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WO1998003641A1 - Transport transdermique de molecules - Google Patents

Transport transdermique de molecules Download PDF

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Publication number
WO1998003641A1
WO1998003641A1 PCT/US1997/012970 US9712970W WO9803641A1 WO 1998003641 A1 WO1998003641 A1 WO 1998003641A1 US 9712970 W US9712970 W US 9712970W WO 9803641 A1 WO9803641 A1 WO 9803641A1
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WO
WIPO (PCT)
Prior art keywords
agents
molecules
lecithin
bromelain
composition
Prior art date
Application number
PCT/US1997/012970
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English (en)
Inventor
Wilson T. Crandall
Original Assignee
Crandall Wilson T
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Crandall Wilson T filed Critical Crandall Wilson T
Priority to EP97938029A priority Critical patent/EP0958355A1/fr
Priority to AU40450/97A priority patent/AU4045097A/en
Publication of WO1998003641A1 publication Critical patent/WO1998003641A1/fr

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Classifications

    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Definitions

  • the present invention is related to a composition and a method for topical application of a composition that facilitates transdermal delivery of molecules. More particularly, the present invention is related to the transdermal delivery of molecules including macromolecules.
  • Bromelain is a protease composition that is isolated from pineapple. The composition has been reported to have anti-inflammatory activity when administered orally or parenterally (see Taussig, S.J., "The mechanism of the physiological action of Bromelain", Medical Hypotheses, 6; 99- 104, 1980).
  • Commercially available bromelain used in the manufacture of pharmaceuticals is not a chemically homogeneous substance, but the principal component is a proteolytic enzyme that is a glycoprotein.
  • Capsaicin is an oleoresin obtained by extracting cayenne pepper with ether.
  • the synthetic capsaicin is trans-8- methyl-vanillyl-6-nonenamide.
  • Capsaicin gels have been described in U.S. Patent No. 5,178,879 as being effective in treating topical pain.
  • capsaicin is available commercially in over-the-counter compositions intended for pain relief including lotions such as HEET, OMEGA OIL, SLOAN'S LINIMENT and ZOSTRIX.
  • Bromelain has been reported to be an anti- inflammatory agent, an inhibitor of platelet aggregation, an agent that increases proteolytic and fibrinolytic activity in blood, and a selective prostaglandin inhibitor. Bromelain has been administered by injection and has been reported to be effective after oral administration. However, because bromelain is a relatively large molecule, it cannot be administered transdermally using prior art formulations.
  • compositions that will effectively transport molecules, such as bromelain, that are effective in treating a wide variety of inflammatory conditions by topical application of the composition.
  • Other conditions such as autoimmune diseases that affect the connective tissue and joints could be treated by transdermal delivery of molecules. Alleviation of the pain associated with these conditions and inhibition of inflammatory processes would be of great benefit to these patients.
  • the present invention addresses the needs in the prior art by providing a composition and method for delivering molecules of desired size through the stratum corneum and into the dermis, the hypodermis, or adjacent connective tissue and joints.
  • the present invention also provides a composition and method of transdermal delivery into the bloodstream for systemic action.
  • the present invention is particularly useful for delivering molecules of desired size into the germinal epithelium and nail bed.
  • the present invention provides novel compositions of penetrating agents that permit transdermal delivery of molecules, including macromolecules such as enzymes, and immunoglobulins, after simple topical application to the skin. This novel approach provides a method for treating a variety of conditions without the need for injection or oral administration of molecules.
  • an anti- inflammatory composition containing a proteolytic enzyme, preferably bromelain, and capsaicin.
  • the anti-inflammatory composition is capable of being administered transdermally to a human or animal.
  • the present invention is also a topical anti-inflammatory composition comprising an effective amount of bromelain, an effective amount of capsaicin, and a pharmaceutically effective penetrating agent.
  • Preferred penetrating agents are effective amounts of lecithin organogel, phospholipid gels, and/or poloxamer organogel which are optionally combined with n-decylmethyl sulfoxide.
  • the preferred penetration enhancers are isopropyl palmitate, isopropyl myristate, poloxamer phospholipid gel, ethanol, n- decylmethylsulfoxide [NDMS], and ethoxydiglycol.
  • the present invention provides an easy and safe method of administering an effective anti-inflammatory macromolecule that, in the prior art, could only be administered parenterally or orally.
  • the present invention provides a more effective means of treating the inflammation.
  • the present invention is useful for treating a variety of inflammatory conditions which may be painful conditions including neuralgia, myalgia, rheumatoid arthritis, osteoarthritis, sprains, strains, bursitis, myositis, tendonitis, carpal tunnel syndrome, chondromalacia, eczema, inflammation due to infections by microorganisms, bites, acne, dermatitis, thrombi, phlebitis, hematoma, atopy, psoriasis, and integumental pain.
  • painful conditions including neuralgia, myalgia, rheumatoid arthritis, osteoarthritis, sprains, strains, bursitis, myositis, tendonitis, carpal tunnel syndrome, chondromalacia, eczema, inflammation due to infections by microorganisms, bites, acne, dermatitis, thrombi, phlebitis,
  • the present invention provides a composition and method for the treatment of various conditions, including but not limited to conditions wherein the condition is pain, or deficiencies or imbalances of the integumentary system, immune system, endocrine system, reproductive system, cardiovascular system, musculoskeletal system, nervous system, digestive system, and respiratory system.
  • the present invention provides a composition and method for the treatment of various conditions, including but not limited to fungal conditions.
  • fungal conditions include, but are not limited to conditions such as onchomycosis and other fungal diseases of the skin and scalp.
  • the present invention provides a composition and method for the treatment of the effects of sun exposure on the skin, including the condition of solar elastosis.
  • the present invention provides an alternative composition and method to conventional NSAIDS for treating inflammation.
  • the present composition does not have the side effects that are often seen with NSAIDS. Some of these side effects include, but are not limited to, somnolence, confusion, gastric upset, gastrointestinal bleeding, chondrocyte dysfunction and kidney damage.
  • the composition of the present invention comprises bromelain and capsaicin in a pharmaceutically acceptable penetrating composition optionally containing n-decylmethyl sulf oxide or cholesterol.
  • the present invention can include other pharmaceutically acceptable components such as gelling agents, compounding agents, scents and the like.
  • the composition further contains a lecithin organogel.
  • the composition further contains phospholipids such as phosphatidylcholine, also known as lecithin, phospholipid gels, or a poloxamer organogel.
