Topical formulations of 5-α-reductase inhibitors and uses thereof

Abstract

Disclosed herein are topical compositions of 5-α reductase inhibitors, such as dutasteride or finasteride, or a pharmaceutically acceptable salt, ester, or derivative thereof and the use of the compositions for the treatment of hair loss secondary to endocrine therapy in patients with breast cancer (Endocrine Therapy-Induced Alopecia or ETIA), androgenetic alopecia (AGA), alopecia areata, and hirsutism. The topical composition is advantageous over the existing oral compositions of 5-α reductase inhibitors because the topical composition is safer and more effective. The topical formulation may allow for a slow release of the active ingredient dutasteride, better penetration at the therapeutically effective amount of dutasteride with an improved safety profile because it does not need to travel through the bloodstream to be efficacious, thereby minimizing the risk of systemic side effects.

Claims

1. A method for stimulating hair growth on a scalp of a human subject suffering from endocrine therapy-induced alopecia (ETIA), comprising: a) providing a topical composition comprising a therapeutically effective amount of dutasteride dissolved in a topical pharmaceutically acceptable excipient or carrier, wherein the topical composition is an emulsion comprising diethyl sebacate and oleyl alcohol and does not contain ethyl alcohol; and b) topically applying the composition to the scalp in an amount and for a duration sufficient to stimulate hair growth; wherein hair growth comprises an increase in scalp hair density, hair thickness, or scalp coverage.

2. The method of claim 1, wherein the ETIA is hair loss secondary to endocrine therapy for breast cancer.

3. The method of claim 1, wherein the composition is applied to the scalp in an area comprising the frontal, central, vertex regions, or a combination thereof of the scalp.

4. The method of claim 1, wherein the therapeutically effective amount of dutasteride is about 0.001% to about 1% (w/w).

5. The method of claim 4, wherein the therapeutically effective amount of dutasteride is about 0.075% (w/w).

6. The method of claim 1, wherein the composition does not contain polypropylene glycol.

7. The method of claim 1, wherein the composition further comprises a solvent selected from the group consisting of sterile water, glycerin, medium chain triglycerides, isopropyl myristate, diisopropyl adipate, isopropyl palmitate, propylene glycol, olive oil, castor oil, coconut oil, light mineral oil, diethylene glycol monoethylether, benzyl alcohol, cyclomethicone, PEG 400, dehydrated alcohol, and dimethyl isosorbide.

8. The method of claim 1, wherein the composition further comprises an emulsifier selected from the group consisting of stearalkonium chloride, sodium monostearate Laureth-4, Polysorbate 20, and PEG-35 Castor Oil.

9. The method of claim 1, wherein the dutasteride is dissolved in an oil phase of the emulsion.

10. The method of claim 1, wherein the composition further comprises a humectant, a thickener, a preservative, an emollient, an emulsifier, a pH adjuster, a penetration enhancer, and a conditioning agent.

11. The method of claim 1, wherein the therapeutically effective amount of dutasteride is about 0.002% to about 0.1% (w/w).

12. The method of claim 1, wherein the therapeutically effective amount of dutasteride is about 0.025% (w/w).

13. The method of claim 1, wherein the therapeutically effective amount of dutasteride is about 0.05% (w/w).

14. The method of claim 1, wherein the therapeutically effective amount of dutasteride is about 0.15% (w/w).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the chemical structure of dutasteride.

(2) FIG. 2 shows the results of the binary dutasteride/excipient compatibility study.

DETAILED DESCRIPTION

(3) The present disclosure is directed to topical compositions of 5-α reductase inhibitors, such as dutasteride or finasteride or pharmaceutically acceptable salts, esters, or derivatives thereof for the treatment of hair loss secondary to endocrine therapy in patients with breast cancer (Endocrine Therapy-Induced Alopecia or ETIA), androgenetic alopecia (AGA), Alopecia Areata (AA), and hirsutism. The topical composition of 5-α reductase inhibitors is advantageous over any oral formulation of 5-α reductase inhibitors because it may allow for a slow release of the active ingredient, better penetration at the therapeutically effective amount of the 5-α reductase inhibitor with an improved safety profile since it does not need to travel through the bloodstream to be efficacious, thereby minimizing the risk of systemic side effects.

(4) Dutasteride is chemically designated as (5α,17β)-N-[2,5 bis(trifluoromethyl)phenyl]-3-oxo-4-azaandrost-1-ene-17-carboxamide. The empirical formula of dutasteride is C.sub.27H.sub.30F.sub.6N.sub.2O.sub.2, representing a molecular weight of 528.53 kDa with the following structural formula as shown in FIG. 1. Dutasteride is a selective inhibitor of both the type 1 and type 2 5α-reductase isoenzymes, an intracellular enzyme that converts testosterone to DHT. Additionally, dutasteride may be more effective than another known type 1 5α-reductase inhibitor finasteride because dutasteride inhibits both type 1 and type 2 5α-reductase isoenzymes.

(5) Although dutasteride may be more potent than finasteride in inhibiting 5α-reductase enzymes, they both have published adverse effects. Oral formulations of finasteride and dutasteride have been shown by researchers to be effective in treating androgenetic alopecia (AGA), and proposed as a treatment for hair loss secondary to endocrine therapy in patients with breast cancer (Endocrine Therapy-Induced Alopecia or ETIA). Oral dutasteride has not been approved for any form of treatment of alopecia or hirsutism in the United States.

(6) The present invention provides topical formulations of 5-α reductase inhibitors, such as dutasteride or finasteride or pharmaceutically acceptable salts, esters, or derivatives thereof for the treatment of hair loss secondary to endocrine therapy in patients with breast cancer (Endocrine Therapy-Induced Alopecia or ETIA), androgenetic alopecia (AGA), and hirsutism that is safe and effective because the topical formulation may allow for: a slow release of the active ingredient; better penetration at the therapeutically effective amount of the 5-α reductase inhibitor; and an improved safety profile since it does not need to travel through the bloodstream to be efficacious, thereby minimizing the risk of systemic side effects.

