WO2005007129A2 - Topical formulations with bioactive components - Google Patents

Topical formulations with bioactive components Download PDF

Info

Publication number
WO2005007129A2
WO2005007129A2 PCT/CA2004/001049 CA2004001049W WO2005007129A2 WO 2005007129 A2 WO2005007129 A2 WO 2005007129A2 CA 2004001049 W CA2004001049 W CA 2004001049W WO 2005007129 A2 WO2005007129 A2 WO 2005007129A2
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
drug
paclitaxel
skin lesion
solvent
Prior art date
Application number
PCT/CA2004/001049
Other languages
French (fr)
Other versions
WO2005007129A3 (en
Inventor
Richard T. Liggins
Original Assignee
Angiotech International Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Angiotech International Ag filed Critical Angiotech International Ag
Publication of WO2005007129A2 publication Critical patent/WO2005007129A2/en
Publication of WO2005007129A3 publication Critical patent/WO2005007129A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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

Definitions

  • the present invention is directed to chemical compositions that include a bioactive therapeutic agent, or may be used to deliver a bioactive therapeutic agent, where the agent is delivered via topical application of the composition to a subject in need thereof.
  • the invention also provides methods of using the composition, and related subjects.
  • Topical application is a convenient way to administer a therapeutic agent to a subject.
  • Therapeutic agents may be delivered topically through a variety of routes, including orally, transdermally, and intransally.
  • Many drugs can present problems when the goal is to deliver them topically to a subject, and stable formulations that allow ready transdermal delivery of the drug can be difficult to design.
  • This is particular common in cases when the drug is hydrophobic, or highly hydrophilic (e.g., when it is a salt form, or is ionized at pH 7), when it is prone to degradation, or when it has a high molecular weight.
  • Such characteristics may result in the drug having poor bioavailability.
  • the present invention addresses this need in the art, and provides further related advantages.
  • topical drug formulations i.e., formulations for topical delivery of a drug to a subject.
  • the topical formulations are particularly suited for the delivery of a difficult-to-deliver drug.
  • Topical formulations are described that include one or more penetration enhancers (i.e., organic solvents) which may improve the bioavailability of the drug.
  • One aspect of the present invention provides a topical formulation for drug delivery, where the formulation comprises an organic solvent and a drug, where the drug has a high molecular weight of at least 700 g/mol and additionally has a maximum solubility in the formulation.
  • the drug is present in the formulation at a concentration of at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the drug's maximum solubility in the formulation.
  • the organic solvent is ethanol.
  • the organic solvent is N-methly-pyrrolidone.
  • the organic solvent is ethoxydiglycol.
  • the organic solvent is glycerin.
  • the organic solvent is is isopropyl acetate.
  • the organic solvent is selected according to criteria set forth herein.
  • the present invention provides a topical formulation for drug delivery, where the formulation comprises an organic solvent and a drug, where the drug is highly hydrophilic and additionally has a maximum solubility in the formulation.
  • a highly hydrophilic drug refers to a drug in a salt form, or a drug that is ionized at pH 7, where such drugs tend to be freely soluble in water.
  • the drug is present in the formulation at a concentration of at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the drug's maximum solubility in the formulation.
  • the organic solvent is ethanol.
  • the organic solvent is N-methly-pyrrolidone.
  • the organic solvent is ethoxydiglycol. In another embodiment, the organic solvent is glycerin. In another embodiment the organic solvent is isopropyl acetate. In other embodiments, the organic solvent is selected according to criteria set forth herein.
  • the present invention provides a topical formulation for drug delivery, where the formulation comprises an organic solvent and a drug, where the drug is hydrophobic and additionally has a maximum solubility in the formulation. In various embodiments of the formulation, the drug is present in the formulation at a concentration of at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the drug's maximum solubility in the formulation. In one embodiment, the organic solvent is ethanol.
  • the organic solvent is N-methly- pyrrolidone. In another embodiment, the organic solvent is ethoxydiglycol. In another embodiment, the organic solvent is glycerin. In another embodiment the organic solvent is isopropyl acetate. In other embodiments, the organic solvent is selected according to criteria set forth herein.
  • the present invention provides a topical formulation for drug delivery, where the formulation comprises an organic solvent and a drug, where the drug is prone to degradation and additionally has a maximum solubility in the formulation.
  • the drug is present in the formulation at a concentration of at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the drug's maximum solubility in the formulation.
  • the organic solvent is ethanol.
  • the organic solvent is N-methly- pyrrolidone.
  • the organic solvent is ethoxydiglycol.
  • the organic solvent is glycerin.
  • the organic solvent is is isopropyl acetate.
  • the organic solvent is selected according to criteria set forth herein.
  • the present invention provides a topical formulation comprising a taxane and an organic solvent.
  • the formulation is suited for delivery of a therapeutically effective dose of the taxane through or into the stratum corneum in the treatment of a skin lesion.
  • the organic solvent may be ethoxydiglycol, ethanol, or N-methly-pyrrolidone, or glycerin, or isopropyl acetate, or one or more other solvents selected according to criteria set forth herein.
  • the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to- deliver drug (e.g., is hydrophobic, has a high molecular weight, is prone to degradation, or is highly hydrophilic) and a cyclic amide of a formula N-(R 1 )- pyrrolidone where R 1 is C ⁇ -C 6 alkyl, e.g., R 1 is methyl.
  • the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to-deliver drug and an alcohol of a formula R 1 - OH wherein R 1 is Ci-C ⁇ alkyl, e.g., R 1 is ethyl.
  • the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to-deliver drug and an alkoxy alcohol of a formula R 1 -O-R 2 - OH where R 1 is C-i-C ⁇ alkyl and R 2 is C 2 -C ⁇ alkylene, e.g., R 1 is ethyl and R 2 is ethylene.
  • the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to- deliver drug and a polyol of a formula (R 3 )-(OH) n wherein R 3 is an n-valent C 2 - CQ hydrocarbyl group, e.g., the polyol is glycerin.
  • the organic solvent may be a mixture of at least two organic solvents.
  • the formulation contains two organic solvents.
  • the formulation contains three organic solvents.
  • the at least two organic solvents form a single phase when they are combined.
  • water may optionally be present.
  • the formulation may be in the form of an emulsion or microemulsion, where in two embodiments, the water may be in the continuous or discontinuous phase.
  • one or more of the following optional components may be present: a surfactant or a hydrocarbon oil.
  • the present invention provides topical formulations that are particularly suited for the delivery of a difficult-to-deliver drug to a subject.
  • the drug is hydrophobic.
  • the drug has a molecular weight between 700 and 2,000 g/mol.
  • the drug is a taxane, where in one embodiment the taxane is paclitaxel or an analogue or derivative thereof.
  • the drug may be an anti-inflammatory agent, antibiotic, anti-cancer agent, or anti-proliferative agent.
  • the drug may be an anthracycline, podophyllotoxin, fluoropyrimidine, or camptothecin.
  • the formulation contains ingredients such that the drug, e.g., paclitaxel, is soluble in the formulation at a concentration between 0.05-30 mg drug/ml formulation. In other aspects the solubility range is 0.5-30 mg drug/ml formulation. In other aspects, the formulation is in the form of a cream, gel, or powder, or in a liquid form (e.g., solution, suspension, or emulsion). In yet other aspects, the formulation may be associated with a device, such as a pledget, gauze, mesh, or bandage. In other aspects, the present invention provides methods of using topical formulations, and methods of preparing topical formulations.
  • the drug e.g., paclitaxel
  • the present invention provides a method of delivering in a therapeutically effective amount a drug, e.g., a taxane, through or into the stratum corneum, where in one embodiment the therapeutically effective extent treats a skin lesion.
  • a drug e.g., a taxane
  • the present invention provides a method of delivering a difficult-to-deliver drug through the stratum corneum, where in one embodiment the therapeutically effective aspect treats a skin lesion.
  • a method for treating a skin lesion in a subject comprising delivering a therapeutically effective amount of a formulation, the formulation comprising an organic solvent and a drug, the drug having a maximum solubility in the formulation, wherein the drug is present in the formulation at a concentration of at least 50% of the drug's maximum solubility, to a skin lesion through the stratum corneum of the subject, such that the skin lesion is treated.
  • the present invention provides a method of delivering a difficult-to-deliver drug through the stratum corneum in a therapeutically effective amount such that a skin lesion is treated, where the method comprises applying a formulation comprising said drug to the skin in conjunction with at least one organic solvent, where suitable and exemplary organic solvents are described herein.
  • the methods described herein may be used to deliver to a skin lesion through the stratum corneum at least about 0.001 mg to about 50 mg per kg of a subject's body weight per day or at least about 0.1 mg to 20 mg per kg of a subject's body weight per day.
  • the skin lesion may be, in various exemplary embodiments, a psoriatic lesion, an infection, a cancerous lesion, an inflamed skin lesion, or a lesion characterized by abnormal cell proliferation or differentiation, where cancer cells are one type of cell that may exhibit abnormal differentiation.
  • the skin lesion may be in one or more layers of the skin, including in an epidermal, in a dermal, or in a subcutaneous layer of the skin.
  • Figure 1 provides the chemical structure of paclitaxel.
  • Figure 2 provides a ternary phase diagram depicting the miscibility of ethanol/isopropyl acetate/water mixtures. The diagram illustrates three regions: Region A - the solvent mixtures are miscible; Region B - the solvent mixtures are immiscible; and Region C - the solvent mixtures will not dissolve more than 10% glycerin.
  • Figure 3 provides a ternary phase diagram depicting the effect of the addition of ethoxydiglycol to ethanol/isopropyl acetate/water mixtures on solvent miscibility.
  • Region A in indicates compositions that are miscible with the addition of ethoxydiglycol
  • Region B indicates compositions that area miscible with the addition of >2 ml ethoxydiglycol to 10 ml of the solvent mixture
  • Region C indicates compositions that are miscible with the addition of >4 ml ethoxydiglycol to 10 ml of the solvent mixture
  • Region D indicates compositions that are miscible with the addition of >6 ml ethoxydiglycol to 10 ml of the solvent mixture
  • Region E indicates compositions that are miscible with the addition of >8 ml ethoxydiglycol to 10 ml of the solvent mixture.
  • Figure 4 provides a ternary phase diagram depicting the effect of the addition of 1-methyl-2-pyrrolidinone (NMP) to ethanol/isopropyl acetate/water mixtures on solvent miscibility.
  • Region A indicates compositions that are miscible without the addition of NMP;
  • Region B indicates compositions that are miscible with the addition of >1 ml NMP to 10 ml of the solvent mixture;
  • Region C indicates compositions that are miscible with the addition of >2 ml NMP to 10 ml of the solvent mixture;
  • Region D indicates compositions that are miscible with the addition of >4 ml NMP to 10 ml of the solvent mixture;
  • Region E indicates compositions that are miscible with the addition of >8 ml NMP to 10 ml of the solvent mixture; and
  • Region F indicates compositions that are immiscible with the addition of >10 ml NMP to 10 ml of the solvent mixture.
  • Figure 5 provides a solubility phase diagram illustrating the solubility of paclitaxel in binary solvent mixtures (i.e., Solvent "A'VSolvent “B") having varying proportions of each solvent.
  • Figure 6 provides a solubility phase diagram illustrating the solubility of paclitaxel in ternary solvent mixtures of ethanol, isopropyl acetate, and water.
  • the diagram illustrates two shaded regions: Region A - the solvent mixtures were not miscible; and Region B - the drug was unstable with 5-15% of the dissolved paclitaxel converted to 7-epitaxol.
  • Figure 7 provides a solubility phase diagram illustrating the solubility of paclitaxel in quaternary solvent mixtures of ethanol, isopropyl acetate, water and 1-methyl-2-pyrrolidinone (NMP). Each mixture was prepared as a ternary system described by the axes of the diagram, followed by dilution of 5 ml of each mixture with 0.5 ml NMP. The diagram illustrates a two shaded regions: Region A - the solvent mixtures were not miscible, and Region B - the drug was unstable with greater than 5% of the dissolved paclitaxel converted to 7-epitaxol.
  • Figures 9A and 9B illustrates the effect of different solvents on the ex vivo penetration of paclitaxel through human stratum corneum with the administration of an infinite dose.
  • the open square ( ⁇ ) indicates data from 1-methyl-2-pyrrolidinone and the open triangle ( ⁇ ) indicates data from ethanol.
  • the filled square ( ⁇ ) indicates data from isopropyl acetate; the open diamond (0) indicates data from isopropyl myristate, the filled triangle (A) indicates data from ethoxydiglycol, and the filled circle (•) indicates data from 1 ,2-propanediol (propylene glycol).
  • Figure 10 provides representative profiles of paclitaxel penetration through stratum corneum from 1% solutions in various solvent mixtures and from the Gel Formulation (see Example 1).
  • the open circle (o) indicates data from the Gel Formulation (containing 1% paclitaxel)
  • the filled square ( ⁇ ) indicates data from 35/30/5/10/20 ethoxydiglycol/ water/ glycerin/ NMP/ isopropyl acetate
  • the open triangle ( ⁇ ) indicates data from 50/50 ethoxydiglycol/ NMP
  • the filled triangle (A) indicates data from ethoxydiglycol/ water/ isopropyl acetate/ ethanol
  • the open square ( ⁇ ) indicates data from 55/30/5/10 ethoxydiglycol/ water/ glycerin/ NMP
  • the open diamond (0) indicates data from 30/20/10/40 ethoxydiglycol/ water/ NMP/ ethanol
  • the filled circle (•) indicates data from 50/20/5/15 ethoxydiglycol/ water/ g
  • Figure 11 is a schematic illustration of the effect of solvent system composition on paclitaxel penetration rates through stratum corneum. Penetration rates are normalized relative to the rate from the Gel Formulation (see Example 1 ; 1% paclitaxel content). Each solvent mixture is outlined by a rectangle and the proportions for the mixtures providing the three greatest penetration rates are listed above the corresponding rectangles.
  • the filled square ( ⁇ ) represents ethoxydiglycol
  • the open square ( ⁇ ) indicates isopropyl acetate
  • the filled triangle (A) indicates 1-methyl-2-pyrrolidinone
  • the open triangle ( ⁇ ) indicates ethanol
  • the filled circle (•) indicates glycerin
  • the open circle (o) indicates water
  • the "X" indicates propylene glycol.
  • Figure 12 shows a representative microscopic image of an emulsion (Formulation 5, refer to Table 2) containing by weight: 9% isopropyl acetate, 21% water, 31% ethoxydiglycol, 36% mineral oil and 1% each of BRIJ 72 and 721 (polyoxyethylene 2 stearyl ether and polyoxyethylene 21 stearyl ether, respectively).
  • the width of the image is 200 ⁇ m.
  • the present invention provides chemical compositions that either may be combined with a drug, or include a drug.
  • drug and “bioactive agent” will be used synonymously herein.
  • a composition of the invention without a drug will be referred to herein as a drug delivery vehicle.
  • a composition of the invention with a drug will be referred to herein as a therapeutic composition.
  • compositions facilitate the bioavailabity of a drug to a subject that has received the composition by topical administration.
  • topical application of the therapeutic compositions of the present invention may enhance the bioavailability of the drug to the subject.
  • the compositions of the present invention are therefore useful in drug delivery.
  • an “adjuvant” refers to a substance that, when included in a therapeutic composition, will improve or enhance the therapeutic efficiacy of one or more of the active agents contained within the composition, i.e., the adjuvant enhances the overall therapeutic effectiveness of the composition.
  • An adjuvant may, for instance, counteract a negative effect associated with the composition and/or a bioactive agent therein.
  • excipient refers to an inert or substantially inert, non-toxic substance present in a therapeutic compositions which can confer some benefit thereto, such as improved physical and/or chemical stability or improved handling characteristics (e.g., flowability and consistency).
  • the excipient may, for example, function solely or primarily as a bulking agent, i.e., a material that reduces the concentration of the bioactive agent in the therapeutic composition.
  • a “stabilizer” refers to an excipient that improves the physical or chemical stability (e.g., the storage stability) of the therapeutic composition. The stabilizer assists in maintaining the therapeutic efficacy of the active agent(s) present in the therapeutic compositions.
  • An exemplary stabilizer is an "antioxidant", where this term refers to synthetic or natural substances that prevent or delay the oxidative deterioration of a bioactive agent.
  • antioxidants include lecithin, gamma oryzanol; ubiquinone (ubidecarenone) and coenzyme Q; vitamins, such as vitamins A, C (ascorbic acid) and E and beta- carotene; natural components such as camosol, carnosic acid and rosmanol found in rosemary and hawthorn extract, proanthocyanidins such as those found in grapeseed or pine bark extract, and green tea extract.
  • a "difficult-to-deliver” drug refers to a drug that is hydrophobic, and/or has a molecular weight of greater than 700 g/mol. It also refers to drugs that are very hydrophilic, e.g., are present in the formulation in the form of a salt, or are ionized at neutral pH, i.e., pH of about 7. This term also refers to drugs that are prone to degradation when in a drug delivery formulation.
  • the present invention provides a topical formulation for drug delivery, where the formulation comprises an organic solvent and a drug.
  • the formulation and drug are selected such that the drug is present in the formulation at a concentration of at least 50% of the maximum possible concentration of the drug.
  • concentration of drug refers to the weight percent of drug in the formulation, e.g., a formulation containing 1 gram of drug and 100 grams total weight would have 1% concentration.
  • concentration refers to the weight percent of drug in the formulation, e.g., a formulation containing 1 gram of drug and 100 grams total weight would have 1% concentration.
  • the maximum possible concentration (i.e., solubility) of a drug in a formulation is reached when the drug is no longer homogeneously distributed in the formulation.
  • the maximum possible concentration of the drug in the formulation is reached when the drug is present in the formulation at such a high concentration that not all of the drug dissolves in the formulation. In this case, the maximum solubility of the drug is reached just before the point at which the drug ceases to dissolve in the formulation.
  • the maximum possible concentration of the drug in the emulsion or microemulsion is reached when increasing the loading of the drug in the formulation results in an inhomogenous emulusion or microemulsion form.
  • the formulation contains drug at a concentration of at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the drug's maximum solubility in the formulation.
  • the present inventor has discovered that when the drug is at, or near, its maximum concentration in a therapeutic composition, then the therapeutic composition is relatively more effective at making the drug, and particularly a hydrophobic drug, bioavailable to a subject that has received the drug by topical administration.
  • the drug is present in the formulation at a concentration, relative to its maximum concentration, of 50-60%, 50-70%, 50-80%, 50-90%, 50-95%, 50- 100%, 60-70%, 60-80%, 60-90%, 60-95%, 60-100%, 70-80%, 70-90%, 70- 95%, 70-100%, 80-90%, 80-95%, 80-100%, 90-95%, 90-100%, or 95-100%.
  • the formulations of the present invention contain at least one drug and at least one organic solvent. When the formulation contains more than one drug, then either drug may be considered in determining whether the formulation contains that drug at a concentration of at least 50% of the drug's maximum concentration in the formulation.
  • the formulations may comprise of the present invention contain only two ingredients, namely, a single drug and a single organic solvent.
  • a homogeneous formulation is created when the drug is soluble in the solvent, and the maximum concentration (i.e., solubility) of the drug in the solvent is identified when no additional drug will dissolve in the formluation.
  • the formulation may contain only three ingredients.
  • the formulation may contain a single drug, an organic solvent, and a second solvent.
  • the second solvent is water.
  • the second solvent is another organic solvent, different from the first solvent.
  • the formulation containing one drug and two solvents is a single phase that is homogeneous, i.e., the two solvents are miscible with one another, and the drug is soluble in the mixture of two solvents.
  • the formulations of the present invention contain only four ingredients.
  • the formulation may contain a single drug, an organic solvent, and a second and third solvent.
  • the second solvent is water.
  • the formulation containing one drug and three solvents is a single phase that is homogeneous, i.e., the three solvents are miscible with one another, and the drug is soluble in the mixture of the three solvents.
  • the formulation contains at least four ingredients.
  • the formulations may contain a single drug, an organic solvent, and second and third solvents.
  • the second solvent is water.
  • the formulation containing at least one drug and three solvents is homogeneous.
  • An additional component may be included in the formulation in order for the at least one drug and three solvents to reach a homogeneous state.
  • the formulations of the present invention contain a difficult-to-deliver drug, a first solvent which is an organic solvent, and one or more additional solvents, i.e., second, third, etc. solvents.
  • the combination of solvents is not a single phase or homogeneous, i.e., the combination forms two distinct phases or more than two distinct phases.
  • the second solvent is water and the first solvent is an organic solvent that is immiscible in water at the specific weight ratio of first and second solvents employed.
  • the formulation may contain one or more additional components which function to homogenize to the formulation.
  • the additional component may be a surfactant, e.g., a nonionic surfactant.
  • the surfactant may cause the formulation to adopt an emulsion or microemulsion form, where the water may be the continuous or discontinuous phase, and the drug, when hydrophobic, will be dissolved in the non-aqueous phase.
  • the drug may also be present in some concentration or as a solid in the aqueous phase.
  • Suitable exemplary surfactants are described below.
  • the formulations of the present invention contain a hydrophobic drug, a first solvent which is an organic solvent, a second solvent, and a third solvent.
  • the combination of first, second and third solvents is not a single phase or homogeneous, i.e., the combination forms two distinct phases or more than two distinct phases.
  • the second solvent is water and the first solvent is an organic solvent that is immiscible in water at the specific weight ratio of first and second solvents employed.
  • the formulation contains one or more additional components which function to homogenize the formulation.
  • organic (first) solvents a) cosmetic features of the solvent such as acceptable aroma and texture; b) chemical stability of the drug dissolved in the solvent; c) toxicology of the solvent; d) biocompatibility, irritancy or allergenicity of the solvent; e) solubility of the drug in the solvent; f) ability of the solvent to affect drug permeability through or into skin; and g) miscibility of the solvent with other solvents or exeipients in the formulation.
  • the organic (first) solvent is ethanol. In another embodiment the organic (first) solvent is N-methly-pyrrolidone. In another embodiment, the organic (first) solvent is glycerin. In another embodiment the organic (first) solvent is isopropyl acetate. Based on the data presented herein, several solvents and ranges at which they may be incorporated into a vehicle to provide skin penetration and suitable solubility for a hydrophobic drug in general, and paclitaxel in particular, may be recommended as shown in Table A. Table A RECOMMENDED SOLVENTS AND CONCENTRATION RANGES
  • the present invention provides a topical formulation comprising a taxane and an organic solvent.
  • the formulation is suited for delivery of a therapeutically effective dose of the taxane through the stratum corneum in the treatment of a skin lesion.
  • the organic solvent may be, e.g., ethanol, or N-methly-pyrrolidone, or glycerin, or isopropyl acetate, or one or more other solvents selected according to criteria set forth above
  • the present invention provides a topical formulation for drug delivery, where the formulation comprises a hydrophobic drug and a cyclic amide of a formula N-(R 1 )-pyrrolidone where R 1 is Ci-C ⁇ alkyl, e.g., R 1 is methyl.
  • the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to- deliver drug and an alcohol of a formula R 1 -OH wherein R 1 is C ⁇ -C 6 alkyl, e.g., R 1 is ethyl.
  • the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult- to-deliver drug and an alkoxy alcohol of a formula R 1 -O-R 2 -OH where R 1 is Ci-C ⁇ alkyl and R 2 is C 2 -C 6 alkylene, e.g., R 1 is ethyl and R 2 is ethylene.
  • the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to-deliver drug and a polyol of a formula (R 3 )-(OH) n wherein R 3 is an n-valent C2-C 6 hydrocarbyl group, e.g., the polyol is glycerin.
  • the organic solvent may be a mixture of at least two organic solvents.
  • the formulation contains two organic solvents.
  • the formulation contains three organic solvents.
  • the at least two organic solvents may form a single phase when they are combined.
  • the formulation may be in the form of an emulsion or microemulsion.
  • water may optionally be present in either the continuous or discontinuous phase.
  • compositions and methods of the present invention include a drug.
  • inventive compositions and methods include a drug that is difficult to deliver to a subject via a conventional topical formulation.
  • drugs include hydrophobic drugs, where the term "hydrophobic drug” refers to drugs that are insoluble or sparingly or poorly soluble in water. As used herein, such drugs will have solubility below 10 mg/ml, usually below 1 mg/ml, sometimes below 0.01 mg/ml, and sometimes below 0.001 mg/ml.
  • the drugs also include drugs with molecular weights in excess of about 700 g/mol, drugs that are unstable, and drugs that are highly hydrophilic such as salts and drugs that are at least partly ionized at neutral pH.
  • Exemplary drugs that may be included in formulations of the present invention include: anti-microtubule agents, anti-inflammatory agents, anti-cancer agents, anti-proliferative agents, anti-angiogenic agents, anti-fibrotic agents, analgesic agents, immunosupressants, anaesthetics, anti-infectives, and antibiotics.
  • the drug is selected from paclitaxel, hydrophobic paclitaxel derivatives and hydrophobic paclitaxel analogues.
  • the hydrophobic drug is paclitaxel. Examples of these and other types of drugs are provided below.
  • the drug is paclitaxel, a compound currently recognized to disrupt mitosis (M-phase) by binding to tubulin to form abnormal mitotic spindles or an analogue or derivative thereof.
  • paclitaxel is a highly derivatized diterpenoid (Wani et al., J. Am. Chem. Soc. 93:2325 (1971)). It may be obtained, for example, from the harvested and dried bark of Taxus brevifolia (Pacific Yew) and Taxomyces Andreanae and Endophytic Fungus of the Pacific Yew (Stierle et al., Science 60:214-16 (1993)).
  • “Paclitaxel” as used herein refers to hydrophobic formulations including paclitaxel, prodrugs, analogues and derivatives such as, for example, TAXOL, TAXOTERE, docetaxel, 10-desacetyl analogues of paclitaxel and 3'N-desbenzoyl-3'N-t-butoxy carbonyl analogues of paclitaxel, may be readily prepared utilizing techniques known to those skilled in the art (see, e.g., Schiff et al., Nature 277:665-67 (1979); Long and Fairchild, Cancer Research 54:4355-61 (1994); Ringel and Horwitz, J. Nat'l Cancer Inst.
  • paclitaxel derivatives and analogues include 7-deoxy-docetaxol, 7,8-cyclopropataxanes, N-substituted 2-azetidones, 6,7-epoxy paclitaxels, 6,7-modified paclitaxels, 10-desacetoxytaxol, 10- deacetyltaxol (from 10-deacetylbaccatin III), phosphonooxy and carbonate derivatives of taxol, taxol 2',7-di(sodium 1 ,2-benzenedicarboxylate, 10- desacetoxy-11 ,12-dihydrotaxol-10,12(18)-diene derivatives, 10- desacetoxytaxol, Protaxol (2'-and/or 7-O-ester derivatives), (2'-and/or 7-O- carbonate derivatives), fluoro taxols, 9-deoxotaxane, 9-deoxotaxol, 7-deoxy-9- deo
  • the drug is a taxane having the formula (1):
  • a side-chain (labeled "A" in the diagram) is desirably present in order for the compound to have good activity as a cell cycle inhibitor.
  • compounds having this structure include paclitaxel (Merck Index entry 7117), docetaxol (Taxotere, Merck Index entry 3458), and 3'-desphenyl- 3'-(4-ntirophenyl)-N-debenzoyl-N-(t-butoxycarbonyl)-10-deacetyltaxol.
  • suitable taxanes such as paclitaxel and its hydrophobic analogues and derivatives are disclosed in Patent No.
  • X may be oxygen (paclitaxel), hydrogen (9-deoxy derivatives), thioacyl, or dihydroxyl precursors;
  • Ri is selected from paclitaxel or taxotere side chains or alkanoyl of the formula (3):
  • R 7 is selected from hydrogen, alkyl, phenyl, alkoxy, amino, phenoxy (substituted or unsubstituted);
  • R 8 is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, phenyl (substituted or unsubstituted), alpha or beta- naphthyl; and
  • Rg is selected from hydrogen, alkanoyl, substituted alkanoyl, and aminoalkanoyl; where substitutions refer to hydroxyl, sulfhydryl, allalkoxyl, carboxyl, halogen, thioalkoxyl, N,N-dimethylamino, alkylamino, dialkylamino, nitro, and -OSO 3 H, and/or may refer to groups containing such substitutions;
  • R2 is selected from hydrogen or oxygen-containing groups, such as hydrogen, hydroxyl, alkoyl, alkanoyloxy, aminoal
  • the paclitaxel analogues and derivatives useful as a hydrophobic drug according to the present invention are disclosed in PCT International Patent Application No. WO 93/10076.
  • the analogue or derivative should have a side chain attached to the taxane nucleus at C13, as shown in the structure below (formula 4), in order to confer antitumor activity to the taxane.
  • PCT International Publication No. WO 93/10076 discloses that the taxane nucleus may be substituted at any position with the exception of the existing methyl groups.
  • the substitutions may include, for example, hydrogen, alkanoyloxy, alkenoyloxy, aryloyloxy.
  • oxo groups may be attached to carbons labeled 2, 4, 9, 10.
  • an oxetane ring may be attached at carbons 4 and 5.
  • an oxirane ring may be attached to the carbon labeled 4.
  • the taxane-based drug useful in the present invention is disclosed in U.S. Patent 5,440,056, which discloses 9-deoxo taxanes.
  • the taxane ring may be substituted at the carbons labeled 1 , 7 and 10 (independently) with H, OH, O-R, or O-CO-R where R is an alkyl or an aminoalkyl. As well, it may be substituted at carbons labeled 2 and 4 (independently) with aryol, alkanoyl, aminoalkanoyl or alkyl groups.
  • the side chain of formula (C3) may be substituted at R7 and R 8 (independently) with phenyl rings, substituted phenyl rings, linear alkanes/alkenes, and groups containing H, O or N.
  • Rg may be substituted with H, or a substituted or unsubstituted alkanoyl group.
  • the taxane-based drug useful in the present invention is disclosed in U.S. Patent 6,107,332.
  • the following compounds may also, depending on the R group or ligand, etc., be a hydrophobic and/or high molecular weight, or unstable, or highly hydrophilic drug.
  • Anthracyclines have the following general structure, where the R groups may be a variety of organic groups:
  • R groups are as follows: Ri is CH 3 or CH 2 OH; R is daunosamine or H; R 3 and R are independently one of OH, NO 2 , NH 2 , F, Cl, Br, I, CN, H or groups derived from these; R 5 is hydrogen, hydroxy, or methoxy; and R 6 -s are all hydrogen. Alternatively, R 5 and Re are hydrogen and R 7 and Rs are alkyl or halogen, or vice versa. According to U.S. Patent 5,843,903, Ri may be a conjugated peptide. According to U.S. Patent 4,296,105, R 5 may be an ether linked alkyl group. According to U.S.
  • R 5 may be OH or an ether linked alkyl group.
  • Ri may also be linked to the anthracycline ring by a group other than C(O), such as an alkyl or branched alkyl group having the C(O) linking moiety at its end, such as -CH 2 CH(CH 2 -X)C(O)-R ⁇ , wherein X is H or an alkyl group (see, e.g., U.S. Patent 4,215,062).
  • R 3 may have the following structure: in which R 9 is OH either in or out of the plane of the ring, or is a second sugar moiety such as R 3 .
  • R 1 0 may be H or form a secondary amine with a group such as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Patent 5,843,903).
  • R 10 may be derived from an amino acid, having the structure - C(O)CH(NHR ⁇ )(R ⁇ 2 ), in which Rn is H, or forms a C 3 . membered alkylene with R 12 .
  • R 12 may be H, alkyl, aminoalkyl, amino, hydroxy, mercapto, phenyl, benzyl or methylthio (see U.S. Patent 4,296,105).
  • anthracyclines are Doxorubicin, Daunorubicin, Idarubicin, Epirubicin, Pirarubicin, Zorubicin, and Carubicin.
  • Suitable compounds have the structures:
  • Doxorubicin OCH 3 C(O)CH 2 OH plane
  • Epirubicin (4' epimer of OCH3 C(O)CH 2 OH OH in ring plane doxorubicin)
  • Daunorubicin OCH3 C(O)CH 3 plane
  • Pirarubicin OCH3 C(O)CH 2 OH
  • anthracyciines are Anthramycin, Mitoxantrone, Menogaril, Nogalamycin, Aclacinomycin A, Olivomycin A, Chromomycin A 3 , and Plicamycin having the structures:
  • anthracyciines include, FCE 23762 doxorubicin derivative (Quaglia et al, J. Liq. Chromatogr. 17(18):3911-3923, 1994), annamycin (Zou et al, J. Pharm. Sci. 82(11):1151-1154, 1993), ruboxyl (Rapoport ef /., J. Controlled Release 58(2): 153-162, 1999), anthracycline disaccharide doxorubicin analogue (Pratesi et al, Clin. Cancer Res.
  • deoxydihydroiodooxorubicin EPA 275966
  • adriblastin Kalishevskaya et al, Vestn. Mosk. Univ., 76(Biol. 1):21-7, 1988
  • 4'-deoxydoxorubicin Schoelzel et al, Leuk. Res. 70(12): 1455-9, 1986
  • 4-demethyoxy-4'-o-methyldoxorubicin (Giuliani et al, Proc. Int. Congr. Chemother. 76:285-70-285-77, 1983), 3'- deamino-3'-hydroxydoxorubicin (Horton et al, J.
  • the drug may be a fluoropyrimidine analog, such as 5- fluorouracil, or an analogue or derivative thereof, including Carmofur, Doxifluridine, Emitefur, Tegafur, and Floxuridine.