  • the combination of a transdermal formulation of bromelain and capsaicin act synergistically to reduce pain.
  • the composition of the present invention can also include other pharmaceutically active agents such as antibacterial, anticancer, antihelminthic, antifungal, antiprotozoal or antiviral agents.
  • the present invention also includes methods for topically treating inflammation due to a wide variety of causes comprising the step of topically administering a therapeutically effective amount of a composition comprising bromelain and capsaicin in a pharmaceutically acceptable vehicle.
  • the vehicle may include lecithin organogel, phospholipids, poloxamer lecithin organogel, optionally combined with n-decylmethyl sulfoxide or cholesterol, and/or ethanol.
  • Another object of the present invention is to provide a composition and method for facilitating transdermal transport of molecules. Included in this category are molecules as large as 500,000 Daltons as well as dimers, trimers and tetramers of these molecules, although the present invention encompasses transport of larger molecules and constructs such as plasmids.
  • the molecules include, but are not limited to the following; enzymes including but not limited to antiinflammatory enzymes, proteolytic enzymes and elastase, enzyme inhibitors, including but not limited to protease inhibitors, coenzymes, proteins, receptors, peptides, amino acids, hormones, hormone agonists and antagonists, interleukins, immunoglobulins, antibodies, cytokines, monokines, immunosuppressants, immunomodulators, drugs, growth factors including epidermal growth factor, vitamins, plant extracts, lipids, plasmids, nucleic acids, including but not limited to ribonucleic acids and deoxyribonucleic acids, nucleotides, neurotransmitters, neurotransmitter receptor agonists and antagonists, mitotic inhibitors, steroids, lipids, fatty acids, and carbohydrates.
  • enzymes including but not limited to antiinflammatory enzymes, proteolytic enzymes and elastase
  • enzyme inhibitors including but not limited to protease inhibitors, coen
  • compositions and methods of the present invention include, but are not limited to the following: skin moisturizers (for example alpha hydroxyacids, etc.), ultraviolet blockers, protease inhibitors, inhibitors of pain transmission, vasodilators, vasoconstrictors, antibiotics, antifungal drugs, antiprotozoal drugs, antihelminthic drugs, antibacterial drugs, antiviral agents, and anticancer drugs, including drugs that affect nucleotides and DNA replication, drugs that affect transcription and/or translation, inhibitors of signal transduction systems, and stimulators of signal transduction systems.
  • skin moisturizers for example alpha hydroxyacids, etc.
  • ultraviolet blockers include, but are not limited to the following: skin moisturizers (for example alpha hydroxyacids, etc.), ultraviolet blockers, protease inhibitors, inhibitors of pain transmission, vasodilators, vasoconstrictors, antibiotics, antifungal drugs, antiprotozoal drugs, antihelminthic drugs, antibacterial drugs, antiviral
  • Another object of the present invention is to provide a composition and method for topically treating painful conditions in patients. Yet another object of the present invention to provide a composition and method for topically treating inflammatory conditions.
  • Yet another object of the present invention is to provide a composition and method for treating solar elastosis. It is a specific object of the present invention to provide a composition and method for the topical treatment of fungal disease of the skin and scalp.
  • the present invention provides a composition comprising a pharmaceutically effective penetrating agent, and a method for transdermally administering molecules.
  • the composition and method or the present invention may be used to treat numerous conditions by transdermally delivering desired molecules.
  • the term "condition" means any biological state of a patient.
  • Conditions may include numerous biological states including, but not limited to, deficiencies or imbalances of the following systems: immune, endocrine, reproductive, integumentary, cardiovascular, musculoskeletal, nervous, digestive, and respiratory.
  • Conditions include other biological states including, but not limited to, painful conditions, inflammatory conditions, fungal conditions including fungal disease of the skin and scalp, and specifically onchomycosis.
  • Conditions may include biological states of different tissues including, but not limited to, the following: connective, muscle, nervous, skeletal, lymphoreticular, cutaneous, endocrine, and exocrine. Conditions may also refer to the need for a particular treatment with medicines, such as a vaccination, a hormone supplementation, an anti-inflammatory regimen, an antifungal regimen, and/or pain medication.
  • patient means any human or animal.
  • pharmaceutically effective penetrating agent means n-decylmethyl sulfoxide (NDMS), lecithin organogel, phospholipids gels, cholesterol with or without ethanol, ethoxy diglycol, poloxamer organogel, poloxamer phospholipid gel and poloxamer organogels in combination with phospholipids.
  • an effective amount of a pharmaceutically effective penetrating agent means that amount of the pharmaceutically effective penetrating agent that is capable of transdermally transporting a molecule.
  • an effective amount of a pharmaceutically effective penetrating agent means that the pharmaceutically effective penetrating agent is capable of bringing therapeutic levels of antifungal to the germinal epithelium as well as to the nail bed.
  • Topical administration means application to the surface of the skin. Topical administration may take many forms including, but not limited to, gels, creams, sprays, rinses, ointments, salves, balms, liposomes, time release vehicles, micelles, and skin patches or other forms of pads.
  • phospholipids is used to mean water- insoluble biomolecules that are highly soluble in organic solvents.
  • Phospholipids are generally derived from glycerol and consist of a glycerol backbone, two fatty acid chains, and a phosphorylated alcohol.
  • Phospholipids, either singularly, or in combination with other phospholipids can form gels capable of transdermal delivery.
  • phospholipids can be used individually and do not have to be combined with other components such as lecithin organogel or poloxamer organogel.
  • phospholipids may be used in combination with lecithin organogel and/or poloxamer organogel.
  • Phospholipids may also be optionally combined with n-decylmethyl sulfoxide (NDMS), ethoxy diglycol, cholesterol and/or ethanol.
  • NDMS n-decylmethyl sulfoxide
  • a preferred phospholipid for use in the present invention is phosphatidylcholine, also known as lecithin.
  • lecithin As any of a group of phospholipids which upon hydrolysis yield two fatty acid molecules and a molecule each of glycerophosphoric acid and choline.
  • Lecithin is a mixture of the diglycerides of ste ⁇ iric, palmitic, and oleic acids, linked to the choline ester of phosphoric acid.
  • Soybean lecithin is a preferred lecithin and may contain the following acids; palmitic, stearic, palmitoleic, oleic, linoleic, linolenic and arachidonic.
  • lecithins both fatty acids are saturated while others contain only unsaturated fatty acids for example, oleic, linoleic or arachidonic. In other lecithins one fatty acid is saturated, the other unsaturated.
