AU2019201399B2

AU2019201399B2 - Treatment of autoimmune disease

Info

Publication number: AU2019201399B2
Application number: AU2019201399A
Authority: AU
Inventors: Yuk-Shui Andrew LAU; Rodney Sinclair
Original assignee: Samson Clinical Pty Ltd
Current assignee: Samson Clinical Pty Ltd
Priority date: 2019-02-27
Filing date: 2019-02-27
Publication date: 2021-11-04
Anticipated expiration: 2039-02-27
Also published as: AU2022200479A1; AU2019201399A1

Abstract

The present invention relates to methods and compositions for treatment of autoimmune disease in a subject. The present invention relates to methods and compositions for treatment of excessive hair shedding or hair loss in a subject or for promoting hair growth in a subject.

Description

TREATMENT OF AUTOIMMUNE DISEASE

Technical Field

[0001] The present invention relates to methods and compositions for treatment of autoimmune disease in a subject. The present invention relates to methods and compositions for treatment of excessive hair shedding or hair loss in a subject or for promoting hair growth in a subject.

Background

[0002] Hair follicles on the scalp do not continuously produce hair. They cycle through a growth stage that can last two or more years, then regress to a resting stage for up to three months before starting to grow a new hair fiber again. At any time on a healthy human scalp, about 80% to 90% of the hair follicles are growing hair. These active follicles are in what is called the anagen phase. That leaves up to 10% to 20% percent of scalp hair follicles in a resting state called telogen, when they don't produce any hair fiber. Changes in actual amount of hair fall occur in number of hair loss conditions including for example anagen effluvium, chemotherapy induced hair loss, acute and chronic telogen effluvium, alopecia areata, cicatricial alopecia, male pattern hair loss (MPHL) and female pattern hair loss (FPHL).

[0003] Men commonly complain of increased hair loss or hair shedding, especially after washing their hair. Changes in actual amount of hair fall occur in number of hair loss conditions including anagen effluvium, chemotherapy induced hair loss, acute and chronic telogen effluvium, alopecia areata, cicatricial alopecia and male pattern hair loss (MPHL).

[0004] Female pattern hair loss (FPHL) is the most common cause of hair loss encountered in clinical practice for women (Messenger et al. 2010). FPHL is a complex polygenic disorder characterised clinically by diffuse hair thinning over the mid frontal scalp and histologically by hair follicle miniaturization. The proportion of miniaturized follicles increases with the severity of hair loss (Messenger et al. 2006).

FPHL adversely impacts quality of life and the prevalence of FPHL increases with age. In a population study of over 700 women, FPHL was found in 12% of women aged 20 29 and 57% of women aged > 80. Hair loss severity also increases with age.

[0005] There are creams and lotions available for the treatment of hair loss and hair shedding disorders which can often leave hair look oily which is undesirable.

[0006] There is a requirement for new treatments for conditions of hair loss and excessive hair shedding, autoimmune disease and for the promotion of hair growth (including increasing hair length and beard growth).

Summary

[0007] The present invention relates to methods and compositions for the treatment of autoimmune disease in a subject by administration of a dose of JAK inhibitor absorbed through the oral mucosa, preferably, through the sublingual mucosa.

[0008] The present invention relates to methods and compositions for the treatment of hair loss or excessive hair shedding in a subject or for promoting hair growth in a subject by administration of a dose of JAK inhibitor absorbed through the oral mucosa, preferably, through the sublingual mucosa. Such compositions are easy to administer and likely to achieve increased patient compliance compared to traditional treatments i.e. such as tablets which are absorbed in the lower gastrointestinal tract and thus must be swallowed by patients and topical lotions which can leave hair looking oily or negatively impact on the look and feel of the hair.

[0009] In an aspect, the present invention provides a method of treating hair loss or excessive hair shedding in a subject or for promoting hair growth in a subject by administering to a subject an effective dose of ajanus kinase inhibitor (JAK) inhibitor that is predominantly absorbed through the oral mucosa.

[0010] In an embodiment, the present invention provides a method of treating autoimmune disease in a subject by administering to a subject an effective dose of a janus kinase inhibitor (JAK) inhibitor that is predominantly absorbed through the oral mucosa.

[0011] In an embodiment, the present invention provides a method of treating hair loss in a subject by administering to a subject an effective dose of a janus kinase inhibitor (JAK) inhibitor that is predominantly absorbed through the oral mucosa.

[0012] In an aspect, the present invention provides a method of treating excessive hair shedding in a subject by administering to a subject an effective dose of a janus kinase inhibitor (JAK) inhibitor that is predominantly absorbed through the oral mucosa.

[0013] In an aspect, the present invention provides a method of promoting hair growth in a subject by administering to a subject an effective dose of ajanus kinase inhibitor (JAK) inhibitor that is predominantly absorbed through the oral mucosa.

[0014] In an embodiment, the oral mucosa is the sublingual mucosa.

[0015] In an embodiment, the JAK inhibitor is tofacitinib. In an embodiment, tofacitinib is tofacitinb citrate.

[0016] In an embodiment, the dose comprises asublingual adhesion agent.

[0017] In an embodiment, tofacitinib is in the range of from about 0.1 mg to 20 mg, or from about 0.1 mg to 18 mg, or from about 1.5 mg to 15 mg, or from about 0.2 mg to 12.5 mg, or from about 0.2 mg to 10 mg, or from about 0.5 mg to 8 mg, or from about 1 mg to 6 mg, or from about 1 mg to 5 mg, or from about 1 mg to 4 mg, or from about 1 mg to 3 mg, or from about 1 mg to 2 mg, or is about 5 mg, or is about 4 mg, or is about 3 mg, or is about 2 mg, or is about 0.5 mg daily.

[0018] In an embodiment, the dose is administered at least every 3 days, at least every 2 days, or daily. In an embodiment, the dose is administered daily.

[0019] In an embodiment, the dose is in a form selected from a: strip, wafer, pellet, film, troche, tablet, lipid matrix tablet, capsule, pill, granule, pellet, powder, drop, spray and lozenge. In an embodiment, the dose is a strip. In an embodiment, the dose is a wafer. In an embodiment, the dose is a film.

[0020] In an embodiment, the method further comprises administering one or more of a: (i) further JAK inhibitor, (ii) vasodilator, (iii) aldosterone antagonist, (iv) 5a reductase inhibitor, (v) non-steroidal antiandrogen drug, (vi) steroidal antiandrogen, (vii) prostaglandin D2 receptor antagonist, (viii) immunosuppressant, and (ix) glucocorticoid.

