Composition comprising taxane-based nanoparticles and use thereof

Abstract

Compositions and uses useful for enhancing skin penetration of drug nanoparticles are disclosed. The composition may be hydrophobic and include a hydrophobic carrier, a volatile silicone fluid, and drug nanoparticles. Also disclosed are methods for inhibiting crystal growth of drug nanoparticles in aqueous or hydrophobic carriers. In addition, methods of topical treatment of psoriasis using compositions containing paclitaxel or other taxane-based nanoparticles are disclosed.

Description

[0001] This application is a divisional application of a Chinese invention patent application with an application date of September 16, 2016, application number 202210249200.5, and invention name “Compositions containing taxane nanoparticles and uses thereof”, and the patent application with application number 202210249200.5 is a divisional application of a Chinese invention patent application with an application date of September 16, 2016, invention name “Delivery of drug nanoparticles and methods of use thereof” and application number 201680065699.7. Technical Field

[0002] The present invention generally relates to the field of drug delivery. In particular, the present invention relates to the delivery of drug nanoparticles, and includes enhancing skin penetration, inhibiting crystal growth in formulations, and / or treating psoriasis. In addition, the present invention relates to the delivery of drug nanoparticles to keratinous tissue, and methods of treating keratinous tissue diseases and disorders. Background Art

[0003] Due to the barrier properties of the stratum corneum, the outermost layer of the epidermis, delivering therapeutic drugs into the viable epidermis and dermis of the skin can be a challenge. Delivering poorly water-soluble drugs into the skin can be even more challenging. Transdermal absorption enhancers have been used in topical drug formulations to increase the penetration of drugs into the skin with some success. However, some transdermal absorption enhancers, such as solvents and surfactants, can irritate the skin. Volatile silicone fluids have been used in topical formulations to increase the penetration of drugs into the skin; however, high concentrations of volatile silicone fluids, i.e., 25% and higher, and / or volatile silicone fluids are required in combination with other potential skin irritants, such as alcohols such as C 1 To C 4 The combination of fatty alcohol, surfactant, other penetration enhancer and other volatile solvents produces penetration enhancement. In addition, some transdermal absorption enhancers can cause the drug to penetrate through the skin and be absorbed systemically, which is undesirable when only treating skin (e.g., epidermis and / or dermis) disorders. When the drug is chemically modified with surfactants and other substances, other local delivery systems have been adopted, but these substances can also irritate the skin.

[0004] Taxanes, including paclitaxel and docetaxel, have been used to treat cancer for many years. They were originally developed for intravenous (IV) infusion as a cancer treatment. (BMS) is paclitaxel dissolved in polyethoxylated castor oil ( However, systemic use of this formulation has resulted in significant clinical toxicity (Rowinsky et al., 1993). Development of EL's paclitaxel formulation (Ma and Mumper, 2013). One such formulation is disclosed in US 8221779, which is incorporated herein by reference, which discloses an injectable aqueous composition of anti-mitotic drug microparticles comprising paclitaxel, which can be used to treat cancer by intraperitoneal and intravenous (IV) injection of the composition.

[0005] However, a problem with water-based compositions containing drug nanoparticle crystals, including taxanes, is that the drug nanoparticle crystals can grow multiple times in the water-based composition during storage. This is particularly problematic for injectable dosage forms, including compositions for (IV) infusion, where the presence of large crystals in the composition can cause serious harm to the patient.

[0006] Psoriasis is a chronic, disfiguring, immune-mediated skin disease that affects approximately 2% to 4% of the population worldwide (Parisi et al., 2013). The disease is characterized by excessive growth and angiogenesis of epidermal keratinocytes and accumulation of inflammatory cells (Heidenreich et al., 2009; Schon and Boehncke, 2005). Psoriasis can lead to erythematous skin lesions (plaques), psoriatic arthritis, and nail dystrophy; in addition, it is associated with Crohn's disease and other systemic diseases and depression, thus causing significant morbidity and leading to early mortality (Henseler and Christophers, 1995; Mak et al., 2009; Nickoloff and Nestle, 2004).

[0007] Routine observations of improvement in cancer patients with psoriasis who received paclitaxel led to the hypothesis that taxanes (e.g., paclitaxel, docetaxel) may have the potential to be used as an alternative therapy for the treatment of psoriasis. An open-label, prospective Phase II study of 12 subjects with severe psoriasis concluded that intravenous (IV) infusion of micellar (without Cremophor EL) paclitaxel over a weekly period provided therapeutic activity in these patients while being generally well tolerated (Ehrlich et al., 2004). Nonclinical evaluations disclosed in U.S. Pat. No. 6,515,016 demonstrated a reduction in inflammation, swelling, and erythema in a skin inflammation model following treatment with topical paclitaxel. However, topical treatment of psoriasis can be particularly problematic because psoriasis plaques accumulate on the skin, impeding drug delivery into the skin. There are currently no FDA-approved topical taxane formulations for the treatment of psoriasis.

[0008] Treatment of diseases and disorders of keratinous tissue, including nails, nail beds, and hair, is difficult due to the tough protective layer of keratin that inhibits drug penetration through the affected tissue. Although the nail is a skin appendage, nail diseases are distinct from skin diseases. Common diseases of the nail include onychomycosis, fungal diseases, and nail psoriasis, which commonly affects patients with skin psoriasis. Summary of the invention

[0009] The present invention provides solutions to the above-mentioned limitations and deficiencies in the field related to drug delivery, inhibiting crystals in aqueous formulations and anhydrous hydrophobic compositions of drug nanoparticles, and / or treating psoriasis.

[0010] It was found that the hydrophobic composition of the present invention having a volatile silicone fluid in a concentration of less than 25% by weight in combination with an anhydrous hydrophobic carrier exhibited higher skin penetration (i.e., penetration into the epidermis and dermis of the skin) of the drug nanoparticles compared to the skin penetration of the drug nanoparticles from the hydrophobic carrier alone. Surprisingly, it was also found that, except for a small amount of volatile silicone (less than 25% by weight), the addition of other skin penetration enhancers to the hydrophobic composition had little or no effect on the skin penetration of the composition. Therefore, the composition of the present invention may be free of (does not have or does not contain) these other skin penetration enhancers (e.g., surfactants, volatile solvents, alcohols, C 1 To C 5 Fatty alcohols), which can help reduce skin irritation when the compositions of the present invention are applied to the skin. Even more surprisingly, enhanced penetration is achieved with low concentrations, i.e., less than 25% by weight, of cyclomethicone. In addition, after the initial application, the drug nanoparticles are not delivered transdermally with these compositions, which is an advantageous feature because transdermal delivery (systemic absorption) is not desired when treating the skin (epidermis and dermis). In addition, the skin penetration (i.e., penetration into the dermis or epidermis portion of the skin) of the drug nanoparticles from the compositions of the present invention is far superior to the skin penetration of drug nanoparticles from water-based compositions, even if the water-based compositions contain a transdermal absorption enhancer. In addition, it was found that the drug nanoparticles in the hydrophobic compositions of the present invention are stable and do not show crystal growth over time.

[0011] Hydrophobic compositions comprising drug nanoparticles of taxanes such as paclitaxel with volatile silicone fluids and hydrophobic carriers are particularly suitable for topical treatment of psoriasis because these compositions have enhanced permeation properties into the epidermis and dermis of the skin. However, it is worth noting that these hydrophobic compositions have reduced to no percutaneous permeation, thus reducing or avoiding systemic administration of paclitaxel. In contrast, the compositions of the present invention can treat psoriasis topically rather than systemically.

[0012] It has also been found that crystal growth of drug nanoparticles in an aqueous carrier is inhibited by including poloxamer 407, a quaternary ammonium compound, or a cross-linked acrylic acid polymer in the aqueous carrier.

[0013] The compositions of the present invention can also be used to locally deliver drug nanoparticles to keratinous tissues including nails and hair, and to treat diseases and conditions of keratinous tissues. The compositions of the present invention comprising taxane nanoparticles or antifungal nanoparticles are particularly useful for treating certain diseases and conditions of nails.

[0014] The following embodiments 1 to 155 are also disclosed in the context of the present invention:

[0015] Embodiment 1 is a method for enhancing the penetration of drug nanoparticles into the skin, the method comprising applying to the skin surface a hydrophobic composition comprising a continuous hydrophobic carrier, 5 wt% to 24 wt% of one or more than one volatile silicone fluid, and a plurality of drug nanoparticles, wherein the average particle size (number) of the drug nanoparticles is 0.1 microns to 1.5 microns, and wherein the composition does not comprise C 1 To C 5 Fatty alcohol.

[0016] Embodiment 2 is the method of embodiment 1, wherein the volatile silicone fluid is cyclomethicone.

[0017] Embodiment 3 is the method of embodiment 2, wherein the cyclomethicone is cyclopentasiloxane.

[0018] Embodiment 4 is the method of any one of embodiments 1 to 3, wherein the composition does not comprise an additional transdermal absorption enhancer.

[0019] Embodiment 5 is the method of any one of embodiments 1 to 4, wherein the composition does not comprise additional volatile solvents.

[0020] Embodiment 6 is the method of any one of embodiments 1 to 5, wherein the composition does not comprise a surfactant.

[0021] Embodiment 7 is the method of any one of embodiments 1 to 6, wherein the composition is anhydrous.

[0022] Embodiment 8 is the method of any one of embodiments 1 to 7, wherein the hydrophobic carrier is non-volatile.

[0023] Embodiment 9 is the method of any one of embodiments 1 to 8, wherein the hydrophobic carrier is non-polar.

[0024] Embodiment 10 is the method of any one of embodiments 1 to 9, wherein the hydrophobic carrier comprises a hydrocarbon.

[0025] Embodiment 11 is the method of embodiment 10, wherein the hydrocarbon is petrolatum, mineral oil, or paraffin, or a mixture thereof.

[0026] Embodiment 12 is the method of embodiment 11, wherein the petrolatum is white petrolatum.

[0027] Embodiment 13 is the method of embodiment 11 or 12, wherein the mineral oil is a heavy mineral oil.

[0028] Embodiment 14 is the method of any one of embodiments 1 to 13, wherein the drug nanoparticles are crystalline nanoparticles.

[0029] Embodiment 15 is the method of any one of embodiments 1 to 13, wherein the drug nanoparticles are amorphous nanoparticles.

[0030] Embodiment 16 is the method of any one of embodiments 1 to 13, wherein the drug nanoparticles are a combination of amorphous nanoparticles and crystalline nanoparticles.

[0031] Embodiment 17 is the method of any one of embodiments 1 to 16, wherein the average particle size of the drug nanoparticles does not grow by more than 20% of the initial average particle size when the composition is stored at room temperature for at least 1 month.

[0032] Embodiment 18 is the method of any one of embodiments 1 to 16, wherein the average particle size of the drug nanoparticles does not grow by more than 20% of the initial average particle size when the composition is stored at room temperature for at least 3 months.

[0033] Embodiment 19 is the method of any one of embodiments 1 to 18, wherein the drug nanoparticles are water soluble.

[0034] Embodiment 20 is the method of any one of embodiments 1 to 18, wherein the drug nanoparticles are poorly water soluble.

[0035] Embodiment 21 is the method of embodiment 20, wherein the drug nanoparticles are taxane nanoparticles.

[0036] Embodiment 22 is the method of embodiment 21, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.

[0037] Embodiment 23 is the method of embodiment 21, wherein the taxane nanoparticles are paclitaxel nanoparticles.

[0038] Embodiment 24 is the method of any one of embodiments 1 to 23, wherein the skin is diseased skin.

[0039] Embodiment 25 is the method of embodiment 24, wherein the diseased skin is psoriasis-affected skin.

[0040] Embodiment 26 is the method of any one of embodiments 1 to 25, wherein when the composition is applied to human cadaver skin, the relative humidity is less than 0.01 μg / cm 2 of drug nanoparticles penetrating human cadaver skin.

[0041] Embodiment 27 is the method of any one of embodiments 1 to 26, wherein the composition is a semisolid composition.

[0042] Embodiment 28 is the method of embodiment 27, wherein the semisolid composition is an ointment.

[0043] Embodiment 29 is the method of embodiment 27 or 28, wherein the viscosity of the composition is 12500 cps to 247500 cps as measured by a Brookfield RV viscometer at room temperature, 5 rpm, and an equilibrium time of 2 minutes, using a small sample adapter with an SC4-14 spindle and a 6R chamber.

[0044] Embodiment 30 is a hydrophobic composition comprising a continuous hydrophobic carrier, 5 wt% to 24 wt% of one or more than one volatile silicone fluid, and a plurality of drug nanoparticles, wherein the average particle size (number) of the drug nanoparticles is 0.1 microns to 1.5 microns, and wherein the composition does not comprise C 1 To C 5 Fatty alcohol.

[0045] Embodiment 31 is the composition of embodiment 30, wherein the volatile silicone fluid is cyclomethicone.

[0046] Embodiment 32 is the composition of embodiment 31, wherein the cyclomethicone is cyclopentasiloxane.

[0047] Embodiment 33 is the composition of any one of embodiments 30 to 32, wherein the composition does not comprise an additional transdermal absorption enhancer.

[0048] Embodiment 34 is the composition of any one of embodiments 30 to 33, wherein the composition does not comprise additional volatile solvents.

[0049] Embodiment 35 is the composition of any one of embodiments 30 to 34, wherein the composition does not comprise a surfactant.

[0050] Embodiment 36 is the composition of any one of embodiments 30 to 35, wherein the composition is anhydrous.

[0051] Embodiment 37 is the composition of any one of embodiments 30 to 36, wherein the hydrophobic carrier is non-volatile.

[0052] Embodiment 38 is the composition of any one of embodiments 30 to 37, wherein the hydrophobic carrier is non-polar.

[0053] Embodiment 39 is the composition of any one of embodiments 30 to 38, wherein the hydrophobic carrier comprises a hydrocarbon.

[0054] Embodiment 40 is the composition of embodiment 39, wherein the hydrocarbon is petrolatum, mineral oil, or paraffin, or a mixture thereof.

[0055] Embodiment 41 is the composition of embodiment 40, wherein the petrolatum is white petrolatum.

[0056] Embodiment 42 is the composition of embodiment 40 or 41, wherein the mineral oil is a heavy mineral oil.

[0057] Embodiment 43 is the composition of any one of embodiments 30 to 42, wherein the drug nanoparticles are crystalline nanoparticles.

[0058] Embodiment 44 is the composition of any one of embodiments 30 to 42, wherein the drug nanoparticles are amorphous nanoparticles.

[0059] Embodiment 45 is the composition of any one of embodiments 30 to 42, wherein the drug nanoparticles are a combination of amorphous nanoparticles and crystalline nanoparticles.

[0060] Embodiment 46 is the composition of any one of embodiments 30 to 45, wherein the average particle size of the drug nanoparticles does not grow by more than 20% of the initial average particle size when the composition is stored at room temperature for at least 1 month.

[0061] Embodiment 47 is the composition of any one of embodiments 30 to 45, wherein the average particle size of the drug nanoparticles does not grow by more than 20% of the initial average particle size when the composition is stored at room temperature for at least 3 months.

[0062] Embodiment 48 is the composition of any one of embodiments 30 to 47, wherein the drug nanoparticles are water soluble.

[0063] Embodiment 49 is the composition of any one of embodiments 30 to 47, wherein the drug nanoparticles are poorly water soluble.

[0064] Embodiment 50 is the composition of embodiment 49, wherein the drug nanoparticles are taxane nanoparticles.

[0065] Embodiment 51 is the composition of embodiment 50, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.

[0066] Embodiment 52 is the composition of embodiment 50, wherein the taxane nanoparticles are paclitaxel nanoparticles.

[0067] Embodiment 53 is the composition of any one of embodiments 30 to 52, wherein when the composition is applied to human cadaver skin, the relative humidity is less than 0.01 μg / cm 2 of drug nanoparticles penetrating human cadaver skin.

[0068] Embodiment 54 is the composition of any one of embodiments 30 to 53, wherein the composition is a semisolid composition.

[0069] Embodiment 55 is the composition of embodiment 54, wherein the semisolid composition is an ointment.

[0070] Embodiment 56 is the composition of embodiment 54 or 55, wherein the viscosity of the composition measured by a Brookfield RV viscometer at room temperature, 5 rpm and an equilibrium time of 2 minutes is 12500 cps to 247500 cps, the Brookfield RV viscometer using a small sample adapter with an SC4-14 spindle and a 6R chamber.

[0071] Embodiment 57 is a method of treating psoriasis in a patient, the method comprising topically applying to the affected area of ​​the patient a continuous hydrophobic composition comprising a hydrophobic carrier, 5 wt% to 24 wt% of one or more than one volatile silicone fluid, and a plurality of taxane nanoparticles, wherein the average particle size (number) of the taxane nanoparticles is 0.1 μm to 1.5 μm, wherein the composition does not contain C 1 To C 5 A fatty alcohol, and wherein the concentration of the taxane nanoparticles is an effective concentration to provide therapeutic improvement for psoriatic conditions.

[0072] Embodiment 58 is the method of embodiment 57, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.

[0073] Embodiment 59 is the method of embodiment 57, wherein the taxane nanoparticles are paclitaxel nanoparticles.

[0074] Embodiment 60 is the method of any one of embodiments 57 to 59, wherein the volatile silicone fluid is cyclomethicone.

[0075] Embodiment 61 is the method of embodiment 60, wherein the cyclomethicone is cyclopentasiloxane.

[0076] Embodiment 62 is the method of any one of embodiments 57 to 61, wherein the composition does not comprise an additional transdermal absorption enhancer.

[0077] Embodiment 63 is the method of any one of embodiments 57 to 62, wherein the composition does not comprise additional volatile solvents.

[0078] Embodiment 64 is the method of any one of embodiments 57 to 63, wherein the composition does not comprise a surfactant.

[0079] Embodiment 65 is the method of any one of embodiments 57 to 64, wherein the composition is anhydrous.

[0080] Embodiment 66 is the method of any one of embodiments 57 to 65, wherein the hydrophobic carrier is non-volatile.

[0081] Embodiment 67 is the method of any one of embodiments 57 to 66, wherein the hydrophobic carrier is non-polar.

[0082] Embodiment 68 is the method of any one of embodiments 57 to 67, wherein the hydrophobic carrier comprises a hydrocarbon.

[0083] Embodiment 69 is the method of embodiment 68, wherein the hydrocarbon is petrolatum, mineral oil, or paraffin, or a mixture thereof.

[0084] Embodiment 70 is the method of embodiment 69, wherein the petrolatum is white petrolatum.

[0085] Embodiment 71 is the method of embodiment 69 or 70, wherein the mineral oil is a heavy mineral oil.

[0086] Embodiment 72 is the method of any one of embodiments 57 to 71, wherein the taxane nanoparticles are crystalline nanoparticles.

[0087] Embodiment 73 is the method of any one of embodiments 57 to 71, wherein the taxane-based nanoparticles are amorphous nanoparticles.

[0088] Embodiment 74 is the method of any one of embodiments 57 to 71, wherein the taxane-based nanoparticles are a combination of amorphous nanoparticles and crystalline nanoparticles.

[0089] Embodiment 75 is the method of any one of embodiments 57 to 74, wherein the average particle size of the taxane nanoparticles does not grow by more than 20% of the initial average particle size when the composition is stored at room temperature for at least 3 months.

[0090] Embodiment 76 is the method of any one of embodiments 57 to 75, wherein when the composition is applied to human cadaver skin, the relative humidity is less than 0.01 μg / cm 2 Taxane nanoparticles penetrate human cadaver skin.

[0091] Embodiment 77 is the method of any one of embodiments 57 to 76, wherein the composition is a semisolid composition.

[0092] Embodiment 78 is the method of embodiment 77, wherein the semisolid composition is an ointment.

[0093] Embodiment 79 is the method of embodiment 77 or 78, wherein the viscosity of the composition is 12500 cps to 247500 cps as measured by a Brookfield RV viscometer at room temperature, 5 rpm, and an equilibrium time of 2 minutes, using a small sample adapter with an SC4-14 spindle and a 6R chamber.