  • Lecithins are found in nervous tissue, cardiac tissue, in egg yolks and in soy which constitutes the most common and economical source of phosphatidylcholine. It is therefore to be understood that any reference herein to lecithin or phosphatidylcholine is intended to include any combination of lecithin-like phospholipid compounds as is well known in the art.
  • Examples of other phospholipids which can be used in accordance with the present invention include phosphatidyl ethanol amine, phosphatidylserine , phosphatidylinositol, and phosphatidic acid. A mixture of any of the above phospholipids may be also be used in the present invention.
  • PLURONIC refers to poloxamer compounds and are sold collectively under the trademark PLURONIC (BASF, Parsippany, NJ).
  • PLURONIC F- 127 (PL 127) corresponds to poloxamer 407, a polyoxypropylene- polyoxyethylene block copolymer described by Schmolka in the Journal ofBiomedical Materials Research 6:571 -582, 1972.
  • PLURONICS may be used in the present invention.
  • PLURONIC organogel, poloxamer organogel, and polyoxyethylene/polyoxypropylene organogel are synonymous.
  • PLURONIC phospholipid gel and poloxamer phospholipid gel are synonymous.
  • compositions of this invention as used in topical application with this method, means increased penetration into the skin, and is achieved with compounds such as lecithin organogel, poloxamer organogel, phospholipid gels or poloxamer phospholipid gels including but not limited to phosphatidylethanolamine , phosphatidylserine , phosphatidylinositol, and phosphatidic acid and phosphatidylcholine optionally combined with n-decylmethyl sulfoxide (NDMS), PLURONIC F127, ethoxy diglycol, ethanol, or cholesterol.
  • NDMS n-decylmethyl sulfoxide
  • PLURONIC F127 ethoxy diglycol
  • ethanol ethanol
  • cholesterol cholesterol
  • the present invention is a composition and method for transdermally transporting molecules to treat conditions in patients. As defined above, these conditions include numerous biological states.
  • the pharmaceutically effective penetrating agents of the present invention transport different molecules across the stratum corneum and into the lower layers of the epidermis, into the dermis, the hypodermis and into the bloodstream, lymphatic circulation, and adjacent connective tissue and joints.
  • the pharmaceutically effective penetrating agents of the present invention facilitate access of the molecules to the nervous system.
  • transdermally transported molecules such as calcitonin gene-related peptide, inhibitors of substance P, opiate agonists or various types of anesthesia may affect peripheral nerve endings for modulation of pain transmission in primary sensory afferents.
  • the pharmaceutically effective penetrating agents of the present invention also facilitate access of therapeutic substances, such as antifungal agents, to the germinal level as well as to the nail bed.
  • the present invention is a composition and method for topically treating conditions such as inflammation caused by a wide variety of causes including, but not limited to, arthritis, bursitis, phlebitis, sprains, muscle strains, bruises, phlebitis, flea allergy, bites, phlebitis, atopy, and hematomas.
  • the present invention is a composition containing bromelain and capsaicin.
  • the composition further comprises lecithin organogel, and/or poloxamer organogel and/or phospholipids optionally combined with NDMS or cholesterol, as agents to increase the transport of molecules across the skin.
  • proteolytic enzymes can be transported through the use of the present invention, including but not limited to, bromelain, collagenase, gelatinase, trypsin, chymotrypsin, papain and elastase.
  • the present invention comprises bromelain (PCAA, Kinghurst, Houston, TX) at a concentration of between approximately 0.5% and 40% by weight, with a preferred concentration of between approximately 3% and 25% by weight, with the most preferred concentration of approximately 7.5% by weight.
  • the anti-inflammatory composition of the present invention also optionally contains capsaicin.
  • the capsaicin can be either naturally occurring capsaicin oleo resin (PCAA,
  • the capsaicin is present in the transdermal anti-inflammatory of the present invention at a concentration of between approximately 0.01% and 0.5% by weight, with a preferred concentration of between approximately 0.1% and 0.35% by weight, with the most preferred concentration of approximately 0.25% by weight.
  • Other molecules which affect pain transmission are considered within the scope of this invention.
  • Some of these molecules include but are not limited to, anesthetics, analgesics, ganglionic blockers, receptor blockers, receptor antagonists and agonists, enzymes and enzyme inhibitors, catecholamines, indoleamines such as histamine, serotonin and related analogs, molecules that affect neurotransmitter reuptake mechanisms, peptides and peptide analogs such as those related to calcitonin gene-related peptide, substance P, bradykinin, opiate agonists and antagonists, and steroids.
  • the present invention also includes a pharmaceutically acceptable penetrating agent.
  • a preferred penetrating agent is NDMS used in combination with lecithin organogel, phospholipid gels, poloxamer organogel, and poloxamer organogel combined with phospholipid gels.
  • NDMS has been described as an agent that is useful in facilitating the delivery of small molecules transdermally (see Hoo-Kyun, C, et al. "Transdermal delivery of bioactive peptides: The Effect of n-Decylmethyl Sulfoxide, pH, and Inhibitors on Enkephalin Metabolism and Transport", Pharm. Res., Vol. 7, No. 11, pgs. 1099-1106, 1990; Hoo-Kyun, C, et al.
  • NDMS (PCAA Kinghurst, Houston, TX) is present in the transdermal anti-inflammatory composition of the present invention at a concentration of between approximately 0.1% and 1% by weight, with a preferred concentration of between approximately 0.15% and 0.8% by weight, with the most preferred concentration of approximately 0.5% by weight.
  • NDMS is dissolved in 10 mL of a 75% solution of ethanol.
  • purified water is added.
  • Ethanol (98%) may also be used to dissolve lecithin and then either boiled off completely or partially to leave a final ethanol concentration of 3% to 8.5%. While not wanting to be bound by the following statement, it is believed that 3% to 8.5% ethanol may enhance penetration.
  • lecithin organogel which is a combination of lecithin, isopropyl palmitate, or isopropyl myristate and/or ethanol and water.
  • Lecithin organogels have been described as vehicles that are useful in facilitating the delivery of low molecular weight compounds transdermally (Willimann, H., et al., "Lecithin Organogel as Matrix for Transdermal Transport of Drugs", J. Pharm. Sci., Vol. 81, 1992, which is incorporated herein by reference).
  • the lecithin organogels are obtained by adding small amounts of water to a solution of lecithin in organic solvents and/or ethanol.
  • lecithin organogels are prepared at room temperature by first dissolving lecithin in an organic solvent such as isopropyl palmitate or isopropyl myristate and then adding enough water while stirring to obtain the desired gel.