  • fluoropyrimidine analog such as 5- fluorouracil
  • an analogue or derivative thereof including Carmofur, Doxifluridine, Emitefur, Tegafur, and Floxuridine.
  • Exemplary compounds have the structures:
  • fluoropyrimidine analogues include 5-FudR (5- fluoro-deoxyuridine), or an analogue or derivative thereof, including 5- iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), Fluorouridine triphosphate (5-FUTP), and Fluorodeoxyuridine monophosphate (5-dFUMP).
  • 5-FudR 5- fluoro-deoxyuridine
  • an analogue or derivative thereof including 5- iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), Fluorouridine triphosphate (5-FUTP), and Fluorodeoxyuridine monophosphate (5-dFUMP).
  • Exemplary compounds have the structures:
  • fluoropyrimidine analogues include N3-aIkylated analogues of 5-fluorouracil (Kozai et al, J. Chem. Soc, Perkin Trans. 7(19):3145-3146, 1998), 5-fluorouracil derivatives with 1 ,4- oxaheteroepane moieties (Gomez et al, Tetrahedron 54(43): 13295-13312,
  • the drug may be a folic acid antagonist, such as Methotrexate or derivatives or analogues thereof, including Edatrexate, Trimetrexate, Raltitrexed, Piritrexim, Denopterin, Tomudex, and Pteropterin.
  • Methotrexate analogues have the following general structure:
  • R group may be selected from organic groups, particularly those groups set forth in U.S. Patent Nos. 5,166,149 and 5,382,582.
  • Ri may be N
  • R 2 may be N or C(CH 3 )
  • R3 and R3 1 may H or alkyl, e.g., CH 3
  • R 4 may be a single bond or NR, where R is H or alkyl group.
  • R 5 , 6 , 8 may be H, OCH 3 , or alternately they can be halogens or hydro groups.
  • R 7 is a side chain of the general structure:
  • the carboxyl groups in the side chain may be esterified or form a salt such as a Zn 2+ salt.
  • Rg and R10 and R 11 can be NH 2 or may be alkyl substituted, where Rn may also be hydrogen.
  • Exemplary folic acid antagonist compounds have the structures:
  • Tomudex Other representative examples include 6-S-aminoacyloxymethyl mercaptopurine derivatives (Harada et al, Chem. Pharm. Bull. 43(10):793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al, Biol. Pharm. Bull 78(11):1492- 7, 1995), 7,8-polymethyleneimidazo-1 ,3,2-diazaphosphorines (Nilov et al, Mendeleev Commun. 2:67, 1995), azathioprine (Chifotides et al, J. Inorg. Biochem.
  • N-( ⁇ -aminoacyl) methotrexate derivatives Cheung et al, Pteridines 3(1-2):101-2, 1992
  • biotin methotrexate derivatives Fean et al, Pteridines 3(1-2):131-2, 1992
  • D-glutamic acid or D-erythrou threo-4-fluoroglutamic acid methotrexate analogues
  • Pteridines Folic Acid Deriv., 1154-7, 1989 N-(L- ⁇ -aminoacyl) methotrexate derivatives (Cheung et al, Heterocycles 28(2):751-8, 1989), meta and ortho isomers of aminopterin (Rosowsky et al, J. Med. Chem. 32(12):2582, 1989), hydroxymethylmethotrexate (DE 267495), ⁇ -fluoromethotrexate (McGuire et al, Cancer Res. 49(16):4517-25, 1989), polyglutamyl methotrexate derivatives (Kumar et al, Cancer Res.
  • cysteic acid and homocysteic acid methotrexate analogues (4,490,529), ⁇ -tert-butyl methotrexate esters (Rosowsky et al, J. Med. Chem. 28(5):660-7, 1985), fluorinated methotrexate analogues (Tsushima et al, Heterocycles 23(1):45-9, 1985), folate methotrexate analogue (Trombe, J. Baderiol 760(3):849-53, 1984), phosphonoglutamic acid analogues (Sturtz & Guillamot, Eur. J. Med. Chem.-Chim. Ther.
  • the drug may be a Podophyllotoxin, or a derivative or an analogue thereof.
  • exemplary compounds of this type are Etoposide or Teniposide, which have the following structures:
  • podophyllotoxins include Cu(II)- VP-16 (etoposide) complex (Tawa et al, Bioorg. Med. Chem. 6(7): 1003-1008, 1998), pyrrolecarboxamidino-bearing etoposide analogues (Ji et al, Bioorg. Med. Chem. Lett. 7(5):607-612, 1997), 4 ⁇ -amino etoposide analogues (Hu, University of North Carolina Dissertation, 1992), ⁇ -lactone ring-modified arylamino etoposide analogues (Zhou et al, J. Med. Chem.
  • the drug may be Camptothecin, or an analogue or derivative thereof.
  • Camptothecins have the following general structure.
  • X is typically O, but can be other groups, e.g., NH in the case of 21-lactam derivatives.
  • R-i is typically H or OH, but may be other groups, e.g., a terminally hydroxylated C 1 - 3 alkane.
  • R2 is typically H or an amino containing group such as (CH 3 ) 2 NHCH 2 , but may be other groups e.g., NO 2 , NH 2 , halogen (as disclosed in, e.g., U.S. Patent 5,552,156) or a short alkane containing these groups.
  • R 3 is typically H or a short alkyl such as C 2 H 5 .
  • R 4 is typically H but may be other groups, e.g., a methylenedioxy group with R-i.
  • camptothecin compounds include topotecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactam-20(S)-camptothecin, 10,11-methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin, 10- hydroxycamptothecin.
  • Exemplary compounds have the structures:
  • Camptothecins have the five rings shown here.
  • E must be intact (the lactone rather than carboxylate form) for maximum activity and minimum toxicity.
  • Camptothecins are believed to function as Topoisomerase I Inhibitors and/or DNA cleavage agents.
  • the drug may be a hydroxyurea. Hydroxyureas have the following general structure:
  • Suitable hydroxyureas are disclosed in, for example, U.S. Patent No. 6,080,874, wherein Ri is: and R 2 is an alkyl group having 1-4 carbons and R 3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methylether.
  • Ri is a cycloalkenyl group, for example N-[3-[5-(4- fluorophenylthio)-furyl]-2-cyclopenten-1-yl]N-hydroxyurea; R 2 is H or an alkyl group having 1 to 4 carbons and R 3 is H; X is H or a cation.
  • Suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 4,299,778, wherein Ri is a phenyl group substituted with one or more fluorine atoms; R 2 is a cyclopropyl group; and R 3 and X is H.
  • hydroxyurea has the structure:
  • the drug may be a platinum compound.
  • suitable platinum complexes may be of Pt(ll) or Pt(IV) and have this basic structure: wherein X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen; Ri and R 2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups.
  • X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen
  • Ri and R 2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups.
  • Pt(ll) complexes Zi and Z 2 are non-existent.
  • Z-i and Z2 may be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See, e.g., U.S. Patent Nos. 4,588,831 and
  • Suitable platinum complexes may contain multiple Pt atoms. See, e.g., U.S. Patent Nos. 5,409,915 and 5,380,897.
  • Exemplary platinum compounds are Cisplatin, Carboplatin, Oxaliplatin, and Miboplatin having the structures:
  • platinum compounds include (CPA) 2 Pt[DOLYM] and (DACH)Pt[DOLYM] cisplatin (Choi et al, Arch. Pharmacal Res. 22(2):151-156, 1999), Cis-[PtCI 2 (4,7-H-5-methyl-7- oxo]1,2,4[triazolo[1,5-a]pyrimidine)2] (Navarro et al, J. Med. Chem. 47(3):332- 338, 1998), [Pt(cis-1 ,4-DACH)(trans-CI 2 )(CBDCA)] . 1 / 2 MeOH cisplatin (Shamsuddin et al, Inorg. Chem.
  • gem-diphosphonate cisplatin analogues (FR 2683529), (meso-1 ,2-bis(2,6-dichloro-4-hydroxyplenyl)ethylenediamine) dichloroplatinum(ll) (Bednarski et al, J. Med. Chem. 35(23) :4479-85, 1992), cisplatin analogues containing a tethered dansyl group (Hartwig et al, J. Am. Chem. Soc. 774(21):8292-3, 1992), platinum(ll) polyamines (Siegmann et al, Inorg. Met.-Containing Polym. Mater, (Proc.
  • the drug in the composition may have anti-inflammatory activity or analgesic activity.
  • an antibiotic may be incorporated into a formulation of the present invention.
  • the antibiotic suitable to be incorporated into the inventive composition may act by a number of mechanisms. It may be from the anthelmintics (including mebendazole, niclosamide, piperazine, praziquante, thibendazole and pyrantel pamoate); aminoglycosides (including tobramycin, gentamicin, amikacin and kanamycin); antifungals (including amphotericin B, clotrimazole, fluconazole, ketoconazole, itraconazole, miconazole, nystatin, and griseofulvin); cephalosporins (including cefazolin, cefotaxime, cefoxitin, defuroxime, cefaclor, cefonicid, cefotetan, cefoperazone, ceftriaxone, moxalactam, and ceftazidime, and salts thereof); ⁇ -
  • Suitable anti-cancer agents may act by any of a number of mechanisms. They may be antimetabolites, antimicrotubule agents, chelating agents, immunosupressants, antibiotics or anti-angiogenic agents.
  • Exemplary anti- cancer agents within the scope of the invention include: alkylating agents such as bis(chloroethyl)amines (including cyclophosphamide, mechlorethamine, chlorambucil, or melphalan), nitrosoureas (including carmustine, estramustine, lomustine or semustine), aziridines (including thiotepa or triethylenemelamine), alkylsulfonates including busulfan, other agents with possible alkylating agent activity (including procarbazine, cisplatin, carboplatin, dacarbazine, or hexamethylmelamine); antimetabolites such as methotrexate, mercaptopurine, thioguanine, 5-fluorouracil, c
  • Additional anti-cancer agents may be defined as compounds which exhibit therapeutic activity against cancer, as defined using standard tests known in the art, including in vitro cell studies, in vivo and ex vivo animal studies and clinical human studies. Suitable tests are described in texts such as "Anti-cancer Drug Development Guide” (B.A. Teicher ed., Humana Press, 1997 Totowa, NJ).
  • anti-cancer agents include anti-angiogenic agents such as active taxanes as described above, including paclitaxel and docetaxol; angiostatic steroids including squaline; cartilage derived proteins and factors; thrombospondin; matrix metalloproteinases (including collagenases, gelatinases A and B, stromelysins 1 , 2 and 3, martilysin, metalloelastase, MT1- MMP (a progelatenase), MT2-MMP, MT3-MMP, MT4-MMP, Bay 12-9566 (Bayer), AG-3340 (Agouron), CGS27023!
  • active taxanes as described above, including paclitaxel and docetaxol
  • angiostatic steroids including squaline
  • cartilage derived proteins and factors including thrombospondin
  • matrix metalloproteinases including collagenases, gelatinases A and B, stromelysins 1 , 2 and 3, mart
  • Anti-angiogentic agents include active analogues and derivatives of the aforementioned anti-angiogenic agents.
  • various exemplary drugs include certain steroids, such as budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone; dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone, and the like; certain peptides, such as cyclosporin cyclic peptide, retinoids, such as all-cis retinoic acid, 13- trans retinoic acid, and other vitamin A and beta carotene derivatives; vitamins D, E, and K and water insoluble precursors and derivatives thereof; prostaglandins and leukotrienes and their activators and inhibitors including prostacyclin (epoprostanol), and prostaglandins; tetrahydrocannabinol; lung surfactant lipids; lipid soluble antioxidants; hydrophobic antibiotics and chemotherapeutic drugs such as amphotericin B and ad
  • the formulation contains ingredients such that the drug, e.g., paclitaxel, is soluble in the formulation at a concentration between about 0.05 to about 30 mg drug / ml formulation, more preferably between 0.5 to about 30 mg/ml.
  • the drug e.g., paclitaxel
  • the drug is a hydrophobic taxane, where in one embodiment the taxane is paclitaxel or an analogue or derivative thereof.
  • Paclitaxel whose structure is shown in Figure 1, is a hydrophobic molecule having a molecular weight of 854 g/mol and poor water solubility.
  • a wide range of aqueous solubilities have been reported for paclitaxel, ranging from 0.3 ⁇ g/ml to 11 ⁇ g/ml (Sharma et al, 1997; Lundberg, 1997). This apparent contradiction is explained by the existence of different solid forms of paclitaxel having varying solubilities.
  • anhydrous crystalline, hydrated and amorphous solid forms of paclitaxel have been identified (Liggins and Burt, 1998).
  • Solid paclitaxel is stable, having a degradation half-life at 37°C of 137 years (MacEachern-Keith et al, 1997).
  • paclitaxel is known to convert to an epimer form by changing the configuration of a hydroxyl group on the C 7 position of the structure to form 7-epitaxol (see Figure 1). This conversion is favored in hydrophilic environments, proceeding very slowly in chloroform (MacEachern-Keith et al, 1997).
  • Other degradation products such as Baccatin III and 10-deactyltaxol have been described (Ringel and Horwitz, 1987; Lataste et al, 1984).
  • Preferred compositions of the invention provide for adequate stability to ensure therapeutic effectiveness over the life of the product. As such, degradation by these or other mechanisms are desirably reduced in the formulation relative to rates or extents of degradation provided in the prior art.
  • compositions of the present invention in addition to containing a difficult-to-deliver drug and a penetration enhancer, may contain one or more optional components, e.g., surfactants, emollients, exeipients, etc., where exemplary optional components are described below.
  • optional components e.g., surfactants, emollients, exeipients, etc., where exemplary optional components are described below.
  • compositions of the present invention may comprise a surfactant, where the surfactant is optionally a nonionic surfactant as exemplified by the nonionic surfactants disclosed in Table B.
  • compositions of the present invention comprise an emollient, where exemplary emollients are set forth in Table C.
  • compositions of the present invention comprise a speciality vehicle, where an exemplary specialty vehicle is set forth in Table D.
  • compositions of the present invention comprise a humectant, where an exemplary humectant is glycerin.
  • compositions of the present invention comprise additional agents, such as, for example, fragrances, including pharmaceutically acceptable perfumes; exeipients for providing texture (e.g., abrasives or microabrasives); and exeipients for providing a cooling or heating sensation (e.g., camphor).
  • fragrances including pharmaceutically acceptable perfumes
  • exeipients for providing texture e.g., abrasives or microabrasives
  • exeipients for providing a cooling or heating sensation e.g., camphor
  • D-lnsoluble, self-emulsifying, on standing separates into distinct phases may be clear, translucent or milky, l-lnsoluble, gross separation into distinct phases which separate rapidly on standing after shaking.
  • D-lnsoluble, self-emulsifying, on standing separates into distinct phases may be clear, translucent or milky. I-lnsoluble, gross separation into distinct phases which separate rapidly on standing after shaking.
  • Composition C at 25° C or Pour Point
  • D-Insoluble, self-emulsifying, on standing separates into distinct phases may be clear, translucent or milky, l-lnsoluble, gross separation into distinct phases which separate rapidly on standing after shaking.
  • the treatment compositions will often be sterilized or formulated to contain one or more preservatives for incorporation into pharmaceutical, cosmetic or veterinary 5 formulations.
  • These treatment compositions can be sterilized by conventional, well-known sterilization techniques, e.g., boiling or pasteurization when the drug is thermally stable.
  • irradiation and/or a preservative may be utilized to provide a sterile composition.
  • a preservative may be incorporated into a formulation of the
  • microbes such as bacteria, yeast and molds.
  • Any conventional preservative against microbial growth can be employed so long as it is pharmaceutically acceptable, is unreactive with the drug(s) contained in the formulation, and is non-irritating or non-sensitizing to human skin.
  • Exemplary preservatives include
  • antimicrobial aromatic alcohols such as benzyl alcohol, phenoxyethanol, phenethyl alcohol, and the like
  • esters of parahydroxybenzoic acid commonly referred to as paraben compounds, such as methyl, ethyl, propyl, and butyl esters of parahydroxybenzoic acid and the like.
  • the amount of preservative is typically not more than about two weight percent, based on the
  • compositions of the present invention include one or more coloring agents, also referred to as dyestuffs, which will be present in an effective amount to impart observable coloration to the composition.
  • coloring agents include dyes suitable for food such as those known as F. D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta carotene, annato, carmine, turmeric, paprika, and so forth. 8. pH Adjusters
  • compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions and as necessary to prepare compositions for convenient administration, such as pH 5 adjusting and buffering agents.
  • auxiliary substances as required to approximate physiological conditions and as necessary to prepare compositions for convenient administration, such as pH 5 adjusting and buffering agents.
  • Actual methods for preparing pharmaceutically administrable compounds will be known or apparent to those skilled in the art and are described in detail in, for example, Remington's Pharmaceutical Science.
  • compositions of the present invention can take a form that is suitable for topical application to a subject.
  • the formulation may be in the form of an aerosol, oil, cream, foam, gel, jelly, lotion, ointment, paste, powder, solution or suspension.
  • the form may be in the form of an aerosol, oil, cream, foam, gel, jelly, lotion, ointment, paste, powder, solution or suspension.
  • one or more of the following ingredients may be included in the formulation:
  • formulations of the present invention may optionally contain a en
  • the gelling agent imparts gel-like rheology to the formulation.
  • gelled morphology is particularly useful in a formulation of the present invention intended for topical delivery of a bioactive agent because a gel is easily applied, e.g., smeared or wiped onto a surface.
  • the formulation of the invention contains both water and a pharmaceutically acceptable water-gelling agent.
  • exemplary water-gelling agent exemplary water-
  • 25 gelling agents are carbomers and glyceryl polyacrylates.
  • Carbomers are a series of water-gelling homopolymers of acrylic acid crosslinked with an allyl ether of pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene available in various viscosity grades sold under the trademark designation CARBOPOL by B.F. Goodrich Company, Cleveland, Ohio.
  • Glyceryl polyacrylates are esters of glycerine and polyacrylic acid available in various viscosity grades sold as an aqueous jelly under the trademark designation, 5 HISPAGEL, by Hispano Quimica S. A., Barcelona, Spain.
  • a typical formulation will comprise at least about 50 percent by weight water, more preferably at least 75 percent by weight water, based on the total weight of the gel.
  • the amount of gelling agent can vary depending on the degree of gel viscosity desired.
  • a typical 10 concentration of water gelling agent is in the range of about 0.1 to about 2 weight percent, based on the total weight of the gel.
  • Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch.
  • Solutions may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.
  • the formulation contains drug at a concentration of at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the drug's maximum solubility in the formulation.
  • 25 depends on the type of formulation to be prepared and will generally be within the range of from about 0.001 to about 10% by weight. Generally, for most types of preparations the proportion of drug present in the formulation will be within the range of from about 0.005% to about 1% and preferably about 0.01%o to about 0.5%.
  • the ingredients of the formulation may be combined in any order 5 and manner that produces a formulation of the desired consistency.
  • the drug should be distributed, e.g., dissolved or dispersed, evenly throughout the formulation.
  • One approach to achieve this goal is to dissolve the drug in one or more of the formulation solvents, and then combine the remaining ingredients with the dissolved drug.
  • Other methods of preparing the formulation are readily 10 apparent to one of ordinary skill in the art.
  • the formulations of the present invention may be packaged in any suitable container that facilitates stable storage and subsequent dispension of 15 the formulation.
  • the formulation when the formulation is in the form of a gel, the gel may be packaged in a container from which it may be extruded, such as a squeezable tube, syringe, or the like, directly onto the subject's surface.
  • the package can be initially sealed and be opened at the time of use. If more than o a single dose is present, the package is preferably resealable by a suitable
  • closure means such as a valve, cap or plug.
  • a suitable container is a bottle, e.g., a bottle that is fitted with a delivery device, e.g., a pump, particularly a pump that delivers a metered predetermined standardized unit dose.
  • a delivery device e.g., a pump, particularly a pump that delivers a metered predetermined standardized unit dose.
  • a moisture-impermeable packet containing an intended single unit dose. The 25 packet can be initially sealed, and be opened at the time of use by tearing, cutting, or the like, at a desired or planned location in the packet after which the packet is manually squeezed so that the contents are directly administratable as desired.
  • kits will include multiple dosage forms of the composition, e.g., multiple packets or a bottle of formulation with a delivery pump.
  • the composition will be preformulated, however, the invention also provides that one or more components be held in separate contains, with instructions for preparing the final formulation.
  • the kit may optionally contain instructions for 10 using the formulation.
  • formulations of the present invention are sterile.
  • transdermal patches are matrix or monolithic-type laminated structures.
  • a protective release liner is adhered to a monolithic body that functions both as
  • compositions of the present invention provide for topical administration of a difficult-to-deliver drug. Appropriate dosages and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease and the method of administration. In general, an appropriate dosage
  • a typical dosage will range from 0.001 to 50 mg drug/kg subject's body weight, preferably from 0.1 to 20 mg/kg, on a regimen of single or multiple daily doses. Appropriate dosages may generally be determined using experimental models and/or clinical trials. In general, the
  • Formulations of the present invention may be applied to any external surface of a subject.
  • the formulation may be applied to 20 the subject's skin, so as to provide transdermal drug delivery.
  • the formulation w may be in any form suitable for topical application, including, for example, gel, cream, foam, powder.
  • the formulation may be applied as a liquid, e.g., in the form of a spray.
  • Spray compositions may be formulated, for example, as aqueous 25 solutions or suspensions or as aerosols delivered from pressurized packs, such as a metered dose pump (e.g., inhaler), with the use of a suitable liquefied propellant.
  • Suitable propellants are known in the art, and include fluorocarbons and hydrogen-containing chlorofluorocarbon, e.g., hydrofluoroalkanes, especially 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane.
  • Pressurised formulations will generally be retained in a canister (e.g., an aluminium canister) closed with a valve (e.g., a metering valve).
  • a valve e.g., a metering valve
  • Formluations for aerosol topical delivery will generally be either a suspension or a solution. These formulations are readily sprayed onto the subject's skin.
  • the therapeutic compositions may be in association with and/or form part of a device. In each case, when the device is applied or delivered to the subject, the therapeutic composition contacts the subject and the bioactive agent thereby gains entry to the subject.
  • Devices may take a variety of forms, including, e.g., rod-shaped devices, pellets, slabs, particulates, films, molds,
  • the device may be a bandage (adhesive or non-adhesive) or a fabric,
  • the fabric or bandage may be so designed as to be useful for covering a wound, for example, on the skin, or to be used as a packing into a wound or to be used as an adjunct in a surgical procedure.
  • Gauze e.g., a woven or non-woven mesh material
  • a gauze or mesh material may be incorporated onto the surface of such a device, or into the porous structure of a gauze or mesh material (e.g., within the interstitial spaces of the
  • the composition may be incorporated into the interstitial space of the gauze or mesh by soaking the material in the composition.
  • the composition may comprise a sponge,
  • Such a device may be fabricated of materials and by methods known to those skilled in the art.
  • porous materials may be made of materials such as collagen, gelatin (e.g., GELFOAM), hyaluronic acid and derivatives thereof (e.g., SEPRAMESH or SEPRAFILM from Genzyme Corporation), and cellulose.
  • the sponge may be a pledget comprising materials such as cotton, cellulose, gelatin, or a fluoropolymer, such as TEFLON.
  • the composition may be incorporated into a pledget, for example, by soaking the pledget in the composition.
  • the composition may be loaded in this manner immediately prior to use, or at an earlier time of manufacture.
  • the therapeutic compositions may be formed as a film or associated with a film device.
  • films are generally less than 5, 4, 3, 2 or 1 mm thick, more preferably less than 0.75 mm or 0.5 mm thick, and most preferably less than 500 ⁇ m.
  • Such films are preferably flexible with a good tensile strength (e.g., greater than 50, preferably greater than 100, and more preferably greater than 150 or 200 N/cm 2 ), good adhesive properties (i.e., readily adheres to moist or wet surfaces), and have controlled permeability.
  • a good tensile strength e.g., greater than 50, preferably greater than 100, and more preferably greater than 150 or 200 N/cm 2
  • good adhesive properties i.e., readily adheres to moist or wet surfaces
  • topical application shall include mouth washes and gargles.
  • the formulations of the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may advantageously be used. Continuous or prolonged delivery may be achieved by an adhesive reservoir system.
  • the present invention provides methods of using topical formulations as described herein to achieve therpeutic benefits.
  • the present invention provides methods for treating skin lesions.
  • a method is provided that includes delivering a taxane (e.g., paclitaxel) through or into the stratum corneum in a therapeutically effective amount to treat the skin lesion, such that the skin lesion is reduced in size or severity, or heals entirely.
  • the present invention provides a method of delivering a drug, e.g., a hydrophobic drug having a molecular weight of at least 700 g/mol, in a therapeutically effective amount through or into the stratum corneum, such that the skin lesion is treated.
  • the present invention provides a method of delivering a therapeutically effective amount of a hydrophobic drug having a molecular weight of at least 700 g/mol through the stratum corneum, such that a skin lesion is treated.
  • the method may include applying a formulation comprising a hydrophobic drug to the skin in conjunction with at least one organic solvent, where suitable and exemplary organic solvents are described herein.
  • the skin lesion may be, in various exemplary embodiments, a psoriatic lesion, a cancerous lesion, an infection, or an inflamed skin lesion or a lesion characterized by cell proliferation or differentiation.
  • Paclitaxel used for all studies was initially an anhydrous crystalline form, prior to its exposure to solvents.
  • EXAMPLE 1 THE GEL FORMULATION This example describes the preparation of a gel formulation.
  • This gel formulation is referred to throughout the present specifation as the "Gel Formulation” and serves, in some instances, as a control to measure the performance of other formulations of the present invention.
  • a mixture of 16.4 parts ethoxydiglycol (also knows as diethylene glycol monoethyl ether, and sold as TRANSCUTOL P) and 1.5 parts hydroxyethylcellulose were stirred together at room temperature for about 5 minutes. Sterile water, 30.9 parts, was gradually added and the resulting mixture stirred for about 1 hour to form the so-called "gum phase".
  • solubility of paclitaxel in various solvent systems was measured in order to predict the degree of solution saturation that would exist in a given formulation, providing a driving force for drug penetration through the skin.
  • Glass vials sealed with polypropylene caps containing pure solvents or solvent mixtures were prepared and solid paclitaxel added. Vials were maintained sealed at 25°C for several hours with occasional mild shaking and then observed visually. To vials in which a clear solution had formed, more paclitaxel was added. Saturation solubility was assumed to have been attained after a solution was observed to be in contact with excess solid drug for a period of 12 hours.
  • Paclitaxel solubility in a number of solvents is summarized in Table 1. Generally, paclitaxel exhibited greater solubility in more hydrophobic solvents. For binary solvent mixtures, the effect of increasing the proportion of e-o one of the solvents is illustrated by the solubility phase diagrams in Figure 5. In all mixtures, as the proportion of the more hydrophobic solvent was increased, the solubility of paclitaxel was observed to increase. In binary mixtures
  • FIG. 15 6 shows the effect on paclitaxel solubility of adding 0.5 ml NMP to 5 ml of the ternary mixtures.
  • paclitaxel solubility is increased by the addition of NMP.
  • the effect of adding 0.5 and 1.5 ml of ethoxydiglycol to 5 ml of the ternary mixtures was also assessed. As observed with the addition of NMP, paclitaxel was increasingly soluble in mixtures with the addition of ethoxydiglycol.
  • water should be in the range of 30-60% of the solvent mixture in order to allow sufficient paclitaxel solubility to prepare a formulation with a drug loading in the range of 0.01 to 0.5%.
  • solvent mixtures containing ethoxydiglycol, NMP, ethanol, isopropyl acetate and water are shown to have a wide range of paclitaxel solubility, depending on the composition.
  • a final drug concentration in the formulation to provide adequate driving force could be predicted.
  • PBS phosphate buffered saline
  • Stability in ethanol was assessed by dissolving paclitaxel in 95% ethanol to a concentration of 500 ⁇ g/ml and maintaining aliquots of the solution at 4, 25 and 40°C. At sampling intervals, aliquots of the solution were injected directly and analyzed by HPLC. The chromatography was performed using a Ci 8 column, a gradient mobile phase (37% acetonitrile for 40 minutes, increasing to 60% over fifteen minutes thereafter) flowing at 2 ml/min and uv detection at 232 nm. The run-time was 55 minutes.
  • Stability in Ethoxydiglycol Stability in ethoxydiglycol was assessed by dissolving paclitaxel to make a 500 ⁇ g/ml solution. Stability in this solvent was assessed at 100°C. At sampling intervals, 200 ⁇ l of the solution was diluted to 1 ml with acetonitrile and analyzed by HPLC using the same method described for studies of stability in ethanol. Stability in Solvent Mixtures
  • the stability of paclitaxel in various solvent mixtures was characterized by analysis of the data obtained from solubility studies, based on the chromatographic separation of degradants identified in the study of 5 aqueous paclitaxel stability.
  • the conversion of paclitaxel to 7-epitaxol was determined and expressed as a percentage of the concentration of paclitaxel measured in the solution.
  • Other degradants were not characterized in the solvent mixtures.
  • the degradation rate constant describing loss of paclitaxel by all mechanisms of degradation was 0.025 h "1 .
  • Degradation was further characterized in terms of three major mechanisms. The most rapid was
  • Paclitaxel is stable in ethanol; over the course of a 100 day stability study at temperatures between 4 to 40°C, there was no observed decrease in paclitaxel concentration.
  • preliminary data are available from observations made during solubility studies. Over the course of the solubility studies of paclitaxel in ternary solvent mixtures it was observed that paclitaxel was being converted, to a significant extent, to 7-epitaxol in a period of less than 24 hours.
  • region C shows solvent compositions for which 5-15% of the paclitaxel was converted to 7-epitaxol during the solubility study. Mixtures containing only water and ethanol showed the highest levels of 7-epitaxol. As the level of isopropyl acetate was increased the conversion was greatly reduced.
  • ternary mixtures were prepared by 5 combining various proportions of each component on a %v/v basis. Each mixture was shaken and gas bubbles allowed to diffuse to the air-liquid interface. The mixtures were then observed visually to determine whether there were one or two liquid phases present. Miscibility studies were conducted using mixtures having proportions changed in increments of 10%. 10 The effect of adding a fourth component to ternary mixtures was assessed as follows. To 5 ml of ternary mixtures displaying solvent immiscibility, another solvent, either NMP or ethoxydiglycol was added in 0.5 ml aliquots until to mixture formed a single phase.
  • the rate of diffusion of paclitaxel through split thickness human skin was assessed as follows. Human skin was acquired from the abdomen of healthy subjects and the subcutaneous fat removed. The subjects included one 72 year old male and nine females ranging in age from 28 to 57. Among the subjects were one East Indian and nine Caucasians. The stratum corneum of the skin was removed by heat separation at 60°C, blotted dry and stored between two sheets of REXAM polyethylene terephthalate, at -70°C. At the time of analysis, skin samples were cut into 2 cm squares using a scalpel blade and transferred from the REXAM liner onto a Franz cell. The reservoir of the Franz cell was then filled with 10 ml of PBS previously heated to 40°C.
  • Figure 9 shows profiles of paclitaxel diffusion through separated human stratum corneum from an infinite dose of various saturated solutions. No paclitaxel levels were measured for drug residing in the skin sample. The amounts of paclitaxel plotted represent the cumulative amount of paclitaxel recovered from the receptor fluid in Franz cells used for paclitaxel penetration studies. Rates calculated from these profiles are summarized in Table 2. NMP allowed the most rapid penetration of paclitaxel through the stratum corneum, approximately an order of magnitude greater than for solutions of ethoxydiglycol, isopropyl acetate, isopropyl myristate, propylene glycol and polyethylene glycol.
  • NMP, ethanol and isopropyl acetate were identified as having good potential to enhance paclitaxel penetration through the skin. Based on the low rates of penetration of paclitaxel from isopropyl myristate, PEG 200 and 1 ,2-propanediol, these solvents were not studied any further. The solvents identified as having good potential were studied further in
  • FIGS. 10 and 11 summarize the effect on paclitaxel diffusion through skin of using various solvent systems as
  • Emulsions containing solvent mixtures of ethanol, isopropyl acetate, water, NMP and ethoxydiglycol in the aqueous phase, and mineral oil, glycerin, stearyl alcohol and beeswax in the oil phase were prepared.
  • the emulsions were stabilized with polyoxyethylene stearyl ethers (BRIJ 72 and 721 surfactants).
  • Emulsions were prepared as follows.
  • the aqueous and oil phases were prepared separately by combining the aqueous phase components with BRIJ 72 surfactant and the oil phase components with BRIJ 721 surfactant. Both phases were heated to 70°C for approximately 5 minutes to produce clear liquids.
  • the aqueous phase was slowly added to the oil phase with gentle shaking to mix the components.
  • the emulsion was then shaken for 15 minutes over which it cooled to room temperature.
  • Emulsions were characterized by visual and microscopic observation for evidence of emulsion stability. Oil droplet size within the emulsions was measured using a microscope equipped with a stage micrometer.

