Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • 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
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
  • A61K8/04—Dispersions; Emulsions
  • A61K8/06—Emulsions
  • A61K8/062—Oil-in-water emulsions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/34—Alcohols
  • A61K8/345—Alcohols containing more than one hydroxy group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/35—Ketones, e.g. benzophenone
  • A61K8/355—Quinones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/60—Sugars; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/67—Vitamins
  • A61K8/678—Tocopherol, i.e. vitamin E
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
  • A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9771—Ginkgophyta, e.g. Ginkgoaceae [Ginkgo family]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
  • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
  • A61K8/9783—Angiosperms [Magnoliophyta]
  • A61K8/9789—Magnoliopsida [dicotyledons]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
  • A61K2800/21—Emulsions characterized by droplet sizes below 1 micron

Definitions

• the present invention relates to compositions enabling the external administration of various pharmaceutical or cosmetic agents having at ieast one hydrophobic moiety in a sub-micron oil-in-glycerin composition made of highly biodegradable ingredients of vegetable origin and more particularly to their enhanced stratum corneum penetration and dermal and transdermal applications.
• the stratum corneum the outer horny layer of the skin, is a complex structure of compact keratinized cell remnants separated by lipid domains. Compared to the oral or gastric mucous, the stratum corneum is much less permeable to outside molecules.
• the flux of a drug across the skin can be increased by changing either a) the resistance (the diffusion coefficient), or b) the driving force (the solubility of the drug in the stratum corneum and consequently the gradient for diffusion).
• Many enhancer compositions have been developed to change one or more of these factors, and are known in the art.
• enhancers consisting of diethylene glycol monoethyl or monomethyl ether with propylene glycol monolaurate and methyl laurate are disclosed in U.S. Pat. No. 4,973,468 as enhancing the transdermal delivery of steroids such as progestogens and estrogens.
• a dual enhancer consisting of glycerol monolaurate and ethanol for the transdermal delivery of drugs is shown in U.S. Pat. No. 4,820,720.
• 4,863,970 shows penetration-enhancing compositions for topical application comprising an active permeant contained in a penetration-enhancing vehicle containing specified amounts of one or more cell-envelope disordering compounds such as oleic acid, oleyl alcohol, and glycerol esters of oleic acid; a C.sub.2 or C.sub.3 alkanol and an inert diluent such as water.
• a penetration-enhancing vehicle containing specified amounts of one or more cell-envelope disordering compounds such as oleic acid, oleyl alcohol, and glycerol esters of oleic acid; a C.sub.2 or C.sub.3 alkanol and an inert diluent such as water.
• World Patent 96/37231 teaches the use of acyl lactylates as permeation enhancers for drug delivery purposes.
• This patent is specific to esters of fatty acids and lactic acid such as caproyl lactylic acid and lauroyl lactylic acid. It is stated that the salt form of acyl lactylates are not effective as permeation enhancers.
• U.S. Pat. No. 4,855,294 discloses compositions for reducing skin irritation caused by drug/enhancer compositions having skin irritation properties comprising a percutaneously absorbable drug, a binary enhancer composition consisting of a solvent and a cell envelope disordering compound, combined with an amount of glycerin sufficient to provide an anti-irritating effect.
• U.S. Pat. No 6,004,566 disclose oil-in-water sub micron emulsions that enhance absorption due reduction of mean particles size to below half a micron. However, two components are needed for stabilizing the emulsion, an emulsifying stabilizer and a surfactant.
• a permeation enhancer should have the ability to enhance the permeability of the skin for at least one and preferably a significant number of agents. More importantly, it should be able to enhance the skin permeability such that the agent delivery rate from a reasonably sized system (preferably 5-50 cm. sup.2) is at therapeutic levels. Additionally, the enhancer when applied to the skin surface, should be non-toxic, non-irritating on prolonged exposure and under occlusion, and non-sensitizing on repeated exposure. Preferably, it should be odorless and capable of delivering agents without producing burning or tingling sensations.
• the objective of the present invention to furnish a carrier system for bioactive agents comprising at least one hydrophobic moiety, whereas an enhanced absorption is obtained while avoiding the side effects associated with many of the chemical enhancers such as alcohols or sodium lauryl sulfate and also provide for safe and biodegradable product and also free of synthetic polymers and also free of preservatives.
• the advent of genetic engineering and especially recombinant DNA technology has made available many biologically active peptides.
• the peptides include human insulin, human growth hormone, bovine growth hormone, endorphins and enkephalines, calcitonin, interferons, interleukins and other lymphokines, TPA, vasopressin, oxytocin and many others.