  • Lecithin used in the gel preparations of the present invention generally contain at least 95% phosphatidylcholine.
  • solvents include the following: ethyl laurate, butyl laurate, ethyl myristate, isopropyl myristate, isopropyl palmitate, isooctane, cyclooctane, cyclododecane, methyl cyclohexane, tert- butylcyclohexane, phenylcyclohexane, bicyclohexyl, 1,3,5- triisopropylbenzene, octylbenzene, trans-decalin, ( lR)-(+)- trans-pinane, (lR)-(+)-cis-pinane, n-pentane, n-hexane, n- heptane, n-octane, n-nonane, n-decane, n-undecane, n- dodecane, n-tridecan
  • solvents include, but are not limited to the following: mineral spirits, kerosene, isooctane, petroleum ether, diethyl ether, benzene, toluene, methanol, ethanol, heptanol, methyl isobutyl ketone, cyclohexanone, methylene chloride, choloroform, chlorodifluoromethane, tetrahydrofuran, oleyoleate, 2-octyldodecanol, cetyl and stearyl 2-ethylhexanoate, n-octanol, ethyl laurate, isooctane, cyclopentane, cyclohexane, and cycloheptane.
  • lecithin organogel may be made from PHOSPHOLIPON 90 (American Lecithin Co., Oxford, CT).
  • lecithin organogel comprises 1: 1 to 1.5:5 (weight/vol) of PHOSPHOLIPON 90 to isopropyl palmitate. Water is added to form the desired gel.
  • Other penetrating agents including, but not limited to cholesterol (2% to 100%) with a preferred range of cholesterol to PHOSPHOLIPON 90 of 3:7 to 3: 10. These ingredients are combined with sufficient ethanol to solubilize the mixture. Ethanol is subsequently evaporated, leaving a complex of cholesterol:PHOSPHOLIPON 90. Alternatively, 3.5% - 8% ethanol may be retained in the complex to enhance penetration.
  • soy lecithin of the present invention is a preferred lecithin source and a preferred source of phosphatidylcholine.
  • lecithin may be obtained from other sources.
  • Lecithin at 98% is dissolved gram per gram of isopropyl palmitate to yield a 49% solution of lecithin in isopropyl palmitate.
  • Lecithins may optionally be derived from eggs, and organs such as heart, brain, and liver, and used at concentrations of approximately 10% - 100%, with more preferred final concentrations of from approximately 10% - 50% when dissolved in isopropyl palmitate, isopropyl myristate or ethanol.
  • PLURONIC F-127 or another poloxamer is not used in combination with lecithin organogel, a range of final concentrations of lecithin in the organogel is about 0.5% - 98% and the amount of water in the composition is varied accordingly.
  • 95% phosphatidylcholine dissolved in equal amounts of isopropyl palmitate or isopropyl myristate may be diluted with 10% to 30% water to produce a final phosphatidylcholine concentration of from 12.5% to 32.5%.
  • 100% phosphatidylcholine may be dissolved 1 : 1 in isopropyl palmitate or isopropyl myristate followed by dilution with 10% to 30% water to produce a final phosphatidylcholine concentration of from 20% to 40%.
  • 100% phosphatidylcholine may be dissolved in 98% ethanol which is then boiled off before addition of 10% to 30% water to produce a final phosphatidylcholine concentration of 70% to 90%.
  • the use of PLURONIC 127 will further reduce the phosphatidylcholine content of the gel by a factor of 3 to 4 depending on the amount of PLURONIC 127 added to the mixture.
  • Another penetrating agent of the present invention includes lecithin dissolved in isopropyl palmitate or another solvent in combination with a final concentration of approximately 0.1% - 45% of PLURONIC F-127 (BASF, Parsippany, NJ), otherwise known as poloxamer 407, in a ratio of approximately 1:2 to 1:4.
  • a preferred final concentration of PLURONIC F-127 is 5% to 20%.
  • the lecithin dissolved in isopropyl palmitate is added to 3 to 4 parts PLURONIC F-127
  • PLURONIC 127 for example, 20 ml lecithin in isopropyl palmitate plus 60-80 ml PLURONIC 127.
  • Water, or any other agent known in the art may be added to effect a gel.
  • Other PLURONICS may be used in the present invention. This mixture is called PLURONIC organogel or poloxamer organogel (PLO).
  • PLO poloxamer organogel
  • Other penetrating agents of the present invention associated with lecithin are phospholipids.
  • Phospholipids that may be used in the present invention include, but are not limited to the following: phosphatidylethanolamine; phosphatidylcholineserine; dipalmitoylphosphatidyl choline; dimyristoylphosphatidylcholine, 1 ,2-dipalmitoyl-sn-glycerol phosphocholine; 1 ,2-dimyristoyl-sn-gly(3)phosphoglycerol; PHOSPHOLIPON 80TM 3-sn-phosphatidylcholine soya; PHOSPHOLIPON 90/90 G TM 3-sn-phosphatidylcholine soya; PHOSPHOLIPON 90 HTM 3-sn-phosphatidylcholine soya hydrogenated; PHOSPHOLIPON CCTM 1,2-dicaproyl-sn- glycero (3) phosphocholine; PHOSPHOLIPON LCTM 1,2- dilauroyl sn-glycero (3)
  • Phospholipid gels are made by dissolving the desired phospholipid in any appropriate organic solvent.
  • Organic solvents which may be used include but are not limited to methanol: chloroform (2: 1 vol:vol) isopropyl palmitate, isopropyl myristate or ethanol. After the phospholipid is dissolved, 2 to 4 parts of PLURONIC 127 is added. Water may be added in an amount required to obtain the desired consistency.
  • the organic solvents used for lecithin organogels, such as isopropyl palmitate and isopropyl myristate and others described in the present application are also useful for preparation of gels containing natural and synthetic phospholipids.
  • composition according to the present invention can be in the form of lotions, salves, creams, ointments, liposomes, micelles, sprays, gels, or administered in a pad or patch.
  • the desired form is lotions, ointments and salves.
  • Preferred embodiments include lecithin organogels, PLURONIC organogels, and phospholipid PLURONIC gels.
  • a gelling agent optionally may be added to the formulation.
  • Gelling agents that are suitable for use in the present invention include, but are not limited to, carboxycellulose, alginates, polyacrylates, bentonite, gelatin, tragacanth, polyvinylpyrrolidone, polyvinyl alcohol, and polyoxyethylene/polyoxypropylene block copolymers.
