Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/69—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing fluorine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q7/00—Preparations for affecting hair growth
  • A61Q7/02—Preparations for inhibiting or slowing hair growth
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
  • A61K9/122—Foams; Dry foams

Definitions

• the invention relates to topical compositions for modulating hair growth and the treatment of various types of alopecia, for example, female and male androgenetic alopecia (AGA), alopecia areata, hair loss secondary to endocrine therapy in patients with breast cancer (Endocrine Therapy-Induced Alopecia or ETIA), and hirsutism.
• AGA female and male androgenetic alopecia
• ETIA Enddocrine Therapy-Induced Alopecia
• Hair loss or alopecia is a common and embarrassing problem for many people.
• One of the most frequent types of alopecia is androgenetic alopecia, which is a common form of hair loss in both men and women. In men, this condition is also known as male-pattern baldness.
• the pattern of hair loss in women differs from male-pattern baldness. In women, the hair becomes thinner all over the head, and the hairline does not always recede.
• DHT dihydrotestosterone
• SERMs Selective Estrogen Receptor Modulators
• AIs Aromatase Inhibitors
• Alopecia areata is a common autoimmune disorder, which results in unpredictable hair loss. Hair often falls out in small patches, e.g., around the size of a quarter. In more extreme cases, however, it can lead to complete hair loss on the scalp and even on the entire body.
• hirsutism which is an excessive facial and/or body hair growth, particularly in women, is another common and embarrassing problem. Hirsutism can occur if the levels of female and male sex hormones become unbalanced with too high a proportion of male sex hormones (androgens) in women.
• vasodilators such as potassium channel agonists including minoxidil and minoxidil derivatives such as diaminopyrimidine oxide; and an oral formulation of inhibitors for 5-a reductase enzyme that converts testosterone to DHT for the treatment of alopecia.
• Use of such oral formulations of such inhibitors such as oral finasteride has resulted in mixed success and with a risk of adverse side effects.
• Avodart® (dutasteride) has been shown to be safe and effective for oral use through both extensive nonclinical testing and data obtained from over 18 years of clinical use.
• Dutasteride reduces circulating levels of DHT by inhibiting both type 1 and type 2 5a-reductase isoenzymes that are responsible for the conversion of testosterone to DHT, which is known to be the most potent natural androgen in the human body.
• DHT is believed to potently regulate the transcription of androgen-sensitive genes within the follicle, thereby affecting hair growth. See Jain, R. and De-Ekanumkul.“Potential targets in the discovery of new hair growth promoters for androgenic alopecia.” Expert Opin Ther Targets (2014) 18(7): 787-086.
• anti-5a-reductase agents such as oral Avodart® (dutasteride) soft gelatin capsules, 0.5mg
• AGA Herskovitz, I. and Tosti, A.“Female Pattern Hair Loss.” Int J Endocrinol Metab (2013) 11(4): e9860 (published online October 21, 2013)
• those patients using 5a-reductase enzyme inhibitors have a significant improvement in hair loss (see Olsen, E. et al. “The importance of dual 5a-reductase inhibition in the treatment of male pattern hair loss:
• oral finasteride is the older drug. Oral finasteride was developed in the l970s and received FDA approval as a treatment for BPH in 1992. Oral finasteride was eventually approved for use as an AGA treatment in 1997 at a lower dose (lmg) than the higher-dosed BPH treatment version of oral finasteride (5mg). Dutasteride, on the other hand, was only patented in 1996 and became approved by the FDA as an oral treatment for BPH in 2001 at a dose of 0.5mg.
• oral dutasteride is, milligram for milligram, more effective at lowering DHT than oral finasteride. It also shows that oral dutasteride is more consistent at blocking DHT than oral finasteride. The level of variability for the oral dutasteride group was +/- 1.2%, showing an almost total elimination of DHT, with far less variation between patients than the +/- 18.3% of the oral finasteride group. Study data also shows that oral dutasteride is more effective at promoting hair growth in people with male AGA than finasteride.
• the present disclosure provides topical compositions of 5-a 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
• ETIA Enddocrine Therapy-Induced Alopecia
• AGA androgenetic alopecia
• alopecia areata
• hirsutism alopecia areata
• compositions and formulations described in the working examples are included within the scope of the invention.
• the present disclosure provides a topical composition
• a topical composition comprising a therapeutically effective amount of 5-a reductase inhibitors, such as dutasteride or finasteride or pharmaceutically acceptable salts, esters, or derivatives thereof, and appropriate topical pharmaceutically acceptable excipients or carriers.