Abstract

A topical formulation for drug delivery, the formulation comprising an organic solvent and a drug, the drug having a maximum solubility in the formulation, where the drug is present in the formulation at a concentration of at least 50% of the drug's maximum solubility.

Description

TOPICAL FORMULATIONS WITH BIOACTIVE COMPONENTS
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention is directed to chemical compositions that include a bioactive therapeutic agent, or may be used to deliver a bioactive therapeutic agent, where the agent is delivered via topical application of the composition to a subject in need thereof. The invention also provides methods of using the composition, and related subjects.
Description of the Related Art Topical application is a convenient way to administer a therapeutic agent to a subject. Therapeutic agents may be delivered topically through a variety of routes, including orally, transdermally, and intransally. Many drugs, however, can present problems when the goal is to deliver them topically to a subject, and stable formulations that allow ready transdermal delivery of the drug can be difficult to design. This is particular common in cases when the drug is hydrophobic, or highly hydrophilic (e.g., when it is a salt form, or is ionized at pH 7), when it is prone to degradation, or when it has a high molecular weight. Furthermore, such characteristics may result in the drug having poor bioavailability. The present invention addresses this need in the art, and provides further related advantages.
BRIEF SUMMARY OF THE INVENTION
Briefly, the present invention is directed to topical drug formulations, i.e., formulations for topical delivery of a drug to a subject. The topical formulations are particularly suited for the delivery of a difficult-to-deliver drug. Topical formulations are described that include one or more penetration enhancers (i.e., organic solvents) which may improve the bioavailability of the drug.
One aspect of the present invention provides a topical formulation for drug delivery, where the formulation comprises an organic solvent and a drug, where the drug has a high molecular weight of at least 700 g/mol and additionally has a maximum solubility in the formulation. In various embodiments of the formulation, the drug is present in the formulation at a concentration of at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the drug's maximum solubility in the formulation. In one embodiment, the organic solvent is ethanol. In another embodiment the organic solvent is N-methly-pyrrolidone. In another embodiment, the organic solvent is ethoxydiglycol. In another embodiment, the organic solvent is glycerin. In another embodiment the organic solvent is isopropyl acetate. In other embodiments, the organic solvent is selected according to criteria set forth herein.
In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises an organic solvent and a drug, where the drug is highly hydrophilic and additionally has a maximum solubility in the formulation. A highly hydrophilic drug refers to a drug in a salt form, or a drug that is ionized at pH 7, where such drugs tend to be freely soluble in water. In various embodiments of the formulation, the drug is present in the formulation at a concentration of at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the drug's maximum solubility in the formulation. In one embodiment, the organic solvent is ethanol. In another embodiment the organic solvent is N-methly-pyrrolidone. In another embodiment, the organic solvent is ethoxydiglycol. In another embodiment, the organic solvent is glycerin. In another embodiment the organic solvent is isopropyl acetate. In other embodiments, the organic solvent is selected according to criteria set forth herein. In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises an organic solvent and a drug, where the drug is hydrophobic and additionally has a maximum solubility in the formulation. In various embodiments of the formulation, the drug is present in the formulation at a concentration of at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the drug's maximum solubility in the formulation. In one embodiment, the organic solvent is ethanol. In another embodiment the organic solvent is N-methly- pyrrolidone. In another embodiment, the organic solvent is ethoxydiglycol. In another embodiment, the organic solvent is glycerin. In another embodiment the organic solvent is isopropyl acetate. In other embodiments, the organic solvent is selected according to criteria set forth herein.
In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises an organic solvent and a drug, where the drug is prone to degradation and additionally has a maximum solubility in the formulation. In various embodiments of the formulation, the drug is present in the formulation at a concentration of at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the drug's maximum solubility in the formulation. In one embodiment, the organic solvent is ethanol. In another embodiment the organic solvent is N-methly- pyrrolidone. In another embodiment, the organic solvent is ethoxydiglycol. In another embodiment, the organic solvent is glycerin. In another embodiment the organic solvent is isopropyl acetate. In other embodiments, the organic solvent is selected according to criteria set forth herein. In another aspect, the present invention provides a topical formulation comprising a taxane and an organic solvent. The formulation is suited for delivery of a therapeutically effective dose of the taxane through or into the stratum corneum in the treatment of a skin lesion. The organic solvent may be ethoxydiglycol, ethanol, or N-methly-pyrrolidone, or glycerin, or isopropyl acetate, or one or more other solvents selected according to criteria set forth herein.
In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to- deliver drug (e.g., is hydrophobic, has a high molecular weight, is prone to degradation, or is highly hydrophilic) and a cyclic amide of a formula N-(R1)- pyrrolidone where R1 is Cι-C6 alkyl, e.g., R1 is methyl. In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to-deliver drug and an alcohol of a formula R1- OH wherein R1 is Ci-Cβalkyl, e.g., R1 is ethyl. In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to-deliver drug and an ester of a formula R1-O-C(=O)-CH3 wherein R1 is Ci-Cβ alkyl, e.g., R1 is iso-propyl. In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to-deliver drug and an alkoxy alcohol of a formula R1-O-R2- OH where R1 is C-i-Cβ alkyl and R2 is C2-Cβ alkylene, e.g., R1 is ethyl and R2 is ethylene. In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to- deliver drug and a polyol of a formula (R3)-(OH)n wherein R3 is an n-valent C2- CQ hydrocarbyl group, e.g., the polyol is glycerin.
In each of the formulations of the present invention, the organic solvent may be a mixture of at least two organic solvents. In one aspect, the formulation contains two organic solvents. In another embodiment the formulation contains three organic solvents. Optionally, the at least two organic solvents form a single phase when they are combined.
In each of the formulations of the present invention, water may optionally be present. For example, the formulation may be in the form of an emulsion or microemulsion, where in two embodiments, the water may be in the continuous or discontinuous phase. In each of the formulations of the present invention, one or more of the following optional components may be present: a surfactant or a hydrocarbon oil.
The present invention provides topical formulations that are particularly suited for the delivery of a difficult-to-deliver drug to a subject. In one embodiment, the drug is hydrophobic. In another embodiment, the drug has a molecular weight between 700 and 2,000 g/mol. Optionally, the drug is a taxane, where in one embodiment the taxane is paclitaxel or an analogue or derivative thereof. In one aspect, the drug may be an anti-inflammatory agent, antibiotic, anti-cancer agent, or anti-proliferative agent. For example, the drug may be an anthracycline, podophyllotoxin, fluoropyrimidine, or camptothecin.
In various aspects of the invention, the formulation contains ingredients such that the drug, e.g., paclitaxel, is soluble in the formulation at a concentration between 0.05-30 mg drug/ml formulation. In other aspects the solubility range is 0.5-30 mg drug/ml formulation. In other aspects, the formulation is in the form of a cream, gel, or powder, or in a liquid form (e.g., solution, suspension, or emulsion). In yet other aspects, the formulation may be associated with a device, such as a pledget, gauze, mesh, or bandage. In other aspects, the present invention provides methods of using topical formulations, and methods of preparing topical formulations. For example, the present invention provides a method of delivering in a therapeutically effective amount a drug, e.g., a taxane, through or into the stratum corneum, where in one embodiment the therapeutically effective extent treats a skin lesion. In another aspect, the present invention provides a method of delivering a difficult-to-deliver drug through the stratum corneum, where in one embodiment the therapeutically effective aspect treats a skin lesion. In one aspect, a method is provided for treating a skin lesion in a subject, comprising delivering a therapeutically effective amount of a formulation, the formulation comprising an organic solvent and a drug, the drug having a maximum solubility in the formulation, wherein the drug is present in the formulation at a concentration of at least 50% of the drug's maximum solubility, to a skin lesion through the stratum corneum of the subject, such that the skin lesion is treated. In a related aspect, the present invention provides a method of delivering a difficult-to-deliver drug through the stratum corneum in a therapeutically effective amount such that a skin lesion is treated, where the method comprises applying a formulation comprising said drug to the skin in conjunction with at least one organic solvent, where suitable and exemplary organic solvents are described herein. The methods described herein may be used to deliver to a skin lesion through the stratum corneum at least about 0.001 mg to about 50 mg per kg of a subject's body weight per day or at least about 0.1 mg to 20 mg per kg of a subject's body weight per day.
In the methods of the invention, the skin lesion may be, in various exemplary embodiments, a psoriatic lesion, an infection, a cancerous lesion, an inflamed skin lesion, or a lesion characterized by abnormal cell proliferation or differentiation, where cancer cells are one type of cell that may exhibit abnormal differentiation. The skin lesion may be in one or more layers of the skin, including in an epidermal, in a dermal, or in a subcutaneous layer of the skin. These and other aspects and embodiments of the present invention are described in further detail below, in reference to the following figures.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S) Figure 1 provides the chemical structure of paclitaxel. Figure 2 provides a ternary phase diagram depicting the miscibility of ethanol/isopropyl acetate/water mixtures. The diagram illustrates three regions: Region A - the solvent mixtures are miscible; Region B - the solvent mixtures are immiscible; and Region C - the solvent mixtures will not dissolve more than 10% glycerin. Figure 3 provides a ternary phase diagram depicting the effect of the addition of ethoxydiglycol to ethanol/isopropyl acetate/water mixtures on solvent miscibility. In Figure 3, Region A in indicates compositions that are miscible with the addition of ethoxydiglycol; Region B indicates compositions that area miscible with the addition of >2 ml ethoxydiglycol to 10 ml of the solvent mixture; Region C indicates compositions that are miscible with the addition of >4 ml ethoxydiglycol to 10 ml of the solvent mixture; Region D indicates compositions that are miscible with the addition of >6 ml ethoxydiglycol to 10 ml of the solvent mixture; Region E indicates compositions that are miscible with the addition of >8 ml ethoxydiglycol to 10 ml of the solvent mixture.
Figure 4 provides a ternary phase diagram depicting the effect of the addition of 1-methyl-2-pyrrolidinone (NMP) to ethanol/isopropyl acetate/water mixtures on solvent miscibility. In Figure 4, Region A indicates compositions that are miscible without the addition of NMP; Region B indicates compositions that are miscible with the addition of >1 ml NMP to 10 ml of the solvent mixture; Region C indicates compositions that are miscible with the addition of >2 ml NMP to 10 ml of the solvent mixture; Region D indicates compositions that are miscible with the addition of >4 ml NMP to 10 ml of the solvent mixture; Region E indicates compositions that are miscible with the addition of >8 ml NMP to 10 ml of the solvent mixture; and Region F indicates compositions that are immiscible with the addition of >10 ml NMP to 10 ml of the solvent mixture.
Figure 5 provides a solubility phase diagram illustrating the solubility of paclitaxel in binary solvent mixtures (i.e., Solvent "A'VSolvent "B") having varying proportions of each solvent.
Figure 6 provides a solubility phase diagram illustrating the solubility of paclitaxel in ternary solvent mixtures of ethanol, isopropyl acetate, and water. The diagram illustrates two shaded regions: Region A - the solvent mixtures were not miscible; and Region B - the drug was unstable with 5-15% of the dissolved paclitaxel converted to 7-epitaxol.
Figure 7 provides a solubility phase diagram illustrating the solubility of paclitaxel in quaternary solvent mixtures of ethanol, isopropyl acetate, water and 1-methyl-2-pyrrolidinone (NMP). Each mixture was prepared as a ternary system described by the axes of the diagram, followed by dilution of 5 ml of each mixture with 0.5 ml NMP. The diagram illustrates a two shaded regions: Region A - the solvent mixtures were not miscible, and Region B - the drug was unstable with greater than 5% of the dissolved paclitaxel converted to 7-epitaxol.
Figures 8A and 8B provide first order plots of paclitaxel degradation in an aqueous buffer (pH =7.4) at 30°C. Figure 8A shows the change in concentration of paclitaxel over 24 hours, where the first order rate constant for paclitaxel degradation is k = 0.025 h"1. Figure 8B shows the change in concentration of paclitaxel over 96 hours, expressed as the loss of paclitaxel due to degradation by three different mechanisms, where the first order rate constant for paclitaxel degradation by ester cleavage at C13 to form Baccatin III and V is k = 0.0028 h"1 (see filled diamond (♦) data); epimerization at C7 to form 7 epitaxol is k = 0.016 h"1 (see filled square (■) data); and deacetylation at Cio to form 10-deacetyl paclitaxel is k=0.00037 h"1 (see filled triangle (A) data).
Figures 9A and 9B illustrates the effect of different solvents on the ex vivo penetration of paclitaxel through human stratum corneum with the administration of an infinite dose. In Figure 9A, the open square (□) indicates data from 1-methyl-2-pyrrolidinone and the open triangle (Δ) indicates data from ethanol. In Figure 9B, the filled square (■) indicates data from isopropyl acetate; the open diamond (0) indicates data from isopropyl myristate, the filled triangle (A) indicates data from ethoxydiglycol, and the filled circle (•) indicates data from 1 ,2-propanediol (propylene glycol). Figure 10 provides representative profiles of paclitaxel penetration through stratum corneum from 1% solutions in various solvent mixtures and from the Gel Formulation (see Example 1). In Figure 10, the open circle (o) indicates data from the Gel Formulation (containing 1% paclitaxel), the filled square (■) indicates data from 35/30/5/10/20 ethoxydiglycol/ water/ glycerin/ NMP/ isopropyl acetate, the open triangle (Δ) indicates data from 50/50 ethoxydiglycol/ NMP, the filled triangle (A) indicates data from ethoxydiglycol/ water/ isopropyl acetate/ ethanol, the open square (α) indicates data from 55/30/5/10 ethoxydiglycol/ water/ glycerin/ NMP, the open diamond (0) indicates data from 30/20/10/40 ethoxydiglycol/ water/ NMP/ ethanol, and the filled circle (•) indicates data from 50/20/5/15 ethoxydiglycol/ water/ glycerin/ ethanol.
Figure 11 is a schematic illustration of the effect of solvent system composition on paclitaxel penetration rates through stratum corneum. Penetration rates are normalized relative to the rate from the Gel Formulation (see Example 1 ; 1% paclitaxel content). Each solvent mixture is outlined by a rectangle and the proportions for the mixtures providing the three greatest penetration rates are listed above the corresponding rectangles. The filled square (■) represents ethoxydiglycol, the open square (α) indicates isopropyl acetate, the filled triangle (A) indicates 1-methyl-2-pyrrolidinone, the open triangle (Δ) indicates ethanol, the filled circle (•) indicates glycerin, the open circle (o) indicates water, and the "X" indicates propylene glycol.
Figure 12 shows a representative microscopic image of an emulsion (Formulation 5, refer to Table 2) containing by weight: 9% isopropyl acetate, 21% water, 31% ethoxydiglycol, 36% mineral oil and 1% each of BRIJ 72 and 721 (polyoxyethylene 2 stearyl ether and polyoxyethylene 21 stearyl ether, respectively). The width of the image is 200 μm. DETAILED DESCRIPTION OF THE INVENTION
A. Overview
The present invention provides chemical compositions that either may be combined with a drug, or include a drug. The terms "drug" and "bioactive agent" will be used synonymously herein. A composition of the invention without a drug will be referred to herein as a drug delivery vehicle. A composition of the invention with a drug will be referred to herein as a therapeutic composition. When discussion contained herein applies both to the drug delivery vehicles and the therapeutic compositions, then these aspects of the invention will be referred to jointly by the term "chemical compositions of the invention".
The therapeutic compositions facilitate the bioavailabity of a drug to a subject that has received the composition by topical administration. In other words, relative to topical application of the drug alone (i.e., in "neat" or non-formulated form), topical application of the therapeutic compositions of the present invention may enhance the bioavailability of the drug to the subject. The compositions of the present invention are therefore useful in drug delivery.
Before further describing the formulations and methods of the present invention, the following definitions are provided to assist the reader.
B. Definitions
An "adjuvant" refers to a substance that, when included in a therapeutic composition, will improve or enhance the therapeutic efficiacy of one or more of the active agents contained within the composition, i.e., the adjuvant enhances the overall therapeutic effectiveness of the composition. An adjuvant may, for instance, counteract a negative effect associated with the composition and/or a bioactive agent therein.
An "excipient" refers to an inert or substantially inert, non-toxic substance present in a therapeutic compositions which can confer some benefit thereto, such as improved physical and/or chemical stability or improved handling characteristics (e.g., flowability and consistency). The excipient may, for example, function solely or primarily as a bulking agent, i.e., a material that reduces the concentration of the bioactive agent in the therapeutic composition. A "stabilizer" refers to an excipient that improves the physical or chemical stability (e.g., the storage stability) of the therapeutic composition. The stabilizer assists in maintaining the therapeutic efficacy of the active agent(s) present in the therapeutic compositions. An exemplary stabilizer is an "antioxidant", where this term refers to synthetic or natural substances that prevent or delay the oxidative deterioration of a bioactive agent. Exemplary antioxidants include lecithin, gamma oryzanol; ubiquinone (ubidecarenone) and coenzyme Q; vitamins, such as vitamins A, C (ascorbic acid) and E and beta- carotene; natural components such as camosol, carnosic acid and rosmanol found in rosemary and hawthorn extract, proanthocyanidins such as those found in grapeseed or pine bark extract, and green tea extract.
A "difficult-to-deliver" drug refers to a drug that is hydrophobic, and/or has a molecular weight of greater than 700 g/mol. It also refers to drugs that are very hydrophilic, e.g., are present in the formulation in the form of a salt, or are ionized at neutral pH, i.e., pH of about 7. This term also refers to drugs that are prone to degradation when in a drug delivery formulation.
C. Formulations
In one aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises an organic solvent and a drug. The formulation and drug are selected such that the drug is present in the formulation at a concentration of at least 50% of the maximum possible concentration of the drug. The term "concentration of drug" refers to the weight percent of drug in the formulation, e.g., a formulation containing 1 gram of drug and 100 grams total weight would have 1% concentration. The maximum possible concentration (i.e., solubility) of a drug in a formulation is reached when the drug is no longer homogeneously distributed in the formulation. For example, if the drug is completely soluble in a formulation, then the maximum possible concentration of the drug in the formulation is reached when the drug is present in the formulation at such a high concentration that not all of the drug dissolves in the formulation. In this case, the maximum solubility of the drug is reached just before the point at which the drug ceases to dissolve in the formulation. As another example, if the drug is dispersed in an emulsion or microemulsion form, then the maximum possible concentration of the drug in the emulsion or microemulsion is reached when increasing the loading of the drug in the formulation results in an inhomogenous emulusion or microemulsion form. In this case, the maximum solubility of the drug is reached just before the point at which the (micro) emulsion becomes inhomogenous. In all cases, homogeneity is judged based on the macroscopic properties of the formulation. In various embodiments of the present invention, the formulation contains drug at a concentration of at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the drug's maximum solubility in the formulation. The present inventor has discovered that when the drug is at, or near, its maximum concentration in a therapeutic composition, then the therapeutic composition is relatively more effective at making the drug, and particularly a hydrophobic drug, bioavailable to a subject that has received the drug by topical administration. In various embodiments of the present invention, the drug is present in the formulation at a concentration, relative to its maximum concentration, of 50-60%, 50-70%, 50-80%, 50-90%, 50-95%, 50- 100%, 60-70%, 60-80%, 60-90%, 60-95%, 60-100%, 70-80%, 70-90%, 70- 95%, 70-100%, 80-90%, 80-95%, 80-100%, 90-95%, 90-100%, or 95-100%. The formulations of the present invention contain at least one drug and at least one organic solvent. When the formulation contains more than one drug, then either drug may be considered in determining whether the formulation contains that drug at a concentration of at least 50% of the drug's maximum concentration in the formulation. In a simple embodiment, the formulations may comprise of the present invention contain only two ingredients, namely, a single drug and a single organic solvent. In this case, a homogeneous formulation is created when the drug is soluble in the solvent, and the maximum concentration (i.e., solubility) of the drug in the solvent is identified when no additional drug will dissolve in the formluation.
In another embodiment, the formulation may contain only three ingredients. For example, the formulation may contain a single drug, an organic solvent, and a second solvent. In one aspect, the second solvent is water. In another aspect, the second solvent is another organic solvent, different from the first solvent. In one embodiment, the formulation containing one drug and two solvents is a single phase that is homogeneous, i.e., the two solvents are miscible with one another, and the drug is soluble in the mixture of two solvents. In yet another embodiment, the formulations of the present invention contain only four ingredients. For example, the formulation may contain a single drug, an organic solvent, and a second and third solvent. In one aspect, the second solvent is water. In one embodiment, the formulation containing one drug and three solvents is a single phase that is homogeneous, i.e., the three solvents are miscible with one another, and the drug is soluble in the mixture of the three solvents.
In a related embodiment, the formulation contains at least four ingredients. For example, the formulations may contain a single drug, an organic solvent, and second and third solvents. In one aspect, the second solvent is water. In another embodiment, the formulation containing at least one drug and three solvents is homogeneous. An additional component may be included in the formulation in order for the at least one drug and three solvents to reach a homogeneous state.
Optionally, the formulations of the present invention contain a difficult-to-deliver drug, a first solvent which is an organic solvent, and one or more additional solvents, i.e., second, third, etc. solvents. Furthermore, the combination of solvents is not a single phase or homogeneous, i.e., the combination forms two distinct phases or more than two distinct phases. For example, the second solvent is water and the first solvent is an organic solvent that is immiscible in water at the specific weight ratio of first and second solvents employed. In this embodiment of the invention, the formulation may contain one or more additional components which function to homogenize to the formulation. For example, when the second solvent is water, the additional component may be a surfactant, e.g., a nonionic surfactant. The addition of the surfactant may cause the formulation to adopt an emulsion or microemulsion form, where the water may be the continuous or discontinuous phase, and the drug, when hydrophobic, will be dissolved in the non-aqueous phase. Optionally, the drug may also be present in some concentration or as a solid in the aqueous phase. Suitable exemplary surfactants are described below. Optionally, the formulations of the present invention contain a hydrophobic drug, a first solvent which is an organic solvent, a second solvent, and a third solvent. Furthermore, the combination of first, second and third solvents is not a single phase or homogeneous, i.e., the combination forms two distinct phases or more than two distinct phases. For example, the second solvent is water and the first solvent is an organic solvent that is immiscible in water at the specific weight ratio of first and second solvents employed. In this embodiment of the invention, the formulation contains one or more additional components which function to homogenize the formulation.
The following criteria may be used to select organic (first) solvents: a) cosmetic features of the solvent such as acceptable aroma and texture; b) chemical stability of the drug dissolved in the solvent; c) toxicology of the solvent; d) biocompatibility, irritancy or allergenicity of the solvent; e) solubility of the drug in the solvent; f) ability of the solvent to affect drug permeability through or into skin; and g) miscibility of the solvent with other solvents or exeipients in the formulation.
The following are exemplary organic (first) solvents that may be included in the formulations of the present invention. These exemplary organic solvents may also function as a second, third, fourth, etc. solvent: a cyclic amide of the formula N-(R1)-pyrrolidone where R1 is Cι-C6 alkyl, for example, a cyclic amide of a formula N-(R1)-pyrrolidone where R1 is methyl; an alcohol of the formula R1-OH wherein R1 is Cι-C6alkyl, for example, an alcohol of the formula R1-OH wherein R1 is ethyl; an ester of the formula R -O-C(=O)-CH3 wherein R1 is Cι-C6 alkyl, for example, an ester of the formula R1-O-C(=O)-CH3 wherein R1 is iso-propyl; an alkoxy alcohol of the formula R1-O-R2-OH where R1 is Cι-C6 alkyl and R2 is C2-C6 alkylene, for example, an alkoxy alcohol of the formula R - O-R2-OH where R1 is ethyl and R2 is ethylene; and a polyol of a formula (R3)-(OH)n wherein R3 is an n-valent C2-C6 hydrocarbyl group, for example, glycerin.