[0021] In an embodiment, the method further comprises administering one or more of: (i) a further JAK inhibitor in the range of from about 0.1 mg to 20 mg; (ii) minoxidil in the range of from about 0.1 mg to 20 mg; (iii) spironolactone in the range of from about 10 mg to 500 mg; (iv) finasteride in the range of from about 0.1 mg to 1 mg; (v) dutasteride in the range of from about 0.01 mg to 1 mg; (vi)flutamide in the range of from about 10 mg to 500 mg; (vii) cyproterone acetate in the range of from about 1 mg to 100 mg; (viii) bicalutamide in the range of from about 1 mg to 100 mg; (xi) enzalutamide in the range of from about 1 mg to 100 mg; (x) nilutamide in the range of from about 1 mg to 100 mg; (xi) drosperidone in the range of from about 0.1 mg to 10 mg; (xii) apalutamide in the range of from about 1 mg to 100 mg; (xiii) buseralin in the range of from about 0.1 mg to 10 mg; (xiv) setipiprant in the range of from about 50 mg to 4000 mg; (xv) fevipiprant in the range of from about 50 mg to 1000 mg; (xvi) cyclosporin in the range of from about 10 mg to 600 mg; (xvii) methotrexate in the range of from about 2.5 mg to 40 mg; (xviii) azathioprine in the range of from about 25 mg to 200 mg; (xix) prednisolone in the range of from about 0.1 mg to 40 mg; and (xx) dexamethasone in the range of from about 0.1 mg to 5 mg. In an embodiment, the further JAK inhibitor is selected from baracitinib and ruxolitinib. In an embodiment, baricitinib is in the range of from about 0.1 mg to 4 mg. In an embodiment, ruxolitinib is in the range of from about 0.1 mg to 40 mg.

[0022] In an embodiment, the hair loss or excessive hair shedding is the result of one or more of the following; alopecia areata, alopecia totalis, alopecia universalis, androgenetic alopecia, hair follicle miniaturization, telogen effluvium, anagen effluvium, chemotherapy induced hair loss, male pattern baldness, female pattern baldness, monilethrix, thyroid problems, anaemia, polycystic ovary syndrome, cicatricial alopecia (lichen planopilaris, discoid lupus erythematosus, folliculitis decalvans), congenital hypotrichosis, loose anagen hair syndrome, hypotrichosis and malnutrition. In an embodiment, the hair loss or excessive hair shedding is the result of alopecia areata.

[0023] In an embodiment, promoting hair growth comprises promoting beard growth in a subject. In an embodiment, promoting hair growth comprises increasing hair length in a subject.

[0024] In an aspect, the present invention provides an oral composition predominantly absorbed through the oral mucosa for treating hair loss or excessive hair shedding in a subject or for promoting hair growth in a subject comprising a JAK inhibitor.

[0025] In an embodiment, the JAK inhibitor is in the range of from about 0.1 to about mg.

[0026] In an embodiment, tofacitinib is in the range of from about 0.1 to about 20 mg.

[0027] In an embodiment, the oral composition is a sublingual composition predominantly absorbed through the sublingual mucosa.

[0028] In an embodiment, the JAK inhibitor is tofacitinib. In an embodiment, tofacitinib is in the range of from about 0.1 mg to 20 mg, or from about 0.1 mg to 18 mg, or from about 0.1 mg to 15 mg, or from about 0.2 mg to 12.5 mg, or from about 0.2 mg to 10 mg, or from about 0.5 mg to 8 mg, or from about 1 mg to 6 mg, or from about 1 mg to 5 mg, or from about 1 mg to 4 mg, or from about 1 mg to 3 mg, or from about

1 mg to 2 mg, or is about 5 mg, or is about 4 mg, or is about 3 mg, or is about 2 mg, or is about 1 mg, or is about 0.5 mg daily.

[0029] In an embodiment, the composition additionally comprises one or more of: (i) a further JAK inhibitor in the range of from about 0.1 mg to 20 mg; (ii) minoxidil in the range of from about 0.1 mg to 20 mg; (iii) spironolactone in the range of from about 10 mg to 500 mg; (iv) finasteride in the range of from about 0.1 mg to 1 mg; (v) dutasteride in the range of from about 0.01 mg to 1 mg; (vi) flutamide in the range of from about 10 mg to 500 mg; (vii) cyproterone acetate in the range of from about 1 mg to 100 mg; (viii) bicalutamide in the range of from about 1 mg to 100 mg; (ix) enzalutamide in the range of from about 1 mg to 100 mg; (x) nilutamide in the range of from about 1 mg to 100 mg; (xi) drosperidone in the range of from about 0.1 mg to 10 mg; (xii) apalutamide in the range of from about 1 mg to 100 mg; (xiii) buseralin in the range of from about 0.1 mg to 10 mg; (xiv) setipiprant in the range of from about 50 mg to 4000 mg; (xv) fevipiprant in the range of from about 50 mg to 1000 mg; (xvi) cyclosporin in the range of from about 10 mg to 600 mg; (xvii) methotrexate in the range of from about 2.5 mg to 40 mg; (xviii) azathioprine in the range of from about 25 mg to 200 mg; (xix) prednisolone in the range of from about 0.1 mg to 40 mg; and (xx) dexamethasone in the range of from about 0.1 mg to 5 mg.

[0030] In an embodiment, the further JAK inhibitor is selected from baracitinib and ruxolitinib. In an embodiment, baricitinib is in the range of from about 0.1 mg to 4 mg. In an embodiment, ruxolitinib is in the range of from about 0.1 mg to 40 mg.

[0031] In an embodiment, the composition comprises a sublingual adhesion agent. In an embodiment, the composition comprises a disintegration agent which aids disintegration of the composition in the presence of saliva. In an embodiment, the composition comprises a taste modifying agent.

[0032] In an embodiment, the composition is in a form selected from a: strip, wafer, pellet, film, troche, tablet, lipid matrix tablet, capsule, pill, granule, pellet, powder, drop, spray and lozenge. In an embodiment, the composition is in a form selected from a: strip, wafer, and film.

[0033] In an aspect, the present invention provides use of a JAK inhibitor in the preparation of a medicament for the treatment of autoimmune disease, hair loss or excessive hair shedding in a subject or for promoting hair growth in a subject by administering to a subject an effective dose of a JAK inhibitor through the sublingual mucosa.

[0034] In an aspect, the present invention provides use of tofacitinib in the preparation of a medicament for the treatment of autoimmune disease, hair loss or excessive hair shedding in a subject or for promoting hair growth in a subject by administering to a subject an effective dose of tofacitinib through the oral mucosa.

[0035] In an aspect, the present invention provides use of tofacitinib in the preparation of a medicament for the treatment of autoimmune disease, hair loss or excessive hair shedding in a subject or for promoting hair growth in a subject by administering to a subject an effective dose of tofacitinib through the sublingual mucosa.

[0036] In an aspect, the present invention provides an oral composition predominantly absorbed through the oral mucosa for treating autoimmune disease in a subject comprising a JAK inhibitor.

[0037] In an aspect, the present invention provides use of a JAK inhibitor in the preparation of a medicament for the treatment of autoimmune disease in a subject or for promoting hair growth in a subject by administering to a subject an effective dose of a JAK inhibitor through the sublingual mucosa.

[0038] In an aspect, the present invention provides use of tofacitinib in the preparation of a medicament for the treatment of autoimmune disease in a subject or for promoting hair growth in a subject by administering to a subject an effective dose of tofacitinib through the oral mucosa.

[0039] In an aspect, the present invention provides use of tofacitinib in the preparation of a medicament for the treatment of autoimmune disease in a subject by administering to a subject an effective dose of tofacitinib through the sublingual mucosa.

[0040] In an embodiment, the autoimmune disease is selected from rheumatoid arthritis, psoriasis, psoriatic arthritis, vitiligo, sarcoid, atopic dermatitis, ulcerative colitis, lupus erythematosus, lichen planus, Hashimoto's disease, Graves' disease, Crohn's disease, alopecia and alopecia areata.