• Peptides are made up of groups of amino acid linked together by amide bonds.
• the distinction between peptides and proteins which also are groups of amino acids linked by amide bonds is somewhat vague, but usually they are separated by molecular weight or the number of amino acids in the chain.
• peptidases break down these peptides, rapidly destroying their biological activity, some peptides, e.g., Angiotensin 1 and bradykinin, have a half-life of less than 30 seconds.
• a transdermal delivery system for peptides would be ideal in many ways.
• Oil in glycerin emulsions have been claimed in PCT/IL00/00142.
• Said specification describes a composition of matter comprising a stable oil-in-glycerin emulsion containing at least one oil, at least one emulsifying stabilizer and glycerin.
• Said invention relates to oil-in-glycerin emulsions in which the oil is the internal phase and the glycerin is the external, continuous phase.
• bioactive agents having at least one hydrophobic moiety such as phytomedicine, peptides, drugs and cosmeceuticals formulated in homogenized oil in glycerin permeation enhancer compositions of mean droplet size of below one micron better penetrate the stratum corneum natural protective layer of the skin and show higher dermal concentration and/or biological dermal effect.
• Bioactive agents that will not be biodegraded in the dermis and that will accumulate in the dermis, will finally diffuse into the circulation and will result in systemic effect via transdermal route.
• a cosmetic or pharmaceutical composition in the form of an oil-in-glycerin emulsion with mean droplet size below one micron, comprising a continuous giycerin phase at least one vegetable oil comprising an internal phase at least one emulsifying stabilizer and at least one bioactive compound comprising at least one hydrophobic moiety within its structure, wherein said composition facilitates stratum corneum penetration and dermal penetration of said bioactive compound.
• the present invention provides a stable oil-in-glycerin sub-micron emulsion that can perform as an adequate storage and delivery vehicle bringing forth enhanced stratum corneum and or skin penetration properties for bioactive ingredients having at least one hydrophobic moiety, including peptides, drugs, phytochemicals and oligonucleotides or liposacharides.
• this invention comprises an admixture of a pharmacologically active agent having at least one hydrophobic moiety formulated in a penetration enhancer oil in glycerin emulsion composition for the administration of therapeutically effective amounts of said active agent.
• the invention provides a method for enhancing the rate of penetration of a pharmacologically active agent having at least one hydrophobic moiety through the stratum corneum, wherein the method comprises administering to the skin of the patient undergoing treatment a mixture of the pharmacologically active agent in the permeation enhancer composition as described herein.
• the emulsifying stabilizer is of vegetable origin made by condensation of at least one fatty acid or alcohol with a carbohydrate or poly-carbohydrate.
• Poration enhancement or “permeation enhancement” as used herein relates to an increase in the permeability of skin to a pharmacologically active agent, having at least one hydrophobic moiety or increase in the rate at which the agent permeates into and through the skin.
• transdermal ⁇ rug delivery as used herein is intended to denote the term in its conventional sense, i.e., to indicate delivery of a drug by passage through the skin and into the blood stream.
• Topical drug delivery is used to mean local administration of a topical drug as in, for example, the treatment of various skin disorders.
• HLB is an arbitrary scale from 0 to 40 depicting the Hydrophilic/Lipophilic Balance of a surfactant. Products with low HLB are more oil soluble. High HLB represents good water solubility. Note that HLB is a numerically calculated number based on the surfactants molecular structure. It is not a measured parameter.
• a cosmetic or pharmaceutical composition of oil-in-glycerin emulsion with mean droplet size below one micron, e.g. sub-micron, comprising:
• bioactive agents incorporated in the present homogenized sub-micron oil-in-glycerin penetration enhancer composition as formed from components A, B and C above of mean droplets size of below 1 micron better penetrates into and through the skin to obtain significant dermai or transdermal activity.
• Even peptides of MW larger then 1 ,000 or with 20 or more amino acids have been unexpectedly found to pass the stratum corneum into the skin inner layers and also sub-dermal.
• oil-in-glycerin emulsion by plain high shear homogenization in contrast to the common art, where a high pressure homogenization is required to reduce emulsions droplet to below one micron.
• high pressure homogenization is required to reduce emulsions droplet to below one micron.
• single pass in high pressure homogenization is enough to further reduce particles size.
• oil-in-glycerin emulsion show lower distribution of sizes around mean in comparison to regular oil- in-water emulsions, especially less energy, time and pressure is required to obtain uniform particle size.