In one embodiment, the organic (first) solvent is ethanol. In another embodiment the organic (first) solvent is N-methly-pyrrolidone. In another embodiment, the organic (first) solvent is glycerin. In another embodiment the organic (first) solvent is isopropyl acetate. Based on the data presented herein, several solvents and ranges at which they may be incorporated into a vehicle to provide skin penetration and suitable solubility for a hydrophobic drug in general, and paclitaxel in particular, may be recommended as shown in Table A. Table A RECOMMENDED SOLVENTS AND CONCENTRATION RANGES
Figure imgf000018_0001
* weight percent values, based on total weight of formulation
In another aspect, the present invention provides a topical formulation comprising a taxane and an organic solvent. The formulation is suited for delivery of a therapeutically effective dose of the taxane through the stratum corneum in the treatment of a skin lesion. The organic solvent may be, e.g., ethanol, or N-methly-pyrrolidone, or glycerin, or isopropyl acetate, or one or more other solvents selected according to criteria set forth above
In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises a hydrophobic drug and a cyclic amide of a formula N-(R1)-pyrrolidone where R1 is Ci-Cβ alkyl, e.g., R1 is methyl. In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to- deliver drug and an alcohol of a formula R1-OH wherein R1 is Cι-C6alkyl, e.g., R1 is ethyl. In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to- deliver drug and an ester of a formula R1-O-C(=O)-CH3 wherein R1 is Ci-Cβ alkyl, e.g., R1 is iso-propyl. In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult- to-deliver drug and an alkoxy alcohol of a formula R1-O-R2-OH where R1 is Ci-Cβ alkyl and R2 is C2-C6 alkylene, e.g., R1 is ethyl and R2 is ethylene. In another aspect, the present invention provides a topical formulation for drug delivery, where the formulation comprises a difficult-to-deliver drug and a polyol of a formula (R3)-(OH)n wherein R3 is an n-valent C2-C6 hydrocarbyl group, e.g., the polyol is glycerin. In each of the formulations of the present invention, the organic solvent may be a mixture of at least two organic solvents. In one aspect, the formulation contains two organic solvents. In another embodiment the formulation contains three organic solvents. The at least two organic solvents may form a single phase when they are combined. The formulation may be in the form of an emulsion or microemulsion. In each of the formulations of the present invention, water may optionally be present in either the continuous or discontinuous phase.
D. Drugs
The compositions and methods of the present invention include a drug. In particular, the inventive compositions and methods include a drug that is difficult to deliver to a subject via a conventional topical formulation. Such drugs include hydrophobic drugs, where the term "hydrophobic drug" refers to drugs that are insoluble or sparingly or poorly soluble in water. As used herein, such drugs will have solubility below 10 mg/ml, usually below 1 mg/ml, sometimes below 0.01 mg/ml, and sometimes below 0.001 mg/ml. The drugs also include drugs with molecular weights in excess of about 700 g/mol, drugs that are unstable, and drugs that are highly hydrophilic such as salts and drugs that are at least partly ionized at neutral pH.
Exemplary drugs that may be included in formulations of the present invention include: anti-microtubule agents, anti-inflammatory agents, anti-cancer agents, anti-proliferative agents, anti-angiogenic agents, anti-fibrotic agents, analgesic agents, immunosupressants, anaesthetics, anti-infectives, and antibiotics. In a preferred aspect, the drug is selected from paclitaxel, hydrophobic paclitaxel derivatives and hydrophobic paclitaxel analogues. In another preferred aspect, the hydrophobic drug is paclitaxel. Examples of these and other types of drugs are provided below.
Within one preferred embodiment of the invention, the drug is paclitaxel, a compound currently recognized to disrupt mitosis (M-phase) by binding to tubulin to form abnormal mitotic spindles or an analogue or derivative thereof. Briefly, paclitaxel is a highly derivatized diterpenoid (Wani et al., J. Am. Chem. Soc. 93:2325 (1971)). It may be obtained, for example, from the harvested and dried bark of Taxus brevifolia (Pacific Yew) and Taxomyces Andreanae and Endophytic Fungus of the Pacific Yew (Stierle et al., Science 60:214-16 (1993)). "Paclitaxel" as used herein refers to hydrophobic formulations including paclitaxel, prodrugs, analogues and derivatives such as, for example, TAXOL, TAXOTERE, docetaxel, 10-desacetyl analogues of paclitaxel and 3'N-desbenzoyl-3'N-t-butoxy carbonyl analogues of paclitaxel, may be readily prepared utilizing techniques known to those skilled in the art (see, e.g., Schiff et al., Nature 277:665-67 (1979); Long and Fairchild, Cancer Research 54:4355-61 (1994); Ringel and Horwitz, J. Nat'l Cancer Inst. 83(4):288-91 (1991); Pazdur et al., Cancer Treat. Rev. 79(4):351-86 (1993); WO 94/07882; WO 94/07881 ; WO 94/07880; WO 94/07876; WO 93/23555; WO 93/10076; WO 94/00156; WO 93/24476; EP 590267; WO 94/20089; U.S. Patent Nos. 5,294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; 5,254,580; 5,412,092; 5,395,850; 5,380,751 ; 5,350,866; 4,857,653 5,272,171; 5,411,984; 5,248,796; 5,248,796; 5,422,364; 5,300,638; 5,294,637 5,362,831 ; 5,440,056; 4,814,470; 5,278,324; 5,352,805; 5,411 ,984; 5,059,699 4,942,184; Tetrahedron Letters 35(52): 9709- 12 (1994); J. Med. Chem. 35:4230-37 (1992); J. Med. Chem. 34:992-98 (1991 ); J. Natural Prod.
57(10): 1404-10 (1994); J. Natural Prod. 57(11): 1580-83 (1994); J. Am. Chem. Soc. 110:6558-60 (1988)), or obtained from a variety of commercial sources, including for example, Sigma Chemical Co., St. Louis, Missouri (T7402 - from Taxus brevifolia). Representative examples of paclitaxel derivatives and analogues include 7-deoxy-docetaxol, 7,8-cyclopropataxanes, N-substituted 2-azetidones, 6,7-epoxy paclitaxels, 6,7-modified paclitaxels, 10-desacetoxytaxol, 10- deacetyltaxol (from 10-deacetylbaccatin III), phosphonooxy and carbonate derivatives of taxol, taxol 2',7-di(sodium 1 ,2-benzenedicarboxylate, 10- desacetoxy-11 ,12-dihydrotaxol-10,12(18)-diene derivatives, 10- desacetoxytaxol, Protaxol (2'-and/or 7-O-ester derivatives), (2'-and/or 7-O- carbonate derivatives), fluoro taxols, 9-deoxotaxane, 9-deoxotaxol, 7-deoxy-9- deoxotaxol, 10-desacetoxy-7-deoxy-9-deoxotaxoI, derivatives containing hydrogen or acetyl group and a hydroxy and tert-butoxycarbonylamino, sulfonated 2'-acryloyltaxol and sulfonated 2'-O-acyl acid taxol derivatives, succinyltaxol, 2'-γ-aminobutyryltaxol formate, 2'-acetyl taxol, 7-acetyl taxol, 7- glycine carbamate taxol, 2'-OH-7-PEG(5000) carbamate taxol, 2'-benzoyl and 2',7-dibenzoyl taxol derivatives, other prodrugs (2'-acetyltaxol; 2',7- diacetyltaxol; 2'-succinyltaxol; 2'-(beta-alanyl)-taxol); 2'-gamma- aminobutyryltaxol formate; ethylene glycol derivatives of 2'-succinyltaxol; 2'- glutaryltaxol; 2'-(N,N-dimethylglycyl) taxol; 2'-(2-(N,N- dimethylamino)propionyl)taxol; 2'orthocarboxybenzoyl taxol; 2'aliphatic carboxylic acid derivatives of taxol, Prodrugs {2'(N,N- diethylaminopropionyl)taxol, 2'(N,N-dimethylglycyl)taxol, 7(N,N- dimethyIglycyl)taxol, 2',7-di-(N,N-dimethylglycyl)taxol, 7(N,N- diethylaminopropionyl)taxol, 2',7-di(N,N-diethylaminopropionyl)taxol, 2'-(L- glycyl)taxol, 7-(L-glycyl)taxol, 2',7-di(L-glycyl)taxol, 2'-(L-alanyl)taxol, 7-(L- alanyl)taxol, 2',7-di(L-alanyl)taxol, 2'-(L-leucyl)taxol, 7-(L-Ieucyl)taxol, 2',7-di(L- leucyl)taxol, 2'-(L-isoleucyl)taxol, 7-(L-isoleucyl)taxol, 2',7-di(L-isoleucyl)taxol, 2'-(L-valyl)taxol, 7-(L-valyl)taxol, 2'7-di(L-valyl)taxoI, 2'-(L-phenylalanyl)taxol, 7- (L-phenylalanyl)taxol, 2',7-di(L-phenylalanyl)taxol, 2'-(L-proIyl)taxol, 7-(L- prolyl)taxol, 2',7-di(L-prolyl)taxol, 2'-(L-lysyl)taxol, 7-(L-lysyl)taxol, 2',7-di(L- Iysyl)taxol, 2'-(L-glutamyl)taxol, 7-(L-glutamyl)taxol, 2',7-di(L-glutamyl)taxol, 2'- (L-arginyl)taxol, 7-(L-arginyl)taxol, 2',7-di(L-arginyl)taxol}, Taxol analogues with modified phenylisoserine side chains (N-debenzoyl-N-tert-(butoxycaronyl)-IO- deacetyltaxol, and taxanes (e.g., cephalomannine, brevifoliol, yunantaxusin and taxusin); and other taxane analogues and derivatives, including debenzoyl-2- acyl paclitaxel derivatives, benzoate paclitaxel derivatives, sulfonated 2'- acryloyltaxol; sulfonated 2'-O-acyl acid paclitaxel derivatives, C18-substituted paclitaxel derivatives, chlorinated paclitaxel analogues, C4 methoxy ether paclitaxel derivatives, sulfenamide taxane derivatives, brominated paclitaxel analogues, Girard taxane derivatives, nitrophenyl paclitaxel, C7 taxane derivatives, C10 taxane derivatives, 2-debenzoyl and -2-acyl paclitaxel derivatives, taxane analogues bearing new C2 and C4 functional groups, n-acyl paclitaxel analogues, 10-deacetyl taxol B, and 10-deacetyl taxol, benzoate derivatives of taxol, 2-aroyl-4-acyl paclitaxel analogues, orthro-ester paclitaxel analogues, 1-deoxy paclitaxel and 1-deoxy paclitaxel analogues.
In one aspect, the drug is a taxane having the formula (1):
Figure imgf000022_0001
where the gray-highlighted portions may be substituted and the non-highlighted portion is the taxane core. A side-chain (labeled "A" in the diagram) is desirably present in order for the compound to have good activity as a cell cycle inhibitor. Examples of compounds having this structure include paclitaxel (Merck Index entry 7117), docetaxol (Taxotere, Merck Index entry 3458), and 3'-desphenyl- 3'-(4-ntirophenyl)-N-debenzoyl-N-(t-butoxycarbonyl)-10-deacetyltaxol. In one aspect, suitable taxanes such as paclitaxel and its hydrophobic analogues and derivatives are disclosed in Patent No. 5,440,056 as having the structure (2):
Figure imgf000023_0001
wherein X may be oxygen (paclitaxel), hydrogen (9-deoxy derivatives), thioacyl, or dihydroxyl precursors; Ri is selected from paclitaxel or taxotere side chains or alkanoyl of the formula (3):
Figure imgf000023_0002
wherein R7 is selected from hydrogen, alkyl, phenyl, alkoxy, amino, phenoxy (substituted or unsubstituted); R8 is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, phenyl (substituted or unsubstituted), alpha or beta- naphthyl; and Rg is selected from hydrogen, alkanoyl, substituted alkanoyl, and aminoalkanoyl; where substitutions refer to hydroxyl, sulfhydryl, allalkoxyl, carboxyl, halogen, thioalkoxyl, N,N-dimethylamino, alkylamino, dialkylamino, nitro, and -OSO3H, and/or may refer to groups containing such substitutions; R2 is selected from hydrogen or oxygen-containing groups, such as hydrogen, hydroxyl, alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy; R3 is selected from hydrogen or oxygen-containing groups, such as hydrogen, hydroxyl, alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy, and may further be a silyl containing group or a sulphur containing group; R4 is selected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl; R5 is selected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl; RQ is selected from hydrogen or oxygen-containing groups, such as hydrogen, hydroxyl alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy. In one aspect, the paclitaxel analogues and derivatives useful as a hydrophobic drug according to the present invention are disclosed in PCT International Patent Application No. WO 93/10076. As disclosed in this publication, the analogue or derivative should have a side chain attached to the taxane nucleus at C13, as shown in the structure below (formula 4), in order to confer antitumor activity to the taxane.
Figure imgf000024_0001
PCT International Publication No. WO 93/10076 discloses that the taxane nucleus may be substituted at any position with the exception of the existing methyl groups. The substitutions may include, for example, hydrogen, alkanoyloxy, alkenoyloxy, aryloyloxy. In addition, oxo groups may be attached to carbons labeled 2, 4, 9, 10. As well, an oxetane ring may be attached at carbons 4 and 5. As well, an oxirane ring may be attached to the carbon labeled 4. In one aspect, the taxane-based drug useful in the present invention is disclosed in U.S. Patent 5,440,056, which discloses 9-deoxo taxanes. These are compounds lacking an oxo group at the carbon labeled 9 in the taxane structure shown above (formula C4). The taxane ring may be substituted at the carbons labeled 1 , 7 and 10 (independently) with H, OH, O-R, or O-CO-R where R is an alkyl or an aminoalkyl. As well, it may be substituted at carbons labeled 2 and 4 (independently) with aryol, alkanoyl, aminoalkanoyl or alkyl groups. The side chain of formula (C3) may be substituted at R7 and R8 (independently) with phenyl rings, substituted phenyl rings, linear alkanes/alkenes, and groups containing H, O or N. Rg may be substituted with H, or a substituted or unsubstituted alkanoyl group. In another aspect, the taxane-based drug useful in the present invention is disclosed in U.S. Patent 6,107,332.
The following compounds may also, depending on the R group or ligand, etc., be a hydrophobic and/or high molecular weight, or unstable, or highly hydrophilic drug.
Anthracyclines have the following general structure, where the R groups may be a variety of organic groups:
Figure imgf000025_0001
According to U.S. Patent 5,594,158, suitable R groups are as follows: Ri is CH3 or CH2OH; R is daunosamine or H; R3 and R are independently one of OH, NO2, NH2, F, Cl, Br, I, CN, H or groups derived from these; R5 is hydrogen, hydroxy, or methoxy; and R6-s are all hydrogen. Alternatively, R5 and Re are hydrogen and R7 and Rs are alkyl or halogen, or vice versa. According to U.S. Patent 5,843,903, Ri may be a conjugated peptide. According to U.S. Patent 4,296,105, R5 may be an ether linked alkyl group. According to U.S. Patent 4,215,062, R5 may be OH or an ether linked alkyl group. Ri may also be linked to the anthracycline ring by a group other than C(O), such as an alkyl or branched alkyl group having the C(O) linking moiety at its end, such as -CH2CH(CH2-X)C(O)-Rι, wherein X is H or an alkyl group (see, e.g., U.S. Patent 4,215,062). R2 may alternately be a group linked by the functional group =N-NHC(O)-Y, where Y is a group such as a phenyl or substituted phenyl ring. Alternately R3 may have the following structure:
Figure imgf000026_0001
in which R9 is OH either in or out of the plane of the ring, or is a second sugar moiety such as R3. R10 may be H or form a secondary amine with a group such as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Patent 5,843,903). Alternately, R10 may be derived from an amino acid, having the structure - C(O)CH(NHRιι)(Rι2), in which Rn is H, or forms a C3. membered alkylene with R12. R12 may be H, alkyl, aminoalkyl, amino, hydroxy, mercapto, phenyl, benzyl or methylthio (see U.S. Patent 4,296,105).
Exemplary anthracyclines are Doxorubicin, Daunorubicin, Idarubicin, Epirubicin, Pirarubicin, Zorubicin, and Carubicin. Suitable compounds have the structures:
Figure imgf000026_0002
Figure imgf000027_0001
OH out of ring
Doxorubicin: OCH3 C(O)CH2OH plane
Epirubicin: (4' epimer of OCH3 C(O)CH2OH OH in ring plane doxorubicin)
OH out of ring
Daunorubicin: OCH3 C(O)CH3 plane
OH out of ring
Idarubicin: H C(O)CH3 plane
Pirarubicin: OCH3 C(O)CH2OH
Figure imgf000027_0002
Zorubicin: OCH3 C(CH3)(=N)NHC(O)C6H5 OH
OH out of ring
Carubicin: OH C(O)CH3 plane
Other suitable anthracyciines are Anthramycin, Mitoxantrone, Menogaril, Nogalamycin, Aclacinomycin A, Olivomycin A, Chromomycin A3, and Plicamycin having the structures:
R, R2 R3
Menogaπl H OCH, H
Nogalamycin O-sugar H COOCH3
Figure imgf000027_0003
Figure imgf000027_0005
Olivomycin A COCH(CH3)2 CH, COCH. H
Chromomycin A3 COCHj CH3 COCHj CH:
Plicamycin H H H CH:
Figure imgf000027_0004
Figure imgf000028_0001
Other representative anthracyciines include, FCE 23762 doxorubicin derivative (Quaglia et al, J. Liq. Chromatogr. 17(18):3911-3923, 1994), annamycin (Zou et al, J. Pharm. Sci. 82(11):1151-1154, 1993), ruboxyl (Rapoport ef /., J. Controlled Release 58(2): 153-162, 1999), anthracycline disaccharide doxorubicin analogue (Pratesi et al, Clin. Cancer Res. 4(11):2833-2839, 1998), N-(trifluoroacetyl)doxorubicin and 4'-O-acetyl-N- (trifluoroacetyl)doxorubicin (Berube & Lepage, Synth. Commun. 28(6):1109- 1116, 1998), 2-pyrrolinodoxorubicin (Nagy et al, Proc. Nat'l Acad. Sci. U.S.A. 95(4): 1794-1799, 1998), disaccharide doxorubicin analogues (Arcamone et al, J. Nat'l Cancer I nst. 89(16):1217-1223, 1997), 4-demefhoxy-7-O-[2,6-dideoxy- 4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-hexopyranosyl)- -L-lyxo-hexopyranosyl]- adriamicinone doxorubicin disaccharide analogue (Monteagudo et al, Carbohydr. Res. 300(1):11-16, 1997), 2-pyrrolinodoxorubicin (Nagy et al, Proc. Nat'l Acad. Sci. U. S. A. 94(2):652-656, 1997), morpholinyl doxorubicin analogues (Duran et al, Cancer Chemother. Pharmacol. 38(3):210-216, 1996), enaminomalonyl-β-alanine doxorubicin derivatives (Seitz et al, Tetrahedron Lett. 36(9):1413-16, 1995), cephalosporin doxorubicin derivatives (Vrudhula et al, J. Med. Chem. 38(8): 1380-5, 1995), hydroxyrubicin (Solary et al, Int. J. Cancer 58(1 ):85-94, 1994), methoxymorpholino doxorubicin derivative (Kuhl et al, Cancer Chemother. Pharmacol. 33(1): 10-16, 1993), (6- maleimidocaproyl)hydrazone doxorubicin derivative (Willner et al, Bioconjugate Chem. 4(6):521-7, 1993), N-(5,5-diacetoxypent-1-yl) doxorubicin (Cherif & Farquhar, J. Med. Chem. 35(17):3208-14, 1992), FCE 23762 methoxymorpholinyl doxorubicin derivative (Ripamonti et al, Br. J. Cancer 65(5):703-7, 1992), N-hydroxysuccinimide ester doxorubicin derivatives (Demant et al, Biochim. Biophys. Ada 7778(1):83-90, 1991), polydeoxynucleotide doxorubicin derivatives (Ruggiero et al, Biochim. Biophys. Ada 7 29(3):294-302, 1991), morpholinyl doxorubicin derivatives (EPA 434960), mitoxantrone doxorubicin analogue (Krapcho et al, J. Med. Chem. 34(8):2373-80. 1991), AD198 doxorubicin analogue (Traganos et al., Cancer Res. 57(14):3682-9, 1991), 4-demethoxy-3'-N-trifluoroacetyldoxorubicin (Horton et al, Drug Des. Delivery 6(2): 123-9, 1990), 4'-epidoxorubicin (Drzewoski et al, Pol. J. Pharmacol. Pharm. 40(2): 159-65, 1988; Weenen et al, Eur. J. Cancer Clin. Oncol. 20(7):919-26, 1984), alkylating cyanomorpholino doxorubicin derivative (Scudder et al, J. Nat'l Cancer Inst. 80(16): 1294-8, 1988), deoxydihydroiodooxorubicin (EPA 275966), adriblastin (Kalishevskaya et al, Vestn. Mosk. Univ., 76(Biol. 1):21-7, 1988), 4'-deoxydoxorubicin (Schoelzel et al, Leuk. Res. 70(12): 1455-9, 1986), 4-demethyoxy-4'-o-methyldoxorubicin (Giuliani et al, Proc. Int. Congr. Chemother. 76:285-70-285-77, 1983), 3'- deamino-3'-hydroxydoxorubicin (Horton et al, J. Antibiot. 37(8):853-8, 1984), 4- demethyoxy doxorubicin analogues (Barbieri et al, Drugs Exp. Clin. Res. 70(2):85-90, 1984), N-L-leucyl doxorubicin derivatives (Trouet et al, Anthracyciines (Proc. Int. Symp. Tumor Pharmacother.), 179-81 , 1983), 31- deamino-3'-(4-methoxy-1-piperidinyl) doxorubicin derivatives (U.S. 4,314,054), 3'-deamino-3'-(4-mortholinyl) doxorubicin derivatives (U.S. 4,301 ,277), 4'- deoxydoxorubicin and 4'-o-methyldoxorubicin (Giuliani et al, Int. J. Cancer 27(1):5-13, 1981), aglycone doxorubicin derivatives (Chan & Watson, J. Pharm. Sci. 67(12): 1748-52, 1978), SM 5887 (Pharma Japan 1468:20, 1995), MX-2 (Pharma Japan 1420Α9, 1994), 4'-deoxy-13(S)-dihydro-4'-iododoxorubicin (EP 275966), morpholinyl doxorubicin derivatives (EPA 434960), 3'-deamino-3'-(4- methoxy-1-piperidinyl) doxorubicin derivatives (U.S. 4,314,054), doxorubicin- 14-valerate, morpholinodoxorubicin (U.S. 5,004,606), 3'-deamino-3'-(3"-cyano- 4"-morpholinyl doxorubicin; 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-13- dihydoxorubicin; (3'-deamino-3'-(3"-cyano-4"-morpholinyl) daunorubicin; 3'- deamino-3'-(3"-cyano-4"-morpholinyl)-3-dihydrodaunorubicin; and 3'-deamino- 3'-(4"-morpholinyl-5-iminodoxorubicin and derivatives (U.S. 4,585,859), 3'- deamino-3'-(4-methoxy-1-piperidinyl) doxorubicin derivatives (U.S. 4,314,054) and 3-deamino-3-(4-morpholinyl) doxorubicin derivatives (U.S. 4,301 ,277).
The drug may be a fluoropyrimidine analog, such as 5- fluorouracil, or an analogue or derivative thereof, including Carmofur, Doxifluridine, Emitefur, Tegafur, and Floxuridine. Exemplary compounds have the structures:
Figure imgf000030_0001
Ri R2
5-Fluorouracil H H
Carmofur C(O)NH(CH2)5CH3 H
Doxifluridine Ai H
Floxuridine A2 H
Emitefur CH2OCH2CH3 B
Tegafur C H
Figure imgf000030_0002
Other suitable fluoropyrimidine analogues include 5-FudR (5- fluoro-deoxyuridine), or an analogue or derivative thereof, including 5- iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), Fluorouridine triphosphate (5-FUTP), and Fluorodeoxyuridine monophosphate (5-dFUMP). Exemplary compounds have the structures:
Figure imgf000031_0001
5-Fluoro-2'-deoxyuridine: R = F 5-Bromo-2'-deoxyuridine: R = Br 5-lodo-2'-deoxyuridine: R = I
Other representative examples of fluoropyrimidine analogues include N3-aIkylated analogues of 5-fluorouracil (Kozai et al, J. Chem. Soc, Perkin Trans. 7(19):3145-3146, 1998), 5-fluorouracil derivatives with 1 ,4- oxaheteroepane moieties (Gomez et al, Tetrahedron 54(43): 13295-13312,
1998), 5-fluorouracil and nucleoside analogues (Li, Anti-cancer Res. 7 (1A):21-
27, 1997), cis- and trans-5-fluoro-5,6-dihydro-6-alkoxyuracil (Van der Wilt et al,
Br. J. Cancer 68(4):702-7, 1993), cyclopentane 5-fluorouracil analogues (Hronowski & Szarek, Can. J. Chem. 70(4): 1162-9, 1992), A-OT-fluorouracil (Zhang et al, Zongguo Yiyao Gongye Zazhi 20 \ 1):513-15, 1989), N4- trimethoxybenzoyl-5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine (Miwa et al, Chem. Pharm. Bull. 38(4):998-1003, 1990), 1-hexylcarbamoyl-5- fluorouracil (Hoshi et al, J. Pharmacobio-Dun. 3(9):478-81 , 1980; Maehara et al, Chemotherapy (Basel) 34(6):484-9, 1988), B-3839 (Prajda et al, In Vivo 2(2):151-4, 1988), uracil-1-(2-tetrahydrofuryl)-5-fluorouracil (Anai et al, Oncology 45(3):144-7, 1988), 1-(2'~deoxy-2'-fluoro-β-D-arabinofuranosyl)-5- fluorouracil (Suzuko et al, Mol. Pharmacol. 37(3):301-6, 1987), doxifluridine (Matuura et al, Oyo Ya t/r/ 29(5):803-31 , 1985), 5'-deoxy-5-fluorouridine (Bollag & Hartmann, Eur. J. Cancer 76(4):427-32, 1980), 1-acetyl-3-O-toluyl-5- fluorouracil (Okada, Hiroshima J. Med. Sci. 28(1):49-66, 1979), 5-fluorouracil- m-formylbenzene-sulfonate (JP 55059173), N'-(2-furanidyl)-5-fluorouracil (JP 53149985) and 1-(2-tetrahydrofuryl)-5-fluorouracil (JP 52089680). These compounds are believed to function as therapeutic agents by serving as antimetabolites of pyrimidine.
The drug may be a folic acid antagonist, such as Methotrexate or derivatives or analogues thereof, including Edatrexate, Trimetrexate, Raltitrexed, Piritrexim, Denopterin, Tomudex, and Pteropterin. Methotrexate analogues have the following general structure:
Figure imgf000032_0001
The identity of the R group may be selected from organic groups, particularly those groups set forth in U.S. Patent Nos. 5,166,149 and 5,382,582. For example, Ri may be N, R2 may be N or C(CH3), R3 and R31 may H or alkyl, e.g., CH3, R4 may be a single bond or NR, where R is H or alkyl group. R5,6,8 may be H, OCH3, or alternately they can be halogens or hydro groups. R7 is a side chain of the general structure:
Figure imgf000032_0002
wherein n = 1 for methotrexate, n = 3 for pteropterin. The carboxyl groups in the side chain may be esterified or form a salt such as a Zn2+ salt. Rg and R10 and R11 can be NH2 or may be alkyl substituted, where Rn may also be hydrogen. Exemplary folic acid antagonist compounds have the structures:
Figure imgf000033_0001
Ro Ri R2 R3 R4 R5 Re R7 R8
Methotrexate NH2 N N H N(CH3) H H A (n=1) H
Edatrexate NH2 N N H CH(CH2CH3) H H A (n=1) H
Trimetrexate NH2 CH C(CH3) H NH H OCH3 OCH3 OCH3
Pteropterin OH N N H NH H H A (n=3) H
Denopterin OH N N CH3 N(CH3) H H A (n=1) H
Peritrexim NH2 N C(CH3) H single bond OCH3 H H OCH3
Figure imgf000033_0002
Tomudex Other representative examples include 6-S-aminoacyloxymethyl mercaptopurine derivatives (Harada et al, Chem. Pharm. Bull. 43(10):793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al, Biol. Pharm. Bull 78(11):1492- 7, 1995), 7,8-polymethyleneimidazo-1 ,3,2-diazaphosphorines (Nilov et al, Mendeleev Commun. 2:67, 1995), azathioprine (Chifotides et al, J. Inorg. Biochem. 56(4):249-64, 1994), methyl-D-glucopyranoside mercaptopurine derivatives (Da Silva et al, Eur. J. Med. Chem. 29(2):149-52, 1994) and s- alkynyl mercaptopurine derivatives (Ratsino et al, Khim.-Farm. Zh. 75(8):65-7, 1981); indoline ring and a modified ornithine or glutamic acid-bearing methotrexate derivatives (Matsuoka et al, Chem. Pharm. Bull. 45(7): 1146- 1150, 1997), alkyl-substituted benzene ring C bearing methotrexate derivatives (Matsuoka et al, Chem. Pharm. Bull. 44(12):2287-2293, 1996), benzoxazine or benzothiazine moiety-bearing methotrexate derivatives (Matsuoka et al, J. Med. Chem. 40(1): 105-111 , 1997), 10-deazaaminopterin analogues (DeGraw et al, J. Med. Chem. 40(3):370-376, 1997), 5-deazaaminopterin and 5,10- dideazaaminopterin methotrexate analogues (Piper et; al, J. Med. Chem. 40(3):377-384, 1997), indoline moiety-bearing methotrexate derivatives (Matsuoka et al, Chem. Pharm. Bull. 44(7): 1332-1337, 1996), lipophilic amide methotrexate derivatives (Pignatello et al, World Meet. Pharm., Biopharm. Pharm. Technol., 563-4, 1995), L-threo-(2S,4S)-4-fluoroglutamic acid and DL- 3,3-difluoroglutamic acid-containing methotrexate analogues (Hart et al, J. Med. Chem. 39(1):56-65, 1996), methotrexate tetrahydroquinazoline analogue (Gangjee, et al, J. Heterocycl Chem. 32(1):243-8, 1995), N-(α-aminoacyl) methotrexate derivatives (Cheung et al, Pteridines 3(1-2):101-2, 1992), biotin methotrexate derivatives (Fan et al, Pteridines 3(1-2):131-2, 1992), D-glutamic acid or D-erythrou, threo-4-fluoroglutamic acid methotrexate analogues (McGuire et al, Biochem. Pharmacol 42(12):2400-3, 1991), β,γ-methano methotrexate analogues (Rosowsky et al, Pteridines 2(3): 133-9, 1991), 10- deazaaminopterin (10-EDAM) analogue (Braakhuis et al, Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv., 1027-30, 1989), γ- tetrazole methotrexate analogue (Kalman et al, Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv., 1154-7, 1989), N-(L-α-aminoacyl) methotrexate derivatives (Cheung et al, Heterocycles 28(2):751-8, 1989), meta and ortho isomers of aminopterin (Rosowsky et al, J. Med. Chem. 32(12):2582, 1989), hydroxymethylmethotrexate (DE 267495), γ-fluoromethotrexate (McGuire et al, Cancer Res. 49(16):4517-25, 1989), polyglutamyl methotrexate derivatives (Kumar et al, Cancer Res. 46(10):5020-3, 1986), gem- diphosphonate methotrexate analogues (WO 88/06158), α- and γ-substituted methotrexate analogues (Tsushima et al, Tetrahedron 44(17):5375-87, 1988), 5-methyl-5-deaza methotrexate analogues (4,725,687), Nδ-acyl-Nα-(4-amino-4- deoxypteroyl)-L-omithine derivatives (Rosowsky et al, J. Med. Chem. 37(7): 1332-7, 1988), 8-deaza methotrexate analogues (Kuehl etal, Cancer Res. 48(6):1481-8, 1988), acivicin methotrexate analogue (Rosowsky ef al, J. Med. Chem. 30(8):1463-9, 1987), polymeric platinol methotrexate derivative (Carraher ef a/., Polym. Sci. Technol (Plenum), 35(Adv. Biomed. Polym.):2>'W 24, 1987), methotrexate-γ-dimyristoylphophatidylethanolamine (Kinsky et al, Biochim. Biophys. Ada 977(2):211-18, 1987), methotrexate polyglutamate analogues (Rosowsky et al, Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 985-8, 1986), poly-γ-glutamyl methotrexate derivatives (Kisliuk et al, Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 989-92, 1986), deoxyuridylate methotrexate derivatives (Webber ef al, Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 659-62, 1986), iodoacetyl lysine methotrexate analogue (Delcamp ef al, Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects: 807-9, 1986), 2,.omega.~diaminoalkanoid acid-containing methotrexate analogues (McGuire et al, Biochem. Pharmacol. 35(15):2607-13, 1986), polyglutamate methotrexate derivatives (Kamen & Winick, Methods Enzymol. 722(Vitam. Coenzymes, Pt. G):339-46, 1986), 5-methyl-5-deaza analogues (Piper et al, J. Med. Chem. 29(6): 1080-7, 1986), quinazoline methotrexate analogue (Mastropaolo et al, J. Med. Chem. 29(1):155-8, 1986), pyrazine methotrexate analogue (Lever & Vestal, J. Heterocycl Chem. 22(1):5-6, 1985), cysteic acid and homocysteic acid methotrexate analogues (4,490,529), γ-tert-butyl methotrexate esters (Rosowsky et al, J. Med. Chem. 28(5):660-7, 1985), fluorinated methotrexate analogues (Tsushima et al, Heterocycles 23(1):45-9, 1985), folate methotrexate analogue (Trombe, J. Baderiol 760(3):849-53, 1984), phosphonoglutamic acid analogues (Sturtz & Guillamot, Eur. J. Med. Chem.-Chim. Ther. 79(3):267-73, 1984), poly (L-lysine) methotrexate conjugates (Rosowsky et al, J. Med. Chem. 27(7):888-93, 1984), dilysine and trilysine methotrexate derivates (Forsch & Rosowsky, J. Org. Chem. 49(7): 1305-9, 1984), 7-hydroxymethotrexate (Fabre et al, Cancer Res. 43(10):4648-52, 1983), poly-γ-glutamyl methotrexate analogues (Piper & Montgomery, Adv. Exp. Med. Biol, 163(Folyl Antifolyl Polyglutamates):95^00, 1983), 3',5'-dichloromethotrexate (Rosowsky & Yu, J. Med. Chem. 26(10):1448- 52, 1983), diazoketone and chloromethylketone methotrexate analogues (Gangjee et al, J. Pharm. Sci. 77(6):717-19, 1982), 10-propargylaminopterin and alkyl methotrexate homologs (Piper et al, J. Med. Chem. 25(7):877-80, 1982), lectin derivatives of methotrexate (Lin et al, JNCI 66(3):523-8, 1981), polyglutamate methotrexate derivatives (Galivan, Mol. Pharmacol 77(1): 105- 10, 1980), halogentated methotrexate derivatives (Fox, JNCI 58(4):J955-8, 1977), 8-alkyl-7,8-dihydro analogues (Chaykovsky et al, J. Med. Chem. 20(10):J 1323-7, 1977), 7-methyl methotrexate derivatives and dichloromethotrexate (Rosowsky & Chen, J. Med. Chem. 77(12):J1308-11 , 1974), lipophilic methotrexate derivatives and 3',5'-dichloromethotrexate (Rosowsky, J. Med. Chem. 76(10):J1190-3, 1973), deaza amethopterin analogues (Montgomery et al, Ann. N.Y. Acad. Sci. 786:J227-34, 1971), MX068 (Pharma Japan, 1658:18, 1999) and cysteic acid and homocysteic acid methotrexate analogues (EPA 0142220); These compounds are believed to act as antimetabolites of folic acid.
