US20190083386A1 - Methods and formulations for transdermal administration of buffering agents - Google Patents

Methods and formulations for transdermal administration of buffering agents Download PDF

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Publication number
US20190083386A1
US20190083386A1 US16/132,358 US201816132358A US2019083386A1 US 20190083386 A1 US20190083386 A1 US 20190083386A1 US 201816132358 A US201816132358 A US 201816132358A US 2019083386 A1 US2019083386 A1 US 2019083386A1
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United States
Prior art keywords
formulation
amount
total
penetrant portion
amount less
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Abandoned
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US16/132,358
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English (en)
Inventor
Seth Brunner
Ryan Beal
Bruce Sand
Brandon Sand
Kilmar Martinez
Luke Gonzales
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Dyve Biosciences Inc
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Ampersand Biopharmaceuticals Inc
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Priority claimed from PCT/US2018/028017 external-priority patent/WO2018195111A1/en
Priority to US16/132,358 priority Critical patent/US20190083386A1/en
Application filed by Ampersand Biopharmaceuticals Inc filed Critical Ampersand Biopharmaceuticals Inc
Publication of US20190083386A1 publication Critical patent/US20190083386A1/en
Priority to US16/546,260 priority patent/US10632146B2/en
Priority to US16/546,256 priority patent/US10639326B2/en
Priority to US16/866,466 priority patent/US10933088B2/en
Assigned to Ampersand Biopharmaceuticals, Inc. reassignment Ampersand Biopharmaceuticals, Inc. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GONZALES, Luke
Assigned to DYVE BIOSCIENCES, INC. reassignment DYVE BIOSCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SAND, Bruce
Assigned to DYVE BIOSCIENCES, INC. reassignment DYVE BIOSCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MARTINEZ, Kilmar
Assigned to DYVE BIOSCIENCES, INC. reassignment DYVE BIOSCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SAND, Brandon
Assigned to DYVE BIOSCIENCES, INC. reassignment DYVE BIOSCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BEAL, RYAN
Assigned to DYVE BIOSCIENCES, INC. reassignment DYVE BIOSCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: Ampersand Biopharmaceuticals, Inc.
Priority to US17/168,111 priority patent/US20210228623A1/en
Priority to US17/168,114 priority patent/US11730756B2/en
Priority to US17/488,154 priority patent/US20220016159A1/en
Priority to US17/488,132 priority patent/US11357792B2/en
Priority to US17/488,143 priority patent/US20220016158A1/en
Priority to US17/497,799 priority patent/US11389472B2/en
Priority to US17/497,794 priority patent/US11793830B2/en
Priority to US17/514,653 priority patent/US11744853B2/en
Priority to US18/331,875 priority patent/US20240033284A1/en
Abandoned legal-status Critical Current

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    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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    • 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
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Definitions

  • the subject of this patent application relates generally to topical treatments that effect transdermal transport of carbonate salts through the skin. More particularly, it concerns direct application of a penetrating formulation containing a carbonate salt topically to a subject.
  • Transdermal delivery of therapeutic agents has made an important contribution to medical practice but has yet to fully achieve its potential. Moreover, the benefits of buffering therapy have not been achieved due to the adverse effects with oral delivery of sufficient quantities of an alkali agent to a subject. Transdermal delivery represents an attractive alternative to oral delivery of drugs and is poised to provide an alternative to hypodermic injection.
  • Transdermal and topical formulations known in the art may be buffered to slightly acid pH (7-5.5) as the epidermis and dermis are slightly acidic.
  • Alkaline formulations are understood to disrupt the skin barrier function which would allow for increased permeation but are avoided, because they tend to cause irritation and other adverse side effects.
  • the present invention solves the problems described above by providing buffering formulations with improved penetration.
  • disclosed herein are formulations containing carbonate salts useful in conditions where buffering therapy is needed.
  • a formulation for transdermal delivery of one or more buffering agents through the skin of a subject comprising: a buffering agent comprising at least one carbonate salt, lysine, tris, a phosphate buffer and/or 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA), or a combination thereof in an amount between about 10-56% w/w; and a penetrant portion in an amount between about 44 to 90% w/, wherein the penetrant portion comprises water in an amount less than about 85% w/w.
  • a buffering agent comprising at least one carbonate salt, lysine, tris, a phosphate buffer and/or 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA), or a combination thereof in an amount between about 10-56% w/w
  • IEPA 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid
  • a method for transdermal delivery of one or more buffering agents through the skin of a subject comprising: a buffering agent comprising at least one carbonate salt, lysine, tris, a phosphate buffer and/or 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA), or a combination thereof in an amount between about 10-56% w/w; and a penetrant portion in an amount between about 44 to 90% w/, wherein the penetrant portion comprises water in an amount less than about 85% w/w.
  • a buffering agent comprising at least one carbonate salt, lysine, tris, a phosphate buffer and/or 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA), or a combination thereof in an amount between about 10-56% w/w
  • IEPA 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid
  • a formulation for transdermal delivery of one or more buffering agents through the skin of a subject comprising: a buffering agent comprising at least one carbonate salt, lysine, tris, a phosphate buffer and/or 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA), or a combination thereof in an amount between about 10-56% w/w; and a penetrant portion in an amount between about 44 to 90% w/w, wherein the penetrant portion comprises water in an amount less than about 85% w/w, and wherein the formulation comprises less than about 12% w/w lecithin.
  • a buffering agent comprising at least one carbonate salt, lysine, tris, a phosphate buffer and/or 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA), or a combination thereof in an amount between about 10-56% w/w
  • a penetrant portion in an amount between about 44 to 90% w
  • a method for transdermal delivery of one or more buffering agents through the skin of a subject comprising: a buffering agent comprising at least one carbonate salt, lysine, tris, a phosphate buffer and/or 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA), or a combination thereof in an amount between about 10-56% w/w; and a penetrant portion in an amount between about 44 to 90% w/, wherein the penetrant portion comprises water in an amount less than about 85% w/w, and wherein the formulation comprises less than about 12% w/w lecithin.
  • a buffering agent comprising at least one carbonate salt, lysine, tris, a phosphate buffer and/or 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA), or a combination thereof in an amount between about 10-56% w/w
  • a penetrant portion in an amount between about 44 to 90% w/
  • the formulations and methods of the present discloser are attributable to an improved formulation that enhances delivery of a carbonate salt through the skin.
  • the formulation employs penetrants described US2009/0053290 ('290), WO2014/209910 ('910), and WO2017/127834.
  • the present formulations may include a nonionic surfactant.
  • Applicant has found that by employing carbonate salts with particle sizes as disclosed herein, delivered with the penetrants as disclosed herein, and in some embodiments providing a combination of a nonionic surfactant and a polar gelling agent, the penetration capabilities of the carbonate salts of the resulting formulation and the effective level of delivery of the carbonate salts have been enhanced. This enhanced level of penetration was also achieved using significantly less lecithin than anticipated or none at all. This result was completely unexpected as it was believed that a somewhat higher concentration of lecithin organogel were responsible for the level of penetration achieved by prior art formulations.
  • the penetrants described in the above-referenced US and PCT applications are based on combinations of synergistically acting components.
  • Many such penetrants are based on combinations of an alcohol, such as benzyl alcohol to provide a concentration of 0.5-20% w/w of the final formulation with lecithin organogel present in the penetrant to provide 25-70% w/w of the formulation.
  • These penetrants are also useful when the agent is a buffer, such as sodium bicarbonate, but less lecithin organogel may be required—e.g. less than 12% w/w when the sodium bicarbonate is present at high concentration as disclosed herein.