  • a preservative such as benzyl alcohol
  • concentration range of 0.05-5.0%, with a preferred concentration of 2.5%) or potassium sorbate may be added to the composition.
  • An antioxidant such as vitamin E tocopherol, proanthocyanidins, ascorbyl palmitate, ascorbic acid, or lipoic acid may be added to lecithin organogels.
  • Other preservatives well known to those of ordinary skill in the art can be used in the composition, for example, 0.1% butylated hydroxide toluene (BHT), or 0.1% butylated hydroxide anisole (BTA).
  • BHT butylated hydroxide toluene
  • BTA butylated hydroxide anisole
  • Other preservatives well known to those of ordinary skill in the art can be used in the composition.
  • a desired aroma improving agent is honey almond oil (PCAA).
  • PCAA honey almond oil
  • Other aroma improving agents include, but are not limited to, avocado oil, sesame oil, castor oil, olive oil, grapeseed oil, clove oil, groundnut oil, corn oil, lemon oil, coconut oil, lime oil, hazelnut oil, jojoba oil, carthamus oil and wheatgerm oil.
  • the oils can be added individually or in combination. It is to be understood that various fragrances and assorted floral scents may be optionally added to the composition and are commercially available (PCAA).
  • Stabilizers antioxidants, preservatives, humectants, regreasing agents, solvents or auxiliaries can be added to improve stability and/or adhesiveness of the formulations.
  • Cosmetic agents such as panthenol may also optionally be added to the formulation.
  • the method of the present invention includes topical administration of a pharmaceutically acceptable composition containing molecules in combination with a penetrating agent consisting of either lecithin organogel or poloxamer organogel optionally combined with phospholipid gels, any of which may be optionally combined with NDMS, cholesterol or ethanol.
  • a penetrating agent consisting of either lecithin organogel or poloxamer organogel optionally combined with phospholipid gels, any of which may be optionally combined with NDMS, cholesterol or ethanol.
  • lecithin organogel, phospholipids or poloxamer organogel and/or cholesterol may be optionally combined with NDMS to act as penetrating agents.
  • lecithin organogel, phospholipids and poloxamer organogel and/or cholesterol may be used optionally in combination with NDMS to act as penetrating agents.
  • composition of the present invention can be administered topically either once daily or several times per day depending upon the nature and severity of the condition being treated.
  • bromelain and capsaicin may be combined with NDMS and/or lecithin organogel, phospholipids and/or poloxamer organogel for the treatment of inflammation.
  • the anti-inflammatory composition of the present invention can be administered topically either once daily or several times per day depending upon the nature and severity of the inflammatory condition being treated.
  • the anti-inflammatory composition of the present invention is applied topically at the site of the inflammation.
  • the anti-inflammatory composition of the present invention is applied topically around the knee by rubbing the composition on the skin.
  • the anti-inflammatory composition of the present invention is applied in widths of approximately 1.5 cm, 2.5 cm or 3.5 cm. If the composition is applied to a painful joint, it can be applied directly on one side of the joint or can be evenly rubbed around the entire joint. If severe pain exists, it is helpful to apply an equal amount of the anti- inflammatory composition of the present invention on the anterior and posterior surface between 1 and 4 times daily for 2 weeks.
  • the anti-inflammatory composition of the present invention should be applied until the pain subsides.
  • the amount of the composition that is applied to the skin is not critical to the invention. It is important that the composition be thoroughly rubbed into the skin.
  • composition of the present invention causes at least a portion of a molecule, for example bromelain, to be transdermally delivered to the site of the inflammation.
  • bromelain can exert its anti- inflammatory effect at the site of inflammation.
  • the present invention causes more capsaicin to be delivered to the inflammatory site thereby relieving pain presumably by inhibiting release of substance P.
  • bromelain may increase levels of cyclic AMP which may cause a down-regulation of interleukin- 1.
  • This reduction in interleukin- 1 may affect the processing of hapten by Langerhans cells in the skin.
  • reduction of interleukin- 1 can decrease production of collagenase and prostaglandin by synovial fibroblasts and articular chondrocytes, as well as production of interleukin 8. It is also believed that the elevation of cyclic
  • AMP in psoriasis helps to stabilize the activity of keratinocytes by down regulating colony stimulating factor and interleukin- 1.
  • a variety of other molecules may be administered for transdermal transport using the composition and method of the present invention.
  • the molecules include, but are not limited to molecules that may be classified in the following categories; enzymes, coenzymes, protease inhibitors, proteins, peptides, amino acids, hormones, growth factors, interleukins, immunoglobulins, cytokines, monokines, drugs, vitamins, plant extracts, lipids, plasmids, nucleic acids, including but not limited to ribonucleic acids and deoxyribonucleic acids, nucleotides, neurotransmitters, neurotransmitter agonists and antagonists, steroids, lipids, fatty acids, carbohydrates and antifungal agents.
  • molecule is used to describe any compound or substance, such as those compounds or substances that fall into the categories described in this paragraph.
  • the word “molecule” is not limited to a single molecule or to any number of molecules.
  • the present invention and method permits the transdermal transport of the different types of molecules recited above for the treatment of a wide variety of conditions.
  • Some of these conditions include but are not limited to the following; tendonitis, desmitis, bursitis, thrombophlebitis, cellulitis, muscular inflammation, myalgia, arthritis including osteoarthritis and rheumatoid arthritis, synovitis, carpal tunnel syndrome, venomous and non-venomous insect bites, onchomycosis of the toenail and fingernail, fungal diseases of the skin and scalp, and joint strain and sprain.
  • autoimmune phenomena in joints could be treated with antiinflammatory agents such as polyclonal or monoclonal antibodies designed to bind autoimmune antibodies.
  • immunomodulatory molecules may be transdermally transported with the present invention including but not limited to interleukins, immunoglobulins, cytokines, and monokines.
  • the effective .amount of molecule selected to treat a particular condition will depend on the specific condition being treated.
  • the present invention may be placed in the form of a skin patch or ointment for use to transdermally transport one or multiple antigens used for immunization, thereby avoiding the use of injections and needles.
  • a skin patch may be placed on the lower back, neck, shoulder or other site for relief of pain.
  • non-steroidal hormones such as natural or recombinant pituitary hormones or hypothalamic releasing and inhibiting factors may be transdermally transported with the present invention to affect a variety of conditions, including but not limited to growth, reproduction, inflammation, metabolism, bone metabolism, electrolyte balance, water balance, glucose homeostasis, diabetes, production of blood cells, and hypertension.
