WO2022238965A1 - Veterinary transdermal formulation - Google Patents

Veterinary transdermal formulation Download PDF

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Publication number
WO2022238965A1
WO2022238965A1 PCT/IB2022/054450 IB2022054450W WO2022238965A1 WO 2022238965 A1 WO2022238965 A1 WO 2022238965A1 IB 2022054450 W IB2022054450 W IB 2022054450W WO 2022238965 A1 WO2022238965 A1 WO 2022238965A1
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WO
WIPO (PCT)
Prior art keywords
formulation
transdermal formulation
anhydrous transdermal
anhydrous
veterinary acceptable
Prior art date
Application number
PCT/IB2022/054450
Other languages
French (fr)
Inventor
Desmond Ian John Morrow
Tay Haw Chait
Bo Jade Robyn Lam
Original Assignee
Argenta Innovation Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2021901413A external-priority patent/AU2021901413A0/en
Application filed by Argenta Innovation Limited filed Critical Argenta Innovation Limited
Publication of WO2022238965A1 publication Critical patent/WO2022238965A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

Definitions

  • the present invention relates to an anhydrous transdermal formulation that contains a terpene, and more specifically a formulation suitable for transdermal delivery of active therapeutic agents to mammals.
  • the present invention also relates to methods of manufacturing such formulations, and the use such formulationsfor treating animals.
  • Transdermal formulations typically include permeation enhancers, which improve the rate of transfer of the drug across the skin.
  • Permeation enhancers may act by disrupting the highly ordered structure of stratum corneum lipid, interacting with intercellular protein, and/or improving partition of the drug into the stratum corneum.
  • a problem with transdermal formulations is that these permeation enhancers can cause skin irritation and inflammation.
  • anhydrous transdermal formulation comprising
  • a veterinary acceptable C2 to C6 volatile solvent having a flash point of less than 20° C.
  • anhydrous transdermal formulation comprising
  • a veterinary acceptable aprotic solvent having a flash point higher than a physiological body temperature of a non-human mammal
  • a method of manufacturing a transdermal formulation comprising mixing a first composition comprising an active ingredient that is substantially insoluble in water, and a terpene, with a veterinary acceptable aprotic solvent, and a veterinary acceptable C2 to C6 alcohol solvent having a flash point of less than 20° C, thereby providing the transdermal formulation.
  • the active agent has an apparent partition coefficient (log P) in n-octanol/buffer pH 7.4 of about 1, 2, 3, 4, 5 , 6, 7 or 8, and useful ranges may be selected between any of these values.
  • the anhydrous transdermal formulation may comprise a veterinary acceptable C2 to C6 aprotic solvent.
  • the anhydrous transdermal formulation may comprise a veterinary acceptable aprotic solvent having at least one double bond.
  • the veterinary acceptable C2to C6 volatile solvent may begin to vaporise at a body surface temperature of about 24° to about 40° C.
  • the veterinary acceptable C2to C6 volatile solvent may have a molecular weight of about 40 to about 100 g/mol.
  • the veterinary acceptable C2to C6 volatile solvent may have a flash point of less than about 20° C.
  • anhydrous transdermal formulation may comprise
  • a veterinary acceptable aprotic solvent selected from dimethyl sulfoxide (DMSO), dimethylformamide, propylene carbonate, ethyl acetate, 2- pyrrolidone, dimethylacetamide (DMA), N-methyl pyrrolidone, and ethyl acetoacetate; and
  • a veterinary acceptable C2 to C6 volatile solvent selected from acetone, ethanol, and isopropyl alcohol.
  • the formulation comprises two or more veterinary agents.
  • an active ingredient may be selected from
  • an anthelmintic a non-steroidal anti-inflammatory
  • a steroidal anti-inflammatory a steroidal anti-inflammatory
  • the composition comprises at least 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25% terpene by weight of the formulation, and useful ranges may be selected between any of these values.
  • the hydrocarbon terpene is selected from pinene, limonene, terpinene, cymene, aromadendrene, or a combination thereof.
  • the terpene is limonene.
  • the formulation comprises about 20, 25, 30, 35, 40,
  • the volatile solvent is selected from isopropyl alcohol, ethanol and acetone.
  • the formulation comprises one or more antioxidants surfactants, or dispersants.
  • composition may also include a lipophilic organic antioxidant compound.
  • the lipophilic organic antioxidant compound is present at about 0.01, 0.02, 0.04 0.06, 0.08, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5,
  • composition 0.55, 0.6, 0.65, 0.7, 0.75. 0.8, 0.85, 0.9, 0.95, 1.0, 1.5 or 2% by weight of the composition, and useful ranges may be selected between any of these values.
  • the lipophilic organic antioxidant compound is a phenol derivative such as butylated hydroxytoluene, BHA, tocopherol, propyl gallate, or any combination thereof.
  • the antioxidant is selected from butylated hydroxytoluene, butylated hydroxyanisole, or a combination thereof.
  • the composition may be heated to at least 20°C.
  • the heating may be performed for between 10 minutes to 1 hour.
  • the dissolved mixture may be heated to 20, 25, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 or 50°C, and useful ranges may be selected between any of these values.
  • composition is physically and chemically stable, providing at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 months shelf life, and useful ranges may be selected between any of these values.
  • the formulation may be effective to reduce parasitic faecal egg count by at least 90, 95, 96, 97, 98 or 99%.
  • the invention may be the use of any one or more of the compositions described above.
  • the non-human mammal includes farmed or unfarmed animals, domestic or companion animals (e.g. cattle, sheep, horses, deer, swine, dogs, cats, etc).
  • domestic or companion animals e.g. cattle, sheep, horses, deer, swine, dogs, cats, etc.
  • the composition is a veterinary composition.
  • the composition is a pour on or spot on formulation.
  • the composition is fast acting with respect to at least one active ingredient.
  • the composition is fast acting with respect to at least one active ingredient relative to at least one other active ingredient in the composition.
  • the fast acting active ingredient acts within at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 48, 72, 96, 120 hours and useful ranges may be selected from within these values
  • the action of at least one of the active ingredients is delayed relative to at least one other active ingredient in the composition.
  • the action is delayed by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, and useful ranges may be selected from within these values.
  • the composition provides sustained or prolonged release of at least one of the active ingredients.
  • alkenyl employed alone or in combination with other terms means, unless otherwise stated, a monovalent straight chain hydrocarbon group including a carbon-carbon double bond.
  • This invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, and any or all combinations of any two or more said parts, elements or features, and where specific integers are mentioned herein which have known equivalents in the art to which this invention relates, such known equivalents are deemed to be incorporated herein as if individually set forth.
  • veterinary agent is intended to capture any agent that is used for improving the health and well being of an animal.
  • a non-aqueous formulation that comprises a terpene in combination with a solvent system that comprises an aprotic solvent and a volatile solvent.
  • the composition delivers an active ingredient or ingredients transdermally to non-human mammals.
  • the composition may be used to deliver a range of actives, such as anthelmintics.
  • suitable anthelmintics includes moxidectin, levamisole and macrocyclic lactones.
  • a platform formulation that may be used to deliver a wide variety of active ingredients transdermally.
  • the platform formulation delivers a therapeutic quantity of the active ingredient or ingredients.
  • the active ingredient or ingredients once applied to the skin of the recipient animal, may be absorbed into the systemic circulation.
  • the active agent may be lipophilic. Lipophilicity can be described by the partition coefficient, log P, which is defined as the ratio of the concentration of the unionised compound at equilibrium between organic and aqueous phases. Lipophilicity of a molecule is expressed as a partition coefficient (Log P ) of an n-octanol/water system, where more lipophilic compounds are partitioned in the n-octanol layer.
  • log P partition coefficient of an n-octanol/water system, where more lipophilic compounds are partitioned in the n-octanol layer.
  • An example of a method to measure Log P is given by pION Inc., Brookline, MA (A. Avdeef and C. Berger) (1997).
  • the active agent may have a Log P of about 1, 2, 3, 4, 5, 6, 7 or 8, and useful ranges may be selected between any of these values (for example, about 1 to about 9, about 1 to about 6, about 1 to about 4, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 3 to about 8, about 3 to about 7 or about 3 to about 6).
  • the platform formulation may deliver multiple lipophilic active ingredients. For example, 2, 3, 4 or 5 actives delivered transdermally in a single composition.
  • the active ingredients account for 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90% of the composition, and useful ranges may be selected between any of these values (for example, from about 1 to about 90, about 1 to about 75, about 1 to about 60, about 5 to about 100, about 5 to about 80, about 5 to about 55, about 25 to about 90, about 25 to about 65, about 25 to about 50, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 55, about 50 to about 90, about 50 to about 75, about 65 to about 90, about 65 to about 75 or about 70 to about
  • the active ingredients account for 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90% of the composition, and useful ranges may be selected between any of these values (for example, from
  • the platform formulation may deliver active ingredients with a molecular weight of less than about 1000, 900, 800, 700, 600, 500, 400, 300, 200 gmol ⁇ and useful ranges may be selected between any of these values (for example, from about 100 to about 1000, about 100 to about 900, about 100 to about 800, about 100 to about 600, about 100 to about 500, about 200 to about 1000, about 200 to about 900, about 200 to about 800, about 200 to about 700, about 200 to about 500, about 200 to about 400, about 300 to about 1000, about 300 to about 900, about 300 to about 700, about 300 to about 500, about 500 to about 1000, about 500 to about 800, about 500 to about 700, about 500 to about 600, about 700 to about 1000, about 700 to about 900, about 800 to about 1000 gmol 1 ).
  • At least one of the active ingredients may have a molecular weight of at least about 300, at least about 400, at least about 500, or at least about 600 gmol-i.
  • anthelmintic agents may be delivered transdermally by the platform composition of the present invention.
  • a candidate anthelmintic agent includes imidazothiazoles.
  • the imidazothiazole may be selected from levamisole, pyrantel pamoate, butamisol or tetramisole.
  • Macrocyclic lactones are also candidate agents for delivery transdermally.
  • the macrocyclic lactone may be selected from avermectin, ivermectin, abamectin, eprinomectin, moxidectin, selamectin, doramectim, milbemycin, abamectin or cydectin.
  • the composition may contain 1, 5, 10,
  • 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60% imidazothiazole, and useful ranges may be selected between any of these values (for example, from about 1 to about 60, about 1 to about 40, about 1 to about 30, about 5 to about 60, about 5 to about 45, about 5 to about 35, about 5 to about 25, about 10 to about 60, about 10 to about 45, about 10 to about 30, about 10 to about 20, about 15 to about 60, about 15 to about 40, about 15 to about 30, about 15 to about 35, about 15 to about 30, about 15 to about 25, about 20 to about 60, about 20 to about 40, about 20 to about 30, about 25 to about 60, about 25 to about 45, about 25 to about 35, about 30 to about 60, about 30 to about 40, about 40 to about 60% imidazothiazole).
  • these values for example, from about 1 to about 60, about 1 to about 40, about 1 to about 30, about 5 to about 60, about 5 to about 45, about 5 to about 35, about 5 to about 25, about 10 to about 60, about 10 to about 45, about
  • the composition may contain 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% macrocyclic lactone, and useful ranges may be selected between any of these values (for example, from about 0.1 to about 20, about 0.1 to about 15, about 0.1 to about 12, about 0.1 to about 10, about 0.1 to about 5, about 0.1 to about 4, about 0.5 to about 20, about 0.5 to about 14, about 0.5 to about 10, about 0.5 to about 5, about 1 to about 20, about 1 to about 16, about 1 to about 11, about 1 to about 6, about 3 to about 20, about 3 to about 13, about 3 to about 7, about 5 to about 20, about 5 to about 14, about 5 to about 10, about 8 to about 20, about 8 to about 12, about 14 to about 20, about 16 to about 20% macrocyclic lactone).
  • Anthelmintics include benzimidazoles, imidazothiazoles, tetrahydropyrimidines, macrocyclic lactones, salicylanilides, substituted phenols, aromatic amides, isoquinolines, amino acetonitriles, spiroindoles, and the like.
  • Anthelmintic benzimidazoles include mebendazole, flubendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, albendazole sulfoxide, thiabendazole, thiophanate, febantel, netobimin, and triclabendazole. Further examples include mebendazole, and ricobendazole.
  • Benzimidazole based anthelmintics interfere with the worm's energy metabolism on a cellular level. They bind to a specific building block called beta tubulin and prevent its incorporation into certain cellular structures called microtubules, which are essential for energy metabolism. Interfering with energy metabolism is a much more basic mode of activity than that which occurs with other classes of anthelmintics. For this reason, benzimidazoles are also able to kill worm eggs. Benzimidazoles have a wide margin of safety and broad spectrum activity.
  • Imidazothiazoles and tetrahydropyrimidines and both nicotinic agonists include levamisole, tetramisole, and butamisole.
  • Tetrahydropyrimidine anthelmintics include, for example, morantel, oxantel, and pyrantel.
  • the tetrahydropyrimidines mimic the activity of acetylcholine, a naturally occurring neurotransmitter that initiates muscular contraction.
  • the worm is unable to feed and quickly starves.
  • Tetrahydroyrimidines only affect adult populations of worms. They do not have activity against the larval stages and are ineffective against cestodes (tapeworms) and trematodes (liver flukes).
  • Imidazothiaoles have a similar mode of action causing spastic paralysis of the worms.
  • Levamisole has a broad spectrum of activity and is effective against many larval stages of parasites.
  • Macrocyclic lactones include abamectins, for example abamectin, doramectin, eprinomectin, ivermectin, and selamectin, and milbemycins, for example milbemycin oxime and moxidectin.
  • the macrocyclic lactones are products or chemical derivatives of soil microorganisms belonging to the genus Streptomyces. All of the macrocyclic lactone anthelmintics have the same mode of action. They interfere with GABA-mediated neurotransmission, causing paralysis and death of the parasite. Macrocyclic lactones are the most potent killer of worms and are more persistent in their effect. The duration of persistent activity varies according to the drug and formulation.
  • Macrocyclic lactones also have the unique quality of also killing several types of external parasite such as lice, mites, and ticks. They have a wide margin of safety for livestock and are effective against all stages of worms, including inactive forms.