• the following quantities are preferable: a) said vegetable oil is present in an amount ranging from about 1-30 wt/wt %, or from 2-20 wt/wt %; b) said emulsifying stabilizer is present in an amount ranging from about 0.1-20 wt/wt %, or from about 0.1-5 wt/wt %; and c) said bioactive component is present in an amount ranging from about 0.1-20 wt/wt %.
• said emulsifying stabilizer is biodegradable (i.e., degradable in the human body and the environment) and is substantially free of polyoxyethylene or propylene glycols and is preferably of botanical origin.
• a hydrophobic moiety in the bioactive agent may be a benzene or cyclic ring or heterocyclic backbone or hydrocarbon side chain, etc.
• said glycerin constitutes a continuous phase of said emulsion and a minor portion of water is included in said glycerin phase.
• Example of vegetable oils are: isopropyl miristate, jojoba oil, almond oil, avocado oil, coconut oil, capric-caprylic tryglyceride of fractionated coconut oil, nutmeg oil, castor oil, olive oil and oleic acid, soybean oil etc.
• the oil may be saponifiable or unsaponifiable and liquid or solid at room temperature.
• composition of matter comprising oil-in-glycerin emulsion and bioactive agent, wherein the bioactive component is selected from the group consisting of a phytochemical (plant origin or plant extract) or drug or a peptide or nucleotide or glycolipid or cosmeceutics.
• bioactive component is selected from the group consisting of a phytochemical (plant origin or plant extract) or drug or a peptide or nucleotide or glycolipid or cosmeceutics.
• anti- histamines anti-inflammatory agents, analgesics, anesthetics, anti-perspirants, anti- dandruffs, anti-microbial agents, astringents, counter-irritants, depigmenting agents, bleaching agents, and steroids
• said emulsifying stabilizer is selected from the group consisting of at least one fatty acid or fatty alcohol condensation with natural hydrophilic molecule to form an amphiphilic and surface active agent with HLB of 5 to 16, that is the emulsifying stabilizer.
• the hydrophilic molecule may be selected from carbohydrates or amino acids or amine containing carbohydrate molecules prevailing in the vegetable kingdom.
• the carbohydrate may be a saccharide or an acid such as tartaric or citric acid and the like.
• the amine carbohydrate molecule is one having a natural carbohydrate backbone and at least one nitrogen atom such as amine or tertiary amine or amide and at least one alcohol or carboxylic acid moiety, for example: betain or choline.
• said emulsifying stabilizer is selected from the group consisting of at least one fatty acid condensation with a carbohydrate or with a polycarbohdrate, wherein said carbohydrate is a saccharide, a disaccharide or a polysaccharide, said surfactant and stabilizer is a liquid crystal lyothropic lamellar forming amphiphil, and said liquid-crystal-forming surfactant and stabilizer is a sucrose ester or cetearyl glucoside.
• the combination of an oil-in-glycerin emulsion and a bioactive agent facilitates the dispersion of a water insoluble bioactive component in a biocompatible, safe and convenient dosage form, while avoiding the disadvantages associated with classical vehicles comprising ionic or polymeric and synthetic surfactants or alcohols or preservatives.
• oil-in-glycerin emulsions are self preserving and passing the preservative efficacy test also named challenge test as specified in USP or BP or CTFA guidance.
• oil-in-glycerin emulsions are pleasant for use on the skin and on mucous membranes such as the oral cavity, ears and scalp and are also ingestable when prepared from food grade ingredients. Additionally, the emulsions of the present invention are well accepted organoleptically and physiologically, hence, offering good patient compliance. Stable oil-in-glycerin emulsions offering water free surrounding with potential for stabilizing bioactive agents that are sensitive to water and that are rapidly degrading in aqueous medium.
• the present invention provides an emulsion which may be produced alcohol and/or water free, has a prolonged shelf life and improved heat stability for withstanding elevated temperatures during a long pereriod of time. Furthermore, the oil-in-emulsion resists sub-zero temperatures, it is stable upon freezing and does not break at minus 20 °C. Thaw of oil-in-glycerin emulsions is simple and does not affect original properties.
• Oil-in-glycerin emulsions are easily prepared. It is possible to produce coarse oil-in-glycerin emulsions of 5 to 10 microns droplet size with simple stirring and without resort to the use of high shear mixers. It is also easy to control droplet size by the utilization of appropriate mixing equipment and energy input. Fine oil-in- glycerin emulsions, having a mean droplet size of 1 to 5 micron, are achieved with a conventional "Silverson" type mixer at moderate speed and a short duration of mixing. High shear homogenizer mixing is sufficient to obtain emulsions containing 0.5 to 1 microns mean droplets size, consequent high pressure homogenization produces 0.5 to 0.1 mean particle size.