(7) As used herein the term “modulating hair growth” refers to an increase or decrease of hair count, hair thickness, or hair structure in scalp or face.

(8) As used herein the term “therapeutically effective amount” is a sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease. A reduction of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).

(9) As used herein, the amount of a dutasteride, when expressed as “%” refers to % (w/w) unless otherwise indicated.

(10) As used herein, the phrase “pharmaceutically acceptable” is used with reference to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.

(11) As used herein, the term “penetration enhancement” or “permeation enhancement” means an increase in the permeability of a biological membrane (i.e. skin or mucosa) to a drug, so as to increase the rate at which the drug is transported through the membrane. “Permeation enhancer”, “enhancer”, “penetration enhancer”, or similar terms mean a material that achieves such permeation or penetration enhancement, and an “effective amount” of an enhancer means an amount effective to enhance penetration through the skin or mucosa of a selected agent to a desired degree.

(12) Suitable penetration enhancers that can be used in the present invention include, but are not limited to: sulfoxides such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C.sub.10 MSO); ethers such as diethylene glycol monoethyl ether (available commercially as TRANSCUTOL® P) and diethylene glycol monomethyl ether; 1-substituted azacycloheptan-2-ones, such as 1-n-dodecyl-cyclazacycloheptan-2-one; alcohols such as propanol, octanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid, and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate; polyol esters such as butanediol and polyethylene glycol monolaurate, amides and other nitrogenous compounds such as urea, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine, and triethanolamine; terpenes and terpinoids; alkanones; organic acids, such as salicylic acid and salicylates, citric acid and succinic-acid and the like; and any mixtures thereof. Suitable penetration enhancers also include, but are not limited to, medium chain triglycerides, isopropyl myristate, diisopropyl adipate, isopropyl palmitate, propylene glycol, diethylene glycol monoethylether (TRANSCUTOL® P), oleyl alcohol, dehydrated alcohol, benzyl alcohol, laureth-4, diethyl sebacate, and dimethyl isosorbide.

(13) Suitable solvents that can be used in the present invention include, but are not limited to: sterile water, glycerin, medium chain triglycerides, isopropyl myristate, diisopropyl adipate, isopropyl palmitate, propylene glycol, olive oil, castor oil, coconut oil, light mineral oil, diethylene glycol monoethylether (TRANSCUTOL® P), diethyl sebacate, benzyl alcohol, cyclomethicone, PEG 400, dehydrated alcohol, and dimethyl isosorbide.

(14) Suitable humectants that can be used in the present invention include, but are not limited to: sodium hyaluronate, glycerin, sorbitol solution, 70%, and methyl gluceth-20 (GLUCAM® E20).

(15) Suitable thickeners that can be used in the present invention include, but are not limited to: xanthan gum, cetearyl alcohol, PROMULGEN® D, CARBOPOL® 974P NF Polymer, PEMULEN® TR-2, PEMULEN® TR-1, KLUCEL® HG Pharm, CARBOPOL® 980 NF, Polymer, and SEPINEO® P 600.

(16) Suitable preservatives that can be used in the present invention include, but are not limited to: methylparaben and propylparaben.

(17) Suitable emollients that can be used in the present invention include, but are not limited to: olive oil, medium chain triglycerides, isopropyl myristate, diisopropyl adipate, isopropyl palmitate, castor oil, light mineral oil, cyclomethicone, diethyl sebacate, benzyl alcohol, PEG-35 castor oil, and coconut oil.

(18) Suitable emulsifiers that can be used in the present invention include, but are not limited to: BRIJ® L4, ARLACEL® 165, TWEEN® 20, BRIJ® 5721, BRIJ® S2, PROMULGEN® D, Stearalkonium Chloride, PEMULEN® TR-2, PEMULEN® TR-1, Sodium Monostearate, SEPINEO® P 600, Laureth-4, Polysorbate 20, Sorbitan Monostearate, and PEG-35 Castor Oil. Non-ionic emulsifiers include, but are not limited to, BRIJ® L4, ARLACEL® 165, Sodium Monostearate, Laureth-4, Polysorbate 20, and PEG-35 Castor Oil. Cationic surfactants include, but are not limited to, stearalkonium chloride.

(19) Suitable pH adjusters that can be used in the present invention include, but are not limited to: NaOH and HCl solutions.

(20) Suitable conditioning agents that can be used in the present invention include, but are not limited to: stearalkonium chloride and Polyquaternium-10.

(21) Suitable solubilizers that can be used in the present invention include, but are not limited to: Laureth-4.

(22) Suitable viscosity enhancers that can be used in the present invention include, but are not limited to: PEG 3350.

EXAMPLES

Example 1: Topical Formulation Comprising Dutasteride

(23) A topical formulation of 0.10% w/v may be prepared as follows.

(24) TABLE-US-00001 Ingredient Final Concentration Amount per 30 ml Dutasteride  0.10% 0.030 g Ethyl Alcohol (95%) 55.00% (v/v) 16.50 ml Polypropylene glycol  5.00% (v/v) 1.50 ml Purified Water 39.90% (v/v) 11.97 ml TOTAL 100.00% 30.00 ml

Example 2: Topical Cream Formulations Comprising Dutasteride (Dutasteride Dissolved in Oil Phase)

(25) A. A topical formulation of 0.05% w/w may be prepared as follows:

(26) TABLE-US-00002 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Sterile Water for q.s. to 100 100.00 Solvent Irrigation (64.15) B Sodium 0.10 2.50 Humectant Hyaluronate C Glycerin 5.00 20.00 Humectant Solvent Xanthan Gum 0.50 2.85 Thickener D Methylparaben 0.18 0.50 Preservative E Olive Oil 3.00 27.75 Emollient Medium Chain 10.00 15.00 Solvent Triglycerides Emollient Penetration Enhancer Isopropyl 10.00 50.30 Solvent Myristate Emollient Penetration Enhancer BRIJ ® L4 1.00 5.22 Emulsifier Dutasteride 0.05 N/A API F ARLACEL ® 165 4.00 7.50 Emulsifier Cetearyl Alcohol 2.00 12.00 Thickener Propylparaben 0.02 5.25 Preservative Total 100.00

(27) The components of Phase A were combined in the main vessel until a solution was obtained. With high agitation, Phase B was sprinkled into the main vessel and mixed until a homogenous gel was obtained. Phase C was pre-mixed in a separate container and added to the main vessel until it was uniformly dispersed. The batch was then heated to 70-75° C. Phase D was then added to the main vessel and mixed until Phase D was solubilized. The components of Phase E were combined in a separate vessel and mixed until a solution was obtained. Phase F was then added to Phase E in the separate vessel and heated until the mixture was 70-75° C.

(28) The When the mixture in the main vessel and the Phase E+F mixture are both at 70-75° C., Phase E+F was added to the main vessel for homogenization. The batch was then cooled down to less than 30° C.

(29) The Hydrophilic-lipophilic balance (HLB), which is the balance of the size and strength of the hydrophilic and lipophilic moieties of a surfactant molecule, was calculated.

(30) TABLE-US-00003 % Required % Ingredient HLB w/w Ingredient HLB w/w ARLACEL ® 11.00 4.00 Olive Oil 7.70  3.00 165 BRIJ ® 4 9.70 1.00 MCT 10.00 10.00 Isopropyl 11.50 10.00 Myristate Cetearyl Alcohol 15.50  2.00 Total HLB/ 10.74 5.00 Total Required 10.76 25.00 Total % w/w HLB/Total % W/W

(31) B. A topical formulation of 0.05% w/w may be prepared as follows. (2019-045-31R)

(32) TABLE-US-00004 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Sterile Water for q.s. to 100 100.00 Solvent Irrigation (46.35) B Sodium 0.10 2.50 Humectant Hyaluronate C Glycerin 5.00 20.00 Humectant Solvent Xanthan Gum 0.50 2.85 Thickener D Methylparaben 0.18 0.50 Preservative E Diisopropyl 20.00 20.00 Solvent Adipate Emollient Penetration Enhancer Medium Chain 15.00 15.00 Solvent Triglycerides Emollient Penetration Enhancer Isopropyl 7.30 7.30 Solvent Palmitate Emollient Penetration Enhancer BRIJ ® L4 2.00 5.22 Nonionic Emulsifier Dutasteride 0.05 N/A API F ARLACEL ® 1.00 7.50 Nonionic 165 Emulsifier Cetearyl Alcohol 2.50 12.00 Thickener Propylparaben 0.02 5.25 Preservative Total 100.00

(33) The components of Phase A were combined in the main vessel until a solution was obtained. With high agitation, Phase B was sprinkled into the main vessel and mixed until a homogenous gel was obtained. Phase C was pre-mixed in a separate container and added to the main vessel until it was uniformly dispersed. The batch was then heated to 70-75° C. Phase D was then added to the main vessel and mixed until Phase D was solubilized. The components of Phase E were combined in a separate vessel and mixed until a solution was obtained. Phase F was then added to Phase E in the separate vessel and heated until the mixture was 70-75° C. When the mixture in the main vessel and the Phase E+F mixture are both at 70−75° C., Phase E+F was added to the main vessel for homogenization. The batch was then cooled down to less than 30° C.

(34) The Hydrophilic-lipophilic balance (HLB), which is the balance of the size and strength of the hydrophilic and lipophilic moieties of a surfactant molecule, was calculated.

(35) TABLE-US-00005 Required Ingredient HLB % w/w Ingredient HLB % w/w BRIJ ® L4 9.70 2.00 Diisopropyl Adipate 9.00 20.00 ARLACEL ® 11.00 1.00 Medium Chain 10.00 15.00 165 Triglycerides Isopropyl 11.50 7.30 Palmitate Cetearyl Alcohol 15.50 2.50 Total HLB/ 10.13 3.00 Total Required 10.10 44.80 Total % W/W HLB/Total % W/W

Example 3: Topical Cream Formulation Comprising Dutasteride (Dutasteride Dissolved in Water Phase)

(36) A topical formulation of 0.05% w/w may be prepared as follows.

(37) TABLE-US-00006 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Sterile Water for q.s. to 100 100.00 Solvent Irrigation (63.55) TWEEN ® 20 1.00 15.00 Emulsifier B Propylene Glycol 5.00 99.98 Solvent Penetration Enhancer Methylparaben 0.18 0.50 Preservative Propylparaben 0.02 5.25 Preservative C BRIJ ® S721 2.00 3.00 Emulsifier BRIJ ® S2 2.00 5.00 Emulsifier Castor Oil 5.00 14.90 Solvent Emollient Light Mineral 2.00 43.40 Solvent Oil Emollient Cyclomethicone 3.00 13.00 Emollient Cetearyl Alcohol 1.00 12.00 Thickener D SEPINEO  ® 0.20 4.00 Thickener P 600 Emulsifier E TRANSCUTOL ® 15.00 49.91 Solvent P Penetration Enhancer Dutasteride 0.05 — API Total 100.00

(38) The components of Phase A were combined in the main vessel. The components of Phase B were combined in a separate vessel and mixed until a solution was obtained. Phase B was then added to the main vessel and mixed until a solution was obtained. The main vessel was then heated to 70-75° C. The components of Phase C were mixed in a separate vessel and heated to 70-75° C. Phase C was then added to the main vessel with homogenization. The contents of the main vessel were mixed until the oil phase was fully incorporated. Phase D was then added to the main vessel and homogenized until the batch temperature was 60° C. The main vessel was cooled down to <30° C. Phase E was combined in a separated container until a solution was obtained. Phase E was then added to the main vessel and mixed.