  • Salicylanilides include brotianide, clioxanide, closantel, niclosamide, oxyclozanide, rafoxanide, substituted phenols include bithionol, disophenol, hexachlorophene, niclofolan, menichlopholan, nitroxynil, and aromatic amides include diamfenetide (diamphenethide).
  • Insoquinoline anthelmintics include praziquantel and epsiprantel.
  • Praziquantel and epsiprantel have high efficacy against cestode parasites at relatively low dose rates but no effect on nematodes.
  • Praziquantel is rapidly and almost completely absorbed from the GI tract.
  • Amino-acetonitrile derivatives include monepantel, which acts by paralyzing worms by attacking a previously undiscovered receptor HCO-MPTL-1, present only in nematodes.
  • anthelmintics include piperazine and derivatives thereof such as piperazine and diethylcarbamazine (DEC, a derivative of piperazine), benzenesulfonamides such as clorsulon, amidines such as bunamidine, isothiocyantes such as nitroscanate, and organophosphates such as dichlorvos, and spiroindoles such as derquantel (2- deoxoparaherquamide).
  • DEC diethylcarbamazine
  • benzenesulfonamides such as clorsulon
  • amidines such as bunamidine
  • isothiocyantes such as nitroscanate
  • organophosphates such as dichlorvos
  • spiroindoles such as derquantel (2- deoxoparaherquamide).
  • the active ingredient may be a non-steroidal or steroidal anti inflammatory.
  • non-steroidal anti-inflammatory drugs include, but are not limited to, acemetacin, acetylsalicylic acid (aspirin), alminoprofen, benoxaprofen, bucloxic acid, carprofen, celecoxib, clidanac, deracoxib, diclofenac, diflunisal, dipyrone, etodolac, fenoprofen, fentiazac, firocoxib, flobufen, flufenamic acid, flufenisal, flunixin, fluprofen, flurbiprofen, ibuprofen, indomethacin, indoprofen, isoxicam, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, miroprofen, nabumetone, naproxen,
  • NSAIDs non steroidal anti- inflammatory drugs
  • carboxylic acid carboxylic acid
  • enolic acid derivatives The main groups of enolic acids are the pyrazolones (phenylbutazone, oxyphenbutazone, and ramifenazone) and the oxicams (meloxicam, piroxicam, and tenoxicam).
  • Carboxylic acid groups include the salicylates (aspirin), propionic acids (ibuprofen, naproxen, carprofen, ketoprofen, and vedaprofen), anthranilic acids (tolfenamic and meclofenamic acids), phenylacetic acids (acetaminophen), aminonicotinic acids (flunixin), and indolines (indomethacin).
  • Anti-inflammatory steroids include steroids which have an anti inflammatory activity either locally or systemically. These are well-known within the art.
  • steroids include the adrenocorticoid steroids, whether endogenous or synthetic. These include, without limitation, hydrocortisone, betamethasone, cortisone, dexamethasone, prednisolone, prednisone, methylprednisilone, triamcinolone, flumethasone, and their pharmaceutically acceptable derivitives.
  • the steroid is hydrocortisone or cortisone. These steroids may be used at levels known in the art.
  • the composition may comprise a steroid hormone.
  • Steroid hormones include growth promoters and production enhancers.
  • the steroid hormone is a natural steroid hormone, such as estradiol, progesterone, and testosterone, or a synthetic steroid hormone, such as trenbolone acetate, estradiol benzoate, estradiol 17b, and melengestrol acetate, and zeranol.
  • Steroid hormones include natural and synthetic steroid hormones, steroid hormone precursors, steroid hormone metabolites, and derivatives thereof that are structurally derived from cholesterol. Steroid hormones can be synthesized from cholesterol via pathways that involve cytochrome P450 (cP450) enzymes, which are heme-containing proteins. Exemplary steroid hormones, include, but are not limited to, androgens, estrogens, progestogens, mineralcorticoids, and glucocorticoids.
  • Exemplary androgens include, but are not limited to, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulphate, dihydrotestosterone, androstenedione, androstenediol, androstanedione, androstanediol, and any combination thereof.
  • Exemplary estrogens include, but are not limited to, estrone, estradiol, estriol, estetrol, equilin, equilenin, and any combination thereof.
  • Exemplary progestogens include, but are not limited to, progesterone, 17-hydroxy- progesterone, pregnenolone, dihydroprogesterone, allopregnanolone, 17-hydroxy- pregnenolone, 17-hydroxy-dihydroprogesterone, 17- hydroxy-allopregnanolone, and any combination thereof.
  • Exemplary mineralcorticoids include, but are not limited to, aldosterone, 11- deoxycorticosterone, fludrocortisones, 1 1-deoxy-cortisol, pregnenedione, and any combination thereof.
  • Exemplary glucocorticoids include, but are not limited to, cortisol (hydrocortisone), corticosterone, 18-hydroxy-corticosterone, cortisone, and any combination thereof.
  • the composition may comprise an anti-histamine.
  • suitable antihistamines include clemastine, clemastine fumarate (2(R)-[2-[l-(4- Chlorophenyl)-l-phenyl-ethoxy]ethyl-l-methylpyrrolidine), dexmedetomidine, doxylamine, loratidine, desloratidine and promethazine, and diphenhydramine, or pharmaceutically acceptable salts, solvates or esters thereof.
  • the composition may comprise an anti-emetic.
  • suitable anti-emetic agents include phenothiazines (e.g., prochloperazine, promethazine, thiethylperazine, perphenazine, chlorpromazine, metopimazine, acepromazine, etc.); 5HT-3 receptor antagonists such as ondansetron, granisetron, tropisetron, dolasetron, hydrodolasetron, azasetron, ramosetron, lerisetron, indisetron and palonosetron; and others such as dimenhydrinate, diphenhydramine (which can also act as an antihistamine), cyclizine, meclizine, promethazine, hyroxyzine, metoclopramide, domperidone, hyoscine, hyoscine hydrobromide, hyoscine hydrochloride, scopolamine, clebopride, al
  • the composition may comprise a metabolic regulator, such a hypothyroidism treatment.
  • a metabolic regulator such as a hypothyroidism treatment.
  • Metabolic diseases may be inherited or acquired and are clinically important because they affect energy production or damage critical tissues. Storage diseases and inborn defects in metabolism may be either genetic or acquired.
  • the diseases are characterized by the accumulation or storage of specific lysosomal enzyme substrates or byproducts within cells due to the partial or complete deficiency of those enzymes.
  • the development of the metabolic diseases is largely related to production or management factors.
  • the pathogenesis of the diseases is primarily related to alterations in metabolism. In many cases the basis of disease is not a congenital or inherited metabolic defect, but rather an increased demand for a specific nutrient that has become deficient.
  • the metabolic regulator is a growth promoter, probotic or prebiotic, antibiotic or anti -infective supplement, electrolyte, mineral, vitamin, or other nutritional additive.
  • the composition may comprise a productivity regulator, for example polyethers such as monensin.
  • the productivity regulator is a productivity enhancer.
  • the composition may comprise a hypothyroidism treatment.
  • Suitable hypothyroidism treatments include treatment with thyroid hormones and derivatives thereof.
  • thyroid hormones include thyroixines such as T2, T3and T4.
  • T3 refers to the art recognized thyroid hormone, triiodothyronine (also known as (2S)-2- amino-3-[4-(4-hydroxy-3-iodo-phenoxy)-3,5-diiodo-phenyl]propanoic acid).
  • T4 refers to the art recognized thyroid hormone, thyroxine, or 3,5,3',5'-tetraiodothyronine (also known as (2S)-2-amino-3-[4-(4-hydroxy-3,5-diiododophenoxy)-3,5- diiodophenyl]propanoic acid).
  • T2 refers to the thyroid hormone iodothyronine or 3,5- diiodo-l-thyronine.
  • the composition may comprise a behavioural treatment agent.
  • Behavioural treatments include, for example, serotonin reuptake inhibitors and tricyclic antidepressants, pheromones, nutritional products, and calming agents.
  • serotonin reuptake inhibitors and tricyclic antidepressants include, clomipramine.
  • the composition may comprise an analgesic.
  • Analgesics include the opioid analgesics such as buprenorphine, butorphanol, dextromoramide, dezocine, dextropropoxyphene, diamorphine, fentanyl, alfentanil, sufentanil, hydrocodone, hydromorphone, ketobemidone, levomethadyl acetate, mepiridine, methadone, morphine, nalbuphine, opium, oxycodone, papaveretum, pentazocine, pethidine, phenoperidine, piritramide, dextropropoxyphene, remifentanil, tilidine, tramadol, codeine, dihydrocodeine, meptazinol, dezocine, eptazocine and flupirtine.
  • Analgesics also include non-opioid analgesics, for example, non-steroidal anti-inflammator
  • the composition may comprise a parasiticide.
  • Parasiticides include, for example the macrocyclic lactones such as abamectin, ivermectin, eprinomectin, doramectin, moxidectin, selamectin, milbemycin oxime.
  • the antiparasitic agents include, but are not limited to, endoparasiticidal agents, ectoparaciticidal agents, and endectoparaciticidal agents.
  • Ectoparasiticides include, for example, organochlorines, organophosphates, carbamates, amidines, pyrethrins and synthetic pyrethroids, benzoylureas, juvenile hormone analogues, macrocyclic Lactones, neonicotinoids, phenylpyrazoles, and spinosyns.
  • Endectoparaciticides include, for example, macrocyclic lactones, such as ivermectin.
  • Endoparasiticides include, for example, anhelmintics, such as those described herein.
  • the antiparasitic agent is an avermectin, milbemycin, phenylpyrazole, nodulisporic acid, clorsulon, closantel, quinacrine, chloroquine, vidarabine, nitenpyram, ivermectin, milbemycine oxime, lufenuron, salimectin, moxidectin, or dorimectin.
  • the antiparasitic agent is nitenpyram, ivermectin, milbemycine oxime, lufenuron, salimectin, moxidectin, dorimectin, or paraherquamide, or pharmaceutically acceptable salts, solvates or esters thereof.
  • the composition comprises an insecticide.
  • insecticides include, but are not limited to, pyrethrins, pyrethroids, and limonene. Insecticides also include certain parasiticides.
  • the formulation may comprise a skin treatment agent.
  • Skin treatment agents include skin conditioning agents, for example glycerine. Other skin conditioning agents may be used. Categories of skin conditioning agents include, but are not limited to emollients, humectants and plasticizers.
  • Humectants include, but are not limited to sorbitol, propylene glycol, alkoxylated glucose, hexanetriol, ethanol, and the like.
  • Emollients include, but are not limited to, hydrocarbon oils and waxes; silicone oils; triglyceride esters, acetoglyceride esters, ethoxylated glycerides; alkyl esters; alkenyl esters; fatty acids, fatty alcohols; fatty alcohol ethers; ether-esters (fatty acid esters of ethoxylated fatty alcohols); lanolin and its derivitives; polyhydric alcohols and polyether derivatives; polyhydric alcohol esters; wax esters; beeswax derivatives; vegetable waxes; phospholipids; steroids; and amides. These may all be used at art-established levels.
  • skin treatment agents include anti-ageing agents and wound care agents.
  • the formulation may comprise an anti-microbial.
  • Anti-microbials include antibiotics, antifungals, antivirals, anhelmintics, and the like.
  • the formulation may comprise an antibiotic, antifungal, or antiviral.
  • the anti-biotic may be an inhibitor of cell wall synthesis (e.g. penicllins, cephalosporins, bacitracin and vancomycin), inhibitor of protein synthesis (aminoglycosides, macrolides, lincosamides, streptogramins, chloramphenicol, tetracyclines), inhibitor of membrane function (e.g. polymixin B and colistin), an inhibitor of nucleic acid synthesis (e.g. quinolones, metronidazole, and rifampin), or an inhibitor of other metabolic processes (e.g.
  • antibiotics include polyethers ionophores such as monensin and salinomycin, beta-lactams such as penicillins, aminopenicillins (e.g., amoxicillin, ampicillin, hetacillin, etc.), penicillinase resistant antibiotics (e.g., cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, etc.), extended spectrum antibiotics (e.g., axlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, etc.); cephalosporins (e.g., cefadroxil, cefazolin, cephalixin, cephalothin, cephapirin, cephradine, cefaclor, cefacmandole, cefmetazole, cefonicid, ceforanide
  • polyethers ionophores such as monensin and salinomycin
  • Antifungals include polyenes, azoles, allylamines, morpholines, anti metabolites, and combinations thereof.
  • Non-limiting examples of antivirals include didanosine, lamivudine, stavudine, zidovudine, indinavir, and ritonavir.
  • the formulation may comprise a coccidostat.
  • Coccidiostats are antiprotozoal agents that acts on Coccidia parasites. Examples include, but are not limited to, amprolium, arprinocid, artemether, clopidol, decoquinate, diclazuril, dinitolmide, ethopabate, halofuginone, lasalocid, monensin, narasin, nicarbazin, oryzalin, robenidine, roxarsone, salinomycin, spiramycin, sulfadiazine, and toltrazuril.
  • the formulation may comprise an anesthetic such as tetracaine, bupivacaine, etidocaine, procaine, prilocaine, and lidocaine.
  • anesthetic such as tetracaine, bupivacaine, etidocaine, procaine, prilocaine, and lidocaine.
  • the active ingredient(s) is stable in the formulation.
  • the active ingredient(s) in the composition is typically stable to chemical reaction with other components in the reaction mixture or to degradation or decomposition by other means.
  • the formulation may comprise levamisole base and the recovery of levamisole base after 3 months at 75% relative humidity and 40°C is at least about 95, 96, 97, 98, or 99%. In one embodiment, the recovery is at least about 95%.
  • the formulation may comprise abamectin and the recovery of abamectin after 3 months at 75% relative humidity and 40°C is at least about 95, 96, 97, 98, or 99%. In one embodiment, the recovery is at least about 95%.
  • the composition comprises abamectin and at least one surfactant. In one embodiment, at least one of the surfactants is a polyoxyethylene alkenyl ether as described herein.
