WO2011094219A1 - Formulations vésiculaires - Google Patents

Formulations vésiculaires Download PDF

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Publication number
WO2011094219A1
WO2011094219A1 PCT/US2011/022439 US2011022439W WO2011094219A1 WO 2011094219 A1 WO2011094219 A1 WO 2011094219A1 US 2011022439 W US2011022439 W US 2011022439W WO 2011094219 A1 WO2011094219 A1 WO 2011094219A1
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WIPO (PCT)
Prior art keywords
edta
glycerol
buffer
ethanol
bht
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PCT/US2011/022439
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English (en)
Inventor
Hendrick-Andre Kroon
William Henry
Stephen Evans-Freke
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Hendrick-Andre Kroon
William Henry
Stephen Evans-Freke
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Publication of WO2011094219A1 publication Critical patent/WO2011094219A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/26—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests in coated particulate form
    • A01N25/28—Microcapsules or nanocapsules
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/30—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests characterised by the surfactants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes

Definitions

  • compositions and methods relating to formulations of phospholipids and surfactants relate to methods of using such formulations, including agricultural methods.
  • the three amphiphats include at least one membrane forming compound (MFC), which can form the membrane of [the aggregates], and at least two membrane destabilising compounds (MDCi and MDC 2 ) differentiated by their capability of forming smaller aggregates (with no extended surfaces) by either themselves or else in combination with each other and/or characterized by their relatively high solubility in [the] suitable liquid medium.
  • MFC membrane forming compound
  • MDCi and MDC 2 membrane destabilising compounds
  • the three amphiphats include at least one membrane forming compound (MFC), which can form the membrane of [the aggregates], and at least two membrane destabilising compounds (MDCi and MDC 2 ) differentiated by their capability of forming smaller aggregates (with no extended surfaces) by either themselves or else in combination with each other and/or characterized by their relatively high solubility in [the] suitable liquid medium.
  • compositions and methods related to vesicular formulations that include one or more phospholipids and one or more nonionic surfactants.
  • the formulations are effective for the delivery of fatty acids and/or
  • the vesicular formulations include about 25% to about 30% surfactant by weight based on the total weight of the vesicular formulation.
  • These vesicular formulations are suitable for any method of administration, e.g., subcutaneously, topically, or intravenously.
  • formulation refers to any composition as described herein, for example, a formulation that includes one or more phospholipids and one or more nonionic surfactants.
  • a formulation may include one or more active agents as described herein; in other embodiments a formulation may specifically not include any active agents, for example active agents as disclosed herein.
  • the formulation may include an active agent that is selected from the group consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, pesticide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, synergist, and/or the like.
  • an active agent that is selected from the group consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, pesticide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, synergist,
  • the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9. In some embodiments, a formulation includes ingredients or components as described herein, for example such as described in Table 8 A and Table 8B. In various embodiments, a formulation similar to or the same as the Example Formulations 1- 129; in some embodiments, the formulations are similar or the same as the Example
  • Formulations 1-129 except they further include at least one active agent such as described herein (for example the active agent may be present in the formulation in an amount as described herein).
  • the formulation is suitable for use in agriculture, for example it is suitable to apply to plants and crops intended for human consumption.
  • the formulation is suitable for administration to a human as a pharmaceutical compositon, for example it does meet criteria for administration to humans by one or more government agencies such as the United States FDA.
  • an active agent includes any agent that can exert one or more actions, for example an action which affects some sort of biological process.
  • an active agent may be a pharmaceutical agent or pharmaceutically active agent.
  • an active ingredient may be an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, pesticide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, synergist or the like.
  • an active agent may be an agent listed on Table 9.
  • the vesicular formulations may be formulated to deliver fatty acids and phosphatidyl derivatives of fatty acids, such as arachidonic acid or omega-3 or omega-6 fatty acids.
  • the vesicular formulations may optionally be formulated to include other lipids described herein, such as phophatidyl choline, and surfactants.
  • the vesicular formulations may deliver essential fatty acids, such as omega-3 fatty acids, to decrease the levels of triglycerides.
  • Vesicular formulations disclosed herein which deliver essential fatty acids, such as omega-3 fatty acids, may be useful in the treatment of fatty acid metabolic disorders, such as essential fatty acid deficiency and hypertriglyceridemia.
  • the vesicular formulations which deliver essential fatty acids include a phosphatidyl chlo line derivative of a fatty acid, e.g., a phosphatidylcholine derivative of an omega-3 fatty acid.
  • the vesicular formulation is one of the formulations set forth in Examples 1-129.
  • Fatty acid metabolic disorder means a defect in one of the enzymes involved in fatty acid metabolism, and include fatty oxidation disorders, whereby the body is unable to oxidize and metabolize fatty acids due to a failure in the enzymatic pathway.
  • Essential fatty acid deficiency means a deficiency in the essential fatty acids, e.g., omega-3 and omega-6 fatty acids, which can lead to physical symptoms such as hemorrhagic dermatitis skin atrophy, scaly dermatitis, dry skin, weakness, impaired vision, tingling sensations, mood swings, edema, high blood pressure, high triglycerides, hemorrhagic folliculitis, hemotologic disturbances, immune and mental deficiencies, and impaired growth.
  • essential fatty acids e.g., omega-3 and omega-6 fatty acids
  • the vesicular formulations maty deliver fats and fat soluble vitamins, such as vitamin E, for the treatment of disorders related to hypolididemia, including, abetalipoproteinemia,
  • the vesicular formulations which deliver fats and fat soluble vitamins include a phosphatidylchloline derivative of a fatty acid, e.g., a phosphatidylcholine derivative of vitamin E.
  • the vesicular formulation is one of the formulations set forth in Examples 1- 129.
  • compositions and methods encompassing vesicular formulations that include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering organic matter once delivered to the subject.
  • These vesicular formulations are suitable for any method of administration, e.g. , subcutaneously, topically, or intravenously. Without in any way being limited by theory, it is believed that the surprisingly effective and capacious sequestration of native organic compounds by the vesicular formulations disclosed herein occurs because of liquid crystallinity of the vesicular formulations mediated by the presence of membrane adapters such as surfactants.
  • the vesicular formulation is one of the formulations set forth in Examples 1- 129. In a preferred embodiment, the vesicular formulations include about 25% to about 30% surfactant by weight.
  • the vesicular formulations of lipids and surfactants are capable of sequestering native organic compounds, including arachidonic acid, upon delivery to human skin for the treatment of pain or inflammation.
  • these formulations are designed such that the vesicles are able to penetrate deep tissue without diversion into the blood vessels. That is, the formulations are able to travel to the site of the pain in sufficient amount to alleviate that pain to some extent.
  • delivery to the deep tissue includes delivery of the formulation beneath the skin to the muscle tissue and to the joint itself, while limiting systemic delivery and exposure to the formulation.
  • the vesicular formulation is capable of sequestering arachidonic acid upon administration to human skin, and therefore is capable of altering the pathology of, e.g., pain or inflammation.
  • vesicular formulations designed to sequester arachidonic acid may also be used to prevent the formation of metabolites, including eicosanoids, for the prevention and/or treatment of asthma, seborrheic eczema, bronchospasm, atherothrombatic cardiovascular disorders, venous thrombatic disorders, pain, and dysmenorrhea.
  • sequestering arachidonic acid is one of the formulations set forth in Examples 1-129.
  • vesicular formulations include one or more phospholipids and one or more nonionic surfactants can sequester cholesterol upon administration to human skin, thus decreasing the accumulation of or uptake of cholesterol for the treatment of hypercholesterolemia.