[0094] Embodiment 80 is a method of inhibiting the growth of crystalline drug nanoparticles, the method comprising contacting the drug nanoparticles with a hydrophobic carrier, wherein the average particle size (number) of the drug nanoparticles is from 0.1 microns to 1.5 microns.

[0095] Embodiment 81 is the method of embodiment 80, wherein the drug nanoparticles are water soluble.

[0096] Embodiment 82 is the method of embodiment 80, wherein the drug nanoparticles are poorly water soluble.

[0097] Embodiment 83 is the method of embodiment 82, wherein the drug nanoparticles are taxane nanoparticles.

[0098] Embodiment 84 is the method of embodiment 83, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.

[0099] Embodiment 85 is the method of embodiment 83, wherein the taxane-based nanoparticles are paclitaxel particles.

[0100] Embodiment 86 is the method of any one of embodiments 80 to 85, wherein the hydrophobic carrier is anhydrous.

[0101] Embodiment 87 is the method of any one of embodiments 80 to 85, wherein the hydrophobic carrier comprises a hydrocarbon.

[0102] Embodiment 88 is the method of embodiment 87, wherein the hydrocarbon is petrolatum, mineral oil, or paraffin, or a mixture thereof.

[0103] Embodiment 89 is the method of any one of embodiments 80 to 88, wherein the composition further comprises one or more than one volatile silicone fluid.

[0104] Embodiment 90 is the method of embodiment 89, wherein the volatile silicone fluid is cyclomethicone.

[0105] Embodiment 91 is the method of embodiment 90, wherein the cyclomethicone is cyclopentasiloxane.

[0106] Embodiment 92 is a method for inhibiting the growth of a dispersion of poorly water-soluble crystalline drug nanoparticles in an aqueous carrier, the method comprising adding poloxamer 407, a quaternary ammonium compound, or a cross-linked acrylic acid polymer, or a mixture thereof, to the aqueous carrier during processing, wherein the average particle size (number) of the drug nanoparticles is 0.1 microns to 1.5 microns.

[0107] Embodiment 93 is the method of embodiment 92, wherein the quaternary ammonium compound is benzalkonium chloride or benzethonium chloride.

[0108] Embodiment 94 is the method of embodiment 92, wherein the cross-linked acrylic acid polymer is a carbomer.

[0109] Embodiment 95 is the method of any one of embodiments 92 to 94, wherein the drug nanoparticles are taxane nanoparticles.

[0110] Embodiment 96 is the method of embodiment 95, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.

[0111] Embodiment 97 is the method of embodiment 95, wherein the taxane nanoparticles are paclitaxel nanoparticles.

[0112] Embodiment 98 is a method of topically treating a disease or condition of keratinous tissue, the method comprising topically applying to the keratinous tissue a hydrophobic composition comprising a continuous hydrophobic carrier, 5 wt% to 24 wt% of one or more than one volatile silicone fluid, and a plurality of drug nanoparticles, wherein the average particle size (number) of the drug nanoparticles is 0.1 microns to 1.5 microns, wherein the concentration of the drug nanoparticles is an effective concentration to provide therapeutic improvement for the disease or condition, and wherein the composition does not comprise C 1 To C 5 Fatty alcohol.

[0113] Embodiment 99 is the method of embodiment 98, wherein the volatile silicone fluid is cyclomethicone.

[0114] Embodiment 100 is the method of embodiment 99, wherein the cyclomethicone is cyclopentasiloxane.

[0115] Embodiment 101 is the method of any one of embodiments 98 to 100, wherein the composition does not comprise an additional transdermal absorption enhancer.

[0116] Embodiment 102 is the method of any one of embodiments 98 to 101, wherein the composition does not comprise additional volatile solvents.

[0117] Embodiment 103 is the method of any one of embodiments 98 to 102, wherein the composition does not comprise a surfactant.

[0118] Embodiment 104 is the method of any one of embodiments 98 to 103, wherein the composition is anhydrous.

[0119] Embodiment 105 is the method of any one of embodiments 98 to 104, wherein the hydrophobic carrier is non-volatile.

[0120] Embodiment 106 is the method of any one of embodiments 98 to 105, wherein the hydrophobic carrier is non-polar.

[0121] Embodiment 107 is the method of any one of embodiments 98 to 106, wherein the hydrophobic carrier comprises a hydrocarbon.

[0122] Embodiment 108 is the method of embodiment 107, wherein the hydrocarbon is petrolatum, mineral oil, or paraffin, or a mixture thereof.

[0123] Embodiment 109 is the method of embodiment 107, wherein the petrolatum is white petrolatum.

[0124] Embodiment 110 is the method of embodiment 108 or 109, wherein the mineral oil is a heavy mineral oil.

[0125] Embodiment 111 is the method of any one of embodiments 98 to 110, wherein the drug nanoparticles are crystalline nanoparticles.

[0126] Embodiment 112 is the method of any one of embodiments 98 to 110, wherein the drug nanoparticles are amorphous nanoparticles.

[0127] Embodiment 113 is the method of any one of embodiments 98 to 110, wherein the drug nanoparticles are a combination of amorphous nanoparticles and crystalline nanoparticles.

[0128] Embodiment 114 is the method of any one of embodiments 98 to 113, wherein the average particle size of the drug nanoparticles does not grow by more than 20% of the initial average particle size when the composition is stored at room temperature for at least 1 month.

[0129] Embodiment 115 is the method of any one of embodiments 98 to 113, wherein when the composition is stored at room temperature for 3 months, the average particle size of the drug nanoparticles does not grow by more than 20% of the initial average particle size.

[0130] Embodiment 116 is the method of any one of embodiments 98 to 115, wherein the drug nanoparticles are water soluble.

[0131] Embodiment 117 is the method of any one of embodiments 98 to 115, wherein the drug nanoparticles are poorly water soluble.

[0132] Embodiment 118 is the method of embodiment 117, wherein the drug nanoparticles are taxane nanoparticles.

[0133] Embodiment 119 is the method of embodiment 118, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.

[0134] Embodiment 120 is the method of embodiment 118, wherein the taxane nanoparticles are paclitaxel nanoparticles.

[0135] Embodiment 121 is the method of any one of embodiments 98 to 117, wherein the drug nanoparticles are nanoparticles of an antifungal agent.

[0136] Embodiment 122 is the method of any one of embodiments 98 to 121, wherein the composition is a semisolid composition.

[0137] Embodiment 123 is the method of embodiment 122, wherein the semisolid composition is an ointment.

[0138] Embodiment 124 is the method of embodiment 122 or 123, wherein the viscosity of the composition is 12500 cps to 247500 cps as measured by a Brookfield RV viscometer at room temperature using a small sample adapter with an SC4-14 spindle and a 6R chamber, 5 rpm and an equilibrium time of 2 minutes.

[0139] Embodiment 125 is the method of any one of embodiments 98 to 124, wherein the disease or disorder of keratinous tissue is nail psoriasis.

[0140] Embodiment 126 is the method of any one of embodiments 98 to 124, wherein the disease or disorder of keratinous tissue is a fungal infection.

[0141] Embodiment 127 is the method of embodiment 126, wherein the fungal infection is onychomycosis.

[0142] Embodiment 128 is the method of any one of embodiments 98 to 127, wherein the keratinous tissue is a nail, or a nail bed, or both.

[0143] Embodiment 129 is the method of any one of embodiments 98 to 124 or 126, wherein the keratinous tissue is hair.

[0144] Embodiment 130 is a water-based composition comprising an aqueous carrier; a plurality of poorly water-soluble drug nanoparticles; and a quaternary ammonium compound, or a cross-linked acrylic polymer, or a mixture thereof; wherein the average particle size (number) of the drug nanoparticles is 0.1 microns to 1.5 microns, wherein when the composition is stored at room temperature for at least 6 months, the average particle size growth of the drug nanoparticles does not exceed 20% of the initial average particle size.

[0145] Embodiment 131 is the composition of embodiment 130, wherein the composition further comprises poloxamer 407.

[0146] Embodiment 132 is the method of any one of embodiments 1 to 29, 57 to 79, or 98 to 129, wherein the hydrophobic carrier is greater than 50% by weight of the composition.

[0147] Embodiment 133 is the composition of any one of embodiments 30 to 56, wherein the hydrophobic carrier is greater than 50% by weight of the composition.

[0148] Embodiment 134 is the method of any one of embodiments 27, 28, 77, 78, 122 or 123, wherein the viscosity of the composition is from 25,000 cps to 500,000 cps as measured using a Brookfield RV viscometer on a lift stand with the lift stand open and a TE spindle at 10 RPM for 45 seconds at room temperature.

[0149] Embodiment 135 is the composition of any of embodiments 54 or 55, wherein the viscosity of the composition is 25,000 cps to 500,000 cps as measured using a Brookfield RV viscometer on a lift stand with the lift stand open and a TE spindle at 10 RPM for 45 seconds at room temperature.

[0150] Embodiment 136 is the method of any one of embodiments 23, 59, 85, 97, or 120, wherein the paclitaxel nanoparticles have at least 18 m 2 / g specific surface area (SSA).

[0151] Embodiment 137 is the composition of embodiment 52, wherein the paclitaxel nanoparticles have at least 18 m 2 / g specific surface area (SSA).

[0152] Embodiment 138 is the method of embodiment 59, wherein the concentration of the paclitaxel nanoparticles is about 0.1 wt % to about 2 wt %.

[0153] Embodiment 139 is the composition of embodiment 52, wherein the concentration of the paclitaxel nanoparticles is about 0.1 wt % to about 2 wt %.

[0154] Embodiment 140 is the method of any one of embodiments 1 to 29, 57 to 79, 80 to 91, 92 to 97, or 98 to 129, wherein the composition does not comprise protein or albumin.

[0155] Embodiment 141 is the composition of any one of embodiments 30 to 56, or 130 to 131, wherein the composition does not comprise protein or albumin.

[0156] Embodiment 142 is the composition of embodiment 130 or 131, wherein the drug nanoparticles are taxane nanoparticles.

[0157] Embodiment 143 is the composition of embodiment 142, wherein the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.

[0158] Embodiment 144 is the composition of embodiment 142, wherein the taxane nanoparticles are paclitaxel nanoparticles.

[0159] Embodiment 145 is the composition of any one of embodiments 142 to 144, wherein the composition does not comprise protein or albumin.

[0160] Embodiment 146 is a method of enhancing penetration of drug nanoparticles into the skin, the method comprising applying to the skin surface a hydrophobic composition consisting essentially of a continuous hydrophobic carrier, 5 wt % to 24 wt % of one or more than one volatile silicone fluid, and a plurality of drug nanoparticles,

[0161] wherein the average particle size (number) of the drug nanoparticles is 0.1 microns to 1.5 microns;

[0162] wherein the volatile silicone fluid is cyclopentasiloxane;

[0163] wherein the continuous hydrophobic carrier is nonvolatile and nonpolar, is greater than 50% by weight of the composition, and consists essentially of petrolatum, heavy mineral oil, and paraffin;

[0164] wherein the composition is an anhydrous, non-polar semisolid ointment; and

[0165] Where the composition does not contain C 1 To C 5Aliphatic alcohols.

[0166] Embodiment 147 is the method of embodiment 146, wherein:

[0167] The hydrophobic composition does not contain additional transdermal absorption enhancers or additional volatile solvents other than cyclopentasiloxane; and

[0168] The hydrophobic composition does not include a surfactant.

[0169] Embodiment 148 is the method of any one of embodiments 146 or 147, wherein the drug nanoparticles are paclitaxel nanoparticles, wherein the concentration of the paclitaxel nanoparticles is about 0.1 wt% to about 2 wt%, and wherein the composition does not comprise protein or albumin.

[0170] Embodiment 149 is a hydrophobic composition consisting essentially of a continuous hydrophobic carrier, 5 wt % to 24 wt % of one or more than one volatile silicone fluid, and a plurality of drug nanoparticles,

[0171] wherein the average particle size (number) of the drug nanoparticles is 0.1 microns to 1.5 microns;

[0172] wherein the volatile silicone fluid is cyclopentasiloxane;

[0173] wherein the continuous hydrophobic carrier is nonvolatile and nonpolar, is greater than 50% by weight of the composition, and consists essentially of petrolatum, heavy mineral oil, and paraffin;

[0174] wherein the composition is an anhydrous semisolid ointment; and

[0175] Where the composition does not contain C 1 To C 5 Aliphatic alcohols.

[0176] Embodiment 150 is the hydrophobic composition of embodiment 149, wherein:

[0177] The hydrophobic composition does not contain additional transdermal absorption enhancers or additional volatile solvents other than cyclopentasiloxane; and

[0178] The hydrophobic composition does not include a surfactant.

[0179] Embodiment 151 is the composition of any one of embodiments 149 or 150, wherein the drug nanoparticles are paclitaxel nanoparticles, wherein the concentration of the paclitaxel nanoparticles is about 0.1 wt% to about 2 wt%, and wherein the composition does not comprise protein or albumin.

[0180] Embodiment 152 is a method of treating psoriasis in a patient, the method comprising topically applying to the affected area of ​​the patient a hydrophobic composition comprising a continuous hydrophobic carrier, 5 wt% to 24 wt% of one or more than one volatile silicone fluid, and a plurality of paclitaxel nanoparticles,

[0181] wherein the average particle size (number) of paclitaxel nanoparticles is 0.1 microns to 1.5 microns;

[0182] wherein the volatile silicone fluid is cyclomethicone;

[0183] wherein the continuous hydrophobic carrier is nonvolatile and nonpolar, is greater than 50% by weight of the composition, and consists essentially of petrolatum, heavy mineral oil, and paraffin;

[0184] Wherein the composition is an anhydrous semisolid ointment; Wherein the composition does not contain C 1 To C 5 Fatty alcohols;

[0185] wherein the composition does not comprise protein or albumin;

[0186] wherein the concentration of the paclitaxel nanoparticles is from about 0.1 wt % to about 2 wt %; and

[0187] Therein a therapeutic improvement in psoriatic conditions is achieved.

[0188] Embodiment 153 is the method of embodiment 152, wherein the concentration of the paclitaxel nanoparticles is about 0.1 wt % to about 0.2 wt %.

[0189] Embodiment 154 is the method of any one of embodiments 152 or 153, wherein the hydrophobic composition does not comprise additional transdermal absorption enhancers or additional volatile solvents other than cyclopentasiloxane; and

[0190] The hydrophobic composition does not include a surfactant.

[0191] Embodiment 155 is the method of embodiment 138, wherein the concentration of the paclitaxel nanoparticles is about 0.1 wt % to about 0.2 wt %.

[0192] As used herein with respect to drug particles, the terms "nanoparticles" and "nanomicroparticles" mean drug particles having an average particle size (based on a number-weighted differential distribution, expressed as "number") of 0.01 microns to 1.5 microns (10 nm to 1500 nm) or preferably 0.1 microns to 1.5 microns (100 nm to 1500 nm).

[0193] As used herein, the term "water soluble" describes a compound having a solubility in water of greater than 10 mg / mL or greater at room temperature.

[0194] As used herein, the term "poorly water soluble" describes a compound having a solubility in water of less than or equal to 10 mg / mL at room temperature.

[0195] As used herein, the term "hydrophobic" describes a compound, composition, or carrier that has a solubility in water at room temperature of less than or equal to 10 mg / mL.

[0196] As used herein, the term "volatile" describes a compound, composition, or carrier that has a vapor pressure greater than or equal to 10 Pa at room temperature.

[0197] As used herein, the term "nonvolatile" describes a compound, composition, or carrier having a vapor pressure of less than 10 Pa at room temperature.

[0198] As used herein with respect to the compositions or carriers of the present invention, the term "anhydrous" means that less than 3 wt%, preferably less than 2 wt%, more preferably less than 1 wt%, or most preferably 0 wt% of water is present in the composition or carrier. This can account for the presence of small amounts of water (e.g., water inherently contained in any component of the composition or carrier, water absorbed from the atmosphere, etc.).

[0199] As used herein, the term "skin" refers to the epidermis and dermis.

[0200] As used herein, the term "room temperature" (RT) refers to 20°C to 25°C.

[0201] As used herein, the term "transdermal absorption enhancer" or "skin transdermal absorption enhancer" refers to a compound or material or substance that enhances the absorption of a drug into the skin (epidermis and dermis).

[0202] As used herein, the term "surfactant" or "surface active agent" refers to a compound or material or substance that exhibits the ability to reduce the surface tension of water or reduce the interfacial tension between two immiscible substances.

[0203] Unless otherwise stated, the percentage values ​​expressed herein are % by weight and relate to the weight of the total composition.

[0204] The term "about" or "approximately" is defined as close to as understood by one of ordinary skill in the art. In a non-limiting embodiment, the term is defined as within 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%.

[0205] For this application, values ​​with one or more decimal places can be rounded to the nearest integer using standard rounding guidelines, i.e., round up if the value being rounded is 5, 6, 7, 8, or 9, and round down if the value being rounded is 0, 1, 2, 3, or 4. For example, 3.7 can be rounded to 4.

[0206] The words "comprising," "having," "including," or "containing" are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0207] When used in conjunction with the word "a" and the terms "including," "having," "comprising," or "containing," it may mean "one," but it also has the meaning of "one or more," "at least one," and "one or more than one."

[0208] The compositions and methods of use thereof may "comprise," "consist essentially of," or "consist of" any of the ingredients or steps disclosed throughout the specification. With respect to the phrase "consist essentially of," the basic and novel property of the hydrophobic compositions of the present invention is their ability to penetrate into the epidermis and dermis of the skin without percutaneous penetration. This can be accomplished without the use of C 1 To C 5 This is achieved in the absence of aliphatic alcohols, surfactants, additional transdermal absorption enhancers and additional volatile solvents other than volatile silicone fluids (such as cyclomethicone or cyclopentasiloxane or a combination thereof).

[0209] "Limited," "reduced," or "minimal" when used to modify the phrase "permeate transdermally" means that when the composition is applied to human cadaver skin, the permeation rate is less than 0.01 μg / cm 2 of drug nanoparticles penetrating human cadaver skin.

[0210] It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the invention, and vice versa. In addition, the compositions of the invention can be used to implement the methods of the invention.

[0211] Other objects, features and advantages of the present invention will become apparent from the following detailed description. However, it should be understood that although specific embodiments of the present invention are indicated, the detailed description and specific examples are given by way of illustration only, because various changes and modifications within the spirit and scope of the present invention will become apparent to those skilled in the art from the detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0212] Figure 1The concentration of paclitaxel (μg / cm 2 ).

[0213] Figure 2 The concentration of paclitaxel (μg / cm2) delivered to the epidermis in vitro for formulations F6* (analyzed in duplicate) and F8 to F13 is shown. 2 ).

[0214] Figure 3 The concentration of paclitaxel (μg / cm 2 ).

[0215] Figure 4 The concentration of paclitaxel (μg / cm2) delivered into the dermis in vitro for formulations F6* (analyzed in duplicate) and F8 to F13 is shown. 2 ). DETAILED DESCRIPTION

[0216] In one aspect, the present invention relates to compositions and methods that can be used to enhance the penetration of drug nanoparticles into the epidermal and dermal portions of the skin. In another aspect, the present invention relates to inhibiting crystal growth of drug nanoparticles in a carrier. In another aspect, the present invention relates to compositions and methods that can be used for topical treatment of immune-mediated diseases such as psoriasis. In another aspect, the present invention relates to compositions and methods for delivering drug nanoparticles to keratinous tissues including nails and hair. In another aspect, the present invention relates to compositions and methods for topical treatment of keratinous tissues including nails and hair. The compositions of the present invention comprise a plurality of drug nanoparticles in a carrier. The carrier can be hydrophobic based or water based.

[0217] I. Composition

[0218] In one aspect of the invention, the composition of the invention is hydrophobic and comprises a continuous hydrophobic carrier, one or more than one volatile silicone fluid (e.g., cyclomethicone) and drug nanoparticles. The composition is a suspension of multiple drug nanoparticles in a mixture of a hydrophobic carrier and a volatile silicone fluid. The drug nanoparticles may be fully dispersed or partially dispersed and partially dissolved in the composition, but not completely dissolved in the composition. The hydrophobic composition may be anhydrous. The hydrophobic carrier is the continuous phase of the composition. Therefore, the composition of the invention may include at least two phases: a continuous hydrophobic carrier phase and a suspended drug nanoparticle phase. The volatile silicone fluid may be dissolved in the continuous phase.