  • the formulation may comprise moxidectin and the recovery of moxidectin after 3 months at 75% relative humidity and 40°C is at least about 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%. In one embodiment, the recovery is at least about 90%.
  • the at least one active ingredient is soluble in at least one of the other liquid components of the composition.
  • At least one of the active ingredients is substantially insoluble in water.
  • the terpene helps to maximise the transport of the active ingredient(s) across the skin by improving partitioning of the active ingredients, and minimises the residency time of the active ingredient(s) on the surface of the skin, reducing the potential for irritation.
  • the terpene acts as a penetration or permeation enhancer, sorption promoter or accelerant.
  • Terpenes are a diverse class of organic compounds produced from a wide variety of sources.
  • the fundamental building block of terpenes is the isoprene unit, CsHs. Larger structures are then formed from multiples of isoprene.
  • Terpenes can be cyclic or acyclic.
  • the terpene hydrocarbon is selected from pinene, limonene, terpinene, cymene, aromadendrene, or a combination thereof.
  • the terpene may be limonene.
  • the composition does not comprise a terpene alcohol. In one embodiment, the composition does not comprise menthol.
  • the terpene is the sole permeation enhancer in the composition.
  • the composition comprises a single terpene.
  • terpenes such as limonene may result in contact sensitisation (initial process of an allergic reaction).
  • the terpene may be present in an amount suitable for maximising the transport of the active ingredient(s) across the skin without causing irritation to the skin of the non-human mammal.
  • the terpene permeation enhancer may be present from at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 36,
  • the terpene permeation enhancer may be limonene present from at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,
  • the composition may comprise one or more veterinary acceptable volatile solvents.
  • Volatile solvents are solvents that easily vaporise into a gas at relatively low temperatures.
  • volatile solvents may vaporise at physiological temperature such as the body surface temperature.
  • vaporisation (hence removal) of the volatile solvent from the composition may be modulated.
  • the veterinary acceptable volatile solvent may remain in the composition at low ambient temperatures (or storage temperatures) and may only begin vaporising after application on the skin or body surface of the non-human mammal.
  • the inclusion of a veterinary acceptable volatile solvent may improve the diffusion of the composition across skin of the non-human mammal. Without wishing to be bound by theory, as the volatile solvent evaporates from the composition, the composition may become more saturated resulting in a higher diffusion gradient across of the skin, therefore, may improve the delivery of the active ingredient.
  • the body surface temperature of non-human mammals may be affected by a number of factors including the ambient temperature, location of body surface, hair coverage etc.
  • the body surface temperature of non-human mammals may vary from species to species. For example, cattle ( Bos taurus ) may have a body surface temperature of approximately 33° C, while sheep (Ov/s aries) may have a body surface temperature of approximately 29° C.
  • the composition may comprise a veterinary acceptable volatile solvent that begin to vaporise at a body surface temperature of the non-human mammal.
  • the composition may comprise a veterinary acceptable volatile solvents that begin to vaporise at a body surface temperature of about 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5, 37.0, 37.5, 38.0, 38.5, 39.0, 39.5, 40.0° C, and useful ranges may be selected between any of these values.
  • the volatility of the veterinary acceptable volatile solvent may be affected by factors such as intermolecular forces and/or molecular weight of the solvent. Solvent having a weak overall intermolecular force may result in a more volatile solvent.
  • solvents having a low molecular weight may result in a more volatile solvent.
  • molecular weight may be used interchangeably with molecular mass or molar mass.
  • the formulation may comprise a veterinary acceptable C2 to C6 volatile solvent that is miscible in water.
  • the formulation may comprise a veterinary acceptable C2 to C6 alcohol such as ethanol, propanol, butanol, pentanol, hexanol including but not limited to isopropyl alcohol, 1-propanol, n-butanol, isobutanol, tert-butyl alcohol, 1-pentanol, isoamyl alcohol, and 1-hexanol.
  • a veterinary acceptable C2 to C6 ketone including but not limited to acetone, and butanone (methyl ethyl ketone), and methyl isobutyl ketone.
  • the formulation may comprise a volatile solvent having a molecular weight of about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 g/mol, and useful ranges may be selected between any of these values.
  • the formulation may comprise a volatile solvent having a boiling point of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140 “ C, and useful ranges may be selected between any of these values.
  • the formulation may comprise a volatile solvent having a flash point of about -20, -15, -10, -5, 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60°C, and useful ranges may be selected between any of these values.
  • the formulation may comprise about 20, 25, 30, 35, 40, 45, 50, 55 or 60% w/v of the veterinary acceptable C2 to C6 volatile solvent, and useful ranges may be selected between any of these values.
  • the formulation comprises a veterinary acceptable aprotic solvent.
  • An aprotic solvent is a solvent that has no O-H or N-H bond (non ionic).
  • Aprotic solvents may improve the solvency and transport of the active ingredient(s).
  • the active ingredient When combined in a composition of the invention comprising a volatile solvent and penetration enhancer, the active ingredient may be more effectively transported across the skin of a non-human mammal.
  • the volatile solvent evaporates to increase the concentration of the formulation, the penetration enhancer disrupts the body surface (e.g. stratum corneam) and the aprotic solvent transports the concentrated active ingredient through the skin.
  • the formulation may comprise about 30, 35, 40, 45, 50, 55, 60, 65, 70,
  • the formulation may comprise a veterinary acceptable C2 to C6 aprotic solvent.
  • the aprotic solvent may be selected from acetonitrile, dimethyl sulfoxide (DMSO), dimethylformamide, propylene carbonate, ethyl acetate, 2-pyrrolidone, dimethylacetamide (DMA), /V-methyl pyrrolidone, ethyl acetoacetate.
  • the veterinary acceptable aprotic solvent has a boiling point and/or flash point that is higher than a physiological temperature of the non-human mammal
  • Described is a method of manufacturing a transdermal formulation that may comprise mixing a first composition comprising an active ingredient(s) that is substantially insoluble in water, and a terpene, with a veterinary acceptable aprotic solvent, and a veterinary acceptable C2 to C6 alcohol solvent having a flash point of less than 20° C, thereby providing the transdermal composition.
  • composition ingredients are mixed by stirring until a homogenous mixture if the ingredients is formed.
  • the formulation may be combined with another mixture that contains a further active ingredient.
  • the active ingredient of this second composition may be different to the active ingredient of the first composition.
  • the active ingredient of the second composition may be a macrocyclic lactone or levamisole.
  • the formulation may include a lipophilic organic antioxidant compound.
  • the lipophilic organic antioxidant compound is present at about 0.01, 0.02, 0.04 0.06, 0.08, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65,
  • 0.7, 0.75. 0.8, 0.85, 0.9, 0.95, 1.0, 1.5 or 2% by weight of the composition, and useful ranges may be selected between any of these values (for example, from about 0.01 to about 2. 0.01 to about 1, about 0.01 to about 0.85, about 0.01 to about 0.35, about 0.010.2, about 0.01 to about 0.08, about 0.06 to about 2, about 0.06 to about 1.5, about 0.06 to about 0.85, about 0.06 to about 0.45, about 0.06 to about 0.25, about 0.08 to about 2, about 0.08 to about 1.5, about 0.08 to about 0.85, about 0.08 to about 0.45, about 0.08 to about 0.25, about 0.1 to about 2, about 0.1 to about 0.95, about 0.1 to about 0.5, about 0.1 to about 0.25, about 0.15 to about 2, about 0.15 to about 0.95, about 0.15 to about 0.5, about 0.15 to about 0.25, about 0.4 to about 2, about 0.4 to about 1, about 0.4 to about 0.9, about 0.4 to about 0.7, about 0.7 to
  • the lipophilic organic antioxidant compound may be required to assist or enhance the stability of one or more of the active ingredients.
  • the lipophilic organic antioxidant compound may enhance the stability of the levamisole base, the macrocyclic lactone or the levamisole base and the macrocyclic lactone.
  • the lipophilic organic antioxidant compound may assist or enhance the stability of the terpene penetration enhancer.
  • the lipophilic organic antioxidant compound may assist or enhance the stability of the limonene penetration enhancer.
  • the mixtures may be mixed until dissolved.
  • additional terpene penetration enhancer may be added to the dissolved composition such as q.s
  • the mixture may then be incubated above room temperature. In one embodiment the incubation is carried out with stirring.
  • the dissolved mixture may be heated at any suitable temperature.
  • the temperature may depend on the active ingredient(s) present in the mixture.
  • the dissolved mixture may be heated to 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 or 50°C, and useful ranges may be selected between any of these values (for example, from about 20 to about 50, about 20 to about 44, about 20 to about 40, about 20 to about 30, about 20 to about 26, about 24 to about 50, about 24 to about
  • the dissolved mixture may be heated for 10, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, 480, 540, 600, 660, or 720 minutes, and useful ranges may be selected between any of these values (for example, from about 10 to about 720, about 10 to about 660, about 10 to about 600, about 10 to about 540, about 10 to about 480, about 10 to about 360, about 10 to about 240, about 10 to about 120, about 10 to about 60, about 60 to about 720, about 60 to about 660, about 60 to about 600, about 60 to about 540, about 60 to about 480, about 60 to about 390, about 60 to about 330, about 60 to about 240, about 60 to about 180, about 60 to about 120, about 120 to about 720, about 120 to about 660, about 120 to about 600, about 120 to about 540, about 120 to about 480, about 120 to about 420, about 120 to
  • the heated composition may be then cooled and packaged for use.
  • composition may be assayed for the active ingredient(s) activity.
  • composition may have good physical and chemical stability, providing at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 months shelf life, and useful ranges may be selected between any of these values (for example, from about 12 to about 30, about 12 to about 26, about 12 to about 20, about
  • the formulation may be in a solution form. This may make formulating more straightforward.
  • the formulation is capable of delivering a range of actives/drug candidates, including anthelmintics, as single entities or in combination.
  • the platform composition delivers the actives to the systemic circulation by passive diffusion.
  • the formulation is for treating an animal in need thereof.
  • the suitability of the composition for treating a particular disease or condition depends on the active ingredients present in the composition.
  • treatment relates generally to treatment, of either a human or a non-human animal, in which some desired therapeutic effect is achieved.
  • the therapeutic effect may, for example, be the inhibition of progress of a disease or condition, including a reduction in the rate of progress, a halt in the rate of progress, amelioration, and cure.
  • Treatment as a prophylactic measure is also included.
  • Treatment also includes combination treatments and therapies, in which two or more treatments or therapies are used, for example, sequentially or simultaneously, in combination.
  • the formulation provides a method of treating an animal in need thereof, comprising administering transdermally a therapeutically effective amount of a formulation as described.
  • the formulation also provides use of a composition of the present invention in the manufacture of a medicament for treating an animal in need thereof.
  • the animal to be treated may be selected from production animals, such as, cattle, sheep, swine, deer, and goats; companion animals, such as, dogs, cats, and horses; zoo animals, such as, zebras, elephants, giraffes, and large cats; research animals, such as, mice, rats, rabbits, and guinea pigs; fur-bearing animals, such as, mink; birds, such as, ostriches, emus, hens, geese, turkeys, and ducks.
  • production animals such as, cattle, sheep, swine, deer, and goats
  • companion animals such as, dogs, cats, and horses
  • zoo animals such as, zebras, elephants, giraffes, and large cats
  • research animals such as, mice, rats, rabbits, and guinea pigs
  • fur-bearing animals such as, mink
  • birds such as, ostriches, emus, hens,
  • the formulation may be for treating a helminth infection or infestation in which case the formulation comprises at least one anthelmintic.
  • Helminths include, but are not limited to, cestodes (flatworms), nematodes (roundworms), and trematodes (flukes), such as, Trichostrongyloidea, inlcuding Haemonchus contortus ; Trichostrongylus spp.; Dictyocaulus spp.; Ascaridoidea, including Toxocara spp.; Strongylus spp.; Filarioidea, including Dirofilariaimmitis and Onchocerca spp: Trematoda, including Fasciolahepatica and Schistosoma spp.; Taenia spp.; and Moniezia spp.; Ostertagia spp.; Nematodirus spp.; Cooperia spp.; Bunostomum spp.;
  • the helminth may be selected from Haemonchus spp.; Ostertagia spp.; Trichostrongylus spp.; Nematodirus spp.; and Cooperia spp.
  • the formulation is for topical administration.
  • the composition may be administered, for example, in the form of a sterile cream, gel, pour-on or spot-on formulation, suspension, lotion, ointment, dusting powder, spray, drug- incorporated dressing, skin patch, dip, spray, emulsion, jetting fluid, or shampoo.
  • the formulation may comprise doses at low volume.
  • the formulation is administered at 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or 1 ml_/kg of live weight animal and useful ranges may be selected between any of these values (for example, from about 0.005 to about 1, from 0.005 to about 0.8, from 0.005 to about 0.6, from 0.005 to about 0.5, from 0.005 to about 0.3, from 0.005 to about 0.2, from 0.005 to about 0.1, from 0.005 to about 0.05, from 0.005 to about 0.01, from 0.008 to about 1, from 0.008 to about 0.8, from 0.008 to about 0.6, from 0.008 to
  • the volume of the dose may depend on the active ingredients present in the formulation and also on the animal to be treated.
  • the formulation may be administered at from about 0.025 mL/ kg to about 0.1 mL/kg for production animals, such as cattle, or from about 0.01 mL/kg to about 0.1 mL/kg for companion animals, such as cats and dogs.
  • the formulation may provide a number of advantages including
  • Spreadability can be measured directly by applying a known volume and measuring wetted area. UV light can be used to visualize certain formulations. Residue on skin can be measured by swabbing/extraction. Hair loss and photosensitivity may be evaluated by field observation.
  • Bovine ( ⁇ 500 pm) skin samples were excised from above the scapular and over the withers regions. The bovine samples were obtained from a local abattoir. Immediately after excision, the skin was put into plastic bags, and stored on ice packs for delivery to the research laboratory. Hair of the collected skin was cut using a hair clipper and the underlying excessive fat layer was also carefully removed from the hypodermis using a scalpel and discarded. Skin was sheared to remove the entire hair layer and skin samples of 500 ⁇ 30 pm thickness were cut using a dermatome. The dermatome was fitted with dermatome blades from Humeca, Reference 5.BLPG10. The skin samples were then frozen at -18 - -20°C for further preparation and stored for no more than 1 year prior to use.