  • vesicular formulations include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering triglycerides, thus decreasing the accumulation or uptake of triglycerides for the treatment of hypertriglyceridemia.
  • the vesicular formulation capable of sequestering cholesterol or triglycerides is one of the formulations set forth in Examples 1- 129.
  • the vesicular formulations disclosed herein may also be used to sequester factors involved in fatty acid metabolism, such as hormone sensitive lipase (HSL). Inhibition of HSL inhibits the conversion of triglycerides to glycerol and fatty acids, resulting in a decrease in plasma free fatty acids.
  • HSL hormone sensitive lipase
  • the vesicular formualtions disclosed herein may have utility where the decrease in plasma fatty acids is desired, including insulin resistance, metabolic syndrome X, dyslipidemias and abnormal lipoprotein metabolism.
  • the vesicular formulation capable of sequestering factors involved in fatty acid metabolism is one of the formulations set forth in Examples 1-129.
  • the vesicular formulation capable of sequestering metals is one of the formulations set forth in Examples 1-129.
  • the vesicular formulation capable of sequestering toxins such as DDT is one of the formulations set forth in Examples 1-129.
  • formulations that include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering inflammatory mediators (e.g., cytokines, such as interleukins, or presenting antigens) upon administration to human skin for the treatment of inflammation and inflammatory related disorders, such as asthma.
  • sequestering inflammatory mediators e.g., cytokines, such as interleukins, or presenting antigens
  • the vesicular formulation capable of sequestering inflammatory mediators is one of the formulations set forth in Examples 1-129.
  • the vesicular formulation capable of sequestering amyloid is one of the formulations set forth in Examples 1-129.
  • the vesicular formulation capable of sequestering uric acid is one of the formulations set forth in Examples 1-129.
  • Provided herein are methods and compositions that relate to vesicular formulations that include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering squalene, thus leading to fungistatic activity against, e.g. , hyphal fungi.
  • vesicular formulations are suitable for any method of administration, e.g., subcutaneously, topically, or intravenously.
  • the vesicular formulation capable of sequestering squalene is one of the formulations set forth in Examples 1-129.
  • formulation is not necessarily meant to imply that the ingredients or components are in combination with a pharmaceutically active agent, i.e., any non-lipid non-surfactant active agent that has received regulatory approval for the treatment of fatty acid related disorders, hypocholesterolemia, hypertriclyceridemia, pain, including osteoarthritic pain, inflammation, infection, or toxicity, including metal toxicity or any of the disorders listed above.
  • a pharmaceutically active agent i.e., any non-lipid non-surfactant active agent that has received regulatory approval for the treatment of fatty acid related disorders, hypocholesterolemia, hypertriclyceridemia, pain, including osteoarthritic pain, inflammation, infection, or toxicity, including metal toxicity or any of the disorders listed above.
  • the vesicles elicit a therapeutic effect, namely the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any of the disorders listed above.
  • a therapeutic effect namely the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any of the disorders listed above.
  • Applicant believes that the vesicle components themselves are responsible for this effect.
  • a pharmaceutical package or kit includes one or more containers filled with a formulation disclosed herein, and instructions for administration of the formulation to a patient or subject in need thereof for the treatment of any disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and
  • the formulation includes one or more phospholipids and one or more surfactants.
  • the formulation does not include a pharmaceutically active agent, i.e., any nonlipid, non-surfactant pharmaceutically active agent that has received marketing or regulatory approval in any country for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia, pain, including osteoarthritic pain, inflammation, infection, including fungal or bacterial infection, or toxicity, including metal toxicity, or any of the other disorders listed above.
  • the container includes a formulation formulated as a suspension, emulsion, gel, cream, lotion, spray, film forming solution or lacquer.
  • packages or kits that can be used in any of the above-described methods.
  • methods for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia, or any of the disorders listed above wherein the vesicular formulations are administered over a period of one or more weeks, for example for at least five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, sixteen weeks, twenty four weeks, four months, six months, eight months, ten months, one year, two or more years, or indefinitely.
  • the formulations include one or more phospholipids, one or more nonionic surfactants, in the absence of any pharmaceutically active agent, i.e., any nonlipid non-surfactant pharmaceutically active agent that has received regulatory approval for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism,
  • hypertriglyceridemia hypercholesterolemia pain, including osteoarthritic pain, inflammation, infection, including fungal or bacterial infection, or toxicity, including metal toxicity, or any of the disorders listed above.
  • a 0.1 to 10 gram dose of the formulation is administered to the patient for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any of the disorders listed above;
  • a 1 to 10 gram dose of the formulation is administered to the patient for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia, or any of the disorders listed above;
  • a 1 to 5 gram dose of the formulation is administered to the patient for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia, pain, including osteoarthritic pain, inflammation, infection, including fungal or bacterial infection, or toxicity, including metal toxicity, or any of the disorders listed above; or a 1 gram, 2 gram, 3 gram, 4 gram, 5 gram, 6 gram, 7 gram, 8 gram, 9 gram or 10 gram dose of the formulation is administered to the patient
  • the dose is measured as the total weight of the deformasome. In some embodiments, the dose is measured as the total weight of the lipid(s) and surfactant(s) in the deformasome.
  • the dose may be administered once or twice daily for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any of the disorders listed above.
  • the dose may be administered once, twice, three, four, five, six, or seven times per week in accordance with the compositions and methods disclosed herein.
  • the dose may be administered every day, every other day, or two to three times a week in accordance with the compositions and methods disclosed herein.
  • the lipid in the pharmaceutical composition is a phospholipid.
  • the second lipid is a lysophospholipid.
  • the surfactant is a non-ionic surfactant.
  • the compositions form vesicles or other extended surface aggregates (ESAs), wherein the vesicular preparations have improved permeation capability through the semi-permeable barriers, such as skin.
  • ESAs extended surface aggregates
  • the adapatability and deformability of the vesicles allow the vesicles to penetrate beneath the skin to the muscle and the joint itself, however, the size of the vesicle prevents penetration into the vasculature and as a result prevents systemic delivery.
  • the formulations are able to form vesicles characterized by their deformability and/or
  • the adaptability or deformability of the vesicles may be determined by the ability of the vesicles to penetrate a barrier with pores having an average pore diameter at least 50% smaller than the average vesicle diameter before the penetration.
  • the vesicular compositions provide for targeted delivery of e.g., fatty acids to phospholipase-rich sites, e.g., tissues that are part of an inflammatory process or sites containing microorganisms such as bacteria (including narcadia) or fungi. While not to be limited to any mechanism of action or by any theory, the vesicular compositions disclosed herein are broken down by phospholipases.
  • phospholipases that are released as part of the inflammatory process ⁇ e.g., cancer or asthma) or that are released upon contact with a microorganism such as bacteria or fungi can lead to a number of effects including but not limited to rapid entry of the vesicular compositions into the target tissue, changes in the intracellular or intramembraneous lipid homeostasis, which may lead to increased apoptosis or altered membrance function, including increased permeability, and rapid metabolism of the vesicular composition with release of its consituents.
  • a method that includes administering a formulation as described herein to a plant, seed or soil.
  • the formulation is effective as one or more selected from the group consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, pesticide, plant activator, and synergist.
  • the formulation includes an active agent that is selected from the group consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, and synergist.
  • the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9.
  • a method for controlling weeds, pests, insects, diseases in or on a plant, a field of plants or a crop that includes administering a formulation as described herein to the plant, field of plants or crop.
  • a method of administering a vesicular formulation directly to the surface of a leaf includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9. In a particular embodiment, the formulation includes terbinafme or an agriculturally acceptable salt thereof. In a particular embodiment, administration of the formulation directly to the surface of a leaf results in an antifungal effect.