[0041] Any embodiment herein shall betaken to apply mutatis mutandis to any other embodiment unless specifically stated otherwise. For instance, as the skilled person would understand examples of JAK inhibitors outlined for compositions of the invention equally apply to the methods of the invention.

[0042] The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the invention, as described herein.

[0043] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.

[0044] The invention is hereinafter described by way of the following non-limiting Examples and with reference to the accompanying figures.

Brief Description of Drawings

[0045] Figure 1: Examples of photos and correlating scores at each time point.

[0046] Figure 2: Box and Whisker plot of all scores of all patients. The black continuous line highlights the median scores at each time point. The mean score at 3 months was 0.8, at 6 months was 1.1, at 9 months was 1.1, at 12 months was 1.6, at 15 months was 1.9, and at 18 months was 2.4. The boxes represent the inter-quartile range (IQR). The whiskers denote the upper and lower absolute scores.

Description of Embodiments

[0047] As described herein a "janus kinase inhibitor", "JAK inhibitor" or "JAK kinase inhibitor" is an inhibitor of a member of the janus kinase (JAK) family of kinases. In an embodiment, the JAK inhibitor is a JAKi, JAK2 and/or JAK3 inhibitor. In an embodiment, the JAK inhibitor is an inhibitor of a kinase in the enzyme class EC 2.7.10.2. In an embodiment, the JAK inhibitor is a JAK3 inhibitor. In an embodiment, the JAK inhibitor is a JAK2 inhibitor. In an embodiment, the JAK inhibitor is a JAKi inhibitor. In an embodiment, the JAK inhibitor is an inhibitor of tyrosine kinase 2 (TyK2). In an embodiment, the JAK inhibitor is a small molecule inhibitor. In an embodiment, the JAK inhibitor is a binding protein. In an embodiment, the binding protein is an antibody. In an embodiment, the JAK inhibitor is an aptamer. In an embodiment, the JAK inhibitor is a polynucleotide. In an embodiment, the JAK inhibitor is selected from: tofacitinib, baractinib, ruxolitinib, decemotinib, R348, WHI P131, WHI-P 154, JAK3 Inhibitor IV, NSC114792, tyrphostin AG 490, momelotinib, pacritinib, fedratinib, and BMS-911543.

[0048] It will be understood by the skilled person that all forms of JAK inhibitors are encompassed, including any tautomeric forms.

[0049] Whilst some embodiments may involve use of the parent compound, in other embodiments a salt form is utilised, e.g. a pharmaceutically acceptable salt. Examples of salts include those formed with sulphuric acid (sulfate salt) and citric acid (citrate salt). In a preferred embodiment a citrate sal is used, typically themonocitrate salt.

[0050] Whilst in some embodiments, the parent compound is utilised, in other embodiments a derivative of the parent compound may be used, for example a physiological functional derivative. Examples of derivativesinclude sulphonamides, amides, and carbamates. A prodrug form of JAK inhibitor may be utilized. A prodrug is a compound which, upon administration to the recipient, is capable of being converted into the tofacitinib parent compound described above.

[00511 Those skilled in the art of organic chemistry will appreciatethat many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate"

[0052] It will be understood by the skilled person that many organic compounds can exist in amorphous and crystalline forms, Different crystalline forms of a compound are known as polymorphs. All such forms (e.g. amorphous andcystalline polymorphs) of JAK inhibitors are encompassed.

[0053] As described herein, the term "tofacitinib" includes a compound having the formula:

Me

MN N H

[0054) and salts thereof.

[0055] Tofacitinib is also known as "tasocitinib", "tofacitinibum" "CP-690550" or "CP690550". Tofacitinib (CAS ID: 540737-29-9) (UNII: O1FF4DIVOD) (PubChem CID: 10174505) is a janus kinase (JAK) inhibitor. It will be understood by the skilled person that all forms of tofacitinib are encompassed, including any tautomeric forms. Whilst some embodiments may involve use of the parent compound, in other embodiments a salt form is utilised, e.g. a pharmaceutically acceptable salt. Examples of salts include those formed with sulphuric acid (sulfate salt) and citric acid (citrate salt). In a preferred embodiment a citrate salt is used, typically the monocitrate salt, referred to for example as tofacitinib citrate, tasocitinib citrate, tofacitinib monocitrate or tasocitinib monocitrate. In one embodiment, tofacitinib citrate is made by combining equimolar amounts of tofacitinib free base and citric acid.

[0056] Whilst in some embodiments, the parent compound is utilised, in other embodiments a derivative of the parent compound may be used, for example a physiological functional derivative. Examples of derivatives include sulphonamides, amides, and carbamates. A prodrug form of tofacitinib may be utilised. A prodrug is a compound which, upon administration to the recipient, is capable of being converted into the tofacitinib parent compound described above.

[0057] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate".

[0058] It will be understood by the skilled person that solvates of tofacitinib, as well as solvates of salts and derivatives thereof are encompassed. Solvates of tofacitinib which are suitable for use in medicine are those wherein an associated solvent is pharmaceutically acceptable. For example, a hydrate is an example of a pharmaceutically acceptable solvate. In some embodiments, a solvate is used. In some embodiments, a hydrate is used.

[0059] It will be understood by the skilled person that many organic compounds can exist in amorphous and crystalline forms. Different crystalline forms of a compound are known as polymorphs. All such forms (e.g. amorphous and crystalline polymorphs) of tofacitinib are encompassed.

[0060] As described herein, "tofacitinib" also known as "tasocitinib", "tofacitinibum" "CP-690550" or "CP690550" is a janus kinase inhibitor (CAS ID: 540737-29-9) (UNII: O1FF4DIVOD) (PubChem CID: 10174505). Tofacitinib is primarily metabolized by the enzymatic hepatic pathway cytochrome P450 (CYP-450) 3A4, with minor metabolism using the CYP2C19 pathway. The term "tofacitinib" is also used in a broad sense to include derivatives thereof. Suitable derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable sulfates, pharmaceutically acceptable anhydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable isomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable tautomers, pharmaceutically acceptable complexes etc. In a preferred embodiment, tofacitnib is tofacitinib citrate also referred to as "tofacitinib monocitrate" or "tasocitinib monocitrate". In an embodiment, tofacitinib citrate is made by combining equimola amounts of tofacitinib and citric acid.

[0061] As described herein, "baracitinib" also known as LY 3009104 is a JAK1/JAK2 inhibitor (CAS ID: 1187594-09-7).

[0062] As described herein, "ruxolitinib" also known as "INCB 018424" is a JAK1/JAK2/JAK3 inhibitor (CAS ID: 1092939-17-7).

[0063] As described herein, "R348" is a JAK/SYK inhibitor (spleen tyrosine kinase).

[0064] As described herein, "WHI-P131" also known as "Janex 1" is aJAK3 inhibitor (CAS ID: 202475-60-3).

[0065] As described herein, "WHI-P 154" is a JAK3 inhibitor (CAS ID: 211555-04 3).

[0066] As described herein, "decernotinib" also known as "VX-509" is a JAK3 inhibitor (CAS ID: 944842-54-0).

[0067] As described herein, "JAK3 Inhibitor IV" also known as "ZM 39923 hydrochloride" is a JAK3 inhibitor (CAS ID: 58753-54-1).

