can be chosen, as an example, from amongst butylated hydroxytoluene (BHT), hydroxyanisole and tocopherol and their derivatives.
  • the chelating agent can be chosen, for example, from the group formed by ethylenediaminetetraacetic acid (EDTA), ethylene glycol bis (2-aminoethyl ether) tetraacetic acid (EGTA) and citric acid or their salts.
  • the APP compositions as provided herein may also include one or more pH regulator systems.
  • Suitable pH regulator systems can be chosen, as an example, from between a phosphate buffer solution, sodium hydroxide, citric acid, a citrate buffer solution, or any combination thereof.
  • the APP compositions as provided herein may also include one or more gelling agents.
  • Suitable gelling agents can be selected, for example, from amongst carbopols, poloxamers, carboxymethylcellulose (CMC), hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose (HPMC), methylcellulose (MC) or any combination thereof.
  • the APP compositions as provided herein may also include one or more excipients.
  • Suitable excipients include acidifying agents (acetic acid, glacial acetic acid, citric acid, fumaric acid, hydrochloric acid, diluted hydrochloric acid, malic acid, nitric acid, phosphoric acid, diluted phosphoric acid, sulfuric acid, tartaric acid); alkalizing agents (ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, trolamine); antifoaming agents (dimethicone, simethicone); antimicrobial preservatives (benzalkonium chloride, benzalkonium chloride solution, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol, dehydroace
  • the APP compositions as provided herein may include or be delivered in combination with one or more pharmacologically active agents or drugs suitable for administration according to the methods provided herein.
  • Suitable pharmacologically active agents or drugs include in all of the major therapeutic areas including, but not limited to, steroids (e.g., corticosteroids), anti inflammatory agents, anti-infectives such as antibiotics and antiviral agents, analgesics and analgesic combinations, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antiseptics, antimigraine preparations, antimotion sickness agents, antinauseants, diagnostics, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, psychostimulants, sedatives, tranquilizers, anesthetics, vitamins and combinations of the above.
  • steroids e.g., corticosteroids
  • anti inflammatory agents such as antibiotics and antiviral agents
  • the amount of the pharmacologically active agent is an effective amount defined as a non-toxic but sufficient amount of a compound to provide the desired local or systemic effect and performance at a reasonable benefit/risk ratio attending any medical treatment.
  • the APP compositions as provided herein may be formulated for topical mucous membrane administration. According to one embodiment, the APP compositions as provided herein may be formulated to be applied to any part of the body where one or more mucous membrane application is acceptable. According to a particular embodiment, the APP compositions as provided herein may be formulated as an aqueous emulsion.
  • the APP compositions as provided herein may be formulated as lotions, creams, ointments, foam, sprays, emulsions, microemulsions, adhesive patches, powders, oils, gels, a solid stick, salve, milk, paste or polish.
  • an APP composition as provided herein may be applied or administered to the target site at least once daily.
  • the APP composition as provided herein is applied or administered at least twice daily. The frequency of application or administration may depend on the severity of the condition of the target area but may be applied multiple times.
  • the APP compositions as provided herein may be delivered by a therapeutically acceptable vehicle.
  • the transmucosal delivery system (such as a mucoadhesive) as provided herein may include at least one reservoir to hold the APP composition until release.
  • the transmucosal patch as provided herein may include at least one membrane that aids in controlling the release of the APP composition from the reservoir.
  • the APP compositions as provided herein are suitable for various regenerative purposes on mucous membranes of a mammalian body. According to a particular embodiment, the APP compositions as provided herein may be utilized to treat mucous membranes. According to one embodiment, the APP compositions as provided herein may be utilized for the treatment of mucous membranes and various conditions associated with the mucous membranes. The APP compositions as provided herein can also be used to treat various wounds of mucous membranes. Suitable wound and conditions include, for example, burns, cuts, scrapes and ulcers. The APP compositions as provided herein can also be used for various therapeutic purposes including a condition associated with aging, smoking, poor hydration, and various other factors.