  • provided herein is a method of administering a vesicular formulation directly to the ground surrounding certain plants or weeds.
  • the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9. In a particular embodiment, the formulation includes terbinafme or an agriculturally acceptable salt thereof. In a particular embodiment, administration of the formulation directly to the ground surrounding certain plants or weeds results in an antifungal effect at the plants or weeds.
  • a method of exposing an insect to a vesicular formulation by applying the vesicular formulation to a plant or plant leaf.
  • the vesicular formulation is absorbed by the leaf and introduced into the insect upon ingestion of the leaf by the insect.
  • the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9. In a particular embodiment, the formulation includes one or more insecticides.
  • the term "plant” refers to a plant as well as any part of a plant or plant product, including but not limited to, plant tissue, a leaf, a leaf primordial, a stem, a flower, a fruit, a root, a root hair, a protoplast, a germ plasm, a stamen, an anther, a filament, a petal, a pistel, a bud, a node, an internode, a shoot, a shoot apex, an apical meristem, a seed, a trunk, and the like.
  • the term "plant” also includes multiple plants, for example a field of plants or a crop.
  • plants as disclosed herein can be of any species of dicotyledonous, monocotyledonous or gymnospermous plant, including any woody plant species that grows as a tree or shrub, any herbaceous species, or any species that produces edible fruits, seeds or vegetables, or any species that produces colorful or aromatic flowers.
  • the plant may be selected from a species of plant from the group consisting of Alfalfa; Almond; Anise (fennel); Anona; Apple; Apricot; Aquatic Weeds; Artichoke;
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, pig, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • cow, sheep, goat, pig, horse, dog, cat, rabbit, rat, or mouse e.g., cow, sheep, goat, pig, horse, dog, cat, rabbit, rat, or mouse.
  • subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • the term subject can refer to a plant, seed or soil.
  • a "sufficient amount,” “amount effective to” or an “amount sufficient to” achieve a particular result refers to an amount of the formulation disclosed herein is effective to produce a desired effect, which is optionally a therapeutic effect (i.e., by administration of a therapeutically effective amount).
  • a “therapeutically effective” amount is an amount that provides some alleviation, mitigation, and/or decrease in at least one clinical symptom.
  • Clinical symptoms associated with the disorder that can be treated by the methods disclosed herein are well-known to those skilled in the art. Further, those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.
  • a "sufficient amount” or “an amount sufficient to” can be an amount that is effective to treat the symptoms of fatty acid deficiencies, hypertriglyceridemia or hypercholesterolemia or other joint or muscle pain.
  • the terms “treat”, “treating” or “treatment of mean that the severity of a subject's condition is reduced or at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom is achieved and/or there is an inhibition or delay in the progression of the condition and/or delay in the progression of the onset of disease or illness.
  • the terms “treat”, “treating” or “treatment of” mean that the severity of a subject's condition is reduced or at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom is achieved and/or there is an inhibition or delay in the progression of the condition and/or delay in the progression of the onset of disease or illness.
  • treatment of also means managing the disease state.
  • such level will be sufficiently low to provide a formulation suitable for approval by regulatory authorities.
  • the term “about” means a range surrounding a particular numeral value which includes that which would be expected to result from normal experimental error in making a measurement.
  • the term “about” when used in connection with a particular numerical value means ⁇ 20%, unless specifically stated to be ⁇ 1%, ⁇ 2%, ⁇ 3%, ⁇ 4%, ⁇ 5%, ⁇ 10%, ⁇ 15%, or ⁇ 20% of the numerical value.
  • the term “about” is used herein in conjunction with a quantitative term it is understood that in addition to the value plus or minus percentage, the exact value of the quantitative term is also contemplated and described.
  • the term “about 3%” expressly contemplates, describes and includes exactly 3%.
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl may optionally be substituted with one or more substituents Q as described herein.
  • alkyl also encompasses both linear and branched alkyl, unless otherwise specified.
  • the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) carbon atoms, or a branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 12 (C3-12), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.
  • linear Ci_ 6 and branched C 3 _6 alkyl groups are also referred as "lower alkyl.”
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).
  • Ci_ 6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • aryl refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C 6 - 2 o), from 6 to 15 (C 6-15 ), or from 6 to 10 (C 6 -io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
  • aryl may also be optionally substituted with one or more substituents Q as described herein.
  • heteroaryl refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N.
  • Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
  • Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl,
  • benzimidazolyl benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl.
  • tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl.
  • heteroaryl may also be optionally substituted with one or more substituents Z as described herein.
  • alkenoyl refers to -C(0)-alkenyl.
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds. The alkenyl may be optionally substituted with one or more substituents Z as described herein.
  • alkenyl also embraces radicals having "cis” and “trans” configurations, or alternatively, “Z” and “E” configurations, as appreciated by those of ordinary skill in the art.
  • alkenyl encompasses both linear and branched alkenyl, unless otherwise specified.
  • C 2 _6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenyl is a linear monovalent hydrocarbon radical of 2 to 30 (C 2 _3o), 2 to 24 (C 2 _ 24 ), 2 to 20 (C 2 _ 20 ), 2 to 15 (C 2 _i 5 ), 2 to 12 (C2-12), to 10 (C2-10), or 2 to 6 (C 2 -6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 30 (C3_3o), 3 to 24 (C 3 _ 24 ), 3 to 20 (C 3 _2o), 3 to 15 (C 3 _ 15 ), 3 to 12 (C 3 _ 12 ), 3 to 10 (C 3 _ 10 ), or 3 to 6 (C 3 _ 6 ) carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, propen-1- yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.
  • the alkenoyl is mono-alkenoyl, which contains one carbon-carbon double bond.
  • the alkenoyl is di-alkenoyl, which contains two carbon-carbon double bonds.
  • the alkenoyl is poly-alkenoyl, which contains more than two carbon-carbon double bonds.
  • heterocyclyl refers to a monocyclic non-aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms.
  • the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclic radicals include, but are not limited to, acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzoisoxazolyl, benzisoxazinyl, benzodioxanyl, benzodioxolyl,
  • benzofuranonyl benzofuranyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl,
  • phenanthridinyl phenathrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, tetrazol
  • halogen refers to fluorine, chlorine, bromine, and/or iodine.
  • the term "optionally substituted” is intended to mean that a group, including alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl, may be substituted with one or more substituents Z, in one embodiment, one, two, three or four substituents Z, where each Z is independently selected from the group consisting of cyano, halo, oxo, nitro, Ci_ 6 alkyl, halo-Ci_6 alkyl, C 2 -6 alkenyl, C 2 _ 6 alkynyl, C3-7 cycloalkyl, C 6-14 aryl, C7-14 aralkyl, heteroaryl, heterocyclyl, -C(0)R e , -C(0)OR e , -C(0)NR f R g , - C(NR e )NR f R g , -OR e , -OC(0)R
  • solvate refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non- covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. [0052] In accordance with this disclosure, the term “comprising” is inclusive or open- ended and does not exclude additional, unrecited elements or method steps; the term
  • the formulation provided herein includes at least one lipid, preferably a phospholipid, at least one surfactant, preferably a nonionic surfactant, optionally suspended in a pharmaceutically acceptable medium, preferably an aqueous solution, preferably having a pH ranging from 3.5 to 9.0, preferably from 4 to 7.5.
  • the formulations disclosed herein may optionally contain buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and/or thickeners.
  • the formulations disclosed herein include a mixture of more than one lipid, preferably more than one phospholipids.