• 5-a reductase inhibitors such as dutasteride or finasteride or pharmaceutically acceptable salts, esters, or derivatives thereof, and appropriate topical pharmaceutically acceptable excipients or carriers.
• the present disclosure provides methods for preparing 5-a reductase inhibitor (e.g., dutasteride) formulations as set forth in the examples.
• 5-a reductase inhibitor e.g., dutasteride
• the present disclosure provides a method for stimulating the hair growth on the scalp of a human subject suspected of affected by endocrine-therapy induced alopecia from breast cancer treatment.
• the method includes a) providing a topical composition comprising a therapeutically effective amount of 5-a reductase inhibitors, such as dutasteride or finasteride or pharmaceutically acceptable salts, esters, or derivatives thereof, and appropriate topical pharmaceutically acceptable excipients or carriers; and b) topically applying the composition to the subject’s skin or scalp on and/or adjacent to the area in which hair growth is desired.
• An increase in scalp hair density, hair thickness, or scalp coverage in the human subject receiving the topical composition as compared to an untreated individual is indicative of stimulation of hair growth on the scalp of the human subject.
• the present disclosure provides a method for stimulating the hair growth on the scalp of a human subject suspected of being affected by androgenetic alopecia.
• the method includes a) providing a topical composition comprising a therapeutically effective amount of 5-a reductase inhibitors, such as dutasteride or finasteride or pharmaceutically acceptable salts, esters, or derivatives thereof, and appropriate topical pharmaceutically acceptable excipients or carriers; and b) topically applying the composition to the subject’s skin or scalp on and/or adjacent to the area in which hair growth is desired.
• 5-a reductase inhibitors such as dutasteride or finasteride or pharmaceutically acceptable salts, esters, or derivatives thereof, and appropriate topical pharmaceutically acceptable excipients or carriers.
• the present disclosure provides a method for reducing the facial hair growth of a human subject suspected of being affected by hirsutism.
• the method includes a) providing a topical composition comprising a therapeutically effective amount of 5-a reductase inhibitors, such as dutasteride or finasteride or pharmaceutically acceptable salts, esters, or derivatives thereof, and appropriate topical pharmaceutically acceptable excipients or carriers; and b) topically applying the composition to the subject’s facial or body skin on and/or adjacent to the area in which reduced hair growth is desired.
• a decrease in facial hair density, hair thickness, or coverage in the human subject receiving the topical composition as compared to an untreated individual is indicative of a reduction of facial hair growth of the human subject.
• the present disclosure provides a topical formulation comprising a therapeutically effective amount of dutasteride or a pharmaceutically acceptable salt, ester, or derivative thereof dissolved in an oil phase; and a topical pharmaceutically acceptable excipient or carrier.
• the topical formulation may be an emulsion.
• the oil phase may include at least one oil, alternatively at least two oils.
• the formulation may further include a humectant, a thickener, an emulsifier, and a preservative.
• the present disclosure provides a topical formulation comprising a therapeutically effective amount of dutasteride or a pharmaceutically acceptable salt, ester, or derivative thereof dissolved in an oil phase; and a topical pharmaceutically acceptable excipient or carrier.
• the formulation may not contain ethyl alcohol and/or polypropylene glycol.
• the present disclosure provides a topical formulation comprising a therapeutically effective amount of dutasteride or a pharmaceutically acceptable salt, ester, or derivative thereof dissolved in an aqueous phase; and a topical pharmaceutically acceptable excipient or carrier.
• the topical formulation may be an emulsion.
• the aqueous phase may optionally include a solubilizer.
• the aqueous phase may optionally include a penetration enhancer.
• the formulation may further include a thickener, an emollient, a pH adjuster, a preservative, and/or a conditioning agent.
• the present disclosure provides methods for preparing a topical formulation, comprising the steps of mixing a conditioning agent with water to form a conditioning solution; mixing a first emulsifier, a first preservative, and a solvent to obtain an emulsifier solution; mixing dutasteride, at least one oil, and at least one solvent to obtain a dutasteride solution; mixing the dutasteride solution with the emulsifier solution to obtain a combined solution; mixing the combined solution with the conditioning solution to form a dutasteride conditioning mixture; and mixing a second emulsifier and a second preservative into the dutasteride conditioning mixture.
• the present disclosure provides methods for preparing a topical formulation, comprising the steps of mixing a humectant with water to form a humectant solution; mixing a thickener and a first solvent to form a thickener solution; mixing the thickener solution with the humectant solution to form a combined solution; mixing a preservative into the combined solution to form a combined preservative solution; mixing dutasteride and a second solvent to form a dutasteride solution; mixing at least one oil into the dutasteride solution to form a dutasteride oil mixture; mixing at least one emulsifier to the dutasteride oil mixture to form a second dutasteride oil mixture; and mixing the second dutasteride oil mixture with the combined preservative solution in a vessel.