  • the buffering component is any mildly basic compound or combination that will result in a pH of 7-8 in the microenvironment of the tumor cells.
  • the formulation has a pH of 7-10.
  • buffers in addition to carbonate and/or bicarbonate salts, include lysine buffers, chloroacetate buffers, tris buffers (i.e., buffers employing tris (hydroxymethyl) aminoethane), phosphate buffers and buffers employing non-natural amino acids with similar pKa values to lysine, and/or 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA).
  • IEPA 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid
  • the bicarbonate salt is in an amount between about 7-32% w/w of the formulation.
  • Histidine buffers may also be used.
  • the concentration of buffer in the compositions is in the range of 10-56% w/w or 10-36% w/w.
  • the carbonate salt is in an amount between about 15-32% w/w of the formulation. More typical ranges for sodium bicarbonate are 10-36% by weight.
  • the upper limits in terms of skin irritation for sodium carbonate is an amount greater than about 7.0% w/w.
  • Group II carbonate salts have limited solubility and would not dissociate upon contact with skin of a subject.
  • the penetrant component comprises a completion component as well as buffer agent in sufficient quantity to impart viscosity and viscoelasticity, one or more surfactants and an alcohol.
  • the completion component can be a polar liquid, a non-polar liquid or an amphiphilic substance.
  • the percentage of carbonate salt in the formulation will depend upon the amount required to be delivered in order to have a useful effect on treating the disorder.
  • the carbonate salt may be present in the formulation in an amount as low as 1% w/w up to about 56% w/w. Typical concentrations may include 10-56% w/w, 15-36% w/w, or 10-32% w/w. Since the required percentage of carbonate salt depends on the frequency of administration, as well as the time allotted for administration for each application, the level of carbonate salt may be varied over a wide range.
  • the carbonate salt is sodium carbonate and/or sodium bicarbonate milled to a particle size is less than 200 ⁇ m.
  • the carbonate salt is sodium carbonate and/or sodium bicarbonate milled to a particle size is less than 70 ⁇ m. In some embodiments, the carbonate salt is sodium carbonate and/or sodium bicarbonate milled to a particle size is less than 70 ⁇ m, wherein the sodium bicarbonate is solubilized in the formulation in an amount less than about 10% w/w of the formulation. In some embodiments, the sodium bicarbonate is milled to a particle size is less than 70 ⁇ m, less than 1 ⁇ m, less than 500 nm, less than 100 nm, or less than 50 nm, wherein particle sizes less than about 10 ⁇ m have an enhanced penetration thru the skin of a subject. In some embodiments, the sodium bicarbonate is jet milled to a particle size less than about 70 ⁇ m. In some embodiments, the sodium bicarbonate is Sodium Bicarbonate USP Grade 3DF that has a particle size distribution less than 70 ⁇ m.
  • the formulations of the disclosure may be prepared in a number of ways. Typically, the components of the formulation are simply mixed together in the required amounts. However, it is also desirable in some instances to, for example, carry out partial dissolution of a carbonate salt and then add a separate preparation containing the components aiding the delivery of the carbonate salts in the form of a carrier. The concentrations of these components in the carrier, then, will be somewhat higher than the concentrations required in the final formulation.
  • sodium bicarbonate may first be partially dissolved in water and then added to a carrier comprising an alcohol, lecithin and optionally a combination of a nonionic surfactant and polar gelling agent, or of ionic detergent.
  • the water is less than about 85% w/w, 50% w/w, or 45% w/w of the penetrant portion of the formulation.
  • the one or more buffering agents are formulated with Aveeno® moisturizers, cream, oils, lotions; Jergens® moisturizers, cream, oils, lotions; Honest Company® moisturizers, cream, oils, lotions; Dermologica® moisturizers, cream, oils, lotions; or St. IvesTM moisturizers, cream, oils, lotions.
  • the commercial lotions, moisturizers, etc. are formulated with the buffering agent comprising a carbonate salt, lysine, tris, a phosphate buffer and/or 2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA) in an amount between about 10-56% w/w.
  • the penetrant portion is a multi-component mixture, whereby the particular concentrations of the penetration enhancers are informed in part by the particle size of the sodium bicarbonate.
  • the formulation enables the sodium bicarbonate to become bio-available to the target site within minutes of topical administration.
  • the formulations permit the use of minimal concentrations of therapeutic agents, as little as. 1/1000th of concentrations required of alternative processes, while enabling bioactivity and positive clinical outcomes simultaneously.
  • the penetrant portion comprises an alcohol in an amount less than 5% w/w of the formulation.
  • Subjects of the disclosure herein in addition to humans, include veterinary subjects, wherein formulations suitable for these subjects are also appropriate. Such subjects include livestock and pets as well as sports animals such as horses and greyhounds.
  • One aspect of the invention is a method to inhibit cancer growth and metastasis, including diminution of cancer mass by non-systemic parenteral, including topical administration of antimetastatic agents, including those agents that result in buffering the immediate environment of tumor cells, including solid tumors and melanomas.
  • nonsystemic parenteral administration such as intramuscular, intraperitoneal or subcutaneous administration standard formulations are sufficient. These formulations include standard excipients and other ancillary ingredients such as antioxidants, suitable salt concentrations and the like. Such formulations can be found, for example, in the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.—a standard reference for various types of administration.
  • buffer treatment tumor cells from the biopsy of a solid tumor in a subject are therefore preferably cultured and tested in advance of treatment to insure responsiveness to buffer.
  • Such evaluation can be carried out by any suitable means, including measurement of pH, assessment of the levels of relevant proteases, and invasion assays as impacted by buffer treatment as described in Bailey, K. M. et al (2014) supra.
  • One important such assay is a glycolytic stress assay as described therein.
  • Cell cultures of biopsied tumors that appear not to respond to buffer treatment as shown by such assays may benefit from administration of other antimetastatic agents and inclusion of such agents in the compositions of the invention that include buffers would also be beneficial.
  • treatment with buffer-containing compositions alone may be contraindicated and the subject is not administered buffer as the sole active agent but diverted to alternative treatment.
  • the formulations comprise mixtures wherein the components interact synergistically and induce skin permeation enhancements better than that induced by the individual components. Synergies between chemicals can be exploited to design potent permeation enhancers that overcome the efficacy limitations of single enhancers. Several embodiments disclosed herein utilize three to five distinct permeation enhancers.
  • the formulation will comprise penetrants including either or both chemical penetrants (CPEs) and peptide-based cellular penetrating agents (CPPs) that encourage transmission across the dermis and/or across membranes including cell membranes, as would be the case in particular for administration by suppository or intranasal administration, but for transdermal administration as well.
  • CPEs chemical penetrants
  • CPPs peptide-based cellular penetrating agents
  • Particularly suitable penetrants especially for those that contain at least one agent other than buffer include those that are described in the above-referenced US2009/0053290 ('290), WO2014/209910 ('910), and WO2017/127834.
  • transdermal delivery can be effected by mechanically disrupting the surface of the skin to encourage penetration, or simply by supplying the formulation applied to the skin under an occlusive patch.
  • the penetrant portion comprises a completion component as well as one or more electrolytes sufficient to impart viscosity and viscoelasticity, one or more surfactants and an alcohol.
  • the completion component can be a polar liquid, a non-polar liquid or an amphiphilic substance.
  • the penetrant may further comprise a keratinolytic agent effective to reduce thiol linkages, disrupt hydrogen bonding and/or effect keratin lysis and/or a cell penetrating peptide (sometimes referred to as a skin-penetrating peptide) and/or a permeation enhancer.