The drug may be a Podophyllotoxin, or a derivative or an analogue thereof. Exemplary compounds of this type are Etoposide or Teniposide, which have the following structures:
Figure imgf000037_0001
Other representative examples of podophyllotoxins include Cu(II)- VP-16 (etoposide) complex (Tawa et al, Bioorg. Med. Chem. 6(7): 1003-1008, 1998), pyrrolecarboxamidino-bearing etoposide analogues (Ji et al, Bioorg. Med. Chem. Lett. 7(5):607-612, 1997), 4β-amino etoposide analogues (Hu, University of North Carolina Dissertation, 1992), γ-lactone ring-modified arylamino etoposide analogues (Zhou et al, J. Med. Chem. 37(2):287-92, 1994), N-glucosyl etoposide analogue (Allevi et al, Tetrahedron Lett. 34(45):7313-16, 1993), etoposide A-ring analogues (Kadow et al, Bioorg. Med. Chem. Lett. 2(1):17-22, 1992), 4'-deshydroxy-4'-methyl etoposide (Saulnier et al, Bioorg. Med. Chem. Lett. 2(10): 1213-18, 1992), pendulum ring etoposide analogues (Sinha et al, Eur. J. Cancer 26(5): 590-3, 1990) and E-ring desoxy etoposide analogues (Saulnier et al, J. Med. Chem. 32(7): 1418-20, 1989).
These compounds are believed to act as Topoisomerase II Inhibitors and/orDNA cleaving agents.
The drug may be Camptothecin, or an analogue or derivative thereof. Camptothecins have the following general structure.
Figure imgf000037_0002
In this structure, X is typically O, but can be other groups, e.g., NH in the case of 21-lactam derivatives. R-i is typically H or OH, but may be other groups, e.g., a terminally hydroxylated C1-3 alkane. R2 is typically H or an amino containing group such as (CH3)2NHCH2, but may be other groups e.g., NO2, NH2, halogen (as disclosed in, e.g., U.S. Patent 5,552,156) or a short alkane containing these groups. R3 is typically H or a short alkyl such as C2H5. R4 is typically H but may be other groups, e.g., a methylenedioxy group with R-i.
Exemplary camptothecin compounds include topotecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactam-20(S)-camptothecin, 10,11-methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin, 10- hydroxycamptothecin. Exemplary compounds have the structures:
Figure imgf000038_0001
Camptothecin: H H H
Topotecan: OH (CH3)2NHCH2 H
SN-38: OH H α C2,H5
X: O for most analogs, NH for 21-lactam analogs
Camptothecins have the five rings shown here. The ring labeled
E must be intact (the lactone rather than carboxylate form) for maximum activity and minimum toxicity.
Camptothecins are believed to function as Topoisomerase I Inhibitors and/or DNA cleavage agents. The drug may be a hydroxyurea. Hydroxyureas have the following general structure:
Figure imgf000038_0002
Suitable hydroxyureas are disclosed in, for example, U.S. Patent No. 6,080,874, wherein Ri is:
Figure imgf000039_0001
and R2 is an alkyl group having 1-4 carbons and R3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methylether.
Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 5,665,768, wherein Ri is a cycloalkenyl group, for example N-[3-[5-(4- fluorophenylthio)-furyl]-2-cyclopenten-1-yl]N-hydroxyurea; R2 is H or an alkyl group having 1 to 4 carbons and R3 is H; X is H or a cation.
Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 4,299,778, wherein Ri is a phenyl group substituted with one or more fluorine atoms; R2 is a cyclopropyl group; and R3 and X is H.
Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 5,066,658, wherein R2 and R3 together with the adjacent nitrogen form:
Figure imgf000039_0002
wherein m is 1 or 2, n is 0-2 and Y is an alkyl group. In one aspect, the hydroxyurea has the structure:
Figure imgf000039_0003
Hydroxyurea
These compounds are thought to function by inhibiting DNA synthesis.
The drug may be a platinum compound. In general, suitable platinum complexes may be of Pt(ll) or Pt(IV) and have this basic structure:
Figure imgf000040_0001
wherein X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen; Ri and R2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups. For Pt(ll) complexes Zi and Z2 are non-existent. For Pt(IV) Z-i and Z2 may be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See, e.g., U.S. Patent Nos. 4,588,831 and 4,250,189.
Suitable platinum complexes may contain multiple Pt atoms. See, e.g., U.S. Patent Nos. 5,409,915 and 5,380,897. For example bisplatinum and triplatinum complexes of the type:
Figure imgf000040_0002
Exemplary platinum compounds are Cisplatin, Carboplatin, Oxaliplatin, and Miboplatin having the structures:
Figure imgf000041_0001
Cisplatin Carboplatin
Figure imgf000041_0002
Oxaliplatin
Figure imgf000041_0003
Other representative platinum compounds include (CPA)2Pt[DOLYM] and (DACH)Pt[DOLYM] cisplatin (Choi et al, Arch. Pharmacal Res. 22(2):151-156, 1999), Cis-[PtCI2(4,7-H-5-methyl-7- oxo]1,2,4[triazolo[1,5-a]pyrimidine)2] (Navarro et al, J. Med. Chem. 47(3):332- 338, 1998), [Pt(cis-1 ,4-DACH)(trans-CI2)(CBDCA)] .1/2MeOH cisplatin (Shamsuddin et al, Inorg. Chem. 36(25):5969-5971, 1997), 4-pyridoxate diammine hydroxy platinum (Tokunaga et al, Pharm. Sci. 3(7):353-356, 1997), Pt(ll) ... Pt(ll) (Pt2[NHCHN(C(CH2)(CH3))]4) (Navarro et al, Inorg. Chem. 35(26):7829-7835, 1996), 254-S cisplatin analogue (Koga et al, Neurol. Res. 78(3): 244-247, 1996), o-phenylenediamine ligand bearing cisplatin analogues (Koeckerbauer & Bednarski, J. Inorg. Biochem. 62(4):281-298, 1996), trans, • cis-[Pt(OAc)2l2(en)] (Kratochwil et al, J. Med. Chem. 39(13):2499-2507, 1996), estrogenic 1 ,2-diarylethylenediamine ligand (with sulfur-containing amino acids and glutathione) bearing cisplatin analogues (Bednarski, J. Inorg. Biochem. 62(1):75, 1996), cis-1 ,4-diaminocyclohexane cisplatin analogues (Shamsuddin et al, J. Inorg. Biochem. 67(4):291-301 , 1996), 5' orientational isomer of cis- [Pt(NH3)(4-aminoTEMP-O){d(GpG)}] (Dunham & Lippard, J. Am. Chem. Soc. 777(43): 10702-12, 1995), chelating diamine-bearing cisplatin analogues (Koeckerbauer & Bednarski, J. Pharm. Sci. 84(7):819-23, 1995), 1,2- diarylethyleneamine ligand-bearing cisplatin analogues (Otto et al, J. Cancer Res. Clin. Oncol. 727(1):31-8, 1995), (ethylenediamine)platinum(ll) complexes (Pasini et al, J. Chem. Soc, Dalton Trans. 4:579-85, 1995), CI-973 cisplatin analogue (Yang et al, Int. J. Oncol. 5(3):597-602, 1994), cis- diaminedichloroplatinum(ll) and its analogues cis-1 ,1- cyclobutanedicarbosylato(2R)-2-methyl-1 ,4-butanediamineplatinum(ll) and cis- diammine(glycolato)platinum (Claycamp & Zimbrick, J. Inorg. Biochem. 26(4):257-67, 1986; Fan et al, Cancer Res. 48(11):3135-9, 1988; Heiger- Bernays et al, Biochemistry 29(36): 8461-6, 1990; Kikkawa et al, J. Exp. Clin. Cancer Res. 72(4):233-40, 1993; Murray et al, Biochemistry 37(47): 11812-17, 1992; Takahashi et al, Cancer Chemother. Pharmacol. 33(1):31-5, 1993), cis- amine-cyclohexylamine-dichloroplatinum(ll) (Yoshida et al, Biochem. Pharmacol. 48(4):793-9, 1994), gem-diphosphonate cisplatin analogues (FR 2683529), (meso-1 ,2-bis(2,6-dichloro-4-hydroxyplenyl)ethylenediamine) dichloroplatinum(ll) (Bednarski et al, J. Med. Chem. 35(23) :4479-85, 1992), cisplatin analogues containing a tethered dansyl group (Hartwig et al, J. Am. Chem. Soc. 774(21):8292-3, 1992), platinum(ll) polyamines (Siegmann et al, Inorg. Met.-Containing Polym. Mater, (Proc. Am. Chem. Soc. Int. Symp.), 335- 61 , 1990), cis-(3H)dichloro(ethylenediamine)platinum(ll) (Eastman, Anal Biochem. 797(2):311-15, 1991), trans-diamminedichloroplatinum(ll) and cis- (Pt(NH3)2(N3-cytosine)CI) (Bellon & Lippard, Biophys. Chem. 35(2-3): 179-88, 1990), 3H-cis-1 ,2-diaminocyclohexanedichloropIatinum(ll) and 3H-cis-1 ,2- diaminocyclohexanemalonatoplatinum (II) (Oswald et al, Res. Commun. Chem. Pathol. Pharmacol 64(1):41-58, 1989), diaminocarboxylatoplatinum (EPA 296321), trans-(D,1)-1 ,2-diaminocyclohexane carrier ligand-bearing platinum analogues (Wyrick & Chaney, J. Labelled Compd. Radiopharm. 25(4):349-57, 1988), aminoalkylaminoanthraquinone-derived cisplatin analogues (Kitov et al, Eur. J. Med. Chem. 23(4):381-3, 1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogues (Schroyen et al, Eur. J. Cancer Clin. Oncol 24(8): 1309-12, 1988), bidentate tertiary diamine-containing cisplatinum derivatives (Orbell et al, Inorg. Chim. Ada 752(2): 125-34, 1988), platinum(ll), platinum(IV) (Liu & Wang, Shandong Yike Daxue Xuebao 24(1):35-41 , 1986), cis-diammine(1,1-cyclobutanedicarboxylato-)platinum(ll) (carboplatin, JM8) and ethylenediammine-malonatoplatinum(ll) (JM40) (Begg et al, Radiother. Oncol. 9(2):157-65, 1987), JM8 and JM9 cisplatin analogues (Harstrick et al, Int. J. Andro 70(1); 139-45, 1987), (NPr4)2((PtCL4).cis-(PtCI2-(NH2Me)2)) (Brammer et al, J. Chem. Soc, Chem. Commun. 6:443-5, 1987), aliphatic tricarboxylic acid platinum complexes (EPA 185225), and cis-dichloro(amino acid)(tert-butylamine)platinum(ll) complexes (Pasini & Bersanetti, Inorg. Chim. Ada 707(4):259-67, 1985). These compounds are thought to function by binding to DNA, i.e., acting as alkylating agents of DNA.
In certain embodiments, the drug in the composition may have anti-inflammatory activity or analgesic activity. In these embodiments, the drug is selected from a non-steroidal anti-inflammatory agent (including aspirin, ibuprofen, indomethacin, naproxen, prioxicam, diclofenac, tolmetin, fenoclofenac, meclofenamate, mefenamic acid, etodolac, sulindac, carprofen, fenbufen, fenoprofen, flurbiprofen, ketoprofen, oxaprozin, tiaprofenic acid, phenylbutazone diflunisal, salsalte, and salts and analogues thereof); opiates (including codeine, meperidine, methadone, morphine, pentazocine, fentanyl, hydromorphone, oxycodone, oxymorphone,and salts and analogues thereof; steroidal antiinflammatories including hydrocortisone and esters thereof.
In certain embodiments, an antibiotic may be incorporated into a formulation of the present invention. The antibiotic suitable to be incorporated into the inventive composition may act by a number of mechanisms. It may be from the anthelmintics (including mebendazole, niclosamide, piperazine, praziquante, thibendazole and pyrantel pamoate); aminoglycosides (including tobramycin, gentamicin, amikacin and kanamycin); antifungals (including amphotericin B, clotrimazole, fluconazole, ketoconazole, itraconazole, miconazole, nystatin, and griseofulvin); cephalosporins (including cefazolin, cefotaxime, cefoxitin, defuroxime, cefaclor, cefonicid, cefotetan, cefoperazone, ceftriaxone, moxalactam, and ceftazidime, and salts thereof); β-lactams (including aztreonam, and imipenem) chloramphenicol and salts thereof; erythromycins and salts thereof (including roxithromycin, erythromycin, and its esters such as ethylsuccinate, guceptate and stearate); penicillins (including penicillin G, amoxicillin, amdinocillin, ampicillin, carbenicillin, ticarcillin, cloxacillin, nafcillin, penicillin V, and their salts and esters); tetracyclines (including tetracycline, and doxycycline, and salts thereof); clindamycin, polymixin B, vancomycin.ethambuto, isoniazid, rifampin, antivirals (including acyclovir, zidovudine, vidarabine), anti-HIV drugs; quinolones (including ciprofloxacin); sulfonamides; nitrofurantoin; metronidazole; and clofazimine. Antibiotic agents also include active analogues and derivatives of the aforementioned antibiotic agents. In certain embodiments, the drug may be an anti-cancer agent.
Suitable anti-cancer agents may act by any of a number of mechanisms. They may be antimetabolites, antimicrotubule agents, chelating agents, immunosupressants, antibiotics or anti-angiogenic agents. Exemplary anti- cancer agents within the scope of the invention include: alkylating agents such as bis(chloroethyl)amines (including cyclophosphamide, mechlorethamine, chlorambucil, or melphalan), nitrosoureas (including carmustine, estramustine, lomustine or semustine), aziridines (including thiotepa or triethylenemelamine), alkylsulfonates including busulfan, other agents with possible alkylating agent activity (including procarbazine, cisplatin, carboplatin, dacarbazine, or hexamethylmelamine); antimetabolites such as methotrexate, mercaptopurine, thioguanine, 5-fluorouracil, cytarabine, azacitidine; plant alkaloids such as vinca alkaloids (including vincristine, vinorelbine, or vinblastine), bleomycin, dactinomycin, anthracyciines (including daunorubicin or doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin carubicin, anthramycin, mitoxantrone, menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin A3, and plicamycin), etoposide, teniposide, mithramycin, mitomycin; hormonal agents such as androgens (including testosterone, or fluoxymestrone), antiandrogens including flutamide, estrogens (including diethylstilbesterol, estradiol, ethylestradiol, or estrogen), antiestrogens including tamoxifen, progestins (including hydroxyprogesterone, progesterone, medroxyprogesterone, or megestrol acetate), adrenocorticosteroids (including hydrocortisone, or prednisone), gonadotropin-releasing hormones and agonists thereof including leuprolide; cytadrenl other anti-cancer agents (including amscarine, asparaginase, hydroxyurea, mitotane, quniacrine); and antimicrtotubule agents including paclitaxel and docetaxol. Also included are analogues and derivatives of the aforementioned compounds.
Additional anti-cancer agents may be defined as compounds which exhibit therapeutic activity against cancer, as defined using standard tests known in the art, including in vitro cell studies, in vivo and ex vivo animal studies and clinical human studies. Suitable tests are described in texts such as "Anti-cancer Drug Development Guide" (B.A. Teicher ed., Humana Press, 1997 Totowa, NJ).
Other anti-cancer agents include anti-angiogenic agents such as active taxanes as described above, including paclitaxel and docetaxol; angiostatic steroids including squaline; cartilage derived proteins and factors; thrombospondin; matrix metalloproteinases (including collagenases, gelatinases A and B, stromelysins 1 , 2 and 3, martilysin, metalloelastase, MT1- MMP (a progelatenase), MT2-MMP, MT3-MMP, MT4-MMP, Bay 12-9566 (Bayer), AG-3340 (Agouron), CGS27023! (Novartis), Chiroscience compounds D5140, D1927, D2163); phytocemicals (including genistein, daidzein, leuteolin, apigenin, 3 hydroxyflavone, 2',3'-dihydroxyflavone, 3',4'-dihydroxyflavone, or fisetin). Anti-angiogentic agents include active analogues and derivatives of the aforementioned anti-angiogenic agents.
Thus, various exemplary drugs include certain steroids, such as budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone; dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone, and the like; certain peptides, such as cyclosporin cyclic peptide, retinoids, such as all-cis retinoic acid, 13- trans retinoic acid, and other vitamin A and beta carotene derivatives; vitamins D, E, and K and water insoluble precursors and derivatives thereof; prostaglandins and leukotrienes and their activators and inhibitors including prostacyclin (epoprostanol), and prostaglandins; tetrahydrocannabinol; lung surfactant lipids; lipid soluble antioxidants; hydrophobic antibiotics and chemotherapeutic drugs such as amphotericin B and adriamycin and the like. In various aspects of the invention, the formulation contains ingredients such that the drug, e.g., paclitaxel, is soluble in the formulation at a concentration between about 0.05 to about 30 mg drug / ml formulation, more preferably between 0.5 to about 30 mg/ml.
Optionally, the drug is a hydrophobic taxane, where in one embodiment the taxane is paclitaxel or an analogue or derivative thereof. Paclitaxel, whose structure is shown in Figure 1, is a hydrophobic molecule having a molecular weight of 854 g/mol and poor water solubility. A wide range of aqueous solubilities have been reported for paclitaxel, ranging from 0.3 μg/ml to 11 μg/ml (Sharma et al, 1997; Lundberg, 1997). This apparent contradiction is explained by the existence of different solid forms of paclitaxel having varying solubilities. To date, anhydrous crystalline, hydrated and amorphous solid forms of paclitaxel have been identified (Liggins and Burt, 1998).
Solid paclitaxel is stable, having a degradation half-life at 37°C of 137 years (MacEachern-Keith et al, 1997). However, paclitaxel is known to convert to an epimer form by changing the configuration of a hydroxyl group on the C7 position of the structure to form 7-epitaxol (see Figure 1). This conversion is favored in hydrophilic environments, proceeding very slowly in chloroform (MacEachern-Keith et al, 1997). Other degradation products such as Baccatin III and 10-deactyltaxol have been described (Ringel and Horwitz, 1987; Lataste et al, 1984). Preferred compositions of the invention provide for adequate stability to ensure therapeutic effectiveness over the life of the product. As such, degradation by these or other mechanisms are desirably reduced in the formulation relative to rates or extents of degradation provided in the prior art. E. Optional Components
The compositions of the present invention, in addition to containing a difficult-to-deliver drug and a penetration enhancer, may contain one or more optional components, e.g., surfactants, emollients, exeipients, etc., where exemplary optional components are described below.
1. Surfactant
In one aspect, the compositions of the present invention may comprise a surfactant, where the surfactant is optionally a nonionic surfactant as exemplified by the nonionic surfactants disclosed in Table B.
2. Emollient
In another aspect, the compositions of the present invention comprise an emollient, where exemplary emollients are set forth in Table C.
3. Speciality Vehicle
In another aspect, the compositions of the present invention comprise a speciality vehicle, where an exemplary specialty vehicle is set forth in Table D.
4. Humectant
In another aspect, the compositions of the present invention comprise a humectant, where an exemplary humectant is glycerin.
5. Other Agents
In another aspect, the compositions of the present invention comprise additional agents, such as, for example, fragrances, including pharmaceutically acceptable perfumes; exeipients for providing texture (e.g., abrasives or microabrasives); and exeipients for providing a cooling or heating sensation (e.g., camphor). TABLE B GENERAL CHARACTERISTICS OF EXEMPLARY NONIONIC SURFACTANTS
Figure imgf000048_0001
-
Figure imgf000049_0001
--0
Figure imgf000050_0001
4-- CΩ
Figure imgf000051_0001
en o
Figure imgf000052_0001
C I
Figure imgf000053_0001
n
K3
Figure imgf000054_0001
Figure imgf000055_0001
NF- National Fromulary Key to Solubility Data S- Soluble
H-Soluble with haze, hazy, turbid or opalescent in appearance but with no gross separation. D-lnsoluble, self-emulsifying, on standing separates into distinct phases, may be clear, translucent or milky, l-lnsoluble, gross separation into distinct phases which separate rapidly on standing after shaking.
TABLE C GENERAL CHARACTERISTICS OF EXEMPLARY EMOLLIENTS
Figure imgf000056_0001
Figure imgf000057_0001
NF- National Fromulary Key to Solubility Data S- Soluble
H-Soluble with haze, hazy, turbid or opalescent in appearance but with no gross separation. D-lnsoluble, self-emulsifying, on standing separates into distinct phases, may be clear, translucent or milky. I-lnsoluble, gross separation into distinct phases which separate rapidly on standing after shaking.
en en
TABLE D
GENERAL CHARACTERISTICS OF EXEMPLARY SPECIALITY VEHICLE
Solubility Tendencies
Product Common Name or INCI Adopted Color and HLB Approx. Distilled Alcohol Cotton- Mineral Propylene
Chemical Name Form at 25° Viscosity Water (USP) seed Oil Oil Glycol
Composition C at 25° C or Pour Point
ARLASOLVE DMI Dimethyl isosorbide Dimethyl Colorless N/A 6 cps S S s 1 S isosorbide liquid
NF- National Fromulary Key to Solubility Data S- Soluble
H-Soluble with haze, hazy, turbid or opalescent in appearance but with no gross separation. D-Insoluble, self-emulsifying, on standing separates into distinct phases, may be clear, translucent or milky, l-lnsoluble, gross separation into distinct phases which separate rapidly on standing after shaking.
6. Preservatives
For administration to the skin of a human or other mammal, the treatment compositions will often be sterilized or formulated to contain one or more preservatives for incorporation into pharmaceutical, cosmetic or veterinary 5 formulations. These treatment compositions can be sterilized by conventional, well-known sterilization techniques, e.g., boiling or pasteurization when the drug is thermally stable. For drugs that are not thermally stable, then irradiation and/or a preservative may be utilized to provide a sterile composition.
A preservative may be incorporated into a formulation of the
10 present invention in an amount effective for inhibiting the growth of microbes, such as bacteria, yeast and molds. Any conventional preservative against microbial growth can be employed so long as it is pharmaceutically acceptable, is unreactive with the drug(s) contained in the formulation, and is non-irritating or non-sensitizing to human skin. Exemplary preservatives include
15 antimicrobial aromatic alcohols, such as benzyl alcohol, phenoxyethanol, phenethyl alcohol, and the like, and esters of parahydroxybenzoic acid commonly referred to as paraben compounds, such as methyl, ethyl, propyl, and butyl esters of parahydroxybenzoic acid and the like. The amount of preservative is typically not more than about two weight percent, based on the
20 total weight of the formulation. en
7. Colorant
In one aspect, the compositions of the present invention include one or more coloring agents, also referred to as dyestuffs, which will be present in an effective amount to impart observable coloration to the composition. 25 Examples of coloring agents include dyes suitable for food such as those known as F. D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta carotene, annato, carmine, turmeric, paprika, and so forth. 8. pH Adjusters
The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions and as necessary to prepare compositions for convenient administration, such as pH 5 adjusting and buffering agents. Actual methods for preparing pharmaceutically administrable compounds will be known or apparent to those skilled in the art and are described in detail in, for example, Remington's Pharmaceutical Science.
F. Additional Formulation Specifics
10 1. Morphology of Formulation
The therapeutic compositions of the present invention can take a form that is suitable for topical application to a subject. For example, the formulation may be in the form of an aerosol, oil, cream, foam, gel, jelly, lotion, ointment, paste, powder, solution or suspension. Depending on the form
15 desired for the formulation, one or more of the following ingredients may be included in the formulation:
a. Gels
The formulations of the present invention may optionally contain a en
00 gelling agent. The gelling agent imparts gel-like rheology to the formulation. A
20 gelled morphology is particularly useful in a formulation of the present invention intended for topical delivery of a bioactive agent because a gel is easily applied, e.g., smeared or wiped onto a surface.
In one aspect, the formulation of the invention contains both water and a pharmaceutically acceptable water-gelling agent. Exemplary water-
25 gelling agents are carbomers and glyceryl polyacrylates. Carbomers are a series of water-gelling homopolymers of acrylic acid crosslinked with an allyl ether of pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene available in various viscosity grades sold under the trademark designation CARBOPOL by B.F. Goodrich Company, Cleveland, Ohio. Glyceryl polyacrylates are esters of glycerine and polyacrylic acid available in various viscosity grades sold as an aqueous jelly under the trademark designation, 5 HISPAGEL, by Hispano Quimica S. A., Barcelona, Spain. When a gelling agent for water is included in the formulation, a typical formulation will comprise at least about 50 percent by weight water, more preferably at least 75 percent by weight water, based on the total weight of the gel. The amount of gelling agent can vary depending on the degree of gel viscosity desired. A typical 10 concentration of water gelling agent is in the range of about 0.1 to about 2 weight percent, based on the total weight of the gel.
b. Powders
Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch.
15 c. Solutions
Solutions may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.
en
<° 2. Concentration of Drug
20 As mentioned above, in various embodiments of the present invention, the formulation contains drug at a concentration of at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the drug's maximum solubility in the formulation.
The proportion of the bioactive compound in a formulation
25 depends on the type of formulation to be prepared and will generally be within the range of from about 0.001 to about 10% by weight. Generally, for most types of preparations the proportion of drug present in the formulation will be within the range of from about 0.005% to about 1% and preferably about 0.01%o to about 0.5%.
G. Methods for Preparing Formulations
The ingredients of the formulation may be combined in any order 5 and manner that produces a formulation of the desired consistency. The drug should be distributed, e.g., dissolved or dispersed, evenly throughout the formulation. One approach to achieve this goal is to dissolve the drug in one or more of the formulation solvents, and then combine the remaining ingredients with the dissolved drug. Other methods of preparing the formulation are readily 10 apparent to one of ordinary skill in the art.
H. Drug Delivery Systems
1. Packaging
The formulations of the present invention may be packaged in any suitable container that facilitates stable storage and subsequent dispension of 15 the formulation. For example, when the formulation is in the form of a gel, the gel may be packaged in a container from which it may be extruded, such as a squeezable tube, syringe, or the like, directly onto the subject's surface. The package can be initially sealed and be opened at the time of use. If more than o a single dose is present, the package is preferably resealable by a suitable
20 closure means such as a valve, cap or plug.
Another suitable container is a bottle, e.g., a bottle that is fitted with a delivery device, e.g., a pump, particularly a pump that delivers a metered predetermined standardized unit dose. Yet another suitable container is a moisture-impermeable packet containing an intended single unit dose. The 25 packet can be initially sealed, and be opened at the time of use by tearing, cutting, or the like, at a desired or planned location in the packet after which the packet is manually squeezed so that the contents are directly administratable as desired.
Optionally, the formulation will be distributed, either to physicians or to patients, in an administration kit, and the invention provides such an kit. 5 Typically, such kits will include multiple dosage forms of the composition, e.g., multiple packets or a bottle of formulation with a delivery pump. Typically, the composition will be preformulated, however, the invention also provides that one or more components be held in separate contains, with instructions for preparing the final formulation. The kit may optionally contain instructions for 10 using the formulation.
In one embodiment the formulations of the present invention are sterile.
2. Transdermal Patch
Transdermal patches without the therapeutic compositions of the