  • the formulations disclosed herein consists essentially of at least one lipid, preferably a phospholipid, at least one surfactant, preferably a nonionic surfactant, a pharmaceutically acceptable carrier, and optionally buffers,
  • the formulations disclosed herein include least one lipid, preferably a phospholipid, at least one surfactant, preferably a nonionic surfactant, a pharmaceutically acceptable carrier, and one or more of the following: buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and thickeners.
  • lipid is any substance, which has properties like or similar to those of a fat. As a rule, it has an extended apolar group (the “chain”, X) and generally also a water-soluble, polar hydrophilic part, the “head” group (Y) and has the basic Formula II:
  • n is equal to or larger than zero.
  • all amphiphilic substances including, but not limited to glycerides, glycerophospholipids, glycerophosphinolipids, glycerophosphonolipids, sulfolipids, sphingolipids, isoprenoid lipids, steroids or sterols and carbohydrate-containing lipids can generally be referred to as lipids, and are included as such in this disclosure.
  • a list of relevant lipids and lipid related definitions is provided in EP 0 475 160 Al (see, e.g. p. 4, 1. 8 to p. 6, 1. 3) and U.S. Patent No. 6,165,500 (see, e.g., col. 6, 1. 10 to col. 7, 1. 58), each incorporated herein by reference in their entirety.
  • a phospholipid is, for example, a compound of Formula II:
  • R 1 CH 2 — CHR 2 — CR 3 H— O— PH0 2 — O— R 4 (II) wherein R 1 and R 2 cannot both be hydrogen, OH or a C1-C3 alkyl group, and typically are independently, an aliphatic chain, most often derived from a fatty acid or a fatty alcohol; R generally is a hydrogen.
  • the OH-group of the phosphate is a hydroxyl radical or hydroxyl anion (i.e., hydroxide) form, dependent on degree of the group ionization.
  • R 4 may be a proton or a short-chain alkyl group, substituted by a tri-short-chain alkylammonium group, such as a trimethylammonium group, or an amino-substituted short-chain alkyl group, such as 2-trimethylammonium ethyl group (cholinyl) or 2-dimethylammonium short alkyl group.
  • a sphingophospho lipid is, for example, a compound of Formula IIB:
  • R 1 is a fatty-acid attached via an amide bond to the nitrogen of the sphingosine and R 4 has the meanings given under Formula II.
  • a lipid preferably is a substance of formulae II or IIB, wherein R and/or R are acyl or alkyl, n-hydroxyacyl or n-hydroxyalkyl, but may also be branched, with one or more methyl groups attached at almost any point of the chain; usually, the methyl group is near the
  • R and R may moreover either be saturated or unsaturated (mono-, di- or poly-unsaturated).
  • R 3 is hydrogen and R 4 is 2-trimethylammonium ethyl (the latter corresponds to the phosphatidyl choline head group), 2-dimethylammonium ethyl, 2-methylammonium ethyl or 2-aminoethyl (corresponding to the phosphatidyl ethanolamine head group).
  • R 4 may also be a proton (giving phosphatidic acid), a serine (giving phosphatidylserine), a glycerol (giving phosphatidylglycerol), an inositol (giving phosphatidylinositol), or an alkylamine group (giving phosphatidylethanolamine in case of an ethylamine), if one chooses to use a naturally occurring glycerophospholipid. Otherwise, any other sufficiently polar phosphate ester, such that will form a lipid bilayer, may be considered as well for making the formulations of the disclosure.
  • Table 1 lists preferred phospholipids in accordance with the disclosure. Table 1
  • Total Lipid * concentration range (w-%) 0.5-45 0.5-45 0.5-40 0.5-40 0.5-40 0.5-40
  • Total Lipid includes phospholipid (s), surfactant (s)t and all lipophilic excipients
  • the preferred lipids in context of this disclosure are uncharged and form stable, well hydrated bilayers; phosphatidylcholines, phosphatidylethanolamine, and sphingomyelins are the most prominent representatives of such lipids. Any of those can have chains as listed in the Table 1, the ones forming fluid phase bilayers, in which lipid chains are in disordered state, being preferred.
  • Different negatively charged, i.e., anionic, lipids can also be incorporated into vesicular lipid bilayers.
  • Attractive examples of such charged lipids are phosphatidylglycerols, phosphatidylinositols and, somewhat less preferred, phosphatidic acid (and its alkyl ester) or phosphatidylserine. It will be realized by anyone skilled in the art that it is less commendable to make vesicles just from the charged lipids than to use them in a combination with electro- neutral bilayer component(s).
  • the charged bilayer lipid components can in principle have any of the chains listed in the Table 1.
  • the chains forming fluid phase lipid bilayers are clearly preferred, however, both due to vesicle adaptability increasing role of increasing fatty chain fluidity and due to better ability of lipids in fluid phase to mix with each other.
  • the fatty acid- or fatty alcohol-derived chain of a lipid is typically selected amongst the basic aliphatic chain types given in the following tables:
  • Suitable fatty residues can furthermore be branched, for example, can contain a methyl group in an iso or anteiso position of the fatty acid chain, or else closer to the chain middle, as in 10-i?-methyloctadecanoic acid or tuberculostearic chain.
  • Relatively important amongst branched fatty acids are also isoprenoids, many of which are derived from 3,7,1 l,15-tetramethylhexadec-trans-2-en-l-ol, the aliphatic alcohol moiety of chlorophyll.
  • Examples include 5,9,13,17-tetramethyloctadecanoic acid and especially 3,7,11,15- tetramethylhexadecanoic (phytanic) and 2,6,10,14-tetramethylpentadecanoic (pristanic) acids.
  • a good source of 4,8,12-trimethyltridecanoic acid are marine organisms. Combination of double bonds and side chains on a fatty residue are also possible.
  • suitable fatty residues may carry one or a few oxy- or cyclic groups, especially in the middle or towards the end of a chain.
  • alicyclic fatty acids are those that include a cyclopropane (and sometimes
  • 2-(D)-Hydroxy fatty acids are more ubiquitous than alicyclic fatty acids, and are also important constituents of sphingolipids. Also interesting are 15-hydroxy-hexadecanoic and 17-hydroxy-octadecanoic acids, and maybe 9-hydroxy- octadeca-tra/?s-10,tra/?s-12-dienoic (dimorphecolic) and 13-hydroxy-octadeca-czs-9,zra/?s-l 1- dienoic (coriolic) acid.
  • hydroxyl-fatty acid Arguably the most prominent hydroxyl-fatty acid in current pharmaceutical use is ricinoleic acid, (D-(-)12-hydroxy-octadec-cz ' s-9-enoic acid, which includes up to 90% of castor oil, which is also often used in hydrogenated form.
  • Epoxy-, methoxy-, and furanoid-fatty acids are of only limited practical interest in the context of this disclosure.
  • unsaturation, branching or any other kind of derivatization of a fatty acid is best compatible with the intention of present disclosure of the site of such modification is in the middle or terminal part of a fatty acid chain.
  • the cz ' s -unsaturated fatty acids are also more preferable than trans -unsaturated fatty acids and the fatty radicals with fewer double bonds are preferred over those with multiple double bonds, due to oxidation sensitivity of the latter.
  • symmetric chain lipids are generally better suited than asymmetric chain lipids.
