WO2018170210A1 - Thérapie topique pour le traitement de la néoplasie intraépithéliale vulvaire (vin) et des verrues génitales à l'aide de nanoparticules de taxanes - Google Patents

Thérapie topique pour le traitement de la néoplasie intraépithéliale vulvaire (vin) et des verrues génitales à l'aide de nanoparticules de taxanes Download PDF

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Publication number
WO2018170210A1
WO2018170210A1 PCT/US2018/022557 US2018022557W WO2018170210A1 WO 2018170210 A1 WO2018170210 A1 WO 2018170210A1 US 2018022557 W US2018022557 W US 2018022557W WO 2018170210 A1 WO2018170210 A1 WO 2018170210A1
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nanoparticles
composition
microns
hydrophobic
taxane
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PCT/US2018/022557
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English (en)
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Gere Dizerega
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Dfb Soria, Llc
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    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids

Definitions

  • the present invention generally relates to the field of topical therapeutic treatment of vulvar intraepithelial neoplasia (VIN) and genital warts.
  • the invention relates to the use of topical compositions comprising taxane nanoparticles for treatment of VIN and genital warts.
  • Vulvar intraepithelial neoplasia is a skin condition that can include lesions of abnormal cells on a woman's vulva. VIN is a precancerous condition and if left untreated, can progress into invasive carcinoma. Generally, there are two classifications of VIN. One type known as “classic” or “usual" vulvar intraepithelial neoplasia (uVIN) is associated with infection of the human papilloma virus (HPV).
  • HPV human papilloma virus
  • Usual type VIN can be either a vulvar low-grade squamous intraepithelial lesion (vulvar LSIL) or a vulvar high-grade squamous intraepithelial lesion (vulvar HSIL).
  • vulvar LSIL vulvar low-grade squamous intraepithelial lesion
  • vulvar HSIL vulvar high-grade squamous intraepithelial lesion
  • the second type of VIN known as differentiated VIN (dVIN) or simplex-type VIN is not associated with HPV, but is associated with chronic inflammatory skin conditions such as lichen sclerosus.
  • Genital warts also known as anogenital warts, venereal warts, or condyloma acuminatum, are growths (lesions) consisting of fibrous overgrowths covered by a thickened epithelium (outer layer) that appear in the genital or anal (anogenital) areas.
  • Genital warts are a common sexually transmitted infection (STI) in men and women caused by certain strains of the human papilloma virus (HPV).
  • Genital warts generally occur in and around the vagina, under the foreskin of the uncircumcised penis, and on the shaft of the circumcised penis.
  • anogenital epithelium can also appear at multiple sites in the anogenital epithelium or within the anogenital tract (e.g., cervix, vagina, vaginal introitus, vulva, urethra, penis, perineum, perianal skin, intra-anus, external anus, rectum, perianus, groin, and scrotum).
  • External genital warts are those that appear on the penis, groin, scrotum, vulva, perineum, external anus, external vagina, and/or perianal area.
  • genital warts are those that appear on the anogenital epithelium within the anogenital tract, e.g., rectum, intra-anus, urethra, cervix, and/or vaginal introitus.
  • Genital warts are usually flat, papular, or pedunculated growths. Some genital warts are visibly undetectable, but can be detected with a colposcopic exam of the cervix and vagina or a Pap smear.
  • Current treatments of genital warts include administration of topical formulations, cryotherapy, electrocautery, surgical removal, or laser treatment.
  • Topical therapies include administration of topical formulations with therapeutic agents that include imiquimod, podofilox (podophyllo toxin), podophyllin resin, 5-fluorouracil, trichloroacetic acid, bichloroacetic acid, cidofovir, or sinecatechins.
  • therapeutic agents include imiquimod, podofilox (podophyllo toxin), podophyllin resin, 5-fluorouracil, trichloroacetic acid, bichloroacetic acid, cidofovir, or sinecatechins.
  • Topical formulations are disclosed in US 9,056,137 for the treatment of genital warts containing chemotherapeutic agents such as paclitaxel, propylene glycol, the penetration enhancer laurocapram (AZONE), and poloxamers; however, these formulations are primarily designed for transdermal and transmucosal delivery of the chemotherapeutic agent.
  • Delivery of therapeutic drugs into lesions of the skin and anogenital epithelial tissue can be a challenge due to the barrier properties of the stratum corneum of the skin.
  • the delivery of poorly water soluble drugs into these tissues can be even more of a challenge.
  • Skin penetration enhancers such as laurocapram (AZONE), diethylene glycol monoethyl ether (DGME or TRANSCUTOL), and isopropyl myristate, have been employed in topical drug formulations to increase the penetration of drugs into the skin and anogenital epithelial tissues and have had some success.
  • some penetration enhancers such as solvents and surfactants can be irritating to the skin and other anogenital epithelial tissues.
  • Volatile silicone fluids have been employed in topical formulations to increase the penetration of drugs into the skin; however, high concentrations of volatile silicone fluids, i.e., 25% and greater, and/or combinations of volatile silicone fluids with other potential skin irritating compounds such as alcohols, e.g., Ci to C 4 aliphatic alcohols, surfactants, other penetration enhancers, and other volatile solvents have been needed to produce the penetration enhancement effect. Additionally, some penetration enhancers will cause the drug to penetrate transdermally and be systemically absorbed, which is not desirable when only treating a condition of the skin, such as a lesion of the skin.
  • US 9,056,137 discloses the use of solid-phase room-temperature compositions that convert to flowable compositions in response to physiological temperatures.
  • compositions can include a chemotherapeutic agent along with propylene glycol, a penetration enhancer laurocapram (AZONE), and poloxamers.
  • the compositions are designed for transdermal and transmucosal delivery of the chemotherapeutic agent. Local irritation could occur with laurocapram as edema and erythema have been observed with laurocapram in a Draize rabbit skin test model (Okabe et. al., Percutaneous absorption enhancing effect and skin irritation of monocyclic monoterpenes, Drug Des Deliv, 1990 Sep;6(3)229-38).
  • Other topical delivery systems have been employed where the drug is chemically modified with surfactants, polymers, and other substances, but these materials can also be irritating to the skin and anogenital epithelial tissues.
  • Taxanes including paclitaxel and docetaxel, have been used for the treatment of cancer for many years. These compounds are typically characterized as being poorly water soluble.
  • the cancer treatment formulation initially developed for intravenous (IV) infusion injection, TAXOL® (BMS) is paclitaxel dissolved in a 50:50 v/v mixture of polyethoxylated castor oil (CREMOPHOR® EL) and dehydrated ethanol.
  • CREMOPHOR® EL polyethoxylated castor oil
  • Substantial effort has been devoted to the development of CREMOPHOR EL-free formulations of paclitaxel for systemic use (Ma and Mumper, 2013).
  • the present invention provides solutions to the aforementioned limitations and deficiencies in the art relating to the treatment of vulvar intraepithelial neoplasia (VIN) and/or genital warts.
  • a topical therapy that utilizes a topical composition with enhanced penetration for the delivery of taxane nanoparticles to the VIN and/or genital warts providing effective treatment with low to negligible local skin irritation.
  • the treatment methods of the present invention can be used without the need to combine them with other known skin-directed therapies such as those discussed above.
  • a method of treating vulvar intraepithelial neoplasia (VIN) in a subject in need of treatment comprising topically administering (topically applying) to an affected area of the subject having the VIN a composition comprising a plurality of taxane nanoparticles.
  • the "affected area" of the subject having the VIN includes one or more lesions that are visible on the outermost surface of the skin of the vulva, or directly underneath the surface of the skin of the vulva, and can include areas of the skin of the vulva in the proximity of the one or more lesions likely to contain visibly undetectable preclinical lesions.
  • the taxane nanoparticles are suspended within the composition. In other embodiments, the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns, or from 0.1 microns to less than 1 micron. In various embodiments, the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles, or any combination of such nanoparticles. In some embodiments, the taxane nanoparticles are paclitaxel nanoparticles.
  • the paclitaxel nanoparticles have a specific surface area (SSA) of at least 18 m 2 /g, or from 18 m 2 /g to 40 m 2 /g.
  • the concentration of the taxane nanoparticles in the compositions is at a concentration effective to provide a therapeutic improvement in the VIN.
  • the effective concentration of the taxane nanoparticles or paclitaxel nanoparticles is about 0.15 to about 2% w/w, or 0.1 to 5% w/w.
  • the composition is anhydrous.
  • the composition is a hydrophobic composition and can comprise a hydrophobic carrier.
  • the hydrophobic carrier is non-volatile and/or is non-polar.
  • the hydrophobic carrier comprises a hydrocarbon which can be petrolatum, mineral oil, or paraffin wax, or mixtures thereof.
  • the mineral oil is heavy mineral oil.
  • the hydrophobic carrier is greater than 50% w/w of the composition.
  • the hydrophobic composition can further comprise one or more volatile silicone fluids.
  • the volatile silicone fluid is at a concentration of 5 to 24% w/w of the composition and can be cyclomethicone.
  • the cyclomethicone is cyclopentasiloxane.
  • the composition is a semi-solid composition and can be an ointment.
  • the composition does not contain volatile Ci - C 4 aliphatic alcohols or Ci - Cs aliphatic alcohols, and/or does not contain additional penetration enhancers, and/or does not contain laurocapram, and/or does not contain diethylene glycol monoethyl ether, and/or does not contain isopropyl myristate, and/or does not contain alpha tocopherol, and/or does not contain additional volatile solvents, and/or does not contain surfactants, and/or does not contain a protein or albumin, and/or does not contain hyaluronic acid, and/or does not contain a conjugate of hyaluronic acid and a taxane, and/or does not contain a conjugate of hyaluronic acid and paclitaxel, and/or does not contain a polymer or copolymer.
  • the VIN is usual
  • a method of enhancing penetration of taxane nanoparticles into a vulvar intraepithelial neoplasia (VIN) of a subject comprising topically applying to an affected area of the subject having the VIN a hydrophobic composition comprising a continuous hydrophobic carrier, one or more volatile silicone fluids, and a plurality of taxane nanoparticles.
  • the taxane nanoparticles are suspended within the composition.
  • the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns, or from 0.1 microns to less than 1 micron.
  • the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles, or any combinations of such nanoparticles.
  • the taxane nanoparticles are paclitaxel nanoparticles.
  • the paclitaxel nanoparticles have a specific surface area (SSA) of at least 18 m 2 /g, or from 18 m 2 /g to 40 m 2 /g.
  • the concentration of the taxane nanoparticles or paclitaxel nanoparticles is about 0.15 to about 2% w/w, or 0.1 to 5% w/w.
  • the composition is anhydrous.
  • the composition is a hydrophobic composition and can comprise a hydrophobic carrier.
  • the hydrophobic carrier is non-volatile and/or is non-polar.
  • the hydrophobic carrier comprises a hydrocarbon which can be petrolatum, mineral oil, or paraffin wax, or mixtures thereof.
  • the mineral oil is heavy mineral oil.
  • the hydrophobic carrier is greater than 50% w/w of the composition.
  • the hydrophobic composition can further comprise one or more volatile silicone fluids.
  • the volatile silicone fluid is at a concentration of 5 to 24% w/w of the composition and can be cyclomethicone.
  • the cyclomethicone is cyclopentasiloxane.
  • the composition is a semisolid composition and can be an ointment and can have a viscosity of 25,000 cps to 500,000 cps as measured with a Brookfield RV viscometer on a helipath stand with the helipath on, with a T-E spindle at 10 RPM at room temperature for 45 seconds.
  • the composition does not contain volatile Ci - C 4 aliphatic alcohols or Ci - Cs aliphatic alcohols, and/or does not contain additional penetration enhancers, and/or does not contain laurocapram, and/or does not contain diethylene glycol monoethyl ether, and/or does not contain isopropyl myristate, and/or does not contain alpha tocopherol, and/or does not contain additional volatile solvents, and/or does not contain surfactants, and/or does not contain a protein or albumin, and/or does not contain hyaluronic acid, and/or does not contain a conjugate of hyaluronic acid and a taxane, and/or does not contain a conjugate of hyaluronic acid and paclitaxel, and/or does not contain a polymer or copolymer.
  • the VIN is usual vulvar intraepithelial neoplasia (uVIN). In some embodiments, the VIN is differentiated intraepithelial neoplasia (dVIN). In some embodiments, the penetration of the taxane nanoparticles from the hydrophobic composition into the VIN is greater than the penetration of taxane nanoparticles into the VIN from topically applying a hydrophobic composition that comprises a plurality of taxane nanoparticles and that does not contain one or more volatile silicone fluids.
  • a method of enhancing penetration of taxane nanoparticles into a vulvar intraepithelial neoplasia (VIN) of a subject comprising topically applying a hydrophobic composition comprising a plurality of taxane nanoparticles to an affected area of the subject having the VIN, wherein the penetration of the taxane nanoparticles from the hydrophobic composition into the VIN is greater than the penetration of taxane nanoparticles into the VIN from topically applying an aqueous based composition comprising a plurality of taxane nanoparticles.
  • VIN vulvar intraepithelial neoplasia
  • the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns, or from 0.1 microns to less than 1 micron.
  • taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles, or any combination of such nanoparticles.
  • hydrophobic composition further comprises a hydrophobic carrier.
  • the VIN is usual VIN (uVIN). In some embodiments, the VIN is differentiated VIN (dVIN).
  • a method of treating genital warts in a subject in need of treatment comprising topically administering (topically applying) to an affected area of the subject having genital warts a composition comprising a plurality of taxane nanoparticles.
  • the "affected area" of the genital warts includes one or more genital warts that are visible on the outermost surface of the skin or epithelial tissue, or directly underneath the surface of the skin or epithelial tissue, and can include areas of the skin or epithelial tissue in the proximity of the one or more genital warts likely to contain visibly undetectable preclinical lesions.
  • the taxane nanoparticles are suspended within the composition. In other embodiments, the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns, or from 0.1 microns to less than 1 micron. In various embodiments, the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles, or any combination of such nanoparticles. In some embodiments, the taxane nanoparticles are paclitaxel nanoparticles.
  • the paclitaxel nanoparticles have a specific surface area (SSA) of at least 18 m 2 /g, or from 18 m 2 /g to 40 m 2 /g.
  • the concentration of the taxane nanoparticles in the compositions is at a concentration effective to provide a therapeutic improvement in the genital warts.
  • the effective concentration of the taxane nanoparticles or paclitaxel nanoparticles is about 0.15 to about 2% w/w, or 0.1 to 5% w/w.
  • the composition is anhydrous.
  • the composition is a hydrophobic composition and can comprise a hydrophobic carrier.
  • the hydrophobic carrier is non-volatile and/or is non-polar.
  • the hydrophobic carrier comprises a hydrocarbon which can be petrolatum, mineral oil, or paraffin wax, or mixtures thereof.
  • the mineral oil is heavy mineral oil.
  • the hydrophobic carrier is greater than 50% w/w of the composition.
  • the hydrophobic composition can further comprise one or more volatile silicone fluids.
  • the volatile silicone fluid is at a concentration of 5 to 24% w/w of the composition and can be cyclomethicone.
  • the cyclomethicone is cyclopentasiloxane.
  • the composition is a semi-solid composition and can be an ointment.
  • the composition does not contain volatile Ci - C 4 aliphatic alcohols or Ci - Cs aliphatic alcohols, and/or does not contain additional penetration enhancers, and/or does not contain laurocapram, and/or does not contain diethylene glycol monoethyl ether, and/or does not contain isopropyl myristate, and/or does not contain alpha tocopherol, and/or does not contain additional volatile solvents, and/or does not contain surfactants, and/or does not contain a protein or albumin, and/or does not contain hyaluronic acid, and/or does not contain a conjugate of hyaluronic acid and a taxane, and/or does not contain a conjugate of hyaluronic acid and paclitaxel, and/or does not contain a polymer or copolymer.
  • the genital warts are external genital warts. In some embodiments, the external genital warts are on the penis, groin, scrotum, vulva, perineum, external anus, external vagina, and/or perianal area. In some embodiments, the genital warts are internal genital warts. In some embodiments, the internal genital warts are in the rectum, intra- anus, urethra, cervix, and/or vaginal introitus.
  • a method of enhancing penetration of taxane nanoparticles into genital warts of a subject comprising topically applying to an affected area of the subject having genital warts a hydrophobic composition comprising a continuous hydrophobic carrier, one or more volatile silicone fluids, and a plurality of taxane nanoparticles.
  • the taxane nanoparticles are suspended within the composition.
  • the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns, or from 0.1 microns to less than 1 micron.
  • the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles, or any combination of such nanoparticles.
  • the taxane nanoparticles are paclitaxel nanoparticles.
  • the paclitaxel nanoparticles have a specific surface area (SSA) of at least 18 m 2 /g, or from 18 m 2 /g to 40 m 2 /g.
  • the concentration of the taxane nanoparticles or paclitaxel nanoparticles is about 0.15 to about 2% w/w, or 0.1 to 5% w/w.
  • the composition is anhydrous.
  • the composition is a hydrophobic composition and can comprise a hydrophobic carrier.
  • the hydrophobic carrier is non-volatile and/or is non-polar.
  • the hydrophobic carrier comprises a hydrocarbon which can be petrolatum, mineral oil, or paraffin wax, or mixtures thereof.
  • the mineral oil is heavy mineral oil.
  • the hydrophobic carrier is greater than 50% w/w of the composition.
  • the hydrophobic composition can further comprise one or more volatile silicone fluids.
  • the volatile silicone fluid is at a concentration of 5 to 24% w/w of the composition and can be cyclomethicone.
  • the cyclomethicone is cyclopentasiloxane.
  • the composition is a semi- solid composition and can be an ointment and can have a viscosity of 25,000 cps to 500,000 cps as measured with a Brookfield RV viscometer on a helipath stand with the helipath on, with a T-E spindle at 10 RPM at room temperature for 45 seconds.
  • the composition does not contain volatile Ci - C 4 aliphatic alcohols or Ci - Cs aliphatic alcohols, and/or does not contain additional penetration enhancers, and/or does not contain laurocapram, and/or does not contain diethylene glycol monoethyl ether, and/or does not contain isopropyl myristate, and/or does not contain alpha tocopherol, and/or does not contain additional volatile solvents, and/or does not contain surfactants, and/or does not contain a protein or albumin, and/or does not contain hyaluronic acid, and/or does not contain a conjugate of hyaluronic acid and a taxane, and/or does not contain a conjugate of hyaluronic acid and paclitaxel, and/or does not contain a polymer or copolymer.
  • the genital warts are external genital warts. In some embodiments, the external genital warts are on the penis, groin, scrotum, vulva, perineum, external anus, external vagina, and/or perianal area. In some embodiments, the genital warts are internal genital warts. In some embodiments, the internal genital warts are in the rectum, intra-anus, urethra, cervix, and/or vaginal introitus.
  • the penetration of the taxane nanoparticles from the hydrophobic composition into the genital warts is greater than the penetration of taxane nanoparticles into the genital warts from topically applying a hydrophobic composition that comprises a plurality of taxane nanoparticles and that does not contain one or more volatile silicone fluids.