  • the Franz Cell chamber is an in vitro skin permeation assay that consists of two primary chambers separated by a membrane.
  • Bovine skin was used as the membrane.
  • the sub-cutaneous layer was first removed by scalpel having a thickness of 0.1 to 1 mm.
  • the bovine epidermis hair was sheared to 0.4 cm and the remaining hair sheared to just above the stratum corneum layer.
  • the epidermis and some dermis was removed (approximately 500 pm) and sections were cut to 2 cm by 2 cm for each Franz cell unit.
  • the skin samples were then mounted between the top and bottom chambers to equilibrate for a minimum of 30 minutes.
  • the test composition was loaded into a loading volume of 1.0 ml. and applied to the membrane via the top chamber.
  • the bottom chamber contains fluid from which samples are taken at regular intervals for analysis. This testing determines the amount of active that has permeated the membrane at each time point.
  • the chamber is maintained at a constant temperature of 40° C.
  • the in vitro method differs to in vivo because it uses dead skin with no functioning vascular system. Therefore, the drug needs to permeate through the entire piece of skin before being collected in the receptor fluid for analysis. To compare the actual flux rates of the drugs, the lag time before drug enters the receptor fluid was ignored, and the rate of increasing concentration was calculated from when the active was detected in the fluid. This removes some of the variability due to skin thickness.
  • the bovine skin was mounted on the receptor compartment with the SC side facing upwards into the donor compartment (5 ml. and up to 1 ml_, respectively).
  • Receptor medium was composed of ethanol (up to 50%). Ethanol was added to the receptor medium to maintain sink condition for the lipophilic drugs which only partially mimics in vivo where blood flow provides constant elimination by transport of the drug away from the site of delivery.
  • the receptor compartment was maintained at 39 ⁇ 1°C and stirred by a magnetic bar at 600 rpm, which also helps improve the problem of a static diffusion cell system (i.e. increased drug dissolution).
  • samples 300 pL were withdrawn from the sampling port and immediately replaced by an equal volume of fresh receptor medium. The samples were then analyzed by an HPLC method with UV detection. All formulations were tested at least in triplicate.
  • test platform formulation provided better transdermal permeation when compared against a marketed commercial formulation.
  • the formulations for this study are listed in Table 3 below.
  • the formulations vary in the type of aprotic solvents, short-chain, volatile components, and types of API.
  • a representation of common excipients is used for each class of aprotic solvent, short-chain volatile components and different types of API. These are dimethyl sulfoxide (DMSO), dimethyl isosorbide, dimethyl acetamide (DMA) and 2-pyrrolidone for the aprotic solvents, ethanol, isopropanol (IPA) and acetone for the short-chain, volatile solvents and meloxicam and tetracaine as the alternative types of API.

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Abstract

Described is an anhydrous transdermal formulation comprising one or more active agents, at least 15% by weight terpene hydrocarbon, a veterinary acceptable aprotic solvent, and a veterinary acceptable C2 to C6 volatile solvent having a flash point of less than 20° C or a flash point lower than the body surface temperature of the non-human mammal. The anhydrous transdermal formulation may comprise a veterinary acceptable C2 to C6 aprotic solvent.

Description

VETERINARY TRANSDERMAL FORMULATION
TECHNICAL FIELD
[0001] The present invention relates to an anhydrous transdermal formulation that contains a terpene, and more specifically a formulation suitable for transdermal delivery of active therapeutic agents to mammals. The present invention also relates to methods of manufacturing such formulations, and the use such formulationsfor treating animals.
BACKGROUND OF THE INVENTION
[0002] Skin forms an excellent barrier against drug permeation, due to the rigid lamellar structure of the stratum corneum (SC) lipids. The SC limits the rate of drug transfer through the skin. The rate of transfer is generally too slow for massive systemic absorption, making transdermal application unsuitable for the delivery of large amounts of drug in short periods of time. Transdermal application is more commonly used for the sustained delivery of drugs over a prolonged period of time.
[0003] Transdermal formulations typically include permeation enhancers, which improve the rate of transfer of the drug across the skin. Permeation enhancers may act by disrupting the highly ordered structure of stratum corneum lipid, interacting with intercellular protein, and/or improving partition of the drug into the stratum corneum. A problem with transdermal formulations is that these permeation enhancers can cause skin irritation and inflammation.
[0004] Small molecules of moderate lipophilicity permeate through skin most easily. The partition co-efficient P in water and a hydrophobic organic solvent, such as octanol or hexane, is a useful measure lipophilicity. Molecules having a low log P (i.e. hydrophilic compounds) have low permeability because partitioning into the skin lipids is low. Permeability at high log P is also low. This may be due to the accumulation of lipophilic drugs in the stratum corneum due to low water solubility.
[0005] There is a need for new transdermal formulations that avoid one or more of the aforementioned disadvantages. It is desirable that the present invention goes some way to meeting this need; and/or to at least provide more choice or alternative transdermal therapeutics.
[0006] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date.
SUMMARY OF THE INVENTION
[0007] In one aspect of the present disclosure there is provided an anhydrous transdermal formulation comprising
■ one or more active agents,
■ at least 15% by weight terpene hydrocarbon,
■ a veterinary acceptable aprotic solvent, and
■ a veterinary acceptable C2 to C6 volatile solvent having a flash point of less than 20° C.
[0008] In a further aspect of the present disclosure there is provided an anhydrous transdermal formulation comprising
■ one or more active agents,
■ at least 15% by weight terpene hydrocarbon,
■ a veterinary acceptable aprotic solvent having a flash point higher than a physiological body temperature of a non-human mammal, and
■ a veterinary acceptable C2 to C6 volatile solvent having a flash point lower than the body surface temperature of the non-human mammal.
[0009] In another aspect there is described a method of manufacturing a transdermal formulation comprising mixing a first composition comprising an active ingredient that is substantially insoluble in water, and a terpene, with a veterinary acceptable aprotic solvent, and a veterinary acceptable C2 to C6 alcohol solvent having a flash point of less than 20° C, thereby providing the transdermal formulation.
[0010] The following embodiments may relate to any of the above aspects.
[0011] In one configuration the active agent has an apparent partition coefficient (log P) in n-octanol/buffer pH 7.4 of about 1, 2, 3, 4, 5 , 6, 7 or 8, and useful ranges may be selected between any of these values.
[0012] In one configuration the anhydrous transdermal formulation may comprise a veterinary acceptable C2 to C6 aprotic solvent.
[0013] In one configuration the anhydrous transdermal formulation may comprise a veterinary acceptable aprotic solvent having at least one double bond. [0014] In one configuration the veterinary acceptable C2to C6 volatile solvent may begin to vaporise at a body surface temperature of about 24° to about 40° C.
[0015] In one configuration the veterinary acceptable C2to C6 volatile solvent may have a molecular weight of about 40 to about 100 g/mol.
[0016] In one configuration the veterinary acceptable C2to C6 volatile solvent may have a flash point of less than about 20° C.
[0017] In one configuration the anhydrous transdermal formulation may comprise
■ a veterinary acceptable aprotic solvent selected from dimethyl sulfoxide (DMSO), dimethylformamide, propylene carbonate, ethyl acetate, 2- pyrrolidone, dimethylacetamide (DMA), N-methyl pyrrolidone, and ethyl acetoacetate; and
■ a veterinary acceptable C2 to C6 volatile solvent selected from acetone, ethanol, and isopropyl alcohol.
[0018] In one configuration the formulation comprises two or more veterinary agents.
[0019] In one configuration an active ingredient may be selected from
■ an anthelmintic, a non-steroidal anti-inflammatory, a steroidal anti-inflammatory,
■ a steroid hormone,
■ an anti-histamine
■ an anti-emetic,
■ a metabolic regulator,
■ a productivity regulator, a hypothyroidism treatment,
■ a behavioural treatment,
■ an analgesic,
■ a parasiticide,
■ an insecticide,
■ an anti-microbial,
■ an anti-biotic,
■ an anti-fungal,
■ an anti-viral,
■ a coccidostat, ■ a skin treatment agent, or
■ any combination of one or more of the above.
[0020] In one configuration the composition comprises at least 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25% terpene by weight of the formulation, and useful ranges may be selected between any of these values.
[0021] In one configuration the hydrocarbon terpene is selected from pinene, limonene, terpinene, cymene, aromadendrene, or a combination thereof.
[0022] In one configuration the terpene is limonene.
[0023] In one embodiment the formulation comprises about 20, 25, 30, 35, 40,
45, 50, 55 or 60% w/v of the volatile solvent, and useful ranges may be selected between any of these values.
[0024] In one configuration the volatile solvent is selected from isopropyl alcohol, ethanol and acetone.
[0025] In one configuration the formulation comprises one or more antioxidants surfactants, or dispersants.
[0026] In one configuration the composition may also include a lipophilic organic antioxidant compound.
[0027] In one configuration the lipophilic organic antioxidant compound is present at about 0.01, 0.02, 0.04 0.06, 0.08, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5,
0.55, 0.6, 0.65, 0.7, 0.75. 0.8, 0.85, 0.9, 0.95, 1.0, 1.5 or 2% by weight of the composition, and useful ranges may be selected between any of these values.
[0028] In one configuration the lipophilic organic antioxidant compound is a phenol derivative such as butylated hydroxytoluene, BHA, tocopherol, propyl gallate, or any combination thereof.
[0029] In one configuration the antioxidant is selected from butylated hydroxytoluene, butylated hydroxyanisole, or a combination thereof.
[0030] In one configuration the composition may be heated to at least 20°C.
[0031] In one configuration the heating may be performed for between 10 minutes to 1 hour. [0032] In one configuration the dissolved mixture may be heated to 20, 25, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 or 50°C, and useful ranges may be selected between any of these values.
[0033] In one configuration the composition is physically and chemically stable, providing at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 months shelf life, and useful ranges may be selected between any of these values.
[0034] In one configuration the formulation may be effective to reduce parasitic faecal egg count by at least 90, 95, 96, 97, 98 or 99%.
[0035] In another aspect the invention may be the use of any one or more of the compositions described above.
[0036] In one configuration the non-human mammal includes farmed or unfarmed animals, domestic or companion animals (e.g. cattle, sheep, horses, deer, swine, dogs, cats, etc).
[0037] In one configuration the composition is a veterinary composition.
[0038] In one configuration the composition is a pour on or spot on formulation.
[0039] In one configuration the composition is fast acting with respect to at least one active ingredient. In one embodiment, the composition is fast acting with respect to at least one active ingredient relative to at least one other active ingredient in the composition. In one embodiment, the fast acting active ingredient acts within at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 48, 72, 96, 120 hours and useful ranges may be selected from within these values
[0040] In one configuration the action of at least one of the active ingredients is delayed relative to at least one other active ingredient in the composition. In one embodiment, the action is delayed by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, and useful ranges may be selected from within these values.
[0041] In one configuration, the composition provides sustained or prolonged release of at least one of the active ingredients.
[0042] As used herein "(s)" following a noun means the plural and/or singular forms of the noun.
[0043] As used herein the term "and/or" means "and" or "or" or both. [0044] It is intended that reference to a range of numbers disclosed herein (for example, 1 to 10) also incorporates reference to all rational numbers within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7) and, therefore, all sub-ranges of all ranges expressly disclosed herein are hereby expressly disclosed. These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.
[0045] The term "alkenyl" employed alone or in combination with other terms means, unless otherwise stated, a monovalent straight chain hydrocarbon group including a carbon-carbon double bond.
[0046] This invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, and any or all combinations of any two or more said parts, elements or features, and where specific integers are mentioned herein which have known equivalents in the art to which this invention relates, such known equivalents are deemed to be incorporated herein as if individually set forth.
[0047] Although the present invention is broadly as defined above, those persons skilled in the art will appreciate that the invention is not limited thereto and that the invention also includes embodiments of which the following description gives examples.
[0048] As used herein, the term "veterinary agent" is intended to capture any agent that is used for improving the health and well being of an animal.
[0049] The term "comprising" as used in this specification means "consisting at least in part of". When interpreting statements in this specification which include that term, the features, prefaced by that term in each statement, all need to be present but other features can also be present. Related terms such as "comprise" and "comprised" are to be interpreted in the same manner.
DETAILED DESCRIPTION OF THE INVENTION
[0050] Described is a non-aqueous formulation that comprises a terpene in combination with a solvent system that comprises an aprotic solvent and a volatile solvent. The composition delivers an active ingredient or ingredients transdermally to non-human mammals. [0051] The composition may be used to deliver a range of actives, such as anthelmintics. A non-limiting example of suitable anthelmintics includes moxidectin, levamisole and macrocyclic lactones.
[0052] Also described is a platform formulation that may be used to deliver a wide variety of active ingredients transdermally.
[0053] The platform formulation delivers a therapeutic quantity of the active ingredient or ingredients. The active ingredient or ingredients, once applied to the skin of the recipient animal, may be absorbed into the systemic circulation.
[0054] The active agent may be lipophilic. Lipophilicity can be described by the partition coefficient, log P, which is defined as the ratio of the concentration of the unionised compound at equilibrium between organic and aqueous phases. Lipophilicity of a molecule is expressed as a partition coefficient (Log P ) of an n-octanol/water system, where more lipophilic compounds are partitioned in the n-octanol layer. An example of a method to measure Log P is given by pION Inc., Brookline, MA (A. Avdeef and C. Berger) (1997). A negative value for log P means the compound has a higher affinity for the aqueous phase (it is more hydrophilic); when log P = 0 the compound is equally partitioned between the lipid and aqueous phases; a positive value for log P denotes a higher concentration in the lipid phase (i.e., the compound is more lipophilic). The active agent may have a Log P of about 1, 2, 3, 4, 5, 6, 7 or 8, and useful ranges may be selected between any of these values (for example, about 1 to about 9, about 1 to about 6, about 1 to about 4, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 3 to about 8, about 3 to about 7 or about 3 to about 6).