  • a preferred lipid of the Formula II is, for example, a natural phosphatidylcholine, which used to be called lecithin. It can be obtained from egg (rich in palmitic, Ci6:o, and oleic, Ci8:i, but also including stearic,Ci8 : o, palmitoleic, Ci6:i, linolenic, C 18:2 , and
  • soybean rich in unsaturated Cig chains, but also containing some palmitic radical, amongst a few others
  • coconut rich in saturated chains
  • olives rich in monounsaturated chains
  • saffron safflower
  • sunflowers rich in n-6 linoleic acid
  • linseed rich in n-3 linolenic acid
  • whale fat rich in monounsaturated n-3 chains
  • primrose or chemo
  • sphingomyelins of biological origin are typically prepared from eggs or brain tissue.
  • phosphatidylserines also typically originate from brain material whereas phosphatidylglycerol is preferentially extracted from bacteria, such as E. Coli, or else prepared by way of transphosphatidylation, using phospholipase D, starting with a natural phosphatidylcholine.
  • bacteria such as E. Coli
  • phospholipase D phospholipase D
  • the preferred phosphatidic acid is either extracted from any of the mentioned sources or prepared using phospholipase D from a suitable phosphatidylcholine.
  • R and R are aliphatic chains, as defined in the preceding paragraph with 12 to 30 carbon atoms, preferentially with 14 to 22 carbon atoms, and even more preferred with 16 to 20 carbon atoms, under the proviso that the chains must be chosen so as to ensure that the resulting ESAs include fluid lipid bilayers. This typically means use of relatively short saturated and of relatively longer unsaturated chains.
  • R 4 in Formula IIB corresponds to 2-trimethylammonium ethyl
  • R 1 is an aliphatic chain, as defined in the preceding paragraph, with 10 to 20 carbon atoms, preferentially with 10 to 14 carbon atoms per fully saturated chain and with 16-20 carbon atoms per unsaturated chain.
  • Synthetic phosphatidyl ethanolamines (R 4 is 2-aminoethyl), synthetic phosphatidic acids (R 4 is a proton) or its ester (R 4 corresponds, for example, to a short-chain alkyl, such as methyl or ethyl), synthetic phosphatidyl serines (R 4 is L- or D-serine), or synthetic
  • phosphatidyl (poly)alcohols such as phosphatidyl inositol, phosphatidyl glycerol (R 4 is L- or
  • D-glycerol are preferred as lipids, wherein R and R are fatty residues of identical or moderately different type and length, especially such as given in the corresponding tables given before in the text.
  • R 1 can represent alkenyl and R 2 identical hydroxyalkyl groups, such as tetradecylhydroxy or hexadecylhydroxy, for example, in ditetradecyl or
  • R 1 2 dihexadecylphosphatidyl choline or ethanolamine, R can represent alkenyl and R
  • hydroxyacyl such as a plasmalogen (R 4 trimethylammonium ethyl), or R 1 can be acyl, such as lauryl, myristoyl or palmitoyl and R can represent hydroxy as, for example, in natural or synthetic lysophosphatidyl cholines or lysophosphatidyl glycerols or lysophosphatidyl ethanolamines, such as 1 -myristoyl or 1-palmitoyllysophosphatidyl choline or -phosphatidyl ethanolamine; frequently, R represents hydrogen.
  • a lipid of Formula IIB is also a suitable lipid within the sense of this disclosure.
  • n l
  • R 1 is an alkenyl group
  • R 2 is an acylamido group
  • R 3 is hydrogen
  • R 4 represents 2-trimethylammonium ethyl (choline group).
  • a lipid is known under the name of sphingomyelin.
  • Suitable lipids furthermore are a lysophosphatidyl choline analog, such as 1- lauroyl-l,3-dihydroxypropane-3-phosphoryl choline, a monoglyceride, such as monoolein or monomyristin, a cerebroside, ceramide polyhexoside, sulfatide, sphingoplasmalogen, a ganglioside or a glyceride, which does not contain a free or esterified phosphoryl or phosphono or phosphino group in the 3 position.
  • a lysophosphatidyl choline analog such as 1- lauroyl-l,3-dihydroxypropane-3-phosphoryl choline
  • a monoglyceride such as monoolein or monomyristin
  • a cerebroside such as monoolein or monomyristin
  • ceramide polyhexoside such as monoolein or monomyristin
  • sulfatide
  • a glyceride is diacylglyceride or 1 -alkenyl- l-hydroxy-2-acyl glyceride with any acyl or alkenyl groups, wherein the 3 -hydroxy group is etherified by one of the carbohydrate groups named, for example, by a galactosyl group such as a monogalactosyl glycerin.
  • Lipids with desirable head or chain group properties can also be formed by biochemical means, for example, by means of phospholipases (such as phospholilpase Al, A2, B, C and, in particular, D), desaturases, elongases, acyl transferases, etc., from natural or synthetic precursors.
  • phospholipases such as phospholilpase Al, A2, B, C and, in particular, D
  • desaturases elongases
  • acyl transferases etc.
  • a suitable lipid is any lipid, which is contained in biological membranes and can be extracted with the help of apolar organic solvents, such as chloroform.
  • lipids also include, for example, steroids, such as estradiol, or sterols, such as cholesterol, beta-sitosterol, desmosterol, 7-keto-cholesterol or beta-cholestanol, fat-soluble vitamins, such as retinoids, vitamins, such as vitamin Al or A2, vitamin E, vitamin K, such as vitamin Kl or K2 or vitamin Dl or D3, etc.
  • the less soluble amphiphilic components include or preferably include a synthetic lipid, such as myristoleoyl, palmitoleoyl, petroselinyl, petroselaidyl, oleoyl, elaidyl, cis- or trans-vaccenoyl, linolyl, linolenyl, linolaidyl, octadecatetraenoyl, gondoyl, eicosaenoyl, eicosadienoyl, eicosatrienoyl, arachidoyl, cis- or trans-docosaenoyl, docosadienoyl, docosatrienoyl, docosatetraenoyl, lauroyl, tridecanoyl, myristoyl, pentadecanoyl, palmitoyl, heptadecanoyl, stea
  • the more soluble amphiphilic components(s) is/are frequently derived from the less soluble components listed above and, to increase the solubility, substituted and/or complexed and/or associated with a butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl or undecanoyl substituent or several, mutually independent, selected substituents or with a different material for improving the solubility.
  • a further suitable lipid is a diacyl- or dialkyl-glycerophosphoetha- nolamine azo polyethoxylene derivative, a didecanoylphosphatidyl choline or a
  • the amount of lipid in the formulation is from about 1% to about 12%, about 1% to about 10%>, about 1% to about 4%, about 4% to about 7% or about 7%) to about 10%) by weight.
  • the lipid is a phospholipid.
  • the phospholipid is a phosphatidylcholine.
  • the lipid in the formulation does not include an alkyl- lysophospholipid. In some embodiments, the lipid in the formulation does not include a polyeneylphosphatidylcholine .
  • surfactant has its usual meaning.
  • a list of relevant surfactants and surfactant related definitions is provided in EP 0 475 160 Al (see, e.g., p. 6, 1. 5 to p.14. 1.17)and U.S. Pat. No. 6,165,500 (see, e.g., col. 7, 1. 60 to col. 19, 1. 64), each herein incorporated by reference in their entirety, and in appropriate surfactant or pharmaceutical Handbooks, such as Handbook of Industrial Surfactants or US Pharmacopoeia, Pharm. Eu.
  • the surfactants are those described in Tables 1-18 of U.S. Patent Application Publication No.
  • Preferred surfactants to be used in accordance with the disclosure include those with an HLB greater than 12.