  • a method of enhancing penetration of taxane nanoparticles into genital warts of a subject comprising topically applying a hydrophobic composition comprising a plurality of taxane nanoparticles to an affected area of the subject having genital warts, wherein the penetration of the taxane nanoparticles from the hydrophobic composition into the genital warts is greater than the penetration of taxane nanoparticles into the genital warts from topically applying an aqueous based composition comprising a plurality of taxane nanoparticles.
  • the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns, or from 0.1 microns to less than 1 micron.
  • taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles, or any combination of such nanoparticles.
  • hydrophobic composition further comprises a hydrophobic carrier.
  • the genital warts are external genital warts. In some embodiments, the genital warts are internal genital warts.
  • hydrophobic compositions of the present invention having a volatile silicone fluid at concentrations less than 25% w/w in combination with an anhydrous hydrophobic carrier exhibited greater skin penetration (i.e., penetration into the epidermal and dermal portions of the skin) of taxane nanoparticles as compared to the skin penetration of taxane nanoparticles from the hydrophobic carrier alone.
  • compositions of the present invention can be free of (do not have to include) these additional skin penetration enhancers (e.g., surfactants, volatile solvents, alcohols, Ci - C 4 aliphatic alcohols or Ci - Cs aliphatic alcohols), which can be helpful in reducing skin irritation when the compositions of the present invention are applied to the skin.
  • these additional skin penetration enhancers e.g., surfactants, volatile solvents, alcohols, Ci - C 4 aliphatic alcohols or Ci - Cs aliphatic alcohols
  • the enhanced penetration was accomplished with low concentrations of cyclomethicone, i.e., less than 25% w/w.
  • the taxane nanoparticles are not transdermally delivered with these compositions initially after administration, which is a favorable feature because transdermal delivery (systemic absorption) is not desired when treating the skin (epidermis and dermis) or other epithelial tissues.
  • the skin penetration (i.e., penetration into the dermal or epidermal portions of the skin) of taxane nanoparticles from the compositions of the present invention was far superior to the skin penetration of taxane nanoparticles from aqueous based compositions, even though the aqueous based compositions contained a skin penetration enhancer. Additionally, it was found that the taxane nanoparticles were stable and did not exhibit crystal grow over time in the hydrophobic compositions of the present invention.
  • Hydrophobic compositions which comprise nanoparticles of a taxane, e.g., paclitaxel, and a volatile silicone fluid in combination with a hydrophobic carrier, are especially suitable for the topical treatment of VIN and genital warts because of the aforementioned enhanced penetration properties of these compositions into the epidermis and dermis portions of the skin.
  • the hydrophobic carrier can be the continuous phase of the composition with the nanoparticles suspended therein.
  • Embodiment 1 is a method of treating vulvar intraepithelial neoplasia (VIN) in a subject in need of treatment, the method comprising topically administering to an affected area of the subject having the VIN a composition comprising a plurality of taxane nanoparticles.
  • Embodiment 2 is the method of embodiment 1, wherein the taxane nanoparticles are suspended within the composition.
  • Embodiment 3 is the method of any one of embodiments 1 to 2, wherein the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns.
  • Embodiment 4 is the method of embodiment 3, wherein the taxane nanoparticles have a mean particle size (number) from 0.1 microns to less than 1 micron.
  • Embodiment 5 is the method of any one of embodiments 1 to 4, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.
  • Embodiment 6 is the method of embodiment 5, wherein the taxane nanoparticles are paclitaxel nanoparticles.
  • Embodiment 7 is the method of embodiment 6, wherein the paclitaxel nanoparticles have a specific surface area (SSA) of at least 18 m 2 /g.
  • SSA specific surface area
  • Embodiment 8 is the method of embodiment 7, wherein the paclitaxel nanoparticles have a specific surface area (SSA) of 18 m 2 /g to 40 m 2 /g.
  • SSA specific surface area
  • Embodiment 9 is the method of any of embodiments 1 to 8, wherein the concentration of the taxane nanoparticles is at a concentration effective to provide a therapeutic improvement of the VIN.
  • Embodiment 10 is the method of embodiment 9, wherein the concentration of the paclitaxel nanoparticles is about 0.15 to about 2% w/w, or 0.1 to 5% w/w.
  • Embodiment 11 is the method of any one of embodiments 1 to 10, wherein the composition is anhydrous.
  • Embodiment 12 is the method of any one of embodiments 1 to 11, wherein the composition is a hydrophobic composition.
  • Embodiment 13 is the method of embodiment 12, wherein the hydrophobic composition comprises a hydrophobic carrier.
  • Embodiment 14 is the method of embodiment 13, wherein the hydrophobic carrier is nonvolatile.
  • Embodiment 15 is the method of any one of embodiments 13 to 14, wherein the hydrophobic carrier is non-polar.
  • Embodiment 16 is the method of any one of embodiments 13 to 15, wherein the hydrophobic carrier comprises a hydrocarbon.
  • Embodiment 17 is the method of embodiment 16, wherein the hydrocarbon is petrolatum, mineral oil, or paraffin wax, or mixtures thereof.
  • Embodiment 18 is the method of embodiment 17, wherein the mineral oil is heavy mineral oil.
  • Embodiment 19 is the method of any one of embodiments 13 to 18, wherein the hydrophobic carrier is greater than 50% w/w of the composition.
  • Embodiment 20 is the method of any one of embodiments 13 to 19, wherein the hydrophobic composition comprises one or more volatile silicone fluids.
  • Embodiment 21 is the method of embodiment 20, wherein the concentration of the one or more volatile silicone fluids is from 5 to 24% w/w of the composition.
  • Embodiment 22 is the method of embodiment 21, wherein the volatile silicone fluid is cyclomethicone.
  • Embodiment 23 is the method of embodiment 22, wherein the cyclomethicone is cyclopentasiloxane.
  • Embodiment 24 is the method of any one of embodiments 1 to 23, wherein the composition is a semi-solid composition.
  • Embodiment 25 is the method of embodiment 24, wherein the semi-solid composition is an ointment.
  • Embodiment 26 is the method of any one of embodiments 1 to 25, wherein the composition does not contain volatile Ci - C 4 aliphatic alcohols.
  • Embodiment 27 is the method of any one of embodiments 1 to 26, wherein the composition does not contain additional penetration enhancers.
  • Embodiment 28 is the method of any one of embodiments 1 to 27, wherein the composition does not contain additional volatile solvents.
  • Embodiment 29 is the method of any one of embodiments 1 to 28, wherein the composition does not contain surfactants.
  • Embodiment 30 is the method of any one of embodiments 1 to 29, wherein the composition does not contain a protein or albumin.
  • Embodiment 31 is the method of any one of embodiments 1 to 30, wherein the composition does not contain a polymer or copolymer.
  • Embodiment 32 is the method of any one of embodiments 1 to 31, wherein the VIN is usual vulvar intraepithelial neoplasia (uVIN).
  • VIN vulvar intraepithelial neoplasia
  • Embodiment 33 is the method of any one of embodiments 1 to 31, wherein the VIN is differentiated vulvar intraepithelial neoplasia (dVIN).
  • VIN is differentiated vulvar intraepithelial neoplasia
  • Embodiment 34 is a method of enhancing penetration of taxane nanoparticles into a vulvar intraepithelial neoplasia (VIN) of a subject, the method comprising topically applying to an affected area of the subject having the VIN a hydrophobic composition comprising a continuous hydrophobic carrier, one or more volatile silicone fluids, and a plurality of taxane nanoparticles.
  • VIN vulvar intraepithelial neoplasia
  • Embodiment 35 is the method of embodiment 34, wherein the taxane nanoparticles are suspended within the hydrophobic composition.
  • Embodiment 36 is the method of any one of embodiments 34 to 35, wherein the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns.
  • Embodiment 37 is the method of embodiment 36, wherein the taxane nanoparticles have a mean particle size (number) from 0.1 microns to less than 1 micron.
  • Embodiment 38 is the method of any one of embodiments 34 to 37, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.
  • Embodiment 39 is the method of embodiment 38, wherein the taxane nanoparticles are paclitaxel nanoparticles.
  • Embodiment 40 is the method of embodiment 39, wherein the paclitaxel nanoparticles have a specific surface area (SSA) of at least 18 m 2 /g.
  • SSA specific surface area
  • Embodiment 41 is the method of embodiment 40, wherein the paclitaxel nanoparticles have a specific surface area (SSA) of 18 m 2 /g to 40 m 2 /g.
  • SSA specific surface area
  • Embodiment 42 is the method of any one of embodiments 39 to 41 wherein the concentration of the paclitaxel nanoparticles is about 0.15 to about 2% w/w, or 0.1 to 5% w/w.
  • Embodiment 43 is the method of any one of embodiments 34 to 42, wherein the composition is anhydrous.
  • Embodiment 44 is the method of any one of embodiments 34 to 43, wherein the hydrophobic carrier is non- volatile.
  • Embodiment 45 is the method of any one of embodiments 34 to 44, wherein the hydrophobic carrier is non-polar.
  • Embodiment 46 is the method of any one of embodiments 34 to 45, wherein the hydrophobic carrier comprises a hydrocarbon.
  • Embodiment 47 is the method of embodiment 46, wherein the hydrocarbon is petrolatum, mineral oil, or paraffin wax, or mixtures thereof.
  • Embodiment 48 is the method of embodiment 47, wherein the mineral oil is heavy mineral oil.
  • Embodiment 49 is the method of any one of embodiments 34 to 48, wherein the hydrophobic carrier is greater than 50% w/w of the composition.
  • Embodiment 50 is the method of any one of embodiments 34 to 49, wherein the concentration of the one or more volatile silicone fluids is from 5 to 24% w/w of the composition.
  • Embodiment 51 is the method of embodiment 50, wherein the volatile silicone fluid is cyclomethicone.
  • Embodiment 52 is the method of embodiment 51, wherein the cyclomethicone is cyclopentasiloxane.
  • Embodiment 53 is the method of any one of embodiments 34 to 52, wherein the composition is a semi-solid composition.
  • Embodiment 54 is the method of embodiment 53, wherein the semi-solid composition is an ointment.
  • Embodiment 55 is the method of any one of embodiments 53 to 54, wherein the viscosity of the composition is 25,000 cps to 500,000 cps as measured with a Brookfield RV viscometer on a helipath stand with the helipath on, with a T-E spindle at 10 RPM at room temperature for 45 seconds.
  • Embodiment 56 is the method of any one of embodiments 34 to 55, wherein the composition does not contain volatile Ci - C 4 aliphatic alcohols.
  • Embodiment 57 is the method of any one of embodiments 34 to 56, wherein the composition does not contain additional penetration enhancers.
  • Embodiment 58 is the method of any one of embodiments 34 to 57, wherein the composition does not contain additional volatile solvents.
  • Embodiment 59 is the method of any one of embodiments 34 to 58, wherein the composition does not contain surfactants.
  • Embodiment 60 is the method of any one of embodiments 34 to 59, wherein the composition does not contain a protein or albumin.
  • Embodiment 61 is the method of any one of embodiments 34 to 60, wherein the composition does not contain a polymer or copolymer.
  • Embodiment 62 is the method of any one of embodiments 34 to 61, wherein the VIN is usual vulvar intraepithelial neoplasia (uVIN).
  • VIN vulvar intraepithelial neoplasia
  • Embodiment 63 is the method of any one of embodiments 34 to 61, wherein the VIN is differentiated vulvar intraepithelial neoplasia (dVIN).
  • VIN differentiated vulvar intraepithelial neoplasia
  • Embodiment 64 is the method of any one of embodiments 34 to 63, wherein the penetration of the taxane nanoparticles from the hydrophobic composition into the VIN is greater than the penetration of taxane nanoparticles into the VIN from topically applying a hydrophobic composition that comprises a plurality of taxane nanoparticles and that does not contain one or more volatile silicone fluids.
  • Embodiment 65 is a method of enhancing penetration of taxane nanoparticles into a vulvar intraepithelial neoplasia (VIN) of a subject, the method comprising topically applying a hydrophobic composition comprising a plurality of taxane nanoparticles to an affected area of the subject having the VIN, wherein the penetration of the taxane nanoparticles from the hydrophobic composition into the VIN is greater than the penetration of taxane nanoparticles into the VIN from topically applying an aqueous based composition comprising a plurality of taxane nanoparticles.
  • VIN vulvar intraepithelial neoplasia
  • Embodiment 66 is the method of embodiment 65, wherein the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns.
  • Embodiment 67 is the method of embodiment 66, wherein the taxane nanoparticles have a mean particle size (number) from 0.1 microns to less than 1 micron.
  • Embodiment 68 is the method of any one of embodiments 65 to 67, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.
  • Embodiment 69 is the method of any one of embodiments 65 to 68, wherein the hydrophobic composition further comprises a hydrophobic carrier.
  • Embodiment 70 is the method of any one of embodiments 65 to 69, wherein the VIN is usual vulvar intraepithelial neoplasia (uVIN).
  • VIN vulvar intraepithelial neoplasia
  • Embodiment 71 is the method of any one of embodiments 65 to 70, wherein the VIN is differentiated vulvar intraepithelial neoplasia (dVIN).
  • VIN differentiated vulvar intraepithelial neoplasia
  • Embodiment 72 is the method of any one of embodiments 65 to 71, wherein the hydrophobic composition comprises a continuous hydrophobic phase having the plurality of taxane nanoparticles suspended therein.
  • Embodiment 73 is a method of treating genital warts in a subject in need of treatment, the method comprising topically administering to an affected area of the subject having the genital warts a composition comprising a plurality of taxane nanoparticles.
  • Embodiment 74 is the method of embodiment 73, wherein the taxane nanoparticles are suspended within the composition.
  • Embodiment 75 is the method of any one of embodiments 73 to 74, wherein the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns.
  • Embodiment 76 is the method of embodiment 75, wherein the taxane nanoparticles have a mean particle size (number) from 0.1 microns to less than 1 micron.
  • Embodiment 77 is the method of any one of embodiments 73 to 76, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.
  • Embodiment 78 is the method of embodiment 77, wherein the taxane nanoparticles are paclitaxel nanoparticles.
  • Embodiment 79 is the method of embodiment 78, wherein the paclitaxel nanoparticles have a specific surface area (SSA) of at least 18 m 2 /g.
  • SSA specific surface area
  • Embodiment 80 is the method of embodiment 79, wherein the paclitaxel nanoparticles have a specific surface area (SSA) of 18 m 2 /g to 40 m 2 /g.
  • SSA specific surface area
  • Embodiment 81 is the method of any of embodiments 73 to 80, wherein the concentration of the taxane nanoparticles is at a concentration effective to provide a therapeutic improvement of the genital warts.
  • Embodiment 82 is the method of embodiment 81, wherein the concentration of the paclitaxel nanoparticles is about 0.15 to about 2% w/w, or 0.1 to 5% w/w.
  • Embodiment 83 is the method of any one of embodiments 73 to 82, wherein the composition is anhydrous.
  • Embodiment 84 is the method of any one of embodiments 73 to 83, wherein the composition is a hydrophobic composition.
  • Embodiment 85 is the method of embodiment 84, wherein the hydrophobic composition comprises a hydrophobic carrier.
  • Embodiment 86 is the method of embodiment 85, wherein the hydrophobic carrier is nonvolatile.
  • Embodiment 87 is the method of any one of embodiments 85 to 86, wherein the hydrophobic carrier is non-polar.
  • Embodiment 88 is the method of any one of embodiments 85 to 87, wherein the hydrophobic carrier comprises a hydrocarbon.
  • Embodiment 89 is the method of embodiment 88, wherein the hydrocarbon is petrolatum, mineral oil, or paraffin wax, or mixtures thereof.
  • Embodiment 90 is the method of embodiment 89, wherein the mineral oil is heavy mineral oil.
  • Embodiment 91 is the method of any one of embodiments 85 to 90, wherein the hydrophobic carrier is greater than 50% w/w of the composition.
  • Embodiment 92 is the method of any one of embodiments 85 to 91, wherein the hydrophobic composition comprises one or more volatile silicone fluids.
  • Embodiment 93 is the method of embodiment 92, wherein the concentration of the one or more volatile silicone fluids is from 5 to 24% w/w of the composition.
  • Embodiment 94 is the method of embodiment 93, wherein the volatile silicone fluid is cyclomethicone.
  • Embodiment 95 is the method of embodiment 94, wherein the cyclomethicone is cyclopentasiloxane.
  • Embodiment 96 is the method of any one of embodiments 73 to 95, wherein the composition is a semi-solid composition.
  • Embodiment 97 is the method of embodiment 96, wherein the semi-solid composition is an ointment.
  • Embodiment 98 is the method of any one of embodiments 73 to 97, wherein the composition does not contain volatile Ci - C 4 aliphatic alcohols.
  • Embodiment 99 is the method of any one of embodiments 73 to 98, wherein the composition does not contain additional penetration enhancers.
  • Embodiment 100 is the method of any one of embodiments 73 to 99, wherein the composition does not contain additional volatile solvents.
  • Embodiment 101 is the method of any one of embodiments 73 to 100, wherein the composition does not contain surfactants.
  • Embodiment 102 is the method of any one of embodiments 73 to 101, wherein the composition does not contain a protein or albumin.
  • Embodiment 103 is the method of any one of embodiments 73 to 102, wherein the composition does not contain a polymer or copolymer.
  • Embodiment 104 is the method of any one of embodiments 73 to 103, wherein the genital warts are external genital warts.
  • Embodiment 105 is the method of any one of embodiments 73 to 104, wherein the genital warts are internal genital warts.
  • Embodiment 106 is a method of enhancing penetration of taxane nanoparticles into genital warts of a subject, the method comprising topically applying to an affected area of the subject having the genital warts a hydrophobic composition comprising a continuous hydrophobic carrier, one or more volatile silicone fluids, and a plurality of taxane nanoparticles.
  • Embodiment 107 is the method of embodiment 106, wherein the taxane nanoparticles are suspended within the hydrophobic composition.
  • Embodiment 108 is the method of any one of embodiments 106 to 107, wherein the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns.
  • Embodiment 109 is the method of embodiment 108, wherein the taxane nanoparticles have a mean particle size (number) from 0.1 microns to less than 1 micron.
  • Embodiment 110 is the method of any one of embodiments 106 to 109, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.
  • Embodiment 111 is the method of embodiment 110, wherein the taxane nanoparticles are paclitaxel nanoparticles.
  • Embodiment 112 is the method of embodiment 111, wherein the paclitaxel nanoparticles have a specific surface area (SSA) of at least 18 m 2 /g.
  • SSA specific surface area
  • Embodiment 113 is the method of embodiment 112, wherein the paclitaxel nanoparticles have a specific surface area (SSA) of 18 m 2 /g to 40 m 2 /g.