[0219] Surprisingly, compared to the skin penetration of drug nanoparticles from hydrophobic carriers alone, the hydrophobic compositions of the present invention comprising low concentrations, i.e., less than 25% by weight, of volatile silicone fluids and continuous anhydrous hydrophobic carriers exhibit higher skin penetration of drug nanoparticles (i.e., penetration into the epidermis and / or dermis of the skin). In fact, even more surprisingly, the addition of other transdermal absorption enhancers has little or no effect on the skin penetration of these compositions. However, it is worth noting that the drug nanoparticles do not penetrate the skin (i.e., percutaneous penetration) or only have negligible amounts of percutaneous penetration of the skin, i.e., less than 0.01 μg / cm 2 . In addition, the skin penetration (i.e., epidermal or dermal penetration) of drug nanoparticles from anhydrous hydrophobic compositions is far superior to the skin penetration of drug nanoparticles from water-based compositions, even if the water-based compositions contain transdermal absorption enhancers. In addition, and surprisingly, the hydrophobic compositions of the present invention comprising less than 25% of a volatile silicone fluid and a hydrophobic carrier do not need to contain alcohol, additional volatile solvents, additional transdermal absorption enhancers, or surfactants to provide enhanced skin penetration, thereby obtaining the most cost-effective and simplified composition that can reduce skin irritation when applied topically. However, if desired, these components may be included in the compositions of the present invention. In some embodiments, the hydrophobic composition does not / does not include or does not contain an additional transdermal absorption enhancer. In other embodiments, the hydrophobic composition does not / does not include or does not contain an additional volatile solvent or compound. In some embodiments, the hydrophobic composition does not / does not include or does not contain alcohol or C 1 To C 5 In some embodiments, the hydrophobic composition is a semisolid composition. In other embodiments, the hydrophobic composition is an ointment. In some embodiments, the hydrophobic composition is not a spray and is not sprayable.

[0220] In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and its viscosity is 12500 cps to 247500 cps, or 25000 cps to 150000 cps, as measured by a Brookfield RV viscometer at room temperature, 5 rpm and 2 minutes of equilibrium time, using a small sample adapter with an SC4-14 rotor and a 6R chamber. An alternative method for performing viscosity measurements of hydrophobic semisolid compositions is a Brookfield RV viscometer on a lift stand, the lift stand being open, using a TE rotor at room temperature at 10 RPM for 45 seconds. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and has a viscosity of 25,000 cps to 500,000 cps, or 2500 cps to 400,000 cps, or 25,000 cps to 350,000 cps, or 25,000 cps to 300,000 cps, or 50,000 cps to 500,000 cps, or 50,000 cps to 400,000 cps, or 50,000 cps to 350,000 cps, or 50,000 cps to 300,000 cps. cps, or 75,000 cps to 500,000 cps, or 75,000 cps to 400,000 cps, or 75,000 cps to 350,000 cps, or 75,000 cps to 300,000 cps, or 100,000 cps to 500,000 cps, or 100,000 cps to 400,000 cps, or 100,000 cps to 350,000 cps, or 100,000 cps to 300,000 cps, the viscosity being measured using a Brookfield RV viscometer on a lift stand with the lift stand open and a TE rotor at room temperature at 10 RPM for 45 seconds.

[0221] In another aspect, the present invention relates to a composition for inhibiting the crystal growth of drug nanoparticles in a carrier. In some embodiments, the inhibition of crystal growth of drug nanoparticles in a carrier is achieved by including the nanoparticles in a hydrophobic carrier. In some embodiments, the hydrophobic carrier comprises a hydrocarbon. In some embodiments, the hydrophobic carrier comprises petrolatum, mineral oil, and / or paraffin. In some embodiments, the mineral oil is a heavy mineral oil. In other embodiments, the hydrophobic carrier also comprises one or more than one volatile silicone fluid. In other embodiments, the volatile silicone fluid is cyclomethicone. In other embodiments, cyclomethicone is cyclopentasiloxane. In other embodiments, the inhibition of crystal growth of drug nanoparticles in an aqueous carrier is achieved by including the nanoparticles in an aqueous carrier comprising poloxamer 407, a quaternary ammonium compound or a cross-linked acrylic polymer, or a mixture thereof.

[0222] The composition of the present invention can be formulated into various forms suitable for drug delivery and topical delivery. Non-limiting examples include semisolid compositions, lotions, liquid suspensions, emulsions, creams, gels, ointments, pastes, aerosol sprays, aerosol foams, non-aerosol sprays, non-aerosol foams, films and sheets. Semisolid compositions include ointments, pastes and creams. For purposes of the present invention, semisolid compositions are non-sprayable. Compositions can be impregnated in gauze, bandages or other skin dressing materials. In some embodiments, compositions are semisolid compositions. In some embodiments, compositions are ointments. In other embodiments, compositions are gels. In other embodiments, compositions are liquid suspensions. In some embodiments, compositions are not sprays and are non-sprayable.

[0223] The compositions of the present invention can be packaged in any packaging configuration suitable for topical products. Non-limiting examples include bottles, bottles with pumps, toddles, tubes (aluminum, plastic or laminated), jars, non-aerosol pump sprayers, aerosol containers, pouches and packets. The packaging can be configured for single-dose or multi-dose administration.

[0224] In various embodiments, the compositions of the present invention are hydrophobic. In other embodiments, the hydrophobic compositions are anhydrous. In various embodiments, the hydrophobic carrier is non-polar and / or non-volatile. In other embodiments, the composition is water-based. In other embodiments, the compositions of the present 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 present invention do not contain additional transdermal absorption enhancers. In other embodiments, the hydrophobic compositions of the present invention do not contain additional volatile solvents. In other embodiments, the hydrophobic compositions of the present invention do not contain surfactants. In other embodiments, the hydrophobic compositions of the present invention do not contain alcohol or C 1 To C 5 Fatty alcohol.

[0225] A. Drug Nanoparticles

[0226] The drug nanoparticles of the present invention are particles of a physiologically active pharmaceutical ingredient (API) having an average particle size (number) of 0.1 micron to 1.5 microns (100 nanometers to 1500 nanometers) or 0.01 micron to 1.5 microns, which is determined by a particle size analysis instrument such as the one discussed below. In some embodiments, the drug nanoparticles have an average particle size (number) of 0.01 micron to 1.5 microns. In other embodiments, the drug nanoparticles have an average particle size (number) of 0.01 micron to 1.2 microns, or 0.01 micron to less than 1 micron, or 0.01 micron to 1 micron. In other embodiments, the drug nanoparticles have an average particle size (number) of 0.05 micron to 1.5 microns, or 0.05 micron to 1.2 microns, or 0.05 micron to less than 1 micron, or 0.05 micron to 1 micron. In various embodiments, the drug nanoparticles have an average particle size (number) of 0.1 micron to 1.5 microns, or 0.1 micron to 1.2 microns, or 0.1 micron to less than 1 micron, or 0.1 micron to 1 micron, or 0.4 micron to 1.5 microns, or 0.4 micron to 1.2 microns, or 0.4 micron to less than 1 micron, or 0.4 micron to 1 micron, or 0.6 micron to 1.5 microns, or 0.6 micron to 1.2 microns, or 0.6 micron to less than 1 micron, or from 0.6 micron to 1 micron. In some embodiments, the drug nanoparticles of the present invention are uncoated (pure) individual particles and are not combined with any substance. In a specific embodiment, no substance is absorbed or adsorbed on the surface of the drug nanoparticles. In a specific embodiment, the drug nanoparticles are not encapsulated in any substance. In a specific embodiment, the drug nanoparticles are not coated with any substance. In a specific embodiment, the drug nanoparticles are not microemulsions or nanoemulsions of the drugs in the specific embodiments.

[0227] When incorporated into the composition, the particle size of the drug is determined by a particle size analyzer, and the measured value is expressed as a mean diameter based on a number distribution. A suitable particle size analyzer is an instrument that employs an analysis technique based on opacity, also known as photozone or single particle optical sensing (SPOS). A suitable opacity particle size analyzer is the ACCUSIZER available from Particle Sizing Systems in Port Richey, Florida.

[0228] In various embodiments, when the composition is stored at room temperature for at least 1 month, or at least 3 months, or at least 6 months, or at least 12 months, the average particle size growth of the drug nanoparticles incorporated into the composition does not exceed 20% of the initial average particle size. As used herein with respect to the particle size of drug nanoparticles, the term "initial average particle size" refers to the average particle size of the drug incorporated into the composition measured by a particle size analyzer within 45 days after the manufacture of the composition is completed (manufacturing date), and the initial average particle size is 0.1 micron to 1.5 microns (quantity) or 0.01 micron to 1.5 microns (quantity). In various embodiments, the composition is anhydrous.

[0229] The nanoparticles of the drug can be manufactured using various particle size reduction methods and equipment known in the art. These methods include but are not limited to wet grinding or dry grinding, micronization, decomposition, grinding and supercritical carbon dioxide particle size reduction methods. This supercritical carbon dioxide particle size reduction method (also referred to as compressed anti-solvent precipitation method or PCA) is disclosed in U.S. Patents US5874029, US 5833891, US 6113795, US 7744923, US 8778181, the U.S. Publication US2014 / 0296140 and International Application PCT / US16 / 35993, all of which are incorporated herein by reference.

[0230] In the supercritical carbon dioxide particle size reduction method, the drug is dissolved in a solvent, such as an organic solvent, and exposed to supercritical carbon dioxide (anti-solvent) to precipitate uncoated drug nanoparticles within a well-characterized particle size distribution. Ultrasonication is often used in the process to promote precipitation. The carbon dioxide (anti-solvent) and solvent are removed during the treatment, leaving uncoated drug nanoparticle powder.

[0231] The drug nanoparticles can be in crystalline form or amorphous form or a combination of both. The drug nanoparticles can be water-soluble or poorly water-soluble drugs.

[0232] (i) Poorly water-soluble drugs

[0233] The compositions of the present invention are particularly suitable for delivering poorly water-soluble drugs with a solubility in water of less than or equal to 10 mg / mL at room temperature. Non-limiting examples of poorly water-soluble drugs are: anticancer agents, such as paclitaxel (taxanes), cabazitaxel (taxanes), camptothecin, docetaxel (taxanes), adriamycin, daunomycin, cisplatin, 5-fluorouracil, mitomycin, methotrexate, and etoposide; anti-inflammatory agents, such as indomethacin, ibuprofen, ketoprofen, flurbiprofen, diclofenac, piroxicam, tenoxicam, naproxen, aspirin, and acetaminophen; antifungal agents, such as acetaminophen, tadalafil ... hormones, such as testosterone, estrogen, progesterone, and estradiol; steroids, such as desonide, dexamethasone, hydrocortisone, prednisolone, and triamcinolone; antihypertensives, such as captopril, ramipril, terazosin, minoxidil, and prazosin; antiemetics, such as ondansetron and granisetron; and antibiotics, such as metronidazole, mupirocin, fusidic acid, cyclosporine, and diphenylmethane.

[0234] (ii) Taxane Nanoparticles

[0235] The drug nanoparticles of the present invention may be taxane nanoparticles, which are generally poorly water-soluble drugs. Taxanes are widely used as chemotherapeutic agents. Taxanes include paclitaxel (I), docetaxel (II), cabazitaxel (III) and other taxane derivatives.

[0236] (I) Paclitaxel

[0237]

[0238] (II) Docetaxel

[0239]

[0240] (III) Cabazitaxel

[0241]

[0242] The taxane nanoparticles can be paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles, or nanoparticles of other taxane derivatives. Paclitaxel and docetaxel API are commercially available from Phyton Biotech LLC in Vancouver, Canada. Docetaxel API and nanoparticles contain no less than 90%, or no less than 95%, or no less than 97.5% of docetaxel calculated on an anhydrous and solvent-free basis. Paclitaxel API and nanoparticles contain no less than 90%, or no less than 95%, or no less than 97% of paclitaxel calculated on an anhydrous and solvent-free basis. Paclitaxel is sometimes also referred to as the trade name TAXOL. Paclitaxel is a poorly water-soluble drug. The solubility of paclitaxel in water is less than 0.05 ppm, which is experimentally determined by the solubility method described in Example 1. In the context of the present invention, the taxane or paclitaxel nanoparticles are uncoated (pure) individual particles; the taxane or paclitaxel nanoparticles are not bound to any substance; no substance is 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 taxane or paclitaxel; the taxane or paclitaxel particles are not bound to polymers (or biocompatible polymers), proteins or albumin, the taxane or paclitaxel particles are not encapsulated in polymers (or biocompatible polymers), proteins or albumin, the taxane or paclitaxel particles are not coated with polymers (or biocompatible polymers), proteins or albumin; the polymers (or biocompatible polymers), proteins or albumin are not absorbed or adsorbed onto the surface of the taxane or paclitaxel nanoparticles. In some embodiments, the composition does not / does not comprise or contains a polymer or a biocompatible polymer. In some embodiments, the composition does not / does not comprise or contains a protein. In some embodiments, the composition does not / does not comprise or contains albumin.

[0243] The taxane nanoparticles including paclitaxel nanoparticles or docetaxel nanoparticles may have an average particle size (number) of 0.01 μm to 1.5 μm, or 0.01 μm to less than 1 μm, or 0.01 μm to 1 μm, or 0.1 μm to 1.5 μm, or 0.1 μm to 1.2 μm, or 0.1 μm to less than 1 μm, or 0.1 μm to 1 μm, or 0.2 μm to 1.5 μm, or 0.2 μm to 1.2 μm, or 0.2 μm to less than 1 μm, or 0.2 μm to 1 μm, or 0.4 μm to 1.5 μm, or 0.4 μm to 1.2 μm, or 0.4 μm to less than 1 μm, or 0.4 μm to 1 μm, or 0.6 μm to 1.5 μm, or 0.6 μm to 1.2 μm, or 0.6 to less than 1 μm, or 0.6 μm to 1 μm.

[0244] In various embodiments, taxane and paclitaxel nanoparticles are prepared by a supercritical carbon dioxide particle size reduction method (also known as "compressed antisolvent precipitation" or "PCA") as disclosed in U.S. Pat. Nos. 5,874,029, 5,833,891, 6,113,795, 7,744,923, 8,778,181, U.S. Publication No. US2014 / 0296140, and International Patent Application No. PCT / US16 / 35993, all of which are incorporated herein by reference.

[0245] In the supercritical carbon dioxide particle size reduction process, supercritical carbon dioxide (anti-solvent) and solvents such as acetone or ethanol are used to generate uncoated taxane nanoparticles within a well-characterized particle size distribution. The carbon dioxide and acetone are removed during the process (residual solvent may remain up to 0.5%), leaving behind a powder of taxane nanoparticles with a size of about 200 nm to about 800 nm. Stability studies have shown that the powder in vial dosage form is stable 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.

[0246] Compared to taxane nanoparticles produced by conventional particle size reduction methods using physical impact, or grinding such as wet or dry grinding, micronization, disintegration, pulverization, microfluidization or milling, taxane nanoparticles produced by various supercritical carbon dioxide particle size reduction methods can have unique physical properties. As disclosed in International Patent Application PCT / US16 / 35993, incorporated herein by reference, such unique features include 0.05 g / cm 3 Up to 0.15g / cm 3 Bulk density (not shown) and at least 18m 2 / g taxane (paclitaxel and docetaxel) nanoparticles obtained by supercritical carbon dioxide particle size reduction methods described in International Patent Application PCT / US16 / 35993 as described below. This bulk density range is generally lower than the bulk density of taxane particles produced by conventional methods, and the SSA is generally higher than the SSA of taxane particles produced by conventional methods. These unique characteristics result in a significant increase in dissolution rate in water / methanol media compared to taxanes produced by conventional methods. As used herein, "specific surface area (SSA)" is the total surface area of ​​the taxane nanoparticles per unit mass of taxane, which is measured by the Brunauer-Emmett-Teller ("BET") isotherm by the following method: 200 mg to 300 mg of a known mass of analyte is added to a 30 mL sample tube. The loaded tube is then mounted on a Porous Materials Inc. model BET-202A Then use The software package performs automated testing and subsequently calculates the surface area of ​​each sample. Bulk density measurements can be performed by pouring the taxane nanoparticles into a graduated cylinder at room temperature without tapping, measuring the mass and volume, and calculating the bulk density.

[0247] As disclosed in International Patent Application PCT / US16 / 35993, it was shown that the SSA of paclitaxel nanoparticles prepared by grinding paclitaxel at 600 RPM for 60 minutes at room temperature using a 5 mm ball size in a Deco-PBM-V-0.41 ball mill was 15.0 m 2 / g, volume density is 0.31g / cm 3 PCT / US16 / 35993 also discloses a batch of paclitaxel nanoparticles prepared by supercritical carbon dioxide method using the following method with an SSA of 37.7 m 2 / g, volume density is 0.085g / cm 3 : Prepare a 65 mg / ml paclitaxel solution in acetone. BETE A spray nozzle (BETE Fog Nozzle, Inc) and an acoustic probe (Qsonica, model Q700) are placed in the crystallization chamber at intervals of approximately 8 mm. A stainless steel mesh filter with approximately 100 nm pores is attached to the crystallization chamber to collect precipitated paclitaxel nanoparticles. Supercritical carbon dioxide is placed in the crystallization chamber of the manufacturing equipment and is brought to approximately 1200 psi at approximately 38 ° C and a flow rate of 24 kg / hour. The acoustic probe is adjusted to 60% of the total output power at a frequency of 20 kHz. An acetone solution containing paclitaxel is pumped via a nozzle at a flow rate of 4.5 mL / minute for approximately 36 hours. Other batches of paclitaxel nanoparticles prepared by the above-mentioned supercritical carbon dioxide method have the following SSA values: 22.27 m 2 / g, 23.90m 2 / g, 26.19m 2 / g, 30.02m 2 / g, 21.16m 2 / g, 31.70m 2 / g, 32.59m 2 / g, 33.82m 2 / g, 35.90m 2 / g, 38.22m 2 / g and 38.52m 2 / g.

[0248] As disclosed in International Patent Application PCT / US16 / 35993, it was shown that the SSA of docetaxel nanoparticles prepared by milling docetaxel at 600 RPM for 60 minutes at room temperature using a 5 mm ball size in a Deco-PBM-V-0.41 ball mill was 15.2 m 2 / g, volume density is 0.44g / cm 3 PCT / US16 / 35993 also discloses that docetaxel nanoparticles prepared by supercritical carbon dioxide method using the following method have an SSA of 44.2 m 2 / g, volume density is 0.079g / cm 3: A 79.32 mg / ml docetaxel solution was prepared in ethanol. The nozzle and the sonic probe were placed in a compressible chamber at intervals of approximately 9 mm. A stainless steel mesh filter with approximately 100 nm pores was attached to the compressible chamber to collect precipitated docetaxel nanoparticles. Supercritical carbon dioxide was placed in a compressible chamber of the manufacturing equipment and brought to approximately 1200 psi at a flow rate of approximately 38° C. and 68 slpm. The sonic probe was adjusted to 60% of the total output power at a frequency of 20 kHz. The ethanol solution containing docetaxel was pumped through the nozzle at a flow rate of 2 mL / min for approximately 95 minutes. Then, when the mixture was pumped through the stainless steel mesh filter, the precipitated docetaxel agglomerates and particles were collected from the supercritical carbon dioxide. The filter containing docetaxel nanoparticles was opened and the resulting product was collected from the filter.