  • the APP compositions as provided herein may be utilized to treat other mucous membrane conditions that include, but are not limited to, damage from cancer cells (or treatmen thereof) and smoking.
  • the APP compositions as provided herein may be utilized to treat burns caused by solar radiation, external beam ionizing radiation, thermal or chemical where the chemical burn may dry the mucous membranes.
  • the APP composition penetrates any underlying epidermis to prevent or ameliorate mucositis.
  • the APP composition delivers one or more pharmacologically active agents or drugs as provided herein.
  • the mucous membranes subject to treatment have sustained damage associated with external beam ionizing radiation, thermal radiation, or any type of radiation associated with cancer treatment.
  • the APP compositions as provided herein may be utilized to treat a burn caused by radiation, thermal or chemical where the chemical burn may dry the mucous membranes resulting in a form of mucositis.
  • the APP compositions as provided herein may be utilized to lubricate or aid in the healing cascade for mucous membranes.
  • the mucous membranes may be located in the oral cavity (mouth, tongue, gums, throat), pharynx, larynx, bronchi, esophagus, gastrum, intestines, rectum, vagina, cervix, uterus, ano-rectal area mucosa, exposed mucosa of tracheostomy , gastrostomy, duodenostomy, jejunostomy, ileostomy, colostomy or other exposed mucous membrane sites and all associated canals or channels .
  • the APP composition is introduced directly to the mucous membranes in need of treatment via a formulation as provided herein such as, for example, a spray.
  • the APP composition is introduced to the mucous membranes in need of treatment via a therapeutically acceptable vehicle as provided herein.
  • the APP composition is introduced in a transmucosal manner.
  • a method of preparing an APP composition includes the steps of preparing an aqueous phase, preparing an oil phase, mixing the oil phase and aqueous phase to form an emulsion, and introducing at least one anionic phospholipid component.
  • the APP composition is formulated as a cream, salve or spray.
  • the method further includes the step of suspending the APP composition in an aerosol to form a spray formulation.
  • a method of preparing an APP composition does not include the application of heat (above 90°C) to a point of cooking the APP composition or any individual phases.
  • the anionic polar phospholipid is prepared separately in a separate aqueous phase (e.g., aqueous dispersion phase).
  • aqueous dispersion phase e.g., aqueous dispersion phase
  • Phospholipids when dispersed in aqueous solutions, may form a minimum of three distinct aggregated forms depending on the composition of the aqueous medium and the mechanical factors employed to create the dispersion phase.
  • the specific conditions used to obtain the desired dispersion properties (i.e., aggregate distributions) to obtain the desired APP composition properties has been determined.
  • the method of preparing the aqueous phase includes slowly heating the water to a temperature of from about 30°C to about 55°C with agitation. According to a particular embodiment, the water is slowly heated to a temperature of from about 40°C to about 45°C with agitation.
  • the step of preparing an aqueous phase includes the step of introducing at least one emulsion stabilizer/rheology modifier as provided herein (such as that commercially available as Carbopol® 934 cross-linked polyacrylic acid polymer) to the heated water and slowly heating the resulting composition to about 65°C to about 90°C with agitation.
  • the emulsion stabilizer/rheology modifier is added to the water and heated slowly to about 75°C to about 80°C with agitation.
  • the step of preparing an aqueous phase includes the step of further introducing an emulsifier as provided herein to the heated water.
  • the resulting composition is maintained at about 55°C to about 90°C with agitation.
  • the resulting composition is maintained at about 75°C to about 80°C with agitation.
  • the emulsifier may be a polyethylene glycol sorbitan monostearate (such as that commercially available as Tween® 60 polyethlyene glycol sorbitan monostearate).
  • components suitable for inclusion in the oil phase include, but are not limited to, any one or more thickening agent, emulsion stabilizer, emulsifier, viscosity modifier, antioxidant, emollient, neutraceutical, vitamin, or any combination thereof.