(39) The HLB was Calculated.

(40) TABLE-US-00007 % Required % Ingredient HLB w/w Ingredient HLB w/w BRIJ ® S2 4.90 2.00 Castor Oil 14.00 10.00 BRIJ ® S721 15.50 2.00 Light Mineral Oil 10.00 5.00 TWEEN ® 20 16.70 1.00 Cyclomethicone 7.50 5.00 Cetearyl Alcohol 15.50 1.00 Total HLB 11.50 5.00 Total Req HLB 11.57 21.00

Example 4: Topical Lotions (“Conditioners”) Comprising Dutasteride (Dutasteride Dissolved in Oil Phase)

(41) A topical formulation of 0.05% w/w for a leave-in conditioner may be prepared as follows.

(42) TABLE-US-00008 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Sterile Water for q.s. to 100 100.00 Solvent Irrigation (50.00) Stearalkonium 1.50 3.15 Condition- Chloride ing Agent Methylparaben 0.18 0.50 Preservative Glycerin 5.00 20.00 Humectant Solvent B Olive Oil 3.00 27.75 Emollient Diethyl Sebacate 20.00 24.00 Solvent Emollient Dutasteride 0.05 — API C PROMULGEN ® 5.00 8.00 Emulsifier D Thickener Propylparaben 0.02 5.25 Preservative D Sterile Water for 15.00 100.00 Solvent Irrigation Polyquaternium- 0.25 2.06 Condition- 10 ing Agent Total 100.00

(43) The components of Phase A were combined in the main vessel while heating to 70-75° C. The components were mixed until uniform. The components of Phase B was combined in a separate vessel and mixed until a solution was obtained. The components of Phase C were added to Phase B while heating up to 70-75° C. The combined Phases B and C were added to the main vessel while heating at 70-75° C. and mixed until uniform. The main vessel was then cooled to 40° C. The components of Phase D were combined in a separate vessel. Phase D was then added to the main vessel and the main vessel was then cooled to <30° C.

(44) A topical formulation of 0.05% w/w for a leave-in conditioner may be prepared as follows. (2019-045-34R)

(45) TABLE-US-00009 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Sterile Water for q.s. to 100 100.00 Solvent Irrigation (44.55) Polyquaternium- 0.20 2.06 Condition- 10 ing Agent B Stearalkonium 0.50 3.15 Cationic Chloride Emulsifier Condition- ing Agent Methylparaben 0.18 0.50 Preservative Glycerin 5.00 20.00 Humectant Solvent C Olive Oil 9.00 27.75 Emollient Benzyl Alcohol 0.50 2.70 Solvent Emollient Medium Train 15.00 15.00 Solvent Triglycerides Emollient Penetration Enhancer Diisopropyl 20.00 20.00 Solvent Adipate Emollient Penetration Enhancer Dutasteride 0.05 — API D PROMULGEN ® 5.00 8.00 Emulsifier D Thickener Propylparaben 0.02 5.25 Preservative Total 100.00

(46) The components of Phase A were combined in the main vessel while heating to 70-75° C. The components were mixed until uniform. The components of Phase B combined in a separate vessel and mixed until a solution was obtained. The components of Phase C were combined in a separate vessel and mixed until a solution was obtained. The components of Phase C were added to Phase B while heating up to 70-75° C. The combined Phases B and C were added to the main vessel while heating at 70-75° C. and mixed until uniform. The main vessel was then cooled to 40° C. The components of Phase D were combined in a separate vessel. Phase D was then added to the main vessel and the main vessel was then cooled to <30° C.

Example 5: Topical Lotion Formulation Comprising Dutasteride (Dutasteride Dissolved in Water Phase)

(47) A topical formulation of 0.05% w/w for application may be prepared as follows.

(48) TABLE-US-00010 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Sterile Water for q.s. to 100 100.00 Solvent Irrigation (54.45) Propylene Glycol 5.00 99.98 Solvent Penetration Enhancer Sorbitol Solution, 5.00 36.80 Humectant 70% Dutasteride 0.05 — API B CARBOPOL ® 0.20 1.51 Thickener 974P NF Polymer PEMULEN ® 0.10 0.60 Thickener TR-2 Emulsifier C Propylene Glycol 5.00 99.98 Solvent Penetration Enhancer Methylparaben 0.18 0.50 Preservative Propylparaben 0.02 5.25 Preservative D Cyclomethicone 3.00 13.00 Solvent Emollient Castor Oil 5.00 14.90 Solvent Emollient E 10% NaOH Solution q.s. to pH pH adjuster pH adjuster 6.5-7.0 Sterile Water for (5.00) 100.00 Solvent Irrigation F Sterile Water for 15.00 100.00 Solvent Irrigation Polyquaternium- 2.00 2.06 Conditioning 10 Agent Total 100.00

(49) The components of Phase A were combined in the main vessel and were mixed until a solution was obtained. The components of Phase B were sprinkled into the main vessel with vigorous mixing for no longer than 30 minutes. The components of Phase C were combined in a separate container and mixed until a solution was obtained. Phase C was added to the main vessel and mixed until uniform. The components of Phase D were pre-mixed and then added to the main vessel with vigorous mixing and mixed until fully incorporated. The pH of the mixture in the main vessel was adjusted to pH 6.5-7.0 using the Phase E. The components of Phase F were combined in a separate container and mixed until a solution was obtained, added to the main vessel, and mixed until uniform.

Example 6: Topical Lotion Formulation Comprising Dutasteride (2019-045-71)

(50) A topical formulation of 0.05% w/w for application may be prepared as follows.