15 present invention are well known, and these transdermal patches may be combined with a composition in accordance with the invention to provide a medical device of the present invention. Most commonly, transdermal patches are matrix or monolithic-type laminated structures. In a monolithic-type device, a protective release liner is adhered to a monolithic body that functions both as
20 the matrix to hold the therapeutic composition and as the pressure-sensitive
C7> adhesive that adheres the patch to the subject. Exemplary monolithic-type devices (not containing the chemical compositions of the present invention) are disclosed in, e.g., U.S. Patent Nos. 6,316,022;
I. Specifics of Use
25 1. Dosage
The dosage of the drug being delivered by a formulation of the present invention will depend on the condition being treated, the particular compound, and other clinical factors such as weight and condition of the human or animal and the precise manner of topical administration of the compound. It is to be understood that the present invention has application for both human and veterinary use. 5 Pharmaceutical compositions of the present invention provide for topical administration of a difficult-to-deliver drug. Appropriate dosages and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease and the method of administration. In general, an appropriate dosage
10 and treatment regimen provides the drug(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit. A typical dosage will range from 0.001 to 50 mg drug/kg subject's body weight, preferably from 0.1 to 20 mg/kg, on a regimen of single or multiple daily doses. Appropriate dosages may generally be determined using experimental models and/or clinical trials. In general, the
15 use of the minimum dosage that is sufficient to provide the desired effect is preferred.
2. Delivery Methods
Formulations of the present invention may be applied to any external surface of a subject. For example, the formulation may be applied to 20 the subject's skin, so as to provide transdermal drug delivery. The formulation w may be in any form suitable for topical application, including, for example, gel, cream, foam, powder.
The formulation may be applied as a liquid, e.g., in the form of a spray. Spray compositions may be formulated, for example, as aqueous 25 solutions or suspensions or as aerosols delivered from pressurized packs, such as a metered dose pump (e.g., inhaler), with the use of a suitable liquefied propellant. Suitable propellants are known in the art, and include fluorocarbons and hydrogen-containing chlorofluorocarbon, e.g., hydrofluoroalkanes, especially 1 ,1 ,1 ,2-tetrafluoroethane, 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane. Pressurised formulations will generally be retained in a canister (e.g., an aluminium canister) closed with a valve (e.g., a metering valve). Formluations for aerosol topical delivery will generally be either a suspension or a solution. These formulations are readily sprayed onto the subject's skin. 5 The therapeutic compositions may be in association with and/or form part of a device. In each case, when the device is applied or delivered to the subject, the therapeutic composition contacts the subject and the bioactive agent thereby gains entry to the subject. Devices may take a variety of forms, including, e.g., rod-shaped devices, pellets, slabs, particulates, films, molds,
10 threads, or hydrogels. Representative examples of devices include porous matrices such as sponges made of gelatin (e.g., GELFOAM from Amersham Health), cellulose or derivatives thereof (e.g., SEPRAFILM from Genzyme Corporation, Cambridge, MA); and bandages. In certain embodiments of the invention, the device may be a bandage (adhesive or non-adhesive) or a fabric,
15 such as gauze or mesh material. The fabric or bandage may be so designed as to be useful for covering a wound, for example, on the skin, or to be used as a packing into a wound or to be used as an adjunct in a surgical procedure. Gauze (e.g., a woven or non-woven mesh material) may be formed of materials such as cotton, rayon or polyester fibers. The compositions of the invention
20 may be incorporated onto the surface of such a device, or into the porous structure of a gauze or mesh material (e.g., within the interstitial spaces of the
C35 w weave). For example, the composition may be incorporated into the interstitial space of the gauze or mesh by soaking the material in the composition. In certain embodiments of the invention, the composition may comprise a sponge,
25 pledget or porous membrane that may be used topically on a wound surface. Such a device may be fabricated of materials and by methods known to those skilled in the art. Such porous materials may be made of materials such as collagen, gelatin (e.g., GELFOAM), hyaluronic acid and derivatives thereof (e.g., SEPRAMESH or SEPRAFILM from Genzyme Corporation), and cellulose.
30 In certain embodiments the sponge may be a pledget comprising materials such as cotton, cellulose, gelatin, or a fluoropolymer, such as TEFLON. The composition may be incorporated into a pledget, for example, by soaking the pledget in the composition. The composition may be loaded in this manner immediately prior to use, or at an earlier time of manufacture. Within yet other aspects of the invention, the therapeutic compositions may be formed as a film or associated with a film device. Preferably, such films are generally less than 5, 4, 3, 2 or 1 mm thick, more preferably less than 0.75 mm or 0.5 mm thick, and most preferably less than 500 μm. Such films are preferably flexible with a good tensile strength (e.g., greater than 50, preferably greater than 100, and more preferably greater than 150 or 200 N/cm2), good adhesive properties (i.e., readily adheres to moist or wet surfaces), and have controlled permeability.
J. Methods of Topical Application
For purposes of the present invention, topical application shall include mouth washes and gargles. The formulations of the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may advantageously be used. Continuous or prolonged delivery may be achieved by an adhesive reservoir system.
K. Therapeutic Benefits
In one aspect, the present invention provides methods of using topical formulations as described herein to achieve therpeutic benefits. For example, the present invention provides methods for treating skin lesions. In one aspect, a method is provided that includes delivering a taxane (e.g., paclitaxel) through or into the stratum corneum in a therapeutically effective amount to treat the skin lesion, such that the skin lesion is reduced in size or severity, or heals entirely. In another aspect, the present invention provides a method of delivering a drug, e.g., a hydrophobic drug having a molecular weight of at least 700 g/mol, in a therapeutically effective amount through or into the stratum corneum, such that the skin lesion is treated. In a related aspect, the present invention provides a method of delivering a therapeutically effective amount of a hydrophobic drug having a molecular weight of at least 700 g/mol through the stratum corneum, such that a skin lesion is treated. The method may include applying a formulation comprising a hydrophobic drug to the skin in conjunction with at least one organic solvent, where suitable and exemplary organic solvents are described herein.
In the methods of the invention directed to achieving a therapeutic benefit, the skin lesion may be, in various exemplary embodiments, a psoriatic lesion, a cancerous lesion, an infection, or an inflamed skin lesion or a lesion characterized by cell proliferation or differentiation.
The following examples are provided to illustrate the present invention and are not to be construed as a limitation thereon.
EXAMPLES Paclitaxel used for all studies was initially an anhydrous crystalline form, prior to its exposure to solvents.
EXAMPLE 1 THE GEL FORMULATION This example describes the preparation of a gel formulation. This gel formulation is referred to throughout the present specifation as the "Gel Formulation" and serves, in some instances, as a control to measure the performance of other formulations of the present invention. A mixture of 16.4 parts ethoxydiglycol (also knows as diethylene glycol monoethyl ether, and sold as TRANSCUTOL P) and 1.5 parts hydroxyethylcellulose were stirred together at room temperature for about 5 minutes. Sterile water, 30.9 parts, was gradually added and the resulting mixture stirred for about 1 hour to form the so-called "gum phase". Separately, 50 parts of ethoxydiglycol were combined with 0.1 parts methylparaben, 0.05 parts propyl paraben, and 1 part paclitaxel. This mixture was stirred until the paclitaxel fully dissolved, which took about 20 minutes, in order to form the so- called "active phase". The active phase was slowly added, at room temperature with stirring, to the gum phase, and the resulting mixture was stirred for about 5 hours to provide the Gel Formulation.
EXAMPLE2 PACLITAXEL SOLUBILITY STUDIES
Methods The solubility of paclitaxel in various solvent systems was measured in order to predict the degree of solution saturation that would exist in a given formulation, providing a driving force for drug penetration through the skin. Glass vials sealed with polypropylene caps containing pure solvents or solvent mixtures were prepared and solid paclitaxel added. Vials were maintained sealed at 25°C for several hours with occasional mild shaking and then observed visually. To vials in which a clear solution had formed, more paclitaxel was added. Saturation solubility was assumed to have been attained after a solution was observed to be in contact with excess solid drug for a period of 12 hours. For analysis, samples of the saturated solutions were centrifuged to remove particulates, and the supernatant diluted with acetonitrile to a concentration suitable for HPLC analysis. The chromatography was performed using a Cιs column, a mobile phase of 45/55 acetonitrile/water flowing at 1 ml/min and uv detection at 232 nm. The run-time was 15 minutes. Table 1 SOLUBILITY OF PACLITAXEL IN VARIOUS SOLVENTS
Figure imgf000069_0001
Results
Paclitaxel solubility in a number of solvents is summarized in Table 1. Generally, paclitaxel exhibited greater solubility in more hydrophobic solvents. For binary solvent mixtures, the effect of increasing the proportion of e-o one of the solvents is illustrated by the solubility phase diagrams in Figure 5. In all mixtures, as the proportion of the more hydrophobic solvent was increased, the solubility of paclitaxel was observed to increase. In binary mixtures
10 containing water, only a marginal increase in solubility was observed for mixtures with less than 40% of the more hydrophobic component.
Ternary mixtures of ethanol/isopropyl acetate/water were also assessed as solvent systems for paclitaxel. The solubility of paclitaxel in various solvent compositions is expressed in a ternary phase diagram (Figure
15 6). Generally, as the amount of water in the solvent system was decreased, paclitaxel's solubility increased. Figure 7 shows the effect on paclitaxel solubility of adding 0.5 ml NMP to 5 ml of the ternary mixtures. Generally, paclitaxel solubility is increased by the addition of NMP. The effect of adding 0.5 and 1.5 ml of ethoxydiglycol to 5 ml of the ternary mixtures was also assessed. As observed with the addition of NMP, paclitaxel was increasingly soluble in mixtures with the addition of ethoxydiglycol.
Based on the binary and ternary solvent system solubility data, water should be in the range of 30-60% of the solvent mixture in order to allow sufficient paclitaxel solubility to prepare a formulation with a drug loading in the range of 0.01 to 0.5%.
Thus, solvent mixtures containing ethoxydiglycol, NMP, ethanol, isopropyl acetate and water are shown to have a wide range of paclitaxel solubility, depending on the composition. Depending on the mixture composition, a final drug concentration in the formulation to provide adequate driving force could be predicted.
EXAMPLE 3 PACLITAXEL SOLUTION STABILITY STUDIES The potential of degradation for paclitaxel in aqueous environments has been described previously (MacEachern-Keith et al, 1997), although it has not been characterized in detail. However, we have prepared a gel formulation containing water and ethoxydiglycol which demonstrated good stability characteristics (see Example 1 ). Therefore the inclusion of water in a topical formulation may or may not result in chemical degradation of the drug and this risk of chemical instability needs to be assessed. To characterize paclitaxel degradation in solution its behavior in buffer was examined in detail as well as preliminary investigations made into the stability of paclitaxel in solvent mixtures and organic solvents. Methods
Stability in Aqueous Buffer
The stability of paclitaxel in aqueous medium was assessed by dissolving paclitaxel at 1 μg/ml in phosphate buffered saline (0.02 M, pH = 7.4) (PBS) and incubating the solution at 37°C for up to 96 hours. At various intervals, paclitaxel and its degradants were extracted from 10 ml of the aqueous solution into 1 ml of dichloromethane. The extract was dried under nitrogen at 60°C for one hour and reconstituted in 1 ml of 50/50 acetonitrile/water prior to HPLC analysis using the method described above for solubility studies.
Stability in Ethanol
Stability in ethanol was assessed by dissolving paclitaxel in 95% ethanol to a concentration of 500 μg/ml and maintaining aliquots of the solution at 4, 25 and 40°C. At sampling intervals, aliquots of the solution were injected directly and analyzed by HPLC. The chromatography was performed using a Ci8 column, a gradient mobile phase (37% acetonitrile for 40 minutes, increasing to 60% over fifteen minutes thereafter) flowing at 2 ml/min and uv detection at 232 nm. The run-time was 55 minutes.
Stability in Ethoxydiglycol Stability in ethoxydiglycol was assessed by dissolving paclitaxel to make a 500 μg/ml solution. Stability in this solvent was assessed at 100°C. At sampling intervals, 200 μl of the solution was diluted to 1 ml with acetonitrile and analyzed by HPLC using the same method described for studies of stability in ethanol. Stability in Solvent Mixtures
The stability of paclitaxel in various solvent mixtures was characterized by analysis of the data obtained from solubility studies, based on the chromatographic separation of degradants identified in the study of 5 aqueous paclitaxel stability. The conversion of paclitaxel to 7-epitaxol was determined and expressed as a percentage of the concentration of paclitaxel measured in the solution. Other degradants were not characterized in the solvent mixtures.
Results
10 Stability in Aqueous Buffer
The decrease in paclitaxel concentration observed a PBS drug solution over 24 and 96 hours is shown in Figure 8A and B, respectively. Log- linear plots demonstrate that the degradation occurs as a first order process, with three major mechanisms of degradation. Other mechanisms of
15 degradation made minor contributions to the appearance of other degradation products, however these remain uncharacterized at this time.
The degradation rate constant describing loss of paclitaxel by all mechanisms of degradation was 0.025 h"1. Degradation was further characterized in terms of three major mechanisms. The most rapid was
-v|
° 20 conversion of paclitaxel to 7-epitaxol as the hydroxyl at C7 (Figure 1) is flipped between the β and α configurations (k = 0.016 h"1). The next most rapid mechanism of degradation (k = 0.0028 h"1) was cleavage of the ester bond linking the side chain attached paclitaxel's ring structure at the C13 position (Figure 1). The slowest mechanism of degradation observed over 96 hours 25 was loss of the acetyl group at the C-ι0 position (k = 0.00037 h"1). Stability in Organic Solvents
Paclitaxel is stable in ethanol; over the course of a 100 day stability study at temperatures between 4 to 40°C, there was no observed decrease in paclitaxel concentration. For solvent mixtures containing ethanol, preliminary data are available from observations made during solubility studies. Over the course of the solubility studies of paclitaxel in ternary solvent mixtures it was observed that paclitaxel was being converted, to a significant extent, to 7-epitaxol in a period of less than 24 hours. In Figure 6, region C shows solvent compositions for which 5-15% of the paclitaxel was converted to 7-epitaxol during the solubility study. Mixtures containing only water and ethanol showed the highest levels of 7-epitaxol. As the level of isopropyl acetate was increased the conversion was greatly reduced.
Exposure of paclitaxel to approximately 65% ethoxydiglycol in water in the Gel formulation (see Example 1) does not result in paclitaxel degradation at 25°C over nine months. However, an accelerated stability study of paclitaxel in 100% ethoxydiglycol at 100°C (data not shown) showed very rapid degradation, with 15% of the drug being converted to 7-epitaxol and other unidentified degradants in 48 hours. Degradation in ethoxydiglycol solution followed first-order kinetics having a rate constant k = 0.0021 h"1 and a half-life of 14 days. Thus, while stability in the Gel Formulation containing ethoxydiglycol is good, accelerated stability testing in 100% ethoxydiglycol showed rapid degradation.
EXAMPLE 4 SOLVENT MISCIBILITY STUDIES
Methods
The miscibility of various solvent systems was assessed in order to select solvent compositions which could be tested as penetration enhancing solvent mixtures as well as being formulated into an o/w cream when the solvent mixture included an aqueous phase. Mixtures containing ethanol, isopropyl acetate, water, 1-methyl-2-pyrrolidinone (NMP), and ethoxydiglycol (TRANSCUTOL solvent) and glycerin were studied for solvent miscibility.
To assess solvent miscibility, ternary mixtures were prepared by 5 combining various proportions of each component on a %v/v basis. Each mixture was shaken and gas bubbles allowed to diffuse to the air-liquid interface. The mixtures were then observed visually to determine whether there were one or two liquid phases present. Miscibility studies were conducted using mixtures having proportions changed in increments of 10%. 10 The effect of adding a fourth component to ternary mixtures was assessed as follows. To 5 ml of ternary mixtures displaying solvent immiscibility, another solvent, either NMP or ethoxydiglycol was added in 0.5 ml aliquots until to mixture formed a single phase.
Results
15 The miscibility of ternary mixtures containing ethanol, isopropyl acetate and water is described by the phase diagram in Figure 2. The vertices of intersecting lines illustrating 10% increments in solvent composition represent solvent compositions tested in all miscibility studies. Generally, ethanol/isopropyl acetate/water mixtures containing lower proportions of
20 ethanol were not miscible. Binary mixtures of water and isopropyl acetate werex0 immiscible at all compositions studied. The miscibility of these solvents was altered by the addition of a fourth component, either ethoxydiglycol or NMP (see Figures 3 and 4, respectively). Both NMP and ethoxydiglycol had the effect of enhancing the miscibility of the solvent mixtures in a concentration
25 dependent manner. However, ethoxydiglycol was most effective, forming miscible mixtures at all ternary compositions, with the addition of 8 ml (Figure 3) whereas not all compositions could be made miscible with the addition of 10 ml of NMP (Figure 4). The miscibility of glycerin in the solvent mixtures was also assessed. Figure 2 illustrates that for nearly all compositions except those with greater than 70% isopropyl acetate, glycerin could be incorporated at a level exceeding 10%. For all further studies, glycerin was incorporated at 5%, a concentration that would approximate the amount added to achieve humectant properties.
In solvent mixtures containing ethanol, isopropyl acetate and water, mixtures containing greater than 10% water and less than 30% ethanol were immiscible. A practical limit of 10% NMP was utilized based on anecdotal evidence of solvent induced irritancy at higher levels. Therefore, for further studies of solvent mixtures (solubility and skin penetration studies), not more than 10% NMP was incorporated into the mixtures.
EXAMPLE 5 SKIN PENETRATION STUDIES
Methods
The rate of diffusion of paclitaxel through split thickness human skin was assessed as follows. Human skin was acquired from the abdomen of healthy subjects and the subcutaneous fat removed. The subjects included one 72 year old male and nine females ranging in age from 28 to 57. Among the subjects were one East Indian and nine Caucasians. The stratum corneum of the skin was removed by heat separation at 60°C, blotted dry and stored between two sheets of REXAM polyethylene terephthalate, at -70°C. At the time of analysis, skin samples were cut into 2 cm squares using a scalpel blade and transferred from the REXAM liner onto a Franz cell. The reservoir of the Franz cell was then filled with 10 ml of PBS previously heated to 40°C.
For infinite dosing studies, 300 μl of a 1% drug solution was added to the donor cell of the Franz cell. The penetration cells were then maintained at 32°C with stirring in the donor cell. At various sampling intervals, the donor cell fluid was removed and replaced with fresh PBS. The donor cell fluid was then extracted with dichloromethane and analyzed by HPLC as described for the aqueous solubility study experiments. The only modification was a 30 minute HPLC run-time for penetration study samples. Solvents were tested with replicates of n = 3 or 4.
Skin penetration rates for paclitaxel in various solvent mixtures were compared to the rate of penetration of paclitaxel from 50 mg of the Gel Formulation (see Example 1 , the gel contains 1% paclitaxel but in this instance does not contain preservatives). In each of the skin penetration studies, the Gel Formulation was included as a control.
Results
Figure 9 shows profiles of paclitaxel diffusion through separated human stratum corneum from an infinite dose of various saturated solutions. No paclitaxel levels were measured for drug residing in the skin sample. The amounts of paclitaxel plotted represent the cumulative amount of paclitaxel recovered from the receptor fluid in Franz cells used for paclitaxel penetration studies. Rates calculated from these profiles are summarized in Table 2. NMP allowed the most rapid penetration of paclitaxel through the stratum corneum, approximately an order of magnitude greater than for solutions of ethoxydiglycol, isopropyl acetate, isopropyl myristate, propylene glycol and polyethylene glycol.
Table 2
RATES OF PACLITAXEL PENETRATION THROUGH STRATUM CORNEUM DELIVERED IN
INFINITE DOSES FROM SATURATED SOLUTIONS OF VARIOUS PENETRATION ENHANCERS.
Figure imgf000077_0001
5 From these data, NMP, ethanol and isopropyl acetate were identified as having good potential to enhance paclitaxel penetration through the skin. Based on the low rates of penetration of paclitaxel from isopropyl myristate, PEG 200 and 1 ,2-propanediol, these solvents were not studied any further. The solvents identified as having good potential were studied further in
10 solvent mixtures, along with ethoxydiglycol, the enhancer previously selected for incorporation into the Gel Formulation (see Example 1).
To the solvent mixtures was added 5% glycerin which could be
- i en included in a formulation as a humectant. Figures 10 and 11 summarize the effect on paclitaxel diffusion through skin of using various solvent systems as
15 delivery vehicles. For these experiments all donor solutions contained 1 % drug, equivalent to the concentration in the Gel Formulation (see Example 1) used as a control. Interestingly, a mixture of equal volumes of NMP and ethoxydiglycol (Figure 10, open triangles) showed paclitaxel penetration similar to that of 100%) ethoxydiglycol, which is much slower than was observed for
20 100% NMP. From the skin penetration data obtained from solvent mixtures two generalities became apparent. 1) As the proportion of ethoxydiglycol in the solvent mixture was decreased from 65 to 35% the penetration rate relative to that of the 1% Gel Formulation was increased. (The Gel Formulation contains approximately 65% ethoxydiglycol; see Example 1). 2) The inclusion of isopropyl acetate into solvent mixtures was associated with increased paclitaxel penetration relative to the Gel Formulation. From these studies, the effects of NMP and ethanol are inconclusive. NMP may have a synergistic effect with isopropyl acetate in terms of paclitaxel penetration through stratum corneum. However, in solvent combinations, the overwhelming effect observed with the pure solvent may be greatly diminished. As well, ethanol, which demonstrated a great effect on paclitaxel penetration as a single solvent was not associated with increased penetration rates in the two solvent mixtures containing ethanol that were tested. In summary, various solvent mixtures containing isopropyl acetate, NMP, ethoxydiglycol, water and glycerin demonstrated greater paclitaxel penetration than the Gel Formulation of Example 1.
EXAMPLE 6 PREPARATION & EVALUATIONS OF PACLITAXEL EMULSIONS
Methods
Emulsions containing solvent mixtures of ethanol, isopropyl acetate, water, NMP and ethoxydiglycol in the aqueous phase, and mineral oil, glycerin, stearyl alcohol and beeswax in the oil phase were prepared. The emulsions were stabilized with polyoxyethylene stearyl ethers (BRIJ 72 and 721 surfactants). Emulsions were prepared as follows. The aqueous and oil phases were prepared separately by combining the aqueous phase components with BRIJ 72 surfactant and the oil phase components with BRIJ 721 surfactant. Both phases were heated to 70°C for approximately 5 minutes to produce clear liquids. The aqueous phase was slowly added to the oil phase with gentle shaking to mix the components. The emulsion was then shaken for 15 minutes over which it cooled to room temperature.
Emulsions were characterized by visual and microscopic observation for evidence of emulsion stability. Oil droplet size within the emulsions was measured using a microscope equipped with a stage micrometer.
Results
The feasibility of incorporating the selected penetration enhancers into a cream was assessed. Ten emulsion formulations were prepared with varying amount of each of the components. Their compositions, visual and microscopic size data are summarized in Table 3. The solvents were all successfully incorporated into emulsions. In the oil phase, stearyl alcohol and beeswax were incorporated to act as thickeners, and glycerin was added to act as a humectant. Of the ten formulations, only Formulation 6 produced a visually unstable emulsion, with separation of the components observed immediately upon cooling to room temperature. Microscopic evaluation of the emulsions revealed that most compositions yielded oil phases whose droplet sizes were narrowly distributed with the exception of Formulation 3 which had droplets greater than 10 μm in diameter. A typical microscopic view of the emulsions (Formulation 5) is shown in Figure 12. All compositions other than Formulations 3 and 6 had similar features to the one shown in Figure 12.
Table 3
COMPOSITIONS AND PROPERTIES OF EMULSIONS MADE FROM SOLVENT MIXTURES
AS THE AQUEOUS PHASE AND MINERAL OIL AS THE OIL PHASE.
Component Proportion (%w/w) of Components in Each Formulation (1-10)
2 3 4 5 6 7 8 9 10
(a) Aqueous Phase Components
Ethanol 8
Isopropyl Acetate 9 10
Water 45 39 31 31 21 23 40 43 30 29
Ethoxydiglycol 44 39 30 41 31 35 39 42 39 39
NMP 10 10
Brij 72 (polyoxy-ethylene 2 stearyl ether) 1 1 1 1 1 1 1 1 1 1 ) Oil Phase Components
Mineral Oil 8 8 26 17 36 29 8 6 17 8
Glycerin 6 6 6
Stearyl Alcohol 5 5 2 5 2 5
Beeswax 8 2
Brij 721 (poly-oxyethylene 21 stearyl ether) 1 1 1 1 1 1 1 1 1 1
(c) Emulsion Characteristics
Visually stable Yes Yes Yes Yes Yes No Yes Yes Yes Yes
Microscopic appearance of oil phase
Shape of oil droplets Round Round Irregular Round Round AggreIrregular Irregular Round Round gates
Droplet size distribution Narrow Narrow Broad Narrow Narrow Skewed Narrow Narrow Narrow Narrow
Mode of oil drop-let size range (μm) 2 1 3 1 1 3 1 1 1 2
Maximum oil droplet size (μm) 10 10 15 5 6 80 5 10 9 5
In summary, a number of emulsion systems were prepared, confirming that the solvents identified in the skin penetration studies may be incorporated into an o/w cream.
All of the above U.S. patents, U.S. patent application publications,
U.S. patent applications, foreign patents, foreign patent applications and non- patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety. From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