  • Lecithin organogel is a combination of lecithin with a gelling component. Suitable gelling components also include isopropyl palmitate, ethyl laurate, ethyl myristate and isopropyl myristate. In some embodiments, the formulation comprises a gelling agent in an amount less than 5% w/w of the formulation. Certain hydrocarbons, such as cyclopentane, cyclooctane, trans-decalin, trans-pinane, n-pentane, n-hexane, n-hexadecane may also be used.
  • an important permeation agent is a lecithin organogel, wherein the combination resulting from lecithin and the organic solvent acts as a permeation agent.
  • the formulation comprises less than about 7% w/w or less than about 12% w/w lecithin.
  • the penetrant portion comprises lecithin organogel, an alcohol, a surfactant, and a polar solvent.
  • the lecithin organogel is a combination of soy lecithin and isopropyl palmitate.
  • the penetrant portion comprises lecithin and isopropyl palmitate, undecane, isododecane, isopropyl stearate, or a combination thereof.
  • the formulation comprises LipmaxTM in an amount between about 1-20% w/w or an equivalent 50/50 mixture of isopropyl palmitate and lecithin.
  • Lecithin organogels are not always clear or thermodynamically stable, but are viscoelastic, and biocompatible phases composed of phospholipids and appropriate organic liquid.
  • An example of a suitable lecithin organogel is lecithin isopropyl palmitate, which is formed when isopropyl palmitate is used to dissolve lecithin.
  • the ratio of lecithin to isopropyl palmitate may be 50:50. Illustrated below in the Examples is a formulation containing soy lecithin in combination with isopropyl palmitate; however, other lecithins could also be used such as egg lecithin or synthetic lecithins. Various esters of long chain fatty acids may also be included. Methods for making such lecithin organogels are well known in the art. In most embodiments, the lecithin organogel is present in the final formulation is less than about 20% w/w.
  • the concentration of lecithin organogel may be as low as 0.5% w/w, 1% w/w, 5% w/w, 10% w/w or 20% w/w.
  • the penetrant portion comprises a mixture of xanthan gum, lecithin, sclerotium gum, pullulan, or a combination thereof in an amount less than 2% w/w, 5% w/w, or 10% w/w of the formulation.
  • the formulation comprises SiligelTM in an amount between about 1-5% w/w or 5-15% w/w, or an equivalent mixture of xanthan gum, lecithin, sclerotium gum, and pullulan.
  • the penetrant portion comprises a mixture of caprylic triglycerides and capric triglycerides in amount less than 2% w/w, 8% w/w, or 10% w/w of the formulation.
  • the formulation comprises Myritol® 312 in an amount between about 0.5-10% w/w, or an equivalent mixture of caprylic triglycerides and capric triglycerides.
  • the penetrant portion is in an amount between about 44-90% w/w or 44-80% w/w of the formulation.
  • the penetrant portion comprises phosphatidyl choline in amount less than 7% w/w, less than 12% w/w, or 18% w/w of the formulation.
  • the penetrant portion comprises a phospholipid in amount less than 12% w/w or 18% w/w of the formulation.
  • the penetrant portion comprises a mixture of tridecane and undecane in amount less than 2% w/w, 5% w/w, or 8% w/w of the formulation.
  • the formulation comprises Cetiol Ultimate® in an amount less than about 2% w/w, 5% w/w, or 10% w/w, or an equivalent mixture of tridecane and undecane.
  • the penetrant portion comprises cetyl alcohol in amount less than 2% w/w, 5% w/w, or 8% w/w of the formulation.
  • the penetrant portion comprises benzyl alcohol in an amount less than about 2% w/w, 5% w/w, or 8% w/w.
  • the penetrant portion comprises stearic acid in an amount less than 2% w/w, 5% w/w, or 8% w/w of the formulation.
  • the penetrant portion comprises water in an amount between about 0-85% w/w.
  • the penetrant portion comprises lecithin, phosphatidylcholine, hydrogenated phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, one or more phosphatides, one or more Inositol phosphatides, or combinations thereof, in amount less than 12% w/w or in amount less than 7% w/w of the formulation.
  • Lecithin organogels may be in the form of vesicles, microemulsions and micellar systems.
  • self-assembled structures such as vesicles or micelles, they can fuse with the lipid bilayers of the stratum corneum, thereby enhancing partitioning of encapsulated drug, as well as a disruption of the ordered bilayers structure.
  • An example of a phospholipid-based permeation enhancement agent comprises a micro-emulsion-based organic gel defined as a semi-solid formation having an external solvent phase immobilized within the spaces available of a three-dimensional networked structure.
  • This micro-emulsion-based organic gel in liquid phase is characterized by 1,2-diacyl-sn-glycero-3-phosphatidyl choline, and an organic solvent, which is at least one of: ethyl laureate, ethyl myristate, isopropyl myristate, isopropyl palmitate; cyclopentane, cyclooctane, trans-decalin, trans-pinane, n-pentane, n-hexane, n-hexadecane, and tripropylamine.
  • an organic solvent which is at least one of: ethyl laureate, ethyl myristate, isopropyl myristate, isopropyl palmitate; cyclopentane, cyclooctane, trans-decalin, trans-pinane, n-pentane, n-hexane, n-hexadecane
  • the lecithin organogels are formulated with an additional component to assist in the formation of micelles or vascular structures.
  • the organogels are formulated with a polar component such as water, glycerol, ethyleneglycol or formamide, in particular with water.
  • a nonionic detergent such as a poloxamer in aqueous solution is used to top off.
  • Certain detergents, such as Tween® 80 or Span® 80 may be used as alternatives.
  • the percentage of these components in the anhydrous forms of the composition is in the range of 1-15% w/w.
  • powdered or micronized nonionic detergent is used to top off, typically in amounts of 1-30% w/w of the penetrant portion.
  • the % is calculated by dividing the % w/w of lecithin by 10.
  • An additional component in the formulations of the disclosure is an alcohol.
  • Benzyl alcohol and ethanol are illustrated in the Examples.
  • derivatives of benzyl alcohol which contain substituents on the benzene ring, such as halo, alkyl and the like.
  • the weight percentage of benzyl or other related alcohol in the final composition is 0.5-20% w/w, and again, intervening percentages such as 1% w/w, 2% w/w, 5% w/w, 7% w/w, 10% w/w, and other intermediate weight percentages are incl tided.
  • the molecule Due to the aromatic group present in a permeation enhancement formulation such as benzyl alcohol, the molecule has a polar end (the alcohol end) and a non-polar end (the benzene end). This enables the agent to dissolve a wider variety of drugs and agents.
  • the alcohol concentration is substantially lower than the concentration of the lecithin organogel in the composition.
  • the performance of the formulations is further improved by including a nonionic detergent and polar gelling agent or including a powdered surfactant.
  • detergents typically nonionic detergents are added.
  • the nonionic detergent should be present in an amount between about 1% w/w to 30% w/w of the penetrant portion.
  • the amount of detergent is relatively low—e.g., 2%-25% w/w, or 5-15% w/w or 7-12% w/w of the penetrant portion.
  • relatively higher percentages are usually used—e.g., 20%-60% w/w.
  • the penetrant portion further comprises a detergent portion in an amount between about 1 to 70% w/w or 1-60% w/w of the penetrant portion.
  • the nonionic detergent provides suitable handling properties whereby the formulations are gel-like or creams at room temperature.