(51) TABLE-US-00011 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Sterile Water for 43.20 100.00 Solvent Irrigation Glycerin 3.00 20.00 Humectant Solvent Methylparaben 0.18 0.50 Preservative B CARBOPOL ® 0.10 1.51 Thickener 974P Polymer C Oleyl Alcohol 4.00 10.00 Penetration Enhancer Isopropyl 20.45 35.00 Solvent Myristate Emollient Penetration Enhancer Diethyl Sebacate 24.00 24.00 Solvent Emollient Penetration Enhancer Dutasteride 0.05 — API D Propylparaben 0.02 5.25 Preservative BRIJ ® S2 1.50 5.00 Nonionic Emulsifier BRIJ ® S721 2.00 3.00 Nonionic Emulsifier Cetearyl Alcohol 1.00 12.00 Thickener E Sterile Water for 0.50 100.00 Solvent Irrigation F 10% NaOH Solution q.s. to pH Adj pH pH adjuster 5.5-6.0 G Sterile Water for q.s. to 100 100.00 Solvent Irrigation Total 100.00

(52) The components of Phase A were combined in the main manufacturing vessel and heated to 70-75° C., if necessary, to dissolve methylparaben. Phase B was sprinkled into the main vessel and mixed until no fish eyes were present. The main vessel was then heated until 75-80° C. The components of Phase C were combined in a separate vessel and homogenized until a solution was obtained. The components of Phase C were heated to 75-80° C., if necessary, to dissolve the dutasteride. The components of Phase D were added to Phase C while heating to 75-80° C. and mixed until Phase D was completely melted. Phases C+D were added to the main manufacturing vessel at 75-80° C. with homogenization until the oil phase was fully incorporated. Phase E was used to rinse the Phase C+D vessel. The main manufacturing vessel as cooled to <30° C. Phase F was used to neutralize the batch to pH 5.5-6.0. Phase G was added to the main manufacturing vessel in an amount sufficient such that the total was 100% w/w.

Example 7: Topical Lotion Formulation Comprising Dutasteride (2019-045-76)

(53) A topical formulation of 0.05% w/w for application may be prepared as follows.

(54) TABLE-US-00012 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Sterile Water for 45.65 100.00 Solvent Irrigation Sodium 0.10 2.50 Humectant Hyaluronate B Glycerin 5.00 20.00 Humectant Solvent Xanthan Gum 0.20 2.85 Thickener C Methylparaben 0.18 0.50 Preservative D Diisopropyl 20.00 20.00 Solvent Adipate Emollient Penetration Enhancer Dutasteride 0.05 — API E Medium Chain 15.00 20.00 Solvent Triglycerides Emollient Penetration Enhancer Isopropyl 7.30 7.30 Solvent Palmitate Emollient Penetration Enhancer F ARLACEL ® 3.00 7.50 Nonionic 165 Emulsifier Sodium 0.50 8.00 Nonionic Monostearate Emulsifier Cetearyl Alcohol 3.00 12.00 Thickener Propylparaben 0.02 5.25 Preservative G Sterile Water for q.s. 100.00 Solvent Irrigation to 100 Total 100.00

(55) The components of Phase A were combined in the main manufacturing vessel with high agitation until a homogeneous gel was obtained. The components of Phase B were combined in a separate vessel. Phase B was added to the main manufacturing vessel and mixed until uniformly dispersed. Phase C was added to the main manufacturing vessel and mixed until dissolved. The main manufacturing vessel was then heated to 70-75° C. Phase D was combined in a separate vessel with homogenization until a solution was obtained. The phase was heated to 70-75° C. if necessary to dissolve the dutasteride. The components of Phase E were added to Phase D one at a time until a solution was obtained. The components of Phase F were added to Phases D+E while heating to 70-75° C. until Phase F was completely melted. Phases D+E+F were added to the main manufacturing vessel at 70-75° C. with homogenization until the oil phase was fully incorporated. Phase G was used to rinse the Phase D+E+F vessel. The main manufacturing vessel was cooled down to <30° C.

Example 8: Topical Lotion (Conditioner) Formulation Comprising Dutasteride (2019-045-63)

(56) A topical formulation of 0.05% w/w for application may be prepared as follows.

(57) TABLE-US-00013 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Sterile Water for 35.55 100.00 Solvent Irrigation Stearalkonium 0.50 4.20 Cationic Chloride Emulsifier Condition- ing Agent Methylparaben 0.18 0.50 Preservative Glycerin 5.00 20.00 Humectant Solvent B Olive Oil 9.00 27.75 Emollient Benzyl Alcohol 0.50 10.00 Solvent Preservative Penetration Enhancer Medium Chain 15.00 20.00 Solvent Triglycerides Emollient Penetration Enhancer Diisopropyl 20.00 20.00 Solvent Adipate Emollient Penetration Enhancer Dutasteride 0.05 — API C PROMULGEN ® 5.00 8.00 Emulsifier D Thickener Propylparaben 0.02 5.25 Preservative D Sterile Water for 1.00 100.00 Solvent Irrigation E Sterile Water for 8.00 100.00 Solvent Irrigation Polyquaternium- 0.20 2.06 Condition- 10 ing Agent F Sterile Water for q.s. to 100 100.00 Solvent Irrigation Total 100.00

(58) The components of Phase A were combined in the main manufacturing vessel and heated to 70-75° C., and mixed until uniform. The components of Phase B were combined in a separate vessel with homogenization until a solution was obtained. The components of Phase B were heated to 70-75° C., if necessary, to dissolve the dutasteride. The components of Phase C were added to Phase B while heating to 70-75° C., and mixed until Phase C was completely melted and incorporated. Phases B+C were added to the main manufacturing vessel at 70-75° C. with homogenization and mixed until the oil phase was fully incorporated. Phase D was used to rinse the Phase B+C vessel. The main manufacturing vessel was cooled to <40° C. The components of Phase E were combined in a separate vessel, then added to the main manufacturing vessel and mixed until uniform. The main manufacturing vessel was cooled to ≤30° C. Phase F was added to the batch in an amount sufficient such that the total was 100% w/w.