[0068] As described herein, "JAK3 Inhibitor VIII" also known as "NSC114792" is a JAK3 inhibitor (CAS ID: 17392-79-9).

[0069] As described herein, "tyrphostin AG 490" also known as "AG490" is a JAK2 inhibitor (CAS ID: 133550-30-8).

[0070] As described herein, "memelotinib" also known as "CYT387" is a JAK1/JAK2 inhibitor (CAS ID: 1056634-68-4).

[0071] As described herein, "pacritinib" also known as "SB1518" is a JAK2 inhibitor (CAS ID: 937272-79-2).

[0072] As described herein, "fedratinib" also known as "TG101348" is a JAK2 inhibitor (CAS ID: 936091-26-8).

[0073] As described herein, "BMS-911543" is a JAK2 inhibitor (CAS ID: 1271022 -2).

[0074] As described herein, "WP-1034" is a JAK inhibitor (CAS ID: 1271022-90-2).

[0075] As described herein, "spironolactone" is an aldosterone antagonist and has been used as a potassium-sparing diuretic for over 50 years (CAS ID: 52-01-7). It is structurally a steroid, with basic steroid nuclei with four rings.

[0076] As described herein, "finasteride", also referred to as "propecia", is a type II a-reductase inhibitor, it acts by inhibiting the activity of 5a-reductase, an enzyme that converts testosterone to dihydrotestosterone (CAS ID: 98319-26-7). It is a synthetic drug for the treatment of benign prostatic hyperplasia and male pattern baldness and can be administered orally.

[0077] As described herein, "dutasteride" is a 5-a reductase inhibitor that inhibits conversion of testosterone to dihydrotestosterone (CAS ID: 164656-23-9).

[0078] As described herein, "flutamide" is a non-steroidal antiandrogen (CAS ID: 13311-84-7).

[0079] As described herein, "cyproterone" is a steroidal antiandrogen (CAS ID: 2098 66-0).

[0080] As described herein, "bicalutamide" is a non-steroidal antiandrogen (CAS ID: 90357-06-5).

[0081] As described herein, "enzalutamide" is anon-steroidal antiandrogen (CAS ID: 90357-06-5).

[0082] As described herein, "nilutamide" is a non-steroidal antiandrogen (CAS ID: 90357-06-5).

[0083] As described herein, "drosperidone" is a progestogen (CAS ID: 67392-87-4)

[0084] As described herein, "apalutamide" is a non-steroidal antiandrogen (CAS ID: 90357-06-5).

[0085] As described herein, "buserilin" is a non-steroidal antiandrogen (CAS ID: 90357-06-5).

[0086] As described herein, "saw palmetto" is a non-steroidal antiandrogen (CAS ID: 90357-06-5).

[0087] As described herein, "azeleic acid" is a non-steroidal antiandrogen (CAS ID: 90357-06-5).

[0088] As described herein, "minoxidil" also known as "2,4-Diamino-6 piperidinopyrimidine 3-oxide" or "2,4-Pyrimidinediamine, 6-(1-piperidinyl)-, 3-oxide" or "2,6-Diamino-4-piperidinopyrimidin-1-oxid" is a piperidinopyrimidine derivative and a potent vasodilator (CAS ID: 38304-91-5). The term "minoxidil" is used in broad sense to include not only "minoxidil" per se but also its pharmaceutically acceptable derivatives thereof.

[0089] As described herein, "setipiprant" is a prostaglandin D 2 receptor antagonist (CAS ID: 866460-33-5).

[0090] As described herein, "fevipiprant" is a prostaglandin D2 receptor antagonist (CAS ID: 872365-14-5).

[0091] As described herein, "cyclosporin" also called "cyclosporine" or "ciclosporin" is an immunosuppressant (CAS ID: 59865-13-3).

[0092] As described herein, "methotrexate" is an immunosuppressant (CAS ID: 59 -2).

[0093] As described herein, "azathioprine" is an immunosuppressant (CAS ID: 446 86-6).

[0094] As described herein, "prednisolone" is a glucocorticoid (CAS ID: 50-24-8).

[0095] As described herein, "dexamethasone" is a glucocorticoid (CAS ID: 50-02-2)

[0096] As used herein the term "subject" refers to a mammal, particularly a human. In an embodiment the subject, is male. In an embodiment the subject, is female.

[0097] As used herein, the terms "treating" or "treatment" of hair loss or hair shedding means: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0098] As used herein, the terms "promoting" or "promotion" of hair growth refers to inducing or supporting hair growth. In an embodiment, the present invention promotes beard growth in a subject. In an embodiment, promoting hair growth increases the number of hair follicles in the anagen hair growth phase. In an embodiment, promoting hair growth comprises increasing the length of the anagen hair growth phase. In an embodiment, promoting hair growth comprises increasing the initiation of the anagen hair growth phase. In an embodiment, promoting hair growth decreases the length of the telogen hair growth phase. In an embodiment, promoting hair growth decreases the length of the catgen hair growth phase. In an embodiment, promoting hair growth decreases the length of the kenogen hair growth phase. In an embodiment, promoting hair growth comprises increasing hair length. In an embodiment, promoting hair growth comprises increasing the diameter of hair fibres. In an embodiment, promoting hair growth comprises increasing the number of hairs in a hair follicle. In an embodiment, promoting hair growth increases the number of frontal scalp terminal hairs.

[0099] The methods and compositions as described herein are relevant to the treatment of "autoimmune disease". An autoimmune diseases is a disease caused by an immune response against a normal component of the body (i.e. where the body mounts an immune response against its own components). In an embodiment, the autoimmune disease is selected from one or more of: rheumatoid arthritis, psoriasis, psoriatic arthritis, vitiligo, sarcoid, atopic dermatitis, ulcerative colitis, lupus erythematosus, lichen planus, Hashimoto's disease, Graves' disease, Crohn's disease, alopecia and alopecia areata.

[0100] The methods and compositions as described herein are relevant to the treatmentof "hairloss". One particular form of "hair loss" is "hair shedding" described as where hair falls out from skin areas where it is usually present, such as the scalp. Hair shedding can be described as either normal levels of hair shedding or excessive levels of hair shedding. Excessive hair loss or hair shedding may be a consequence of one of the following conditions: alopecia areata, alopecia totalis, alopecia universalis, androgenetic alopecia, telogen effluvium (chronic and acute), anagen effluvium, chemotherapy induced hair loss, male pattern baldness, female pattern baldness, thyroid problems, monilethrix, anaemia, congenital hypotrichosis, hypotrichosis, short anagen syndrome, loose anagen syndrome, drug induced and chemotherapy induced hair loss, cicatricial alopecia (lichen planopilaris, discoid lupus erythematosus, folliculitis decalvans), polycystic ovary syndrome, cicatricial alopecia (lichen planopilaris, discoid lupus erythematosus, folliculitis decalvans), tinea capitis, hypotrichosis simplex, congenital hypotrichosis, hypotrichosis or malnutrition. In an embodiment, the condition is male pattern baldness. In an embodiment, the condition is androgenic alopecia. In an embodiment, the condition is telogen effluvium. In an embodiment, the condition is chronic telogen effluvium. In an embodiment, the condition is acute telogen effluvium. In an embodiment, the subject is female. In an embodiment, the subject is male. A subject may be diagnosed by one or more of the above conditions by any method known to a person skilled in the art.