[0249] As disclosed in International Patent Application PCT / US16 / 35993, dissolution studies showed that the dissolution rate of paclitaxel and docetaxel nanoparticles prepared by the supercritical carbon dioxide method described in International Patent Application PCT / US16 / 35993 was increased in a methanol / water medium compared to paclitaxel and docetaxel nanoparticles prepared by grinding paclitaxel and docetaxel at 600 RPM for 60 minutes using a Deco-PBM-V-0.41 ball mill using a 5 mm ball size at room temperature. The procedure for determining the dissolution rate is as follows. For paclitaxel, approximately 50 mg of material was coated on approximately 1.5 grams of 1 mm glass beads by tumbling the material and beads in a vial for approximately 1 hour. The beads were transferred to a stainless steel mesh container and placed in a dissolution bath containing a 50 / 50 (volume / volume) methanol / water medium at 37°C, pH 7, and USP Apparatus II (paddle) was operated at 75 rpm. At 10 minutes, 20 minutes, 30 minutes, 60 minutes and 90 minutes, 5 mL aliquots were removed, filtered through a 0.22 μm filter, and analyzed on a UV / VIS spectrophotometer at 227 nm. The absorbance values ​​of the samples were compared with the absorbance values ​​of standard solutions prepared in the dissolution medium to determine the amount of dissolved material. For docetaxel, approximately 50 mg of material was placed directly in a dissolution bath containing 15 / 85 (volume / volume) methanol / water medium at 37°C, pH 7, and USP Apparatus II (paddle) was operated at 75 rpm. At 5 minutes, 15 minutes, 30 minutes, 60 minutes, 120 minutes and 225 minutes, 5 mL aliquots were removed, filtered through a 0.22 μm filter, and analyzed on a UV / VIS spectrophotometer at 232 nm. The absorbance values ​​of the samples were compared with the absorbance values ​​of standard solutions prepared in the dissolution medium to determine the amount of dissolved material. For paclitaxel, the dissolution rate of nanoparticles prepared by supercritical carbon dioxide was 47% within 30 minutes, while the dissolution rate of nanoparticles prepared by milling was 32% within 30 minutes. For docetaxel, the dissolution rate of nanoparticles prepared by supercritical carbon dioxide was 27% within 30 minutes, while the dissolution rate of nanoparticles prepared by milling was 9% within 30 minutes.

[0250] In some embodiments, the paclitaxel nanoparticles have at least 18 m 2 / g, at least 19m 2 / g, at least 20m 2 / g, at least 21m 2 / g, at least 22m 2 / g, at least 23m 2 / g, at least 24m 2 / g, at least 25m 2 / g, at least 26m 2 / g, at least 27m 2 / g, at least 28m 2 / g, at least 29m 2 / g, at least 30m 2 / g, at least 31m 2 / g, at least 32m 2 / g, at least 33m 2 / g, at least 34m 2 / g, or at least 35m 2 In other embodiments, the paclitaxel nanoparticles have an SSA of 18 m 2 / g to 50m 2 / g, or 20m 2 / g to 50m 2 / g, or 22m 2 / g to 50m 2 / g, or 25m 2 / g to 50m 2 / g, or 30m 2 / g to 50m 2 / g, or 18m 2 / g to 45m 2 / g, or 20m 2 / g to 45m 2 / g, or 22 to m 2 / g to 45m 2 / g, or 25m 2 / g to 45m 2 / g, or 30m 2 / g to 45m 2 / g, or 18m 2 / g to 40m 2 / g, or 20 to m 2 / g to 40m 2 / g, or 22m 2 / g to 40m 2 / g, or 25 to m 2 / g to 40m 2 / g, or 30m 2 / g to 40m 2 / g of SSA.

[0251] In some embodiments, the paclitaxel nanoparticles have a mass of 0.05 g / cm 3 Up to 0.15g / cm 3 , or 0.05g / cm 3 Up to 0.20g / cm 3 The bulk density (not shown).

[0252] In some embodiments, the dissolution rate of paclitaxel nanoparticles is at least 40 wt % in 30 minutes or less in a solution of 50% methanol / 50% water (v / v) when the USPII paddle device is operated at 75 RPM, 37°C, and pH 7.

[0253] In some embodiments, docetaxel nanoparticles have a m 2 / g, at least 19m 2 / g, at least 20m 2 / g, at least 21m 2 / g, at least 22m 2 / g, at least 23m 2 / g, at least 24m 2 / g, at least 25m 2 / g, at least 26m 2 / g, at least 27m 2 / g, at least 28m 2 / g, at least 29m 2 / g, at least 30m 2 / g, at least 31m 2 / g, at least 32m 2 / g, at least 33m 2 / g, at least 34m 2 / g, at least 35m 2 / g, at least 36m 2 / g, at least 37m 2 / g, at least 38m 2 / g, at least 39m 2 / g, at least 40m 2 / g, at least 41m 2 / g, or at least 42m 2 In other embodiments, the docetaxel nanoparticles have an SSA of 18 m 2 / g to 60m 2 / g, or 22m 2 / g to 60m 2 / g, or 25m 2 / g to 60m 2 / g, or 30m 2 / g to 60m 2 / g, or 40m 2 / g to 60m 2 / g, or 18m 2 / g to 50m 2 / g, or 22m 2 / g to 50m 2 / g, or 25 to m 2 / g to 50m 2 / g, or 30m2 / g to 50m 2 / g, or 40m 2 / g to 50m 2 / g of SSA.

[0254] In some embodiments, docetaxel nanoparticles have a mass of 0.05 g / cm 3 Up to 0.15g / cm 3 The bulk density (not shown).

[0255] In some embodiments, the dissolution rate of docetaxel nanoparticles is at least 20 wt % in 30 minutes or less in a solution of 15% methanol / 85% water (v / v) when the USPII paddle apparatus is operated at 75 RPM, 37°C, and pH 7.

[0256] It was found that paclitaxel nanoparticle crystals have a tendency to grow over time in suspensions of water or saline solutions, forming large needle-like crystals. Crystal growth studies were performed and the results are shown in Table 2 of Example 2 below. It was found that nanoparticle crystals do not grow in hydrophobic materials. And surprisingly, nanoparticle crystals do not grow in aqueous solutions of benzalkonium chloride, CARBOPOL ULTREZ 10 or poloxamer 407.

[0257] B. Hydrophobic carrier

[0258] The hydrophobic carrier of the present invention may comprise materials from plant, animal, paraffin and / or synthetically obtained sources. The hydrophobic carrier is the continuous phase of the composition. In various embodiments, the hydrophobic carrier is non-polar and / or non-volatile. Non-limiting examples include fats, butters, greases, waxes, solvents and oils; mineral oils; vegetable oils; petrolatum; water-insoluble organic esters and triglycerides; and fluorinated compounds. The hydrophobic carrier may also comprise a silicone material, such as dimethylsiloxane.

[0259] Plant-derived materials include, but are not limited to, arachis (peanut) oil, Peru balsam oil, carnauba wax, candelilla wax, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, corn oil, cottonseed 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 oils and hydrogenated vegetable oils.

[0260] Non-limiting examples of animal-derived materials include beeswax (yellow and white wax), cod liver oil, emu oil, lard, mink oil, shark liver oil, squalane, squalene and tallow. Non-limiting examples of paraffin materials include isoparaffins, microcrystalline wax, heavy mineral oil, light mineral oil, ozokerite, petrolatum, white petrolatum and paraffin.

[0261] Non-limiting examples of organic esters and triglycerides include C12-15 alkyl benzoates, isopropyl myristate, isopropyl palmitate, medium chain triglycerides, mono- and diglycerides, trilaurin, and trihydroxystearin.

[0262] A non-limiting example of a fluorinated compound is a perfluoropolyether (PFPE), such as commercially available from Solvay Specialty Polymers. HC04.

[0263] The hydrophobic carrier of the present invention may comprise a pharmaceutical grade hydrophobic substance. In various embodiments of the present invention, the hydrophobic carrier comprises petrolatum, mineral oil, or paraffin, or a mixture thereof. In some embodiments, the mineral oil is heavy mineral oil.

[0264] In some embodiments, the concentration of the hydrophobic carrier in the composition is greater than 10% by weight of the total composition weight. In other embodiments, the concentration of the hydrophobic carrier in the composition is greater than 15% by weight, or greater than 20% by weight, or greater than 25% by weight, or greater than 30% by weight, or greater than 35% by weight, or greater than 40% by weight, or greater than 45% by weight, or greater than 50% by weight, or greater than 55% by weight, or greater than 60% by weight, or greater than 65% by weight, or greater than 70% by weight, or greater than 75% by weight, or greater than 80% by weight, or greater than 82% by weight, or greater than 85% by weight, or greater than 87% by weight, or greater than 90% by weight of the total composition weight. In other embodiments, the concentration of the hydrophobic carrier in the composition is greater than 10% to 95% by weight of the total composition weight. In other embodiments, the concentration of the hydrophobic carrier in the composition is from 11 wt % to 95 wt %, or from 12 wt % to 95 wt %, or from 13 wt % to 95 wt %, or from 14 wt % to 95 wt %, or from 15 wt % to 95 wt %, or from 16 wt % to 95 wt %, or from 17 wt % to 95 wt %, or from 18 wt % to 95 wt %, or from 19 wt % to 95 wt %, or from 20 wt % to 95 wt %, of the total composition weight.

[0265] (i) Petrolatum

[0266] Petrolatum is a purified mixture of semisolid saturated hydrocarbons obtained from petroleum that varies in color from dark amber to pale yellow. White petrolatum is completely or nearly decolorized and varies in color from cream to snow white. Petrolatum can have different melting points, viscosities, and consistency characteristics. Petrolatum can also contain stabilizers, such as antioxidants. Pharmaceutical grades of petrolatum include Petrolatum USP and White Petrolatum USP.

[0267] Various petrolatums are commercially available from Penreco Corporation under the following trade names: ULTIMA, SUPER, SNOW, REGENT, LILY, CREAM, ROYAL, BLOND, and AMBER. Various grades of petrolatum are also commercially available from Sonneborn Corporation under the following trade names: ALBA, SUPER WHITE PROTOPET, SUPER WHITE FONOLINE, WHITE PROTOPET 1S, 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. Petrolatum is also available from Spectrum Chemical Mfg. Corp.

[0268] (ii) Mineral oil

[0269] 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. The kinematic viscosity of light mineral oil at 40°C is not more than 33.5 centistokes. The kinematic viscosity of heavy mineral oil at 40°C is not less than 34.5 centistokes. Mineral oil may contain a suitable stabilizer. Pharmaceutical grade mineral oil includes mineral oil USP, which is a heavy mineral oil, and light mineral oil NF, which is a light mineral oil. Mineral oil is commercially available from Sonneborn Corporation under the trade name DRAKEOL, and is commercially available from Sonneborn Corporation under the trade names BENOL, BLANDOL, BRITOL, CARNATION, ERVOL, GLORIA, KAYDOL, KLEAROL, PROTOL and RUDOL. Mineral oil is also commercially available from Spectrum Chemical Mfg.Corp.

[0270] (iii) Paraffin

[0271] Paraffin wax is a purified mixture of solid hydrocarbons obtained from petroleum. It can also be synthesized by the Fischer-Tropsch process by catalytic conversion of carbon monoxide and hydrogen into a paraffin mixture. Paraffin wax may contain an antioxidant. Pharmaceutical grade paraffin wax includes paraffin NF and synthetic paraffin NF. Paraffin wax is commercially available from Spectrum Chemical Mfg.Corp, Koster Keunen, Inc, and Frank B.Ross, Inc.

[0272] C. Volatile silicone fluid

[0273] Volatile silicone fluids are also called volatile silicone oils, which are volatile liquid polysiloxanes that can be cyclic or linear. They are liquid at room temperature. Linear volatile silicone fluids include polydimethylsiloxane, hexamethyldisiloxane and octamethyltrisiloxane, and they 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 commonly referred to as cyclomethicone.

[0274] (i) Cyclomethicone

[0275] Cyclomethicones are fully methylated cyclic siloxanes containing repeating units of formula (IV):

[0276] (IV)[-(CH 3 ) 2 SiO-] n

[0277] wherein n is 3, 4, 5, 6 or 7; or a mixture thereof. Cyclomethicone is a clear, colorless, volatile liquid silicone fluid. Cyclomethicone has emollient properties and helps improve the feel of oil-based products by making the skin feel less greasy. Pharmaceutical grade cyclomethicone includes cyclomethicone NF. Cyclomethicone NF is represented by formula (IV) wherein n is 4 (cyclotetramethicone), 5 (cyclopentasiloxane), or 6 (cyclohexamethicone), or a mixture thereof. Cyclopentasiloxane is also known as decamethylcyclopentasiloxane, cyclomethicone D5 or cyclomethicone 5, which is represented by formula (IV) wherein n is 5 (pentamer), but it may contain small amounts (usually less than 1%) of one or more than one other cyclic chain length cyclomethicone. Cyclopentasiloxane is available in pharmaceutical grade as cyclomethicone NF. Cyclomethicone ring is commercially available from Dow Corning under the trade names DOWCORNING ST-Cyclomethicone 5-NF, DOW CORNING ST-Cyclomethicone 56-NF, and XIAMETER PMX-0245. It is also commercially available from Spectrum Chemical Mfg. Corp. Cyclopentasiloxane has a vapor pressure of about 20 Pa to about 27 Pa at 25°C.

[0278] In one embodiment, the concentration of cyclomethicone in the composition is less than 25% by weight. In another embodiment, the concentration of cyclomethicone in the composition is from 5% to 24% by weight. In another embodiment, the concentration of cyclomethicone is from 5% to 20% by weight. In another embodiment, the concentration of cyclomethicone is from 5% to 18% by weight. In another embodiment, the concentration of cyclomethicone is 13% by weight. In various embodiments, 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% by weight of the total composition, or any percentage obtainable therein. In one embodiment, the cyclomethicone is cyclopentasiloxane.

[0279] D. Water-based compositions

[0280] The water-based composition of the present invention comprises poorly water-soluble drug nanoparticles and an aqueous carrier. The aqueous preparation is a dispersion of drug nanoparticles in an aqueous carrier. The drug nanoparticles can be completely dispersed, partially dispersed, and partially dissolved, but not completely dissolved in the aqueous carrier.

[0281] It was observed that poorly water-soluble drug nanoparticle crystals such as paclitaxel nanoparticles grow rapidly in water and water-based carriers. In many cases, growth was observed in just 3 days at room temperature, and in some cases 24 hours. Many crystals are needle-shaped and have a length greater than 5 μm. The study was conducted and the results are shown in Table 2 of Example 2. Unexpectedly, drug nanoparticle crystal growth was inhibited by adding poloxamer 407, quaternary ammonium compounds or cross-linked acrylic acid polymers to the water-based carrier during treatment. The addition of poloxamer 188 did not inhibit the growth of nanoparticle crystals.

[0282] It was also observed that the presence of a quaternary ammonium compound or a cross-linked acrylic polymer or a mixture thereof in an aqueous carrier containing drug nanoparticle crystals prevented the growth of nanoparticle crystals over time. Studies were conducted and the results are shown in Table 11 of Example 8, which reveal that in an aqueous composition containing poloxamer 407, a quaternary ammonium compound, or a cross-linked acrylic polymer, or a mixture thereof, when the aqueous composition is stored at room temperature for 6 months, the average particle size growth of poorly water-soluble drug nanoparticles (paclitaxel) does not exceed 20% of the initial average particle size. In some embodiments, a water-based composition is disclosed, comprising: an aqueous carrier; a plurality of poorly water-soluble drug nanoparticles; and a quaternary ammonium compound, or a cross-linked acrylic polymer, or a mixture thereof; wherein the average particle size of the drug nanoparticles is 0.1 microns to 1.5 microns (number), or 0.01 microns to 1.5 microns (number), wherein when the composition is stored at room temperature for at least 6 months, the average particle size growth of the drug nanoparticles does not exceed 20% of the initial average particle size. In other embodiments, the composition further comprises poloxamer 407.

[0283] In one aspect of the invention, a composition is disclosed, which comprises drug nanoparticles, an aqueous carrier, poloxamer 407, a quaternary ammonium compound, or a cross-linked acrylic polymer, or a mixture thereof. It was unexpectedly found that the addition of poloxamer 407, a quaternary ammonium compound, or a cross-linked acrylic polymer inhibits the crystal growth of drug nanoparticles in an aqueous carrier. The water-based composition of the present invention is suitable for topical, injectable, (IV) infusion, or oral liquid dosage forms. In one embodiment, the additive that inhibits crystal growth is poloxamer 407. In various embodiments, the quaternary ammonium compound is an additive that inhibits crystal growth, which is benzalkonium chloride or benzethonium chloride. In other embodiments, the quaternary ammonium compound is benzalkonium chloride. In other embodiments, the cross-linked acrylic polymer is an additive that inhibits crystal growth, which is carbomer.

[0284] In one aspect of the invention, the composition comprises poloxamer 407 and drug nanoparticles in an aqueous carrier suitable for injection delivery including (IV) infusion. In some embodiments, the drug nanoparticles are taxane nanoparticles. In various embodiments, the taxane nanoparticles are docetaxel nanoparticles, paclitaxel nanoparticles, or cabazitaxel nanoparticles.

[0285] In another aspect of the invention, the composition comprises a quaternary ammonium compound and drug nanoparticles in an aqueous carrier suitable for injection delivery including (IV) infusion. In some embodiments, the drug nanoparticles are taxane nanoparticles. In various embodiments, the taxane nanoparticles are docetaxel nanoparticles, paclitaxel nanoparticles, or cabazitaxel nanoparticles. In other embodiments, the quaternary ammonium compound is benzalkonium chloride or benzethonium chloride.

[0286] In one aspect of the present invention, a method for inhibiting the growth of a dispersion of poorly water-soluble drug nanoparticle crystals in a water-based carrier is disclosed, the method comprising adding poloxamer 407, a quaternary ammonium compound, or a cross-linked acrylic polymer, or a mixture thereof to the water-based carrier during the treatment process, wherein the average particle size of the drug nanoparticles is 0.1 microns to 1.5 microns (number) or 0.01 microns to 1.5 microns (number). In some embodiments, the quaternary ammonium compound is benzalkonium chloride or benzethonium chloride. In some embodiments, the cross-linked acrylic polymer is carbomer. In some embodiments, the drug nanoparticles are taxane nanoparticles. In other embodiments, the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles. In other embodiments, the taxane nanoparticles are paclitaxel nanoparticles.

[0287] (i) Poloxamer 407

[0288] Poloxamer 407 is a solid hydrophilic nonionic synthetic block copolymer of ethylene oxide and propylene oxide according to the general formula (V)

[0289] (V)HO(C 2 H 4 O) a (C 3 H 6 O) b (C 2 H 4 O) a H

[0290] Where a is 101 and b is 56. Poloxamer 407 has an average molecular weight of 9840 to 14600. The term "Poloxamer" is a nonproprietary name for this copolymer. There are several types of poloxamers, which have various physical forms and various average molecular weights. Each specific poloxamer type is identified by the nonproprietary name "Poloxamer" followed by three digits, 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 weight percentage of the polyoxyethylene portion. Poloxamers are available in pharmaceutical, cosmetic and industrial grades. Pharmaceutical grade poloxamers are listed in recognized pharmaceutical compendia such as USP / NF and European Pharmacopoeia (PhEur). According to USP / NF and PhEur, suitable antioxidants may be added. Poloxamer 407 is available from BASF under the trade name F127 is obtained. Adding poloxamer 188 to an aqueous carrier does not inhibit the crystal growth of drug nanoparticles. The concentration of suitable poloxamer 407 is at least 2 wt%, or 0.1 wt% to 25 wt%, or 0.1 wt% to 20 wt%, or 0.1 wt% to 15 wt%, or 0.1 wt% to 10 wt%, or 1 wt% to 10 wt%, or 2 wt% to 10 wt%, or 2 wt% to 15 wt%, or 2 wt% to 20 wt%, or 2 wt% to 25 wt%.