  • the detergent typically a poloxamer, is present in an amount between about 2-12% w/w of the penetrant portion, preferably between about 5-25% w/w in polar formulations.
  • the detergent is added in powdered or micronized form to bring the composition to 100% and higher amounts are used.
  • the nonionic detergent is added as a solution to bring the composition to 100%. If smaller amounts of detergent solutions are needed due to high levels of the remaining components, more concentrated solutions of the nonionic detergent are employed.
  • the percent detergent in the solution may be 10% to 40% or 20% or 30% and intermediate values depending on the percentages of the other components.
  • Suitable nonionic detergents include poloxamers such as the non-ionic surfactant Pluronic® and any other surfactant characterized by a combination of hydrophilic and hydrophobic moieties.
  • Poloxamers are triblock copolymers of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyethyleneoxide.
  • Other nonionic surfactants include long chain alcohols and copolymers of hydrophilic and hydrophobic monomers where blocks of hydrophilic and hydrophobic portions are used.
  • the formulation also contains surfactant, typically, nonionic surfactant at 2-25% w/w of the penetrant portion along with a polar solvent wherein the polar solvent is present in an amount at least in molar excess of the nonionic surfactant.
  • the composition comprises the above-referenced amounts of lecithin organogel and benzyl alcohol along with a carbonate salt with a sufficient amount of a polar solution, typically an aqueous solution or polyethylene glycol solution that itself contains 10%-40% of surfactant, typically nonionic surfactant to bring the composition to 100%.
  • surfactants include polyoxyethylated castor oil derivatives such as HCO-60 surfactant sold by the HallStar Company; nonoxynol; octoxynol; phenylsulfonate; poloxamers such as those sold by BASF as Pluronic® F68, Pluronic® F127, and Pluronic® L62; polyoleates; Rewopal® HVIO, sodium laurate, sodium lauryl sulfate (sodium dodecyl sulfate); sodium oleate; sorbitan dilaurate; sorbitan dioleate; sorbitan monolaurate such as Span® 20 sold by Sigma-Aldrich; sorbitan monooleates; sorbitan trilaurate; sorbitan trioleate; sorbitan monopalmitate such as Span® 40 sold by Sigma-Aldrich; sorbitan stearate such as Span® 85 sold by Sigma-Aldrich
  • the weight percentage range of nonionic surfactant is in the range of 3% w/w-15% w/w, and again includes intermediate percentages such as 5% w/w, 7% w/w, 10% w/w, 12% w/w, and the like.
  • the detergent portion comprises a nonionic surfactant in an amount between about 1-30% w/w of the formulation; and a polar solvent in an amount less than 5% w/w of the formulation.
  • the nonionic surfactant is a poloxamer and the polar solvent is water, an alcohol, or a combination thereof.
  • the detergent portion comprises poloxamer, propylene glycol, glycerin, ethanol, 50% w/v sodium hydroxide solution, or a combination thereof. In some embodiments, the detergent portion comprises glycerin in an amount less than 3% w/w of the formulation.
  • a micellular structure is also often achieved.
  • the polar agent is in molar excess of the nonionic detergent.
  • the inclusion of the nonionic detergent/polar gelling agent combination results in a more viscous and cream-like or gel-like formulation which is suitable for application directly to the skin. This is typical of the aqueous forms of the composition.
  • a gelling agent such as a gelling agent, a dispersing agent and a preservative.
  • a suitable gelling agent is hydroxypropylcellulose, which is generally available in grades from viscosities of from about 5 cps to about 25,000 cps such as about 1500 cps. All viscosity measurements are assumed to be made at room temperature unless otherwise stated. The concentration of hydroxypropylcellulose may range from about I % w/w to about 2% w/w of the composition.
  • Other gelling agents are known in the art and can be used in place of, or in addition to hydroxypropylcellulose.
  • An example of a suitable dispersing agent is glycerin.
  • Glycerin is typically included at a concentration from about 5% w/w to about 25% w/w of the composition.
  • a preservative may be included at a concentration effective to inhibit microbial growth, ultraviolet light and/or oxygen-induced breakdown of composition components, and the like. When a preservative is included, it may range in concentration from about 0.01% w/w to about 1.5% w/w of the composition.
  • Typical components that may also be included in the formulations are fatty acids, terpenes, lipids, and cationic, and anionic detergents.
  • the formulation further comprises tranexamic acid in an amount less than 2% w/w, 5% w/w, or 10% w/w of the formulation.
  • the formulation further comprises a polar solvent in an amount less than 2% w/w, 5% w/w, 10% w/w, or 20% w/w of the formulation.
  • the formulation further comprises a humectant, an emulsifier, an emollient, or a combination thereof.
  • the formulation further comprises almond oil in an amount less than about 5% w/w.
  • the formulation further comprises a mixture of thermoplastic polyurethane and polycarbonate in an amount less than about 5% w/w. In some embodiments, the formulation further comprises phosphatidylethanolamine in an amount less than about 5% w/w. In some embodiments, the formulation further comprises an inositol phosphatide in an amount less than about 5% w/w.
  • solvents and related compounds that may be used in some embodiments include acetamide and derivatives, acetone, n-alkanes (chain length between 7 and 16), alkanols, diols, short chain fatty acids, cyclohexyl-1,1-dimethylethanol, dimethyl acetamide, dimethyl formamide, ethanol, ethanol/d-limonene combination, 2-ethyl-1,3-hexanediol, ethoxydiglycol (Transcutol® by Gattefosse, Lyon, France), glycerol, glycols, lauryl chloride, limonene N-methylformamide, 2-phenylethanol, 3-phenyl-1-propanol, 3-phenyl-2-propen-1-ol, polyethylene glycol, polyoxyethylene sorbitan monoesters, polypropylene glycol 425, primary alcohols (tridecanol), 1,2-propane diol, butanediol, C 3 -
  • Fatty alcohols, fatty acids, fatty esters, are bilayer fluidizers that may be used in some embodiments.
  • suitable fatty alcohols include aliphatic alcohols, decanol, lauryl alcohol (dodecanol), unolenyl alcohol, nerolidol, 1-nonanol, n-octanol, and oleyl alcohol.
  • Suitable fatty acid esters include butyl acetate, cetyl lactate, decyl N,N-dimethylamino acetate, decyl N,N-dimethylamino isopropionate, diethyleneglycol oleate, diethyl sebacate, diethyl succinate, diisopropyl sebacate, dodecyl N,N-dimethyamino acetate, dodecyl (N,N-dimethylamino)-butyrate, dodecyl N,N-dimethylamino isopropionate, dodecyl 2-(dimethyamino) propionate, E0-5-oleyl ether, ethyl acetate, ethylaceto acetate, ethyl propionate, glycerol monoethers, glycerol monolaurate, glycerol monooleate, glycerol monolinoleate,
  • Suitable fatty acid include alkanoic acids, caprid acid, diacid, ethyloctadecanoic acid, hexanoic acid, lactic acid, lauric acid, linoelaidic acid, linoleic acid, linolenic acid, neodecanoic acid, oleic acid, palmitic acid, pelargonic acid, propionic acid, and vaccenic acid.
  • Suitable fatty alcohol ethers include a-monoglyceryl ether, E0-2-oleyl ether, E0-5-oleyl ether, E0-10-oleyl ether, ether derivatives of polyglycerols and alcohols, and (1-O-dodecyl-3-O-methyl-2-O-(2′,3′-dihydroxypropyl glycerol).
  • Examples of completing agents that may be used in some embodiments include ⁇ - and ⁇ -cyclodextrin complexes, hydroxypropyl methylcellulose (e.g., Carbopol® 934), liposomes, naphthalene diamide diimide, and naphthalene diester diimide.