  • SSA specific surface area
  • Embodiment 114 is the method of any one of embodiments 111 to 113 wherein the concentration of the paclitaxel nanoparticles is about 0.15 to about 2% w/w, or 0.1 to 5% w/w.
  • Embodiment 115 is the method of any one of embodiments 106 to 114, wherein the composition is anhydrous.
  • Embodiment 116 is the method of any one of embodiments 106 to 115, wherein the hydrophobic carrier is non-volatile.
  • Embodiment 117 is the method of any one of embodiments 106 to 116, wherein the hydrophobic carrier is non-polar.
  • Embodiment 118 is the method of any one of embodiments 106 to 117, wherein the hydrophobic carrier comprises a hydrocarbon.
  • Embodiment 119 is the method of embodiment 118, wherein the hydrocarbon is petrolatum, mineral oil, or paraffin wax, or mixtures thereof.
  • Embodiment 120 is the method of embodiment 119, wherein the mineral oil is heavy mineral oil.
  • Embodiment 121 is the method of any one of embodiments 106 to 120, wherein the hydrophobic carrier is greater than 50% w/w of the composition.
  • Embodiment 122 is the method of any one of embodiments 106 to 121, wherein the concentration of the one or more volatile silicone fluids is from 5 to 24% w/w of the composition.
  • Embodiment 123 is the method of embodiment 122, wherein the volatile silicone fluid is cyclomethicone.
  • Embodiment 124 is the method of embodiment 123, wherein the cyclomethicone is cyclopentasiloxane.
  • Embodiment 125 is the method of any one of embodiments 106 to 124, wherein the composition is a semi-solid composition.
  • Embodiment 126 is the method of embodiment 125, wherein the semi-solid composition is an ointment.
  • Embodiment 127 is the method of any one of embodiments 125 to 126, wherein the viscosity of the composition is 25,000 cps to 500,000 cps as measured with a Brookfield RV viscometer on a helipath stand with the helipath on, with a T-E spindle at 10 RPM at room temperature for 45 seconds.
  • Embodiment 128 is the method of any one of embodiments 106 to 127, wherein the composition does not contain volatile Ci - C 4 aliphatic alcohols.
  • Embodiment 129 is the method of any one of embodiments 106 to 128, wherein the composition does not contain additional penetration enhancers.
  • Embodiment 130 is the method of any one of embodiments 106 to 129, wherein the composition does not contain additional volatile solvents.
  • Embodiment 131 is the method of any one of embodiments 106 to 130, wherein the composition does not contain surfactants.
  • Embodiment 132 is the method of any one of embodiments 106 to 130, wherein the composition does not contain a protein or albumin.
  • Embodiment 133 is the method of any one of embodiments 106 to 132, wherein the composition does not contain a polymer or copolymer.
  • Embodiment 134 is the method of any one of embodiments 106 to 133, wherein the genital warts are external genital warts.
  • Embodiment 135 is the method of any one of embodiments 106 to 134, wherein the genital warts are internal genital warts.
  • Embodiment 136 is the method of any one of embodiments 106 to 135, wherein the penetration of the taxane nanoparticles from the hydrophobic composition into the genital warts is greater than the penetration of taxane nanoparticles into the genital warts from topically applying a hydrophobic composition that comprises a plurality of taxane nanoparticles and that does not contain one or more volatile silicone fluids.
  • Embodiment 137 is a method of enhancing penetration of taxane nanoparticles into genital warts of a subject, the method comprising topically applying a hydrophobic composition comprising a plurality of taxane nanoparticles to an affected area of the subject having the genital warts, wherein the penetration of the taxane nanoparticles from the hydrophobic composition into the genital warts is greater than the penetration of taxane nanoparticles into the genital warts from topically applying an aqueous based composition comprising a plurality of taxane nanoparticles.
  • Embodiment 138 is the method of embodiment 137, wherein the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns.
  • Embodiment 139 is the method of embodiment 138, wherein the taxane nanoparticles have a mean particle size (number) from 0.1 microns to less than 1 micron.
  • Embodiment 140 is the method of any one of embodiments 137 to 139, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.
  • Embodiment 141 is the method of any one of embodiments 137 to 140, wherein the hydrophobic composition further comprises a hydrophobic carrier.
  • Embodiment 142 is the method of any one of embodiments 137 to 141, wherein the genital warts are external genital warts.
  • Embodiment 143 is the method of any one of embodiments 137 to 142, wherein the genital warts are internal genital warts.
  • Embodiment 144 is the method of any one of embodiments 137 to 143, wherein the hydrophobic composition comprises a continuous hydrophobic phase having the plurality of taxane nanoparticles suspended therein.
  • nanoparticle represents the mean particle size (based on the number- weighted differential distribution, designated as "number") of the taxane particles which is from 0.01 microns to 1.5 microns (10 nm to 1500 nm) or preferably from 0.1 microns to 1.5 microns (100 nm to 1500 nm), or more preferably from 0.1 microns to less than 1 micron (100 nm to less than 1000 nm).
  • water soluble describes compounds that have a solubility in water of greater than 10 mg/mL or greater at room temperature.
  • pooled water soluble describes compounds that have a solubility in water of less than or equal to 10 mg/mL at room temperature.
  • hydrophobic describes compounds, compositions, or carriers that have a solubility in water of less than or equal to 10 mg/mL at room temperature.
  • volatile describes compounds, compositions, or carriers that have a vapor pressure greater than or equal to 10 Pa at room temperature.
  • non-volatile describes compounds, compositions, or carriers that have a vapor pressure less than 10 Pa at room temperature.
  • anhydrous as used herein with regard to the compositions or carriers of the invention, means that less than 3% w/w, preferably less than 2% w/w, more preferably less than 1% w/w, or most preferably 0% w/w of water is present in the compositions or carriers. This can account for small amounts of water being present (e.g., water inherently contained in any of the ingredients of the compositions or carriers, water contracted from the atmosphere, etc.).
  • skin or "cutaneous” as used herein mean the epidermis and/or the dermis.
  • epithelial tissue as used herein with respect to anogenital epithelial tissue means the anogenital epithelium within the anogenital tract, e.g., rectum, intra-anus, urethra, cervix, and/or vaginal introitus.
  • vulva or "vulvar” means all parts of the vulva and include the two labia majora, the two labia minora, the vestibule, the clitoris, the mons pubis, the external urethral meatus, the ostia of the accessory glands, and the perineum.
  • the term "affected area" with respect to vulvar intraepithelial neoplasia (VIN) as used herein includes one or more lesions that are visible on the outermost surface of the skin of the vulva, or directly underneath the surface of the skin of the vulva, and can include areas of the skin of the vulva in the proximity of the one or more lesions likely to contain visibly undetectable preclinical lesions.
  • the term "affected area" with respect to genital warts as used herein includes one or more genital warts that are visible on the outermost surface of the skin or epithelial tissue, or directly underneath the surface of the skin or epithelial tissue, and can include areas of the skin or epithelial tissue in the proximity of the one or more genital warts likely to contain visibly undetectable preclinical lesions.
  • the terms "subject” or "patient” as used herein mean a vertebrate animal.
  • the vertebrate animal can be a mammal.
  • the mammal can be a primate, including a human.
  • room temperature means 20-25°C.
  • penetration enhancer or “skin penetration enhancer” as used herein, means a compound or a material or a substance that facilitates drug absorption into the skin (epidermis and dermis).
  • surfactant or "surface active agent” as used herein, means a compound or a material or a substance that exhibits the ability to lower the surface tension of water or to reduce the interfacial tension between two immiscible substances.
  • percent values expressed herein are weight by weight and are in relation to the weight of the total composition.
  • a number value with one or more decimal places can be rounded to the nearest whole number using standard rounding guidelines, i.e. round up if the number being rounded is 5, 6, 7, 8, or 9; and round down if the number being rounded is 0, 1, 2, 3, or 4. For example, 3.7 can be rounded to 4.
  • compositions and methods for their use can "comprise,” “consist essentially of,” or “consist of any of the ingredients or steps disclosed throughout the specification.
  • consisting essentially of a basic and novel property of the compositions of the present invention are their ability to topically treat VIN and/or genital warts.
  • a basic and novel property includes the ability to treat VIN and the ability to penetrate into the epidermal and dermal layers of the skin and or the anogenital epithelial tissue with limited to no penetration transdermally.
  • Ci - C 4 aliphatic alcohols or Ci - Cs aliphatic alcohols, surfactants, and additional skin penetration enhancers and additional volatile solvents other than a volatile silicone fluid(s) e.g., cyclomethicone or cyclopentasiloxane, or a combination thereof.
  • FIG. 1 graphically shows the concentration of paclitaxel ⁇ g/cm2) delivered in vitro into the epidermis for formulas Fl through F7.
  • FIG. 2 graphically shows the concentration of paclitaxel ⁇ g/cm2) delivered in vitro into the epidermis for formulas F6* (repeat analysis) and F8 through F13.
  • FIG. 3 graphically shows the concentration of paclitaxel ⁇ g/cm2) delivered in vitro into the dermis for formulas Fl through F7.
  • FIG. 4 graphically shows the concentration of paclitaxel ⁇ g/cm2) delivered in vitro into the dermis for formulas F6*(repeat analysis) and F8 through F13.
  • the invention relates to methods of treatment of vulvar intraepithelial neoplasia (VIN) and/or genital warts in a patient by topically applying to the affected area (topical therapy) a composition comprising a taxane(s).
  • the taxane is paclitaxel.
  • the taxane is docetaxel or cabazitaxel.
  • a combination of taxanes can be used (e.g., paclitaxel and docetaxel, or paclitaxel and cabazitaxel, or docetaxel and cabazitaxel, or paclitaxel, docetaxel, and cabazitaxel).
  • the composition comprises a carrier.
  • the carrier is anhydrous and/or hydrophobic.
  • the carrier is aqueous based.
  • the taxane(s) is a plurality of nanoparticles of the taxane(s). In other embodiments, the taxane(s) is solubilized.
  • compositions for use in the methods of the invention are disclosed in international patent publication WO 2017/049083 (application number PCT/US2016/052133), herein incorporated by reference.
  • the composition is a hydrophobic composition comprising a continuous hydrophobic carrier, one or more volatile silicone fluids, and a plurality of taxane nanoparticles, wherein the taxane nanoparticles are suspended within the composition and wherein the mean particle size (number) of the taxane nanoparticles is from 0.1 microns to 1.5 microns or from 0.1 microns to less than 1 micron.
  • the concentration of the one or more volatile silicone fluids is 5 to 24% w/w.
  • the composition does not contain volatile Ci - C 4 aliphatic alcohols or Ci - Cs aliphatic alcohols.
  • the concentration of the taxane nanoparticles is at a concentration effective to provide a therapeutic improvement in the VIN and/or genital warts. In some embodiments, the concentration of the taxane nanoparticles is at a concentration of about 0.1 to about 2% w/w, or about 0.15 to about 2% w/w, or 0.1 to 5% w/w.
  • Vulvar intraepithelial neoplasia includes all forms of VIN including "usual" vulvar intraepithelial neoplasia (uVIN) and “differentiated” vulvar intraepithelial neoplasia (dVIN).
  • the genital warts can be "external” genital warts meaning that they are located on the penis, groin, scrotum, vulva, perineum, external anus, external vagina, and/or perianal area.
  • the genital warts can be "internal” genital warts meaning that they are located on the anogenital epithelium within the anogenital tract, e.g., in the rectum, intra-anus, urethra, cervix, and/or vaginal introitus.
  • the compositions of the present invention are hydrophobic and comprise a continuous hydrophobic carrier, one or more volatile silicone fluids (such as cyclomethicone), and a plurality of taxane nanoparticles.
  • the compositions can be suspensions of a plurality of the taxane nanoparticles within a mixture of the hydrophobic carrier and the volatile silicone fluid.
  • the taxane nanoparticles can be completely dispersed, or partially dispersed and partially dissolved in the compositions. In various embodiments, the taxane nanoparticles are not completely dissolved in the compositions.
  • the hydrophobic compositions can be anhydrous.
  • a hydrophobic composition is a composition in which the total amount of the hydrophobic constituents in the composition is greater than the total amount of the non-hydrophobic constituents in the composition.
  • the hydrophobic carrier can be the continuous phase of the hydrophobic compositions. Therefore, the compositions of the present invention can include at least two phases, a continuous hydrophobic carrier phase and a suspended taxane nanoparticle phase.
  • the volatile silicone fluid can be solubilized and/or dispersed within the continuous phase.
  • the hydrophobic compositions of the invention that include volatile silicone fluids at low concentrations, i.e., less than 25% w/w, in combination with a continuous, anhydrous hydrophobic carrier, exhibited greater skin penetration (i.e., penetration into the epidermal and/or dermal portions of the skin) of taxane nanoparticles as compared to the skin penetration of taxane nanoparticles from the hydrophobic carrier alone.
  • skin penetration enhancers had little or no effect on the skin penetration of these compositions.
  • the taxane nanoparticles did not penetrate through the skin (i.e., transdermal penetration) or only a negligible amount penetrated transdermally through the skin, i.e. less than 0.01 ⁇ g/cm 2 .
  • the skin penetration (i.e., epidermal or dermal penetration) of taxane nanoparticles from the anhydrous hydrophobic compositions was far superior to the skin penetration of taxane nanoparticles from aqueous based compositions even though the aqueous based compositions contained a skin penetration enhancer.
  • the hydrophobic compositions of the invention that include less than 25% of a volatile silicone fluid in combination with a hydrophobic carrier, do not need to contain alcohols, additional volatile solvents, additional penetration enhancers, polymers/copolymers or surfactants to provide enhanced skin penetration, thereby allowing for a most cost-efficient and simplified composition that can have reduced irritancy when topically applied. If desired, however, such components can be included in the compositions of the present invention.
  • the hydrophobic compositions are free of / do not include or contain additional penetration enhancers.
  • the hydrophobic compositions are free of / do not include or contain laurocapram.
  • the hydrophobic compositions are free of / do not include diethylene glycol monoethyl ether (DGME). In some embodiments, the hydrophobic compositions are free of / do not include isopropyl myristate. In other embodiments, the hydrophobic compositions are free of / do not include alpha tocopherol. In other embodiments, the hydrophobic compositions are free of / do not include or contain additional volatile solvents or compounds. In some embodiments, the hydrophobic compositions are free of / do not include or contain any alcohols or Ci - C 4 aliphatic alcohols. In some embodiments, the hydrophobic compositions are free of / do not include or contain alcohol or Ci - Cs aliphatic alcohols.
  • DGME diethylene glycol monoethyl ether
  • the hydrophobic compositions are free of / do not include or contain surfactants. In other embodiments, the hydrophobic compositions are free of / do not include polymers/copolymers (or biodegradable polymers/copolymers). In other embodiments, the hydrophobic compositions are free of / do not include poloxamers, styrene-isobutylene-styrene (SIBS), a polyanhydride copolymer, polycaprolactone, polyethylene glycol, Poly (bis(P- carboxyphenoxy)propane-sebacic acid, and/or poly(D, L lactic-co-glycolic acid (PLGA).
  • SIBS styrene-isobutylene-styrene
  • a polyanhydride copolymer polycaprolactone
  • polyethylene glycol Poly (bis(P- carboxyphenoxy)propane-sebacic acid, and/or poly(D, L lactic-co-glycoli
  • the volatile silicone fluid is a cyclomethicone.
  • the cyclomethicone is cyclopentasiloxane.
  • the hydrophobic compositions comprise one or more volatile silicone fluids, but do not contain additional silicone materials.
  • the hydrophobic compositions are semi-solid compositions.
  • the hydrophobic compositions are ointments.
  • the hydrophobic compositions are not sprays and are not sprayable.
  • the hydrophobic compositions are semi-solid compositions, including ointments, and have a viscosity of from 12,500 cps to 247,500 cps, or from 25,000 cps to 150,000 cps as measured at room temperature by a Brookfield RV viscometer using a small sample adapter with a SC4-14 spindle and a 6R chamber at 5 rpm with an equilibration time of 2 minutes.
  • An alternative method for performing viscosity measurements of the hydrophobic, semi-solid compositions is using a Brookfield RV viscometer on a helipath stand with the helipath on, with a T-E spindle at 10 RPM at room temperature for 45 seconds.
  • the hydrophobic compositions are semi-solid compositions, including ointments, and have a viscosity of from 25,000 cps to 500,000 cps, or from 25,000 cps to 400,000 cps, or from 25,000 cps to 350,000 cps, or from 25,000 cps to 300,000 cps, or from 50,000 cps to 500,000 cps, or from 50,000 cps to 400,000 cps, or from 50,000 cps to 350,000 cps, or from 50,000 cps to 300,000 cps, or from 75,000 cps to 500,000 cps, or from 75,000 cps to 400,000 cps, or from 75,000 cps to 350,000 cps, or from 75,000 cps to 300,000 cps, or from 100,000 cps to 500,000 cps, or from 100,000 cps to 400,000 cps, or
  • the invention relates to compositions that inhibit crystal growth of taxane nanoparticles in carriers.
  • inhibition of crystal growth of taxane nanoparticles in carriers is accomplished by inclusion of the nanoparticles in a hydrophobic carrier.
  • the hydrophobic carriers comprise a hydrocarbon.
  • the hydrophobic carriers comprise petrolatum, mineral oil, and/or paraffin.
  • the mineral oil is heavy mineral oil.
  • the hydrophobic carriers further comprise one or more volatile silicone fluids.
  • the volatile silicone fluid is cyclomethicone.
  • the cyclomethicone is cyclopentasiloxane.
  • inhibition of crystal growth of taxane nanoparticles in aqueous carriers is accomplished by inclusion of the nanoparticles in an aqueous carrier comprising poloxamer 407, a quaternary ammonium compound, or a cross- linked acrylic acid polymer, or mixtures thereof.
  • compositions of the present invention can be formulated in various forms suitable for pharmaceutical and topical delivery.
  • Non-limiting examples include semi-solid compositions, lotions, liquid suspensions, emulsions, creams, gels, ointments, pastes, aerosol sprays, aerosol foams, non-aerosol sprays, non-aerosol foams, films, and sheets.
  • Semi-solid compositions include ointments, pastes, and creams. For purposes of this invention, semi-solid compositions are not sprayable.
  • the compositions can be impregnated in gauzes, bandages, or other skin dressing materials.
  • the compositions are semi-solid compositions.
  • the compositions are ointments.
  • compositions are gels. In still other embodiments, the compositions are liquid suspensions. In some embodiments, the compositions are not sprays and are not sprayable. In some embodiments, the compositions are not dry powders. In some embodiments, the compositions do not solely include the taxane nanoparticles.
  • compositions of the present invention can be packaged in any package configuration suitable for topical products.
  • Non-limiting examples include bottles, bottles with pumps, tottles, tubes (aluminum, plastic or laminated), jars, non-aerosol pump sprayers, aerosol containers, pouches, and packets.
  • the packages can be configured for single-dose or multiple- dose administration.