[0055] The platform formulation may deliver multiple lipophilic active ingredients. For example, 2, 3, 4 or 5 actives delivered transdermally in a single composition. Preferably the active ingredients account for 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90% of the composition, and useful ranges may be selected between any of these values (for example, from about 1 to about 90, about 1 to about 75, about 1 to about 60, about 5 to about 100, about 5 to about 80, about 5 to about 55, about 25 to about 90, about 25 to about 65, about 25 to about 50, about 30 to about 90, about 30 to about 80, about 30 to about 70, about 30 to about 55, about 50 to about 90, about 50 to about 75, about 65 to about 90, about 65 to about 75 or about 70 to about
90% of the formulation).
[0056] The platform formulation may deliver active ingredients with a molecular weight of less than about 1000, 900, 800, 700, 600, 500, 400, 300, 200 gmol^ and useful ranges may be selected between any of these values (for example, from about 100 to about 1000, about 100 to about 900, about 100 to about 800, about 100 to about 600, about 100 to about 500, about 200 to about 1000, about 200 to about 900, about 200 to about 800, about 200 to about 700, about 200 to about 500, about 200 to about 400, about 300 to about 1000, about 300 to about 900, about 300 to about 700, about 300 to about 500, about 500 to about 1000, about 500 to about 800, about 500 to about 700, about 500 to about 600, about 700 to about 1000, about 700 to about 900, about 800 to about 1000 gmol 1).
[0057] At least one of the active ingredients may have a molecular weight of at least about 300, at least about 400, at least about 500, or at least about 600 gmol-i.
[0058] As mentioned above, anthelmintic agents may be delivered transdermally by the platform composition of the present invention. A candidate anthelmintic agent includes imidazothiazoles. For example, the imidazothiazole may be selected from levamisole, pyrantel pamoate, butamisol or tetramisole. Macrocyclic lactones are also candidate agents for delivery transdermally. For example, the macrocyclic lactone may be selected from avermectin, ivermectin, abamectin, eprinomectin, moxidectin, selamectin, doramectim, milbemycin, abamectin or cydectin.
[0059] If an imidazothiazole, such as levamisole, is incorporated into the platform composition for transdermal delivery, preferably the composition may contain 1, 5, 10,
15, 20, 25, 30, 35, 40, 45, 50, 55 or 60% imidazothiazole, and useful ranges may be selected between any of these values (for example, from about 1 to about 60, about 1 to about 40, about 1 to about 30, about 5 to about 60, about 5 to about 45, about 5 to about 35, about 5 to about 25, about 10 to about 60, about 10 to about 45, about 10 to about 30, about 10 to about 20, about 15 to about 60, about 15 to about 40, about 15 to about 30, about 15 to about 35, about 15 to about 30, about 15 to about 25, about 20 to about 60, about 20 to about 40, about 20 to about 30, about 25 to about 60, about 25 to about 45, about 25 to about 35, about 30 to about 60, about 30 to about 40, about 40 to about 60% imidazothiazole).
[0060] If a macrocyclic lactone, such as moxidectin, is incorporated into the platform composition for transdermal delivery, preferably the composition may contain 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% macrocyclic lactone, and useful ranges may be selected between any of these values (for example, from about 0.1 to about 20, about 0.1 to about 15, about 0.1 to about 12, about 0.1 to about 10, about 0.1 to about 5, about 0.1 to about 4, about 0.5 to about 20, about 0.5 to about 14, about 0.5 to about 10, about 0.5 to about 5, about 1 to about 20, about 1 to about 16, about 1 to about 11, about 1 to about 6, about 3 to about 20, about 3 to about 13, about 3 to about 7, about 5 to about 20, about 5 to about 14, about 5 to about 10, about 8 to about 20, about 8 to about 12, about 14 to about 20, about 16 to about 20% macrocyclic lactone).
[0061] It should be appreciated that the exemplification of anthelmintics such as levamisole and moxidectin is not intended to be limiting, and that other lipophilic active ingredients could also be delivered within the composition.
[0062] Anthelmintics include benzimidazoles, imidazothiazoles, tetrahydropyrimidines, macrocyclic lactones, salicylanilides, substituted phenols, aromatic amides, isoquinolines, amino acetonitriles, spiroindoles, and the like.
[0063] Anthelmintic benzimidazoles include mebendazole, flubendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, albendazole sulfoxide, thiabendazole, thiophanate, febantel, netobimin, and triclabendazole. Further examples include mebendazole, and ricobendazole.
[0064] Benzimidazole based anthelmintics interfere with the worm's energy metabolism on a cellular level. They bind to a specific building block called beta tubulin and prevent its incorporation into certain cellular structures called microtubules, which are essential for energy metabolism. Interfering with energy metabolism is a much more basic mode of activity than that which occurs with other classes of anthelmintics. For this reason, benzimidazoles are also able to kill worm eggs. Benzimidazoles have a wide margin of safety and broad spectrum activity.
[0065] Imidazothiazoles and tetrahydropyrimidines and both nicotinic agonists. Anthelmintic imidathiazoles include levamisole, tetramisole, and butamisole. Tetrahydropyrimidine anthelmintics include, for example, morantel, oxantel, and pyrantel.
[0066] The tetrahydropyrimidines mimic the activity of acetylcholine, a naturally occurring neurotransmitter that initiates muscular contraction. The worm is unable to feed and quickly starves. Tetrahydroyrimidines only affect adult populations of worms. They do not have activity against the larval stages and are ineffective against cestodes (tapeworms) and trematodes (liver flukes).
[0067] Imidazothiaoles have a similar mode of action causing spastic paralysis of the worms. Levamisole has a broad spectrum of activity and is effective against many larval stages of parasites. [0068] Macrocyclic lactones include abamectins, for example abamectin, doramectin, eprinomectin, ivermectin, and selamectin, and milbemycins, for example milbemycin oxime and moxidectin.
[0069] The macrocyclic lactones (avermectins and milbemycins) are products or chemical derivatives of soil microorganisms belonging to the genus Streptomyces. All of the macrocyclic lactone anthelmintics have the same mode of action. They interfere with GABA-mediated neurotransmission, causing paralysis and death of the parasite. Macrocyclic lactones are the most potent killer of worms and are more persistent in their effect. The duration of persistent activity varies according to the drug and formulation.
[0070] Macrocyclic lactones also have the unique quality of also killing several types of external parasite such as lice, mites, and ticks. They have a wide margin of safety for livestock and are effective against all stages of worms, including inactive forms.
[0071] Salicylanilides include brotianide, clioxanide, closantel, niclosamide, oxyclozanide, rafoxanide, substituted phenols include bithionol, disophenol, hexachlorophene, niclofolan, menichlopholan, nitroxynil, and aromatic amides include diamfenetide (diamphenethide).
[0072] Insoquinoline anthelmintics include praziquantel and epsiprantel. Praziquantel and epsiprantel have high efficacy against cestode parasites at relatively low dose rates but no effect on nematodes. Praziquantel is rapidly and almost completely absorbed from the GI tract.
[0073] Amino-acetonitrile derivatives include monepantel, which acts by paralyzing worms by attacking a previously undiscovered receptor HCO-MPTL-1, present only in nematodes.
[0074] Further examples of anthelmintics include piperazine and derivatives thereof such as piperazine and diethylcarbamazine (DEC, a derivative of piperazine), benzenesulfonamides such as clorsulon, amidines such as bunamidine, isothiocyantes such as nitroscanate, and organophosphates such as dichlorvos, and spiroindoles such as derquantel (2- deoxoparaherquamide).
[0075] The active ingredient may be a non-steroidal or steroidal anti inflammatory. Examples of non-steroidal anti-inflammatory drugs include, but are not limited to, acemetacin, acetylsalicylic acid (aspirin), alminoprofen, benoxaprofen, bucloxic acid, carprofen, celecoxib, clidanac, deracoxib, diclofenac, diflunisal, dipyrone, etodolac, fenoprofen, fentiazac, firocoxib, flobufen, flufenamic acid, flufenisal, flunixin, fluprofen, flurbiprofen, ibuprofen, indomethacin, indoprofen, isoxicam, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, miroprofen, nabumetone, naproxen, niflumic acid, oxaprozin, oxepinac, phenylbutazone, piroxicam, pirprofen, pramoprofen, sudoxicam, sulindac, suprofen, tepoxalin, tiaprofenic acid, tiopinac, tolfenamic acid, tolmetin, trioxaprofen, zidometacin, or zomepirac, pharmaceutically acceptable salts thereof and mixtures thereof.
[0076] Most commercially available veterinary non steroidal anti- inflammatory drugs (NSAIDs) belong to two broad classes: carboxylic acid and enolic acid derivatives. The main groups of enolic acids are the pyrazolones (phenylbutazone, oxyphenbutazone, and ramifenazone) and the oxicams (meloxicam, piroxicam, and tenoxicam). Carboxylic acid groups include the salicylates (aspirin), propionic acids (ibuprofen, naproxen, carprofen, ketoprofen, and vedaprofen), anthranilic acids (tolfenamic and meclofenamic acids), phenylacetic acids (acetaminophen), aminonicotinic acids (flunixin), and indolines (indomethacin).
[0077] Anti-inflammatory steroids include steroids which have an anti inflammatory activity either locally or systemically. These are well-known within the art. Non-limiting examples of steroids include the adrenocorticoid steroids, whether endogenous or synthetic. These include, without limitation, hydrocortisone, betamethasone, cortisone, dexamethasone, prednisolone, prednisone, methylprednisilone, triamcinolone, flumethasone, and their pharmaceutically acceptable derivitives. In one embodiment, the steroid is hydrocortisone or cortisone. These steroids may be used at levels known in the art.
[0078] The composition may comprise a steroid hormone. Steroid hormones include growth promoters and production enhancers. In one embodiment, the steroid hormone is a natural steroid hormone, such as estradiol, progesterone, and testosterone, or a synthetic steroid hormone, such as trenbolone acetate, estradiol benzoate, estradiol 17b, and melengestrol acetate, and zeranol.
[0079] Steroid hormones include natural and synthetic steroid hormones, steroid hormone precursors, steroid hormone metabolites, and derivatives thereof that are structurally derived from cholesterol. Steroid hormones can be synthesized from cholesterol via pathways that involve cytochrome P450 (cP450) enzymes, which are heme-containing proteins. Exemplary steroid hormones, include, but are not limited to, androgens, estrogens, progestogens, mineralcorticoids, and glucocorticoids. Exemplary androgens include, but are not limited to, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulphate, dihydrotestosterone, androstenedione, androstenediol, androstanedione, androstanediol, and any combination thereof. Exemplary estrogens include, but are not limited to, estrone, estradiol, estriol, estetrol, equilin, equilenin, and any combination thereof. Exemplary progestogens include, but are not limited to, progesterone, 17-hydroxy- progesterone, pregnenolone, dihydroprogesterone, allopregnanolone, 17-hydroxy- pregnenolone, 17-hydroxy-dihydroprogesterone, 17- hydroxy-allopregnanolone, and any combination thereof. Exemplary mineralcorticoids include, but are not limited to, aldosterone, 11- deoxycorticosterone, fludrocortisones, 1 1-deoxy-cortisol, pregnenedione, and any combination thereof. Exemplary glucocorticoids, include, but are not limited to, cortisol (hydrocortisone), corticosterone, 18-hydroxy-corticosterone, cortisone, and any combination thereof.
[0080] The composition may comprise an anti-histamine. Non-limiting examples of suitable antihistamines include clemastine, clemastine fumarate (2(R)-[2-[l-(4- Chlorophenyl)-l-phenyl-ethoxy]ethyl-l-methylpyrrolidine), dexmedetomidine, doxylamine, loratidine, desloratidine and promethazine, and diphenhydramine, or pharmaceutically acceptable salts, solvates or esters thereof.
[0081] The composition may comprise an anti-emetic. Non-limiting examples of suitable anti-emetic agents include phenothiazines (e.g., prochloperazine, promethazine, thiethylperazine, perphenazine, chlorpromazine, metopimazine, acepromazine, etc.); 5HT-3 receptor antagonists such as ondansetron, granisetron, tropisetron, dolasetron, hydrodolasetron, azasetron, ramosetron, lerisetron, indisetron and palonosetron; and others such as dimenhydrinate, diphenhydramine (which can also act as an antihistamine), cyclizine, meclizine, promethazine, hyroxyzine, metoclopramide, domperidone, hyoscine, hyoscine hydrobromide, hyoscine hydrochloride, scopolamine, clebopride, alizapride, itopride, bromopride, droperidol, haloperidol, benzquinamide, cerium oxalate, diphenidol, dronabinol, nabilone, ginger, levosulpiride, butorphanol and aprepitant.
[0082] The composition may comprise a metabolic regulator, such a hypothyroidism treatment. Metabolic diseases may be inherited or acquired and are clinically important because they affect energy production or damage critical tissues. Storage diseases and inborn defects in metabolism may be either genetic or acquired.
The diseases are characterized by the accumulation or storage of specific lysosomal enzyme substrates or byproducts within cells due to the partial or complete deficiency of those enzymes. The development of the metabolic diseases is largely related to production or management factors. However, the pathogenesis of the diseases is primarily related to alterations in metabolism. In many cases the basis of disease is not a congenital or inherited metabolic defect, but rather an increased demand for a specific nutrient that has become deficient. In one embodiment the metabolic regulator is a growth promoter, probotic or prebiotic, antibiotic or anti -infective supplement, electrolyte, mineral, vitamin, or other nutritional additive.
[0083] The composition may comprise a productivity regulator, for example polyethers such as monensin. In one embodiment, the productivity regulator is a productivity enhancer.