  • the list includes ionized long-chain fatty acids or long chain fatty alcohols, long chain fatty ammonium salts, such as alkyl- or alkenoyl-trimethyl-, -dimethyl- and - methyl-ammonium salts, alkyl- or alkenoyl-sulphate salts, long fatty chain dimethyl- aminoxides, such as alkyl- or alkenoyl-dimethyl-aminoxides, long fatty chain, for example alkanoyl, dimethyl-aminoxides and especially dodecyl dimethyl-aminoxide, long fatty chain, for example alkyl-N-methylglucamide- s and alkanoyl-N-methylglucamides, such as MEGA- 8, MEGA-9 and MEGA- 10, N-long fatty chain-N,N-dimethylglycines, for example N-alkyl-
  • polyethylen-glycol- acylphenyl ethers especially nonaethylen-glycol-octyl- phenyl ether, polyethylene-long fatty chain-ethers, especially polyethylene-acyl ethers, such as nonaethylen-decyl ether, nonaethylen-dodecyl ether or octaethylene-dodecyl ether, polyethyleneglycol-isoacyl ethers, such as octaethyleneglycol-isotridecyl ether, polyethyleneglycol-sorbitane-long fatty chain esters, for example polyethyleneglycol-sorbitane-acyl esters and especially polyoxyethylene- monolaurate (e.g.
  • polysorbate 20 or Tween 20 polyoxyethylene-sorbitan-monooleate (e.g. polysorbate 80 or Tween 80), polyoxyethylene-sorbitan-monolauroleylate, polyoxyethylene - sorbitan-monopetroselinate, polyoxyethylene -sorbitan— monoelaidate, polyoxyethylene - sorbitan-myristoleylate, polyoxyethylene -sorbitan-palmitoleinylate, polyoxyethylene- sorbitan-p- etroselinylate, polyhydroxyethylene-long fatty chain ethers, for example polyhydroxyethylene-acyl ethers, such as polyhydroxyethylene-lauryl ethers,
  • polyhydroxyethylene-myristoyl ethers polyhydroxyethylene-cetylst- earyl, polyhyd roxyethylene-palmityl ethers, polyhyd roxyethylene-oleoyl ethers, polyhydroxyethylene- palmitoleoyl ethers, polyhydroxyethylene-lino- leyl, polyhydroxyethylen-4, or 6, or 8, or 10, or 12-lauryl, miristoyl, palmitoyl, palmitoleyl, oleoyl or linoeyl ethers (Brij series), or in the corresponding esters, polyhydroxyethylen-laurate, -myristate, -palmitate, -stearate or -oleate, especially polyhydroxyethylen-8 -stearate (Myrj 45) and polyhydroxyethylen-8-oleate, polyethoxylated castor oil 40 (Cremophor EL), sorbitane-mono
  • lysophospholipids n-octadecylene-glycerophosphatidic acid, octadecylene- phosphorylglycerol, octadecylene-phosphorylserine, n-long fatty chain-glycero-phosphatidic acids, such as n-acyl-glycero-phosphatidic acids, especially lauryl glycero-phosphatidic acids, oleoyl-glycero-phosphatidic acid, n-long fatty chain-phosphorylglycerol, such as n- acyl-phosphorylglycerol, especially lauryl-, myristoyl-, oleoyl- or palmitoeloyl- phosphorylglycerol, n-long fatty chain-phosphorylserine, such as n-acyl-phosphorylserine, especially lauryl-, myristoyl-, oleoyl- or palmitoeloyl
  • Surfactant chains are typically chosen to be in a fluid state or at least to be compatible with the maintenance of fluid-chain state in carrier aggregates.
  • Table 5 lists preferred surfactants in accordance with the disclosure.
  • Myrj-45 Stearoyl-E08; Myrj-49: Stearoyl-EO20 (not in the market); Myrj-59: Stearoyl- EO100; Myrj-52: Stearoyl-EO40;
  • Simulsol-2599 Macrogol-10-oleate
  • the surfactant is a nonionic surfactant.
  • the surfactant may be present in the formulation in about 1% to about 10%, about 1% to about 4%, about 4% to about 7% or about 7% to about 10% by weight.
  • the amount of surfactants in the formulation is from about 0.2% to about 0.5%.
  • the nonionic surfactant is selected from the group consisting of: polyoxyethylene sorbitans (polysobate surfactants), polyhydroxyethylene stearates or polyhydroxyethylene laurylethers (Brij surfactants).
  • the surfactant is a polyoxyethylene-sorbitan- monooleate (e.g.
  • polysorbate 80 or Tween 80 can have any chain with 12 to 20 carbon atoms.
  • the polysorbate is fluid in the formulation, which may contain one or more double bonds, branching, or cyclo-groups.
  • the formulations include only one lipid and only one surfactant. In other embodiments, the formulations include more than one lipid and only one surfactant, e.g., two, three, four, or more lipids and one surfactant. In other embodiments, the formulations include only one lipid and more than one surfactant, e.g., two, three, four, or more surfactants and one lipid. In other embodiments, the formulations include more than one lipid and more than one surfactant, e.g., two, three, four, or more lipids and two, three, four, or more surfactants.
  • the formulations disclosed herein may have a range of lipid to surfactant ratios.
  • the ratios may be expressed in terms of molar terms (mol lipid /mol surfactant).
  • the molar ratio of lipid to surfactant in the formulations may be from about 1 :3 to about 30: 1, from about 1 :2 to about 30: 1, from about 1 : 1 to about 30:1, from about 5: 1 to about 30: 1, from about 10:1 to about 30: 1, from about 15: 1 to about 30:1, or from about 20: 1 to about 30: 1.
  • the molar ratio of lipid to surfactant in the formulations disclosed herein may be from about 1 :2 to about 10: 1.
  • the ratio is from about 1 : 1 to about 2: 1, from about 2 : 1 to about 3: 1, from about 3 : 1 to about 4: 1, from about 4 : 1 to about 5:1 or from about 5: 1 to about 10: 1.
  • the lipid to surfactant ratio is about 1.0: 1.0, about 1.25:1.0, about 1.5/1.0, about 1.75/1.0, about 2.0/1.0, about 2.5/1.0, about 3.0/1.0 or about 4.0/1.0.
  • the formulations disclosed herein may also have varying amounts of total amount of the following components: lipid and surfactant combined (TA).
  • the TA amount may be stated in terms of weight percent of the total composition.
  • the TA is from about 1% to about 40%, about 5% to about 30%>, about 7.5% to about 15%, about 5% to about 10%), about 10% to about 20% or about 20% to about 30%.
  • the TA is 8%, 9%, 10%, 15% or 20%.
  • the TA will be substantially smaller than the TA for pharmaceutical embodiments.
  • the TA may be from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 3%, or from about 0.1% to about 1%.
  • the formulations disclosed herein do not include a pharmaceutically active agent that has received marketing or regulatory approval in any country for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any other disorder listed above.
  • the formulations disclosed herein include one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9.
  • formulations disclosed herein may optionally contain one or more of the following ingredients: co-solvents, chelators, buffers, antioxidants, preservatives,
  • microbicides emollients, humectants, lubricants and thickeners. Preferred amounts of optional components are described in Table 7.
  • the formulations disclosed herein may include a buffer to adjust the pH of the aqueous solution to a range from pH 3.5 to pH 9, pH 4 to pH 7.5, or pH 4 to pH 6.5.
  • buffers include, but are not limited to, acetate buffers, lactate buffers, phosphate buffers, and propionate buffers.
  • formulations disclosed herein are typically formulated in aqueous media.
  • the formulations may be formulated with or without co-solvents, such as lower alcohols
  • microbicide or "antimicrobial” agent is commonly added to reduce the bacterial count in pharmaceutical formulations.