  • One or more anti-oxidants may be included, such as vitamin C, vitamin E, proanthocyanidin and a-lipoic acid typically in concentrations of 0.1%-2.5% w/w.
  • the pH of the formulation is adjusted to a level of pH 9-11 or 10-11 which can be done by providing appropriate buffers or simply adjusting the pH with base.
  • epinephrine or an alternate vasoconstrictor such as phenylephrine or epinephrine sulfate may be included in the formulation if a stabilizing agent is present. Otherwise, the epinephrine should be administered in tandem since epinephrine is not stable at alkali pH.
  • any of the anesthetic compositions it may be desirable to administer the epinephrine in tandem with the transdermal anesthetic.
  • treatment of the epinephrine with a chelator, such as the iron chelator Desferal® may stabilize the epinephrine sufficiently to include it in the transdermal formulation.
  • an additional active agent that is optionally included in the compositions of the invention is one or more appropriate protease inhibitors. Particularly important are inhibitors of cathepsins, for example of cathepsin B, and inhibitors of matrix metalloproteinases (MMPs). These components are active alone or augment the effect of buffer for tumors that are not resistant to buffer treatment.
  • Withaferin A Another active agent is Withaferin A.
  • Withaferin A inhibits tumor metastasis and manifests other anti-cancer activities, e.g., inhibition of the neovascularzation associated with carcinoma, as well as cell proliferation.
  • Withaferin A is also a leptin sensitizer with strong anti-diabetic properties that could induce healthy weight loss and beneficial effects on glucose metabolism.
  • NHE1 target DNA+/H+ exchanger 1
  • Other anti-metastatic agents include inhibitors of the src homology region 2-containing protein tyrosinase phosphatase (Shp2).
  • a multiplicity of inhibitors of this activity is known, including Fumosorine, PHPS (NSC-87877) and NSC-117199, phenylhydrazonopyrazolone sulfonate (PHPS1), DCA, cryptotanshinone, 11-B08 and #220-324, metalloproteinases-2 and -9 (MMP-2 and MMP-9) and certain cathepsins, in particular B, D and L.
  • PHPS1 phenylhydrazonopyrazolone sulfonate
  • DCA phenylhydrazonopyrazolone sulfonate
  • cryptotanshinone 11-B08 and #220-324
  • MMP-2 and MMP-9 metalloproteinases-2 and -9
  • cathepsins in particular B, D and L.
  • agents include inhibitors of E-cadherin and of epidermal growth factor receptor (EGFR).
  • EGFR epidermal growth factor receptor
  • Known inhibitors include erlotinib, an anti-integrin drug (Cilengitide), Cariporide, Eniporide and Amiloride.
  • the formulations may include other components that act as excipients or serve purposes other than active anti-tumor effects.
  • preservatives like antioxidants e.g., ascorbic acid or ⁇ -lipoic acid and antibacterial agents may be included.
  • Other components apart from therapeutically active ingredients and components that are the primary effectors of dermal penetration may include those provided for aesthetic purposes such as menthol or other aromatics, and components that affect the physical state of the composition such as emulsifiers, for example, Durasoft® (which is a mixture of thermoplastic polyurethane and polycarbonate). Typically, these ingredients are present in very small percentages of the compositions.
  • these latter ancillary agents are neither therapeutically ingredients nor are they components that are primarily responsible for penetration of the skin.
  • the components that primarily effect skin penetration have been detailed as described above. However, some of these substances have some capability for effecting skin penetration. See, for example, Kunta, J. R. et al, J. Pharm. Sci. (1997) 86:1369-1373, describing penetration properties of menthol.
  • the aspect of the disclosure that includes administering buffers so as to raise the pH locally at the environment of a solid tumor or in the vicinity of gout or melasma, expands the indications to which the methods of the invention are applicable. It has been found, generally, that the requirements for effective penetration of the skin in the case of buffers as active agents are less restrictive than those required for alternative agents useful in preventing cancer metastasis. In addition, although for these indications delivery to the locus of the solid tumor, including melanoma, or melasma or gout is desirable, effective systemic pH alteration can be used as a way to diagnose the effectiveness of penetration when topical administration is employed.
  • the application method is determined by the nature of the treatment but may be less critical than the nature of the formulation itself. If the application is to a skin area, it may be helpful in some instances to prepare the skin by cleansing or exfoliation. In some instances, it is helpful to adjust the pH of the skin area prior to application of the formulation itself.
  • the application of the formulation may be by simple massaging onto the skin or by use of devices such as syringes or pumps. Patches could also be used. In some cases, it is helpful to cover the area of application to prevent evaporation or loss of the formulation.
  • the application area is essentially skin
  • a convenient way to do this is to apply a composition comprising linoleic acid which effectively closes the entrance pathways that were provided by the penetrants of the invention. This application, too, is done by straightforward smearing onto the skin area or can be applied more precisely in measured amounts.
  • a wide variety of therapeutic agents may be used in the formulations, including anesthetics, fat removal compounds, nutrients, nonsteroidal anti-inflammatory drugs (NSAIDs) agents for the treatment of migraine, hair growth modulators, antifungal agents, anti-viral agents, vaccine components, tissue volume enhancing compounds, anti-cellulite therapeutics, wound healing compounds, compounds useful to effect smoking cessation, agents for prevention of collagen shrinkage, wrinkle relief compounds such as Botox®, skin-lightening compounds, compounds for relief of bruising, cannabinoids including cannabidiols for the treatment of epilepsy, compounds for adipolysis, compounds for the treatment of hyperhidrosis, acne therapeutics, pigments for skin coloration for medical or cosmetic tattooing, sunscreen compounds, hormones, insulin, corn/callous removers, wart removers, and generally any therapeutic or prophylactic agent for which transdermal delivery is desired.
  • the delivery may simply effect transport across the skin into a localized subdermal location, such as treatment of nail fungus or modulation
  • the methods may employ a subsequent treatment with linoleic acid.
  • transdermal treatments generally open up the skin barrier, which is, indeed, their purpose, it is useful to seal the area of application after the treatment is finished.
  • treatment with the formulation may be followed by treating the skin area with a composition comprising linoleic acid to seal off the area of application.
  • the application of linoleic acid is applicable to any transdermal procedure that results in impairing the ability of the skin to act as a protective layer. Indeed, most transdermal treatments have this effect as their function is to allow carbonates to pass through the epidermis to the dermis at least, and, if systemic administration is achieved, through the dermis itself.
  • the local anesthetic may be one or more of the following: benzocaine, lidocaine, tetracaine, bupivacaine, cocaine, etidocaine, mepivacaine, pramoxine, prilocaine, procaine, chloroprocaine, oxyprocaine, proparacaine, ropivacaine, dyclonine, dibucaine, propoxycaine, chloroxylenol, cinchocaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, propoxycaine, pyrrocaine, risocaine, rodocaine, and pharmaceutically acceptable derivatives and bioisosteres thereof.
  • anesthetic agent(s) are included in the composition in effective amount(s). Depending on the anesthetic(s) the amounts of anesthetic or combination is typically in the range of 1% w/w to 50% w/w.
  • the compositions of the invention provide rapid, penetrating relief that is long lasting.
  • the pain to be treated can be either traumatic pain and/or inflammatory pain.
  • the anesthetic is administered to relieve the pain associated with invasive fat deposit removal.
  • Specific removal of fat deposits has been attractive for both health and cosmetic reasons.