[0101] In an embodiment, the methods and compositions as described herein reduce chemotherapy induced hair loss or excessive hair shedding and/or increase the rate of recovery from chemotherapy induced hair loss or excessive hair shedding. In an embodiment, the methods and compositions as described herein reduce the relapse of alopecia areata and/or increase the rate of recovery from alopecia areata.

[0102] As described herein, "predominantly absorbed in the oral mucosa" indicates that the greatest proportion of a dose or composition enters the blood stream by absorption through the oral mucosa compared to other mucosa. For example, a greater proportion of the dose or composition enters that blood stream through the oral mucosa than through the mucosa of the lower gastrointestinal tract (e.g. intestines and stomach). In an embodiment, about 50% to about 98% of an absorbed dose or composition is absorbed through the oral mucosa. In an embodiment, about 55% to about 95% of an absorbed dose or composition is absorbed through the oral mucosa. In an embodiment, about 58% to about 90% of an absorbed dose or composition is absorbed through the oral mucosa. In an embodiment, about 60% to about 85% of an absorbed dose or composition is absorbed through the oral mucosa. In an embodiment, about 65% to about 80% of an absorbed dose or composition is absorbed through the oral mucosa. In an embodiment, about 70% to about 7 5 % of an absorbed dose or composition is absorbed through the oral mucosa.

[0103] A dose or composition that is predominantly absorbed in the oral mucosa can be orodispersible. As used described herein "orodispersible" refers to a dose or dosage form that dissolves, disintegrates and/or disperses in the mouth/oral cavity allowing for absorption in the mouth/oral cavity. Such dosage forms may also be referred to as "mouth dissolving" dosage forms.

[0104] As described herein, "predominantly absorbed in the sublingual mucosa" indicates that the greatest proportion of a dose or composition enters the blood stream by absorption through the oral mucosa. In an embodiment, about 50% to about 98% of an absorbed dose or composition is absorbed through the sublingual mucosa. In an embodiment, about 55% to about 95% of an absorbed dose or composition is absorbed through the sublingual mucosa. In an embodiment, about 58% to about 90% of an absorbed dose or composition is absorbed through the sublingual mucosa. In an embodiment, about 60% to about 85% of an absorbed dose or composition is absorbed through the sublingual mucosa. In an embodiment, about 65% to about 80% of an absorbed dose or composition is absorbed through the sublingual mucosa. In an embodiment, about 70% to about 75% of an absorbed dose or composition is absorbed through the sublingual mucosa.

[0105] As described herein, "orally administered" refers to a dose or composition that is administered orally and predominantly absorbed in the lower gastrointestinal tract e.g. the intestines or stomach (orally administered drugs are not predominantly absorbed in the oral mucosa or sublingual mucosa). Orally administered drugs are e.g. pills or tablets formulated for oral administration (are swallowed) and are absorbed in the intestines/lower gastrointestinal tract/gastrointestinally. Oral bioavailability (F%) is the fraction of an orally administered drug that reaches the systemic circulation unchanged. The oral bioavailability of a drug can be reduced by incomplete absorption in the gastrointestinal tract or degradation into metabolites during first-pass metabolism in the liver.

[0106] As described herein, the "oral mucosa" refers to the mucous membrane lining the inside the oral cavity, which includes the sublingual mucosa, the buccal mucosa, the gingival mucosa, the palatal mucosa, the labial mucosa and/or the alveolar mucosa. A person skilled in the art would appreciate that the methods and compositions as described herein relate to a dose or composition comprising a JAK inhibitor that can enter the blood stream by crossing the oral mucosa. In a preferred embodiment, the JAK inhibitor is tofacitinib.

[0107] As used herein, the term "sublingual" or "sublingually" refers to the pharmacological route of administration wherein a desired substance is transported across the membrane by e.g. diffusion, active transport and/or is endocytosed into the circulartory system through tissues under the tongue (the sublingual mucosa). The sublingual mucosa can be divided into two layers the epithelium and the connective tissue which comprises a large capillary structure. The sublingual epithelium is relatively thin compared to other oral epitheliums like the buccal epithelium which is thicker. It comprises higher amounts of polar lipids (e.g. phospholipids, cholesterol esters and glycocerimides) than e.g. palate and gingival mucosa. The sublingual mucosa has a different permeability profile to other regions of the oral mucosa.

[0108] A dose or composition comprising a JAK inhibitor as described herein is formulated for absorption across the oral mucosa. Absorption across the oral mucosa may include absorption across one or more of the sublingual mucosa, the buccal mucosa, the labial mucosa, the gingival mucosa, the palatal mucosa, and/or the alveolar mucosa. In a preferred embodiment, the dose or the composition comprising a JAK inhibitor is formulated for absorption across the sublingual mucosa.

[0109] A person skilled in the art will appreciate that the dose of tofacitinib or composition comprising tofacitinib may be formulated in any form that allows tofacitinib to cross the oral mucous membrane, such forms include, but are not limited to a; strip, wafer, film, troche, lipid matrix tablet, tablet (including a mini-tablet), capsule, pill, granule, pellet, powder, drop, spray and lozenge. In an embodiment, the dose is formulated as a semi-solid dosage form. In an embodiment, the spray is a powder. In an embodiment, the powder is packaged in a sachet. In an embodiment the dose of tofacitinib or composition comprising tofacitinib is formulated as a strip, wafer, pellet or film which disintegrates when placed under the tongue. In an embodiment the dose of tofacitinib or composition comprising tofacitinib is formulated as an "orodispersible strip", "orodispersible wafer" or an "orodispersible film".

[0110] In an embodiment, the strip, wafer or film disperses/disintegrates sublingually. In an embodiment, the film may be selected from a flash release, mucoadhesive melt away or a mucoadhesive sustained release film for example as described in Nagaraju et al. (2013). In an embodiment, the dose of tofacitinib or composition comprising tofacitinib is formulated in a spray. In an embodiment, the spray can be applied to the buccal mucosa and/or the sublingual mucosa. In an embodiment, the dose of tofacitinib or composition comprising tofacitinib is not a nanoparticle composition.

[0111] The dose or composition comprising a JAK inhibitor maybe formulated for rapid disintegration to ensure the JAK inhibitor is absorbed through the oral mucosa or the sublingual mucosa. In an embodiment, such doses or compositions will be formulated to disintegrate in the presence of saliva and/or water. In an embodiment, such formulations may comprise a disintegration agent which aids disintegration of the dose or composition in the presence of saliva and/or the presence of water.

[0112] In an embodiment, the dose or composition comprising aJAK inhibitor is stable at between about 0°C to about 40°C.

[0113] In an embodiment, the dose or composition comprising aJAK inhibitor is a sublingual composition. In an embodiment, the sublingual composition is a sublingual strip.

[0114] As used herein the "disintegrating agent", "disintegration agent" or "disintegrant/s" refers to an agent added to the dose or composition that facilitates disintegration/dispersion of the formulation in the oral cavity or sublingually and includes superdisintegrating agents and effervescent agents. Disintegrants may act by water wicking, capillary action, swelling, deformation, repulsion (e.g. release of gasses), and heat of wetting.