[0291] (ii) Quaternary ammonium compounds

[0292] Quaternary ammonium compounds (including salts) are positively charged tetrasubstituted nitrogen derivatives of formula (VI)

[0293] (VI)

[0294]

[0295] Where R 1 , R 2 , R 3 and R 4 may be the same or different and may not be hydrogen. -Represents typical anion, for example chloride ion.Suitable quaternary ammonium compound comprises benzalkonium chloride and benzethonium chloride.Benzalkonium chloride can be commercially available with 100% powder or 50% aqueous solution.Other examples of quaternary ammonium compound are disclosed in International Cosmetic Ingredient Dictionaryand Handbook, the 12th edition, 2008, which is incorporated herein by reference.The concentration of suitable quaternary ammonium compound is at least 0.05 % by weight, or at least 0.1 % by weight, or at least 1 % by weight, or at least 2 % by weight, or 0.05 % by weight to 5 % by weight, or 0.1 % by weight to 5 % by weight, or 1 % by weight to 5 % by weight, or 2 % by weight to 5 % by weight.

[0296] (iii) Cross-linked acrylic acid polymer

[0297] Crosslinked acrylic acid polymers are high molecular weight homopolymers and copolymers of acrylic acid crosslinked with polyalkenyl polyethers. Suitable crosslinked acrylic acid polymers include Carbomer (INCI name), Acrylates Copolymer (INCI name), Acrylates / C10-C30 Alkyl Acrylate Crosspolymer (INCI name), Acrylates Crosspolymer-4 (INCI name), and Polyacrylate-1 Crosspolymer (INCI name). All of the above polymers are available from Lubrizol Corporation under the trade name Commercially available. Examples of carbomers available from Lubrizol Corporation include CARBOPOL 934, CARBOPOL 934P, CARBOPOL 940, CARBOPOL 980, CARBOPOL 941, CARBOPOL 981, CARBOPOL 2984, CARBOPOL 5984, CARBOPOLSILK 100, CARBOPOL ETD 2050, ULTREZ 10, and ULTREZ 30. Examples of acrylate copolymers available from Lubrizol Corporation include CARBOPOLAQUASF-1 and CARBOPOL AQUASF-1OS. Examples of acrylate / C10-C30 alkyl acrylate crosspolymers available from Lubrizol Corporation include CARBOPOL ULTREZ 20, CARBOPOL ULTREZ 21, CARBOPOL ETD 2020, CARBOPOL 1342, CARBOPOL 1382, and CARBOPOL SC-200. An example of an acrylate crosspolymer-4 is CARBOPOLAQUASF-2. An example of a polyacrylate-1 crosspolymer is CARBOPOL AQUACC. Suitable concentrations of the crosslinked acrylic polymer are at least 0.1 wt%, or 0.5 wt%, or 0.1 wt% to 5 wt%, or 0.5 wt% to 5 wt%.

[0298] E. Additional ingredients and adjuvants

[0299] The composition of the present invention can also include functional ingredients suitable for pharmaceutical compositions. Non-limiting examples include absorbents, acidulants, antimicrobials, antioxidants, binders, antimicrobials, buffers, fillers, crystal growth inhibitors, chelating agents, colorants, deodorants, emulsion stabilizers, film formers, fragrances, wetting agents, solubilizers, enzyme reagents, sunscreens, oxidants, pH regulators, plasticizers, preservatives, reducing agents, emollients, moisturizing skin conditioners, moisturizers, surfactants, emulsifiers, cleansers, foaming agents, hydrotropes, solvents, suspending agents, viscosity control agents (rheology modifiers), tackifiers (thickeners) and propellants. The list of examples of functional ingredients described herein and monographs are disclosed in International Cosmetic Ingredient Dictionary and Handbook (INCI), the 12th edition, 2008, which are incorporated herein by reference.

[0300] The compositions of the present invention may also contain additional pharmaceutical active ingredients, cosmetic active ingredients and veterinary agents suitable for topical use.

[0301] Although the hydrophobic composition of the present invention may also include additional transdermal absorption enhancers, it is found that it is not necessary to include additional transdermal absorption enhancers to increase the skin penetration (i.e., into the epidermis and dermis of the skin) of the drug nanoparticles in the hydrophobic composition comprising a hydrophobic carrier and one or more than one volatile silicone fluid. In fact, the addition of a transdermal absorption enhancer has little or no effect on the skin penetration of the hydrophobic composition.

[0302] The term "transdermal absorption enhancer" has been used to describe compounds or materials or substances that promote drug absorption through the skin. These compounds or materials or substances can directly affect the permeability of the skin, or they can increase percutaneous absorption by increasing the thermodynamic activity of the penetrant, thereby increasing the effective escape trend and concentration gradient of the diffused substance. The main effect of these enhancers is to increase the hydration of the stratum corneum or destroy its lipoprotein matrix, ultimately resulting in reduced resistance to drug (penetrant) diffusion (Remington, The Science and Practice of Pharmacy, 22nd edition).

[0303] Non-limiting examples of skin permeation enhancers include oleyl alcohol, isopropyl myristate, and diethylene glycol monoethyl ether (DGME), which is available under the trade name TRANSCUTOL P. Other examples of skin permeation enhancers can be found in "Skin Penetration Enhancers Cited in the Technical Literature", Osborne, David W. and Henke, Jill J., Pharmaceutical Technology, November 1997, which is incorporated herein by reference. Examples include fatty alcohols such as fatty alcohol, decyl alcohol, lauryl alcohol (dodecanol), linolenic acid, nerolidol, 1-nonanol, n-octanol, oleyl alcohol; fatty acid esters, butyl acetate, cetyl lactate, decyl N,N-dimethylaminoacetate, decyl N,N-dimethylaminoisopropionate, diethylene glycol oleate, diethyl sebacate, diethyl succinate, diisopropyl sebacate, dodecyl N,N-dimethylaminoacetate, dodecyl N,N-dimethylaminobutyrate, dodecyl N,N-dimethylaminoisopropionate, 2-( dimethylamino) dodecyl propionate, EO-5-oleyl ester, ethyl acetate, ethyl acetoacetate, ethyl propionate, glyceryl monoether, glyceryl monolaurate, glyceryl monooleate, glyceryl monolinoleate, isopropyl isostearate, isopropyl linoleate, isopropyl myristate, isopropyl myristate / fatty acid monoglyceride combination, isopropyl myristate / ethanol / L-lactic acid (87:10:3) combination, isopropyl palmitate, methyl acetate, methyl caprate, methyl laurate, methyl propionate, methyl valerate, 1-monocaproylglycerol, monoglyceride ( medium chain length), nicotinate (benzyl), octyl acetate, octyl N,N-dimethylaminoacetate, oleyl oleate, n-acetyl proline, propylene glycol monolaurate, sorbitan dilaurate, sorbitan dioleate, sorbitan monolaurate, sorbitan monooleate, sorbitan trilaurate, sorbitan trioleate, sucrose coconut fatty ester mixture, sucrose monolaurate, sucrose monooleate and tetradecyl N,N-dimethylaminoacetate; fatty acids such as alkanoic acid, capric acid, diacid, ethyl decadecanoate; Octanoic acid, caproic acid, lactic acid, lauric acid, trans-linolenic acid, linoleic acid, linolenic acid, neodecanoic acid, oleic acid, palmitic acid, nonanoic acid, propionic acid and vaccenic acid; fatty alcohol ethers, such as α-monoglycerol ether, EO-2-oleyl ether, EO-5-oleyl ether, EO-10-oleyl ether and polyglycerol and alcohol ether derivatives (1-O-dodecyl-3-O-methyl-2-O-(2',3'-dihydroxypropyl)glycerol); biological products, such as L-α-amino acids, lecithin, phospholipids, saponins / phospholipids, sodium deoxycholate, sodium taurocholate and sodium cholate;Enzymes, such as acid phosphatase, Calonase, hyaluronidase, papain, phospholipase A-2, phospholipase C and triglyceride hydrolase; amines and amides, such as acetamide derivatives, acyclic amides, N-adamantyl n-alkane amide, choline amide, N,N-didodecylacetamide, di-2-ethylhexylamine, diethylmethylbenzamide, N,N-diethyl-m-toluamide, N,N-dimethyl-m-toluamide, Ethomeen S12 [bis-(2-hydroxyethyl) oleylamine], hexamethylene lauramide, lauryl-amine (dodecylamine), octyl amide, oleylamine, unsaturated cyclic ureas and ureas; complexing agents such as β-cyclodextrin and γ-cyclodextrin complexes, hydroxypropyl methylcellulose, liposomes, naphthalene diamide diimide and naphthalene diester diimide; macrocycles such as macrolides, ketones and anhydrides (preferably ring-16) and unsaturated cyclic ureas; classical surfactants such as Brij 30, Brij 36T, Brij 35, Brij 52, Brij 56, Brij 58, Brij 72, Brij 76, Brij 78, Brij 92, Brij 96, Brij 98, hexadecyltrimethylammonium bromide, Empicol ML26 / F, HCO-60 surfactants, hydroxypolyethoxydodecane, ionic surfactants (ROONa, ROSO; 3 Na、RNH 3Cl, R = 8-16), lauroyl sarcosine, nonionic surfactant, nonoxynol ether, octoxynol, benzenesulfonate CA, Pluronic F68, Pluronic F127, Pluronic L62, polyoleate (nonionic surfactant), Rewopal HV 10, sodium laurate, sodium lauryl sulfate (sodium dodecyl sulfate), sodium oleate, sorbitan dilaurate, sorbitan dioleate, sorbitan monolaurate, sorbitan monooleate, sorbitan trilaurate, sorbitan trioleate, Span 20, Span 40, Span 85, Poloxamer NP, Triton X-100, Tween 20, Tween 40, Tween 60, Tween 80 and Tween 85; N-methylpyrrolidone and related compounds, such as N-cyclohexyl-2-pyrrolidone, 1-butyl-3-dodecyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, 1,5-dimethyl-2-pyrrolidone, 4,4-dimethyl-2-undecyl-2-oxazoline, 1-ethyl-2-pyrrolidone, 1-hexyl-4-methoxycarbonyl-2-pyrrolidone, 1-hexyl-2 -pyrrolidone, 1-(2-hydroxyethyl)pyrrolidone, 3-hydroxy-N-methyl-2-pyrrolidone, 1-isopropyl-2-undecyl-2-imidazoline, 1-lauryl-4-methoxycarbonyl-2-pyrrolidone, N-methyl-2-pyrrolidone, poly(N-vinylpyrrolidone), pyroglutamate and 2-pyrrolidone; ionic compounds such as ascorbate, zwitterionic cations and anions, calcium thioglycolate, cetyltrimethylammonium bromide, sodium 3,5-diiodosalicylate, lauryl choline iodide, sodium 5-methoxysalicylate, monoalkyl phosphates, 2-PAM chloride, 4-PAM chloride (derivative of N-methylpyridinium chloride), sodium carboxylates, and sodium hyaluronate; dimethyl sulfoxide and related compounds, such as cyclic sulfoxide, decyl methyl sulfoxide, dimethyl sulfoxide (DMSO), and 2-hydroxyundecyl methyl sulfoxide; solvents and related compounds, such as acetone, n-alkanes (chain length 7 to 16), cyclohexyl-1,1-dimethylethanol, dimethylacetamide, dimethyl methylformamide, ethanol, ethanol / d-limonene combination, 2-ethyl-1,3-hexanediol, ethoxylated glycol (TRANSCUTOL), glycerol, ethylene glycol, lauroyl chloride, limonene, N-methylformamide, 2-phenylethanol, 3-phenyl-1-propanol, 3-phenyl-2-propen-1-ol, polyethylene glycol, polyoxyethylene sorbitan monoester, polypropylene glycol, primary alcohol (tridecanol), propylene glycol, squalene, triacetin, trichloroethanol, trifluoroethanol, trimethylene glycol and xylene;Azones and related compounds, such as N-acyl-hexahydro-2-oxo-1H-azepine, N-alkyl-dihydro-1,4-oxazepine-5,7-dione, N-alkylmorpholine-2,3-dione, N-alkylmorpholine-3,5-dione, azacycloalkane derivatives (-ketones, -thiones), azacycloalkenone derivatives, 1-[2-(decylthio)ethyl]azacyclopentane-2-one (HPE-101), N-(2,2- dihydroxyethyl) dodecylamine, 1-dodecanoylhexahydro-1-H-azepine, 1-dodecylazacycloheptan-2-one (azepine or lauroyl azoline), N-dodecyldiethanolamine, N-dodecyl-hexahydro-2-thio-1H-azepine, N-dodecyl-N-(2-methoxyethyl)acetamide, N-dodecyl-N-(2-methoxyethyl)isobutyramide, N-dodecyl-piperidine-2-thione, N-dodecyl-2-piperidone, N-dodecylpyrrolidine-3,5-dione, N-dodecylpyrrolidine-2-thione, N-dodecyl-2-pyrrolidone, 1-farnesylazepan-2-one, 1-farnesylazepan-2-one, 1-geranylazepan-2-one, 1-geranylazepan-2-one, hexahydro-2-oxo-azepan-1-acetate, N-(2-hydroxyethyl)- 2-pyrrolidone, 1-laurylazepane, 2-(1-nonyl)-1,3-dioxolane, 1-N-octylazepane-2-one, N-(1-oxododecyl)-hexahydro-1H-azepine, N-(1-oxododecyl)-morpholine, 1-oxoalkyl-substituted azepanes, N-(1-oxotetradecyl)-hexahydro-2oxo-1H-azepine and N-(1-thiodecyl)-morpholine;and others, such as aliphatic thiols, N,N-dialkyl-substituted aminoacetic acid alkyl esters, anise oil, anticholinergic agent pretreatment, ascaridin, two-phase group derivatives, bisabolol, cardamom oil, 1-carvone, quinoa (70% ascaridin), quinoa oil, 1,8-cineole (eucalyptol), cod liver oil (fatty acid extract), 4-decyloxazolidin-2-one, dicyclohexylmethylamine, hexadecylphosphonic acid diethyl ester, hexadecylphosphamide diethyl ester, N,N-dimethyldodecylamine-N-oxide, 4,4-dimethyl-2-undecyl-2-oxazoline, N-dodecanoyl-L-amino acid methyl ester, 1,3-dioxacycloalkane (SEPA), disulfide Threitol, eucalyptol (eucalyptol), eucalyptus oil, eugenol, herbal extracts, lactam N-acetate, N-hydroxyacetamide, 2-hydroxy-3-oleyloxy-1-pyroglutamyloxypropane, menthol, menthone, morpholine derivatives, N-oxides, nerolidinol, octyl-β-D-(thio) glucopyranoside, oxazolidinone, piperazine derivatives, polar lipids, polydimethylsiloxane, poly[2-(methylsulfinyl)ethyl acrylate], polyrotaxane, polyvinylbenzyldimethylalkylammonium chloride, poly(N-vinyl-N-methylacetamide), sodium pyroglutamate, terpenes and nitrogen heterocyclic compounds, vitamin E (α-tocopherol) and ylang ylang oil. Other examples of transdermal absorption enhancers not listed above can be found in the fifth edition of "Handbook of Pharmaceutical Excipients" and include tetraethylene glycol, lanolin, light mineral oil, myristic acid, polyoxyethylene alkyl ether and thymol. ;

[0304] Although the hydrophobic composition of the present invention may also include alcohol, the composition need not contain alcohol or C1-C5 fatty alcohol. In some embodiments, the composition is free of / does not include or does not contain C1-C5 fatty alcohol.

[0305] Although the hydrophobic composition of the present invention may also include additional volatile solvents, it is not necessary for the hydrophobic composition to contain additional volatile solvents. Volatile solvents are also referred to as "fugitive" solvents. Non-limiting examples of volatile solvents include volatile alcohols, such as volatile C1-C4 fatty alcohols; and volatile C1-C4 aliphatic ketones, such as acetone. In some aspects of the present invention, the composition is free of / does not include or does not contain volatile C1-C4 aliphatic ketones.

[0306] Although the hydrophobic composition of the present invention may also include a surfactant, the hydrophobic composition need not contain a surfactant. The term "surfactant" or "surfactant agent" refers to a compound or material or substance that exhibits the ability to reduce the surface tension of water or reduce the interfacial tension between two immiscible substances, including anionic surfactants, cationic surfactants, nonionic surfactants, amphoteric surfactants and / or phospholipid surfactants. Non-limiting examples of surfactants can be found in McCutcheon's Emulsifiers & Detergents, 2001 North American Edition, which is incorporated herein by reference, and can also be found in International Cosmetic Ingredient Dictionary and Handbook (INCI), 12th Edition, 2008, which is incorporated herein by reference. Examples include, but are not limited to, the following: block polymers such as poloxamer 124; ethoxylated alcohols such as ceteth-2, ceteareth-20, laureth-3; ethoxylated fatty esters and oils such as PEG-40 hydrogenated castor oil, PEG-36 castor oil, PEG-150 distearate; glyceryl esters such as polyglyceryl-3 diisostearate, glyceryl stearate; glycol esters, PEG-12 dioleate, LEXEMUL P; phosphates, such as hexadecyl phosphate; polymeric surfactants, such as PVM / MA copolymers, PVM / MA copolymers, acrylates / C10-C30 alkyl acrylate crosspolymers; quaternary ammonium surfactants, such as hexadecyl trimethyl ammonium chloride; silicone-based surfactants, such as PEG / PPG-20 / 6 dimethicone; sorbitan derivatives, such as sorbitan stearate, polysorbate 80; sucrose and glucose esters and derivatives, such as PEG-20 methyl glucose sesquistearate; and alcohol sulfates, such as sodium lauryl sulfate. More generally, surfactants can be classified by their ion type, such as anionic, cationic, nonionic or amphoteric. They can also be classified by their chemical structure, such as block polymers, ethoxylated alcohols, ethoxylated fatty esters and oils, glycerides, glycol esters, phosphates, polymeric surfactants, quaternary ammonium surfactants, silicone-based surfactants, sorbitan derivatives, sucrose and glucose esters and derivatives, and alcohol sulfates.

[0307] F. Manufacturing

[0308] The composition of the present invention can be manufactured by methods and equipment known in the art for manufacturing pharmaceutical products, including topical products, injectable products and oral liquid products. These methods include, but are not limited to, the use of mechanical mixers, dissolvers, dispersers, homogenizers and grinders. Non-limiting examples include LIGHTNIN propeller mixers, COWLES dissolvers, IKA ULTRA TURRAX dispersers, SILVERSON homogenizers, LEE counter-rotating side scraping mixers, online and in-tank rotor-stator homogenizers, 3-roller grinders, ointment grinders and rotor-stator grinders. An "integrated" vacuum mixing system can also be used, which has a rotating side scraping mixer and a homogenizer in a tank. Such mixers include, but are not limited to, OLSA mixers, FRYMA-KORUMA mixers and LEE TRI-MIX TURBO-SHEAR pots. The composition of the present invention can be manufactured from small laboratory scale batches using laboratory mixing equipment to full-scale production batches.