  • a cytolytic agent for fat such as deoxycholic acid (DCA).
  • DCA deoxycholic acid
  • a series of patents issued or licensed to Kythera Biopharmaceuticals is directed to methods and compositions for non-surgical removal of localized fat that involves injecting compositions containing DCA or a salt thereof.
  • Representative issued patents are directed to formulation (U.S. Pat. No. 8,367,649); method-of-use (U.S. Pat. Nos. 8,846,066; 7,622,130; 7,754,230; 8,298,556); and synthetic DCA (U.S. Pat. No. 7,902,387).
  • conventional invasive fat removal techniques are employed along with administering a pain-relieving effective agent—typically lidocaine or related anesthetics via transdermal administration.
  • a pain-relieving effective agent typically lidocaine or related anesthetics via transdermal administration.
  • the pain-relieving transdermal formulation is applied to the area experiencing pain immediately before, during or immediately after the invasive fat-removal procedure.
  • hydrocortisone or hydrocortisone acetate may be included in an amount ranging from 0.25% w/w to about 0.5% w/w.
  • Menthol, phenol, and terpenoids, e.g., camphor can be incorporated for cooling pain relief.
  • menthol may be included in an amount ranging from about 0.1% w/w to about 1.0% w/w.
  • compositions containing anesthetics are useful for temporary relief of pain and itching associated with minor burns, cuts, scrapes, skin irritations, inflammation and rashes due to soaps, detergents or cosmetics, or, as noted above, pain associated with removal of fat deposits.
  • the benefits of alkaline pH include higher penetration capability and adjustment of the active form of the fat dissolving compound when the anesthetic is used in conjugation therewith.
  • the pKa of the deoxycholic acid is 6.58 and the pH of fat is neutral.
  • DCA deoxycholic acid
  • nutrients are supplied via transdermal administration.
  • the formulations of the invention can deliver to tired muscles sufficient amounts of a neutralizing agent for lactic acid, such as sodium bicarbonate, to relieve the burning sensation felt by the athlete due to the buildup of lactic acid. This permits the athlete to continue to perform at optimum level for longer periods of time.
  • athletes or others “working out” are expending high amounts of energy and are in need of energy generation especially in those areas of their musculature that are involved in performing workouts and, therefore, need to consume large numbers of calories.
  • These nutrients can be supplied directly rather than requiring oral ingestion which is counterproductive and relatively slow.
  • the formulations of the invention and methods of the invention are useful in promoting weight loss as the caloric intake required to assuage feelings of hunger is lower than that ordinarily experienced by consuming food conventionally.
  • suitable subjects for the methods of the invention include individuals seeking to control their caloric intake in order to adjust their weight. In view of the generally acknowledged obesity epidemic in the United States in particular, this is an important group of subjects benefitting from the methods of the invention.
  • ingredients will vary depending on the object of the administration.
  • Simple nutrients such as amino acids, glucose, fructose, simple fats, various vitamins, cofactors and antioxidants as well as somewhat more complex foodstuffs can be administered as well as neutralizing agents, depending on the need.
  • the components for athletic performance include beta-alanine, L-carnitine, adenosine triphosphate, dextrose, creatine monohydrate, beta hydroxy-betamethylbutyrate (HMB), branched chain amino acids (leucine, isoleucine, valine), glutathione, sodium phosphate, and caffeine.
  • Components for medical nutrition include amino acids, dextrose, lipids, Na + , K + , Ca 2+ , Mg 2+ , acetate, Cl ⁇ , P, multivitamin, and trace elements. While components for weight loss include conjugated linoleic acids, ephedra, caffeine, and salicin.
  • the formulation comprises:
  • LipmaxTM in an amount between about 1-20% w/w
  • Benzyl alcohol in an amount between about 0.25 to 5% w/w;
  • Menthol in an amount between about 0.1-5% w/w;
  • Pluronic® in an amount between about 0.1-5% w/w
  • Propylene glycol in an amount between about 0.5-10% w/w;
  • Almond oil in an amount between about 0.5-10% w/w;
  • Cetyl alcohol in an amount between about 0.5-10% w/w;
  • Lecithin in an amount less than about 12% w/w;
  • Cetiol Ultimate® in an amount less than about 10% w/w
  • Ethanol in an amount between about 0.5-10% w/w.
  • the formulation comprises:
  • LipmaxTM in an amount between about 1-20% w/w
  • Benzyl alcohol in an amount between about 0.25 to 5% w/w;
  • Menthol in an amount between about 0.1-5% w/w;
  • Durasoft® in an amount between about 0.1-5% w/w
  • Pluronic® in an amount between about 0.1-5% w/w
  • Propylene glycol in an amount between about 0.5-10% w/w;
  • Almond oil in an amount between about 0.5-10% w/w;
  • Zinc oxide in an amount less than about 2% w/w;
  • Cetyl alcohol in an amount between about 0.5-10% w/w;
  • Ethanol in an amount between about 0.5-10% w/w.
  • the formulation comprises:
  • Phospholipon® 90G in an amount between about 0.5-16% w/w;
  • Myritol® 312 in an amount between about 0.5-10% w/w;
  • Isopropyl palmitate in an amount between about 1-10% w/w;
  • Cetiol® Ultimate in an amount between about 0.25-5% w/w;
  • Stearic Acid in an amount between about 0.25-5% w/w;
  • Cetyl alcohol in an amount between about 0.25-5% w/w;
  • Benzyl alcohol in an amount between about 0.25-5% w/w;
  • Propylene glycol in an amount between about 0.25-5% w/w;
  • Glycerin in an amount between about 0.25-5% w/w;
  • Ethanol in an amount between about 0.25-5% w/w;
  • Pluronic® in an amount between about 0.1-5% w/w
  • LipmaxTM in an amount between about 1-20% w/w
  • Sodium bicarbonate in an amount between about 1-32% w/w.
  • the formulation comprises:
  • SiligelTM in an amount between about 1-5% w/w
  • Phospholipon® 90G in an amount between about 0.5-16% w/w;
  • Myritol® 312 in an amount between about 0.5-10% w/w;
  • Isopropyl palmitate in an amount between about 1-10% w/w;
  • Cetiol® Ultimate in an amount between about 0.25-5% w/w;
  • Stearic Acid in an amount between about 0.25-5% w/w;
  • Cetyl alcohol in an amount between about 0.25-5% w/w;
  • Benzyl alcohol in an amount between about 0.25-5% w/w;
  • Propylene glycol in an amount between about 0.25-5% w/w;
  • Glycerin in an amount between about 0.25-5% w/w;
  • Ethanol in an amount between about 0.25-5% w/w;
  • LipmaxTM in an amount less than about 20% w/w
  • Sodium bicarbonate in an amount between about 1-32% w/w.
  • the formulation comprises:
  • Phospholipon® 90G in an amount between about 0.5-10% w/w;
  • Myritol® 312 in an amount between about 0.5-10% w/w;
  • Isopropyl palmitate in an amount between about 0.5-10% w/w;
  • Cetiol® Ultimate in an amount less than about 10% w/w;
  • Stearic Acid in an amount between about 0.25-5% w/w;
  • Cetyl alcohol in an amount between about 0.25-5% w/w;
  • Benzyl alcohol in an amount between about 0.25-5% w/w;
  • Propylene glycol in an amount between about 0.25-5% w/w;
  • Glycerin in an amount between about 0.25-5% w/w;
  • Ethanol in an amount between about 0.25-5% w/w;
  • Sodium bicarbonate in an amount between about 1-35% w/w.