  • Some examples of microbicides are short chain alcohols, including ethyl and isopropyl alcohol, chlorbutanol, benzyl alcohol, chlorbenzyl alcohol, dichlorbenzylalcohol, hexachlorophene; phenolic compounds, such as cresol, 4-chloro-m-cresol, p-chloro-m-xylenol, dichlorophene, hexachlorophene, povidon- iodine; parabenes, especially alkyl-parabenes, such as methyl-, ethyl-, propyl-, or butyl- paraben, benzyl paraben; acids, such as sorbic acid, benzoic acid and their salts; quaternary ammonium compounds, such as alkonium salts, e.g., a bromide, benzalkonium
  • antioxidants are butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT) and di-tert-butylphenol (LY178002, LY256548, HWA-131, BF-389, CI-986, PD-127443, E-51 19, BI-L-239XX, etc.), tertiary butylhydroquinone (TBHQ), propyl gallate (PG), l-0-hexyl-2,3,5-trimethylhydroquinone (HTHQ); aromatic amines
  • BHA butylated hydroxyanisol
  • BHT butylated hydroxytoluene
  • LY178002 di-tert-butylphenol
  • LY256548 LY256548, HWA-131, BF-389, CI-986, PD-127443, E-51 19, BI-L-239XX, etc.
  • TBHQ tertiary butylhydroquinone
  • phenols and phenolic acids include tocopherols (alpha, beta, gamma, delta) and their derivatives, such as tocopheryl-acylate (e.g., -acetate, - laurate, myristate, -palmitate, -oleate, -linoleate, etc., or an y other suitable tocopheryl- lipoate), tocopheryl-POE-succinate; trolox and corresponding amide and thiocarboxamide analogues; ascorbic acid and its salts, isoascorbate, (2 or 3 or 6)-o-alkylas
  • miscellaneous endogenous defence systems such as transferrin, lactoferrin, ferritin, cearuloplasmin, haptoglobion, heamopexin, albumin, glucose, ubiquinol-10); enzymatic antioxidants, such as superoxide dismutase and metal complexes with a similar activity, including catalase, glutathione peroxidase, and less complex molecules, such as beta- carotene, bilirubin, uric acid; flavonoids (flavones, flavonols, flavonones, flavanonals, chacones, anthocyanins), N-acetylcystein, mesna, glutathione, thiohistidine derivatives, triazoles; tannines, cinnamic acid, hydroxycinnamatic acids and their esters (coumaric acids and esters, caffeic acid and their esters, ferulic acid, (iso-) chlorogenic acid,
  • Thickeners are used to increase the viscosity of pharmaceutical formulations to and may be selected from selected from pharmaceutically acceptable hydrophilic polymers, such as partially etherified cellulose derivatives, including carboxymethyl-, hydroxyethyl-, hydroxypropyl-, hydroxypropylmethyl- or methyl-cellulose; completely synthetic hydrophilic polymers including polyacrylates, polymethacrylates, poly(hydroxyethyl)-,
  • the formulations disclosed herein may also include a polar liquid medium.
  • the formulations disclosed herein may be administered in an aqueous medium.
  • the formulations disclosed herein may be in the form of a solution, suspension, emulsion, cream, lotion, ointment, gel, spray, film forming solution or lacquer.
  • compositions and methods disclosed herein relate to the use of a vesicular formulation as described above for the preparation of a pharmaceutical composition for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia.
  • a vesicular formulation or pharmaceutical composition includes at least one phospholipid and one nonionic surfactant for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia wherein the formulation or pharmaceutical composition is formulated for subcutaneous, topical or intravenous delivery.
  • Table 7 lists preferred excipients for the formulation.
  • EGTA Ethylene glycol-bis-(2-aminoethyl)-N,N,N', N'-tetraacetic acid
  • EDTA Ethylenedioxy-diethylene-dinitrilo-tetraacetic acid
  • formulations disclosed herein may form vesicles or ESAs characterized by their adaptability, deformability, or penetrability.
  • vesicle or aggregate “adaptability" which governs the "tolerable surface curvature” is defined as the ability of a given vesicle or aggregate to change easily its properties, such as shape, elongation ratio, and surface to volume ratio.
  • the vesicles disclosed herein may be characterized by their ability to adjust the aggregates' shape and properties to the anisotropic stress caused by pore crossing.
  • Sufficient adaptability implies that a vesicle or an aggregate can sustain different unidirectional forces or stress, such as one caused by pressure, without extensive fragmentation, which defines a "stable" aggregate.
  • a “barrier” is (as in, for example, EP 0 475 160 and WO 98/17255) a body with through- extending narrow pores, such narrow pores having a radius which is at least 25% smaller than the radius of the ESAs (considered as spherical) before the ESAs permeate through such pores.
  • the term "narrow" used in connection with a pore implies that the pore radius is significantly, typically at least 25%, smaller than the radius of the entity tested with regard to its ability to cross the pore.
  • the necessary difference typically should be greater for the narrower pores. Using 25% limit is therefore quite suitable for >150 nm diameter whereas >100% difference requirement is more appropriate for the smaller systems, e.g., with ⁇ 50 nm diameter. For diameters around 20 nm, aggregate diameter difference of at least 200% is often required.
  • Non-destructing passage of ultradeformable, mixed lipid aggregates through narrow pores in a semi-permeable barrier is thus diagnostic of high aggregate adaptability. If pore radius is two times smaller than the average aggregate radius the aggregate must change its shape and surface-to-volume ratio at least 100% to pass without fragmentation through the barrier.
  • An easy and reversible change in aggregate shape inevitably implies high aggregate deformability and requires large surface-to-volume ratio adaptation.
  • a change in surface-to- volume ratio per se implies: a) high volume compressibility, e.g. in the case of compact droplets containing material other than, and immiscible with, the suspending fluid; b) high aggregate membrane permeability, e.g. in the case of vesicles that are free to exchange fluid between inner and outer vesicle volume.
  • 2 r ves (Ap) is the vesicle diameter after semipermeable barrier passage driven by ⁇ and 2 r veS;0 is the starting vesicle diameter, and if necessary make corrections for the flow-effects; and 4) aligh both data sets ⁇ ( ⁇ ) vs.
  • barrier penetratibility of a given suspension is a function of transport driving pressure by the following formula, where P max is the maximum possible penetratability of a given barrier (for the aggregates with zero transport resistance this penetrability is identical to the penetrability of the suspending medium flux), and p* is an adjustable parameter that describes the pressure sensitivity, and thus the transport resistance, of the tested system (for barriers with a fixed pore radius this sensitivity is a function of aggregate properties solely; for non-interacting particles the sensitivity is dominated by aggregate adaptability, allowing to make the assumption: a a proportional to 1/p*
  • a pharmaceutical composition including at least one phospholipid and one nonionic surfactant.
  • a pharmaceutical composition consisting essentially of at least one phospholipid and one nonionic surfactant, a pharmaceutically acceptable carrier, and optionally buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and/or thickeners.
  • a pharmaceutical composition consisting of at least one phospholipid and one nonionic surfactant, a pharmaceutically acceptable carrier, and one or more of the following: buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and thickeners.
  • a pharmaceutical composition including at least one phospholipid and one nonionic surfactant, wherein the pharmaceutical composition sequesters organic matter upon administration.
  • a pharmaceutical composition consisting essentially of at least one phospholipid and one nonionic surfactant, a pharmaceutically acceptable carrier, and optionally buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and/or thickeners, wherein the pharmaceutical composition sequesters organic matter upon administration.
  • a pharmaceutical composition consisting of at least one phospholipid and one nonionic surfactant, a pharmaceutically acceptable carrier, and one or more of the following: buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and thickeners, wherein the pharmaceutical composition sequesters organic matter upon administration.