• Typical oil-in-glycerin emulsions are characterized by having viscosity of 5,000 to 25,000 centipoise and newtonian flow. Viscosity may be reduced by the addition of water.
• the oil-in-glycerin emulsion viscosity may be controlled by addition of viscosity forming agents, such as, carbomers, carbopol, cellulose derivatives or natural gums, such as xanthan gum or colloidal fumed silica. Also, non neutinian characteristics are easily achieved by the same additives.
• Oil-in-glycerin emulsions are suitable for use in humans and animals, on skin, scalp, mucous membrane, ear instillation, oral rinse, and f. Buccal transmucosal applications
• oil-in-glycerin emulsions are basically newtonian and flow easily out of any commercial consumer product orifice opening or dropper. Oil-in-glycerin emulsions may be packaged in glass, aluminum or plastic containers or designed into patch device.
• a bioactive agent may be a phytochemical, drug, cosmeceutical, peptide, oligonucleotide or liposaccharide or combinations thereof.
• the botanical extract of the present invention may have anti-inflammatory, anti-allergic, anti-bacterial, anti-parasitic, anti-viral, immunity modulation and/or anti- oxidant, anti-psoriatic, sun-protecting, anti-aging, rejuvenating, anti-wrinkle or anti- cancer properties.
• Example of botanical bioactive agents are: polyphenols, isoflavones, resveratrol, soy isoflavones, grape seed extract polyphenols, curcumin, epigenin.
• Anti-inflammatory plant extracts such as aloe vera, echinacea and chamomile hammamekis extracts, anti-psoriatic such as Chinese zizipus jujuba.
• Astringents such as hammamelis anti bacterial such as artemisia, chamomile, golden seal.
• Immune modulators such as echinacea, anti-aging or anti-cancer or anti-photo damage, anti-inflammatory such as feverfew parthenolides, rejuvenation agents, carotenoids, beta-carotene, lycopene, tocopheryl and retinol.
• drug or "pharmacologically active agent” as used herein is intended to mean a compound or composition of matter which, when administered to an organism (human or animal) induces a desired pharmacological and/or physiologic effect by local and/or systemic action.
• the terms include the therapeutic or prophylactic agents in all major therapeutic or prophylactic areas of medicine.
• drugs useful in conjunction with the present invention include: anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antihelminthics; antiarthritics; antiasthmatic agents; anficholinergic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents, antimigraine preparations; , anti-motion sickness drugs; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; antihypertensives; diuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough and cold preparations, including decon
• drug as used herein also include locally administered topical medicaments such as antibacterial agents, antifungals, antimicrobials, cutaneous growth enhancers, antipsoriatics, anti-acne medicaments, and the like.
• the invention is thus, in one embodiment, a method for enhancing the rate of penetration of a pharmacologically active agent into and/or through the skin, wherein the method involves co-administration of the agent through a predetermined area of intact skin, and for a predetermined period of time, of the selected agent in a permeation enhancer composition comprising oil in glycerin emulsion.
• a transdermal delivery system for the administration of drug and enhancer composition as described herein may take the form of a depot-type device, matrix or laminate-type device, bandages, or the like.
• a preferred transdermal delivery system for use herein is a laminated composite that contains one or more drug/permeation enhancer reservoirs, a backing layer and, optionally, one or more other layers, e.g., additional drug and/or enhancer reservoirs, release rate controlling membranes, or the like (as those skilled in the art of transdermal delivery will readily appreciate).
• the backing layer will function as the primary structural element of the device and provide the device with much of its flexibility.
• This layer also serves as a protective covering to prevent loss of drug and enhancer via transmission through the upper surface of the device.
• the backing layer may also be used to impart the device with a desirable or necessary degree of occlusivity which in turn causes the area of skin on which the device is placed to become hydrated.
• the backing is preferably made of a sheet or film of a flexible elastomeric material. Suitable, flexible elastomeric materials include polyether block amide copolymers, polyurethanes, silicone elastomers, rubber-based polyisobutylene, styrene, polyethylene, polypropylene, polyesters, or the like.
• the preferred polymer used for the backing will depend primarily on the particular pharmacologically active agent incorporated into the device.
• the laminated composite Prior to use, also includes a release liner layer. Just prior to use, this layer is removed from the device to expose the basal surface of the device.
• the release liner will normally be made from a drug/enhancer impermeable material that is inherently “strippable” or rendered so by techniques such as silicone or fluorocarbon treatment.
• Preferred daily dosages obtained with the present methods and systems will, similarly, vary with the drug administered.