  • the compositions of the invention are hydrophobic. In other embodiments, the hydrophobic compositions are anhydrous. In various embodiments, the hydrophobic carriers are non-polar and/or non-volatile. In still other embodiments, the compositions are aqueous based. In other embodiments, the compositions of the invention are sterile. In other embodiments, the hydrophobic compositions are non-sterile. In other embodiments, the hydrophobic compositions have a low bioburden. In various embodiments, the hydrophobic compositions of the invention do not contain additional skin penetration enhancers. In other embodiments, the hydrophobic compositions of the invention do not contain additional volatile solvents.
  • the hydrophobic compositions of the invention do not contain surfactants. In other embodiments, the hydrophobic compositions of the invention do not contain alcohols, Ci - C 4 aliphatic alcohols, or Ci - Cs aliphatic alcohols. In other embodiments, the hydrophobic compositions do not contain polymers or copolymers.
  • Taxanes are poorly water soluble drugs having a solubility of less than or equal to 10 mg/niL in water at room temperature. Taxanes are widely used as chemotherapy agents.
  • the term "taxanes” as used herein include paclitaxel (I), docetaxel (II), cabazitaxel (III), and/or any other taxane derivatives.
  • the taxane nanoparticles can be paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles, or nanoparticles of other taxane derivatives.
  • Paclitaxel and docetaxel active pharmaceutical ingredients are commercially available from Phyton Biotech LLC, Vancouver, Canada.
  • the docetaxel API and nanoparticles contain not less than 90%, or not less than 95%, or not less than 97.5% docetaxel calculated on the anhydrous, solvent-free basis.
  • the paclitaxel API and nanoparticles contain not less than 90%, or not less than 95%, or not less than 97% paclitaxel calculated on the anhydrous, solvent-free basis.
  • Paclitaxel API and nanoparticles can be prepared from a semisynthetic chemical process or from a natural source such as plant cell fermentation or extraction.
  • Paclitaxel is also sometimes referred to by the trade name TAXOL, although this is a misnomer because TAXOL is the trade name of a solution of paclitaxel in polyoxyethylated castor oil and ethanol intended for dilution with a suitable parenteral fluid prior to intravenous infusion.
  • Paclitaxel is a poorly water soluble drug.
  • the solubility of paclitaxel in water is less than 0.05 ppm as determined experimentally by the solubility method described in Example 1.
  • the taxane nanoparticles can be in a crystalline form or in an amorphous form or a combination of both.
  • the taxane or paclitaxel nanoparticles are uncoated (neat) individual particles; the taxane or paclitaxel nanoparticles are not bound to or conjugated to any substance; no substances are absorbed or adsorbed onto the surface of the taxane or paclitaxel nanoparticles; the taxane or paclitaxel nanoparticles are not encapsulated in any substance; the taxane or paclitaxel nanoparticles are not coated with any substance; the taxane or paclitaxel nanoparticles are not microemulsions, nanoemulsions, microspheres, or liposomes of a taxane or paclitaxel; the taxane or paclitaxel particles are not bound to, attached to, encapsulated in, or coated with a monomer, a polymer (or biocompatible polymer), a protein, a surfactant, or albumin; and/or a monomer, a poly
  • the compositions are free of / do not include or contain a polymer/copolymer or biocompatible polymer/copolymer. In some embodiments, the compositions are free of / do not include or contain a protein. In some aspects of the invention, the compositions are free of / do not include or contain albumin. In some aspects of the invention, the compositions are free of / do not include or contain hyaluronic acid. In some aspects of the invention, the compositions are free of / do not include or contain a conjugate of hyaluronic acid and a taxane. In some aspects of the invention, the compositions are free of / do not include or contain a conjugate of hyaluronic acid and paclitaxel.
  • compositions are free of / do not include or contain poloxamers, styrene-isobutylene-styrene (SIBS), a polyanhydride copolymer, polycaprolactone, polyethylene glycol, Poly (bis(P-carboxyphenoxy)propane-sebacic acid, and/or poly(D, L lactic-co-glycolic acid (PLGA).
  • SIBS styrene-isobutylene-styrene
  • a polyanhydride copolymer polycaprolactone
  • polyethylene glycol Poly (bis(P-carboxyphenoxy)propane-sebacic acid
  • PLGA poly(D, L lactic-co-glycolic acid
  • the taxane nanoparticles can have a mean particle size (number) of from 0.01 microns to 1.5 microns, or from 0.01 microns to 1.2 microns, or from 0.01 microns to 1 micron, or from 0.01 microns to less than 1 micron, or from 0.01 microns to 0.9 microns, or from 0.01 microns to 0.8 microns, or from 0.01 microns to 0.7 microns, or from 0.1 microns to 1.5 microns, or from 0.1 microns to 1.2 microns, or from 0.1 microns to 1 micron, or from 0.1 microns to less than 1 micron, or from 0.1 microns to 0.9 microns, or from 0.1 microns to 0.8 microns, or from 0.1 to 0.7 microns, or from 0.2 microns to 1.5 micron
  • the particle size of the taxane when incorporated in a composition is determined by a particle size analyzer instrument and the measurement is expressed as the mean diameter based on a number distribution.
  • a suitable particle size analyzer instrument is one which employs the analytical technique of light obscuration, also referred to as photozone or single particle optical sensing (SPOS).
  • a suitable light obscuration particle size analyzer instrument is the ACCUSIZER available from Particle Sizing Systems, Port Richey, Florida.
  • the mean particle size of the taxane nanoparticles incorporated in a composition does not grow larger than 20% of the initial mean particle size when the composition is stored at room temperature for at least 1 month, or for at least 3 months, or for at least 6 months or for at least 12 months.
  • the term "initial mean particle size", as used herein with regard to the particle size of taxane nanoparticles, is the mean particle size of the taxane incorporated in the composition when measured by a particle size analyzer instrument within 45 days after the completion of manufacture of the composition (date of manufacture), and the initial mean particle size is from 0.1 microns to 1.5 microns (number) or from 0.01 microns to 1.5 microns (number).
  • Nanoparticles of taxanes can be manufactured using various particle size-reduction methods and equipment known in the art. Such methods include, but are not limited to, wet or dry milling, micronizing, disintegrating, pulverizing, and supercritical carbon dioxide particle size reduction methods.
  • the taxane or paclitaxel nanoparticles are made by a supercritical carbon dioxide particle reduction method (also known as "precipitation with compressed anti-solvents" or "PCA") as disclosed in US patents US 5874029, US 5833891, US 6113795, US 7744923, US 8778181, US publication 2014/0296140, US publication 2016/0354336, US publication 2016/0374953, and international patent application publication WO 2016/197091 (application no. PCT/US 16/35993) all of which are herein incorporated by reference.
  • PCA supercritical carbon dioxide particle reduction method
  • supercritical carbon dioxide anti- solvent
  • solvent e.g. acetone or ethanol
  • the carbon dioxide and acetone are removed during processing (up to 0.5% residual solvent may remain), leaving taxane nanoparticle powder generally ranging in size from about 200 nm to about 800 nm.
  • Stability studies show that the powder is stable in a vial dose form when stored at controlled room temperature (25°C/60% relative humidity) for up to 59 months and under accelerated conditions (40°C/75% relative humidity) for up to six months.
  • Taxane nanoparticles produced by various supercritical carbon dioxide particle size reduction methods can have unique physical characteristics as compared to taxane nanoparticles produced by conventional particle size reduction methods using physical impacting or grinding, e.g., wet or dry milling, micronizing, disintegrating, comminuting, microfluidizing, or pulverizing.
  • physical impacting or grinding e.g., wet or dry milling, micronizing, disintegrating, comminuting, microfluidizing, or pulverizing.
  • such unique characteristics include a bulk density (not tapped) between 0.05 g/cm 3 and 0.15 g/cm 3 and a specific surface area (SSA) of at least 18 m 2 /g of taxane (paclitaxel and docetaxel) nanoparticles, which are produced by the supercritical carbon dioxide particle size reduction methods described in US publication 2016/0354336 and international patent application publication WO 2016/197091 and as described below.
  • This bulk density range is generally lower than the bulk density of taxane particles produced by conventional means, and the SSA is generally higher than the SSA of taxane particles produced by conventional means.
  • the "specific surface area (SSA)” is the total surface area of the taxane nanoparticle per unit of taxane mass as measured by the Brunauer-Emmett-Teller ("BET") isotherm by the following method: a known mass between 200 and 300 mg of the analyte is added to a 30 mL sample tube. The loaded tube is then mounted to a Porous Materials Inc. SORPTOMETER ® , model BET-202A. The automated test is then carried out using the BETWIN ® software package and the surface area of each sample is subsequently calculated. The bulk density measurement can be conducted by pouring the taxane nanoparticles into a graduated cylinder without tapping at room temperature, measuring the mass and volume, and calculating the bulk density.
  • BET Brunauer-Emmett-Teller
  • paclitaxel nanoparticles had a SSA of 37.7 m 2 /g and a bulk density of 0.085 g/cm 3 when produced by a supercritical carbon dioxide method using the following method: a solution of 65 mg/ml of paclitaxel was prepared in acetone.
  • a BETE Micro Whirl ® fog nozzle (BETE Fog Nozzle, Inc.) and a sonic probe (Qsonica, model number Q700) were positioned in the crystallization chamber approximately 8 mm apart.
  • a stainless steel mesh filter with approximately 100 nm holes was attached to the crystallization chamber to collect the precipitated paclitaxel nanoparticles.
  • the supercritical carbon dioxide was placed in the crystallization chamber of the manufacturing equipment and brought to approximately 1200 psi at about 38 °C and a flow rate of 24 kg/hour.
  • the sonic probe was adjusted to 60% of total output power at a frequency of 20 kHz.
  • the acetone solution containing the paclitaxel was pumped through the nozzle at a flow rate of 4.5 mL/minute for approximately 36 hours.
  • paclitaxel nanoparticles produced by the supercritical carbon dioxide method described above had SSA values of: 22.27 m 2 /g, 23.90 m 2 /g, 26.19 m 2 /g, 30.02 m 2 /g, 31.16 m 2 /g, 31.70 m 2 /g, 32.59 m 2 /g, 33.82 m 2 /g, 35.90 m 2 /g, 38.22 m 2 /g, and 38.52 m 2 /g.
  • docetaxel nanoparticles had a SSA of 44.2 m 2 /g and a bulk density of 0.079 g/cm 3 when produced by a supercritical carbon dioxide method using the following method: A solution of 79.32 mg/ml of docetaxel was prepared in ethanol. The nozzle and a sonic probe were positioned in the pressurizable chamber approximately 9 mm apart. A stainless steel mesh filter with approximately 100 nm holes was attached to the pressurizable chamber to collect the precipitated docetaxel nanoparticles.
  • the supercritical carbon dioxide was placed in the pressurizable chamber of the manufacturing equipment and brought to approximately 1200 psi at about 38 °C and a flow rate of 68 slpm.
  • the sonic probe was adjusted to 60% of total output power at a frequency of 20 kHz.
  • the ethanol solution containing the docetaxel was pumped through the nozzle at a flow rate of 2 mL/minute for approximately 95 minutes).
  • the precipitated docetaxel agglomerates and particles were then collected from the supercritical carbon dioxide as the mixture is pumped through the stainless steel mesh filter.
  • the filter containing the nanoparticles of docetaxel was opened and the resulting product was collected from the filter.
  • paclitaxel approximately 50 mg of material were coated on approximately 1.5 grams of 1 mm glass beads by tumbling the material and beads in a vial for approximately 1 hour. Beads were transferred to a stainless steel mesh container and placed in the dissolution bath containing methanol/water 50/50 (v/v) media at 37°C, pH 7, and a USP Apparatus II (Paddle), operating at 75 rpm. At 10, 20, 30, 60, and 90 minutes, a 5 mL aliquot was removed, filtered through a 0.22 ⁇ filter and analyzed on a UV/VIS spectrophotometer at 227 nm. Absorbance values of the samples were compared to those of standard solutions prepared in dissolution media to determine the amount of material dissolved.
  • the dissolution rate was 47% dissolved in 30 minutes for the nanoparticles made by the supercritical carbon dioxide method versus 32% dissolved in 30 minutes for the nanoparticles made by milling.
  • the dissolution rate was 27% dissolved in 30 minutes for the nanoparticles made by the supercritical carbon dioxide method versus 9% dissolved in 30 minutes for the nanoparticles made by milling.
  • the paclitaxel nanoparticles have an SSA of at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, or at least 35 m 2 /g.
  • the paclitaxel nanoparticles have an SSA of 18 m 2 /g to 50 m 2 /g, or 20 m 2 /g to 50 m 2 /g, or 22 m 2 /g to 50 m 2 /g, or 25 m 2 /g to 50 m 2 /g, or 30 m 2 /g to 50 m 2 /g, or 18 m 2 /g to 45 m 2 /g, or 20 m 2 /g to 45 m 2 /g, or 22 m 2 /g to 45 m 2 /g, or 25 m 2 /g to 45 m 2 /g, or 30 m 2 /g to 45 m 2 /g, or 18 m 2 /g to 40 m 2 /g, or 20 m 2 /g to 40 m 2 /g ,or 22 m 2 /g to 40 m 2 /g, or 25 m 2 /g to 40 m 2 /g, or
  • the paclitaxel nanoparticles have a bulk density (not- tapped) of 0.05 g/cm 3 to 0.15 g/cm 3 , or 0.05 g/cm 3 to 0.20 g/cm 3 .
  • the paclitaxel nanoparticles have a dissolution rate of at least 40% w/w dissolved in 30 minutes or less in a solution of 50% methanol/50% water (v/v) in a USP II paddle apparatus operating at 75 RPM, at 37°C, and at a pH of 7.
  • the docetaxel nanoparticles have an SSA of at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, or at least 42 m 2 /g.
  • the docetaxel nanoparticles have an SSA of 18 m 2 /g to 60 m 2 /g, or 22 m 2 /g to 60 m 2 /g, or 25 m 2 /g to 60 m 2 /g, or 30 m 2 /g to 60 m 2 /g, or 40 m 2 /g to 60 m 2 /g, or 18 m 2 /g to 50 m 2 /g, or 22 m 2 /g to 50 m 2 /g, or 25 m 2 /g to 50 m 2 /g, or 30 m 2 /g to 50 m 2 /g, or 40 m 2 /g to 50 m 2 /g.
  • the docetaxel nanoparticles have a bulk density (not-tapped) of 0.05 g/cm 3 to 0.15 g/cm 3 .
  • the docetaxel nanoparticles have a dissolution rate of at least 20% w/w dissolved in 30 minutes or less in a solution of 15% methanol/85% water (v/v) in a USP II paddle apparatus operating at 75 RPM, at 37°C, and at a pH of 7.
  • paclitaxel nanoparticle crystals have a tendency to grow in suspensions of water or saline solutions over time forming large needle-like crystals.
  • a crystal growth study was conducted and the results are shown in Table 2 in Example 2 below. It was found that the nanoparticle crystals did not grow in the hydrophobic materials. Also, and surprisingly, the nanoparticle crystals did not grow in aqueous solutions of benzalkonium chloride, CARBOPOL ULTREZ 10, or poloxamer 407.
  • the hydrophobic carriers of the present invention can comprise substances from plant, animal, paraffinic, and/or synthetically derived sources. Hydrophobic substances are generally known as substances that lack an affinity for and repel water.
  • the hydrophobic carrier can be the continuous phase of the compositions.
  • the hydrophobic carriers are non-polar and/or non-volatile. Non-limiting examples include fats, butters, greases, waxes, solvents, and oils; mineral oils; vegetable oils; petrolatums; water insoluble organic esters and triglycerides; and fluorinated compounds.
  • the hydrophobic carriers can also comprise silicone materials.
  • Silicone materials are defined as compounds based on polydialkylsiloxanes and include polymers, elastomers (crosslinked silicones), and adhesives (branched silicones).
  • Non-limiting examples of silicone materials include dimethicone (polydimethylsiloxane), dimethicone copolyol, cyclomethicone, simethicone, silicone elastomers such as ST-elastomer 10 (DOW CORNING), silicone oils, silicone polymers, volatile silicone fluids, and silicone waxes.
  • the hydrophobic carrier does not comprise silicone materials.
  • Plant derived materials include, but are not limited to, arachis (peanut) oil, balsam Peru oil, carnauba wax, candellila wax, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, corn oil, cotton seed oil, jojoba oil, macadamia seed oil, olive oil, orange oil, orange wax, palm kernel oil, rapeseed oil, safflower oil, sesame seed oil, shea butter, soybean oil, sunflower seed oil, tea tree oil, vegetable oil, and hydrogenated vegetable oil.
  • arachis (peanut) oil balsam Peru oil, carnauba wax, candellila wax, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, corn oil, cotton seed oil, jojoba oil, macadamia seed oil, olive oil, orange oil, orange wax, palm kernel oil, rapeseed oil, safflower oil, sesame seed oil, shea butter, soybean oil, sunflower seed oil, tea tree oil, vegetable oil, and hydrogenated
  • Non-limiting examples of animal derived materials include beeswax (yellow wax and white wax), cod liver oil, emu oil, lard, mink oil, shark liver oil, squalane, squalene, and tallow.
  • Non-limiting examples of paraffinic materials include isoparaffin, microcrystalline wax, heavy mineral oil, light mineral oil, ozokerite, petrolatum, white petrolatum, and paraffin wax.
  • Non-limiting examples of organic esters and triglycerides include CI 2- 15 alkyl benzoate, isopropyl myristate, isopropyl palmitate, medium chain triglycerides, mono- and di- glycerides, trilaurin, and trihydroxystearin.
  • PFPE perfluoropolyether
  • the hydrophobic carriers of the present invention can comprise pharmaceutical grade hydrophobic substances.
  • the hydrophobic carriers comprise petrolatum, mineral oil, or paraffin, or mixtures thereof.
  • the mineral oil is heavy mineral oil.
  • the hydrophobic carriers are not polymeric matrices and do not contain a polymer or biodegradable polymer, such as styrene-isobutylene-styrene (SIBS), a polyanhydride copolymer, polycaprolactone, polyethylene glycol, Poly (bis(P-carboxyphenoxy)propane-sebacic acid, and/or poly(D, L lactic-co-glycolic acid (PLGA), and/or do not contain a copolymer such as a poloxamer.
  • SIBS styrene-isobutylene-styrene
  • a polyanhydride copolymer polycaprolactone
  • polyethylene glycol Poly (bis(P-carboxyphenoxy)propane-sebacic acid
  • PLGA poly(D, L lactic-co-glycolic acid
  • the concentration of the hydrophobic carrier in the compositions is greater than 10% w/w of the total composition weight. In other embodiments, the concentration of the hydrophobic carrier in the compositions is greater than 15%, or greater than 20%, or greater than 25%, or greater than 30%, or greater than 35%, or greater than 40%, or greater than 45%, or greater than 50%, or greater than 55%, or greater than 60%, or greater than 65%, or greater than 70%, or greater than 75%, or greater than 80%, or greater than 82%, or greater than 85%, or greater than 87%, or greater than 90% w/w of the total composition weight.