1. A topical formulation for drug delivery, the formulation comprising an organic solvent and a drug, the drug having a maximum solubility in the formulation, wherein the drug is present in the formulation at a concentration of at least 50% of the drug's maximum solubility.
2. The formulation of claim 1 wherein the organic solvent is selected from ethanol, N-methly-pyrrolidone, glycerin, or isopropyl acetate.
3. The formulation of claim 1 or 2 wherein the drug is hydrophobic.
4. The formulation of any one of claims 1 -3 wherein the drug has a molecular weight in excess of 700 g/mol.
5. The formulation of claim 1 or 2 wherein the drug is a salt or is ionized at pH 7.
6. A topical formulation for treatment of a skin lesion, the formulation comprising a taxane and an organic solvent, wherein the formulation delivers a therapeutically effective dose of the taxane to the lesion through the stratum corneum.
7. The formulation of claim 6 wherein the organic solvent is selected from ethanol, N-methly-pyrrolidone, glycerin, or isopropyl acetate.
8. A topical formulation for drug delivery, the formulation comprising a drug and a cyclic amide of a formula N-(R1)-pyrroIidone where R1 is Ci-Cβ alkyl.
9. The formulation of claim 8 wherein R1 is methyl.
10. A topical formulation for drug delivery, the formulation comprising a drug and an alcohol of a formula R1-OH wherein R1 is Ci-Cβalkyl.
11. The formulation of claim 10 wherein R1 is ethyl.
12. A topical formulation for drug delivery, the formulation comprising a drug and ester of a formula R1-O-C(=O)-CH3 wherein R1 is Cι-C6 alkyl.
13. The formulation of claim 12 wherein R1 is iso-propyl.
14. A topical formulation for drug delivery, the formulation comprising a drug and an alkoxy alcohol of a formula R1-O-R2-OH where R1 is CrC-6 alkyl and R2 is C2-C6 alkylene.
15. The formulation of claim 14 wherein R1 is ethyl and R2 is ethylene.
16. A topical formulation for drug delivery, the formulation comprising a hydrophobic drug and a polyol of a formula (R3)-(OH)n wherein R3 is an n-valent C2-C6 hydrocarbyl group.
17. The topical formulation of claim 16 wherein the polyol is glycerin.
18. The topical formulation of any one of claims 8-17 wherein the drug is hydrophobic.
19. The formulation of any one of claims 8-17 wherein the drug has a molecular weight in excess of 700 g/mol.
20. The formulation of any one of claims 8-17 wherein the drug is in a salt form or is ionized at pH 7.
21. The formulation of any one of claims 1-20 comprising at least two organic solvents.
22. The formulation of claim 21 wherein the at least two organic solvents form a single phase.
23. The formulation of claim 21 comprising at least three organic solvents.
24. The formulation of claim 23 wherein the at least three organic solvents form a single phase.
25. The formulation of any one of claims 1-24 further comprising water.
26. The formulation of claim 25 wherein the formulation is in an emulsion or microemulsion form.
27. The formulation of any one of claims 1-24 further comprising a surfactant.
28. The formulation of any one of claims 1-24 further comprising a hydrocarbon oil.
29. The formulation of any one of claims 1-28 wherein the drug has a molecular weight between 700 and 2,000 g/mol.
30. The formulation of any one of claims 1-5 and 8-29 wherein the drug is a taxane.
31. The formulation of claim 6 or 30 wherein the taxane is paclitaxel or an analogue or derivative thereof.
32. The formulation of claim 31 wherein the paclitaxel is present at a concentration of between about 0.05 mg/ml to about 30 mg/ml.
33. The formulation of claim 31 wherein the paclitaxel is soluble in the formulation at a concentration of between about 0.05 mg/ml to about 30 mg/ml.
34. The formulation of claim 6 or 30 wherein the taxane is present in the formulation at a concentration of between about 0.5 to about 30 mg/ml.
35. The formulation of any one of claims 1-5 and 8-29 wherein the drug is an anthracycline.
36. The formulation of any one of claims 1-5 and 8-29 wherein the drug is a podophyllotoxin.
37. The formulation of any one of claims 1-5 and 8-29 wherein the drug is a fluoropyrimidine analogue.
38. The formulation of any one of claims 1-5 and 8-29 wherein the drug is camptothecin.
39. The formulation of any one of claim 1 to 38 wherein the formulation is in the form of a cream, gel, or powder.
40. The formulation of any one of claims 1 to 38 wherein the formulation is in the form of a solution, suspension, or emulsion.
41. The formulation of any one of claims 1 to 38 further comprising a device, wherein the device is a pledget, gauze, mesh, or bandage.
42. The formulation of any one of claims 1-5 or 8-29 wherein the drug is selected from the group consisting of anti-inflammatory agents, antibiotics, anti-cancer agents, and anti-proliferative agents.
43. A method of delivering a therapeutically effective amount of a taxane to a skin lesion through the stratum corneum such that the skin lesion is treated, comprising applying a formulation to the stratum corneum, the formulation comprising an organic solvent and a drug, the drug having a maximum solubility in the formulation, wherein the drug is present in the formulation at a concentration of at least 50% of the drug's maximum solubility.
44. A method of treating a skin lesion in a subject, comprising delivering a therapeutically effective amount of a formulation, the formulation comprising an organic solvent and a drug, the drug having a maximum solubility in the formulation, wherein the drug is present in the formulation at a concentration of at least 50% of the drug's maximum solubility, to a skin lesion through the stratum corneum of the subject, such that the skin lesion is treated.
45. The method of claim 43 or 44 wherein the drug has a molecular weight of at least 700 g/mol.
46. The method of claim 43 or 44 wherein the drug is hydrophobic.
47. A method of delivering a therapeutically effective amount of a hydrophobic drug having a molecular weight of at least 700 g/mol to a skin lesion through the stratum corneum, such that the skin lesion is treated, comprising applying a formulation, the formulation comprising an organic solvent and a drug, the drug having a maximum solubility in the formulation, wherein the drug is present in the formulation at a concentration of at least 50% of the drug's maximum solubility, to the skin.
48. The method of claim 43, 44, or 47 wherein the drug is a taxane.
49. The method of claim claim 43, 44, or 47 wherein the taxane is paclitaxel or an analogue or derivative thereof.
50. The method of claim claim 43, 44, or 47 wherein the skin lesion is a psoriatic lesion.
51. The method of claim claim 43, 44, or 47 wherein the skin lesion is a cancerous lesion.
52. The method of claim claim 43, 44, or 47 wherein the skin lesion is characterized by inflammation.
53. The method of claim claim 43, 44, or 47 wherein the skin lesion is characterized by cell proliferation.
54. The method of claim claim 43, 44, or 47 wherein the skin lesion is an infection.
55. The method of claim claim 43, 44, or 47 wherein the drug formulation delivers at least 0.001 mg to 50 mg per kg of a subject's body weight per day.
56. The method of claim claim 43, 44, or 47 wherein the drug formulation delivers at least 0.1 mg to 20 mg per kg of a subject's body weight per day.
57. The method of claim claim 43, 44, or 47 wherein the skin lesion is in an epidermal or in a dermal layer of the skin.
58. The method of claim claim 43, 44, or 47 wherein the skin lesion is in a subcutaneous layer of the skin.
PCT/CA2004/001049 2003-07-17 2004-07-19 Topical formulations with bioactive components WO2005007129A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US48870303P 2003-07-17 2003-07-17
US60/488,703 2003-07-17