[0309] II. Enhanced Local Delivery Methods

[0310] In one aspect of the present invention, a method for enhancing the penetration of drug nanoparticles into the skin is disclosed, the method comprising applying a hydrophobic composition to the skin surface, the hydrophobic composition comprising a continuous hydrophobic carrier, one or more volatile silicone fluids and a plurality of drug nanoparticles. In various embodiments, the hydrophobic carrier is non-polar and / or non-volatile. In some embodiments, the hydrophobic carrier comprises hydrocarbons. In other embodiments, the hydrophobic carrier comprises petrolatum, mineral oil and paraffin. In some embodiments, the mineral oil is a heavy mineral oil. In some embodiments, as determined by an in vitro Franz diffusion cell (FDC) system using human cadaver skin, the concentration of the volatile silicone fluid in the composition formulation is an effective amount for enhancing the skin penetration of drug nanoparticles compared to a formulation without volatile silicone fluids. A suitable in vitro Franz diffusion cell system is described in Example 9 below. In some embodiments, the concentration of one or more volatile silicone fluids is 5% to 24% by weight. In other embodiments, the concentration of one or more volatile silicone fluids is 5% to 20% by weight. In other embodiments, the concentration of one or more volatile silicone fluids is 5 wt % to 18 wt %. In other embodiments, the concentration of one or more volatile silicone fluids is 13 wt %. In various embodiments, the concentration of one or more volatile silicone fluids can be 5 wt %, 5.5 wt %, 6 wt %, 6.5 wt %, 7 wt %, 7.5 wt %, 8 wt %, 8.5 wt %, 9 wt %, 9.5 wt %, 10 wt %, 10.5 wt %, 11 wt %, 11.5 wt %, 12 wt %, 12.5 wt %, 13 wt %, 13.5 wt %, 14 wt %, 15 wt %, 16 wt %, 17 wt %, 18 wt %, 19 wt %, 20 wt %, 21 wt %, 22 wt %, 23 wt %, 24 wt %, 25 wt %, 26 wt %, 27 wt %, 28 wt %, 29 wt %, 30 wt %, 31 wt %, 32 wt %, 33 wt %, 34 wt %, 35 wt %, 36 wt %, 37 wt %, 38 wt %, 39 wt %, 40 wt %, 41 wt %, 42 wt %, 43 wt %, 44 wt %, 45 wt %, 46 wt %, 47 wt %, 48 wt %, 49 wt %, 50 %, 14.5 wt%, 15 wt%, 15.5 wt%, 16 wt%, 16.5 wt%, 17 wt%, 17.5 wt%, 18 wt%, 18.5 wt%, 19 wt%, 19.5 wt%, 20 wt%, 20.5 wt%, 21 wt%, 21.5 wt%, 22 wt%, 22.5 wt%, 23 wt%, 23.5 wt%, or 24 wt%, or any percentage available therein. In various embodiments, one or more than one volatile silicone fluid is cyclomethicone. In other embodiments, cyclomethicone is cyclopentasiloxane. In some embodiments, the hydrophobic composition does not include additional transdermal absorption enhancers. In other embodiments, the hydrophobic composition does not include additional volatile solvents. In other embodiments, the hydrophobic composition does not include a surfactant. In other embodiments, the hydrophobic composition does not / does not include or does not contain alcohol or C 1 To C 5In some embodiments, the drug is a poorly water-soluble drug. In various embodiments, the drug is a taxane, and may be paclitaxel, docetaxel, or cabazitaxel. In some embodiments, the skin is diseased skin. In other embodiments, the diseased skin is skin with psoriasis. In some embodiments, the hydrophobic composition is anhydrous. In other embodiments, the hydrophobic composition is sterile. In other embodiments, the hydrophobic composition is non-sterile. In other embodiments, the hydrophobic composition has a low bioburden. In some embodiments, the hydrophobic composition is a semisolid composition. In other embodiments, the hydrophobic composition is an ointment. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and its viscosity is 12500 cps to 247500 cps, or 25000 cps to 150000 cps, measured by a Brookfield RV viscometer at room temperature, 5 rpm and 2 minutes of equilibrium time, using a small sample adapter with an SC4-14 rotor and a 6R chamber. An alternative method for performing viscosity measurements of hydrophobic semisolid compositions is to use a Brookfield RV viscometer on a lift stand, the lift stand is open, and a TE rotor is used at room temperature at 10 RPM for 45 seconds. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and has a viscosity of 25,000 cps to 500,000 cps, or 2500 cps to 400,000 cps, or 25,000 cps to 350,000 cps, or 25,000 cps to 300,000 cps, or 50,000 cps to 500,000 cps, or 50,000 cps to 400,000 cps, or 50,000 cps to 350,000 cps, or 50,000 cps to 300,000 cps. cps, or 75,000 cps to 500,000 cps, or 75,000 cps to 400,000 cps, or 75,000 cps to 350,000 cps, or 75,000 cps to 300,000 cps, or 100,000 cps to 500,000 cps, or 100,000 cps to 400,000 cps, or 100,000 cps to 350,000 cps, or 100,000 cps to 300,000 cps, the viscosity being measured using a Brookfield RV viscometer on a lift stand with the lift stand open and a TE rotor at room temperature at 10 RPM for 45 seconds.

[0311] In some embodiments, the hydrophobic composition is not a spray and is non-sprayable. In other embodiments, when the composition is applied to human cadaver skin, the drug nanoparticles do not penetrate human cadaver skin or are less than 0.01 μg / cm 2 (Negligible amounts) of drug nanoparticles penetrate human cadaver skin. A suitable in vitro Franz diffusion cell system is described in Example 9 below.

[0312] In another aspect of the present invention, a method for enhancing the penetration of taxane nanoparticles into the skin is disclosed, the method comprising applying to the skin surface a hydrophobic composition comprising a continuous hydrophobic carrier, one or more than one volatile silicone fluid and a plurality of taxane nanoparticles. In various embodiments, the hydrophobic carrier is non-polar and / or non-volatile. In various embodiments, the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles. In some embodiments, the taxane nanoparticles are paclitaxel nanoparticles. In other embodiments, the hydrophobic carrier comprises a hydrocarbon. In other embodiments, the hydrophobic carrier comprises petrolatum, mineral oil, and paraffin. In some embodiments, the mineral oil is a heavy mineral oil. In other embodiments, the concentration of the volatile silicone fluid in the hydrophobic composition formulation is an effective amount for enhancing the skin penetration of the taxane nanoparticles as compared to a hydrophobic composition formulation without the volatile silicone fluid as determined by an in vitro Franz diffusion cell system using human cadaver skin. A suitable in vitro Franz diffusion cell system is described in Example 9 below. In some embodiments, the concentration of the volatile silicone fluid is 5 wt % to 24 wt %. In other embodiments, the concentration of the volatile silicone fluid is 5 wt % to 20 wt %. In other embodiments, the concentration of the volatile silicone fluid is 5 wt % to 18 wt %. In other embodiments, the concentration of the volatile silicone fluid is 13 wt %. In various embodiments, the concentration of the volatile silicone fluid can be 5 wt %, 5.5 wt %, 6 wt %, 6.5 wt %, 7 wt %, 7.5 wt %, 8 wt %, 8.5 wt %, 9 wt %, 9.5 wt %, 10 wt %, 10.5 wt %, 11 wt %, 11.5 wt %, 12 wt %, 12.5 wt %, 13 wt %, 13.5 wt %, 14 wt %, 14.5 wt %, 15 wt %, 15.5 wt %, 16 wt %, 16.5 wt %, 17 wt %, 17.5 wt %, 18 wt %, 18.5 wt %, 19 wt %, 19.5 wt %, or 20 wt %, or any percentage available therein, of the total composition weight. In some embodiments, the volatile silicone fluid is cyclomethicone. In other embodiments, the cyclomethicone is cyclopentasiloxane. In some embodiments, the hydrophobic composition does not include additional transdermal absorption enhancers. In other embodiments, the hydrophobic composition does not include additional volatile solvents. In other embodiments, the hydrophobic composition does not include surfactants. In other embodiments, the hydrophobic composition does not include alcohol or C 1 To C 5Fatty alcohol. In some embodiments, the skin is diseased skin. In other embodiments, the diseased skin is skin with psoriasis. In some embodiments, the hydrophobic composition is anhydrous. In other embodiments, the hydrophobic composition is sterile. In other embodiments, the hydrophobic composition is non-sterile. In other embodiments, the hydrophobic composition has a low bioburden. In some embodiments, the hydrophobic composition is a semisolid composition. In other embodiments, the hydrophobic composition is an ointment. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and its viscosity is measured by a Brookfield RV viscometer at room temperature, 5 rpm and an equilibrium time of 2 minutes to be 12500 cps to 247500 cps, or 25000 cps to 150000 cps, and the Brookfield RV viscometer uses a small sample adapter with an SC4-14 rotor and a 6R chamber. An alternative method for performing viscosity measurements of hydrophobic semisolid compositions is to use a Brookfield RV viscometer on a lift stand with the lift stand open, using a TE spindle at room temperature at 10 RPM for 45 seconds. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and has a viscosity of 25,000 cps to 500,000 cps, or 2500 cps to 400,000 cps, or 25,000 cps to 350,000 cps, or 25,000 cps to 300,000 cps, or 50,000 cps to 500,000 cps, or 50,000 cps to 400,000 cps, or 50,000 cps to 350,000 cps, or 50,000 cps to 300,000 cps. cps, or 75,000 cps to 500,000 cps, or 75,000 cps to 400,000 cps, or 75,000 cps to 350,000 cps, or 75,000 cps to 300,000 cps, or 100,000 cps to 500,000 cps, or 100,000 cps to 400,000 cps, or 100,000 cps to 350,000 cps, or 100,000 cps to 300,000 cps, the viscosity being measured using a Brookfield RV viscometer on a lift stand with the lift stand open and a TE rotor at room temperature at 10 RPM for 45 seconds.

[0313] In some embodiments, the hydrophobic composition is not a spray and is non-sprayable. In some embodiments, the taxane nanoparticles do not penetrate / transdermally deliver through human cadaver skin, or less than 0.01 μg / cm 2(negligible amounts) penetrate human cadaver skin. A suitable in vitro Franz diffusion cell system is described in Example 9 below.

[0314] III. Methods for Inhibiting Crystal Growth in Formulations

[0315] In one aspect of the invention, a method of inhibiting drug nanoparticle crystal growth is disclosed, the method comprising contacting the drug nanoparticle with a hydrophobic carrier. In some embodiments, the drug nanoparticle is water-soluble. In other embodiments, the drug nanoparticle is poorly water-soluble. In other embodiments, the drug nanoparticle is a taxane nanoparticle. In other embodiments, the taxane nanoparticle is a paclitaxel nanoparticle, a docetaxel nanoparticle, or a cabazitaxel nanoparticle. In some embodiments, the taxane nanoparticle is a paclitaxel nanoparticle. In other embodiments, the composition is anhydrous. In other embodiments, the hydrophobic carrier comprises a hydrocarbon. In other embodiments, the hydrocarbon is petrolatum, mineral oil, or paraffin, or a mixture thereof. In some embodiments, the mineral oil is a heavy mineral oil. In some embodiments, the composition further comprises one or more than one volatile silicone fluid. In other embodiments, the volatile silicone fluid is cyclomethicone. In other embodiments, cyclomethicone is cyclopentasiloxane.

[0316] In another aspect of the present invention, a method for inhibiting the growth of a dispersion of poorly water-soluble drug nanoparticles in an aqueous carrier is disclosed, the method comprising adding poloxamer 407, a quaternary ammonium compound, or a cross-linked acrylic polymer to the aqueous carrier during manufacture. In some embodiments, the additive is poloxamer 407. In various embodiments, the quaternary ammonium compound is an additive and is benzalkonium chloride or benzethonium chloride. In some embodiments, the quaternary ammonium compound is benzalkonium chloride. In some embodiments, the cross-linked acrylic polymer is an additive and is carbomer. In some embodiments, the drug nanoparticles are taxane nanoparticles. In other embodiments, the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles.

[0317] IV. Topical treatments for psoriasis

[0318] In one aspect of the present invention, a method for topical treatment of psoriasis is disclosed, the method comprising topically applying to the affected area a hydrophobic composition comprising a continuous hydrophobic carrier, one or more than one volatile silicone fluid and a plurality of drug nanoparticles, wherein the average particle size (number) of the drug nanoparticles is 0.1 microns to 1.5 microns or 0.01 microns to 1.5 microns, and wherein the concentration of the drug nanoparticles is an effective amount to provide therapeutic improvement for psoriasis conditions. In some embodiments, the drug nanoparticles are taxane nanoparticles. In some embodiments, the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles. In other embodiments, the taxane nanoparticles are paclitaxel nanoparticles. In various embodiments, the hydrophobic carrier is non-polar and / or non-volatile. In some embodiments, the hydrophobic carrier comprises a hydrocarbon. In other embodiments, the hydrophobic carrier comprises petrolatum, mineral oil, and paraffin. In some embodiments, the mineral oil is a heavy mineral oil. In some embodiments, the concentration of the volatile silicone fluid is 5% to 24% by weight. In other embodiments, the concentration of the volatile silicone fluid is 5% to 20% by weight. In other embodiments, the concentration of the volatile silicone fluid is 5% to 18% by weight. In other embodiments, the concentration of the volatile silicone fluid is 13% by weight. In some embodiments, the volatile silicone fluid is cyclomethicone. In other embodiments, cyclomethicone is cyclopentasiloxane. In various embodiments, the hydrophobic composition does not / does not include or does not contain additional transdermal absorption enhancers. In other embodiments, the hydrophobic composition does not / does not include or does not contain additional volatile solvents. In other embodiments, the hydrophobic composition does not / does not include or does not contain surfactants. In other embodiments, the hydrophobic composition does not / does not include or does not contain alcohol or C 1 To C 5 Fatty alcohol.

[0319] The concentration of the taxane nanoparticles is an effective amount to provide therapeutic improvement for psoriasis conditions. This improvement can be shown by an improvement in the Psoriasis Area and Severity Index (PASI) score. The concentration of the taxane nanoparticles may be 0.05 wt % to 10 wt % of the total composition weight, or the concentration of the taxane nanoparticles may be 0.05 wt % to 5 wt % of the total composition weight, or the concentration of the taxane nanoparticles may be 0.1 wt % to 5 wt % of the total composition weight, or the concentration of the taxane nanoparticles may be 0.05 wt %, 0.1 wt %, 0.15 wt %, 0.2 wt %, 0.25 wt %, 0.3 wt %, 0.4 wt %, 0.5 wt %, 0.6 wt %, 0.7 wt %, 0.75 wt %, 0.8 wt %, 0.9 wt %, 1.0 wt %, 1.1 wt %, 1.2 wt %, 1.25 wt %, 1.3 wt %, 1.4 wt %, 1.5 wt %, 1.6 wt %, 1.7 wt %, 1.75 wt %, 1.8 wt %, or 0.05 wt %, 0.1 wt %, 0.15 wt %, 0.2 wt %, 0.25 wt %, 0.3 wt %, 0.4 wt %, 0.5 wt %, 0.6 wt %, 0.7 wt %, 0.75 wt %, 0.8 wt %, 0.9 wt %, 1.0 wt %, 1.1 wt %, 1.2 wt %, 1.25 wt %, 1.3 wt %, 1.4 wt %, 1.5 wt %, 1.6 wt %, 1.7 wt %, 1.75 wt %, 1.8 %, 1.9 wt%, 2.0 wt%, 2.1 wt%, 2.2 wt%, 2.25 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.75 wt%, 2.8 wt%, 2.9 wt%, 3.0 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%. %, 3.75 wt %, 3.8 wt %, 3.9 wt %, 4.0 wt %, 4.1 wt %, 4.2 wt %, 4.25 wt %, 4.3 wt %, 4.4 wt %, 4.5 wt %, 4.6 wt %, 4.7 wt %, 4.75 wt %, 4.9 wt %, 5 wt %, 6 wt %, 7 wt %, 8 wt %, 9 wt %, or 10 wt %, or any percentage obtainable therein. In some embodiments, the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles. In other embodiments, the taxane nanoparticles are paclitaxel nanoparticles. In some embodiments, the concentration of paclitaxel nanoparticles in the composition is about 0.05 wt % to less than 3 wt %, or about 0.05 wt % to about 0.2 wt %, or about 0.05 wt % to about 0.15 wt %, or about 0.1 wt % to about 2 wt %, or about 0.1 wt % to about 0.2 wt %, or about 0.15 wt % to about 2 wt %, or about 0.15 wt % to about 0.2 wt %.In other embodiments, the concentration of paclitaxel nanoparticles is 1 wt % of 80% to 120% (i.e., 0.8 wt % to 1.2 wt %), or 0.05 wt % of 80% to 120%, or 0.1 wt % of 80% to 120%, or 0.15 wt % of 80% to 120%, or 0.2 wt % of 80% to 120%, or 0.25 wt % of 80% to 120%, or 0.3 wt % of 80% to 120%, or 0.35 wt % of 80% to 120%, or 0.4 wt % of 80% to 120%, or 0.45 wt % of 80% to 120%, or 0.5 wt % of 80% to 120%, or % of 80% to 120%, or 0.55% by weight of 80% to 120%, or 0.6% by weight of 80% to 120%, or 0.65% by weight of 80% to 120%, or 0.7% by weight of 80% to 120%, or 0.75% by weight of 80% to 120%, or 0.8% by weight of 80% to 120%, or 0.85% by weight of 80% to 120%, or 0.9% by weight of 80% to 120%, or 0.95% by weight of 80% to 120%, or 1.5% by weight of 80% to 120%, or 2% by weight of 80% to 120%, or 2.5% by weight of 80% to 120%.

[0320] In some embodiments, the hydrophobic composition is sterile. In other embodiments, the hydrophobic composition is unsterilized. In other embodiments, the hydrophobic composition has a low bioburden. In other embodiments, the hydrophobic composition is anhydrous. In some embodiments, the hydrophobic composition is a semisolid composition. In other embodiments, the hydrophobic composition is an ointment. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and its viscosity is measured by a Brookfield RV viscometer at room temperature, 5rpm and a balance time of 2 minutes to be 12500cps to 247500cps, or 25000cps to 150000cps, and the Brookfield RV viscometer uses a small sample adapter with an SC4-14 rotor and a 6R chamber. An alternative method for implementing the viscosity measurement of a hydrophobic semisolid composition is to use a Brookfield RV viscometer on a lifting stand, the lifting stand is in an open state, and a TE rotor is used at room temperature at 10RPM for 45 seconds. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment and has a viscosity of 25,000 cps to 500,000 cps, or 2500 cps to 400,000 cps, or 25,000 cps to 350,000 cps, or 25,000 cps to 300,000 cps, or 50,000 cps to 500,000 cps, or 50,000 cps to 400,000 cps, or 50,000 cps to 350,000 cps, or 50,000 cps to 300,000 cps. s, or a viscosity of 75,000 cps to 500,000 cps, or 75,000 cps to 400,000 cps, or 75,000 cps to 350,000 cps, or 75,000 cps to 300,000 cps, or 100,000 cps to 500,000 cps, or 100,000 cps to 400,000 cps, or 100,000 cps to 350,000 cps, or 100,000 cps to 300,000 cps, the viscosity being measured using a Brookfield RV viscometer on a lift stand with the lift stand open and a TE spindle at room temperature at 10 RPM for 45 seconds.

[0321] In some embodiments, the hydrophobic composition is not a spray and is not sprayable.

[0322] V. Keratinous tissue

[0323] In one aspect, the present invention relates to compositions for delivering drug nanoparticles to keratinous tissue including nails, nail beds, and hair. In another aspect, the present invention relates to compositions for topical treatment of diseases and disorders of keratinous tissue.

[0324] Keratinous tissue, including nails, nail beds, and hair, is susceptible to a variety of diseases and conditions, including fungal infections. Diseases and conditions of keratinous tissue include, but are not limited to, nail psoriasis, onychomycosis, ingrown toenails, nail dystrophy, onychogryphosis, onycholysis, onycholysis, onychomycosis, keratosis of the nail bed, onycholysis, brittle onychomycosis, paronychia, concave nails, subungual hematomas, onychoma, laminitis, nail pemphigus, rubroonychia, melanonychia, and tinea pedis.

[0325] The compositions of the present invention, including hydrophobic compositions, can be used to locally deliver drug nanoparticles to keratinous tissue and to treat diseases and disorders of keratinous tissue. In some embodiments, the hydrophobic composition comprises a continuous hydrophobic carrier, 5% to 24% by weight of one or more than one volatile silicone fluid and a plurality of drug nanoparticles. In various embodiments, the hydrophobic carrier is non-polar and / or non-volatile. In some embodiments, the hydrophobic carrier comprises a hydrocarbon. In other embodiments, the hydrophobic carrier comprises petrolatum, mineral oil and paraffin. In some embodiments, the mineral oil is a heavy mineral oil.

[0326] In some embodiments, the hydrophobic composition does not include additional transdermal absorption enhancers. In other embodiments, the hydrophobic composition does not include additional volatile solvents or compounds. In some embodiments, the hydrophobic composition does not include alcohol or C 1 -C 5 Fatty alcohol. In other embodiments, the hydrophobic composition does not include a surfactant. In various embodiments, the volatile silicone fluid is cyclomethicone. In other embodiments, the cyclomethicone is cyclopentasiloxane.