Example 9: Topical Lotion “Serum” Formulation Comprising Dutasteride (Dutasteride Dissolved in Oil Phase)

(59) A topical formulation of 0.05% w/w for application may be prepared as follows.

(60) TABLE-US-00014 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Sterile Water for q.s. to 100 100.00 Solvent Irrigation (76.45) Glycerin 5.00 20.00 Humectant Solvent Methylparaben 0.18 0.50 Preservative B CARBOPOL ® 0.15 1.51 Thickener 974PP olymer C Medium Chain 7.00 15.00 Solvent Triglycerides Emollient Penetration Enhancer Isopropyl 3.00 50.30 Solvent Myristate Emollient Penetration Enhancer Diethyl Sebacate 3.00 24.00 Solvent Emollient Propylparaben 0.02 5.25 Preservative D Dutasteride 0.05 — API E PEMULEN ® 0.15 0.80 Thickener TR-1 Emulsifier F 10% NaOH Solution q.s. to pH pH adjuster pH adjuster 5.5-6.0 Sterile Water for (5.00) 100.00 Solvent Irrigation Total 100.00

(61) The components of Phase A were combined in the main vessel and were mixed until a solution was obtained. The components of Phase B were sprinkled into the main vessel with vigorous mixing until no fish eyes were present. The components of Phase C were combined in a separate container and mixed until a solution was obtained. The component of Phase D was then added to Phase C and mixed until a solution was obtained. Phase E was then dispersed in combined Phases C+D. The combined Phases C+D+E were then added to the main vessel with vigorous propeller mixing for 20-30 minutes. The batch was then homogenized for 1 minute at 6,000 rpm. The pH of the batch was adjusted to pH 5.5-6.0 using the Phase F.

(62) A topical lotion (serum) formulation of 0.05% w/w for application may be prepared as follows. (2019-045-25R)

(63) TABLE-US-00015 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Sterile Water for q.s. to 100 100.00 Solvent Irrigation (46.05) Glycerin 5.00 20.00 Humectant Solvent Methylparaben 0.18 0.50 Preservative B CARBOPOL ® 0.10 1.51 Thickener 974P Polymer C Oleyl Alcohol 4.00 10.00 Penetration Enhancer Isopropyl 20.45 50.30 Solvent Myristate Emollient Penetration Enhancer Diethyl Sebacate 24.00 24.00 Solvent Emollient Penetration Enhancer Propylparaben 0.02 5.25 Preservative Dutasteride 0.05 — API D PEMULEN  ® 0.15 0.80 Thickener TR-2 Anionic Emulsifier E 10% NaOH q.s. to pH pH adjuster pH adjuster Solution 5.5-6.0 Sterile Water for 100.00 Solvent Irrigation Total 100.00

(64) The components of Phase A were combined in the main vessel and were mixed until a solution was obtained. The components of Phase B were sprinkled into the main vessel with vigorous mixing until no fish eyes were present. The components of Phase C were combined in a separate container and mixed until a solution was obtained. The component of Phase D was then added to Phase C and mixed until a solution was obtained. Phase E was then dispersed in combined Phases C+D. The combined Phases C+D+E were then added to the main vessel with vigorous propeller mixing for 20-30 minutes. The batch was then homogenized for 1 minute at 6,000 rpm. The pH of the batch was adjusted to pH 5.5-6.0 using the Phase F.

Example 10: Topical Gel Formulation Comprising Dutasteride

(65) A topical formulation of 0.05% w/w for application may be prepared as follows. The light gel with a non-sticky finish can be applied on the scalp/hair and will advantageously not leave much residue after it sets.

(66) TABLE-US-00016 IID Topical Phase Ingredients % w/w Max (% w/w) Category A PEG 400 q.s. to 100 69.9 Solvent (63.45) TRANSCUTOL ® 15.00 49.91 Solvent P Penetration Enhancer Diisopropyl 20.00 20.00 Solvent Adipate Emollient Penetration Enhancer B Dutasteride 0.05 — API C KLUCEL ® HG 1.50 4.00 Thickener Pharm Total 100.00

(67) The components of Phase A were combined in the main vessel and were mixed until a solution was obtained. The components of Phase B were added to the main vessel and were mixed until a solution was obtained. Phase C was sprinkled into the main vessel and mixed until a uniform gel was obtained.

Example 11: Topical Gel Formulation Comprising Dutasteride

(68) A topical formulation of 0.05% w/w for application may be prepared as follows. (2019-045-53)

(69) TABLE-US-00017 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Dehydrated 47.92 96.94 Solvent Alcohol Penetration Enhancer Propylene 50.00 99.98 Solvent Glycol Penetration Enhancer Dutasteride 0.05 — API B CARBOPOL ® 2.03  1.40 Thickener 980 NF, Polymer C Dehydrated q.s. 96.94 Solvent Alcohol to 100 Penetration Enhancer Total 100.00

(70) The components of Phase A were combined in the main manufacturing vessel until a solution was obtained. Phase B was slowly added to the main manufacturing vessel with mixing until a homogenous gel was obtained. Phase C was added to the main manufacturing vessel in an amount sufficient such that the total was 100% w/w.

(71) A topical formulation of 0.05% w/w for application may be prepared as follows.

(72) TABLE-US-00018 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Dehydrated q.s. to 100 60.00 Solvent Alcohol (46.45) Penetration Enhancer Propylene Glycol 50.00 99.98 Solvent Penetration Enhancer Dutasteride 0.05 — API B CARBOPOL  ® 3.50  3.50 Thickener 980 NF, Polymer Total 100.00

(73) The components of Phase A were combined in the main manufacturing vessel until a solution was obtained. Phase B was slowly added to the main manufacturing vessel with mixing until a homogenous gel was obtained.