• the therapeutically effective amount of dutasteride is about 0.001% to about 1% (w/w). In some embodiments, the therapeutically effective amount of 5-a reductase inhibitors, such as dutasteride or finasteride, is about 0.001% to about 0.5% (w/w). In some embodiments, the therapeutically effective amount of 5-a reductase inhibitors, such as dutasteride or finasteride, is about 0.002% to about 0.1% (w/w).
• the therapeutically effective amount of dutasteride is about 0.001%, 0.005%, 0.010%, 0.025%, 0.050%, 0.075%, 0.100%, 0.150%, 0.200%, 0.250%, 0.300%, 0.350%,
• the amount of 5-a reductase inhibitors, such as dutasteride or finasteride, administered in a single topical application is about: O.Olmg, 0.05mg, O.lmg, 0.25mg, 0.5mg, 0.75mg, lmg, l.25mg, l.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, or 5mg.
• the amount of 5- a reductase inhibitors, such as dutasteride or finasteride, administered in a single topical application is about 0.1 to about 3.0 mg, alternatively about 0.3 mg to about 2.5 mg, alternatively about 0.5 mg to about 2.5 mg, alternatively about 0.5 mg to about 2.0 mg, alternatively about 0.5 mg to about 1.5 mg, alternatively about 0.5 mg to about 1.0 mg.
• the dutasteride of the composition is in the form of nanoparticles.
• the nanoparticles are coated with 5-a reductase inhibitors, such as dutasteride or finasteride.
• the 5-a reductase inhibitors, such as dutasteride or finasteride is slowly released to the skin or scalp when the topical composition is applied to the skin or scalp of the human subject.
• the diameter of the nanoparticles is about 25nm to about 500nm. In some embodiments, the diameter of the nanoparticles is about lOOnm to about 500nm. In some embodiments, the diameter of the nanoparticles is about 500nm.
• the topical composition comprises a surfactant, a co- surfactant, a penetration enhancer, an antioxidant, a buffering agent, a preservative, a viscosity modifying agent, a chelating or complexing agent, a coloring agent, a perfume, a polymer, a gelling agent, an alcohol, a liquid or semi-solid oily component, or any combination thereof.
• the topical composition comprises at least two of API (5-a reductase inhibitors, such as dutasteride or finasteride), cationic emulsifier, conditioning agent, emollient, emulsifier, humectant solvent, nonionic emulsifier, penetration enhancer, pH adjuster, preservative, solvent, thickener, viscosity enhancer, or any combination thereof.
• API a reductase inhibitors, such as dutasteride or finasteride
• cationic emulsifier such as dutasteride or finasteride
• conditioning agent such as dutasteride or finasteride
• emollient such as dutasteride or finasteride
• emulsifier such as dutasteride or finasteride
• conditioning agent such as dutasteride or finasteride
• emollient such as dutasteride or finasteride
• emulsifier such as dutasteride
• the topical composition is a cream and comprises a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, and a penetration enhancer.
• the topical composition is a lotion and comprises a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, and a penetration enhancer.
• the topical composition is a lotion and comprises a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, a pH adjuster, and a penetration enhancer.
• the topical composition is a lotion conditioner and comprises a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, and a conditioning agent.
• the topical composition is a lotion serum and comprises a solvent, a humectant, a thickener, a preservative, an emollient, an emulsifier, a pH adjuster, a penetration enhancer, and a conditioning agent.
• the topical composition is a gel and comprises a solvent, a thickener, an emollient, and a penetration enhancer.
• the topical composition is a gel and comprises a solvent, a thickener, and a penetration enhancer.
• the topical composition is a gel and/or serum and comprises a solvent, a viscosity enhancer, an emollient, and a penetration enhancer.
• the topical pharmaceutically acceptable carrier is hydrophilic, hydrophobic, lipophilic, or amphiphilic, or a mixture thereof.
• the pharmaceutically acceptable carrier comprises a hydrophobic or lipophilic substance comprising a paraffin oil, an ester of a Cx-Cix organic acid, a C8-C30 fatty alcohol, a silicone oil, a vegetable oil, a fractionated or hydrogenated vegetable oil, a monoglyceride, a diglyceride, a triglyceride, a phospholipid, dimethylisosorbide, a volatile solvent, N- methylpyrrolidone, dimethylacetamide, dimethylformamide; dimethylsulphoxide, or any combination thereof.