  • the concentration of the hydrophobic carrier in the compositions is from greater than 10% w/w to 95% w/w of the total composition weight. In other embodiments, the concentration of the hydrophobic carrier in the compositions is from 11% w/w to 95% w/w, or from 12% w/w to 95% w/w, or from 13% w/w to 95% w/w, or from 14% w/w to 95% w/w, or from 15% w/w to 95% w/w, or from 16% w/w to 95% w/w, or from 17% w/w to 95% w/w, or from 18% w/w to 95% w/w, or from 19 % w/w to 95% w/w, or from 20% w/w to 95% w/w of the total composition weight,
  • Petrolatum is a purified mixture of semi-solid saturated hydrocarbons obtained from petroleum, and varies from dark amber to light yellow in color.
  • White petrolatum is wholly or nearly decolorized and varies from cream to snow white in color.
  • Petrolatums are available with different melting point, viscosity, and consistency characteristics.
  • Petrolatums may also contain a stabilizer such as an antioxidant.
  • Pharmaceutical grades of petrolatum include Petrolatum USP and White Petrolatum USP.
  • Various petrolatums are available commercially from the Penreco Corporation under the trade names: ULTIMA, SUPER, SNOW, REGENT, LILY, CREAM, ROYAL, BLOND, and AMBER.
  • Various grades of petrolatum are also available commercially from the Sonneborn Corporation under the trade names: ALBA, SUPER WHITE PROTOPET, SUPER WHITE FONOLINE, WHITE PROTOPET IS, WHITE PROTOPET 2L, WHITE PROTOPET 3C, WHITE FONOLINE, PERFECTA, YELLOW PROTOPET 2A, YELLOW FONOLINE, PROTOLINE, SONOJELL #4, SONOJELL #9, MINERAL JELLY #10, MINERAL JELLY #14, MINERAL JELLY #17, AND CARNATION TROUGH GREASE.
  • Petrolatums are also available from the Spectrum Chemical Mfg. Corp.
  • Mineral oil is a mixture of liquid hydrocarbons obtained from petroleum. Mineral oil is available in various viscosity grades, such as light mineral oil, heavy mineral oil, and extra heavy mineral oil. Light mineral oil has a kinematic viscosity of not more than 33.5 centistokes at 40°C. Heavy mineral oil has a kinematic viscosity of not less than 34.5 centistokes at 40°C. Mineral oil may contain a suitable stabilizer. Pharmaceutical grades of mineral oil include Mineral Oil USP, which is heavy mineral oil, and Light Mineral Oil NF, which is light mineral oil.
  • Mineral oil is commercially available from the Penreco Corporation under the DRAKEOL trade name, and the Sonneborn Corporation under the trade names BENOL, BLANDOL, BRITOL, CARNATION, ERVOL, GLORIA, KAYDOL, KLEAROL, PROTOL, and RUDOL. Mineral oil is also commercially available from the Spectrum Chemical Mfg. Corp.
  • Paraffin wax is a purified mixture of solid hydrocarbons obtained from petroleum. It may also be synthetically derived by the Fischer- Tropsch process from carbon monoxide and hydrogen which are catalytically converted to a mixture of paraffin hydrocarbons. Paraffin wax may contain an antioxidant. Pharmaceutical grades of paraffin wax include Paraffin NF and Synthetic Paraffin NF. Paraffin waxes are commercially available from the Spectrum Chemical Mfg. Corp, Koster Keunen, Inc. and Frank B. Ross, Inc.
  • Volatile silicone fluids also known as volatile silicone oils, are volatile liquid polysiloxanes which can by cyclic or linear. They are liquid at room temperature. Volatile silicone fluids are hydrophobic materials. Linear volatile silicone fluids include polydimethylsiloxane, hexamethyldisiloxane and octamethyltrisiloxane and are commercially available from Dow Corning under the trade names DOW CORNING Q7-9180 Silicone Fluid 0.65 cSt and DOW CORNING Q7-9180 Silicone Fluid 1.0 cSt, respectively. Cyclic volatile silicone fluids are generally known as cyclomethicones.
  • Cyclomethicone is a fully methylated cyclic siloxane containing repeating units of formula (IV):
  • Cyclomethicone is a clear, colorless volatile liquid silicone fluid. Cyclomethicone has emollient properties and helps to improve the tactile feel of an oil based product by making it feel less greasy on the skin.
  • Pharmaceutical grade cyclomethicone includes Cyclomethicone NF. Cyclomethicone NF is represented by formula (IV) in which n is 4 (cyclotetrasiloxane), 5 (cyclopentasiloxane), or 6 (cyclohexasiloxane); or mixtures thereof.
  • Cyclopentasiloxane also known as decamethylcylcopentasiloxane, cyclomethicone D5, or cyclomethicone 5, is the cyclomethicone represented by formula (IV) in which n is 5 (pentamer), but it can contain small amounts (generally less than 1%) of one or more of the other cyclic chain length cyclomethicones. Cyclopentasiloxane is available in a pharmaceutical grade as Cyclomethicone NF.
  • Cyclomethicones are commercially available from Dow Corning under the trade names DOW CORNING ST-Cyclomethicone 5-NF, DOW CORNING ST-Cyclomethicone 56-NF, and XIAMETER PMX-0245. It is also commercially available from the Spectrum Chemical Mfg. Corp. Cyclopentasiloxane has a vapor pressure of about 20 to about 27 Pa at 25 °C.
  • Cyclomethicone has been shown to be non-irritating to vaginal tissues.
  • a PK study was performed in rhesus macaques to determine plasma, vaginal fluid and vaginal tissue levels.
  • LDH and other proteins are released from the foot of a slug in response to cell damage, and serve as markers for mucosal toxicity.
  • the test was performed by placing a slug on top of a sample for 30 minutes. The slug was subsequently transferred to a petri dish containing PBS for 60 minutes, and then a second PBS petri dish for an additional 60 minutes. The amounts of LDH protein and mucous left behind in the PBS were measured to determine irritability of the samples. LDH and mucus levels of the silicone elastomer gel and HEC were both comparable to the negative control.
  • the concentration of cyclomethicone in the composition is less than 25% w/w. In another embodiment, the cyclomethicone in the composition is at a concentration from 5 to 24% w/w. In another embodiment, the concentration of cyclomethicone is from 5 to 20% w/w. In another embodiment, the cyclomethicone is at a concentration of from 5 to 18% w/w. In another embodiment, the concentration of cyclomethicone is 13% w/w.
  • the concentration of cyclomethicone can be 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, or 24% w/w or any percentage derivable therein of the total composition weight.
  • the cyclomethicone is cyclopentasiloxane.
  • Aqueous based compositions of the invention comprise taxane nanoparticles and an aqueous carrier.
  • the aqueous formulations are dispersions (suspensions) of the taxane nanoparticles in an aqueous carrier.
  • the taxane nanoparticles can be completely dispersed, partially dispersed and partially dissolved, but not completely dissolved in the aqueous carrier.
  • An aqueous based composition is a composition in which water is the major constituent.
  • Aqueous carriers can include single phase aqueous solutions, and multi-phase aqueous based emulsions such oil-in-water and water-in-oil emulsions.
  • taxane nanoparticle crystals such as paclitaxel nanoparticles
  • paclitaxel nanoparticles rapidly grew in water and in aqueous based carriers. In many cases, the growth was observed in as little as 3 days at room temperature, and some cases in 24 hours. Many of the crystals were needle-like in shape and were larger than 5 ⁇ in length.
  • Table 2 A study was conducted and the results are shown in Table 2 in Example 2.
  • the taxane nanoparticle crystal growth was inhibited by the addition of poloxamer 407, a quaternary ammonium compound, or a cross- linked acrylic acid polymer to the aqueous based carrier during processing. The addition of poloxamer 188 did not inhibit the growth of the nanoparticle crystals.
  • an aqueous based composition comprising an aqueous carrier; a plurality of taxane nanoparticles; and a quaternary ammonium compound, or a cross-linked acrylic acid polymer, or mixtures thereof; wherein the mean particle size of the taxane nanoparticles is from 0.1 microns to 1.5 microns (number) or from 0.01 microns to 1.5 microns (number), and wherein the mean particle size of the taxane nanoparticles does not grow larger than 20% of the initial mean particle size when the composition is stored at room temperature for at least 6 months.
  • the composition further comprises poloxamer 407.
  • compositions comprising taxane nanoparticles, an aqueous carrier, and poloxamer 407, a quaternary ammonium compound, or a cross-linked acrylic acid polymer, or mixtures thereof. It was surprisingly found that the addition of poloxamer 407, a quaternary ammonium compound, or a cross-linked acrylic acid polymer inhibited the crystal growth of the taxane nanoparticles in aqueous carriers.
  • the aqueous based compositions of the invention are suitable for topical, injectable, (IV) infusion, or oral liquid dosage forms.
  • the additive to inhibit crystal growth is poloxamer 407.
  • the quaternary ammonium compound is the additive to inhibit crystal growth and is benzalkonium chloride or benzethonium chloride. In other embodiments, the quaternary ammonium compound is benzalkonium chloride. In other embodiments, the cross-linked acrylic acid polymer is the additive to inhibit crystal growth and is Carbomer.
  • the composition comprises poloxamer 407 and taxane nanoparticles in an aqueous carrier suitable for injection delivery including (IV) infusion.
  • the taxane nanoparticles are docetaxel nanoparticles, paclitaxel nanoparticles, or cabazitaxel nanoparticles.
  • the composition comprises a quaternary ammonium compound and taxane nanoparticles in an aqueous carrier suitable for injection delivery including (IV) infusion.
  • the taxane nanoparticles are docetaxel nanoparticles, paclitaxel nanoparticles, or cabazitaxel nanoparticles.
  • the quaternary ammonium compounds are benzalkonium chloride or benzethonium chloride.
  • aqueous based carrier comprising adding poloxamer 407, a quaternary ammonium compound, or a cross-linked acrylic acid polymer, or mixtures thereof, to the aqueous based carrier during processing, wherein the mean particle size of the taxane nanoparticles is from 0.1 microns to 1.5 microns (number) or from 0.01 microns to 1.5 microns (number).
  • the quaternary ammonium compound is benzalkonium chloride or benzethonium chloride.
  • the cross-linked acrylic acid polymer is carbomer.
  • the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles. In still other embodiments, the taxane nanoparticles are paclitaxel nanoparticles.
  • Poloxamer 407 is a solid, hydrophilic, nonionic, synthetic block copolymer of ethylene oxide and propylene oxide conforming to the general formula (V)
  • Poloxamer 407 has an average molecular weight of 9840-14600.
  • the term "poloxamer” is the nonproprietary name of the copolymer. Poloxamers are available in several types which have various physical forms and various average molecular weights. Each specific poloxamer type is identified by the nonproprietary name "poloxamer” followed by a three digit number, the first two digits of which when multiplied by 100 correspond to the approximate average molecular weight of the polyoxypropylene portion of the copolymer; and the third digit, when multiplied by 10, corresponds to the percentage by weight of the polyoxyethylene portion. Poloxamers are available in pharmaceutical, cosmetic, and industrial grades.
  • poloxamers are listed in recognized pharmaceutical compendia such as USP/NF and European Pharmacopeia (PhEur). According to the USP/NF and PhEur, a suitable antioxidant may be added. Poloxamer 407 is commercially available from BASF under the trade name PLURONIC® F127. The addition of poloxamer 188 to an aqueous carrier did not inhibit crystal growth of the taxane nanoparticles.
  • Suitable concentrations of Poloxamer 407 are at least 2% w/w, or from 0.1 to 25% w/w, or from 0.1 to 20% w/w, or from 0.1 to 15% w/w, or from 0.1 to 10% w/w, or from 1 to 25% w/w, or from 1 to 20% w/w, or from 1 to 15% w/w, or from 1 to 10% w/w, or from 2 to 25% w/w, or from 2 to 20% w/w, or from 2 to 15% w/w, or from 2 to 10% w/w.
  • Quaternary ammonium compounds are positively charged tetra- substituted nitrogen derivatives of formula (VI)
  • R 1 , R 2 , R 3 , and R 4 may be the same or different, but may not be hydrogen.
  • X " represents a typical anion such as chloride.
  • Suitable quaternary ammonium compounds include benzalkonium chloride and benzethonium chloride. Benzalkonium chloride is commercially available in a 100% powder or a 50% aqueous solution. Other examples of quaternary ammonium compounds are disclosed in the International Cosmetic Ingredient Dictionary and Handbook, 12th edition, 2008 herein incorporated by reference.
  • Suitable concentrations of quaternary ammonium compounds are at least 0.05% w/w, or at least 0.1% w/w, or at least 1% w/w, or at least 2% w/w, or from 0.05 to 5% w/w, or from 0.1 to 5% w/w, or from 1 to 5% w/w, or from 2 to 5% w/w.
  • Cross-linked acrylic acid polymers are high molecular weight homo- and copolymers of acrylic acid cross-linked with a polyalkenyl polyether.
  • Suitable cross-linked acrylic acid polymers include Carbomer (INCI name), Acrylates Copolymer (INCI name), Acrylates/C 10-30 Alkyl Acrylate Crosspolymer (INCI name), Acrylates Crosspolymer-4 (INCI name), and Polyacrylate- 1 Crosspolymer (INCI name).
  • the above mentioned polymers are all commercially available from the Lubrizol Corporation under the CARBOPOL® trade name.
  • Carbomer available from the Lubrizol Corporation examples include CARBOPOL 934, CARBOPOL 934P, CARBOPOL 940, CARBOPOL 941, CARBOPOL 980, CARBOPOL 981, CARBOPOL 2984, CARBOPOL 5984, CARBOPOL SILK 100, CARBOPOL ETD 2050, ULTREZ 10, and ULTREZ 30.
  • Examples of Acrylates Copolymer available from the Lubrizol Corporation include CARBOPOL AQUA SF-1, and CARBOPOL AQUA SF-1 OS.
  • Examples of Acrylates/C 10-30 Alkyl Acrylate Crosspolymer available from the Lubrizol Corporation include CARBOPOL ULTREZ 20, CARBOPOL ULTREZ 21, CARBOPOL ETD 2020, CARBOPOL 1342, CARBOPOL 1382, and CARBOPOL SC-200.
  • An example of Acrylates Crosspolymer-4 is CARBOPOL AQUA SF-2.
  • An example of Polyacrylate- 1 Crosspolymer is CARBOPOL AQUA CC. Suitable concentrations of cross- linked acrylic acid polymers are at least 0.1% w/w, or 0.5% w/w, or from 0.1 to 5% w/w, or from 0.5 to 5% w/w. E. Additional Ingredients and Adjuvants
  • compositions of the invention can further comprise functional ingredients suitable for use in pharmaceutical compositions.
  • functional ingredients suitable for use in pharmaceutical compositions include absorbents, acidifying agents, antimicrobial agents, antioxidants, binders, biocides, buffering agents, bulking agents, crystal growth inhibitors, chelating agents, colorants, deodorant agents, emulsion stabilizers, film formers, fragrances, humectants, lytic agents, enzymatic agents, opacifying agents, oxidizing agents, pH adjusters, plasticizers, preservatives, reducing agents, emollient skin conditioning agents, humectant skin conditioning agents, moisturizers, surfactants, emulsifying agents, cleansing agents, foaming agents, hydrotopes, solvents, suspending agents, viscosity control agents (rheology modifiers), viscosity increasing agents (thickeners), and propellants.
  • Listings and monographs of the examples of the functional ingredients described herein are disclosed in The International Cosmetic Ingredient Dictionary and Handbook (INCI), 12
  • compositions of the invention can further comprise additional pharmaceutically active ingredients, cosmetically active ingredients, and veterinary agents suitable for topical use.
  • the hydrophobic compositions of the present invention can further comprise additional penetration enhancers, it was found that it was not necessary to include additional penetration enhancers to increase the skin penetration (i.e., into the epidermal and dermal portions of skin) of the taxane nanoparticles in hydrophobic compositions comprising a hydrophobic carrier and one or more volatile silicone fluids. In fact, the additions of skin penetration enhancers had little or no effect on the skin penetration of the hydrophobic compositions.
  • penetration enhancer has been used to describe compounds or materials or substances that facilitate drug absorption through the skin. These compounds or materials or substances can have a direct effect on the permeability of the skin, or they can augment percutaneous absorption by increasing the thermodynamic activity of the penetrant, thereby increasing the effective escaping tendency and concentration gradient of the diffusing species.
  • Non-limiting examples of skin penetration enhancers include oleyl alcohol, isopropyl myristate, dimethyl isosorbide (DMI) available under the tradename ARLASOLVE DMI, and Diethylene Glycol Monoethyl Ether (DGME) which is available under the trade name TRANSCUTOL P.
  • DMI dimethyl isosorbide
  • DGME Diethylene Glycol Monoethyl Ether
  • Other examples of skin penetration enhancers can be found in "Skin Penetration Enhancers Cited in the Technical Literature", Osborne, David W., and Henke, Jill J., Pharmaceutical Technology, November 1997, herein incorporated by reference.
  • Such examples include: Fatty alcohols such as aliphatic alcohols, Decanol, Lauryl alcohol (dodecanol), Linolenyl alcohol, Nerolidol, 1-Nonanol, n-Octanol, Oleyl alcohol, Fatty acid esters, Butylacetate, Cetyl lactate, Decyl N,N-dimethylamino acetate, Decyl N,N- dimethylamino isopropionate, Diethyleneglycol oleate, Diethyl sebacate, Diethyl succinate, Diisopropyl sebacate, Dodecyl N,N-dimethylamino acetate, Dodecyl (N,N-dimethylamino)- butyrate, Dodecyl N,N-dimethylamino isopropionate, Dodecyl 2-(dimethylamino) propionate, EO-5-oleyl ester, Ethyl acetate
  • penetration enhancers include glycofurol, lanolin, light mineral oil, myristic acid, polyoxyethylene alky ethers, and thymol.
  • Other examples of penetration enhancers include ethanolamine, diethanolamine, triethanolamine, diethylene glycol, monoethyl ether, citric acid, succinic acid, borage oil, tetrahydropiperine (THP), methanol, ethanol, propanol, octanol, benzyl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, and polyethylene glycol monolaurate.
  • compositions of the invention can further comprise alcohols, it is not necessary for the compositions to contain alcohols, Ci -C 4 aliphatic alcohols, or Ci -C5 aliphatic alcohols. In some aspects of the invention, the compositions are free of / do not include or contain Ci -C 4 aliphatic alcohols, or Ci -C5 aliphatic alcohols.
  • the hydrophobic compositions of the invention can further comprise additional volatile solvents, it is not necessary for the hydrophobic compositions to contain additional volatile solvents.
  • Volatile solvents are also known as "fugitive" solvents.
  • volatile solvents include volatile alcohols, such as Ci to C 4 aliphatic alcohols; and volatile Ci to C 4 aliphatic ketones, such as acetone.
  • the compositions are free of / do not include or contain volatile Ci to C 4 aliphatic ketones.