  • the components included in the oil phase include, but are not limited to, one or more of cetyl alcohol, beeswax, isopropyl palmitate, oleic acid (e.g., Emersol® 221), sorbitan stearate emulsifier (e.g., ArlacelTM 60), stearyl alcohol, stearic acid (e.g., Emersol® 132), glyceryl stearate (e.g., Emerest 2400), food shortening, at least one antioxidant such as BHT (butylated hydroxytoluene), vitamin E acetate, ascorbyl palmitate, at least one ester (e.g., CeraphylTM 424), or any combination thereof.
  • cetyl alcohol beeswax
  • isopropyl palmitate e.g., Emersol® 221
  • sorbitan stearate emulsifier e.g., ArlacelTM 60
  • the step of preparing an oil phase includes the step of mixing each of the individual oil phase components together in a single vessel.
  • the step of preparing an oil phase includes the step of heating the various oil phase components provided herein. Any triglyceride or triglyceride-based components present in the oil phase may melt upon application of heat.
  • the oil phase components may be heated to a temperature of from about 20°C to about 80°C.
  • the oil phase components may be heated to a temperature of from about 30°C to about 70°C.
  • the oil phase components may be heated to a temperature of from about 40°C to about 60°C.
  • the method includes the step of forming an emulsion.
  • the step of preparing an emulsion includes slowly adding the oil phase as provided herein to the aqueous phase as provided herein to form an emulsion.
  • the step of preparing an emulsion further includes the step of mixing the aqueous phase and oil phase for about 5 minutes to about 40 minutes at a temperature of from about 60°C to about 90°C.
  • the step of preparing an emulsion further includes the step of mixing the aqueous phase and oil phase for about 10 minutes to about 20 minutes at a temperature of from about 70°C to about 80°C.
  • the method includes the step of preparing a sodium hydroxide solution.
  • the sodium hydroxide solution has a concentration of typically from about 1% w/v to about 20% w/v. According to one embodiment, the sodium hydroxide solution is about 10% w/v.
  • the method includes the step of slowly adding the sodium hydroxide solution to the emulsion.
  • the resulting emulsion may then be heated from a temperature of from about 60°C to about 90°C for about 1 minute to about 20 minutes.
  • the resulting emulsion may then be heated from a temperature of from about 70°C to about 80°C for about 5 minutes to about 15 minutes.
  • the method includes the step of cooling the resulting emulsion to from about 30°C to about 60°C with slow agitation.
  • the method includes the step of cooling the resulting emulsion to from about 40°C to about 50°C with slow agitation.
  • the method includes the step of weighing the one or more phospholipids included in the phospholipid component and adding the one or more phospholipids to a mixing vessel at ambient temperature. Any anhydrous phospholipids may be weighed in a dry hood or under nitrogen to prevent hydration and obtain accurate weight.
  • the method further includes the step of mixing the one or more phospholipids as provided herein which form the phospholipid component with one or more preservatives and, optionally, one or more carriers.
  • the aforementioned method step includes the step of combining or mixing the phospholipid component as provided herein with disodium EDTA and, optionally, water.
  • the phospholipid component disperses into any water present upon mixing.
  • the resulting mixture is agitated or mixed for about 5 minutes to about 40 minutes.
  • the resulting mixture is agitated or mixed for about 10 minutes to about 20 minutes.
  • the method includes the step of adding the mixture to the emulsion at a temperature of from about 20°C to about 50°C to form an emulsion composition.
  • the method includes the step of adding the mixture to the emulsion at a temperature of from about 30°C to about 40°C.
  • the method includes the step of preparing a preservative/fragrance solution.
  • a preservative/fragrance solution To prepare the preservative/fragrance solution, one or more of an antioxidant, preservative, fragrance solution, or any combination thereof may be mixed together.