[0115] Examples of disintegrating agents can be found in Gad et al. (2008) and Rowe et al. (2009) and include for example, but are not limited to, starch, modified starches, crosslinked starches, crosslinked alginic acid, modified cellulose and cross-linked povidone, microcrystalline cellulose, sodium starch glycollate (Primojel, Explotab), cassia fistula gum, crospovidone, croscarmellose sodium, alginic acid, sodium alginate, starch USP, starch 1500, avicel, solka floc, alginic acid, sodium alginate, polyplasdone, amberlite, methyl cellulose, AC-Di-Sol, carbon dioxide, lepidum sativum, locust bean gum, nymce ZSX, primellose, solutab, vivasol crosspovidone, crosspovidon M, kollidon, polyplasdone, plantagoovata husk, plantago ovate mucilage, cetric acid, satialgine, soy polysaccharides, sodium bicarbonate, sodium starch glycolate, treated agar, emcosoy, and calcium silicate. Disintegrating agents that are particularly suitable for use in strips and films are described in Nagaraju et al. (2013).

[0116] In an embodiment, the disintegrating agent swells at least 2 fold in under 10 seconds, or at least 3 fold in under 10 seconds, or at least 4 fold in under 10 seconds, or at least 5 fold in under 10 seconds, or at least 6 fold in under 10 seconds, or at least 7 fold in under 10 seconds, or at least 8 fold in under 10 seconds. In an embodiment, the disintegrating agent swells at least 2 fold in under 30 seconds, or at least 3 fold in under seconds, or at least 4 fold in under 30 seconds, or at least 5 fold in under 30 seconds, or at least 6 fold in under 30 seconds, or at least 7 fold in under 30 seconds, or at least 8 fold in under 30 seconds, or at least 9 fold in under 30 seconds, or at least 10 fold in under 30 seconds, or at least 11 fold in under 30 seconds, or at least 12 fold in under 30 seconds.

[0117] In an embodiment, the dose or composition comprising aJAK inhibitor is formulated so that an oral disintegrating enzyme facilitates disintegration in the oral cavity. In an embodiment, the oral disintegrating enzyme is amylase (which acts upon starch), protease (which acts upon gelatin), cellulase (which acts upon cellulose and/or its derivatives) and/or invertase (which acts upon sucrose).

[0118] In an embodiment, the dose or composition comprising aJAK inhibitor is formulated to disintegrate/disperse in under about 2 minutes, or in under about 1 minute, or in under about 50 seconds, or in under about 40 seconds, or in under about seconds, or in under about 20 seconds, or in under about 15 seconds, or in under about 10 seconds of being placed in the mouth.

[0119] In an embodiment, the dose of composition comprising aJAK inhibitor is formulated to disintegrate/disperse in under about 2 minutes, or in under about 1 minute, or in under about 50 seconds, or in under about 40 seconds, or in under about seconds, or in under about 25 seconds, or in under about 20 seconds, or in under about 18 seconds, or in under about 15 seconds, or in under about 12 seconds, or in under about 10 seconds, or in under about 5 seconds of being placed under the tongue. In an embodiment, the dose or composition comprising a JAK inhibitor is formulated to disintegrate/disperse in under about 30 seconds of being placed under the tongue.

[0120] The disintegration times of oral and sublingual doses as described herein can be assessed as described for example in Narang et al (2001) and USP/NP. Physical Tests: Disintegration (701).

[0121] In an embodiment, the dose or composition comprising a JAK inhibitor may comprise an adhesive agent which aids adherence of the dose or composition to the sublingual mucosa. In an embodiment, the adhesive agent is a bioadhesin. In an embodiment, the adhesive agent is a mucoadhesion. A bioadhesin or mucoadhesin can aid in keeping the dose or composition comprising a JAK inhibitor in intimate contact with the sublingual mucosa, and/or to increase the time in contact with the sublingual mucosa. The presence of an adhesive agent can also prevent inadvertent swallowing of the dose.

[0122] In an embodiment, the dose or composition comprising a JAK inhibitor may comprise a taste modifying agent to improve the taste of the dose or composition for the subject. Taste modifying agents include sweeteners and flavouring agents. Examples of taste modifying agents can be found in Gad et al. (2008), Rowe et al. (2009) and Nagaraju et al. (2013) and include, for example mannitol, aspartame, sucrose, dextrose, fructose, glucose, maltose, neotame, alitame, saccharin and sorbitol.

[0123] A person skilled in the art will appreciate that such dosage forms or compositions may be prepared by any method known to a person skilled in the art and can include, for example: freeze-drying or lyophilisation, sublimation, spray drying, moulding, mass extrusion, direct compression, melt granulation, effervescent method, 3D printing and ink-jet technology (for application of tofacitinib to strips, wafers and films). Examples of such methods can be found in Dey and Maiti (2010); Jamr6z et al (2017); and Singh et al (2012).

[0124] Films as described herein may also be produced by any method known to a person skilled in the art, and for example, by the methods described in Nagaraju et al. (2013), Amin et al. (2015) and Irfan et al. (2016) which include casting and drying

(solvent casting or semi-solid casting), extrusion (hot-melt extrusion or solid dispersion extrusion), rolling method and spray technique.

[0125] In one example, producing films byhot-melt extrusion comprises: mixing of hydrophilic acid insoluble polymers, addition of a JAK inhibitor and plasticizer, extrusion, drying and cutting of the extrusion into films.

[0126] In one example, producing films by solvent casting comprises: preparation of a solvent suspension comprising a JAK inhibitor, casting of a solvent suspension, drying of the solvent suspension, film stripping and film packaging.

[0127] In one example, producing films by solid dispersion extrusion comprises: mixing of a JAK inhibitor with a suitable solvent, adding the mixture of a JAK inhibitor and solvent to a melted polymer along with immiscible components and cutting of the solid dispersion into a film.

[0128] In one example, producing films by the rolling method comprises: preparation of a suspension comprising a JAK inhibitor and polymer in water or alcohol, subjecting the suspension to rollers, evaporation of solvent and cutting into film.

[0129] Films as described herein may comprise one or more of the following: a film forming agent, a plasticizer, taste modifying agent, surfactant, thickener and/or stabilizer, a saliva stimulating agent, an adhesive agent and a colouring agent.

[0130] "Film forming agent" refers to a polymer capable of forming a film. Inan embodiment, the film forming agent may be selected from: hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), pullulan, carboxymethyl cellulose (CMC), pectin, starch, polyvinyl acetate (PVA), and sodium alginate.

[0131] "Plasticizer" refers to an agent which improves the flexibility and/or decreases the brittleness of a film. In an embodiment, the plasticizer may be selected from: glycerine, sorbitol propylene glycerol, glycerol, caster oil, triacetin, trithyl citrate, acetyl triethyl citrate and other citrate esters.

[0132] In an embodiment, the dose or composition comprises a JAK inhibitor in the range from about 0.1 mg to about 20 mg, or from about 0.2 to about 20 mg, or from about 0.5 mg to 20 mg, or from about 0.5 mg to 18 mg, or from about 0.5 mg to 15 mg, or from about 0.5 mg to 12.5 mg, or from about 0.5 mg to 10 mg, or from about 0.5 mg to 8 mg, or from about 1 mg to 6 mg, or from about 1 mg to 5 mg, or from about 1 mg to 4 mg, or from about 1 mg to 3 mg, or from about 1 mg to 2 mg, or is about 5 mg, or is about 4 mg, or is about 3 mg, or is about 2 mg, or is about 1 mg, or is about 0.5 mg.