  • the compositions are free of / do not include or contain volatile Ci to C 4 aliphatic alcohols.
  • hydrophobic compositions of the invention can further comprise surfactants, it is not necessary for the hydrophobic compositions to contain surfactants.
  • surfactant or "surface active agent” means a compound or material or substance that exhibits the ability to lower the surface tension of water or to reduce the interfacial tension between two immiscible substances and includes anionic, cationic, nonionic, amphoteric, and/or phospholipid surfactants.
  • Non-limiting examples of surfactants can be found in McCutcheon's Emulsifiers & Detergents, 2001 North American Edition herein incorporated by reference and also in the International Cosmetic Ingredient Dictionary and Handbook (INCI), 12th Edition, 2008, herein incorporated by reference.
  • Such examples include, but are not limited to, the following: block polymers, e.g., Poloxamer 124; ethoxylated alcohols e.g., Ceteth-2, Ceteareth-20, Laureth-3; ethoxylated fatty esters and oils, e.g., PEG-40 Hydrogenated Castor Oil, PEG-36 Castor Oil, PEG-150 Distearate; glycerol esters, e.g., Polyglyceryl-3 Diisostearate, Glyceryl Stearate; glycol esters, PEG- 12 Dioleate, LEXEMUL P; phosphate esters, e.g., Cetyl Phosphate; polymeric surfactants, e.g., PVM/MA Copolymer, Acrylates/C 10-30 Alkyl Acrylate Crosspolymer; quaternary surfactants, e.g., Cetrimonium Chloride; Silicone Based Surfactants, e.g.
  • surfactants can be classified by their ionic type such as anionic, cationic, nonionic, or amphoteric. They can also be classified by their chemical structures, such as block polymers, ethoxylated alcohols, ethoxylated fatty esters and oils, glycerol esters, glycol esters, phosphate esters, polymeric surfactants, quaternary surfactants, silicone-based surfactants, sorbitan derivatives, sucrose and glucose esters and derivatives, and sulfates of alcohols.
  • ionic type such as anionic, cationic, nonionic, or amphoteric. They can also be classified by their chemical structures, such as block polymers, ethoxylated alcohols, ethoxylated fatty esters and oils, glycerol esters, glycol esters, phosphate esters, polymeric surfactants, quaternary surfactants, silicone-based surfactants, sorbitan derivatives, sucrose and glucose esters and derivative
  • compositions of the invention may be manufactured by methods and equipment known in the art for manufacture of pharmaceutical products including topical, injectable, and oral liquid products. Such methods include, but are not limited to the use of mechanical mixers, dis solvers, dispersers, homogenizers, and mills. Non-limiting examples include LIGHTNIN propeller mixers, COWLES dissolvers, IKA ULTRA TURRAX dispersers, SILVERSON homogenizers, LEE counter-rotating side-scraping mixers, in-line and in-tank rotor-stator homogenizers, 3-roll mills, ointment mills, and rotor-stator mills.
  • All- in-one vacuum mixing systems that have a rotating side-scraping mixer plus an in-tank homogenizer may also be used.
  • Such mixers include, but are not limited to OLSA mixers, FRYMA-KORUMA mixers, and LEE TRI-MIX TURBO-SHEAR kettles.
  • the compositions of the invention can be manufactured from small laboratory scale batches using laboratory mixing equipment to full-scale production batches.
  • a method for enhancing penetration of taxane nanoparticles into vulvar intraepithelial neoplasia (VIN) and/or genital warts comprising applying to the affected area of the VIN and/or genital warts the topical compositions disclosed herein.
  • the method comprises applying to the affected area of the VIN and/or genital warts a hydrophobic composition which comprises a hydrophobic carrier, one or more volatile silicone fluids, and a plurality of taxane nanoparticles.
  • the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.
  • the taxane nanoparticles, including paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles have a mean particle size (number) of from 0.01 microns to 1.5 microns, or from 0.01 microns to 1.2 microns, or from 0.01 microns to 1 micron, or from 0.01 microns to less than 1 micron, or from 0.01 microns to 0.9 microns, or from 0.01 microns to 0.8 microns, or from 0.01 microns to 0.7 microns, or from 0.1 microns to 1.5 microns, or from 0.1 microns to 1.2 microns, or from 0.1 microns to 1 micron, or from 0.1 microns to less than 1 micron, or from 0.1 microns
  • the taxane nanoparticles are paclitaxel nanoparticles.
  • the paclitaxel nanoparticles have an SSA of at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, or at least 35 m 2 /g.
  • the paclitaxel nanoparticles have an SSA of 18 m 2 /g to 50 m 2 /g, or 20 m 2 /g to 50 m 2 /g, or 22 m 2 /g to 50 m 2 /g, or 25 m 2 /g to 50 m 2 /g, or 30 m 2 /g to 50 m 2 /g, or 18 m 2 /g to 45 m 2 /g, or 20 m 2 /g to 45 m 2 /g, or 22 m 2 /g to 45 m 2 /g, or 25 m 2 /g to 45 m 2 /g, or 30 m 2 /g to 45 m 2 /g, or 18 m 2 /g to 40 m 2 /g, or 20 m 2 /g to 40 m 2 /g , or 22 m 2 /g to 40 m 2 /g, or 25 m 2 /g to 40 m 2 m 2 /
  • the paclitaxel nanoparticles have a bulk density (not-tapped) of 0.05 g/cm 3 to 0.15 g/cm 3 , or 0.05 g/cm 3 to 0.20 g/cm 3 .
  • the hydrophobic carriers are non-polar and/or non-volatile.
  • the hydrophobic carriers comprise a hydrocarbon.
  • the hydrophobic carriers comprise petrolatum, mineral oil, and paraffin.
  • the mineral oil is heavy mineral oil.
  • the concentration of the volatile silicone fluid in the composition formulation is at an amount effective to enhance skin penetration of the taxane nanoparticles as compared to the formulation without the volatile silicone fluid.
  • a suitable method for measuring penetration into VIN and/or genital warts can be by use of an in vitro Franz diffusion cell (FDC) system using human cadaver skin or other suitable membrane.
  • FDC in vitro Franz diffusion cell
  • a suitable in vitro Franz diffusion cell system is described in Example 9 below.
  • the one or more volatile silicone fluid is at a concentration from 5 to 24% w/w. In other embodiments, the concentration of the one or more volatile silicone fluid is from 5 to 20% w/w. In other embodiments, the one or more volatile silicone fluid is at a concentration of from 5 to 18% w/w. In still other embodiments, the concentration of the one or more volatile silicone fluid is 13% w/w.
  • the concentration of the one or more volatile silicone fluid can be 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, or 24% w/w or any percentage derivable therein of the total composition weight.
  • the one or more volatile silicone fluid is cyclomethicone.
  • the cyclomethicone is cyclopentasiloxane.
  • the hydrophobic compositions do not contain additional penetration enhancers.
  • the hydrophobic compositions do not contain laurocapram and/or diethylene glycol monoethyl ether (DGME), and/or isopropyl myristate, and/or alpha tocopherol. In other embodiments, the hydrophobic compositions do not contain additional volatile solvents. In still other embodiments, the hydrophobic compositions do not contain a surfactant. In other embodiments, the hydrophobic compositions are free of / do not include or contain alcohols, or Ci to C 4 aliphatic alcohols, or Ci to Cs aliphatic alcohols. In some embodiments, the hydrophobic compositions comprise one or more volatile silicone fluids, but do not contain additional silicone materials.
  • DGME laurocapram and/or diethylene glycol monoethyl ether
  • isopropyl myristate and/or alpha tocopherol.
  • the hydrophobic compositions do not contain additional volatile solvents.
  • the hydrophobic compositions do not contain a surfactant.
  • the compositions do not contain hyaluronic acid, and/or do not contain a conjugate of hyaluronic acid and a taxane, and/or do not contain a conjugate of hyaluronic acid and paclitaxel. In some embodiments, the compositions do not contain a polymer or a biodegradable polymer.
  • the compositions do not contain a poloxamer, styrene-isobutylene-styrene (SIBS), a polyanhydride copolymer, polycaprolactone, polyethylene glycol, Poly (bis(P-carboxyphenoxy)propane-sebacic acid, and/or poly(D, L lactic-co-glycolic acid.
  • the taxane can be paclitaxel, docetaxel, or cabazitaxel.
  • the VIN is usual VIN (uVIN).
  • the VIN is differentiated VIN (dVIN).
  • the genital warts are external genital warts.
  • the hydrophobic compositions are sterile. In other embodiments, the hydrophobic compositions are non-sterile. In other embodiments, the hydrophobic compositions have a low bioburden. In some embodiments, the hydrophobic compositions are semi-solid compositions. In still other embodiments, the hydrophobic compositions are ointments.
  • the hydrophobic compositions are semi-solid compositions, including ointments, and have a viscosity of from 12,500 cps to 247,500 cps, or from 25,000 cps to 150,000 cps as measured at room temperature by a Brookfield RV viscometer using a small sample adapter with a SC4-14 spindle and a 6R chamber at 5 rpm with an equilibration time of 2 minutes.
  • An alternative method for performing viscosity measurements of the hydrophobic, semi-solid compositions is using a Brookfield RV viscometer on a helipath stand with the helipath on, with a T-E spindle at 10 RPM at room temperature for 45 seconds.
  • the hydrophobic compositions are semi-solid compositions, including ointments, and have a viscosity of from 25,000 cps to 500,000 cps, or from 25,000 cps to 400,000 cps, or from 25,000 cps to 350,000 cps, or from 25,000 cps to 300,000 cps, or from 50,000 cps to 500,000 cps, or from 50,000 cps to 400,000 cps, or from 50,000 cps to 350,000 cps, or from 50,000 cps to 300,000 cps, or from 75,000 cps to 500,000 cps, or from 75,000 cps to 400,000 cps, or from 75,000 cps to 350,000 cps, or from 75,000 cps to 300,000 cps, or from 100,000 cps to 500,000 cps, or from 100,000 cps to 400,000 cps, or
  • a method of enhancing penetration of taxane nanoparticles into VIN and/or genital warts comprising topically applying a hydrophobic composition comprising a plurality of taxane nanoparticles to the affected area of the VIN and/or genital warts, wherein the penetration of the taxane nanoparticles from the hydrophobic composition is greater than the penetration of taxane nanoparticles from a suspension of taxane nanoparticles in an aqueous based composition.
  • a suitable method for determining penetration of taxane nanoparticles in VIN and/or genital warts is by an in vitro Franz diffusion cell (FDC) system using human cadaver skin or other suitable membrane.
  • FDC Franz diffusion cell
  • the taxane nanoparticles have a mean particle size (number) from 0.1 microns to 1.5 microns. In other embodiments, the taxane nanoparticles have a mean particle size (number) from 0.1 microns to less than 1 micron. In other embodiments, the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles. In other embodiments, the hydrophobic composition further comprises a hydrophobic carrier.
  • the VIN is usual VIN (uVIN). In other embodiments, the VIN is differentiated VIN (dVIN).
  • the genital warts are external genital warts. In other embodiments, the genital warts are internal genital warts. III. Methods for the Inhibition of Crystal Growth in Formulations
  • the method comprising contacting the taxane nanoparticles with a hydrophobic carrier.
  • the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.
  • the taxane nanoparticles are paclitaxel nanoparticles.
  • the composition is anhydrous.
  • the hydrophobic carriers comprise a hydrocarbon.
  • the hydrocarbon is petrolatum, mineral oil, or paraffin wax, or mixtures thereof.
  • the mineral oil is heavy mineral oil.
  • the compositions further comprises one or more volatile silicone fluids.
  • the volatile silicone fluid is cyclomethicone.
  • the cyclomethicone is cyclopentasiloxane.
  • aqueous based carrier comprising adding poloxamer 407, a quaternary ammonium compound, or a cross-linked acrylic acid polymer to the aqueous based carrier at the time of manufacture.
  • the additive is poloxamer 407.
  • the quaternary ammonium compound is the additive and is benzalkonium chloride or benzethonium chloride.
  • the quaternary ammonium compound is benzalkonium chloride.
  • the cross-linked acrylic acid polymer is the additive and is Carbomer.
  • the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.
  • VIN Vulvar Intraepithelial Neoplasia
  • the methods of the invention include methods of treatment of vulvar intraepithelial neoplasia (VIN) in a patient by topically administering to the affected area (topical therapy) compositions disclosed herein comprising taxanes.
  • the "affected area" of VIN includes one or more lesions that are visible on the outermost surface of the skin of the vulva, or directly underneath the surface of the skin of the vulva, and can include areas of the skin of the vulva in the proximity of the one or more lesions likely to contain visibly undetectable preclinical lesions.
  • the composition can be applied directly to the one or more VIN lesions individually (lesion-directed therapy); or to the entire area known as the "field" which includes the one or more VIN lesions and the areas in the proximity of the one or more VIN lesions likely to contain visibly undetectable preclinical lesions (field-directed therapy).
  • the taxane is paclitaxel.
  • the taxane is docetaxel or cabazitaxel.
  • the compositions are hydrophobic and can comprise a hydrophobic carrier.
  • the compositions are aqueous based compositions and can comprise an aqueous carrier.
  • the carrier is anhydrous.
  • the taxanes are a plurality of taxane nanoparticles. In some embodiments, the plurality of taxane nanoparticles are suspended within the compositions. In other aspects, the taxanes are solubilized in the compositions.
  • a preferred method for the topical treatment of VIN comprises topically administering to the affected area a hydrophobic composition comprising a continuous hydrophobic carrier, one or more volatile silicone fluids, and a plurality of taxane nanoparticles, wherein the taxane nanoparticles are suspended within the composition, wherein the mean particle size (number) of the taxane nanoparticles is from 0.1 microns to 1.5 microns or from 0.1 microns to less than 1 micron, and wherein the concentration of the taxane nanoparticles is at an amount effective to provide a therapeutic improvement in the condition of the VIN.
  • the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.
  • the taxane nanoparticles, including paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles have a mean particle size (number) of from 0.01 microns to 1.5 microns, or from 0.01 microns to 1.2 microns, or from 0.01 microns to 1 micron, or from 0.01 microns to less than 1 micron, or from 0.01 microns to 0.9 microns, or from 0.01 microns to 0.8 microns, or from 0.01 microns to 0.7 microns, or from 0.1 microns to 1.5 microns, or from 0.1 microns to 1.2 microns, or from 0.1 microns to 1 micron, or from 0.1 microns to less than 1 micron, or from 0.1 microns
  • the taxane nanoparticles are paclitaxel nanoparticles.
  • the paclitaxel nanoparticles have an SSA of at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, or at least 35 m 2 /g.
  • the paclitaxel nanoparticles have an SSA of 18 m 2 /g to 50 m 2 /g, or 20 m 2 /g to 50 m 2 /g, or 22 m 2 /g to 50 m 2 /g, or 25 m 2 /g to 50 m 2 /g, or 30 m 2 /g to 50 m 2 /g, or 18 m 2 /g to 45 m 2 /g, or 20 m 2 /g to 45 m 2 /g, or 22 m 2 /g to 45 m 2 /g, or 25 m 2 /g to 45 m 2 /g, or 30 m 2 /g to 45 m 2 /g, or 18 m 2 /g to 40 m 2 /g, or 20 m 2 /g to 40 m 2 /g , or 22 m 2 /g to 40 m 2 /g, or 25 m 2 /g to 40 m 2 m 2 /
  • the paclitaxel nanoparticles have a bulk density (not-tapped) of 0.05 g/cm 3 to 0.15 g/cm 3 , or 0.05 g/cm 3 to 0.20 g/cm 3 .
  • the hydrophobic carriers are non-polar and/or non-volatile.
  • the hydrophobic carriers comprise a hydrocarbon.
  • the hydrophobic carriers comprise petrolatum, mineral oil, and paraffin.
  • the mineral oil is heavy mineral oil.
  • the volatile silicone fluid is at a concentration of from 5 to 24% w/w. In other embodiments, the volatile silicone fluid is at a concentration of from 5 to 20% w/w.
  • the volatile silicone fluid is at a concentration of from 5 to 18% w/w. In other embodiments, the concentration of the volatile silicone fluid is 13% w/w. In some embodiments, the volatile silicone fluid is cyclomethicone. In other embodiments, the cyclomethicone is cyclopentasiloxane. In various embodiments, the hydrophobic compositions are free of / do not include or contain additional penetration enhancers. In some embodiments, the hydrophobic compositions are free of / do not include or contain laurocapram, and/or diethylene glycol monoethyl ether (DGME), and/or isopropyl myristate, and/or alpha tocopherol.
  • DGME diethylene glycol monoethyl ether
  • the hydrophobic compositions are free of / do not include or contain additional volatile solvents. In other embodiments, the hydrophobic compositions are free of / do not include or contain a surfactant. In other embodiments, the hydrophobic compositions are free of / do not include or contain alcohols, Ci - C 4 aliphatic alcohols, or Ci to Cs aliphatic alcohols. In some embodiments, the hydrophobic compositions comprise one or more volatile silicone fluids, but do not contain additional silicone materials.
  • the hydrophobic compositions are free of / do not include hyaluronic acid; and/or are free of / do not include a conjugate of hyaluronic acid and a taxane; and/or are free of / do not include a conjugate of hyaluronic acid and paclitaxel; and/or are free of / do not include a polymer or a biodegradeable polymer; and/or are free of / do not include a poloxamer, styrene-isobutylene-styrene (SIBS), a polyanhydride copolymer, polycaprolactone, polyethylene glycol, Poly (bis(P-carboxyphenoxy)propane-sebacic acid, and/or poly(D, L lactic-co-glycolic acid) (PLGA).
  • SIBS styrene-isobutylene-styrene
  • PLGA poly(D, L lactic-co-gly
  • the concentration of the taxane nanoparticles is at an amount effective to provide a therapeutic improvement in the condition of the VIN. This improvement can be indicated by visual observation and measurement of the affected area after treatment to include a reduction of the size and/or number of VIN lesions; or elimination of the VIN lesions.
  • the concentration of the taxane nanoparticles can be from 0.05 to 10% w/w, or the concentration of the taxane nanoparticles can be from 0.05 to 5% w/w, or the concentration of the taxane nanoparticles can be from 0.1 to 5% w/w, or the concentration of the taxane nanoparticles can be 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9, 1.0, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, 2.0, 2.1, 2.2, 2.25, 2.3, 2.4, 2.5, 2.6, 2.7, 2.75, 2.8, 2.9, 3.0, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4.0, 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6
  • the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles. In other embodiments, the taxane nanoparticles are paclitaxel nanoparticles.