• the targeted daily dosage will depend on the individual being treated, the indication addressed, the length of time the individual has been on the drug, and the like.
• the invention comprises a drug delivery device in the form of a patch administering a pharmacologically active agent through a selected area of skin.
• the device is preferably in the form of a laminated composite which includes a drug reservoir layer containing both the agent to be administered and the permeation enhancer composition of the invention.
• Oil-in-glycerin emulsion may comprise also known in the art additives, such as anti-oxidants, coloring, flavoring and fragrance.
• Oily and glycerin phases are heated separately to 70°C until all ingredients melt and are well dissolved.
• the phases are combined while mixing.
• Mixing may be performed with any mixer, blender, homogenizer, etc. which is used for producing emulsions.
• Oil-in-glycerin emulsions may also be prepared by heating all the ingredients, including oil, glycerin and emulsifying stabilizers, except for heat sensitive bioactives, in a single batch, mixing to achieve melting of solids and with continued mixing until cooled to room temperature, with the addition of any heat sensitive bioactives to the cooling mixture.
• MCT Medium chain tryglyceride
• Table 1 Mean particle size of example 1 formula at various mixing methods.
• Oil-in-glycerin emulsion Oil-in-glycerin emulsion; plain liquid base Ingredient %W/W
• MCT Medium chain tryglyceride
• Sisterna S50 Sucrose ester
• Table 2 Mean particle size formula of example 2 at various mixing methods.
• Oil-in-glycerin emulsion Oil-in-glycerin emulsion; plain liquid base Ingredient %W ⁇ /V
• MCT Medium chain tryglyceride
• S50 Sucrose ester
• Oil-in-glycerin emulsion Oil-in-glycerin emulsion; plain semi-solid base Ingredient %W/W
• MCT Medium chain tryglyceride
• Oil-in-glycerin emulsion Oil-in-glycerin emulsion; Isoflavones Ingredient %W/W
• MCT Medium chain tryglyceride
• MCT Medium chain tryglyceride
• Table 3 example 6 formula dermal tissue levels of Genistein at different mixing methods.
• Oil-in-glycerin emulsion Oil-in-glycerin emulsion; resveratrol Ingredient %W/W
• MCT Medium chain tryglyceride
• Oil-in-glycerin emulsion Oil-in-glycerin emulsion; polyphenols Ingredient %W/W
• MCT Medium chain tryglyceride
• Oil-in-glycerin emulsion Oil-in-glycerin emulsion; polyphenols semi-solid base Ingredient %W/W
• Oil-in-glycerin emulsion Oil-in-glycerin emulsion; CoQ10 Ingredient %W/W
• MCT Medium chain tryglyceride
• Oil-in-glycerin emulsion Oil-in-glycerin emulsion; CoQ10 semi-solid base Ingredient %W/W
• MCT Medium chain tryglyceride
• Oil-in-glycerin emulsion Oil-in-glycerin emulsion; lycopene Ingredient %W/W
• MCT Medium chain tryglyceride
• Oil-in-glycerin emulsion; aloe vera Oil-in-glycerin emulsion; aloe vera
• MCT Medium chain tryglyceride
• Oil-in-glycerin emulsion gi ⁇ gko
• MCT Medium chain tryglyceride
• Oii-in-glycerin emulsion Chinese zizyphus Ingredient %W/W
• MCT Medium chain tryglyceride
• Oil-in-glycerin emulsion a hydrophobic peptide of 30 amino acids
• MCT Medium chain tryglyceride
• Oil-in-glycerin emulsion Oil-in-glycerin emulsion; anti-inflammatory peptide
• MCT Medium chain tryglyceride
• Oil-in-glycerin emulsion Oil-in-glycerin emulsion; analgesic peptide Ingredient %W/W
• MCT Medium chain tryglyceride
• Oil-in-glycerin emulsion; anti-allergic peptide Ingredient %W/W
• MCT Medium chain tryglyceride
• Fluorescein Dilaurate levels in the skin are larger when applied in SM-OG in comparison to the OG of the same formula but larger particles size and also in comparison to Vaselin.
• Example 21 Fluorescein Dilaurate levels in the skin are larger when applied in SM-OG in comparison to the OG of the same formula but larger particles size and also in comparison to Vaselin.
• Oil-in-glycerin emulsion Ingredient %W/W
• MCT Medium chain tryglyceride
• Sisterna S50C Sucrose ester

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• 2001
  • 2001-09-02 EP EP01965547A patent/EP1320353A2/de not_active Withdrawn
  • 2001-09-02 WO PCT/IL2001/000826 patent/WO2002024152A2/en not_active Application Discontinuation
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