[0327] In some embodiments, the hydrophobic composition is sterile. In other embodiments, the hydrophobic composition is unsterilized. In other embodiments, the hydrophobic composition has a low bioburden. In other embodiments, the hydrophobic composition is anhydrous. In some embodiments, the hydrophobic composition is a semisolid composition. In other embodiments, the hydrophobic composition is an ointment. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and its viscosity is measured by a Brookfield RV viscometer at room temperature, 5rpm and a balance time of 2 minutes to be 12500cps to 247500cps, or 25000cps to 150000cps, and the Brookfield RV viscometer uses a small sample adapter with an SC4-14 rotor and a 6R chamber. An alternative method for implementing the viscosity measurement of a hydrophobic semisolid composition is to use a Brookfield RV viscometer on a lifting stand, the lifting stand is in an open state, and a TE rotor is used at room temperature at 10RPM for 45 seconds. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and has a viscosity of 25,000 cps to 500,000 cps, or 2500 cps to 400,000 cps, or 25,000 cps to 350,000 cps, or 25,000 cps to 300,000 cps, or 50,000 cps to 500,000 cps, or 50,000 cps to 400,000 cps, or 50,000 cps to 350,000 cps, or 50,000 cps to 300,000 cps. cps, or 75,000 cps to 500,000 cps, or 75,000 cps to 400,000 cps, or 75,000 cps to 350,000 cps, or 75,000 cps to 300,000 cps, or 100,000 cps to 500,000 cps, or 100,000 cps to 400,000 cps, or 100,000 cps to 350,000 cps, or 100,000 cps to 300,000 cps, the viscosity being measured using a Brookfield RV viscometer on a lift stand with the lift stand open and a TE rotor at room temperature at 10 RPM for 45 seconds.

[0328] In some embodiments, the hydrophobic composition is not a spray and is not sprayable.

[0329] In some embodiments, the concentration of one or more volatile silicone fluids is 5% to 20% by weight. In other embodiments, the concentration of one or more volatile silicone fluids is 5% to 18% by weight. In other embodiments, the concentration of one or more volatile silicone fluids is 13% by weight. In various embodiments, the concentration of one or more volatile silicone fluids 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%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 6 %, 14.5 wt %, 15 wt %, 15.5 wt %, 16 wt %, 16.5 wt %, 17 wt %, 17.5 wt %, 18 wt %, 18.5 wt %, 19 wt %, 19.5 wt %, 20 wt %, 20.5 wt %, 21 wt %, 21.5 wt %, 22 wt %, 22.5 wt %, 23 wt %, 23.5 wt % or 24 wt %, or any percentage obtainable therein.

[0330] In some embodiments, the concentration of the hydrophobic carrier in the composition is greater than 10% by weight of the total composition weight. In other embodiments, the concentration of the hydrophobic carrier in the composition is greater than 15% by weight, or greater than 20% by weight, or greater than 25% by weight, or greater than 30% by weight, or greater than 35% by weight, or greater than 40% by weight, or greater than 45% by weight, or greater than 50% by weight, or greater than 55% by weight, or greater than 60% by weight, or greater than 65% by weight, or greater than 70% by weight, or greater than 75% by weight, or greater than 80% by weight, or greater than 82% by weight, or greater than 85% by weight, or greater than 87% by weight, or greater than 90% by weight. In other embodiments, the concentration of the hydrophobic carrier in the composition is greater than 10% to 95% by weight of the total composition weight. In other embodiments, the concentration of the hydrophobic carrier in the composition is from 11 wt % to 95 wt %, or from 12 wt % to 95 wt %, or from 13 wt % to 95 wt %, or from 14 wt % to 95 wt %, or from 15 wt % to 95 wt %, or from 16 wt % to 95 wt %, or from 17 wt % to 95 wt %, or from 18 wt % to 95 wt %, or from 19 wt % to 95 wt %, or from 20 wt % to 95 wt %, of the total composition weight.

[0331] In some embodiments, the drug nanoparticles are taxane nanoparticles. In some embodiments, the taxane nanoparticles are paclitaxel nanoparticles, docetaxel nanoparticles, or cabazitaxel nanoparticles. In other embodiments, the taxane nanoparticles are paclitaxel nanoparticles. The concentration of the taxane nanoparticles may be 0.05 wt % to 10 wt % of the total composition weight, or the concentration of the taxane nanoparticles may be 0.05 wt % to 5 wt % of the total composition weight, or the concentration of the taxane nanoparticles may be 0.1 wt % to 5 wt % of the total composition weight, or the concentration of the taxane nanoparticles may be 0.05 wt %, 0.1 wt %, 0.15 wt %, 0.2 wt %, 0.25 wt %, 0.3 wt %, 0.4 wt %, 0.5 wt %, 0.6 wt %, 0.7 wt %, 0.75 wt %, 0.8 wt %, 0.9 wt %, 1.0 wt %, 1.1 wt %, 1.2 wt %, 1.25 wt %, 1.3 wt %, 1.4 wt %, 1.5 wt %, 1.6 wt %, 1.7 wt %, 1.75 wt %, 1.8 wt %, 1 .9 wt%, 2.0 wt%, 2.1 wt%, 2.2 wt%, 2.25 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.75 wt%, 2.8 wt%, 2.9 wt%, 3.0 wt%, 3.1 wt%, 3.2 wt%, 3.25 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3. 7 wt %, 3.75 wt %, 3.8 wt %, 3.9 wt %, 4.0 wt %, 4.1 wt %, 4.2 wt %, 4.25 wt %, 4.3 wt %, 4.4 wt %, 4.5 wt %, 4.6 wt %, 4.7 wt %, 4.75 wt %, 4.9 wt %, 5 wt %, 6 wt %, 7 wt %, 8 wt %, 9 wt %, or 10 wt %, or any percentage obtainable therein.

[0332] In some embodiments, the drug nanoparticles are nanoparticles of antifungal agents. Suitable antifungal agents for treating keratinous tissues such as nails, nail beds and hair are azole antifungal agents, such as imidazoles, triazoles and thiazoles; polyene antifungal agents; allylamine antifungal agents; echinocandin antifungal agents; benzoic acid, ciclopirox olamine, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, crystal violet and Peru balsam. Non-limiting examples of polyene antifungal agents include amphotericin B, candidacidin, filipinostatin, hamycin, natamycin, nystatin and chelidoxime. Non-limiting examples of imidazoles include bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole and tioconazole. Non-limiting examples of triazoles include albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole and voriconazole. Non-limiting examples of thiazoles are abafungin. Non-limiting examples of allylamine antifungals include amorolfine, butenafine, naftifine and terbinafine. Non-limiting examples of echinocandin antifungals include anidulafungin, caspofungin and micafungin. Other suitable antifungals include antifungal compounds disclosed in US 7214506, which are incorporated herein by reference.

[0333] In one aspect of the present invention, a method for topically delivering drug nanoparticles to keratinous tissue is disclosed, the method comprising topically applying a hydrophobic composition to the keratinous tissue, the hydrophobic composition comprising a hydrophobic carrier, 5% to 24% by weight of one or more than one volatile silicone fluid and a plurality of drug nanoparticles. In various embodiments, the hydrophobic carrier is non-polar and / or non-volatile. In some embodiments, the hydrophobic carrier comprises a hydrocarbon. In other embodiments, the hydrophobic carrier comprises petrolatum, mineral oil and paraffin. In some embodiments, the mineral oil is a heavy mineral oil. In some embodiments, the hydrophobic composition does not comprise an additional transdermal absorption enhancer. In other embodiments, the hydrophobic composition does not comprise an additional volatile solvent or compound. In some embodiments, the hydrophobic composition does not comprise alcohol or C 1 -C 5Fatty alcohol. In other embodiments, the hydrophobic composition does not include a surfactant. In various embodiments, the volatile silicone fluid is cyclomethicone. In other embodiments, the cyclomethicone is cyclopentasiloxane. In some embodiments, the hydrophobic composition is sterile. In other embodiments, the hydrophobic composition is non-sterile. In other embodiments, the hydrophobic composition has a low bioburden. In other embodiments, the hydrophobic composition is anhydrous. In some embodiments, the hydrophobic composition is a semisolid composition. In other embodiments, the hydrophobic composition is an ointment. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and its viscosity is measured by a Brookfield RV viscometer at room temperature, 5 rpm and 2 minutes of equilibrium time as 12500 cps to 247500 cps, or 25000 cps to 150000 cps, and the Brookfield RV viscometer uses a small sample adapter with an SC4-14 rotor and a 6R chamber. An alternative method for performing viscosity measurements of hydrophobic semisolid compositions is to use a Brookfield RV viscometer on a lift stand with the lift stand open, using a TE spindle at room temperature at 10 RPM for 45 seconds. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and has a viscosity of 25,000 cps to 500,000 cps, or 2500 cps to 400,000 cps, or 25,000 cps to 350,000 cps, or 25,000 cps to 300,000 cps, or 50,000 cps to 500,000 cps, or 50,000 cps to 400,000 cps, or 50,000 cps to 350,000 cps, or 50,000 cps to 300,000 cps. cps, or 75,000 cps to 500,000 cps, or 75,000 cps to 400,000 cps, or 75,000 cps to 350,000 cps, or 75,000 cps to 300,000 cps, or 100,000 cps to 500,000 cps, or 100,000 cps to 400,000 cps, or 100,000 cps to 350,000 cps, or 100,000 cps to 300,000 cps, the viscosity being measured using a Brookfield RV viscometer on a lift stand with the lift stand open and a TE rotor at room temperature at 10 RPM for 45 seconds.

[0334] In some embodiments, the hydrophobic composition is not a spray and is non-sprayable. In some embodiments, the drug nanoparticles are taxane nanoparticles or nanoparticles of antifungal agents. In some embodiments, the keratinous tissue is a nail, a nail bed, and / or hair. In some embodiments, the disease or disorder of keratinous tissue is onychomycosis or nail psoriasis.

[0335] In another aspect of the present invention, a method for topically treating a disease or condition of keratinous tissue is disclosed, the method comprising topically applying a hydrophobic composition to the keratinous tissue, the hydrophobic composition comprising a hydrophobic carrier, 5% to 24% by weight of one or more than one volatile silicone fluid and a plurality of drug nanoparticles, wherein the concentration of the drug nanoparticles is an effective amount to provide therapeutic improvement for the disease or condition. In various embodiments, the hydrophobic carrier is non-polar and / or non-volatile. In some embodiments, the hydrophobic carrier comprises a hydrocarbon. In other embodiments, the hydrophobic carrier comprises petrolatum, mineral oil and paraffin. In some embodiments, the hydrophobic composition does not comprise an additional transdermal absorption enhancer. In other embodiments, the hydrophobic composition does not comprise an additional volatile solvent or compound. In some embodiments, the hydrophobic composition does not comprise alcohol or C 1 -C 5Fatty alcohol. In other embodiments, the hydrophobic composition does not include a surfactant. In various embodiments, the volatile silicone fluid is cyclomethicone. In other embodiments, the cyclomethicone is cyclopentasiloxane. In some embodiments, the hydrophobic composition is sterile. In other embodiments, the hydrophobic composition is non-sterile. In other embodiments, the hydrophobic composition has a low bioburden. In other embodiments, the hydrophobic composition is anhydrous. In some embodiments, the hydrophobic composition is a semisolid composition. In other embodiments, the hydrophobic composition is an ointment. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and its viscosity is measured by a Brookfield RV viscometer at room temperature, 5 rpm and an equilibrium time of 2 minutes to be 12500 cps to 247500 cps, or 25000 cps to 150000 cps, and the Brookfield RV viscometer uses a small sample adapter with an SC4-14 rotor and a 6R chamber. An alternative method for performing viscosity measurements of hydrophobic semisolid compositions is to use a Brookfield RV viscometer on a lift stand with the lift stand open, using a TE spindle at room temperature at 10 RPM for 45 seconds. In some embodiments, the hydrophobic composition is a semisolid composition including an ointment, and has a viscosity of 25,000 cps to 500,000 cps, or 2500 cps to 400,000 cps, or 25,000 cps to 350,000 cps, or 25,000 cps to 300,000 cps, or 50,000 cps to 500,000 cps, or 50,000 cps to 400,000 cps, or 50,000 cps to 350,000 cps, or 50,000 cps to 300,000 cps. cps, or 75,000 cps to 500,000 cps, or 75,000 cps to 400,000 cps, or 75,000 cps to 350,000 cps, or 75,000 cps to 300,000 cps, or 100,000 cps to 500,000 cps, or 100,000 cps to 400,000 cps, or 100,000 cps to 350,000 cps, or 100,000 cps to 300,000 cps, the viscosity being measured using a Brookfield RV viscometer on a lift stand with the lift stand open and a TE rotor at room temperature at 10 RPM for 45 seconds.

[0336] In some embodiments, the hydrophobic composition is not a spray and is non-sprayable. In some embodiments, the drug nanoparticles are taxane nanoparticles or nanoparticles of antifungal agents. In some embodiments, the keratinous tissue is a nail, a nail bed, and / or hair. In some embodiments, the disease or disorder of keratinous tissue is onychomycosis or nail psoriasis.

[0337] Example

[0338] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes only and are not intended to limit the present invention in any way. Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to produce substantially the same result.

[0339] Example 1 - Solubility of Paclitaxel in Various Solvents

[0340] The solubility of paclitaxel in various solvents was determined by the following method:

[0341] For each solvent, weigh approximately 2 g of solvent into a clear glass vial.

[0342] Approximately 0.1 g of paclitaxel was added to each vial.

[0343] Each vial was mixed on a magnetic stirrer with a stir bar for 2 hours at room temperature.

[0344] Each vial was then checked every 1 to 2 hours to see if the solution had become clear. If so, an additional approximately 0.1 g of paclitaxel was added to the vial and mixing continued.

[0345] Continue with step "d" for each vial for a total of 48 hours.

[0346] The paclitaxel concentration of the solution from each vial was measured using an HPLC method based on the Agilent Technologies application note for paclitaxel, "Analysis of Taxol by HPLC," 2002, but with a detection wavelength of 227 nm instead of 204 nm (a wavelength of 227 nm is used in the USP paclitaxel monograph, which reduces solvent effects observed at lower wavelengths).

[0347] The solubility values ​​are shown in Table 1.

[0348] Table 1

[0349]

[0350] Example 2 Observation results of paclitaxel nanoparticle crystals in various substances and solutions of substances

[0351] Paclitaxel nanoparticles were dispersed in various substances and aqueous solutions of the substances and crystal growth was observed. The results are shown in Table 2.

[0352] Table 2

[0353]

[0354] Paclitaxel nanoparticles did not grow in any of the hydrophobic carriers. Furthermore, the nanoparticles did not grow in aqueous solutions of benzalkonium chloride, CARBOPOL ULTREZ 10, or poloxamer 407.

[0355] Example 3 Particle Size, SSA and Volume Density Analysis of Paclitaxel Nanoparticles

[0356] The particle size of the paclitaxel nanoparticles used in the formulations listed in Table 3 and Tables 16 to 19 was analyzed using the ACCUSIZER 780 by the following particle size method:

[0357] Instrument parameters : Maximum concentration: 9000 particles / mL, Container number: 1, Sensor range: Total, Lower detection limit: 0.5 μm, Flow rate: 30 mL / min, Number of analytical extractions: 4, Time between extractions: 1 sec, Extraction volume: 10 mL, Tare volume: 1 mL, Original volume: 1 mL, Include first extraction: Not selected.

[0358] Sample preparation : Place one scoop of paclitaxel nanoparticle API into a clean 20 mL vial, add approximately 3 mL of filtered (0.22 μm) 0.1 wt % SDS solution to wet the API, then fill the remainder of the vial with SDS solution. Vortex for 5-10 minutes and sonicate in a water batch for 1 minute.

[0359] method : Fill a plastic bottle with a 0.1 wt % solution of filtered (0.22 μm) SDS and analyze the background. Pipette a small amount of the paclitaxel nanoparticle sample suspension (<100 μL) into the bottle of 0.1 wt % SDS solution while stirring; place the ACCUSIZER inlet tube into the bottle and run the sample through the instrument. Add more SDS solution or paclitaxel sample suspension as needed to achieve the desired running concentration of 6000 to 8000 particle counts.

[0360] Particle size results (Differential distribution based on number weight): Paclitaxel nanoparticle batches used in the formulations listed in Table 3: Mean: 0.861 μm, Mode: 0.572 μm, Median: 0.710 μm. Paclitaxel nanoparticle batches used in the formulations listed in Tables 16 to 19: Mean: 0.83 μm.

[0361] The specific surface area (SSA) of the paclitaxel nanoparticle batches used in the formulations listed in Table 3 and Tables 16 to 19 was analyzed by the Brunauer-Emmett-Teller ("BET") isotherm method described above. The SSA of the paclitaxel nanoparticle batches used in the formulations listed in Table 3 was 41.24 m 2 / g. The SSA of the paclitaxel nanoparticle batches used in the formulations listed in Tables 16 to 19 was 26.72 m 2 / g.

[0362] The bulk density (not shown) of the paclitaxel nanoparticle batch used in the formulation listed in Table 3 was 0.05 g / cm 3 The bulk density (not shown) of the paclitaxel nanoparticle batches used in the formulations listed in Tables 16 to 19 was 0.09 g / cm 3 .

[0363] Example 4 Anhydrous hydrophobic composition of paclitaxel nanoparticles and a hydrophobic carrier

[0364] Table 3 lists the anhydrous hydrophobic compositions of paclitaxel nanoparticles and hydrophobic carriers.

[0365] Table 3

[0366]

[0367] Procedure for F4 to F13: Prepare a slurry of paclitaxel nanoparticles with a portion of cyclomethicone (or mineral oil (F4) or FOMBLIN (F7)). Heat petrolatum to 52±3°C and add remaining ingredients and mix until melted and homogenous. Add paclitaxel slurry and mix until homogenous. Mix and allow batch to cool to 35°C or below. Form an ointment.

[0368] Example 5 Physical and chemical stability of anhydrous compositions of paclitaxel nanoparticles and hydrophobic carriers

[0369] At 25°C and 30°C, the anhydrous hydrophobic composition samples were stored in 20 mL glass scintillation vials. Analysis of paclitaxel was performed using HPLC. The results of the analysis and the appearance stability study are shown in Tables 4 and 5 below. Viscosity was measured at room temperature, 5 rpm, and a 2-minute equilibrium time using a Brookfield RV viscometer using a small sample adapter with an SC4-14 rotor and a 6R chamber. The viscosity results are shown in Table 6 below.

[0370] Table 4: Stability at 25°C

[0371]

[0372] **Repeat batches

[0373] Table 5: Stability at 30°C

[0374]

[0375] **Repeat batches

[0376] Table 6: Viscosity stability

[0377]

[0378] Example 6 Particle Size Analysis of Paclitaxel Nanoparticles in Anhydrous Compositions with Hydrophobic Carriers The particle size method was used using the ACCUSIZER Model 770 / 770A.

[0379] Instrument parameters : Sensor: LE 0.5μm-400μm, Sensor Range: Total, Lower Detection Limit: 0.5μm, Collection Time: 60 sec, Number of Channels: 128, Vessel Fluid Volume: 100mL, Flow Rate: 60mL / min, Maximum Coincidence: 8000 particles / mL, Sample Container: Accusizer Container, Sample Calculation: No, Voltage Detector: Greater than 10V, Particle Concentration Calculation: No, Concentration Range: 5000 to 8000 particles / mL, Automatic Data Save: Selected, Subtract Background: Yes, Number of Automatic Cycles: 1.

[0380] Sample preparation : Add an aliquot of the sample preparation to a scintillation vial. Use a spatula to spread the sample along the inside of the vial. Add approximately 20 mL of 2% lecithin in ISOPAR-G TM (C10-C11 Isoparaffin) solution into the vial. Sonicate the vial for 1 minute. Ensure that the sample is well dispersed in the solution.

[0381] method : Fill the sample container with filtered (0.22μ) 2% lecithin ISOPAR-G solution and analyze the background. Use a pipette to transfer a portion of the prepared sample to the container while stirring. Dilute or add the sample to the container as needed to provide a coincidence level of 5000 to 8000 particles / mL. Start the analysis by the instrument and verify that the coincidence level is 5000 to 8000 particles / mL for analysis.

[0382] The results of the particle size analysis are shown in Tables 7 and 8 below.