  • the paclitaxel nanoparticles are at a concentration of about 0.05 to less than 3% w/w, or about 0.05 to about 2% w/w, or about 0.05 to about 1% w/w, or about 0.05 to about 0.3% w/w, or about 0.05 to about 0.2% w/w, or about 0.05 to about 0.15% w/w, or about 0.1 to about 2% w/w, or about 0.1 to about 1% w/w, or about 0.1 to about 0.3% w/w, or about 0.1 to about 0.2% w/w, or about 0.15 to about 2% w/w, or about 0.15 to about 1% w/w, or about 0.15 to about 0.3% w/w, or about 0.3 to about 2% w/w, or about 0.3 to about 1% w/w, or about 1 to about 2% w/w, or about 0.2 to about 0.4% w/w, or about 0.5 to about 1.5% w/w,
  • the concentration of the paclitaxel nanoparticles is 80 to 120% of 1% w/w (i.e., 0.8 to 1.2% w/w), or 80 to 120% of 0.05% w/w, or 80 to 120% of 0.1% w/w, or 80 to 120% of 0.15% w/w, or 80 to 120% of 0.2% w/w, or 80 to 120% of 0.25% w/w, or 80 to 120% of 0.3% w/w, or 80 to 120% of 0.35% w/w, or 80 to 120% of 0.4% w/w, or 80 to 120% of 0.45% w/w, or 80 to 120% of 0.5% w/w, or 80 to 120% of 0.55% w/w, or 80 to 120% of 0.6% w/w, or 80 to 120% of 0.65% w/w, or 80 to 120% of 0.7% w/w, or 80 to 120% of 0.75% w/w, or 80 to 120% of 0.8%
  • the hydrophobic compositions are sterile. In other embodiments, the hydrophobic compositions are non-sterile. In other embodiments, the hydrophobic compositions have a low bioburden. In other embodiments, the hydrophobic compositions are anhydrous. In some embodiments, the hydrophobic compositions are semisolid compositions. In still other embodiments, the hydrophobic compositions are ointments.
  • the hydrophobic compositions are semi-solid compositions, including ointments, and have a viscosity of from 12,500 cps to 247,500 cps, or from 25,000 cps to 150,000 cps as measured at room temperature by a Brookfield RV viscometer using a small sample adapter with a SC4-14 spindle and a 6R chamber at 5 rpm with an equilibration time of 2 minutes.
  • An alternative method for performing viscosity measurements of the hydrophobic, semi-solid compositions is using a Brookfield RV viscometer on a helipath stand with the helipath on, with a T-E spindle at 10 RPM at room temperature for 45 seconds.
  • the hydrophobic compositions are semi-solid compositions, including ointments, and have a viscosity of from 25,000 cps to 500,000 cps, or from 25,000 cps to 400,000 cps, or from 25,000 cps to 350,000 cps, or from 25,000 cps to 300,000 cps, or from 50,000 cps to 500,000 cps, or from 50,000 cps to 400,000 cps, or from 50,000 cps to 350,000 cps, or from 50,000 cps to 300,000 cps, or from 75,000 cps to 500,000 cps, or from 75,000 cps to 400,000 cps, or from 75,000 cps to 350,000 cps, or from 75,000 cps to 300,000 cps, or from 100,000 cps to 500,000 cps, or from 100,000 cps to 400,000 cps, or
  • the VIN can be "classic” or “usual" vulvar intraepithelial neoplasia (uVIN) which is associated with infection of the human papilloma virus (HPV).
  • Usual type VIN can be either a vulvar low-grade squamous intraepithelial lesion (vulvar LSIL) or a vulvar high- grade squamous intraepithelial lesion (vulvar HSIL).
  • the VIN can be differentiated VIN (dVIN) or simplex-type VIN which is not associated with HPV, but is associated with chronic inflammatory skin conditions such as lichen sclerosus.
  • the amount of the hydrophobic composition topically applied to the affected area of the VIN can vary depending on the size of the affected area/number of VIN lesions, and the concentration of the paclitaxel in the composition, but generally can be applied at approximately the thickness of a dime to fully cover the affected area.
  • Another suitable method for determining the amount of composition to apply is the "Finger-Tip Unit" (FTU) approach.
  • FTU is the amount of topical composition that is squeezed out from a standard tube along an adult's fingertip (This assumes the tube has a standard 5 mm nozzle). A fingertip is from the very end of the finger to the first crease in the finger.
  • the composition can be applied with a gloved hand or spatula or other means of topical administration.
  • the affected area can be gently cleansed with water (and mild soap if required) and dried prior to application.
  • the application site can be covered with an occlusive dressing such as TEGADERM® or SOLOSITE®.
  • the dosing of the composition can vary, but generally can include an application once, twice, or three times daily at approximately the same time each day until the condition is improved or eliminated.
  • the methods of the invention include methods of treatment of genital warts in a patient by topically administering to the affected area (topical therapy) compositions disclosed herein comprising taxanes.
  • the "affected area" of genital warts includes one or more genital warts that are visible on the outermost surface of the skin or epithelial tissue, or directly underneath the surface of the skin or epithelial tissue, and can include areas of the skin or epithelial tissue in the proximity of the one or more genital warts likely to contain visibly undetectable preclinical lesions.
  • the composition can be applied directly to the one or more genital warts individually (lesion-directed therapy); or to the entire area known as the "field" which includes the one or more genital warts and the areas in the proximity of the one or more genital warts likely to contain visibly undetectable preclinical lesions (field-directed therapy).
  • the taxane is paclitaxel.
  • the taxane is docetaxel or cabazitaxel.
  • the compositions are hydrophobic and can comprise a hydrophobic carrier.
  • the compositions are aqueous based compositions and can comprise an aqueous carrier.
  • the carrier is anhydrous.
  • the taxanes are a plurality of taxane nanoparticles. In some embodiments, the plurality of taxane nanoparticles are suspended within the compositions. In other aspects, the taxanes are solubilized in the compositions. In some embodiments, the compositions do not contain hyaluronic acid, and/or do not contain a conjugate of hyaluronic acid and a taxane, and/or do not contain a conjugate of hyaluronic acid and paclitaxel.
  • a preferred method for the topical treatment of genital warts comprises topically administering to the affected area a hydrophobic composition comprising a continuous hydrophobic carrier, one or more volatile silicone fluids, and a plurality of taxane nanoparticles, wherein the taxane nanoparticles are suspended within the composition, wherein the mean particle size (number) of the taxane nanoparticles is from 0.1 microns to 1.5 microns or from 0.1 microns to less than 1 micron, and wherein the concentration of the taxane nanoparticles is at an amount effective to provide a therapeutic improvement in the condition of the genital warts.
  • the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.
  • the taxane nanoparticles, including paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles have a mean particle size (number) of from 0.01 microns to 1.5 microns, or from 0.01 microns to 1.2 microns, or from 0.01 microns to 1 micron, or from 0.01 microns to less than 1 micron, or from 0.01 microns to 0.9 microns, or from 0.01 microns to 0.8 microns, or from 0.01 microns to 0.7 microns, or from 0.1 microns to 1.5 microns, or from 0.1 microns to 1.2 microns, or from 0.1 microns to 1 micron, or from 0.1 microns to less than 1 micron, or from 0.1 microns
  • the taxane nanoparticles are paclitaxel nanoparticles.
  • the paclitaxel nanoparticles have an SSA of at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, or at least 35 m 2 /g.
  • the paclitaxel nanoparticles have an SSA of 18 m 2 /g to 50 m 2 /g, or 20 m 2 /g to 50 m 2 /g, or 22 m 2 /g to 50 m 2 /g, or 25 m 2 /g to 50 m 2 /g, or 30 m 2 /g to 50 m 2 /g, or 18 m 2 /g to 45 m 2 /g, or 20 m 2 /g to 45 m 2 /g, or 22 m 2 /g to 45 m 2 /g, or 25 m 2 /g to 45 m 2 /g, or 30 m 2 /g to 45 m 2 /g, or 18 m 2 /g to 40 m 2 /g, or 20 m 2 /g to 40 m 2 /g , or 22 m 2 /g to 40 m 2 /g, or 25 m 2 /g to 40 m 2 m 2 /
  • the paclitaxel nanoparticles have a bulk density (not-tapped) of 0.05 g/cm 3 to 0.15 g/cm 3 , or 0.05 g/cm 3 to 0.20 g/cm 3 .
  • the hydrophobic carriers are non-polar and/or non-volatile.
  • the hydrophobic carriers comprise a hydrocarbon.
  • the hydrophobic carriers comprise petrolatum, mineral oil, and paraffin.
  • the mineral oil is heavy mineral oil.
  • the volatile silicone fluid is at a concentration of from 5 to 24% w/w. In other embodiments, the volatile silicone fluid is at a concentration of from 5 to 20% w/w.
  • the volatile silicone fluid is at a concentration of from 5 to 18% w/w. In other embodiments, the concentration of the volatile silicone fluid is 13% w/w. In some embodiments, the volatile silicone fluid is cyclomethicone. In other embodiments, the cyclomethicone is cyclopentasiloxane. In various embodiments, the hydrophobic compositions are free of / do not include or contain additional penetration enhancers. In some embodiments, the hydrophobic compositions are free of / do not include or contain laurocapram, and/or diethylene glycol monoethyl ether (DGME), and/or isopropyl myristate, and/or alpha tocopherol.
  • DGME diethylene glycol monoethyl ether
  • the hydrophobic compositions are free of / do not include or contain additional volatile solvents. In other embodiments, the hydrophobic compositions are free of / do not include or contain a surfactant. In other embodiments, the hydrophobic compositions are free of / do not include or contain alcohols, Ci - C 4 aliphatic alcohols, or Ci to Cs aliphatic alcohols. In some embodiments, the hydrophobic compositions comprise one or more volatile silicone fluids, but do not contain additional silicone materials.
  • the hydrophobic compositions are free of / do not include hyaluronic acid; and/or are free of / do not include a conjugate of hyaluronic acid and a taxane; and/or are free of / do not include a conjugate of hyaluronic acid and paclitaxel; and/or are free of / do not include a polymer or a biodegradeable polymer; and/or are free of / do not include a poloxamer, styrene-isobutylene-styrene (SIBS), a polyanhydride copolymer, polycaprolactone, polyethylene glycol, Poly (bis(P-carboxyphenoxy)propane-sebacic acid, and/or poly(D, L lactic-co-glycolic acid) (PLGA).
  • SIBS styrene-isobutylene-styrene
  • PLGA poly(D, L lactic-co-gly
  • the concentration of the taxane nanoparticles is at an amount effective to provide a therapeutic improvement in the condition of the genital warts. This improvement can be indicated by visual observation and measurement of the affected area after treatment to include a reduction of the size and/or number of genital wart lesions; or elimination of the genital wart lesions.
  • the concentration of the taxane nanoparticles can be from 0.05 to 10% w/w, or the concentration of the taxane nanoparticles can be from 0.05 to 5% w/w, or the concentration of the taxane nanoparticles can be from 0.1 to 5% w/w, or the concentration of the taxane nanoparticles can be 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9, 1.0, 1.1, 1.2, 1.25, 1.3, 1.4, 1.5, 1.6, 1.7, 1.75, 1.8, 1.9, 2.0, 2.1, 2.2, 2.25, 2.3, 2.4, 2.5, 2.6, 2.7, 2.75, 2.8, 2.9, 3.0, 3.1, 3.2, 3.25, 3.3, 3.4, 3.5, 3.6, 3.7, 3.75, 3.8, 3.9, 4.0, 4.1, 4.2, 4.25, 4.3, 4.4, 4.5, 4.6
  • the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles. In other embodiments, the taxane nanoparticles are paclitaxel nanoparticles.
  • the paclitaxel nanoparticles are at a concentration of about 0.05 to less than 3% w/w, or about 0.05 to about 2% w/w, or about 0.05 to about 1% w/w, or about 0.05 to about 0.3% w/w, or about 0.05 to about 0.2% w/w, or about 0.05 to about 0.15% w/w, or about 0.1 to about 2% w/w, or about 0.1 to about 1% w/w, or about O.
  • the concentration of the paclitaxel nanoparticles is 80 to 120% of 1% w/w (i.e., 0.8 to 1.2% w/w), or 80 to 120% of 0.05% w/w, or 80 to 120% of 0.1% w/w, or 80 to 120% of 0.15% w/w, or 80 to 120% of 0.2% w/w, or 80 to 120% of 0.25% w/w, or 80 to 120% of 0.3% w/w, or 80 to 120% of 0.35% w/w, or 80 to 120% of 0.4% w/w, or 80 to 120% of 0.45% w/w, or 80 to 120% of 0.5% w/w, or 80 to 120% of 0.55% w/w, or 80 to 120% of 0.6% w/w, or 80 to 120% of 0.65% w/w, or 80 to 120% of 0.7% w/w, or 80 to 120% of 0.75% w/w, or 80 to 120% of 0.8%
  • the hydrophobic compositions are sterile. In other embodiments, the hydrophobic compositions are non-sterile. In other embodiments, the hydrophobic compositions have a low bioburden. In other embodiments, the hydrophobic compositions are anhydrous. In some embodiments, the hydrophobic compositions are semi- solid compositions. In still other embodiments, the hydrophobic compositions are ointments.
  • the hydrophobic compositions are semi-solid compositions, including ointments, and have a viscosity of from 12,500 cps to 247,500 cps, or from 25,000 cps to 150,000 cps as measured at room temperature by a Brookfield RV viscometer using a small sample adapter with a SC4-14 spindle and a 6R chamber at 5 rpm with an equilibration time of 2 minutes.
  • An alternative method for performing viscosity measurements of the hydrophobic, semi-solid compositions is using a Brookfield RV viscometer on a helipath stand with the helipath on, with a T-E spindle at 10 RPM at room temperature for 45 seconds.
  • the hydrophobic compositions are semi-solid compositions, including ointments, and have a viscosity of from 25,000 cps to 500,000 cps, or from 25,000 cps to 400,000 cps, or from 25,000 cps to 350,000 cps, or from 25,000 cps to 300,000 cps, or from 50,000 cps to 500,000 cps, or from 50,000 cps to 400,000 cps, or from 50,000 cps to 350,000 cps, or from 50,000 cps to 300,000 cps, or from 75,000 cps to 500,000 cps, or from 75,000 cps to 400,000 cps, or from 75,000 cps to 350,000 cps, or from 75,000 cps to 300,000 cps, or from 100,000 cps to 500,000 cps, or from 100,000 cps to 400,000 cps, or
  • the genital warts can be external genital warts.
  • external genital warts include genital warts on the penis, groin, scrotum, vulva, perineum, external anus, external vagina, and/or perianal area.
  • the genital warts can be internal genital warts.
  • internal genital warts are genital warts in the rectum, intra-anus, urethra, cervix, and/or vaginal introitus.
  • the amount of the hydrophobic composition topically applied to the affected area of the genital warts can vary depending on the size of the affected area/number of genital wart lesions, and the concentration of the paclitaxel in the composition, but generally can be applied at approximately the thickness of a dime to fully cover the affected area.
  • Another suitable method for determining the amount of composition to apply is the "Finger- Tip Unit" (FTU) approach.
  • FTU is the amount of topical composition that is squeezed out from a standard tube along an adult's fingertip (This assumes the tube has a standard 5 mm nozzle). A fingertip is from the very end of the finger to the first crease in the finger.
  • composition can be applied with a gloved hand or spatula or other means of topical administration.
  • the affected area can be gently cleansed with water (and mild soap if required) and dried prior to application.
  • the application site can be covered with an occlusive dressing such as TEGADERM® or SOLOSITE®.
  • the dosing of the composition can vary, but generally can include an application once, twice, or three times daily at approximately the same time each day until the condition is improved or eliminated.
  • the solubility of paclitaxel was determined in various solvents by the following method: (a) for each solvent, about 2 g of the solvent was weighed into a clear glass vial, (b) approximately 0.1 g of paclitaxel was added to each vial, (c) each vial was mixed with a stir bar on a magnetic stirrer for 2 hours at room temperature, (d) each vial was then checked every 1-2 hours to see if the solution became clear. If yes, an additional approximately 0.1 g of paclitaxel was added to the vial and mixing was continued. Step "d" was continued for each vial for a total of 48 hours.
  • the paclitaxel nanoparticle crystals did not grow in any of the hydrophobic carriers. Also, the nanoparticles did not grow in aqueous solutions of benzalkonium chloride, CARBOPOL ULTREZ 10, or poloxamer 407.
  • Instrument parameters Max. Concentration: 9000 particles/mL, No. containers: 1, Sensor Range: Summation, Lower Detection Limit: 0.5 ⁇ , Flow Rate: 30 mL/min, No. Analysis pulls: 4, Time between pulls: 1 sec, Pull volume: 10 mL, Tare Volume: 1 mL, Prime volume: 1 mL, Include First Pull: Not Selected.
  • Sample preparation Placed a scoop of paclitaxel nanoparticle API into a clean 20 mL vial and added approximately 3 mL of a filtered (0.22 ⁇ ) 0.1% w/w solution of SDS to wet the API, then filled the remainder of the vial with the SDS solution. Vortexed for 5 - 10 minutes and sonicated in a water batch for 1 minute.
  • Particles size results (based on number- weighted differential distribution): Paclitaxel nanoparticles lot used in formulas listed in Table 3: Mean: 0.861 ⁇ , Mode: 0.572 ⁇ , Median: 0.710 ⁇ . Paclitaxel nanoparticles lot used in formulas listed in Tables 16 - 19: Mean: 0.83 ⁇ .
  • SSA specific surface area
  • the bulk density (not-tapped) of the paclitaxel nanoparticles lot used in the formulas listed in Table 3 was 0.05 g/cm 3 .
  • the bulk density (not-tapped) of the paclitaxel nanoparticles lot used in the formulas listed in Tables 16 - 19 was 0.09 g/cm 3 .
  • Example 4 Anhydrous hydrophobic compositions of pachtaxel nanoparticles with hydrophobic carriers
  • Procedure for F4 - F13 Prepared a slurry of the paclitaxel nanoparticles with a portion of the cyclomethicone (or mineral oil (F4) or FOMBLIN (F7)). Heated the petrolatum to 52 + 3°C and added the remaining ingredients and mixed until melted and homogeneous. Added the paclitaxel slurry and mixed until homogenous. Mixed and allowed the batch to cool to 35° C or below. An ointment was formed.
  • Example 5 Physical and Chemical Stability of anhydrous compositions of paclitaxel nanoparticles with hydrophobic carriers
  • the anhydrous hydrophobic composition samples were stored at 25°C and 30°C in 20 mL glass scintillation vials.
  • the assay of paclitaxel was conducted using HPLC.
  • the results of the assay and appearance stability studies are shown in Table 4 and Table 5 below.
  • the viscosity was measured at room temperature with a Brookfield RV viscometer using a small sample adapter with a SC4-14 spindle and a 6R chamber at 5 rpm with an equilibration time of 2 minutes.
  • the viscosity results are shown in Table 6 below. Table 4 - Stability at 25°C
  • Example 6 Particle size analysis of paclitaxel nanoparticles in anhydrous compositions with hydrophobic carriers
  • Instrument parameters Sensor: LE 0.5 ⁇ - 400 ⁇ , Sensor Range: Summation, Lower Detection Limit: 0.5 ⁇ , Collection time: 60 sec, Number Channels: 128, Vessel Fluid Vol: 100 mL, Flow Rate: 60 mL/min, Max Coincidence: 8000 particles/mL, Sample Vessel: Accusizer Vessel, Sample Calculation: None, Voltage Detector: greater than 10 V, Particle Concentration Calculation: No, Concentration Range: 5000 to 8000 particles/mL, Automatic Data Saving: Selected, Subtract Background: Yes, Number of Autocycles: 1.