• the topical pharmaceutically acceptable excipients or carriers comprise ethanol, polypropylene glycol, purified water, or a combination thereof.
• the topical composition is in the form of foam, cream, paste, gel, aerosol, powder, oil, serum, or liquid.
• the topical composition further comprises a therapeutically effective amount of finasteride, minoxidil, or a combination thereof.
• the amount of finasteride can be about O.Olmg to about 5mg. In some embodiments, the amount of finasteride can be about: O.Olmg, 0.05mg, O.
• the topical composition comprises a propellant.
• propellant include dichloromethane, dimethyl ether, butanes, propane, nitrogen, fluorocarbons, and carbon dioxide.
• the topical composition is applied to the skin or scalp of a human subject for a single day. In some embodiments, the topical composition is applied to the skin or scalp of a human subject for multiple days. In some embodiments, the topical composition is applied each day for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 21 or more days. In some embodiments, the topical composition is applied each day for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more weeks. In some embodiments, the topical 5-a reductase inhibitor formulation is applied QD, bid, tid, qid, or more frequently. In some embodiments, the topical composition is applied multiple times each day for multiple days or multiple weeks, or multiple months. In some embodiments, the skin is abdominal skin. In some embodiments, the skin is skin on the limbs, forehead, throat, or back.
• stimulating the hair growth comprises an increase in hair count.
• stimulating the hair growth comprises hair thickness increase.
• the hair thickness increase comprises an increase in frontal, central, vertex regions, or their combination of the scalp of the human subject.
• stimulating the hair growth comprises improved scalp coverage and improved hair structure.
• the human subject can be a male or a female.
• the human subject suspected of being affected by androgenetic alopecia is a male.
• the male suspected of being affected by androgenetic alopecia has male baldness pattern.
• the term“about” in quantitative terms refers to plus or minus 10%. For example,“about 3%” would encompass 2.7-3.3% and“about 10%” would encompass 9-11%. Moreover, where“about” is used herein in conjunction with a quantitative term it is understood that in addition to the value plus or minus 10%, the exact value of the quantitative term is also contemplated and described. For example, the term “about 3%” expressly contemplates, describes and includes exactly 3%.
• FIG. 1 shows the chemical structure of dutasteride.
• FIG. 2 shows the results of the binary dutasteride/excipient compatibility study.
• the present disclosure is directed to topical compositions of 5-a 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.
• ETIA Enddocrine Therapy-Induced Alopecia
• AGA androgenetic alopecia
• AA Alopecia Areata
• hirsutism hirsutism
• the topical composition of 5-a reductase inhibitors is advantageous over any oral formulation of 5-a reductase inhibitors because it may allow for a slow release of the active ingredient, better penetration at the therapeutically effective amount of the 5-a 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.
• Dutasteride is chemically designated as (5a,17b)-N- ⁇ 2,5 bis(trifluoromethyl)phenyl ⁇ -3- oxo-4- azaandrost-l-ene-l7-carboxamide.
• the empirical formula of dutasteride is C27H30F6N2O2, 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 5a-reductase
• dutasteride may be more effective than another known type 1 5a-reductase inhibitor finasteride because dutasteride inhibits both type 1 and type 2 5a-reductase isoenzymes.
• dutasteride may be more potent than finasteride in inhibiting 5a-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 ETnited States.
• the present invention provides topical formulations of 5-a 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
• ETIA Enddocrine Therapy-Induced Alopecia
• AGA androgenetic alopecia
• 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-a 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.
• modulating hair growth refers to an increase or decrease of hair count, hair thickness, or hair structure in scalp or face.
• 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 means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
• the amount of a dutasteride when expressed as“%” refers to % (w/w) unless otherwise indicated.
• 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.
• 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.
• Suitable penetration enhancers that can be used in the present invention include, but are not limited to: sulfoxides such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (Cio MSO); ethers such as diethylene glycol monoethyl ether (available commercially as Transcutol® P) and di ethylene glycol monomethyl ether; 1 -substituted azacycloheptan-2-ones, such as l-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 monol
• 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.
• 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.
• 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,
• 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).
• 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-l, Klucel HG Pharm, Carbopol 980 NF, Polymer, and Sepineo P 600.
• Suitable preservatives that can be used in the present invention include, but are not limited to: methylparaben and propylparaben.
• 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.
• Suitable emulsifiers that can be used in the present invention include, but are not limited to: Brij L4, Arlacel 165, Tween 20, Brij S721, Brij S2, Promulgen D, Stearalkonium Chloride, Pemulen TR-2, Pemulen TR-l, 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.