Example 12: Topical Gel Formulation Comprising Dutasteride

(74) A topical formulation of 0.05% w/w for application may be prepared as follows. (2019-045-55)

(75) TABLE-US-00019 IID Topical Phase Ingredients % w/w Max (% w/w) Category A Propylene Glycol q.s. to 100 99.98 Solvent (72.95) Penetration Enhancer TRANSCUTOL ® 20.00 49.91 Solvent P Penetration Enhancer Diethyl Sebacate 3.00 24.00 Solvent Emollient Penetration Enhancer Dutasteride 0.05 — API B SEPINEO ® 4.00  4.00 Thickener P 600 Emulsifier Total 100.00

(76) The components of Phase A were combined in the main manufacturing vessel until a solution was obtained. Phase B was added to the main manufacturing vessel with homogenization and mixed until a uniform gel was obtained.

Example 13: Topical Gel (Serum) Formulation Comprising Dutasteride

(77) A topical formulation of 0.05% w/w for application may be prepared as follows. (2019-045-61)

(78) TABLE-US-00020 IID Topical Phase Ingredients % w/w Max (% w/w) Category A PEG 400 q.s. to 100 99.98 Solvent (69.95) TRANSCUTOL ® 15.00 49.91 Solvent P Penetration Enhancer Dutasteride 0.05 — API B PEG 3350 15.00 40.00 Viscosity Enhancer Total 100.00

(79) The components of Phase A were combined in the main manufacturing vessel until a solution was obtained. Phase A was then heated to 60-65° C. Phase B was weighed out in a separate vessel and heated to 60-65° C. Phase B was then slowly added to the main manufacturing vessel and mixed until a homogenous gel was obtained and when the temperature was <30° C.

Example 14: Analysis of Binary Dutasteride/Excipient Compatibility Study

(80) Samples were weighed out (about 500 mg to 100 mg of sample into a 40 mL VOA bottle). The samples were fully dispersed in 5.0 mL of hexane by vortex. Sonication was also used as needed to fully disperse the sample. 10 mL of diluent (water/acetonitrile 40/60) was added to the VOA bottle and mixed by Vortex. An aliquot was filtered through a 0.45 μm PTFE filter into an autosampler vial for HPLC analysis. For the standard, a 6-point calibration curve in the range of 10 μg/mL to 200 μg/mL of dutasteride in diluent was prepared.

(81) The samples were analyzed via HPLC in accordance with the following parameters.

(82) TABLE-US-00021 Column Water Symmetry C18, 3.5 μm, 3.0 × 150 mm Mobile Phase A Water/Acetonitrile/TFA (480/520/0.25) Mobile Phase B Acetonitrile Injection Volume 10 μl Column Temperature 35.0° C. Sampler Temperature Ambient Flow Rate 1.0 mL/min Detection Signal A: 220 nm Run Time 22.0 Gradient Time (min) % Solvent B 0.0 0 20.0 0 21.0 95 24.0 95 24.1 0 28.0 0

(83) Various combinations of dutasteride and excipients were tested at T=0 and T=14 days after being stored at 50° C. to determine their stability and dutasteride's compatibility with different excipients. Results from the study are reported in FIG. 2.

Example 15: Treatment of Human Subjects Suffering from Alopecia with a Topical Composition of Dutasteride

(84) A topical composition of dutasteride, such as those described in Examples 1-13, can be applied to the scalp of a human subject suffering from alopecia for multiple days.

(85) Two randomized, parallel-group studies can be conducted. Group I: 10 human subjects may receive 1 mL (1 mg) of the topical formulation of Example 1, applied to the scalp once a day (qd) or twice a day (b.i.d) for at least 4 weeks, alternatively at least 8 weeks, alternatively at least 12 weeks, alternatively at least 16 weeks.

(86) Group 2 may receive a placebo without the dutasteride applied to the scalp once a day (qd) or twice a day (b.i.d) for at least 4 weeks, alternatively at least 8 weeks, alternatively at least 12 weeks, alternatively at least 16 weeks.

(87) For each of the groups, hair thickness increase, target area hair count (TAHC), hair growth assessment (HGA), target area hair width (TAHW), scalp coverage, hair structure, and target area hair density (TAHD) can be measured every 2 weeks, alternatively every 4 weeks, alternatively every 8 weeks, alternatively every 12 weeks.

(88) An increase in hair thickness, target area hair count (TAHC), target area hair width (TAHW), scalp coverage, hair structure, or target area hair density (TAHD) in Group 1 individual as compared to Group 2 individuals is indicative of a positive response to the topical treatment with dutasteride to alopecia.

Example 16: Treatment of Women Suffering from Hirsutism with a Topical Composition of Dutasteride

(89) Two randomized, parallel-group studies can be conducted. Group I: 10 women suffering from hirsutism can receive 1 mL (1 mg) of a topical formulation of dutasteride, such as those described in Examples 1-13, applied to the face once a day (q.d.) or twice a day (b.i.d) for at least 4 weeks, alternatively at least 8 weeks, alternatively at least 12 weeks, alternatively at least 16 weeks.

(90) Group 2 may receive a placebo without the dutasteride applied to the face once a day (q.d.) or twice a day (b.i.d) for at least 4 weeks, alternatively at least 8 weeks, alternatively at least 12 weeks, alternatively at least 16 weeks.

(91) For each of the groups, hair thickness decrease, target area hair count (TAHC), hair growth assessment (HGA), target area hair width (TAHW), hair structure, and target area hair density (TAHD) can be measured every 2 weeks, alternatively every 4 weeks, alternatively every 8 weeks, alternatively every 12 weeks.

(92) A decrease in facial hair thickness, target area hair count (TAHC), facial hair width (TAHW), hair structure, and facial hair density (TAHD) of the women in Group 1 as compared to Group 2 is indicative of a positive response to the topical treatment with dutasteride to hirsuitism.