  • Sample Preparation Added an aliquot of the sample formulation into a scintillation vial. Using a spatula, smeared the sample along the inner walls of the vial. Added about 20 mL of 2% Lecithin in ISOPAR-GTM (CIO - 11 isoparaffin) solution to the vial. Sonicated the vial for 1 minute. Insured that the sample had adequately dispersed in the solution.
  • ISOPAR-GTM CIO - 11 isoparaffin
  • Method Filled the sample vessel with a filtered (0.22 ⁇ ) 2% Lecithin in ISOPAR-G solution and analyzed the background. Using a pipette, transferred a portion of the prepared sample to the vessel while stirring. Diluted or added sample to the vessel as necessary to provide a coincidence level between 5000 to 8000 particles/mL. Initiated the analysis through the instrument and verified that the coincidence level was 5000 to 8000 particles/mL for the analysis.
  • the particle size of paclitaxel nanoparticles in samples F4 through F6 did not grow larger than 20% of the initial mean particle size when stored at room temperature (25°C) and at 30 °C for 1 month.
  • the particle size of paclitaxel nanoparticles in sample F6 did not grow larger than 20% of the initial mean particle size when stored at room temperature (25°C) and at 30 °C for 6 months and for 12 months.
  • the particle size of paclitaxel nanoparticles in samples F6**(repeat batch with the same formula as F6) and F8 through F13 did not grow larger than 20% of the initial mean particle size when stored at room temperature (25°C) and at 30°C for 3 months.
  • Example 7 Aqueous based compositions of paclitaxel nanoparticles
  • Aqueous based compositions of paclitaxel nanoparticles are shown in Table 9.
  • Instrument parameters Sensor: LE 0.5 ⁇ - 400 ⁇ , Sensor Range: Summation, Lower Detection Limit: 0.5 ⁇ , Collection time: 60 sec, Number Channels: 128, Vessel Fluid Vol: 100 mL, Flow Rate: 60 mL/min, Max Coincidence: 8000 particles/mL, Sample Vessel: Accusizer Vessel, Sample Calculation: None, Voltage Detector: greater than 10 V, Particle Concentration Calculation: No, Concentration Range: 5000 to 8000 particles/mL, Automatic Data Saving: Selected, Subtract Background: Yes, Number of Autocycles: 1.
  • Sample Preparation Added an aliquot of the sample formulation into a scintillation vial. Using a spatula, smeared the sample along the inner walls of the vial. Added about 20 mL of 0.2 ⁇ filtered distilled water to the vial. Sonicated the vial for 1 minute. Insured that the sample had adequately dispersed in the solution.
  • Method Filled the sample vessel with 0.2 ⁇ filtered distilled water and analyzed the background. Using a pipette, transferred a portion of the prepared sample to the vessel while stirring. Diluted or added sample to the vessel as necessary to provide a coincidence level between 5000 to 8000 particles/mL. Initiated the analysis through the instrument and verified that the coincidence level was 5000 to 8000 particles/mL for the analysis.
  • MS Mass spectrometry
  • Receptor Fluid Preparation Based on the results of preliminary solubility data, a receptor fluid of 96 wt% phosphate buffered saline ("PBS") at pH 7.4 and 4 wt% hydroxyl propyl beta cyclodextrin (HPBCD) was chosen. The solubility of the active in the receptor fluid (-0.4 ⁇ g/mL) was shown to be adequate to maintain sink conditions during the studies.
  • the receptor fluid was degassed by filtering the receptor fluid through a ZapCap CR 0.2 ⁇ membrane while pulling vacuum. The filtered receptor fluid was stirred for an additional 20 minutes while maintaining vacuum to ensure complete degassing.
  • Diffusion Cell Assembly The cadaver skin was removed from the freezer and allowed to defrost in a bio-safety hood for 30 minutes. The skin was thoroughly defrosted prior to opening the package. The cadaver skin was removed from the package and placed on the bio-safety hood countertop with the stratum corneum side up. The skin was patted dry with a Kim Wipe, then sprayed with fresh PBS and patted dry again. This process was repeated 3 more times to remove any residues present on the skin. The receptor wells were then filled with the degassed receptor fluid. A Teflon coated stir bar was added to each receptor well. The defrosted cadaver skin was examined and only areas with even thickness and no visible damage to the surface were used.
  • the skin was cut into ⁇ 2 cm x 2 cm squares.
  • the skin piece was centered on the donor wells, stratum corneum (SC) side up.
  • the skin was centered and the edges flattened out.
  • the donor and receptor wells were then aligned and clamped together with a clamp. Additional receptor fluid was added where necessary. Any air bubbles present were removed by tilting the cell, allowing air to escape along the sample port.
  • Diffusion cells were then placed in to the stirring dry block heaters and allowed to rehydrate for 20 minutes from the receptor fluid.
  • the block heaters were maintained at 32°C throughout the experiment with continuous stirring.
  • the skin was allowed to hydrate for 20 minutes and the barrier integrity of each skin section was tested. Once the membrane integrity check study was complete, the entire receptor chamber volume was replaced with the receptor fluid.
  • the epidermis of each piece was then separated from the underlying dermal tissue using tweezers or a spatula.
  • the epidermis and dermal tissue were collected and placed in 4 mL borosilicate glass vials. After all the skin pieces were separated, an aliquot of the extraction solvent was added to the glass vial. This process consisted of adding 2 mL of DMSO to the vial and incubating for 24 hours at 32°C. After the extraction time was over, 300 ⁇ ⁇ sample aliquots of the extraction fluid were collected and filtered.
  • FIG. 1 graphically shows the concentration of paclitaxel ⁇ g/cm 2 ) delivered into the epidermis for formulas Fl through F7.
  • FIG. 2 graphically shows the concentration of paclitaxel ⁇ g/cm 2 ) delivered into the epidermis for formulas F6*(repeat analysis) and F8 through F13.
  • FIG. 1 graphically shows the concentration of paclitaxel ⁇ g/cm 2 ) delivered into the epidermis for formulas Fl through F7.
  • FIG. 2 graphically shows the concentration of paclitaxel ⁇ g/cm 2 ) delivered into the epidermis for formulas F6*(repeat analysis) and F8 through F13.
  • FIG. 3 graphically shows the concentration of paclitaxel ⁇ g/cm2) delivered into the dermis for formulas Fl through F7.
  • FIG. 4 graphically shows the concentration of paclitaxel ⁇ g/cm2) delivered into the dermis for formulas F6* (repeat analysis) and F8 through F13.
  • the transdermal flux of the paclitaxel through the skin was none or only a negligible amount, i.e., less than 0.01 ⁇ g/cm 2 .
  • the penetration of paclitaxel into the skin was far greater with the anhydrous hydrophobic formulations (F4 through F13) than with the aqueous formulations (Fl through F3), even though the aqueous formulations contained the skin penetration enhancer DGME (TRANSCUTOL P).
  • results show that the anhydrous hydrophobic formulations with cyclomethicone exhibited greater skin penetration (epidermis and dermis) over the anhydrous hydrophobic formulations without cyclomethicone. Additionally, the results show that the addition of other skin penetration enhancers to the anhydrous hydrophobic formulations containing cyclomethicone had little or no effect on the skin penetration (epidermis and dermis) of these compositions.
  • the manufacturing processes for lots F14, F15, and F16 were as follows: The petrolatum, mineral oil, paraffin wax, and a portion of the cyclomethicone were added to a vessel and heated to 52+3 °C while mixing with a propeller mixer until melted and homogeneous.
  • the paclitaxel nanoparticles were added to a vessel containing another portion of cyclomethicone and first mixed with a spatula to wet the nanoparticles, then mixed with an IKA Ultra Turrax Homogenizer with a S25-25G dispersing tool until a homogeneous slurry is obtained while keeping the container in an ice/water bath.
  • the slurry was then added to the petrolatum/paraffin wax container while mixing with the propeller mixer followed by rinsing with the remaining portion of cyclomethicone and mixed until the batch was visually homogeneous while at 52+3 °C.
  • the batch was then homogenized using a Silverson homogenizer. Afterward, the batch was mixed with a propeller mixer until a homogeneous ointment was formed and the batch cooled to 35°C or below.
  • the manufacturing process for lot F17 was as follows: The petrolatum and paraffin wax were added to a vessel and heated to 52+3 °C while mixing with a propeller mixer until melted and homogeneous.
  • the paclitaxel nanoparticles were added to a vessel containing the cyclomethicone and a portion of mineral oil, and first mixed with a spatula to wet the nanoparticles, then mixed with an IKA Ultra Turrax Homogenizer with a S25-25G dispersing tool until a homogeneous slurry is obtained while keeping the container in an ice/water bath.
  • the slurry was then added to the petrolatum/paraffin wax container while mixing with the propeller mixer followed by rinsing with the remaining portion of mineral oil and mixed until the batch was visually homogeneous while at 52+3 °C.
  • the batch was then homogenized using a Silverson homogenizer. Afterward, the batch was mixed with a propeller mixer until a homogeneous ointment was formed and the batch cooled to 35°C or below.
  • the topical formulations in Table 15 above are to be used in a Phase II dose-rising, safety study for vulvar intraepithelial neoplasia (VIN) in humans.
  • the study will compare the safety and efficacy of the 4 formulations from Table 15: F14 (0.15%), F15 (0.3%), F16 (1.0%), and F17 (2.0%) applied topically to VIN lesions.
  • the primary objective of the study is to determine the safety and tolerability of the formulations applied to VIN lesions assessed by Treatment Emergent Adverse Events (TEAEs), vital signs, laboratory results, and physical examination.
  • the secondary objectives of the study are to determine the pharmacokinetics of the formulations applied to VIN lesions and obtain preliminary efficacy data of the formulations applied to VIN, defined as regression or clearance of VIN as determined by colposcopic changes documented by photography and clinical review.
  • Subject participation is divided into 3 periods: Screening (Day -14 to Day 0), Treatment (Day 1 - Day 28), and Follow-up (Week 5, Day 29 - Week 12, Day 84). Subjects will be screened up to 14 days prior to administration of the formulations. Eligible subjects require biopsy proven VIN scheduled for laser ablation or surgical excision. Subjects will be enrolled in four dose-escalating cohorts of 6 subjects assigned consecutively, starting with formulation F14 (0.15%) and escalating sequentially in increasing dose viz. F15 (0.3%), F16 (1.0%), and F17 (2.0%).
  • each subject will receive up to 2 FTU (Finger-tip Units) of the formulation applied topically on three occasions by the Investigator to the VIN lesions viz. days 1, 15, and 28. If the VIN is suspected to have resolved on Days 15 or 28, the subject will not receive the formulation and will enter the follow-up period.
  • subjects will return to the clinic on a biweekly basis for a further 8 weeks after treatment, at which point the subject will exit the study. Colposcopy and photography will be performed at all study visits to monitor the effects of the formulations on VIN lesions. The decision to continue with standard of care is at the discretion of the Investigator.
  • PK samples will be obtained on Day 1 at 1, 2, 4, 8, and 24 hours post application of the formulation. A single PK sample will also be taken prior to application of the formulation on Days 15 and 28, and at each biweekly clinic visit thereafter.
  • Safety will be assessed in an ongoing manner and formal safety reviews will be conducted three times for each cohort: after Days 15, 28, and 84 of the last subject in each cohort.
  • the Medical Monitor will review all available data prior to dose escalation. Dose- escalation of the formulation will be determined by the Medical Monitor in conjunction with the Sponsor Medical Director and Principal Investigator. This will be repeated for each dose escalation until all dose levels have been enrolled or a dose is determined unsafe. Efficacy will be assessed as the change in colposcopy findings and photography of the Image J region of interest (ROI) between baseline and Visit 8, 84 days after the first application of the formulation.
  • Primary Endpoint Safety and tolerability as demonstrated by adverse events, laboratory assessments, physical examination, and vital signs. Secondary Endpoint: PK parameters. Regression of VIN as determined by colposcopy, photography, and clinical review.
  • a 2% w/w nanoparticle paclitaxel topical ointment formulation (F17) listed in Table 15 above is to be used in an expanded access study.
  • a 0.1%, 0.15%, 0.3%, 0.5%, 1%, 1.5%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% w/w nanoparticle paclitaxel topical ointment formulation may be used in this study.
  • the expanded access protocol proposes to use the formulation to treat vulvar high-grade squamous intraepithelial lesions (vulvar HSIL) (also known as usual type VIN or uVIN) for use by an intermediate-size population.
  • vulvar HSILs are considered precursors to vulvar squamous cell carcinoma (VSCC), a highly aggressive cancer for which the most successful treatment is excision.
  • vulvar HSIL vulvar high-grade squamous intraepithelial lesions
  • F17 2% w/w nanoparticle paclitaxel ointment
  • Eligible lesions are those that appear on the vulva, mons pubis, and perineal and perianal regions.
  • subjects Prior to study entry, subjects will sign an informed consent form, and historical information will be collected from the subject. Blood will be collected to establish a baseline complete blood count (CBC) with differential and photographs will be taken of the treatment area in the clinic prior to initiation of treatment.
  • CBC complete blood count
  • a FTU finger-tip unit
  • a FTU is defined as the amount of ointment expressed from a tube with a 5- mm diameter nozzle, applied from the distal skin-crease to the tip of the index finger of an adult.
  • the "distal skin-crease” is the skin crease over the joint nearest the end of the finger.
  • a full FTU will cover up to 50 cm 2 of body surface area, therefore the maximum of 1 ⁇ 2 FTU administered in this study will cover lesions with a combined area of up to 25cm 2 .
  • the subject will apply the ointment with a gloved hand to the lesion(s); the ointment will not be applied on ulcerated areas.
  • the subject will re-treat the lesion twice daily at approximately the same times for up to 6 weeks using the same technique as the initial application. During this treatment period, the subject will return to the clinic every 2 weeks. At these biweekly visits, a blood sample will be taken for CBC with differential and a photograph will be taken of the treated area. Adverse events will be recorded in the clinic record. Finally, subjects will return 30 days after the last dose for review of response (photography) and safety assessment (adverse events). A photograph will be taken of the treated area and adverse events will be recorded in the clinic record. There will be a total of 5 visits. The endpoint is a reduction of vulvar high-grade squamous intraepithelial lesions.
  • Example 14 Dose-Rising, Safety, Tolerability and Efficacy Study for External Genital Warts
  • the topical formulations in Table 15 above are to be used in a Phase II dose-rising, safety study for external genital warts in humans. The study will compare the safety, tolerability, and preliminary efficacy of the 4 formulations from Table 15: F14(0.15%), F15 (0.3%), F16 (1.0%), and F17 (2.0%) applied topically to external genital warts. Placebo formulation F18 from Table 20 below will also be used in the study.
  • the primary objective of the study is to determine the safety and tolerability of the formulations applied to the anogenital region in subjects with external genital warts (condyloma acuminatum).
  • the secondary objectives of the study are to obtain preliminary determination of the efficacy of the formulations applied to external warts and to describe the pharmacokinetics of the formulations applied to the anogenital region.
  • Subjects with 1 - 10 external genital wart lesions will be enrolled in three dose- escalating cohorts of six subjects assigned consecutively as follows:
  • Cohort 1 Six subjects with formulation F14 (0.15%) topically applied to lesions; two subjects with placebo formulation F18 applied topically to lesions.
  • Cohort 2 Six subjects with formulation F15 (0.3%) topically applied to lesions; two subjects with placebo formulation F18 applied topically to lesions.
  • Cohort 3 Six subjects with formulation F16 (1%) topically applied to lesions; two subjects with placebo formulation F18 applied topically to lesions.
  • Cohort 4 Six subjects with formulation F17 (2%) topically applied to lesions; two subjects with placebo formulation F18 applied topically to lesions.
  • the formulations will be applied topically to external genital warts at Day 1, Day 15, and Day 28 (three total treatments). PK samples will be obtained on Week 1 at 1, 2, 4, 8, and 24 hours post-application, and at each bi-weekly clinic visit thereafter. If, at any visit, the external genital wart(s) is suspected to be resolved, the subject will receive no further study treatment and enter the follow-up period. During the follow-up period, subjects will return to the clinic on a biweekly basis after treatment until Week 12, at which point study participation will conclude.
  • Safety will be assessed in an ongoing manner and formal safety reviews will be conducted three times for each cohort at Day 15, at Day 28, and at Week 12. The next dose level cohort will enroll upon a finding of safety and tolerability at the previous cohort's first safety review. It will be safe for the next cohort to begin enrolling if ⁇ 33% of subjects experience serious adverse events.
  • Endpoint Safety and tolerability as demonstrated by adverse events, changes in laboratory assessments, physical examination findings, and vital signs.

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Abstract

L'invention concerne des procédés utiles pour le traitement thérapeutique topique de la néoplasie intraépithéliale vulvaire (VIN) et/ou des verrues génitales à l'aide de compositions contenant des nanoparticules de paclitaxel ou d'autres taxanes.
PCT/US2018/022557 2017-03-15 2018-03-15 Thérapie topique pour le traitement de la néoplasie intraépithéliale vulvaire (vin) et des verrues génitales à l'aide de nanoparticules de taxanes WO2018170210A1 (fr)

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US10507195B2 (en) 2015-06-04 2019-12-17 Crititech, Inc. Taxane particles and their use
US11123322B2 (en) 2015-06-04 2021-09-21 Crititech, Inc. Taxane particles and their use
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US10993927B2 (en) 2015-06-04 2021-05-04 Crititech, Inc. Taxane particles and their use
US10894045B2 (en) 2016-04-04 2021-01-19 Crititech, Inc. Methods for solid tumor treatment
US10874660B2 (en) 2016-04-04 2020-12-29 CritlTech, Inc. Methods for solid tumor treatment
US11033542B2 (en) 2016-04-04 2021-06-15 Crititech, Inc. Methods for solid tumor treatment
US11458133B2 (en) 2016-04-04 2022-10-04 Crititech, Inc. Methods for solid tumor treatment
US11523983B2 (en) 2017-06-09 2022-12-13 Crititech, Inc. Treatment of epithelial cysts by intracystic injection of antineoplastic particles
US11737972B2 (en) 2017-06-09 2023-08-29 Crititech, Inc. Treatment of epithelial cysts by intracystic injection of antineoplastic particles
US10507181B2 (en) 2017-06-14 2019-12-17 Crititech, Inc. Methods for treating lung disorders
US11160754B2 (en) 2017-06-14 2021-11-02 Crititech, Inc. Methods for treating lung disorders
US11058639B2 (en) 2017-10-03 2021-07-13 Crititech, Inc. Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer
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WO2022020449A1 (fr) * 2020-07-23 2022-01-27 Crititech, Inc. Particules de sorafénib et leurs utilisations

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