  • the present invention may be used to transport growth factors, including but not limited to, fibroblast growth factor, epidermal growth factor, nerve growth factor, and growth factors that affect granulocytes, macrophages, and reticulocytes.
  • growth factors including but not limited to, fibroblast growth factor, epidermal growth factor, nerve growth factor, and growth factors that affect granulocytes, macrophages, and reticulocytes.
  • a bromelain-capsaicin topical composition (Bromelain 7.5%/PLURONIC organogel) is prepared as follows:
  • Lecithin was prepared by dissolving 10 g of soy lecithin granules (PCAA, Houston TX) in 10 mL of isopropyl palmitate. 1% benzyl alcohol was added as a preservative. The mixture was stirred periodically for 24 hours until the soy lecithin dissolved.
  • the 20% PLURONIC mixture was prepared by dissolving 16 g PLURONIC® 127 (BASF, Parsippany, NJ.) in 80 mL of distilled water. Then PLURONIC organogel was made by adding the 20% PLURONIC mixture to the lecithin-isopropyl palmitate mixture and stirring.
  • the Bromelain 7.5%/PLURONIC organogel was prepared by mixing the bromelain powder with the lecithin organogel and honey almond oil until a smooth mixture is prepared.
  • the 20% PLURONIC mixture was added at 4 parts to 1 part lecithin-isopropyl palmitate and mixed until a gel formed.
  • the composition was stored at room temperature.
  • a bromelain-capsaicin roll-on formulation is prepared as follows:
  • Bovine albumin (molecular weight 66,000 Daltons) conjugated to fluorescein isothiocyanate (FITC from
  • the hand cream contained dimethicone as the active ingredient, and also contained water, glycerin, stearic acid, C n . l 3 isoparaffin glycol stearate, petrolatum, glyceryl stearate, triethanolamine, zinc oxide, cetyl alcohol, potassium cetyl phosphate, carbomer 934, cetyl acetate, acetylated lanolin alcohol, stearamide AMP, magnesium aluminum silicate, methylparaben, and disodium EDTA.
  • PLURONIC Organogel A PLURONIC organogel was prepared (2 parts
  • PLURONIC 127 2 parts lecithin-isopropyl palmitate mixture plus 5% cholesterol
  • 93% phosphatidyl choline Phospholipon 90, American Lecithin Co., Oxford, Connecticut
  • caprine immunoglobulin Goat-IgG, approximate molecular weight of 150,000 Daltons conjugated to FITC (SIGMA)
  • SIGMA caprine immunoglobulin conjugated to FITC
  • IgG-FITC conjugate Three hours later, the auricular skin was thoroughly cleaned with alcohol and soap and biopsies were removed. Examination of the samples from the right auricular skin showed fluorescence in the dermis while the controls did not exhibit fluorescence in the dermis.
  • Collagenase with a molecular weight of about 102,500 Daltons (PCAA, Houston, Texas) was incorporated at
  • mice Five mice were treated with 0.25 mL 8% bromelain in PLURONIC organogel and 5 mice were treated with 0.25 mL hand cream with 8% bromelain as a control.
  • Copperhead venom (0.05 mL of a 0.9 mg/mL solution) was injected intradermally to all mice under isofluorane anesthesia. Five experimental mice survived 48 hours whereas the controls died within 24 hours. The results demonstrate efficacy of transdermally transported bromelain to partially inactivate the active components of the venom.
  • mice were treated with about 0.25 mL bromelain in PLURONIC organogel (experimental) on one location of the skin of the back. The same mice received bromelain in hand cream (control) at another location on the skin of the back.
  • approximately 0.05 mL of a solution of copperhead venom 100 mg/ 20 mL of physiological saline. From this solution 0.15 mL was diluted in 0.85 mL physiological saline).
  • Example VII The same procedure was employed as in Example VII using cottonmouth venom with the following exceptions: bromelain was reduced to 3%, and 10% cholesterol was added to the gel made from phospholipon C and PLURONIC 127 organogel.
  • Five rats were anesthetized and prepared as described in Example VI.
  • the right forearm (experimental) was treated with 0.5 mL bromelain in PLURONIC organogel with cholesterol and the left forearm was used as a control with 0.5 mL of hand cream (Rite aid) containing 3% bromelain.
  • All gel and cream were removed carefully and 0.05 mL venom injected intradermally at these experimental and control sites. Approximately 45 minutes later the necrotic areas were measured with an electrocardiogram caliper.
  • bromelain a molecule of about 33,000 Daltons molecular weight, was effectively transported through the skin and alleviated pain, perhaps by its action on subcutaneous nerve endings, possibly pain afferents.
  • Topical application of about 0.25 mL of an 8% solution of bromelain in PLURONIC-lecithin organogel was followed by thoroughly rubbing it into the skin of the arm of a human volunteer.
  • 0.05 mL of a solution of histamine (5 mg/mL) was injected intradermally into the arm at the site of bromelain application.
  • a second injection was administered in the forearm, a site that was not treated with bromelain.
  • Ten trials employing six different gels revealed a 45% reduction in the size of the wheal produced by histamine injection at the site of bromelain application compared to the site without bromelain application.
  • Wheal size was determined by measuring the greatest diameter with an EKG caliper. The results indicated a 39% decrease in the wheal size at the site of bromelain application, suggesting that transdermal transport of the protease bromelain inhibited the degree of inflammation.
  • a phospholipid organogel was made by dissolving 1.94 g of Phospholipon CC (1,2 dicaproyl-sn glycerol 3 - phosphocholine) (American Lecithin Co., Oxford, CT) in about 1.94 g of isopropyl myristate, 0.5 ml ethanol, 4 ml of PLURONIC 127 (20% solution) and 4 ml of deionized H 2 0. Bromelain was used to evaluate protease activity against fescue grass extract used as the allergen (0.1 ml extract + 9.9 ml H 2 0) (Greer Lab, Lenoir, N.C.).
  • Bromelain 400 mg was added by mechanical stirring until a gel was formed (experimental sample). Next, 400 mg of bromelain was added separately to a hand cream (control) to achieve the same final concentration as the experimental sample.
  • a rat was anesthetized and the back carefully shaved and cleaned with 70% isopropyl alcohol.
  • bromelain was transdermally transported at sites treated with phospholipid organogel.
  • the protease nature of the transdermally transported bromelain partially deactivated the allergen, resulting in reduced wheal diameter at sites treated with phospholipid organogel compared to sites treated with bromelain in hand cream.