[0001] In an embodiment, the dose or composition comprises a JAK inhibitor in the range from about 0.1 mg to about 20 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range from about 0.2 to about 20 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range from about 0.5 mg to 20 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range of from about 0.5 mg to 18 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range of from about 0.5 mg to 15 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range of from about 0.5 mg to 12.5 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range of from about 0.5 mg to 10 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range of from about 0.5 mg to 10 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range of from about 0.5 mg to 8 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range of from about 1 mg to 6 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range of from about 1 mg to 5 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range of from about 1 mg to 4 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range of from about 1 mg to 3 mg. In an embodiment, the dose or composition comprises a JAK inhibitor in the range of from about 1 mg to 2 mg. In an embodiment, the dose or composition comprises a JAK inhibitor at a concentration of about 6mg. In an embodiment, the dose or composition comprises a JAK inhibitor at a concentration of about 5.5mg. In an embodiment, the dose or composition comprises a JAK inhibitor at a concentration of about 5mg. In an embodiment, the dose or composition comprises a JAK inhibitor at a concentration of about 4.5mg. In an embodiment, the dose or composition comprises a JAK inhibitor at a concentration of about 4mg. In an embodiment, the dose or composition comprises a JAK inhibitor at a concentration of about 3mg. In an embodiment, the dose or composition comprises a JAK inhibitor at a concentration of about 2mg. In an embodiment, the dose or composition comprises a JAK inhibitor at a concentration of about 1mg. In an embodiment, the dose or composition comprises a JAK inhibitor at a concentration of about 0.5mg.

[0133] In an embodiment, the dose or composition comprises tofacitinib in the range of from about 0.1 mg to 20 mg, or from about 0.1 mg to 18 mg, or from about 0.1 mg to 15 mg, or from about 0.2 mg to 12.5 mg, or from about 0.2 mg to 10 mg, or from about 0.5 mg to 8 mg, or from about 1 mg to 6 mg, or from about 1 mg to 5 mg, or from about 1 mg to 4 mg, or from about 1 mg to 3 mg, or from about 1 mg to 2 mg, or is about 5 mg, or is about 4 mg, or is about 3 mg, or is about 2 mg, or is about 1 mg, or is about 0.5 mg daily.

[0134] In an embodiment, the dose or composition comprises tofacitinib in the range of from about 0.1 mg to 20 mg. In an embodiment, the dose or composition comprises tofacitinib in the range of from about 0.1 mg to 18 mg. In an embodiment, the dose or composition comprises tofacitinib in the range of from about 0.1 mg to 15 mg. In an embodiment, the dose or composition comprises tofacitinib in the range of from about 0.2 mg to 12.5 mg. In an embodiment, the dose or composition comprises tofacitinib in the range of from about 0.2 mg to 10 mg. In an embodiment, the dose or composition comprises tofacitinib in the range of from about 0.5 mg to 8 mg. In an embodiment, the dose or composition comprises tofacitinib in the range of from about 1 mg to 6 mg. In an embodiment, the dose or composition comprises tofacitinib in the range of from about 1 mg to 5 mg. In an embodiment, the dose or composition comprises tofacitinib in the range of from about 1 mg to 4 mg. In an embodiment, the dose or composition comprises tofacitinib in the range of from about 1 mg to 3 mg. In an embodiment, the dose or composition comprises tofacitinib in the range of from about 1 mg to 2 mg. In an embodiment, the dose or composition comprises tofacitinib at a concentration of about 6mg. In an embodiment, the dose or composition comprises tofacitinib at a concentration of about 5.5mg. In an embodiment, the dose or composition comprises tofacitinib at a concentration of about 5mg. In an embodiment, the dose or composition comprises tofacitinib at a concentration of about 4.5mg. In an embodiment, the dose or composition comprises tofacitinib at a concentration of about 4mg. In an embodiment, the dose or composition comprises tofacitinib at a concentration of about 3mg. In an embodiment, the dose or composition comprises tofacitinib at a concentration of about 2mg. In an embodiment, the dose or composition comprises tofacitinib at a concentration of about 1mg.

[0135] In an embodiment, the dose or composition comprising aJAK inhibitor is administered weekly, bi-weekly, every three days, every second day, one or more times a day. In an embodiment, the dose or composition comprising a JAK inhibitor is administered one or more times a day. In an embodiment, the dose or composition comprising a JAK inhibitor is administered daily.

[0136] In an embodiment, the dose of a JAK inhibitor administered to a subject may be increased over time.

[0137] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application.

[0138] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0139] It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0140] The steps, features, integers, compositions and/or compounds disclosed herein or indicated in the specification of this application individually or collectively, and any and all combinations of two or more of said steps or features.

[0141] Examples

[0142] Example 1: Orally administered and sublingual tofacitinib for chronic, refractory, moderate to severe alopecia areata

[0143] Introduction

[0144] Alopecia areata (AA) is an autoimmune disorder of terminal anagen hair follicles that may produce one or more circular patches of hair loss, complete scalp baldness (alopecia totalis - AT) or universal hair loss (alopecia universalis - AU). AA is the most common autoimmune disease in man. The lifetime risk is estimated to be 2.1% and AA principally affects people aged between 20-40 years. AA has a genetic etiology and cryptogenic environmental trigger. The pathogenesis includes immune dysregulation, loss of hair follicle immune privilege, autoimmunity, hair breakage, hair cycle dysregulation and disturbance of hair pigmentation. There may be associated nail changes.

[0145] The clinical severity, disease trajectory and natural history are heterogeneous and variable. In approximately 40% of affected individuals, the hair loss appears as a single circular patch that resolves spontaneously within six months; a further 27% of affected individuals develop additional patches progressively over a few weeks to months, but still achieve a durable remission within 12 months; while, the remaining 33% of individuals have continued disease at 12 months.

[0146] Persistent disease at 12 months predicts a chronic relapsing and remitting course with a 45% risk of ultimately developing AT or AU. Significant psychological sequelae are recognized associations. Effective treatment of chronic AA remains challenging - there is no consensus agreement on use of systemic treatments such as prednisolone, azathioprine, ciclosporin and methotrexate and these options only infrequently produce a satisfactory, durable response and can be associated with undesirable side effects.

[0147] This study demonstrates the use of tofacitinib in a clinical setting for the treatment of chronic (defined as disease duration > 12 months), moderate to severe AA in 127 patients whose hair loss was refractory to systemic therapy. It is also reported that sublingual tofacitinib treatment produces a response comparable to orally administered tofacitinib in the absence of other components which reduce hepatic metabolism.

[0148] Subjects

[0149] Patients who received tofacitinib treatment (oral administration or sublingual administration) for a minimum 3 months were included in this study.

[0150] Patients' clinical and demographic data were collected. The patients all underwent pre-screening laboratory tests that included: full blood count, biochemistry profile, liver function tests (LFTs), lipid profile, thyroid function tests, HIV, EBV, hepatitis serology, QuantiFERON-TB Gold (Cellestis Limited, Melbourne, Australia), and vitamin D. Additional safety monitoring blood tests including full blood count, biochemistry profile, LFTs and lipid profile were performed at 6-12 weekly intervals.

[0151] Patients were treated for up to 18 months with tofacitinib either as monotherapy, or in combination with intralesional and/or systemic therapies. Treatment was titrated according to response and tolerability.