[0084] The composition may comprise a hypothyroidism treatment. Suitable hypothyroidism treatments include treatment with thyroid hormones and derivatives thereof. Examples of thyroid hormones include thyroixines such as T2, T3and T4. "T3" refers to the art recognized thyroid hormone, triiodothyronine (also known as (2S)-2- amino-3-[4-(4-hydroxy-3-iodo-phenoxy)-3,5-diiodo-phenyl]propanoic acid). "T4" refers to the art recognized thyroid hormone, thyroxine, or 3,5,3',5'-tetraiodothyronine (also known as (2S)-2-amino-3-[4-(4-hydroxy-3,5-diiododophenoxy)-3,5- diiodophenyl]propanoic acid). "T2" refers to the thyroid hormone iodothyronine or 3,5- diiodo-l-thyronine.
[0085] The composition may comprise a behavioural treatment agent. Behavioural treatments include, for example, serotonin reuptake inhibitors and tricyclic antidepressants, pheromones, nutritional products, and calming agents. Examples of serotonin reuptake inhibitors and tricyclic antidepressants include, clomipramine.
[0086] The composition may comprise an analgesic. Analgesics include the opioid analgesics such as buprenorphine, butorphanol, dextromoramide, dezocine, dextropropoxyphene, diamorphine, fentanyl, alfentanil, sufentanil, hydrocodone, hydromorphone, ketobemidone, levomethadyl acetate, mepiridine, methadone, morphine, nalbuphine, opium, oxycodone, papaveretum, pentazocine, pethidine, phenoperidine, piritramide, dextropropoxyphene, remifentanil, tilidine, tramadol, codeine, dihydrocodeine, meptazinol, dezocine, eptazocine and flupirtine. Analgesics also include non-opioid analgesics, for example, non-steroidal anti-inflammatories, such as those described herein.
[0087] The composition may comprise a parasiticide. Parasiticides include, for example the macrocyclic lactones such as abamectin, ivermectin, eprinomectin, doramectin, moxidectin, selamectin, milbemycin oxime. In one embodiment, the antiparasitic agents include, but are not limited to, endoparasiticidal agents, ectoparaciticidal agents, and endectoparaciticidal agents. Ectoparasiticides include, for example, organochlorines, organophosphates, carbamates, amidines, pyrethrins and synthetic pyrethroids, benzoylureas, juvenile hormone analogues, macrocyclic Lactones, neonicotinoids, phenylpyrazoles, and spinosyns. Endectoparaciticides include, for example, macrocyclic lactones, such as ivermectin. Endoparasiticides include, for example, anhelmintics, such as those described herein. In one embodiment, the antiparasitic agent is an avermectin, milbemycin, phenylpyrazole, nodulisporic acid, clorsulon, closantel, quinacrine, chloroquine, vidarabine, nitenpyram, ivermectin, milbemycine oxime, lufenuron, salimectin, moxidectin, or dorimectin. In a more particular embodiment, the antiparasitic agent is nitenpyram, ivermectin, milbemycine oxime, lufenuron, salimectin, moxidectin, dorimectin, or paraherquamide, or pharmaceutically acceptable salts, solvates or esters thereof. In one embodiment, the composition comprises an insecticide. Examples of insecticides include, but are not limited to, pyrethrins, pyrethroids, and limonene. Insecticides also include certain parasiticides.
[0088] The formulation may comprise a skin treatment agent. Skin treatment agents include skin conditioning agents, for example glycerine. Other skin conditioning agents may be used. Categories of skin conditioning agents include, but are not limited to emollients, humectants and plasticizers.
[0089] Humectants include, but are not limited to sorbitol, propylene glycol, alkoxylated glucose, hexanetriol, ethanol, and the like. Emollients include, but are not limited to, hydrocarbon oils and waxes; silicone oils; triglyceride esters, acetoglyceride esters, ethoxylated glycerides; alkyl esters; alkenyl esters; fatty acids, fatty alcohols; fatty alcohol ethers; ether-esters (fatty acid esters of ethoxylated fatty alcohols); lanolin and its derivitives; polyhydric alcohols and polyether derivatives; polyhydric alcohol esters; wax esters; beeswax derivatives; vegetable waxes; phospholipids; steroids; and amides. These may all be used at art-established levels.
[0090] Other examples of skin treatment agents include anti-ageing agents and wound care agents.
[0091] The formulation may comprise an anti-microbial. Anti-microbials include antibiotics, antifungals, antivirals, anhelmintics, and the like.
[0092] The formulation may comprise an antibiotic, antifungal, or antiviral. [0093] The anti-biotic may be an inhibitor of cell wall synthesis (e.g. penicllins, cephalosporins, bacitracin and vancomycin), inhibitor of protein synthesis (aminoglycosides, macrolides, lincosamides, streptogramins, chloramphenicol, tetracyclines), inhibitor of membrane function (e.g. polymixin B and colistin), an inhibitor of nucleic acid synthesis (e.g. quinolones, metronidazole, and rifampin), or an inhibitor of other metabolic processes (e.g. anti-metabolites, sulfonamides, and trimethoprim). Non limiting examples of antibiotics include polyethers ionophores such as monensin and salinomycin, beta-lactams such as penicillins, aminopenicillins (e.g., amoxicillin, ampicillin, hetacillin, etc.), penicillinase resistant antibiotics (e.g., cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin, etc.), extended spectrum antibiotics (e.g., axlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, etc.); cephalosporins (e.g., cefadroxil, cefazolin, cephalixin, cephalothin, cephapirin, cephradine, cefaclor, cefacmandole, cefmetazole, cefonicid, ceforanide, cefotetan, cefoxitin, cefprozil, cefuroxime, loracarbef, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftiofur, ceftizoxime, ceftriaxone, moxalactam, etc.); monobactams such as aztreonam; carbapenems such as imipenem and eropenem; quinolones (e.g., ciprofloxacin, enrofloxacin, difloxacin, orbifloxacin, marbofloxacin, etc.); chloramphenicols (e.g., chloramphenicol, thiamphenicol, florfenicol, etc.); tetracyclines (e.g., chlortetracycline, tetracycline, oxytetracycline, doxycycline, minocycline, etc.); macrolides (e.g., erythromycin, tylosin, tlimicosin, clarithromycin, azithromycin, etc.); lincosamides (e.g., lincomycin, clindamycin, etc.); aminoglycosides (e.g., gentamicin, amikacin, kanamycin, apramycin, tobramycin, neomycin, dihydrostreptomycin, paromomycin, etc.); sulfonamides (e.g., sulfadmethoxine, sfulfamethazine, sulfaquinoxaline, sulfamerazine, sulfathiazole, sulfasalazine, sulfadiazine, sulfabromomethazine, suflaethoxypyridazine, etc.); glycopeptides (e.g., vancomycin, teicoplanin, ramoplanin, and decaplanin; and other antibiotics (e.g., rifampin, nitrofuran, virginiamycin, polymyxins, tobramycin, etc.).
[0094] Antifungals include polyenes, azoles, allylamines, morpholines, anti metabolites, and combinations thereof. For example, fluconazole, itraconazole, clotrimazole, ketoconazole, terbinafine, 5-fluorocytosine, and amphotericin B.
[0095] Non-limiting examples of antivirals include didanosine, lamivudine, stavudine, zidovudine, indinavir, and ritonavir.
[0096] The formulation may comprise a coccidostat. Coccidiostats are antiprotozoal agents that acts on Coccidia parasites. Examples include, but are not limited to, amprolium, arprinocid, artemether, clopidol, decoquinate, diclazuril, dinitolmide, ethopabate, halofuginone, lasalocid, monensin, narasin, nicarbazin, oryzalin, robenidine, roxarsone, salinomycin, spiramycin, sulfadiazine, and toltrazuril.
[0097] The formulation may comprise an anesthetic such as tetracaine, bupivacaine, etidocaine, procaine, prilocaine, and lidocaine.
[0098] The active ingredient(s) is stable in the formulation. For example, the active ingredient(s) in the composition is typically stable to chemical reaction with other components in the reaction mixture or to degradation or decomposition by other means.
[0099] The formulation may comprise levamisole base and the recovery of levamisole base after 3 months at 75% relative humidity and 40°C is at least about 95, 96, 97, 98, or 99%. In one embodiment, the recovery is at least about 95%.
[0100] The formulation may comprise abamectin and the recovery of abamectin after 3 months at 75% relative humidity and 40°C is at least about 95, 96, 97, 98, or 99%. In one embodiment, the recovery is at least about 95%. In one embodiment, the composition comprises abamectin and at least one surfactant. In one embodiment, at least one of the surfactants is a polyoxyethylene alkenyl ether as described herein.
[0101] The formulation may comprise moxidectin and the recovery of moxidectin after 3 months at 75% relative humidity and 40°C is at least about 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99%. In one embodiment, the recovery is at least about 90%.
[0102] In one embodiment, the at least one active ingredient is soluble in at least one of the other liquid components of the composition.
[0103] In one embodiment, at least one of the active ingredients is substantially insoluble in water.
[0104] The terpene, or combination of terpenes, helps to maximise the transport of the active ingredient(s) across the skin by improving partitioning of the active ingredients, and minimises the residency time of the active ingredient(s) on the surface of the skin, reducing the potential for irritation. In some embodiments, the terpene acts as a penetration or permeation enhancer, sorption promoter or accelerant.
[0105] Terpenes are a diverse class of organic compounds produced from a wide variety of sources. The fundamental building block of terpenes is the isoprene unit, CsHs. Larger structures are then formed from multiples of isoprene. Terpenes can be cyclic or acyclic. [0106] In one embodiment the terpene hydrocarbon is selected from pinene, limonene, terpinene, cymene, aromadendrene, or a combination thereof.
[0107] The terpene may be limonene.
[0108] In one embodiment, the composition does not comprise a terpene alcohol. In one embodiment, the composition does not comprise menthol.
[0109] In one embodiment, the terpene is the sole permeation enhancer in the composition.
[0110] In one embodiment, the composition comprises a single terpene.
[0111] Without wishing to be bound by theory, high concentrations of terpenes such as limonene may result in contact sensitisation (initial process of an allergic reaction). In some embodiments, the terpene may be present in an amount suitable for maximising the transport of the active ingredient(s) across the skin without causing irritation to the skin of the non-human mammal.
[0112] The terpene permeation enhancer may be present from at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 36,
38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or
60% by weight of the composition, and useful ranges may be selected between any of these values.
[0113] The terpene permeation enhancer may be limonene present from at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,
35, 36, 36, 38, 39, 40% by weight of the composition, and useful ranges may be selected between any of these values.
[0114] The composition may comprise one or more veterinary acceptable volatile solvents. Volatile solvents are solvents that easily vaporise into a gas at relatively low temperatures. For example, volatile solvents may vaporise at physiological temperature such as the body surface temperature. As a result, vaporisation (hence removal) of the volatile solvent from the composition may be modulated. The veterinary acceptable volatile solvent may remain in the composition at low ambient temperatures (or storage temperatures) and may only begin vaporising after application on the skin or body surface of the non-human mammal. [0115] The inclusion of a veterinary acceptable volatile solvent may improve the diffusion of the composition across skin of the non-human mammal. Without wishing to be bound by theory, as the volatile solvent evaporates from the composition, the composition may become more saturated resulting in a higher diffusion gradient across of the skin, therefore, may improve the delivery of the active ingredient.
[0116] The body surface temperature of non-human mammals may be affected by a number of factors including the ambient temperature, location of body surface, hair coverage etc. The body surface temperature of non-human mammals may vary from species to species. For example, cattle ( Bos taurus ) may have a body surface temperature of approximately 33° C, while sheep (Ov/s aries) may have a body surface temperature of approximately 29° C.
[0117] In some embodiments, the composition may comprise a veterinary acceptable volatile solvent that begin to vaporise at a body surface temperature of the non-human mammal.
[0118] In some embodiments, the composition may comprise a veterinary acceptable volatile solvents that begin to vaporise at a body surface temperature of about 24.0, 24.5, 25.0, 25.5, 26.0, 26.5, 27.0, 27.5, 28.0, 28.5, 29.0, 29.5, 30.0, 30.5, 31.0, 31.5, 32.0, 32.5, 33.0, 33.5, 34.0, 34.5, 35.0, 35.5, 36.0, 36.5, 37.0, 37.5, 38.0, 38.5, 39.0, 39.5, 40.0° C, and useful ranges may be selected between any of these values.
[0119] The volatility of the veterinary acceptable volatile solvent may be affected by factors such as intermolecular forces and/or molecular weight of the solvent. Solvent having a weak overall intermolecular force may result in a more volatile solvent.
Similarly, solvents having a low molecular weight may result in a more volatile solvent. The term molecular weight may be used interchangeably with molecular mass or molar mass.
[0120] The formulation may comprise a veterinary acceptable C2 to C6 volatile solvent that is miscible in water.
[0121] The formulation may comprise a veterinary acceptable C2 to C6 alcohol such as ethanol, propanol, butanol, pentanol, hexanol including but not limited to isopropyl alcohol, 1-propanol, n-butanol, isobutanol, tert-butyl alcohol, 1-pentanol, isoamyl alcohol, and 1-hexanol. [0122] The formulation may comprise a veterinary acceptable C2 to C6 ketone including but not limited to acetone, and butanone (methyl ethyl ketone), and methyl isobutyl ketone.
[0123] The formulation may comprise a volatile solvent having a molecular weight of about 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 g/mol, and useful ranges may be selected between any of these values.
[0124] The formulation may comprise a volatile solvent having a boiling point of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140 “C, and useful ranges may be selected between any of these values.
[0125] The formulation may comprise a volatile solvent having a flash point of about -20, -15, -10, -5, 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60°C, and useful ranges may be selected between any of these values.
[0126] The formulation may comprise about 20, 25, 30, 35, 40, 45, 50, 55 or 60% w/v of the veterinary acceptable C2 to C6 volatile solvent, and useful ranges may be selected between any of these values.
[0127] The formulation comprises a veterinary acceptable aprotic solvent. An aprotic solvent is a solvent that has no O-H or N-H bond (non ionic).
[0128] Aprotic solvents may improve the solvency and transport of the active ingredient(s). When combined in a composition of the invention comprising a volatile solvent and penetration enhancer, the active ingredient may be more effectively transported across the skin of a non-human mammal. Without wishing to be bound by theory, when the composition is applied to the body surface, the volatile solvent evaporates to increase the concentration of the formulation, the penetration enhancer disrupts the body surface (e.g. stratum corneam) and the aprotic solvent transports the concentrated active ingredient through the skin.