  • PLURONIC 127 may also be used for making a gel. If PLURONIC 127 is used, then it is used in a proportion of 1 :4, i.e., one part phospholipid and four parts PLURONIC 127. The use of PLURONIC 127 generally reduces the amount of phospholipids that are utilized, consequently, penetration of the dermis or other desired targets could be affected.
  • Severe knee injury caused by an automobile accident, was treated in a 68 year old woman using a composition consisting of a PLURONIC organogel made with lecithin, isopropyl palmitate, bromelain and capsaicin.
  • the knee injury caused the patient severe discomfort and pain, and also limited flexion and extension.
  • a PLURONIC organogel containing 7.5% bromelain .and 0.25% capsaicin was made.
  • Methotrexate is a highly effective drug administered orally for rheumatoid arthritis, but it is not used at the initial stages of the disease due to its toxicity.
  • lecithin isopropyl palmitate mixture is added to four parts of PLURONIC 127 (20% solution).
  • Methotrexate was added to make a 5% methotrexate gel with a 20% lecithin dissolved in equal parts of isopropyl palmitate.
  • 0.5 ml of the gel was applied to the shaved knee of a 60 lb. dog.
  • the methotrexate concentration in the blood sample was less than 0.01 ⁇ mol/1.
  • the methotrexate concentration in the synovial sample was 0.07 ⁇ mol/1 which was in the low therapeutic range.
  • the same dog was given 2.5 mg orally and 3 hrs. later blood was drawn and the methotrexate concentration was 0.76 ⁇ mol/1.
  • the methotrexate concentration in the synovial fluid was 0.42 ⁇ mol/1.
  • a 120 lb dog was treated with 8 ml of methotrexate on the knee and the synovial fluid and blood samples were drawn 24 hrs. later.
  • the blood level of methotrexate was 0.07 ⁇ mol/1 and the synovial level of methotrexate was 0.17 ⁇ mol 1.
  • Phospholipon 80 (American Lecithin Co., Oxford, CT.) was dissolved in an equal weight (gram for gram) of isopropyl myristate and 30 ml of PLURONIC 127 (20% solution). Deionized water (10 ml) was added to 10 ml of the phospholipid PLURONIC mixture. As the gel was forming, 10 mg collagenase and 2 ml CaCl2 was added. A rat was treated as previously and biopsied. Five days later the experimental animal was rebiopsied 3-5 mm on either side of the first site.
  • lecithin may be dissolved in isopropyl palmitate or isopropyl myristate on a weight basis of 1 g of lecithin per about 0.5 to 1.5 g of isopropyl palmitate or isopropyl myristate and/or ethanol.
  • the preferred ratio of lecithin to these solvents is about 1 g to about 0.75 g to 1 g.
  • Next ethanol (98%) may be added while stirring at 80° C until the alcohol is boiled off. Water is then added with stirring at approximately 20 to 40% with a preferred concentration of about 30%.
  • a penetration enhancer of the present invention is PLURONIC F-127 (BASF, Parsippany, NJ) which permits use of lecithins of lesser purity than those required in formation of lecithin organogels as taught by Willimann et al.
  • PLURONIC F-127 is employed at concentrations of about 0.1% to 45% in a ratio PLURONIC to lecithin of about 1:0.5 to 1 :6.0.
  • a preferred final concentration of PLURONIC F-127 is 5% to 20% in a ratio of PLURONIC to lecithin of 1:2 to 1 :4.
  • Lecithins of concentrations of approximately 5% to 90% are first dissolved in isopropyl palmitate, isopropyl myristate and/or 98% ethanol.
  • PLURONIC F-127 20% solution
  • water, carboxyethyl cellulose, carboxymethyl cellulose, other PLURONICS, and other agents known to one skilled in the art may be used. These mixtures are known PLURONIC organogels or poloxamer organogels.
  • Precept 8140 Central Soya, IN is added to an equal amount of deionized water in a ratio of approximately 10 g lecithin to 10 g deionized water. These reagents are mechanically stirred.
  • ethoxydiglycol may be added in a range of about 5% to 35% with a preferred concentration of approximately
  • Cholesterol may be used in an identical manner in the preparation of other organogels as taught in the present invention. These organogels include lecithin organogels, phospholipid gels, PLURONIC organogels and PLURONIC- phospholipid gels.
  • the use of cholesterol provides increased stability and penetration of the gels.
  • the relative concentration of cholesterol to phospholipid may be determined by one skilled in the art and would involve a consideration of the molecules to be transported as well as the phospholipids employed in forming the phospholipid gel. Molar concentrations of cholesterol to phospholipid in cholesterol phospholipid gels would be approximately 0.1:1.5.
  • cholesterol as a penetration enhancer
  • approximately 7.66 g of water dispersible lecithin at 60% concentration (Precept 8140, Fort Wayne, IN) is added to 7.5 ml of deionized water and 2.5 ml of ethoxydiglycol followed by mechanical stirring.
  • Upon uniform dispersion of the lecithin 1.9 g of cholesterol (0.5 M cholesterol: 1 M lecithin) is added and stirred at about 65° C.
  • Cholesterol disperses and is incorporated into the micelle.
  • 2-10 ml of 98% ethanol may be added to accelerate this process, however, in this case the temperature must be increased to about 80° C.
  • Egg yolk lecithin at approximately 98% concentration (USB Cleveland, OH) was dissolved in about 100 g of isopropyl myristate. Ten ml of this mixture was added to about 10 ml of PLURONIC F127 (20% concentration), 20 ml of water, 10 mg collagenase, and 1 ml CaCh- A control sample was prepared by dissolving collagenase in hand cream until the same final percentage of collagenase was obtained as used in the experimental cream. The backs of rats were shaved in the anterior lumbar region and the experimental composition was applied in a volume of approximately 0.5 ml twice at 12 hour intervals. The next morning the animals were anesthetized and vesicles were evident at biopsy which were not present in controlled treated animals.

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Abstract

Cette invention se rapporte à des compositions et à des procédés qui servent au transport transdermique de molécules, notamment de macromolécules. Cette invention se rapporte également à des compositions et à des procédés servant au transport transdermique de molécules afin de traiter diverses pathologies chez des patients.