  • a pharmaceutical package or kit including one or more containers filled with the formulation disclosed herein, and instructions for administration of the formulation to a patient or subject in need thereof for treating disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and
  • the formulation includes one or more phospholipids and one or more surfactants. In certain embodiments, the formulation does not include a non-lipid non-surfactant pharmaceutically active agent that has received marketing or regulatory approval in any country for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or other disorder listed above.
  • the container includes a formulation formulated as a suspension, emulsion, gel, cream, lotion, spray, film forming solution or lacquer. Also provided are packages or kits that can be used in any of the methods disclosed herein.
  • the formulations as described herein are used for agricultrural puposeses and applications.
  • methods that include administering a formulation as described herein to a plant, seed or soil.
  • the formulation may be effective as an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, pesticide, plant activator, and/or a synergist.
  • a formulation as described herein is applied in any desirable application such as in agricultural applications. For instance, the formulation may be applied to control weeds, insects, and/or fungi. In addition, the formulation may be applied to insects, crops, soils, and the like.
  • the pesticide composition may be applied by any suitable method.
  • the formulations may facilitate the transport of different agents into plant tissues, for example, the formulations may facilitate the penetration of cuticular wax layers.
  • improved penetration into or through the cuticle could reduce the concentration of active agent required for a given application and thus significantly diminish pollution problems (Price, C. E. (1981) In: The plant cuticle (D. F. Cutler, K. L. Alvin, C. E. Price, Edits.), Academic, New York, pp. 237- 252).
  • formulations as described herein are applied to plants, crops, fields and the like and are applied such that the active agent is applied at a rate of 1 g/hectar to 500 g/hectar; or at a rate of 1 g/hectar to 200 g/hectar; at a rate of 100 g/hectar to 350 g/hectar; or at a rate of 30 g/hectar to 100 g/hectar.
  • the formulations are used to prepare a tank mix which may then be applied via spraying to the area, plant matter or crop needing treatment.
  • the active agent concentration in the tank mix is adjusted to the particular application, depending on agricultural or non-agricultural application, the crop and the pest.
  • spraying may be the preferred method of application.
  • Various methods of application can also be employed when necessary. For example, in field crops systemic application via an irrigation system can be combined with foliar application.
  • a package, bag or kit that includes a formulation such as described herein, and instructions for indicating that the formulation is suitable for application to a plant, seed or soil.
  • the instructions indicate that the formulation is suitable for use as one or more selected from the group consisting of consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, pesticide, plant activator, and synergist.
  • the formulation may include an active agent, for example, the active agent may be an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, and/or a synergist.
  • the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9.
  • Fungicides Aliphatic Nitrogen Fungicides
  • pyrametostrobin pyraoxystrobin

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Abstract

L'invention porte sur des formulations vésiculaires qui comprennent un ou plusieurs phospholipides et un ou plusieurs agents tensio-actifs. Dans certains modes de réalisation, l'utilisation de telles formulations est destinée à l'administration d'acides gras pour le traitement de troubles tels que les troubles métaboliques des acides gras, y compris une carence en acides gras essentiels ; la douleur ou l'inflammation ou l'ostéoarthrite. Dans certains modes de réalisation, de telles formulations sont destinées à une utilisation en agriculture, par exemple pour appliquer des agents sur des plantes et des cultures destinées à la consommation humaine.
PCT/US2011/022439 2010-01-26 2011-01-25 Formulations vésiculaires WO2011094219A1 (fr)

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US61/298,532 2010-01-26
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RU2497363C1 (ru) * 2012-07-27 2013-11-10 Ильшат Ахатович Гайсин Состав для стимулирования роста и развития сельскохозяйственных культур
WO2014134371A1 (fr) * 2013-03-01 2014-09-04 Arthropod Biosciences, Llc Dispositif de piège à insectes et procédé d'utilisation
WO2015073439A1 (fr) * 2013-11-12 2015-05-21 Lipotec Laboratories Llc Formulations de liposomes-substances attractives
US9226506B2 (en) 2013-09-25 2016-01-05 Dow Agrosciences Llc Methods of weed control in chicory
US10561135B2 (en) 2015-01-12 2020-02-18 The Procter & Gamble Company Insect trap device and method of using
US10568314B2 (en) 2013-11-27 2020-02-25 The Procter & Gamble Company Insect trap device and method of using
US10588307B2 (en) 2014-04-26 2020-03-17 The Procter & Gamble Company Insect trap device and method of using
CN111467379A (zh) * 2020-04-26 2020-07-31 苏州求是玉泉健康科技有限公司 一种甜菜提取物的制备方法和应用

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US20030224936A1 (en) * 1999-03-13 2003-12-04 Gerhard Kretzschmar Seed treatment composition
US20040071767A1 (en) * 2002-10-11 2004-04-15 Gregor Cevc NSAID formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery

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US5496818A (en) * 1990-05-11 1996-03-05 Knoll Aktiengesellschaft Stable emulsion suitable for pharmaceutical administration, the production thereof and emulsion for pharmaceutical use
US20030224936A1 (en) * 1999-03-13 2003-12-04 Gerhard Kretzschmar Seed treatment composition
US20040071767A1 (en) * 2002-10-11 2004-04-15 Gregor Cevc NSAID formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2497363C1 (ru) * 2012-07-27 2013-11-10 Ильшат Ахатович Гайсин Состав для стимулирования роста и развития сельскохозяйственных культур
US11445716B2 (en) 2013-03-01 2022-09-20 The Procter & Gamble Company Insect trap device and method of using
US20200138004A1 (en) * 2013-03-01 2020-05-07 The Procter & Gamble Company Insect Trap Device and Method of Using
AU2014223364B2 (en) * 2013-03-01 2017-10-05 Arthropod Biosciences, Llc Insect trap device and method of using
US20240057579A1 (en) * 2013-03-01 2024-02-22 The Procter & Gamble Company Insect Trap Device and Method of Using
AU2014223364C1 (en) * 2013-03-01 2018-02-15 Arthropod Biosciences, Llc Insect trap device and method of using
WO2014134371A1 (fr) * 2013-03-01 2014-09-04 Arthropod Biosciences, Llc Dispositif de piège à insectes et procédé d'utilisation
US9226506B2 (en) 2013-09-25 2016-01-05 Dow Agrosciences Llc Methods of weed control in chicory
WO2015073439A1 (fr) * 2013-11-12 2015-05-21 Lipotec Laboratories Llc Formulations de liposomes-substances attractives
US11503820B2 (en) 2013-11-27 2022-11-22 The Procter & Gamble Company Insect trap device and method of using
US10568314B2 (en) 2013-11-27 2020-02-25 The Procter & Gamble Company Insect trap device and method of using
US12041924B2 (en) 2014-04-26 2024-07-23 The Procter & Gamble Company Insect trap device and method of using
US10588307B2 (en) 2014-04-26 2020-03-17 The Procter & Gamble Company Insect trap device and method of using
US10561135B2 (en) 2015-01-12 2020-02-18 The Procter & Gamble Company Insect trap device and method of using
US11533898B2 (en) 2015-01-12 2022-12-27 The Procter & Gamble Company Insect trap device and method of using
US12016322B2 (en) 2015-01-12 2024-06-25 The Procter & Gamble Company Insect trap device and method of using
CN111467379B (zh) * 2020-04-26 2021-09-14 苏州承瑞健康科技有限公司 一种甜菜提取物的制备方法和应用
CN111467379A (zh) * 2020-04-26 2020-07-31 苏州求是玉泉健康科技有限公司 一种甜菜提取物的制备方法和应用

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