[0129] The formulation may comprise about 30, 35, 40, 45, 50, 55, 60, 65, 70,
75, 80, 85 or 90% w/v of the aprotic solvent, and useful ranges may be selected between any of these values.
[0130] The formulation may comprise a veterinary acceptable C2 to C6 aprotic solvent. In some embodiments, the veterinary acceptable C2 to C6 aprotic solvent comprises at least one double bond for example C=0 or S=0 bond. The aprotic solvent may be selected from acetonitrile, dimethyl sulfoxide (DMSO), dimethylformamide, propylene carbonate, ethyl acetate, 2-pyrrolidone, dimethylacetamide (DMA), /V-methyl pyrrolidone, ethyl acetoacetate.
[0131] In some embodiments, the veterinary acceptable aprotic solvent has a boiling point and/or flash point that is higher than a physiological temperature of the non-human mammal
[0132] Described is a method of manufacturing a transdermal formulation that may comprise mixing a first composition comprising an active ingredient(s) that is substantially insoluble in water, and a terpene, with a veterinary acceptable aprotic solvent, and a veterinary acceptable C2 to C6 alcohol solvent having a flash point of less than 20° C, thereby providing the transdermal composition.
[0133] One example is of an anthelmintic composition. In this example the active ingredient may be moxidectin. The composition ingredients are mixed by stirring until a homogenous mixture if the ingredients is formed.
[0134] The formulation may be combined with another mixture that contains a further active ingredient. By way of example, the active ingredient of this second composition may be different to the active ingredient of the first composition. For example, the active ingredient of the second composition may be a macrocyclic lactone or levamisole.
[0135] The formulation may include a lipophilic organic antioxidant compound. In one embodiment the lipophilic organic antioxidant compound is present at about 0.01, 0.02, 0.04 0.06, 0.08, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65,
0.7, 0.75. 0.8, 0.85, 0.9, 0.95, 1.0, 1.5 or 2% by weight of the composition, and useful ranges may be selected between any of these values (for example, from about 0.01 to about 2. 0.01 to about 1, about 0.01 to about 0.85, about 0.01 to about 0.35, about 0.010.2, about 0.01 to about 0.08, about 0.06 to about 2, about 0.06 to about 1.5, about 0.06 to about 0.85, about 0.06 to about 0.45, about 0.06 to about 0.25, about 0.08 to about 2, about 0.08 to about 1.5, about 0.08 to about 0.85, about 0.08 to about 0.45, about 0.08 to about 0.25, about 0.1 to about 2, about 0.1 to about 0.95, about 0.1 to about 0.5, about 0.1 to about 0.25, about 0.15 to about 2, about 0.15 to about 0.95, about 0.15 to about 0.5, about 0.15 to about 0.25, about 0.4 to about 2, about 0.4 to about 1, about 0.4 to about 0.9, about 0.4 to about 0.7, about 0.7 to about 2, about 0.7 to about 1, about 1 to about 2 or about 1.5 to about 2% by weight of the formulation). [0136] The lipophilic organic antioxidant compound may be a phenol derivative such as butylated hydroxytoluene.
[0137] The lipophilic organic antioxidant compound may be required to assist or enhance the stability of one or more of the active ingredients. For example, in an anthelmintic platform compositions the lipophilic organic antioxidant compound may enhance the stability of the levamisole base, the macrocyclic lactone or the levamisole base and the macrocyclic lactone.
[0138] The lipophilic organic antioxidant compound may assist or enhance the stability of the terpene penetration enhancer. For example, the lipophilic organic antioxidant compound may assist or enhance the stability of the limonene penetration enhancer.
[0139] In one embodiment, once combined the mixtures may be mixed until dissolved. Following dissolution, additional terpene penetration enhancer may be added to the dissolved composition such as q.s
[0140] Following the optional addition of q.s. terpene penetration enhancer to the dissolved mixture, in one embodiment the mixture may then be incubated above room temperature. In one embodiment the incubation is carried out with stirring.
[0141] The dissolved mixture may be heated at any suitable temperature. The temperature may depend on the active ingredient(s) present in the mixture. In one embodiment the dissolved mixture may be heated to 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 or 50°C, and useful ranges may be selected between any of these values (for example, from about 20 to about 50, about 20 to about 44, about 20 to about 40, about 20 to about 30, about 20 to about 26, about 24 to about 50, about 24 to about
44, about 24 to about 40, about 24 to about 36, about 24 to about 30, about 30 to about
50, about 30 to about 46, about 30 to about 42, about 30 to about 40, about 34 to about
50, about 34 to about 48, about 34 to about 52, about 34 to about 48, about 34 to about
46, about 34 to about 44, about 34 to about 42, about 34 to about 40, about 36 to about
50, about 36 to about 46, about 36 to about 42, about 36 to about 30, about 38 to about
50, about 38 to about 44, about 38 to about 40, about , about 40 to about 50, about 40 to about 48, about 40 to about 46, about 40 to about 42 or about 44 to about 50°C). Higher temperatures may be suitable, depending on the active ingredient(s) present in the mixture. [0142] In one embodiment the dissolved mixture may be heated for 10, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 390, 420, 450, 480, 540, 600, 660, or 720 minutes, and useful ranges may be selected between any of these values (for example, from about 10 to about 720, about 10 to about 660, about 10 to about 600, about 10 to about 540, about 10 to about 480, about 10 to about 360, about 10 to about 240, about 10 to about 120, about 10 to about 60, about 60 to about 720, about 60 to about 660, about 60 to about 600, about 60 to about 540, about 60 to about 480, about 60 to about 390, about 60 to about 330, about 60 to about 240, about 60 to about 180, about 60 to about 120, about 120 to about 720, about 120 to about 660, about 120 to about 600, about 120 to about 540, about 120 to about 480, about 120 to about 420, about 120 to about 300, about 120 to about 270, about 120 to about 240, about 120 to about 180, about 210 to about 720, about 210 to about 660, about 210 to about 600, about 210 to about 540, about 210 to about 480, about 210 to about 390, about 210 to about 360, about 210 to about 270, about 270 to about 720, about 270 to about 660, about 270 to about 600, about 270 to about 540, about 270 to about 480, about 270 to about 420, about 270 to about 360, about 270 to about 300, about 360 to about 720, about 360 to about 660, about 360 to about 600, about 360 to about 540, about 360 to about 480, about 360 to about 420, about 420 to about 720, about 420 to about 660, about 420 to about 600, about 420 to about 540, about 420 to about 480 or about 450 to about 720, about 450 to about 660, about 450 to about 600, about 450 to about 540, about 450 to about 480, about 540 to about 720, about 540 to about 660, about 540 to about 600, about 600 to about 720, about 600 to about 660, about 660 to about 720 minutes).
[0143] The heated composition may be then cooled and packaged for use.
[0144] Once cooled, in one embodiment the composition may be assayed for the active ingredient(s) activity.
[0145] The composition may have good physical and chemical stability, providing at least 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 months shelf life, and useful ranges may be selected between any of these values (for example, from about 12 to about 30, about 12 to about 26, about 12 to about 20, about
12 to about 17, about 13 to about 30, about 13 to about 25, about 13 to about 17, about
13 to about 15, about 16 to about 30, about 15 to about 30, about 15 to about 27, about
15 to about 22, about 15 to about 19, about 14 to about 30, about 14 to about 28, about
14 to about 22, about 14 to about 18, about 14 to about 17, about 17 to about 30, about
17 to about 28, about 17 to about 23, about 17 to about 20, about 18 to about 30, about 18 to about 27, about 18 to about 24, about 18 to about 22, about 20 to about 30, about 20 to about 28, about 20 to about 26, about 25 to about 30, about 25 to about 28, about or about 27 to about 30 months shelf life).
[0146] The formulation may be in a solution form. This may make formulating more straightforward.
[0147] The formulation is capable of delivering a range of actives/drug candidates, including anthelmintics, as single entities or in combination. The platform composition delivers the actives to the systemic circulation by passive diffusion.
[0148] The formulation is for treating an animal in need thereof. The suitability of the composition for treating a particular disease or condition, for example, depends on the active ingredients present in the composition.
[0149] The term "treatment", and related terms, such as "treating" and "treat" as used herein, relates generally to treatment, of either a human or a non-human animal, in which some desired therapeutic effect is achieved. The therapeutic effect may, for example, be the inhibition of progress of a disease or condition, including a reduction in the rate of progress, a halt in the rate of progress, amelioration, and cure. Treatment as a prophylactic measure is also included. Treatment also includes combination treatments and therapies, in which two or more treatments or therapies are used, for example, sequentially or simultaneously, in combination.
[0150] The formulation provides a method of treating an animal in need thereof, comprising administering transdermally a therapeutically effective amount of a formulation as described.
[0151] The formulation also provides use of a composition of the present invention in the manufacture of a medicament for treating an animal in need thereof.
[0152] The animal to be treated may be selected from production animals, such as, cattle, sheep, swine, deer, and goats; companion animals, such as, dogs, cats, and horses; zoo animals, such as, zebras, elephants, giraffes, and large cats; research animals, such as, mice, rats, rabbits, and guinea pigs; fur-bearing animals, such as, mink; birds, such as, ostriches, emus, hens, geese, turkeys, and ducks.
[0153] The formulation may be for treating a helminth infection or infestation in which case the formulation comprises at least one anthelmintic. [0154] Helminths include, but are not limited to, cestodes (flatworms), nematodes (roundworms), and trematodes (flukes), such as, Trichostrongyloidea, inlcuding Haemonchus contortus ; Trichostrongylus spp.; Dictyocaulus spp.; Ascaridoidea, including Toxocara spp.; Strongylus spp.; Filarioidea, including Dirofilariaimmitis and Onchocerca spp: Trematoda, including Fasciolahepatica and Schistosoma spp.; Taenia spp.; and Moniezia spp.; Ostertagia spp.; Nematodirus spp.; Cooperia spp.; Bunostomum spp.; Oesophagostomum spp.; Chabertia spp, Trichuris spp.; Trichonema spp.; Capillaria spp.; Heterakis spp.; Toxocara spp.;, Oxyuris spp.; Ancylostoma spp.; Uncinaria spp.; Toxascaris spp.; and Para sea ris spp.
[0155] The helminth may be selected from Haemonchus spp.; Ostertagia spp.; Trichostrongylus spp.; Nematodirus spp.; and Cooperia spp.
[0156] The formulation is for topical administration. The composition may be administered, for example, in the form of a sterile cream, gel, pour-on or spot-on formulation, suspension, lotion, ointment, dusting powder, spray, drug- incorporated dressing, skin patch, dip, spray, emulsion, jetting fluid, or shampoo.
[0157] The formulation may comprise doses at low volume. In one embodiment the formulation is administered at 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or 1 ml_/kg of live weight animal and useful ranges may be selected between any of these values (for example, from about 0.005 to about 1, from 0.005 to about 0.8, from 0.005 to about 0.6, from 0.005 to about 0.5, from 0.005 to about 0.3, from 0.005 to about 0.2, from 0.005 to about 0.1, from 0.005 to about 0.05, from 0.005 to about 0.01, from 0.008 to about 1, from 0.008 to about 0.8, from 0.008 to about 0.6, from 0.008 to about 0.5, from 0.008 to about 0.4, from 0.008 to about 0.1, from 0.008 to about 0.09, from 0.008 to about 0.05, from 0.008 to about 0.01, from 0.01 to about 1, from 0.01 to about 0.8, from 0.01 to about 0.6, from 0.01 to about 0.5, from 0.01 to about 0.3, from 0.01 to about 0.1, from 0.01 to about 0.09, from 0.01 to about 0.06, from 0.01 to about 0.05, from 0.01 to about 0.04, from 0.03 to about 1, from 0.03 to about 0.8, from 0.03 to about 0.6, from 0.03 to about 0.5, from 0.03 to about 0.4, from 0.03 to about 0.2, from 0.03 to about 0.1, from 0.03 to about 0.09, from 0.03 to about 0.08, from 0.03 to about 0.06, from 0.03 to about 0.05, from 0.05 to about 1, from 0.05 to about 0.8, from 0.05 to about 0.6, from 0.05 to about 0.5, from 0.05 to about 0.4, from 0.05 to about 0.3, from 0.05 to about 0.1, from 0.05 to about 0.09, from 0.05 to about 0.07, from 0.1 to about 1, from 0.1 to about 0.8, from 0.1 to about 0.6, from 0.1 to about 0.5, from 0.1 to about 0.4, from 0.1 to about 0.3, from 0.3 to about 1, from 0.3 to about 0.8, from 0.3 to about 0.6, from 0.3 to about 0.5, from 0.5 to about 1, from 0.5 to about 0.8, from 0.5 to about 0.6, from 0.6 to about 1, from 0.6 to about 0.8, from 0.8 to about 1 mL/kg of live weight animal). Regardless of this low volume, the platform formulation delivers the active ingredients within their therapeutic dose range to the target animal.
[0158] The volume of the dose may depend on the active ingredients present in the formulation and also on the animal to be treated. For example, the formulation may be administered at from about 0.025 mL/ kg to about 0.1 mL/kg for production animals, such as cattle, or from about 0.01 mL/kg to about 0.1 mL/kg for companion animals, such as cats and dogs.
[0159] The formulation may provide a number of advantages including
■ good wetting/spreading properties,
■ no, or very little, hair loss or skin damage,
■ no, or very little, apparent residue/oil on skin, and/or
■ no, or very little, apparent photosensitivity.
[0160] Spreadability can be measured directly by applying a known volume and measuring wetted area. UV light can be used to visualize certain formulations. Residue on skin can be measured by swabbing/extraction. Hair loss and photosensitivity may be evaluated by field observation.
[0161] The present invention will be further illustrated in the following Examples which are given for illustration purposes only and are not intended to limit the invention in any way.
EXAMPLES
Example 1 - Comparative permeability study
[0162] This example compares the use of the platform composition to deliver moxidectin against a commercial comparator. [0163] The platform composition is shown below in Table 1.