• Suitable pH adjusters that can be used in the present invention include, but are not limited to: NaOH and HC1 solutions.
• Suitable conditioning agents that can be used in the present invention include, but are not limited to: stearalkonium chloride and Polyquaternium-lO.
• Suitable solubilizers that can be used in the present invention include, but are not limited to: Laureth-4.
• Suitable viscosity enhancers that can be used in the present invention include, but are not limited to : PEG 3350.
• Example 1 Topical formulation comprising dutasteride
• a topical formulation of 0.10% w/v may be prepared as follows.
• Example 2 Topical cream formulations comprising dutasteride (dutasteride dissolved in oil phase)
• a topical formulation of 0.05% w/w may be prepared as follows:
• Phase A 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.
• Phase E + F was added to the main vessel for homogenization. The batch was then cooled down to less than 30 °C.
• HLB Hydrophilic-lipophilic balance
• a topical formulation of 0.05% w/w may be prepared as follows. (2019-045-31R)
• Phase A 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.
• HLB Hydrophilic-lipophilic balance
• Example 3 Topical cream formulation comprising dutasteride (dutasteride dissolved in water phase]
• a topical formulation of 0.05% w/w may be prepared as follows.
• Phase A 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.
• the HLB was calculated.
• Example 4 Topical lotions [“conditioners”) comprising dutasteride (dutasteride dissolved in oil phase)
• a topical formulation of 0.05% w/w for a leave-in conditioner may be prepared as follows.
• Phase A The components of Phase A were combined in the main vessel while heating to 70 - 75
• Phase B was combined in a separate vessel and mixed until a solution was obtained.
• 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.
• a topical formulation of 0.05% w/w for a leave-in conditioner may be prepared as follows. (2019-045-34R)
• Phase A 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)
• a topical formulation of 0.05% w/w for application may be prepared as follows.
• Phase A 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]
• a topical formulation of 0.05% w/w for application may be prepared as follows.
• Phase A 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)
• a topical formulation of 0.05% w/w for application may be prepared as follows.
• Phase A 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.
• Example 8 Topical lotion [conditioner) formulation comprising dutasteride
• a topical formulation of 0.05% w/w for application may be prepared as follows.
• Phase A 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
• 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
• a topical formulation of 0.05% w/w for application may be prepared as follows.
• Phase A 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.
• a topical lotion (serum) formulation of 0.05% w/w for application may be prepared as follows. (2019-045 -25R)
• Phase A 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
• 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.
• Phase A The components of Phase A were combined in the main vessel and were mixed until a solution was obtained.
• 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
• a topical formulation of 0.05% w/w for application may be prepared as follows.
• Phase A 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.
• a topical formulation of 0.05% w/w for application may be prepared as follows.
• Phase A 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
• a topical formulation of 0.05% w/w for application may be prepared as follows. (2019-045-55)
• Phase A 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
• Example 13 Topical gel (serum) formulation comprising dutasteride
• a topical formulation of 0.05% w/w for application may be prepared as follows.
• Phase A 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
• Example 14 Analysis of Binary Dutasteride/Excipient Compatibility Study
• 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 pm PTFE filter into an autosampler vial for HPLC analysis. For the standard, a 6-point calibration curve in the range of 10 pg/mL to 200 pg/mL of dutasteride in diluent was prepared.
• Example 15 Treatment of human subjects suffering from alopecia with a topical composition of dutasteride
• 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.
• Group I 10 human subjects may receive 1 mL (lmg) 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.
• 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.
• hair thickness increase can be measured every 2 weeks, alternatively every 4 weeks, alternatively every 8 weeks, alternatively every 12 weeks.
• TAHC target area hair count
• THW target area hair width
• TAHD target area hair density
• Example 16 Treatment of women suffering from hirsutism with a topical composition of dutasteride
• Group I 10 women suffering from hirsutism can receive 1 mL (lmg) 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.
• a topical formulation of dutasteride such as those described in Examples 1-13
• 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.
• hair thickness decrease can be measured every 2 weeks, alternatively every 4 weeks, alternatively every 8 weeks, alternatively every 12 weeks.
• 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
• Group I 10 men suffering from hypertrichosis can receive 1 mL (lmg) 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.
• 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.
• hair thickness decrease can be measured every 2 weeks, alternatively every 4 weeks, alternatively every 8 weeks, alternatively every 12 weeks.
• 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
• 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.
• a topical formulation such as those described in Examples 1-13
• 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.
• hair thickness increase 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.
• TAHC target area hair count
• HGA hair growth assessment
• THW target area hair width
• THD target area hair density
• 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
• 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
• 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
• 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
• 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.

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