Example 17: Treatment of Men Suffering from Hypertrichosis with a Topical Composition of Dutasteride

(93) Two randomized, parallel-group studies can be conducted. Group I: 10 men suffering from hypertrichosis can receive 1 mL (1 mg) of a topical formulation of dutasteride, such as those described in Examples 1-13, applied to the face once a day (q.d.) or twice a day (b.i.d) for at least 4 weeks, alternatively at least 8 weeks, alternatively at least 12 weeks, alternatively at least 16 weeks.

(94) Group 2 may receive a placebo without the dutasteride applied to the face once a day (q.d.) or twice a day (b.i.d) for at least 4 weeks, alternatively at least 8 weeks, alternatively at least 12 weeks, alternatively at least 16 weeks.

(95) For each of the groups, hair thickness decrease, target area hair count (TAHC), hair growth assessment (HGA), target area hair width (TAHW), hair structure, and target area hair density (TAHD) can be measured every 2 weeks, alternatively every 4 weeks, alternatively every 8 weeks, alternatively every 12 weeks.

(96) A decrease in facial hair thickness, target area hair count (TAHC), facial hair width (TAHW), hair structure, and facial hair density (TAHD) of the women in Group 1 as compared to Group 2 is indicative of a positive response to the topical treatment with dutasteride to hirsuitism.

Example 18: Treatment of Women Suffering from Hair Loss Secondary to Endocrine Therapy in Patients with Breast Cancer

(97) Two randomized, parallel-group studies can be conducted. Group I: 20 women suffering from hair loss secondary to endocrine therapy in patients with breast cancer can receive 0.5 mg of dutasteride in a topical formulation, such as those described in Examples 1-13, applied to the affected area of the scalp once a day (q.d.) or twice a day (b.i.d) for at least 4 weeks, alternatively at least 8 weeks, alternatively at least 12 weeks, alternatively at least 16 weeks.

(98) Group 2 may receive a placebo without the dutasteride applied to the affected area of the scalp once a day (q.d.) or twice a day (b.i.d) for at least 1 week, alternatively up to 12 weeks.

(99) For each of the groups, hair thickness increase, target area hair count (TAHC), hair growth assessment (HGA), target area hair width (TAHW), scalp coverage, hair structure, and target area hair density (TAHD) can be measured.

(100) An increase in hair thickness, target area hair count (TAHC), target area hair width (TAHW), scalp coverage, hair structure, or target area hair density (TAHD) in Group 1 individual as compared to Group 2 individuals is indicative of a positive response to the topical treatment with dutasteride to alopecia.

Example 19: Treatment of Human Subjects Suffering from Alopecia with a Topical Composition of Dutasteride

(101) A patient suffering from alopecia may apply a dose of a topical formulation of dutasteride. The dutasteride topical formulation may be a solid formulation, such as a lotion, conditioner, serum, gel, foam, cream, paste, powder, oil, or gel. The dose may be 0.5 mg to 1.5 mg. The dutasteride topical formulation may be administered to the affected area once, hourly, b.i.d., t.i.d., q.i.d., or daily (q.d.) for 1 day, alternatively every 2 days, alternatively every 3 days, alternatively every 4 days, alternatively every 5 days, alternatively every 6 days, alternatively every week for at least 4 weeks, alternatively at least 8 weeks, alternatively at least 12 weeks, alternatively at least 16 weeks.

Example 20: Treatment of Women Suffering from Hirsutism with a Topical Composition of Dutasteride

(102) A patient suffering from hirsuitism may apply a dose of a topical formulation of dutasteride. The dutasteride topical formulation may be a solid formulation, such as a lotion, conditioner, serum, gel, foam, cream, paste, powder, oil, or gel. The dose may be 0.5 mg to 1.5 mg. The dutasteride topical formulation may be administered to the affected area once, hourly, b.i.d., t.i.d., q.i.d., or daily (q.d.) for 1 day, alternatively every 2 days, alternatively every 3 days, alternatively every 4 days, alternatively every 5 days, alternatively every 6 days, alternatively every week for at least 4 weeks, alternatively at least 8 weeks, alternatively at least 12 weeks, alternatively at least 16 weeks.

Example 21: Treatment of Men Suffering from Hypertrichosis with a Topical Composition of Dutasteride

(103) A patient suffering from hypertrichosis may apply a dose of a topical formulation of dutasteride. The dutasteride topical formulation may be a solid formulation, such as a lotion, conditioner, serum, gel, foam, cream, paste, powder, oil, or gel. The dose may be 0.5 mg to 1.5 mg. The dutasteride topical formulation may be administered to the affected area once, hourly, b.i.d., t.i.d., q.i.d., or daily (q.d.) for 1 day, alternatively every 2 days, alternatively every 3 days, alternatively every 4 days, alternatively every 5 days, alternatively every 6 days, alternatively every week for at least 4 weeks, alternatively at least 8 weeks, alternatively at least 12 weeks, alternatively at least 16 weeks.

Example 22: Treatment of Women Suffering from Hair Loss Secondary to Endocrine Therapy in Patients with Breast Cancer

(104) A patient suffering from breast cancer and hair loss secondary to endocrine therapy may apply a dose of a topical formulation of dutasteride. The dutasteride topical formulation may be a solid formulation, such as a lotion, conditioner, serum, gel, foam, cream, paste, powder, oil, or gel. The dose may be 0.5 mg to 1.5 mg. The dutasteride topical formulation may be administered to the affected area once, hourly, b.i.d., t.i.d., q.i.d., or daily (q.d.) for 1 day, alternatively every 2 days, alternatively every 3 days, alternatively every 4 days, alternatively every 5 days, alternatively every 6 days, alternatively every week for at least 4 weeks, alternatively at least 8 weeks, alternatively at least 12 weeks, alternatively at least 16 weeks.

(105) The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the methods. This includes the generic description of the methods with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

(106) Other embodiments are within the following claims. In addition, where features or aspects of the methods are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.