  • the resulting preservative/fragrance solution is mixed for about 5 minutes to about 60 minutes.
  • the resulting preservative/fragrance solution is mixed for about 10 minutes to about 40 minutes.
  • the resulting solution is mixed for about 30 minutes.
  • the preservative/fragrance solution is heated to about 25°C to about 39°C.
  • the preservative/fragrance solution is heated from about 30°C to about 35°C.
  • the method includes the step of adding an optional preservative/fragrance solution to the emulsion composition.
  • the resulting emulsion composition may be slowly cooled from about 10°C to about 45°C while mixing. According to a particular embodiment, the resulting emulsion composition may be slowly cooled from about 20°C to about 35°C while mixing.
  • the method includes the step of adding deionized water to the emulsion composition while mixing from about 10°C to about 45°C. According to a particular embodiment, the method includes the step of adding deionized water to the emulsion composition while mixing from about 20°C to about 35°C. According to one embodiment, the resulting emulsion composition is then left to stand for about 8 hours to about 16 hours.
  • the method includes the step of adding 0.1N sodium hydroxide or citric acid to the emulsion composition to adjust the pH to physiologic pH range.
  • the physiologic pH range is form about 9.0 to about 5.0.
  • the physiologic pH range is from about 7.5 to about 5.5.
  • the physiologic pH range is form about 6.9 to about 6.2.
  • the method includes the step of homogenizing the emulsion composition at a temperature of from about 10°C to about 45°C to form the composition.
  • the method of preparing a topical formulation includes the step of homogenizing the emulsion composition at a temperature of from about 20°C to about 35°C.
  • the APP compositions as provided herein may be applied to any part of the body where application is acceptable, including mucosal membranes.
  • the APP compositions may be applied to mucous membranes located in or on a vaginal mucosa, nasal mucosa, pharyngeal mucosa, respiratory mucosa, gastrointestinal mucosa, cervical mucosa, uterine mucosa, ano-rectal mucosa, or exposed mucosa of a tracheostomy, gastrostomy, duodenostomy, jejunostomy, ileostomy, or colostomy or any other exposed mucosa.
  • the topical formulations as provided herein encompass or may be made a part of a lotion, cream, ointment, foam, spray, emulsion, microemulsion, adhesive patch, oil, gel, a solid stick, salve, milk, paste or polish.
  • a formulation for application to mucous membranes was prepared.
  • the formulatoin included the components (in the noted amounts) set forth below in Table 1.
  • aqueous phase (Phase A - Table 1)
  • deionized water was added to a steam jacketed kettle with an agitator for scraping the walls of the kettle.
  • the water was slowly heated to a temperature of about 40°C to about 45°C with agitation.
  • An emulsion stabilizer (Carbopol® 934 cross-linked polyacrylic acid polymer) was added to the heated water and heated to about 75°C to about 80°C with agitation.
  • An emulsifier (Tween® 60 polyethylene glycol sorbitan monostearate) was then added to the mixture and maintained at about 75°C to about 80°C with agitation.
  • oleic acid e.g., Emersol® 221
  • sorbitan stearate emulsifier e.g., ArlacelTM 60
  • stearyl alcohol stearic acid
  • stearic acid e.g., EmersolTM 132
  • glyceryl stearate e.g.,
  • An emulsion was formed by mixing the aqueous phase and oil phase and mixed for about 10 minutes to about 20 minutes at a temperature of from about 70°C to about 80°C.
  • a 10% sodium hydroxide solution (Phase C - Table 1) was then added to the emulsion and heated from a temperature of from about 70°C to about 80°C for about 5 minutes to about 15 minutes.
  • the emulsion was then cooled down to about 40°C to about 50°C with slow agitation.
  • the phospholipid component was mixed with EDTA and further agitated or mixed for about 10 minutes to about 20 minutes (Phase D - Table 1). The resulting mixture was then added to and mixed with the emulsion at a temperature of from about 30°C to about 40°C to form an emulsion composition.