PCT/US1997/012970 1996-07-23 1997-07-23 Transport transdermique de molecules WO1998003641A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
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WO1998031369A1 (fr) * 1997-01-16 1998-07-23 Sekisui Chemical Co., Ltd. Preparations a usage externe a absorption percutanee
WO1999008713A1 (fr) * 1997-08-13 1999-02-25 The Uab Research Foundation Vaccination par application topique de vecteurs genetiques
WO2001041732A1 (fr) * 1999-12-06 2001-06-14 Gore Stanley L Compositions et procedes d'administration intranasale d'agents actifs destines au cerveau
US6348450B1 (en) 1997-08-13 2002-02-19 The Uab Research Foundation Noninvasive genetic immunization, expression products therefrom and uses thereof
US7524510B2 (en) 2005-02-23 2009-04-28 The Uab Research Foundation Alkyl-glycoside enhanced vaccination
WO2009101412A1 (fr) * 2008-02-13 2009-08-20 Cipla Limited Composition pharmaceutique topique
EP2124938A4 (fr) * 2007-01-24 2010-04-14 Bomac Research Ltd Formulation topique
EP2210589A1 (fr) * 2009-01-22 2010-07-28 Ludwig-Maximilians-Universität München Gels phospholipidiques vésiculaires comportant des substances protéiques
US7943166B2 (en) 2003-04-10 2011-05-17 Neurogesx, Inc. Methods and compositions for administration of TRPV1 agonists
US20130210840A1 (en) * 2010-06-11 2013-08-15 Imprimis Pharmaceuticals, Inc. Anti-Cellulite Composition and Method of Treating Cellulite
EP3236903A4 (fr) * 2014-12-23 2018-08-08 Intellectual Property Associates, LLC Méthodes et formulations pour l'administration transdermique
JP2019502764A (ja) * 2016-01-23 2019-01-31 アンパサンド バイオファーマシューティカルズ インコーポレイテッドＡｍｐｅｒｓａｎｄ Ｂｉｏｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． 活性薬剤の増強された経皮送達
US10993921B2 (en) 2013-10-03 2021-05-04 Harrow Ip, Llc Epinephrine-based ophthalmic compositions for intraocular administration and methods for fabricating thereof
CN115379859A (zh) * 2019-06-18 2022-11-22 黛芙生物科学公司 透皮渗透剂调配物

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EP3613413A1 (fr) * 2011-12-05 2020-02-26 Incept, LLC Procédés d'organogel médical et compositions

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US5264219A (en) * 1992-08-07 1993-11-23 Minnesota Mining And Manufacturing Company Transdermal drug delivery backing

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US5264219A (en) * 1992-08-07 1993-11-23 Minnesota Mining And Manufacturing Company Transdermal drug delivery backing

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998031369A1 (fr) * 1997-01-16 1998-07-23 Sekisui Chemical Co., Ltd. Preparations a usage externe a absorption percutanee
WO1999008713A1 (fr) * 1997-08-13 1999-02-25 The Uab Research Foundation Vaccination par application topique de vecteurs genetiques
US6348450B1 (en) 1997-08-13 2002-02-19 The Uab Research Foundation Noninvasive genetic immunization, expression products therefrom and uses thereof
WO2001041732A1 (fr) * 1999-12-06 2001-06-14 Gore Stanley L Compositions et procedes d'administration intranasale d'agents actifs destines au cerveau
US8734770B2 (en) 2003-04-10 2014-05-27 Acorda Therapeutics, Inc. Methods and compositions for administration of TRPV1 agonists
US10653647B2 (en) 2003-04-10 2020-05-19 Grt Us Holding, Inc. Methods and compositions for administration of TRPV1 agonists
US9750707B2 (en) 2003-04-10 2017-09-05 Acorda Therapeutics, Inc. Methods and compositions for administration of TRPV1 agonists
US7943166B2 (en) 2003-04-10 2011-05-17 Neurogesx, Inc. Methods and compositions for administration of TRPV1 agonists
US8263093B2 (en) 2003-04-10 2012-09-11 Neurogesx, Inc. Methods and compositions for administration of TRPV1 agonists
US8273390B2 (en) 2003-04-10 2012-09-25 Neurogesx, Inc. Methods and compositions for administration of TRPV1 agonists
US7524510B2 (en) 2005-02-23 2009-04-28 The Uab Research Foundation Alkyl-glycoside enhanced vaccination
EP2124938A4 (fr) * 2007-01-24 2010-04-14 Bomac Research Ltd Formulation topique
WO2009101412A1 (fr) * 2008-02-13 2009-08-20 Cipla Limited Composition pharmaceutique topique
EP2601934A1 (fr) * 2009-01-22 2013-06-12 Ludwig-Maximilians-Universität München Gels phospholipidiques vésiculaires comportant des substances protéiques
EP2210589A1 (fr) * 2009-01-22 2010-07-28 Ludwig-Maximilians-Universität München Gels phospholipidiques vésiculaires comportant des substances protéiques
US20130210840A1 (en) * 2010-06-11 2013-08-15 Imprimis Pharmaceuticals, Inc. Anti-Cellulite Composition and Method of Treating Cellulite
US11045432B2 (en) 2013-10-03 2021-06-29 Harrow Ip, Llc Epinephrine-based ophthalmic compositions for intraocular administration and methods for fabricating thereof
US10993921B2 (en) 2013-10-03 2021-05-04 Harrow Ip, Llc Epinephrine-based ophthalmic compositions for intraocular administration and methods for fabricating thereof
EP3236903A4 (fr) * 2014-12-23 2018-08-08 Intellectual Property Associates, LLC Méthodes et formulations pour l'administration transdermique
EP3915542A1 (fr) * 2014-12-23 2021-12-01 Intellectual Property Associates, LLC Méthodes et formulations pour l'administration transdermique
US11491225B2 (en) 2014-12-23 2022-11-08 Dyve Biosciences, Inc. Transdermal carrier
EP4349414A3 (fr) * 2014-12-23 2024-06-19 Dyve Biosciences, Inc. Méthodes et formulations pour l'administration transdermique
US12070503B2 (en) 2014-12-23 2024-08-27 Dyve Biosciences, Inc. Transdermal carrier
EP3405151A4 (fr) * 2016-01-23 2019-09-11 Ampersand Biopharmaceuticals Inc. Administration transdermique améliorée d'agents actifs
JP2019502764A (ja) * 2016-01-23 2019-01-31 アンパサンド バイオファーマシューティカルズ インコーポレイテッドＡｍｐｅｒｓａｎｄ Ｂｉｏｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． 活性薬剤の増強された経皮送達
CN115379859A (zh) * 2019-06-18 2022-11-22 黛芙生物科学公司 透皮渗透剂调配物

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