[0383] Table 7: Particle size stability at 25°C

[0384]

[0385] **Repeat batches

[0386] Table 8: Particle size stability at 30°C

[0387]

[0388] **Repeat batches

[0389] It can be seen from the data that when stored at room temperature (25°C) and 30°C for 1 month, the particle size growth of paclitaxel nanoparticles in samples F4 to F6 does not exceed 20% of the initial average particle size. When stored at room temperature (25°C) and 30°C for 6 months and 12 months, the particle size growth of paclitaxel nanoparticles in sample F6 does not exceed 20% of the initial average particle size. When stored at room temperature (25°C) and 30°C for 3 months, the particle size growth of paclitaxel nanoparticles in samples F6** (a repeated batch with the same formulation as F6) and F8 to F13 does not exceed 20% of the initial average particle size.

[0390] Example 7 Water-based Compositions of Paclitaxel Nanoparticles

[0391] The aqueous composition of paclitaxel nanoparticles is shown in Table 9.

[0392] Table 9

[0393]

[0394] The crystal growth of paclitaxel nanoparticles of the samples was observed. The results are shown in Table 10 below.

[0395] Table 10

[0396]

[0397] From the data it can be seen that the presence of benzalkonium chloride, CARBOPOL 974P or CARBOPOL ULTREZ 10 inhibits the growth of crystals in water-based compositions.

[0398] Example 8 Particle Size Analysis of Paclitaxel Nanoparticles in Water-Based Compositions

[0399] Particle size method using ACCUSIZER Model 770 / 770A.

[0400] Instrument parameters: Sensor: LE 0.5μm to 400μm, Sensor Range: Total, Lower Detection Limit: 0.5μm, Collection Time: 60 sec, Number of Channels: 128, Vessel Fluid Volume: 100mL, Flow Rate: 60mL / min, Maximum Coincidence: 8000 particles / mL, Sample Container: Accusizer Container, Sample Calculation: No, Voltage Detector: Greater than 10V, Particle Concentration Calculation: No, Concentration Range: 5000 to 8000 particles / mL, Automatic Data Save: Selected, Subtract Background: Yes, Number of Automatic Cycles: 1.

[0401] Sample preparation : Add an aliquot of the sample preparation to a scintillation vial. Use a spatula to spread the sample along the inner wall of the vial. Add approximately 20 mL of 0.2 μm filtered distilled water to the vial. Sonicate the vial for 1 minute. Ensure that the sample is well dispersed in the solution.

[0402] method : Fill the sample container with 0.2 μm filtered distilled water and analyze the background. Use a pipette to transfer a portion of the prepared sample to the container while stirring. Dilute or add the sample to the container as needed to provide a coincidence level of 5000 to 8000 particles / mL. Start the analysis with the instrument and verify that the coincidence level is 5000 to 8000 particles / mL for analysis.

[0403] The results of the particle size analysis are shown in Table 11 below.

[0404] Table 11: Particle size of water-based compositions

[0405]

[0406] It can be seen from the data of formulations F1, F2 and F3 in Table 11 that when the compositions are stored at room temperature for 6 months, the presence of benzalkonium chloride, CARBOPOL 974P or CARBOPOLULTREZ 10 inhibits the growth of crystals in the water-based compositions, so that the average particle size of the drug nanoparticles does not grow by more than 20% of the initial average particle size.

[0407] Example 9 In vitro skin permeation and diffusion study

[0408] A study was conducted to determine the in vitro skin permeation rate and extent of Formulations F1 to F13 permeating and crossing intact human cadaver skin using a Franz diffusion cell system. Paclitaxel concentrations were measured in the receptor compartment of the diffusion cell at various time points. At the conclusion of the diffusion study, the skin was tape-stripped and split into the epidermis and dermis. Paclitaxel in the epidermis and dermis tissues was extracted using an extraction solvent and analyzed.

[0409] Analytical methods: Mass spectrometry (MS) was developed for the analysis of paclitaxel. The MS conditions are shown in Table 12 below.

[0410] Table 12

[0411]

[0412] Franz Diffusion Cell (FDC) Studies – Methodology

[0413] Skin penetration: Intact human cadaver skin was purchased from the New York Firefighters Tissue Bank (NFFTB). Skin was collected from the upper back and was removed from the tissue bank at a thickness of ~500 μm. After receiving the skin from the tissue bank, the skin was stored frozen at -20°C until the beginning of the experiment. Prior to use, the skin was removed from the refrigerator and allowed to thaw completely at room temperature. The skin was then briefly soaked in a PBS bath to remove any residual cryoprotectant and preservative. Only visually intact skin areas were used during the experiments. For each study, two independent donors were used, each with three corresponding replicates.

[0414] 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% hydroxypropyl beta-cyclodextrin (HPBCD) was selected. The solubility of the active in the receptor fluid (-0.4 μg / mL) was shown to be sufficient to maintain the sinking state during the study. The receptor fluid was degassed by filtering the receptor fluid through a ZapCapCR 0.2 μm membrane while drawing a vacuum. The filtered receptor fluid was stirred for an additional 20 minutes while maintaining the vacuum to ensure complete degassing.

[0415] Diffusion Cell Assembly: Remove cadaver skin from freezer and thaw in biosafety hood for 30 minutes. Thaw skin thoroughly before opening package. Remove cadaver skin from package and place on biosafety hood bench with stratum corneum facing up. Pat skin dry with Kimwipe, then spray with fresh PBS and pat dry again. Repeat this process 3 times to remove any residue present on skin. Acceptor wells are then filled with degassed acceptor fluid. Add Teflon coated stirring rod to each acceptor well. Inspect thawed cadaver skin and use only areas with uniform thickness and no obvious damage to the surface. Cut skin into ~2 cm x 2 cm squares. Skin piece is placed in the center of donor cell with stratum corneum (SC) facing up. Center skin and flatten edges. Donor well and acceptor well are then aligned and clamped together with clamps. Add additional acceptor fluid if necessary. Remove any bubbles present by tilting the cell to allow air to leak out along the sample end. Diffusion cell is then placed in stirring dry heater and allowed to rehydrate with acceptor fluid for 20 minutes. The heater was maintained at 32°C with continuous stirring throughout the experiment. 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 completed, the entire receptor chamber volume was replaced with receptor fluid.

[0416] Formulation Application: The formulation was applied to the stratum corneum of the skin. A one-time dosing regimen was used for this study. The test article was applied to the skin at a dose of 10 μl using a positive displacement Nichiryo pipette. The formulation was then spread on the skin surface using a glass rod. The pool was not capped during the experiment. The theoretical dose of paclitaxel for each pool is shown in Table 13 below.

[0417] Table 13

[0418]

[0419] * Repeat analysis

[0420] Receptor fluid sampling: At 3 hours, 6 hours, 12 hours and 24 hours, remove 300 μL sample aliquots from the receptor wells using a graduated Hamilton-type syringe. Add fresh receptor medium to replace the 300 μL sample aliquots.

[0421] Tape Stripping and Thermal Splitting: At 24 hours, the skin was wiped with a PBS / ethanol soaked KimWipe. After wiping off the residual formulation and drying the skin with a KimWipe, the stratum corneum was tape stripped three times, each tape stripping consisting of applying a cellophane tape to the skin with even pressure and removing the tape. The tape strips were collected and frozen for future analysis. The first three tape strips removed the uppermost layer of the stratum corneum and served as an additional skin cleansing step. It is generally not considered that the active is completely absorbed in this area. Mass balance analysis is usually performed only on these tapes. After the skin was tape stripped, forceps or a spatula were used to separate the epidermis of each piece from the underlying dermis tissue. The epidermis and dermis tissue were collected and placed in 4 mL borosilicate glass bottles. After all skin pieces were separated, an aliquot of the extraction solvent was added to the glass vial. The process involved adding 2 mL of DMSO to the vial and incubating at 32°C for 24 hours. After the extraction time was completed, a sample aliquot of 300 μL of the extract was collected and filtered.

[0422] Analysis of samples: Sample aliquots were analyzed for paclitaxel using the analytical method described above.

[0423] result:

[0424] The results in Table 14 below show the concentrations of paclitaxel (μg / cm 2 ) and the concentration of paclitaxel (μg / cm ) delivered to the epidermis and dermis (penetration) 2 ). Figure 1 The concentration of paclitaxel (μg / cm2) delivered to the epidermis by formulations F1 to F7 is shown. 2 ). Figure 2 Paclitaxel concentrations (μg / cm2) delivered to the epidermis for formulations F6* (analyzed in duplicate) and F8 to F13 are shown. 2 ). Figure 3 The concentration of paclitaxel (μg / cm2) delivered into the dermis by formulations F1 to F7 is shown. 2 ). Figure 4 Paclitaxel concentrations (μg / cm2) delivered into the dermis for formulations F6* (analyzed in duplicate) and F8 to F13 are shown. 2 ).

[0425] Note: Formulations F1 to F6 were tested in one in vitro study and formulations F6* and F8 to F13 were tested in a second separate in vitro study using different batches of cadaver skin. In the second study, the analysis of formulation F6 (and annotated as F6*) was repeated so that it could be evaluated and compared with the other formulations in the second study.

[0426] Table 14

[0427]

[0428] * Repeat analysis

[0429] As can be seen from the results in Table 14, the transdermal flux of paclitaxel through the skin (epidermis and dermis) is zero or only a negligible amount, i.e., less than 0.01 μg / cm 2 From Table 14 and Figure 1 , Figure 2 , Figure 3 and Figure 4 As can be seen from the results, the amount of paclitaxel that permeates into the skin (epidermis and dermis) in the anhydrous hydrophobic formulations (F4 to F13) is much greater than the amount of paclitaxel that permeates into the skin in the aqueous formulations (F1 to F3), even though the aqueous formulations contain the transdermal absorption enhancer DGME (TRANSCUTOL P). The results also show that the anhydrous hydrophobic formulations with cyclomethicone exhibit greater skin penetration (epidermis and dermis) than the anhydrous hydrophobic formulations without cyclomethicone. In addition, the results show that the addition of other transdermal absorption enhancers to the anhydrous hydrophobic formulations containing cyclomethicone has little or no effect on the skin penetration (epidermis and dermis) of these compositions.

[0430] Example 10 - Human Psoriasis Plaque Study

[0431] The following formulations shown in Table 15 were prepared for human psoriasis plaque studies.

[0432] Table 15

[0433]

[0434] The formulations containing paclitaxel nanoparticles listed in Table 15 were each manufactured in a batch size of 6 kg. The placebo formulation was manufactured in a batch size of 12 kg. The formulations were then packaged in 15 gm laminated tubes.

[0435] The manufacturing process of batches BR16008A, BR16001A and BR16002A is as follows: Petrolatum, mineral oil, paraffin and a portion of cyclomethicone are added to a container and heated to 52±3°C while mixing with a propeller stirrer until melted and homogenous. Paclitaxel nanoparticles are added to a container containing another portion of cyclomethicone, first mixed with a spatula to wet the nanoparticles, and then mixed with an IKA Ultra Turrax homogenizer with an S25-25G dispersion tool until a uniform slurry is obtained while the container is kept in an ice / water batch. The slurry is then added to the petrolatum / paraffin container while mixing with a propeller mixer, and then rinsed with the remaining portion of cyclomethicone and mixed until the batch is visually uniform at 52±3°C. The batch is then homogenized using a Silverson homogenizer. Afterwards, the batch is mixed with a propeller mixer until a uniform ointment is formed, and the batch is cooled to 35°C or below.

[0436] The manufacturing process of batch BR16003A is as follows: petrolatum and paraffin are added to a container and heated to 52±3°C while mixing with a propeller stirrer until melted and uniform. Paclitaxel nanoparticles are added to a container containing cyclomethicone and a portion of mineral oil, first mixed with a spatula to wet the nanoparticles, and then mixed with an IKA Ultra Turrax homogenizer with an S25-25G dispersion tool until a uniform slurry is obtained while the container is kept in an ice / water batch. The slurry is then added to a petrolatum / paraffin container while mixing with a propeller mixer, then rinsed with the remaining portion of mineral oil and mixed until the batch is visually uniform at 52±3°C. The batch is then homogenized using a Silverson homogenizer. Afterwards, the batch is mixed with a propeller mixer until a uniform ointment is formed, and the batch is cooled to 35°C or below.

[0437] For each formulation listed in Table 15, the chemical analysis results and physical analysis results at 25°C at T = 0, 1 month and 3 months are shown in Tables 16 to 20.

[0438] Table 16

[0439]

[0440] Note 1: Off-white to yellow ointment

[0441] Note 2: Brookfield RV Viscometer on lift stand with lift stand open, using TE spindle at 10 RPM for 45 seconds at room temperature.

[0442] Table 17

[0443]

[0444] Note 1: Off-white to yellow ointment

[0445] Note 2: Brookfield RV Viscometer on lift stand with lift stand open, using TE spindle at 10 RPM for 45 seconds at room temperature.

[0446] Table 18

[0447]

[0448] Note 1: Off-white to yellow ointment

[0449] Note 2: Brookfield RV Viscometer on lift stand with lift stand open, using TE spindle at 10 RPM for 45 seconds at room temperature.

[0450] Table 19

[0451]

[0452] Note 1: Off-white to yellow ointment

[0453] Note 2: Brookfield RV Viscometer on lift stand with lift stand open, using TE spindle at 10 RPM for 45 seconds at room temperature.

[0454] Table 20

[0455]

[0456] Note 1: Off-white to yellow ointment

[0457] Note 2: Brookfield RV Viscometer on lift stand with lift stand open, using TE spindle at 10 RPM for 45 seconds at room temperature.

[0458] The formulations listed in Table 15 are used in an ongoing human clinical psoriasis plaque study consisting of a randomized placebo trial at two centers, double-blinded to the IP, and with intra-individual treatment comparisons. This study recruited 12 male and postmenopausal female volunteer subjects aged 18 years or older with psoriasis vulgaris and mild or moderate chronic plaques in stable phase, with an area sufficient for 6 treatment areas. In addition to the placebo formulation, each formulation containing paclitaxel nanoparticles was topically applied once a day for 10 times during the 12-day trial period. Efficacy was determined by measuring psoriasis permeability using 22-MHz ultrasound scanning and clinical scoring with a score of 0 to 3 (0 = no change, 1 = slight improvement, 2 = significantly improved but not completely cured, 3 = completely cured).

[0459] Preliminary results from the plaque study in 2 of the 12 subjects currently available (a 36-year-old male and a 47-year-old female) are as follows:

[0460] Table 21: Mean clinical evaluation of efficacy

[0461]

[0462] Table 22: Ultrasound Evaluation - Mean Change from Baseline (micrometers)

[0463] Baseline Day 4 Day 8 Day 12 BR16005A (placebo) 0 27 50.5 -23.5 BR16008A (0.15%) 0 -11.5 -47 -39 BR16001A (0.3%) 0 35 113.5 31 BR16002A (1%) 0 0 37.5 -3.5 BR16003A (2%) 0 82 35.5 58.5

Claims

1. Use of an anhydrous hydrophobic composition for the preparation of a medicament for enhancing the penetration of taxanes from taxane nanoparticles into the skin, wherein the anhydrous hydrophobic composition comprises greater than 50 wt% of a continuous hydrophobic carrier comprising petrolatum, 5 wt% to 24 wt% of cyclopentasiloxane, and 0.1 wt% to 5 wt% of a plurality of taxane nanoparticles, wherein the number average particle size of the taxane nanoparticles is 0.1 μm to 1.5 μm, wherein the composition does not comprise a C1-C5 fatty alcohol, and wherein the taxane nanoparticles are crystalline taxane nanoparticles, amorphous taxane nanoparticles, or a combination of amorphous taxane nanoparticles and crystalline taxane nanoparticles.

2. The use according to claim 1, wherein the composition does not contain an additional transdermal absorption enhancer.

3. The use according to claim 1, wherein the composition does not contain additional volatile solvents.

4. The use according to claim 1, wherein the composition does not contain a surfactant.

5. The use according to claim 1, wherein the hydrophobic carrier is non-volatile.

6. The use according to claim 1, wherein the hydrophobic carrier is non-polar.

7. The use according to claim 1, wherein the continuous hydrophobic carrier further comprises mineral oil and paraffin.

8. Use according to claim 7, wherein the mineral oil is a heavy mineral oil. 9 . The use according to claim 1 , wherein when the composition is stored at room temperature for at least 1 month, the number average particle size of the taxane nanoparticles does not grow by more than 20% of the initial number average particle size.

10. The use according to claim 1, wherein when the composition is stored at room temperature for at least 3 months, the number average particle size of the taxane nanoparticles does not grow by more than 20% of the initial number average particle size. 11 . The use according to claim 1 , wherein the solubility of the taxane nanoparticles in water at room temperature is less than or equal to 10 mg / mL.

12. The use according to claim 1, wherein the taxane nanoparticles have a m 2 / g specific surface area (SSA).

13. The use according to claim 1, wherein the composition does not contain protein.

14. The use according to claim 1, wherein the skin is diseased skin.

15. The use according to claim 14, wherein the diseased skin is skin suffering from psoriasis.

16. The use according to claim 1, wherein when the composition is applied to human cadaver skin, the OD value is less than 0.01 μg / cm 2 Penetration of taxanes from taxane nanoparticles into human cadaver skin.

17. The use according to claim 1, wherein the composition is a semisolid composition.

18. The use according to claim 17, wherein the semisolid composition is an ointment.

19. The use according to claim 17, wherein The viscosity of the composition is 25,000 cps to 500,000 cps as measured using a Brookfield RV viscometer on a lift stand with the lift stand open and a TE spindle at 10 RPM for 45 seconds at room temperature.

20. The use according to claim 1, wherein the hydrophobic composition is an anhydrous semisolid ointment.

21. The use according to claim 1, wherein: The hydrophobic composition does not contain an additional transdermal absorption enhancer or an additional volatile solvent other than cyclopentasiloxane; and The hydrophobic composition does not include a surfactant.

22. The use according to claim 1, wherein the taxane from the taxane nanoparticles is docetaxel.

23. An anhydrous hydrophobic composition comprising greater than 50 wt% of a continuous hydrophobic carrier comprising petrolatum, 5 wt% to 24 wt% cyclopentasiloxane, and 0.1 wt% to 5 wt% of a plurality of taxane nanoparticles, wherein the number average particle size of the taxane nanoparticles is 0.1 μm to 1.5 μm, wherein the composition does not comprise a C1-C5 fatty alcohol, and wherein the taxane nanoparticles are crystalline taxane nanoparticles, amorphous taxane nanoparticles, or a combination of amorphous taxane nanoparticles and crystalline taxane nanoparticles. The composition according to claim 23 , wherein the taxane nanoparticles are docetaxel nanoparticles.

25. Use of an anhydrous hydrophobic composition for the preparation of a medicament for treating diseased skin of a patient, wherein the anhydrous hydrophobic composition comprises greater than 50 wt% of a continuous hydrophobic carrier comprising petrolatum, 5 wt% to 24 wt% cyclopentasiloxane, and 0.1 wt% to 5 wt% of a plurality of taxane nanoparticles, wherein the taxane nanoparticles are crystalline taxane nanoparticles, amorphous taxane nanoparticles, or a combination of amorphous taxane nanoparticles and crystalline taxane nanoparticles, wherein the number average particle size of the taxane nanoparticles is 0.1 microns to 1.5 microns, wherein the composition does not contain a C1-C5 fatty alcohol, and wherein the concentration of the taxane nanoparticles is an effective concentration to provide a therapeutic improvement in the diseased skin condition.

26. The use according to claim 25, wherein the taxane nanoparticles are docetaxel nanoparticles.

27. A composition comprising a continuous hydrophobic carrier, 5 wt% to 24 wt% of one or more than one volatile silicone fluid, and a plurality of taxane nanoparticles, wherein the number average particle size of the taxane nanoparticles is 0.1 microns to 1.5 microns, and wherein the composition does not comprise a C1 to C5 fatty alcohol.

28. The composition of claim 27, wherein the taxane nanoparticles are docetaxel nanoparticles or cabazitaxel nanoparticles.

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