  • a preservative/fragrance solution was then prepared by mixing the components of Phase D of Table 1 for about 30 minutes and heating to about 30°C to about 35°C.
  • the preservative/fragrance solution was then added to the emulsion composition and slowly cooled from about 10°C to about 45°C while mixing.
  • Deionized water was then added to the emulsion composition while mixing at a temperature of from about 20°C to about 35°C.
  • the resulting emulsion composition was then left to stand for about 8 hours to about 16 hours.
  • a 0.1N sodium hydroxide and citric acid were then added, as needed, to adjust the pH of the emulsion composition to a physiologic range.
  • the emulsion was homogenized at a temperature of from about 20°C to about 35°C to form the formulation.
  • the anionic mole fraction of the total phospholipid component set forth in Table 1 included between from about 20 mole percent to about 100 mole percent of one or more net anionic phospholipid molecules as provided herein, with the balance of the remaining phospholipid component including one or more neutral zwitterionic phospholipids at physiologic pH values.
  • the aggregate of the phospholipid component possessed a net negative charge at physiologic pH.
  • the physiologic pH value was from about 9.0 to about 5.0.
  • EXAMPLE 2 A formulation for application to mucous membranes was prepared. The formulation included the components set forth below in Table 2. The formulation was prepared utilizing the same steps as set forth in Example 1. The formulation was found to have physical properties set forth in Table 3. TABLE 2
  • the anionic mole fraction of the total phospholipid component set forth in Table 2 included between from about 20 mole percent to about 100 mole percent of one or more net anionic phospholipid molecules, with the balance of the remaining phospholipid component including one or more neutral zwitterionic phospholipids at physiologic pH values.
  • the physiologic pH value was from about 9.0 to about 5.0.

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Abstract

Les formulations de phospholipide polaire anionique (APR) décrites dans l'invention pénètrent dans les membranes muqueuses et réparent et/ou remplissent le système compromis. En tant que telles, ces formulations améliorent les résultats de cicatrisation. L'invention concerne une composition de phospholipide polaire anionique qui comprend au moins un composant de phospholipide anionique et au moins un support. L'invention concerne également des procédés de préparation d'une telle composition et des procédés de traitement.
PCT/US2020/050659 2019-09-16 2020-09-14 Composition de phospholipide polaire anionique et procédés associés pour le traitement d'affections des muqueuses WO2021055273A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6335022B1 (en) * 1998-12-17 2002-01-01 L'oreal Nanoemulsion based on oxyethylenated or non-oxyethylenated sorbitan fatty esters, and its uses in the cosmetics, dermatological and/or ophthalmological fields
US20090306019A1 (en) * 2005-08-31 2009-12-10 Modus Biological Membranes Ltd. Compositions for treatment of eosinophilia and related disorders
JP2014088333A (ja) * 2012-10-29 2014-05-15 Univ Of Tokushima 口腔咽頭用組成物
US10028919B2 (en) * 2015-03-10 2018-07-24 Nanosphere Health Sciences, Llc Lipid nanoparticle compositions and methods as carriers of cannabinoids in standardized precision-metered dosage forms

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6335022B1 (en) * 1998-12-17 2002-01-01 L'oreal Nanoemulsion based on oxyethylenated or non-oxyethylenated sorbitan fatty esters, and its uses in the cosmetics, dermatological and/or ophthalmological fields
US20090306019A1 (en) * 2005-08-31 2009-12-10 Modus Biological Membranes Ltd. Compositions for treatment of eosinophilia and related disorders
JP2014088333A (ja) * 2012-10-29 2014-05-15 Univ Of Tokushima 口腔咽頭用組成物
US10028919B2 (en) * 2015-03-10 2018-07-24 Nanosphere Health Sciences, Llc Lipid nanoparticle compositions and methods as carriers of cannabinoids in standardized precision-metered dosage forms

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