Publications (2)

Publication Number Publication Date
WO2005007129A2 true WO2005007129A2 (en) 2005-01-27
WO2005007129A3 WO2005007129A3 (en) 2005-08-04

Family

ID=34079449

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2004/001049 WO2005007129A2 (en) 2003-07-17 2004-07-19 Topical formulations with bioactive components

Country Status (1)

Country Link
WO (1) WO2005007129A2 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110065803A1 (en) * 2005-03-14 2011-03-17 Yaupon Therapeutics, Inc. Stabilized compositions of volatile alkylating agents and methods of using thereof
US8501818B2 (en) 2005-03-14 2013-08-06 Ceptaris Therapeutics, Inc. Stabilized compositions of alkylating agents and methods of using same
US8501817B2 (en) 2005-03-14 2013-08-06 Ceptaris Therapeutics, Inc. Stabilized compositions of alkylating agents and methods of using same
JP2013241363A (en) * 2012-05-21 2013-12-05 Lion Corp Oil-in-water type emulsified composition
US9592188B2 (en) 2014-05-22 2017-03-14 Yansong Liu Method of treating or reducing the severity of dermatological conditions
US9775908B2 (en) 2007-07-10 2017-10-03 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Pharmaceutical preparations containing highly volatile silicones
US10045935B2 (en) 2012-07-31 2018-08-14 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
US20210038729A1 (en) * 2019-07-22 2021-02-11 Oneskin, Inc. Polypeptides having anti-senescent effects and uses thereof
US11154535B2 (en) 2012-07-31 2021-10-26 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
WO2022074649A1 (en) * 2020-10-05 2022-04-14 Ichilov Tech Ltd. Treatment of skin diseases

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5627187A (en) * 1995-04-12 1997-05-06 Katz; Bruce E. 5-FU for treating actinic kerotoses
WO1998024427A2 (en) * 1996-12-02 1998-06-11 Angiotech Pharmaceuticals, Inc. Compositions and methods for treating or preventing inflammatory diseases
WO2000040238A1 (en) * 1999-01-08 2000-07-13 Bionumerik Pharmaceuticals, Inc. Pharmaceutical formulations of taxanes
WO2001036007A2 (en) * 1999-11-12 2001-05-25 Angiotech Pharmaceuticals, Inc. Compositions of a combination of radioactive therapy and cell-cycle inhibitors
WO2003045357A1 (en) * 2001-11-27 2003-06-05 Transform Pharmaceuticals, Inc. Oral pharmaceutical formulations comprising paclitaxel, derivatives and methods of administration thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5627187A (en) * 1995-04-12 1997-05-06 Katz; Bruce E. 5-FU for treating actinic kerotoses
WO1998024427A2 (en) * 1996-12-02 1998-06-11 Angiotech Pharmaceuticals, Inc. Compositions and methods for treating or preventing inflammatory diseases
WO2000040238A1 (en) * 1999-01-08 2000-07-13 Bionumerik Pharmaceuticals, Inc. Pharmaceutical formulations of taxanes
WO2001036007A2 (en) * 1999-11-12 2001-05-25 Angiotech Pharmaceuticals, Inc. Compositions of a combination of radioactive therapy and cell-cycle inhibitors
WO2003045357A1 (en) * 2001-11-27 2003-06-05 Transform Pharmaceuticals, Inc. Oral pharmaceutical formulations comprising paclitaxel, derivatives and methods of administration thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SASAKI H ET AL: "ENHANCING EFFECT OF PYRROLIDONE DERIVATIVES ON TRANSDERMAL PENETRATION OF 5-FLUOROURACIL, TRIAMCINOLONE ACETONIDE, INDOMETHACIN, AND FLURBIPROFEN" JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN PHARMACEUTICAL ASSOCIATION. WASHINGTON, US, vol. 80, no. 6, June 1991 (1991-06), pages 533-538, XP009020814 ISSN: 0022-3549 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8664278B2 (en) 2005-03-14 2014-03-04 Actelion Pharmaceuticals, Ltd. Stabilized compositions of volatile alkylating agents and methods of using thereof
US20110065803A1 (en) * 2005-03-14 2011-03-17 Yaupon Therapeutics, Inc. Stabilized compositions of volatile alkylating agents and methods of using thereof
US8501818B2 (en) 2005-03-14 2013-08-06 Ceptaris Therapeutics, Inc. Stabilized compositions of alkylating agents and methods of using same
US8501819B2 (en) 2005-03-14 2013-08-06 Ceptaris Therapeutics, Inc. Stabilized compositions of volatile alkylating agents and methods of using thereof
US8501817B2 (en) 2005-03-14 2013-08-06 Ceptaris Therapeutics, Inc. Stabilized compositions of alkylating agents and methods of using same
US9382191B2 (en) 2005-03-14 2016-07-05 Actelion Pharmaceuticals, Ltd. Stabilized compositions of volatile alkylating agents and methods of using thereof
US8450375B2 (en) 2005-03-14 2013-05-28 Ceptaris Therapeutics, Inc. Stabilized compositions of volatile alkylating agents and methods of using thereof
US9775908B2 (en) 2007-07-10 2017-10-03 Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag Pharmaceutical preparations containing highly volatile silicones
JP2013241363A (en) * 2012-05-21 2013-12-05 Lion Corp Oil-in-water type emulsified composition
US10045935B2 (en) 2012-07-31 2018-08-14 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
US11154535B2 (en) 2012-07-31 2021-10-26 Egis Pharmaceuticals Plc Transdermal formulation containing COX inhibitors
US9592188B2 (en) 2014-05-22 2017-03-14 Yansong Liu Method of treating or reducing the severity of dermatological conditions
US20210038729A1 (en) * 2019-07-22 2021-02-11 Oneskin, Inc. Polypeptides having anti-senescent effects and uses thereof
WO2022074649A1 (en) * 2020-10-05 2022-04-14 Ichilov Tech Ltd. Treatment of skin diseases

Also Published As

Publication number Publication date
WO2005007129A3 (en) 2005-08-04

Similar Documents

Publication Publication Date Title
US20080146652A1 (en) Micellar drug delivery vehicles and precursors thereto and uses thereof
EP2437596B1 (en) Skin treatment compositions
JP5612578B2 (en) Lipid formulations containing thiolated antioxidants
US20090192214A1 (en) Drug delivery from rapid gelling polymer composition
RU2341296C2 (en) Compositions and methods of medical implant covering
ES2343208T3 (en) GEL FOR WOUND TREATMENT.
US20040219214A1 (en) Tissue reactive compounds and compositions and uses thereof
ES2608850T3 (en) Thermogelling anesthetic compositions
WO2005007129A2 (en) Topical formulations with bioactive components
KR20050025136A (en) Surgical patches with a biological active agent
CA2586927A1 (en) Antimicrobial needle coating for extended infusion
WO2001036007A2 (en) Compositions of a combination of radioactive therapy and cell-cycle inhibitors
CA2520775A1 (en) Non-aqueous single phase vehicles and formulations utilizing such vehicles
EP2077106A1 (en) W/o/w emulsion composition
EP2520279A1 (en) Thermoreversible gel pharamaceutical compositions for odontoiatric use
CN104582688A (en) Compositions and uses of antimicrobial materials with tissue-compatible properties
EA022847B1 (en) Disinfectant and antiseptic formulation having reduced iodine content
WO2006091719A3 (en) Compositions and methods enhancing transdermal delivery of drugs and biologics
KR102646865B1 (en) Precipitation-resistant small molecule drug formulation
RU2519723C1 (en) Composition for preparing dosage form having prolonged action
EP3542862A1 (en) Production method of pregabalin-containing composition and pregabalin-containing composition
ES2456115T3 (en) Pressurized propellant composition substantially free of water
US20200164078A1 (en) Applicable chemical composition comprising an agent conjugated to a hydrophobic moiety and a carrier
WO2023227517A1 (en) Formulation of api&#39;s and excipient&#39;s in an icell via hydrophobic ion pairing

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase