Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
  • A61K9/122—Foams; Dry foams
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—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
  • A61K8/046—Aerosols; Foams
• • 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
• • 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
  • A61K8/37—Esters of carboxylic acids
  • A61K8/375—Esters of carboxylic acids the alcohol moiety 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
  • A61K8/92—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
  • A61K8/9783—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
  • A61P31/22—Antivirals for DNA viruses for herpes viruses
• • 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
  • 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

Definitions

• the present disclosure relates to pharmaceutical formulations derived from the extracts of birch bark.
• BACKGROUND OF THE DISLOSURE [003]
• the triterpenes found in birch bark extracts are known to have wound healing properties. Methods of extracting these triterpenes from birch bark are reported in U.S. Patent No. 7,482,383. These methods provide solid birch bark extracts that may be used in pharmaceutical formulations. For example, emulsions containing such extracts are described in U.S. Patent No. 7,482,383, and oleogels containing such extracts are described in U.S. Patent Nos. 9,352,041; 8,828,444 and 8,536,380.
• an oleogel or cream For clinical use in wound healing, an oleogel or cream must be applied by touch (e.g., by application with the fingers, a spatula or other applicator) to the area of the skin where treatment is needed.
• Touch application is disadvantageous for the treatment of certain skin conditions (e.g., epidermolysis bullosa) because the simple act of applying the oleogel or cream may lead to worsening of the skin condition. Touch application to injured skin can also cause significant physical stress and can be painful to the patient. As a result, patient compliance is at risk, which is particularly problematic for the treatment of chronic wounds.
• wound-healing formulations containing solid birch bark extracts that may be applied to the skin without worsening the patient’s condition or causing additional pain.
• the present disclosure provides clinically-advantageous wound-healing formulations with improved rheological properties which overcome the disadvantages of the known solid birch bark-containing emulsions and oleogels.
• the present disclosure provides emulsion foams comprising solid birch bark extracts dispersed in one or more nonpolar liquids.
• the solid birch bark extracts described herein may be formulated as emulsion foams that possess clinically-advantageous rheological properties.
• the foams as described herein are prepared from emulsions of solid birch bark extracts that contain at least about 70% by weight of betulin and one or more triterpenes selected from the group consisting of betulinic acid, oleanolic acid, erythrodiol and lupeol.
• the solid birch bark extracts can be dispersed in a nonpolar solvent.
• the nonpolar liquid is selected from the group consisting of sunflower oil, medium chain triglycerides, and paraffin.
• the nonpolar liquid comprises at least one triglyceride.
• the triglyceride is medium chain triglycerides.
• the nonpolar liquid comprises at least one C7 or greater hydrocarbon.
• the nonpolar liquid comprises one or more vegetable oils.
• the nonpolar liquid comprises sunflower oil.
• the present disclosure provides emulsion foams, wherein the nonpolar liquid has a peroxide value less than about 10. In another embodiment, the peroxide number is no more than about 3. In still other embodiments, the peroxide value is less than 15, less than 14, less than 13, less than 12, less than 11, less than 10, less than 9, less than 8, less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, less than 1, and including all values therebetween. [011] The foams of the present disclosure are prepared from emulsions.
• the foams comprising solid birch bark extracts dispersed in one or more nonpolar liquids further comprise water.
• foams are based on oil-in-water emulsions where the propellant (commonly propane/butane mixtures) is mixed with the dispersed lipid phase of the emulsion.
• propellant commonly propane/butane mixtures
• various embodiments of the present disclosure describe foams, wherein the foams comprise water-in-oil emulsions. This concept allows for the combination of the advantages of a touchless application with those of the healing effects of the birch bark triterpenes in a formulation which advantageously contains only triterpene extracts (TE), oil and water.
• TE triterpene extracts
• the present disclosure provides a foam comprising an emulsion, referred to herein interchangeably as an emulsion foam.
• the present disclosure provides a foam comprising an emulsion, wherein the emulsion comprises the oleogel provided herein.
• the emulsion used to prepare the foam is prepared from an oleogel comprising solid birch bark extracts. Mixed with oils, the birch bark extract of the present disclosure forms stable oleogels, which can absorb up to 60% of water forming a water-in-oil emulsion.
• the foam of the present disclosure provided by an emulsified oleogel, wherein the oleogel comprises about 5 wt. % to about 10 wt. % solid birch bark extract and the emulsion is a water-in-oil emulsion consisting of the oleogel and about 20 wt. % to about 30 wt. % of water.
• the oleogel being emulsified comprises about 7 wt.% solid birch bark extract and the amount of water in the emulsion is about 25 wt.%.
• the present disclosure provides an emulsion foam comprising about 1% to about 20% by weight of particles of the solid birch bark extract dispersed in about 80% to about 99% of one or more nonpolar liquids, wherein the solid birch bark extracts are dispersed in a suitable nonpolar liquid to form an oleogel, wherein the oleogel is emulsified, and wherein the emulsion is used to prepare a foam comprising the solid birch bark extract.
• the present disclosure provides a foam comprising an emulsion, wherein the emulsion does not comprise, or is not prepared from an oleogel.
• the foam is a water-in-oil foam. In other embodiments, the foam is an oil-in- water foam.
• the emulsion foams of the present disclosure are essentially free of viable micro-organisms, fulfilling the requirements of sterile products according to pharmacopeias, e.g. USP, or PhEur. In other embodiments, the foams are substantially free of emulsifier. [017] In some embodiments, the foams comprise an emulsifier.
• the emulsifier is selected from the group consisting of phosphatidyl choline, polyglyceryl-3-methyl glucose distearate, PEG/dodecyl glycol copolymer, polyglyceryl-2 sesquioleate, polyglyceryl- 3 diisostearate, polyglyceryl-3 polyricinoleate, sorbitan fatty acid, and combinations thereof.
• Emulsifiers are agents used to stabilize an emulsion by facilitating dispersion of the droplets in the non-miscible liquid component.
• an emulsifier may be added to the formulation to maintain a dispersion of water in the nonpolar liquid (or alternatively a dispersion of nonpolar liquid in water).
• the foams of the present disclosure comprise about 1 wt. % to about 20 wt. % of particles of the solid birch bark extract as disclosed herein, having an average particle size of less than about 50 ⁇ m, dispersed in about 80 wt. % to about 99 wt. % of one or more nonpolar liquids.
• the foam of the present disclosure comprises about 10 wt. % of particles of the solid birch bark extract.
• the foam of the present disclosure is substantially free of solid birch bark extract particles having a size greater than about 50 ⁇ m.
• the foams comprise an emulsion, wherein the interfacial surface tension of the emulsion is greater than about 4 mN/m determined with the pendant drop method.
• the emulsion foams of the present disclosure have a foam index that is greater than about 2. The foam index is a measurement of the volume expansion; it is calculated by measuring the mass of a defined volume of the emulsion divided by the mass of the same volume of the foam.
• the present disclosure also provides a method of making foams from a solid birch bark extract that in some embodiments may be dispersed in a nonpolar solvent to provide a clinically-advantageous oleogel comprising the steps of (a) contacting birch bark with a suitable solvent to form an extraction solution containing betulin and at least one triterpene; (b) separating the birch bark from the extraction solution; (c) cooling the extraction solution to crystallize a portion of the betulin and triterpene from the solution; (d) separating the crystallized betulin and triterpene; (e) drying the separated, crystallized betulin and triterpene to form a solid birch bark extract; (f) preparing an oleogel by dispersing a betulin-containing triterpene extract in a nonpolar liquid; (g) optionally storing the oleogel for a period of about 24 h; (h) adding an amount of water to thereby form an
• the oleogel comprises from about 1 wt. % to about 30 wt. % of a triterpene extract as described herein dispersed in about 70 wt. % to about 99 wt. % of one or more nonpolar liquids.
• the amount of water added to form an emulsion of the oleogel is in a ratio of about 1:100 to about 1:1, or in other embodiments, about 2:1 to about 1:2, with the nonpolar liquid.
• the pharmaceutically acceptable propellant is selected from the group consisting of carbon dioxide, nitrous oxide, propane, butane, isobutane, dimethyl ether, chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs).
• CFCs chlorofluorocarbons
• HCFCs hydrochlorofluorocarbons
• HFCs hydrofluorocarbons
• the wound treated is selected from the group consisting of a burn, surgical skin lesions, superficial injuries; chronic wounds such as pressure ulcers, diabetic foot ulcers, chronic venous ulcers, artery insufficiency ulcers; aesthetic skin treatments such as ablative laser skin treatments, chemical peels, dermabrasion; wounds resulting from adverse drug reactions such as toxic epidermal necrolysis, Lyell syndrome, Stevens-Johnson syndrome or radiation dermatitis; rare skin diseases such as epidermolysis bullosa, pemphigus vulgaris or pemphigoid, and combinations thereof.
• the present disclosure also provides methods of treating various diseases or conditions that result in or are associated with wounds requiring treatment.
• a method for treating epidermolysis bullosa in a patient in need thereof comprising topically administering to at least a portion of a wound resulting from or associated with epidermolysis bullosa in the patient an effective amount of a foam as presently disclosed.
• the method is useful in treating necrotizing herpes zoster in a patient in need thereof comprising topically administering to an area of the skin undergoing necrosis in such a patient an effective amount of a foam presently disclosed.
• the present disclosure provides a comparison of the wound healing effect of the betulin-containing foams of the present disclosure with those of betulin-containing oleogels, for example by comparing the betulin permeation from these novel foams to the permeation of betulin from oleogels, which have already been shown to promote wound healing.
• the foams of the present disclosure are water-in-oil foams.
• the skin permeation rates of betulin, the main constituent of the foams of the present disclosure, were studied. Special emphasis was put on the influence of (1) the depth of the skin lesion of artificially injured skin and (2) the different types of oils used as a carrier.
• FIG.1 illustrates the continuous extraction of birch bark to provide an extraction solution comprising betulin and one or more triterpenes.
• FIG.2 is a microscopic image of untreated porcine skin (left), skin after tape stripping (middle), and grafted skin (right).
• the range“from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).
• the verb“comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.
• administering includes any mode of administration, such as oral, subcutaneous, sublingual, transmucosal, parenteral, intravenous, intra-arterial, buccal, sublingual, topical, vaginal, rectal, ophthalmic, otic, nasal, inhaled, and transdermal.
• administering can also include prescribing or filling a prescription for a dosage form comprising a particular compound. “Administering” can also include providing directions to carry out a method involving a particular compound or a dosage form comprising the compound. [039]
• the term “treating” means one or more of relieving, alleviating, delaying, reducing, reversing, improving, or managing at least one symptom of a condition in a subject.
• the term “treating” may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition.
• “Therapeutically effective amount” means the amount of an active substance that, when administered to a subject for treating a disease, disorder, or other undesirable medical condition, is sufficient to have a beneficial effect with respect to that disease, disorder, or condition.
• the therapeutically effective amount will vary depending on the chemical identity and formulation form of the active substance, the disease or condition and its severity, and the age, weight, and other relevant characteristics of the patient to be treated. Determining the therapeutically effective amount of a given active substance is within the ordinary skill of the art and typically requires no more than routine experimentation.
• the term“birch bark” means the cortex of white-barked birch trees.
• Preferred embodiments include birch bark derived from Betula pendula Roth and Betula pubescens Ehrh as well as hybrids of both species.
• the present disclosure provides solid birch bark extracts that may be formulated into clinically-advantageous emulsion foams.
• the solid birch bark extracts of the present disclosure may be characterized on the basis of their chemical composition.
• the solid birch bark extracts of the present disclosure comprise lupane and oleanane triterpenes.
• the birch bark extracts may contain the lupane triterpenes: betulin, lupeol, and betulinic acid, and the oleanane triterpenes: erythrodiol and oleanolic acid.
• the solid birch bark extract comprises at least about 50 wt. %, at least about 55 wt. %, at least about 60 wt. %, at least about 65 wt. %, at least about 70 wt. %, at least about 75 wt. %, at least about 80 wt. %, at least about 85 wt.
• the one or more triterpenes is selected from the group consisting of betulinic acid, oleanolic acid, erythrodiol and lupeol.
• the solid birch bark extract comprises at least one of the following substances: 3-b-caffeoyl betulin, acetate of the methylester of betulinic acid, acetyloleanolic acid, allobetulin, betulinic aldehyde, betulonic acid, betulonic aldehyde, lupane-3 ⁇ ,20,28-triol, lupane-3 ⁇ ,20-diol (monogynol), oleanolic aldehyde, sitosterol, ursolic acid, or ⁇ -amyrin
• the solid birch bark extract of the present disclosure may be characterized by the particle size of the particles of the solid birch bark extract.
• the average particle size of the particles of the solid birch bark extract is less than about 100 ⁇ m, less than about 90 ⁇ m, less than about 80 ⁇ m, less than about 70 ⁇ m, less than about 60 ⁇ m, less than about 50 ⁇ m, less than about 40 ⁇ m, less than about 30 ⁇ m or less than about 25 ⁇ m.
• the solid birch bark extract of the present disclosure is substantially free of solid birch bark extract particles having a particle size greater than about 30 ⁇ m, greater than about 40 ⁇ m, greater than about 50 ⁇ m, greater than about 60 ⁇ m, greater than about 70 ⁇ m, greater than about 80 ⁇ m, greater than about 90 ⁇ m or greater than about 100 ⁇ m.
• the solid birch bark extracts are derived from Betula pendula Roth and Betula pubescens Ehrh as well as hybrids of both species.
• the present disclosure provides methods for preparing solid birch bark extracts that may be formulated into clinically-advantageous emulsion foams.
• the methods include the steps of obtaining birch trees, stripping and processing the bark from said birch trees, contacting the processed birch bark with a suitable solvent to provide an extraction solution comprising betulin and one or more triterpenes, and isolating and drying the birch bark extract comprising betulin and one or more triterpenes from the extraction solution.
• the isolated birch bark extract is in the form of a solid.
• the birch bark extracts of the present disclosure can be prepared by the methods disclosed in U.S. Patent Nos. 7,482,383, 8,536,380, 8,828,444 9,352,041, each of which is incorporated herein by reference in its entirety for all purposes.
• the present disclosure provides clinically-advantageous wound-healing emulsion foam compositions and formulations comprising solid birch bark extracts that are useful as topical wound healing agents.
• the foams of the present disclosure comprise emulsions.
• the emulsions useful in preparing the emulsion foams of the present disclosure are obtained from oleogels. Gels are finely dispersed systems comprising a liquid phase and a solid phase. The solid phase forms a coherent three-dimensional framework, and the two phases permeate one another.
• Oleogels are hydrophobic gels based on a nonpolar liquid (for example, an oil, a wax, or a paraffin) to which a gel-forming agent is added to achieve the desired physical properties.
• a nonpolar liquid for example, an oil, a wax, or a paraffin
• the present disclosure provides emulsion foams from oleogels comprising a nonpolar liquid and an oleogel-forming agent.
• Suitable nonpolar liquids for use in oleogels of the present disclosure include, for example, plant, animal, or synthetic oils, waxes, and paraffins.
• the nonpolar liquids are lipids.
• the nonpolar liquid is a vegetable oil selected from the group consisting of: castor oil, peanut oil, jojoba oil, sunflower oil, olive oil, avocado oil, and almond oil. In a specific embodiment, the nonpolar liquid is sunflower oil. [053] In some embodiments, the nonpolar liquids are medium chain triglycerides. In some embodiments, the nonpolar liquid comprises at least one triglyceride. In certain embodiments, the at least one triglyceride is Miglyol. In other embodiments, the nonpolar liquid comprises at least one C7 or greater hydrocarbon. In certain embodiments, the at least one C7 or greater hydrocarbon is a paraffin.
• the peroxide value of the nonpolar liquid is less than 15, less than 14, less than 13, less than 12, less than 11, less than 10, less than 9, less than 8, less than 7, less than 6, less than 5, less than 4, less than 3, less than 2, less than 1, and including all values therebetween.
• the present disclosure provides emulsion foams, wherein the nonpolar liquid has a peroxide value of less than about 10.
• the nonpolar liquid has a peroxide number of no more than about 3.
• the term“peroxide value” is a term known in the art to describe the extent of autoxidation the nonpolar liquid has undergone. Lower values indicate less decomposition of the nonpolar liquids.
• the present disclosure provides methods of making foams from emulsions comprising oleogels.
• the solid birch bark extract is dried, about 1 wt. % to about 20 wt. % of the dried solid birch bark extract is dispersed in nonpolar liquid to form an oleogel.
• the nonpolar liquid is sunflower oil.
• the oleogel can be emulsified to form an emulsion by adding water (e.g., by a syringe-to-syringe technique, or using a high shear mixer or other large scale method) to yield a homogeneous water-in-oil emulsion, and that can be dispensed from a container as a foam using a pharmaceutically acceptable propellant.
• water e.g., by a syringe-to-syringe technique, or using a high shear mixer or other large scale method
• the oleogel is sterile.
• the oleogel may be sterilized by suitable methods known to those skilled in the art.
• the oleogel prior to emulsification comprises between about 1 wt. % and about 30 wt.
• the oleogel contains at least one oleogel forming agent in addition to the solid birch bark extract particles.
• the oleogel comprises between about 1 wt. % and about 20 wt. % solid birch bark extract dispersed in about 80 wt. % to about 99 wt. % of one or more nonpolar liquids, wherein the oleogel contains at least one oleogel forming agent in addition to the solid birch bark extract particles.
• the oleogel prior to emulsification comprises between about 1 wt. % and about 30 wt. % solid birch bark extract particles dispersed in about 70 wt. % to about 99 wt. % of one or more nonpolar liquids, wherein the dispersed solid birch bark extract particles are the only oleogel forming agent in the oleogel.
• the oleogel comprises between about 1 wt. % and about 20 wt. % solid birch bark extract particles dispersed in about 80 wt. % to about 99 wt.
• the oleogel prior to emulsification comprises: about 5 wt. % solid birch bark extract particle dispersed in about 95 wt. % of one or more nonpolar liquids; about 10 wt. % solid birch bark extract particle dispersed in about 90 wt. % of one or more nonpolar liquids; about 15 wt. % solid birch bark extract particles dispersed in about 85 wt. % of one or more nonpolar liquids; or about 20 wt.
• the amount of solid birch bark extract particles includes up to about 0.5 wt. % of solid birch bark extract particles that are dissolved in the nonpolar liquid.
• the present disclosure provides methods for preparing emulsion foams comprising solid birch bark extract.
• the term emulsion relates to heterogeneous systems consisting of two liquids that are not miscible with each other or only miscible to a limited extent, which are typically designated as phases.
• an emulsion comprising the solid birch bark extract of the present disclosure is provided.
• Other embodiments provide emulsions comprising the oleogels of the present disclosure.
• the emulsions of the present disclosure are provided by dispersing a polar liquid in the nonpolar liquid.
• the polar liquid is water.
• the emulsions of the present disclosure include an emulsifier.
• the emulsifier is a surfactant or other ingredient that promotes the stability of the emulsion.
• the emulsifier is (hydroxypropyl)methyl cellulose. In certain other embodiments, the emulsions are substantially free of an emulsifier.
• foams may offer several advantages over oleogels because foams can be applied to wounds almost touchless, whereas the application of an oleogel requires touch.
• Foams are generally based on emulsions where a propellant is mixed with the dispersed lipid phase of an emulsion. In some embodiments the propellant is carbon dioxide (CO 2 ).
• the propellant is one or more of propane, butane, isobutane, dimethyl ether, chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs), hydrofluorocarbons (HFCs), and nitrous oxide (N 2 O).
• CFCs chlorofluorocarbons
• HCFCs hydrochlorofluorocarbons
• HFCs hydrofluorocarbons
• N 2 O nitrous oxide
• the present disclosure provides foams comprising a solid birch bark extract-containing emulsion as described above.
• the emulsion comprises an oleogel consisting of about 5 wt. % to about 10 wt. % solid birch bark extract, wherein the emulsion is a water-in-oil emulsion consisting of the oleogel and about 20 wt.
• the emulsion comprises an oleogel consisting of about 7 wt. % solid birch bark extract, wherein the emulsion is a water-in-oil emulsion consisting of the oleogel and about 25 wt. % of water.
• the foams of the present disclosure further comprise an emulsifier.
• the emulsifier is selected from the group consisting of phosphatidyl choline, polyglyceryl-3-methyl glucose, PEG/dodecyl glycol copolymer, polyglyceryl-2 sesquioleate, polyglyceryl-3 diisostearate, polyglyceryl-3 polyricinoleate, sorbitan fatty acid esters, etc., and combinations thereof.
• the foams of the present disclosure possess certain physical properties.
• the foam index is greater than about 2.
• the emulsion used in the foam exhibits an interfacial surface tension of greater than about 4 mN/m determined with the pendant drop method.
• the present disclosure also provides for pressurized containers filled with an emulsion of the present invention and a pharmaceutically acceptable propellant whereby the emulsion forms a foam upon decanting at least a portion of the mixture from the container.
• the present disclosure also provides methods of treating a wound in a patient by topically administering an effective amount of a foam of the present disclosure to at least a portion of the wound.
• the wound treated is selected from the group consisting of burns, surgical skin lesions, superficial injuries; chronic wounds such as pressure ulcers, diabetic foot ulcers, chronic venous ulcers, artery insufficiency ulcers; aesthetic skin treatments such as ablative laser skin treatments, chemical peels, dermabrasion; wounds resulting from adverse drug reactions such as toxic epidermal necrolysis, Lyell syndrome, Stevens-Johnson syndrome or radiation dermatitis, rare skin diseases such as epidermolysis bullosa, pemphigus vulgaris or pemphigoid, and combinations thereof.
• the present disclosure also provides methods that are useful in treating various diseases and conditions afflicting a patient that result in formation of a wound comprising topically administering an effective amount of a foam described herein to an area of a wound of a patient in need thereof.
• the diseases or conditions are selected from the group comprising burns, surgical skin lesions, superficial injuries; chronic wounds such as pressure ulcers, diabetic foot ulcers, chronic venous ulcers, artery insufficiency ulcers; aesthetic skin treatments such as ablative laser skin treatments, chemical peels, dermabrasion; wounds resulting from adverse drug reactions such as toxic epidermal necrolysis, Lyell syndrome, Stevens-Johnson syndrome or radiation dermatitis, rare skin diseases such as epidermolysis bullosa, pemphigus vulgaris, and so forth.
• Triterpene extract from the outer bark of birch, TE was obtained from Birken AG, Niefern- ⁇ schelbronn, Germany, and had the composition and physical properties shown in Table 1.
• paraffin, sunflower oil or medium-chain triglycerides served as the basis of the different oleogels.
• These oleogels containing 10 % (w/w) TE were prepared by dispersing the TE in the respective oil using an Ultra-Turrax T25 (IKA, Staufen, Germany) at 8000 rpm for 3 min.
• the pig ears were washed with isotonic saline solution, cleaned of blood with cotton swaps and dried.
• the excised postauricular skin was wrapped in aluminum foil and stored at - 30 °C. On the day of the experiment, it was thawed at room temperature and was pinned to a styrofoam block. If not otherwise pre-treated as described below, the porcine skin was then cut with the dermatome (Dermatom GA 630, Aesculap AG & Co. KG) to a thickness of 0.8 mm.
• Injuring skin Superficial wounds are limited to the outer skin layers and are often caused by abrasion. Depending on the depth of the abrasion process the different layers of the epidermis or the dermis can be involved. The severity of the injury has a clear impact on the healing process, and also on the penetration of an active as the barrier properties of the remaining skin tissue varies.
• porcine skin was“injured” for this study in two different ways.
• the skin was prepared as previously described and subsequently injured by either of the following two methods:
• the first method involved skin (tape) stripping to remove the horny layer of the skin.
• tape skin stripping
• the skin on the styrofoam block was pressed to the tape (tesa No 4124, Beiersdorf AG, Hamburg, Germany) and stripped in one quick move. This procedure was repeated 20 times.
• the second method involved skin grafting using a dermatome to remove the outer 200 ⁇ m of the skin.
• a dermatome Dermatome
• the untreated skin shows the typical layer structure of skin including stratum corneum, epidermis and dermis.
• stratum corneum as the outermost layer of the skin has been removed completely from the skin.
• skin grafting leads to a more severe damage, cutting directly deep into the living epidermal layers of the skin.
• Betulin was quantified by HPLC using the following system: LC-20A prominence HPLC system (Shimadzu, Duisburg, Germany), HPLC column Nucleosil 100-5 C18 EC 125/4, HPLC pre-column Universal RP EC 4/3 (both Macherey-Nagel, Düren, Germany). The temperature for the column was set to 40 °C and the flow rate to 1.5 mL/min. The composition of the mobile phase was 70 % of acetonitrile and 30 % of water. Limit of detection was 0.0491 ⁇ g/ml and limit of quantification 0.1473 ⁇ g/ml. A volume of 20 ⁇ l of every sample was injected and the UV absorbance was measured at 210 nm. The retention time for betulin was approx.10.3 min.
• the lag time defining the time taken until betulin initially enters the receptor fluid, is shorter for the permeation through the skin damaged by a dermatome compared to stripped skin (4.02 ⁇ 1.02 vs.6.51 ⁇ 1.48 h).
• the flux is inversely proportional to the thickness of the skin, this variable was kept constant throughout all experiments. Therefore it is only influenced by the diffusion coefficient which is dependent on the structure of tissue that has to be crossed.

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