  • the formulation comprises:
  • Phospholipon® 90H in an amount between about 0.5-20% w/w;
  • Myritol® 312 in an amount between about 0.5-10% w/w;
  • Isopropyl palmitate in an amount between about 0.5-20% w/w;
  • Cetiol® Ultimate in an amount less than about 10% w/w;
  • Stearic Acid in an amount between about 0.25-5% w/w;
  • Cetyl alcohol in an amount between about 0.25-5% w/w;
  • Benzyl alcohol in an amount between about 0.25-5% w/w;
  • Propylene glycol in an amount between about 0.25-5% w/w;
  • Glycerin in an amount between about 0.25-5% w/w;
  • Ethanol in an amount between about 0.25-5% w/w;
  • Sodium bicarbonate in an amount between about 1-35% w/w.
  • the formulation comprises:
  • Phospholipon® 90H in an amount between about 0.5-20% w/w;
  • Phospholipon® 90G in an amount between about 0.5-20% w/w;
  • Myritol® 312 in an amount between about 0.5-10% w/w;
  • Isopropyl palmitate in an amount between about 0.5-20% w/w;
  • Cetiol® Ultimate in an amount less than about 10% w/w;
  • Stearic Acid in an amount between about 0.25-5% w/w;
  • Cetyl alcohol in an amount between about 0.25-5% w/w;
  • Benzyl alcohol in an amount between about 0.25-5% w/w;
  • Propylene glycol in an amount between about 0.25-5% w/w;
  • Glycerin in an amount between about 0.25-5% w/w;
  • Ethanol in an amount between about 0.25-5% w/w;
  • Sodium bicarbonate in an amount between about 1-35% w/w.
  • the formulation comprises:
  • Pluronic® gel 30% in an amount between about 5-30% w/w;
  • Isopropyl palmitate in an amount between about 0.5-20% w/w;
  • Stearic Acid in an amount between about 0.25-10% w/w;
  • Cetyl alcohol in an amount between about 0.25-10% w/w;
  • Benzyl alcohol in an amount between about 0.25-5% w/w;
  • Almond oil in an amount between about 0.5-10% w/w;
  • Propylene glycol in an amount between about 0.25-10% w/w;
  • Ethanol in an amount between about 0.25-5% w/w;
  • Sodium bicarbonate in an amount between about 1-32% w/w.
  • the formulation comprises:
  • SiligelTM in an amount less than about 5% w/w
  • Isopropyl palmitate in an amount between about 0.5-10% w/w;
  • Stearic Acid in an amount between about 0.25-10% w/w;
  • Cetyl alcohol in an amount between about 0.25-10% w/w;
  • Glycerin in an amount between about 0.25-5% w/w;
  • LipmaxTM in an amount between about 0.25-10% w/w
  • Ethanol in an amount less than about 5% w/w
  • Benzyl alcohol in an amount less than about 5% w/w;
  • Sodium bicarbonate in an amount between about 1-32% w/w.
  • the formulation comprises:
  • Aveeno® in an amount between about 20-85% w/w
  • the formulation comprises:
  • Aveeno® in an amount between about 20-85% w/w
  • Sodium bicarbonate (Milled #7) in an amount between about 15-45% w/w.
  • the formulation comprises:
  • SiligelTM in an amount less than about 5% w/w
  • Isopropyl palmitate in an amount between about 0.5-10% w/w;
  • Stearic Acid in an amount between about 0.25-5% w/w;
  • Cetyl alcohol in an amount between about 0.25-10% w/w;
  • Almond oil in an amount between about 0.5-10% w/w;
  • Propylene glycol in an amount between about 0.25-10% w/w;
  • Ethanol in an amount less than about 5% w/w
  • Benzyl alcohol in an amount less than about 5% w/w;
  • Sodium bicarbonate in an amount between about 1-32% w/w.
  • the formulation itself is simply placed on the skin and spread across the surface and/or massaged to aid in penetration.
  • the amount of formulation used is typically sufficient to cover a desired surface area.
  • a protective cover is placed over the formulation once it is applied and left in place for a suitable amount of time, i.e., 5 minutes, 10 minutes, 20 minutes or more; in some embodiments an hour or two.
  • the protective cover can simply be a bandage including a bandage supplied with a cover that is impermeable to moisture. This essentially locks in the contact of the formulation to the skin and prevents distortion of the formulation by evaporation in some cases.
  • the schedule of application is dependent on the nature of the treatment being administered. Repeated application is often desirable, for example, during intermittent types of exercise. Alternatively, the formulation may be left in place, preferably covered during athletic performance. Application to supply nutrients to patients may also be for prolonged periods of time.
  • composition may be applied to the skin using standard procedures for application such as a brush, a syringe, a gauze pad, a dropper, or any convenient applicator. More complex application methods, including the use of delivery devices, may also be used, but are not required.
  • the surface of the skin may also be disrupted mechanically by the use of spring systems, laser powered systems, systems propelled by Lorentz force or by gas or shock waves including ultrasound and may employ microdermabrasion such as by the use of sandpaper or its equivalent or using microneedles or electroporation devices.
  • Simple solutions of the agent(s) as well as the above-listed formulations that penetrate intact skin may be applied using occlusive patches, such as those in the form micro-patches.
  • External reservoirs of the formulations for extended administration may also be employed.
  • the penetrants of the invention have wide application and are applicable to a number of drug delivery scenarios and can be adapted to the administration of a wide variety of therapeutic agents in addition to carbonate salts.
  • the extent of delivery is dependent on the application—simple transdermal transmission to a site of action as in the case of local anesthetics, treatment of fingernails or toenails, or volume and texture enhancement of tissue are examples of local delivery.
  • delivery of nutrients and in some cases antiviral agents and anti-infective agents as well as cannabinoids and pain killers such as NSAIDs can be systemic.
  • epinephrine is beneficial as is the use of alkali pH—e.g., pH 8-10. Because epinephrine is not stable at high pH's, either it should be delivered separately in tandem with the delivery of the anesthetic itself in a composition of suitable pH, or it may be stabilized by adding an appropriate stabilizing agent such as Desferal® in the context of the anesthetic composition itself.
  • the disclosure is directed to administering a local anesthetic to a subject transdermally and a formulation which contains an effective amount of anesthetic along with 25%-70% w/w or 30%-60% w/w or 30%-40% w/w of lecithin organogel typically wherein the lecithin organogel comprises soy lecithin in combination with isopropyl palmitate or isopropyl myristate and benzyl alcohol in the range of 0.5%-20% w/w or 0.9%-2% w/w benzyl alcohol optionally including 1%-5% w/w or 2%-4% w/w menthol wherein the composition is topped off with a polar solution, typically an aqueous solution comprising 15%-50% w/w or 20%-40% w/w or 20%-30% w/w poloxamer, typically Pluronic® or alternatively may be an anhydrous composition comprising bile salts such as deoxycholic acid or sodium deoxycholate in the
  • bile salts are facial amphiphiles and include salts of taurocholic acid, glycocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, cholic acid, deoxycholic acid, Detergents are also useful in lieu of bile salts and include Tween® 80 and Span® 80.
  • the pH of the compositions is adjusted to 9-11, typically 10-11.
  • the formulations are applied to the desired area of the skin and may be covered, for example, with SaranTM wrap for a suitable amount of time. Following the treatment, the skin can be repaired by applying a composition comprising linoleic acid.
  • the active component is a nutrient or combination of nutrients, or a dicarboxylic anhydride.
  • Systemic administration of nutrients is especially important as is the treatment of viral infection, bacterial infection or other microbial infection using standard methods.