Table 1. Formulation of the platform composition
Ingredient Amount Role
(w/v)
Moxidectin 0.5 Active
BHA 0.16 Antioxidant
BHT 0.04 Antioxidant
Limonene 20 Terpene
Isopropanol 40 Volatile solvent
N-methyl pyrrolidone QS Aprotic solvent
1.1 Methods
Skin Sample Preparation
[0164] Bovine (~500 pm) skin samples were excised from above the scapular and over the withers regions. The bovine samples were obtained from a local abattoir. Immediately after excision, the skin was put into plastic bags, and stored on ice packs for delivery to the research laboratory. Hair of the collected skin was cut using a hair clipper and the underlying excessive fat layer was also carefully removed from the hypodermis using a scalpel and discarded. Skin was sheared to remove the entire hair layer and skin samples of 500 ± 30 pm thickness were cut using a dermatome. The dermatome was fitted with dermatome blades from Humeca, Reference 5.BLPG10. The skin samples were then frozen at -18 - -20°C for further preparation and stored for no more than 1 year prior to use.
[0165] Skin samples were thawed overnight under refrigerated conditions prior to use. On the day of use, epidermis/dermis were then finally cut into approximately 2 to 2.5 cm2 and placed on a Franz cell between the donor (containing up to 1 ml. formulation) and receptor compartments (5 ml_).
[0166] The ex vivo permeation of each drug was determined by using V6 Franz diffusion cell; by PermeGear Corporation (New Jersey, USA), which takes its name from Dr. Thomas Franz who first popularised this method. This method has been used in many skin permeation studies, including topical and transdermal drug delivery formulations, as well as opthalmics, cosmetics, skin care products and pesticides. This system is approved by the FDA. See "Guidance for Industry Nonsterile Semisolid Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo Bioequivalence Documentation", U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), May 1997, SUPAC-SS, CMC 7.
[0167] Briefly described, the Franz Cell chamber is an in vitro skin permeation assay that consists of two primary chambers separated by a membrane. Bovine skin was used as the membrane. The sub-cutaneous layer was first removed by scalpel having a thickness of 0.1 to 1 mm. The bovine epidermis hair was sheared to 0.4 cm and the remaining hair sheared to just above the stratum corneum layer. The epidermis and some dermis was removed (approximately 500 pm) and sections were cut to 2 cm by 2 cm for each Franz cell unit. The skin samples were then mounted between the top and bottom chambers to equilibrate for a minimum of 30 minutes. The test composition was loaded into a loading volume of 1.0 ml. and applied to the membrane via the top chamber. The bottom chamber contains fluid from which samples are taken at regular intervals for analysis. This testing determines the amount of active that has permeated the membrane at each time point. The chamber is maintained at a constant temperature of 40° C.
[0168] The moxidectin test on bovine skin was tested using the Franz cell system V6 (PermeGear Inc., USA).
[0169] The samples were taken up to 24 hrs post-administration and drug concentrations were measured by UHPLC.
[0170] The in vitro method (Franz Cell) differs to in vivo because it uses dead skin with no functioning vascular system. Therefore, the drug needs to permeate through the entire piece of skin before being collected in the receptor fluid for analysis. To compare the actual flux rates of the drugs, the lag time before drug enters the receptor fluid was ignored, and the rate of increasing concentration was calculated from when the active was detected in the fluid. This removes some of the variability due to skin thickness.
[0171] The bovine skin was mounted on the receptor compartment with the SC side facing upwards into the donor compartment (5 ml. and up to 1 ml_, respectively). Receptor medium was composed of ethanol (up to 50%). Ethanol was added to the receptor medium to maintain sink condition for the lipophilic drugs which only partially mimics in vivo where blood flow provides constant elimination by transport of the drug away from the site of delivery. The receptor compartment was maintained at 39 ± 1°C and stirred by a magnetic bar at 600 rpm, which also helps improve the problem of a static diffusion cell system (i.e. increased drug dissolution). At periodic intervals, samples (300 pL) were withdrawn from the sampling port and immediately replaced by an equal volume of fresh receptor medium. The samples were then analyzed by an HPLC method with UV detection. All formulations were tested at least in triplicate.
1.2 Results
[0172] The results are shown below in Table 2.
Table 2. Permeation of moxidectin across excised bovine skin (n=3) ± Std error
Figure imgf000029_0001
0 0.00 0.00
1 hr 0.00 0.00
2 hrs 0.00 0.00
4 hrs 8.70 ±1.53 0.00
8 hrs 32.80 ± 4.27 3.57 ±0.57
24 hrs 105.82 ± 15.61 38.70 ± 13.58
[0173] The results of Table 2 demonstrates that the test platform formulation provided better transdermal permeation when compared against a marketed commercial formulation.
EXAMPLE 2
[0174] This sample examines the effects of different aprotic solvents and short- chain, volatile components on the performance of the formulation across different classes of molecules.
1.3 Methods
[0175] The formulations for this study are listed in Table 3 below. The formulations vary in the type of aprotic solvents, short-chain, volatile components, and types of API. A representation of common excipients is used for each class of aprotic solvent, short-chain volatile components and different types of API. These are dimethyl sulfoxide (DMSO), dimethyl isosorbide, dimethyl acetamide (DMA) and 2-pyrrolidone for the aprotic solvents, ethanol, isopropanol (IPA) and acetone for the short-chain, volatile solvents and meloxicam and tetracaine as the alternative types of API.
Table 3: Test formulations
Figure imgf000030_0001
Meloxicam 0.5 0.5
Tetracaine 0.5 0.5
Limonene 15 15 15 20
Dimethyl sulfoxide (DMSO) QS
Brij 93 8
Dimethyl isosorbide (DMI) QS
Dimethyl Acetamide (DMA) QS
2-pyrrolidone QS
Ethanol 20
Isopropanol (IPA) 25 20 Acetone 30
Butylated hydroxyanisole (BHA) 0.2 0.1 0.1 Butylated hydroxytoluene (BHT) 0.1 0.2
Franz cell analysis
[0176] Franz cell analysis was used to examine the formulations as described above. Dermatomed bovine skin was used as the membrane for this example, each formulation being analysed in triplicate. The prepared skins were stored at -20°C until required for analysis.
1.4 Results
[0177] The results for the two meloxicam formulations are shown in Table 4 below.
Table 4. Permeation of moxidectin across excised bovine skin (n=3) ± Std error ormulation (pg/cm2)
Figure imgf000030_0002
Figure imgf000030_0003
0 0 0 30 15.7 ± 8.3 0
1 hr 60.6 ± 12.7 2.4 ± 0.0
2 hrs 139.0 ± 20.5 7.8 ± 2.4
4 hrs 253.2 ± 31.5 29.8 ± 2.0
8 hrs 423.5 ± 25.4 98.8 ± 3.3
12 hrs 471.0 ± 22.6 183.5 ± 22.6
24 hrs 543.0 ± 16.4 391.2 ± 35.7
[0178] The results of Table 4 show good flux rates of both formulations indicating that both formulations perform well.
[0179] The results for the two Tetracaine HCI formulations are shown in Table 5 below.
Table 5. Permeation of Tetracaine HCI across excised bovine skin (n=3) ± Std error
Figure imgf000031_0001
0 0 0 30 0.6 ± 0.1 0.3 ± 0.0
1 hr 4.6 ± 1.0 2.7 ± 0.1
2 hrs 39.0 ± 8.3 17.5 ± 0.3
4 hrs 264.7 ± 42.9 118.9 ± 1.2
6 hrs 403.9 ± 39.4 289.1 ± 6.9
24 hrs 582.1 ± 3.5 540.4 ± 14.4
[0180] The results of Table 5 show good flux rates of both formulations indicating that both formulations perform well.
[0181] Although embodiments have been described with reference to a number of illustrative embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

WE CLAIM:
1. An anhydrous transdermal formulation comprising one or more active agents, at least 15% by weight terpene hydrocarbon, a veterinary acceptable aprotic solvent, and a veterinary acceptable C2 to C6 volatile solvent having i) a flash point of less than 20° C, or ii) a flash point lower than the body surface temperature of the non-human mammal.
2. An anhydrous transdermal formulation of claim 1 comprising a veterinary acceptable C2 to C6 aprotic solvent.
3. An anhydrous transdermal formulation of claim 1 or 2 comprising a veterinary acceptable aprotic solvent having at least one double bond.
4. An anhydrous transdermal formulation of any one of claims 1 to 3 wherein the veterinary acceptable C2 to C6 volatile solvent vaporises at a body surface temperature of about 24° to about 40° C.
5. An anhydrous transdermal formulation of any one of claims 1 to 4 wherein the veterinary acceptable C2 to C6 volatile solvent has a molecular weight of about 40 to about 100 g/mol.
6. An anhydrous transdermal formulation of any one of claims 1 to 5 wherein the veterinary acceptable C2 to C6 volatile solvent has a flash point of less than about 20° C.
7. An anhydrous transdermal formulation of any one of claims 1 to 6 wherein the anhydrous transdermal formulation comprises
• a veterinary acceptable aprotic solvent selected from dimethyl sulfoxide (DMSO), dimethylformamide, propylene carbonate, ethyl acetate, 2- pyrrolidone, dimethylacetamide (DMA), N-methyl pyrrolidone, and ethyl acetoacetate, and
• a veterinary acceptable C2 to C6 volatile solvent selected from acetone, ethanol, and isopropyl alcohol.
8. An anhydrous transdermal formulation of any one of claims 1 to 7 wherein the formulation comprises two or more veterinary agents. An anhydrous transdermal formulation of any one of claims 1 to 8 wherein the composition comprises at least 15% to about 30% terpene by weight of the formulation. An anhydrous transdermal formulation of any one of claims 1 to 9 wherein the terpene is limonene. An anhydrous transdermal formulation of any one of claims 1 to 10 wherein the formulation comprises about 20% to about 60% w/v of the volatile solvent. An anhydrous transdermal formulation of any one of claims 1 to 11 wherein the volatile solvent is selected from isopropyl alcohol, ethanol and acetone, or a combination thereof. An anhydrous transdermal formulation of any one of claims 1 to 12 wherein the formulation comprises one or more antioxidants surfactants, or dispersants. An anhydrous transdermal formulation of any one of claims 1 to 13 wherein the formulation may also include a lipophilic organic antioxidant compound. An anhydrous transdermal formulation of any one of claims 1 to 14 wherein the lipophilic organic antioxidant compound is present at about 0.01% to about 2% by weight of the formulation. An anhydrous transdermal formulation of any one of claims 1 to 15 wherein the lipophilic organic antioxidant compound is a phenol derivative such as butylated hydroxytoluene, BHA, tocopherol, propyl gallate, or any combination thereof. An anhydrous transdermal formulation of any one of claims 1 to 16 wherein the antioxidant is selected from butylated hydroxytoluene, butylated hydroxyanisole, or a combination thereof. An anhydrous transdermal formulation of any one of claims 1 to 17 wherein the composition is physically and chemically stable, providing at least 12 to 30 months shelf life. An anhydrous transdermal formulation of any one of claims 1 to 18 wherein the non-human mammal includes farmed or unfarmed animals, domestic or companion animals. An anhydrous transdermal formulation of any one of claims 1 to 19 wherein the composition is a pour on or spot on formulation. An anhydrous transdermal formulation of any one of claims 1 to 20 wherein the active agent has an apparent partition coefficient (log P) in n-octanol/buffer pH 7.4 of about 1 to about 8.
PCT/IB2022/054450 2021-05-12 2022-05-12 Veterinary transdermal formulation WO2022238965A1 (en)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002036103A1 (en) * 2000-11-06 2002-05-10 Samyang Corporation Transdermal drug delivery system with improved water absorbability and adhesion properties
FR2877576A1 (en) * 2004-11-08 2006-05-12 Ahmed Kadri Composition containing eucalyptol, linalool, itaconic or methylsuccinic anhydride, terpinen-4-ol, alpha-terpineol, camphor, bornyl acetate, geranyl formate, geraniol and coumarin as mast cell proliferation stimulant e.g. to treat infections
WO2008082507A2 (en) * 2006-12-20 2008-07-10 Schering-Plough Ltd. Pharmaceutical compositions and method for treating inflammation in cattle and other animals
WO2014132227A1 (en) * 2013-02-27 2014-09-04 Batt Laurie Robert Transdermal formulations
CN106334144A (en) * 2016-08-26 2017-01-18 王立平 External use medicine for treating skin diseases
CN106344548A (en) * 2016-08-26 2017-01-25 王立平 Externally-used medicine for treating skin diseases
CN105434351B (en) * 2015-12-23 2019-06-18 内蒙古大唐药业股份有限公司 A kind of compound fluocinonide spray and preparation method thereof
WO2021222453A1 (en) * 2020-05-01 2021-11-04 Achelon, Inc. Fast-acting topical anesthetic formulations

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002036103A1 (en) * 2000-11-06 2002-05-10 Samyang Corporation Transdermal drug delivery system with improved water absorbability and adhesion properties
FR2877576A1 (en) * 2004-11-08 2006-05-12 Ahmed Kadri Composition containing eucalyptol, linalool, itaconic or methylsuccinic anhydride, terpinen-4-ol, alpha-terpineol, camphor, bornyl acetate, geranyl formate, geraniol and coumarin as mast cell proliferation stimulant e.g. to treat infections
WO2008082507A2 (en) * 2006-12-20 2008-07-10 Schering-Plough Ltd. Pharmaceutical compositions and method for treating inflammation in cattle and other animals
WO2014132227A1 (en) * 2013-02-27 2014-09-04 Batt Laurie Robert Transdermal formulations
CN105434351B (en) * 2015-12-23 2019-06-18 内蒙古大唐药业股份有限公司 A kind of compound fluocinonide spray and preparation method thereof
CN106334144A (en) * 2016-08-26 2017-01-18 王立平 External use medicine for treating skin diseases
CN106344548A (en) * 2016-08-26 2017-01-25 王立平 Externally-used medicine for treating skin diseases
WO2021222453A1 (en) * 2020-05-01 2021-11-04 Achelon, Inc. Fast-acting topical anesthetic formulations

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