  • the therapeutic agent is cytisine, also known as baptitoxine and sophorine, and is an alcohol that occurs naturally in several plant genera.
  • Suitable therapeutic agents to be delivered in using the buffering formulations for treatment of post procedural bruising include helenalin, a sesquiterpene, a lactone as well as Vitamin K.
  • the formulation based on helenalin may be accompanied by irradiation with light of wavelength 577-595 nm.
  • Other therapeutic agents include Botox®, flavonoids, skin lighteners and materials that promote collagen biosynthesis.
  • LIP lecithin organogel comprised of a 1:1 molar mixture of soy lecithin containing 96% phosphatidyl choline and isopropyl palmitate
  • PLU-F127 represents the detergent poloxamer F127 granules
  • PLU-Water represents PLU-F127 dissolved in deionized water.
  • Pluronic® F127 30% gel could be used
  • Durasoft® is a commercially available form of emulsifier.
  • Formulation Formulation Component 28 (% w/w) 28 (% w/w) LIP 6 12 Benzyl alcohol 1 1 Menthol 0.5 0.5 Pluronic ® Granules 4.2 4.2 Water 37.8 37.8 Sodium Carbonate 7 7 Sodium 28 28 Bicarbonate Propylene Glycol 3 3 Almound Oil 3 3 Acetyl Alcohol 2 2 Lecithin 3 Cetiol ® Ultimate 3 (mixture of tridecane and undecane) Ethanol 1.5 1.5
  • Phase Chemicals wt % mass (g) A Tranexamic Acid 0.00% 0.00 A Water 43.00% 47.30 Phase A Used 43.00% 43.00 B Phospholipon ® 90G 8.00% 8.00 B Myritol ® 312 5.00% 5.00 B Isopropyl palmitate 6.00% 6.00 B Cetiol ® Ultimate 2.00% 2.00 B Stearic Acid 2.00% 2.00 B Cetyl alcohol 2.00% 2.00 B Benzyl alcohol 1.00% 1.00 C Propylene glycol 0.90% 0.90 C Glycerin 0.60% 0.60 C EtOH 1.00% 1.00 C NaOH sol.
  • the formulation for transdermal delivery of a buffering agent through the skin of a subject comprises a formulation of Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12, Table 13, Table 14, Table 15, Table 16, Table 17, Table 18, Table 19, Table 20, Table 21, Table 22, Table 23, Table 24, Table 25, Table 26, Table 27, Table 28, Table 29, Table 30, Table 31, Table 32, Table 33, Table 34, Table 35, Table 36, Table 37, Table 38, Table 39, Table 40, Table 41, or Table 42.
  • the formulations disclosed herein are configured for buffering therapy with or without an additional therapeutic agent. Because the principles of the invention may be practiced in a number of configurations beyond those shown and described, it is to be understood that the invention is not in any way limited by the exemplary embodiments but is generally directed to a transdermal formulation and is able to take numerous forms to do so without departing from the spirit and scope of the invention. It will also be appreciated by those skilled in the art that the present invention is not limited to the particular components disclosed but may instead entail other functionally comparable formulation components, now known or later developed, without departing from the spirit and scope of the invention.
  • the open-ended transitional term “comprising” encompasses all the expressly recited elements, limitations, steps and/or features alone or in combination with un-recited subject matter; the named elements, limitations and/or features are essential, but other unnamed elements, limitations and/or features may be added and still form a construct within the scope of the claim.
  • the meaning of the open-ended transitional phrase “comprising” is being defined as encompassing all the specifically recited elements, limitations, steps and/or features as well as any optional, additional unspecified ones.
  • the meaning of the closed-ended transitional phrase “consisting of” is being defined as only including those elements, limitations, steps and/or features specifically recited in the claim, whereas the meaning of the closed-ended transitional phrase “consisting essentially of” is being defined as only including those elements, limitations, steps and/or features specifically recited in the claim and those elements, limitations, steps and/or features that do not materially affect the basic and novel characteristic(s) of the claimed subject matter.
  • the open-ended transitional phrase “comprising” (along with equivalent open-ended transitional phrases thereof) includes within its meaning, as a limiting case, claimed subject matter specified by the closed-ended transitional phrases “consisting of” or “consisting essentially of.”
  • embodiments described herein or so claimed with the phrase “comprising” are expressly or inherently unambiguously described, enabled and supported herein for the phrases “consisting essentially of” and “consisting of.”

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US16/132,358 US20190083386A1 (en) 2017-09-15 2018-09-14 Methods and formulations for transdermal administration of buffering agents
US16/546,260 US10632146B2 (en) 2017-09-15 2019-08-20 Method of administration and treatment
US16/546,256 US10639326B2 (en) 2017-09-15 2019-08-20 Method of administration and treatment
US16/866,466 US10933088B2 (en) 2017-09-15 2020-05-04 Method of administration and treatment
US17/168,111 US20210228623A1 (en) 2017-09-15 2021-02-04 Method of administration and treatment
US17/168,114 US11730756B2 (en) 2017-09-15 2021-02-04 Method of administration and treatment
US17/488,143 US20220016158A1 (en) 2017-09-15 2021-09-28 Method of administration and treatment
US17/488,132 US11357792B2 (en) 2017-09-15 2021-09-28 Method of administration and treatment
US17/488,154 US20220016159A1 (en) 2017-09-15 2021-09-28 Method of administration and treatment
US17/497,794 US11793830B2 (en) 2017-09-15 2021-10-08 Method of administration and treatment
US17/497,799 US11389472B2 (en) 2017-09-15 2021-10-08 Method of administration and treatment
US17/514,653 US11744853B2 (en) 2017-09-15 2021-10-29 Method of administration and treatment
US18/331,875 US20240033284A1 (en) 2017-09-15 2023-06-08 Method of administration and treatment

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US201862639904P 2018-03-07 2018-03-07
PCT/US2018/028017 WO2018195111A1 (en) 2017-04-17 2018-04-17 Parenteral non-systemic administration of buffering agents for inhibiting metastasis of solid tumors, hyperpigmentation and gout
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US17/168,111 Abandoned US20210228623A1 (en) 2017-09-15 2021-02-04 Method of administration and treatment
US17/168,114 Active 2038-12-31 US11730756B2 (en) 2017-09-15 2021-02-04 Method of administration and treatment
US17/488,143 Abandoned US20220016158A1 (en) 2017-09-15 2021-09-28 Method of administration and treatment
US17/488,154 Abandoned US20220016159A1 (en) 2017-09-15 2021-09-28 Method of administration and treatment
US17/488,132 Active US11357792B2 (en) 2017-09-15 2021-09-28 Method of administration and treatment
US17/497,794 Active US11793830B2 (en) 2017-09-15 2021-10-08 Method of administration and treatment
US17/497,799 Active US11389472B2 (en) 2017-09-15 2021-10-08 Method of administration and treatment
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US16/546,256 Expired - Fee Related US10639326B2 (en) 2017-09-15 2019-08-20 Method of administration and treatment
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US17/168,111 Abandoned US20210228623A1 (en) 2017-09-15 2021-02-04 Method of administration and treatment
US17/168,114 Active 2038-12-31 US11730756B2 (en) 2017-09-15 2021-02-04 Method of administration and treatment
US17/488,143 Abandoned US20220016158A1 (en) 2017-09-15 2021-09-28 Method of administration and treatment
US17/488,154 Abandoned US20220016159A1 (en) 2017-09-15 2021-09-28 Method of administration and treatment
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