[0152] Forty-two (37%) males and 85 (67%) females were included in the analysis. The mean age was 34 years (range 11 - 68). Twenty-four (19%) were paediatric patients. Sixteen (12.6%) had an autoimmune disease, the majority of which was thyroid disease, or vitiligo. Forty-five had a personal history of atopy. A positive family history of an autoimmune disorder was present in 39 (31%). Ninety (70.8%) had patchy disease, while 35 (26.5%) had AT/AU. Two (1.8%) had exclusive beard AA. The average age of onset of disease was 24 years (range 1 - 63) and the average duration of disease at baseline was 9.8 years (range 1- 40). Duration of disease was determined as starting from the onset of their first AA episode.

[0153] In AA, AT and AU, a partial response may not be clinically significant and may be detrimental to patient satisfaction. The ultimate goal of therapy is complete or near complete response/remission, where the patient can readily conceal any residual hair loss. The Severity of Alopecia Tool (SALT) is an ideal means of monitoring incremental or partial responses to therapy but is impossible to estimate retrospectively from photographs (Olsen et al 2004; and Olsen et al 2016). To score clinically meaningful hair regrowth in a retrospective clinical context, we devised a 7-point assessment scale that assigns a simple numerical value to reflect a global impression of treatment response compared to a pre-determined baseline. This was adapted from the classification of severity of AA, first published by Olsen et al (1992) and (1997) and which was formalized by the National Alopecia Areata Foundation Guidelines Committee (Olsen et al 1999), and revised 2004 (Olsen et al 2004). A +3 pertains to a complete response (SALT 0) and -3 represents complete hair loss (SALT 100). This is a dynamic scoring system which we believe is easy to use in a real-world setting and is also easily understood by patients.

Table 1 - The 7-point assessment scale

Table 1: The 7-point assessment scale

Score Scalp Hair Loss Percentage Clinical Definition

-3 100% hair loss (SALT 100) Complete hair loss

-2 75-99% hair loss Extensive hair loss

-1 50-74% hair loss Some hair loss

0 No change from baseline No change

+1 25-49% hair loss Some hair growth

+2 1-24% hair loss Extensive hair growth

+3 No hair loss (SALT 0) Complete response

[0154] Review of standardized serial photographs (performed as part of routine care) were conducted independently by three individuals to attribute a score on the 7-point assessment scale at three monthly intervals, relative to baseline (pre-first tofacitinib prescription).

[0155] Outcomemeasures

[0156] The primary endpoint was the percentage of patients who achieved +3 (complete response (CR)) at each time point. The secondary endpoints were the mean and median scores and the percentage of patients who achieved a +1 or +2 response at each time point. Early responders- patients who achieved a >+1 score within 3 months of commencing treatment. Late responders - patients who did not achieve a >+1 score until at least 6 months of treatment. Further endpoints of interest were: Prolonged disease duration - patients who had current disease duration >10 years. This was defined based on the patient's report of the first instance of AA. Relapse - at least one grade deterioration in score from the last score. Treatment Failure:Primary failures were patients who failed to achieve a +1 outcome. Secondary failures were patients who achieved >+1 regrowth but then had sustained, at least one grade deterioration from baseline score, for at least 6 months. Patients who withdrew from treatment were considered non-responders. Tofacitinib monotherapy - patients who were not taking any other immunosuppressant medications when they started tofacitinib.

[0157] Results

[0158] One-hundred and twenty-seven patients were treated for >3 months and were included in the analysis. Fourteen patients ceased treatment and were considered non responders.

[0159] Table 2- Baseline patient characteristics

Table 2: Baseline characteristics of our patients

Gender: • Male - n = 42 (37%) • Female - n = 85 (67%)

Age: Median 34 years (Range 11 - 68) • 18 years and under - 24 (19%) • 19 to 35 years - 47 (37%) • 36 to 45 years - 24 (19%) • 46 to 59 years - 23 (18%) • 60 years and over - 9 (7%)

A personal history of another autoimmune disease - 16 patients (12.6%) • Thyroid disease - 10 • Vitiligo - 4 • Coeliac disease and Inflammatory bowel disease - 4

Personal history of atopy - 45 patients (35%) • Atopic dermatitis - 39 • Asthma - 19

A family history of autoimmune disorders - 39 patients (31%)

Type of AA at baseline: • Patchy AA - 51 (40%) • Ophiasis &/or Sisaihpo pattern AA - 39 (30.7%) • AT/AU - 35 (27.5%) • Beard only - 2 (1.8%)

Family history of AA: 26 of 88 patients (29.5%)

Average age of onset of AA was 24 years (range 1 - 63)

Average duration of disease at baseline was 9.8 years (range 1 - 40)

Area affected by AA: • Scalp - 123 (96.8%) • Eyelashes - 44 (34.6%) • Eyebrows - 59 (46.4%) • Beard - 29 (69% of males) • Nails - 22 (17.3%)

[0160] TofacitinibDose

[0161] Tofacitinib is commercially available in Australia in a 5mg dose tablet. Tofacitinib undergoes extensive first pass metabolism in the liver by the CYP3A4 enzyme. CYP3A4 is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids components. Agents such as clarithromycin, cimetidine and grapefruit seed extract are strong inhibitors of CYP3A4 and co-administration with tofacitinib leads to reduced metabolism and increased serum and tissue levels of tofacitinib. Sublingual dosing bypasses the liver and produces higher serum levels of tofacitinib and higher tissue levels of tofacitinib in the hair follicles.

[0162] Orally administereddoses:. Orally administered tofacitinb doses were compounded extemporaneously. The starting dose was determined by the attending physician, taking into consideration the patient's age, weight, extent of hair loss, previous treatment responses and complications, and patient preferences.

[0163] The orally administered doses were compounded with either cimetidine 200 mg daily, clarithromycin 250 mg daily or grapefruit seed extract 200 mg in a single capsule to reduce hepatic metabolism and to increase the serum levels.

[0164] In the pediatric group the mean baseline dose was 3mg daily (1-5mg), and mean overall treatment dose was 4.7mg (1-12.5mg). In the adult group the mean baseline dose was 4.4mg daily (1-10mg), and mean overall treatment dose was 5.6mg (1-20mg). The maximum treatment dose was 20mg daily, prescribed for one adult patient. Dosage was titrated in a non-standardized manner by the attending physician according to patient tolerability and response.

[0165] Sublingual doses: A sublingual tofactinib min-tablet was prepared comprising Tofacitinib citrate (Astral Scientific BIOTFCOO1), PCCA Polyglycol Troche Base; PCCA, #30-1013) and Silica Gel PPTD Micronized (PCCA #30-1009). To prepare 1725 5 mg doses of sublingual tofacitinib 8.625 g/ml of tofacitinib Citrate was combined with 1.725 g/ml silica gel and 162.84 g/ml troche base using the following procedure. One side of the min-tab mold was covered with Lab Film-Parafilm MTM. In an appropriate size beaker, PCCA Polyglycol Troche was melted at 50°C. Using a mortar and pestle, tofacitinib was titurated with silica gel together to a fine powder. The powder was sifted into a melted base while stirring. A strainer was used to reduce the particle size. The heat was discontinued and stirred until suspended. Using an appropriate size syringe, the melted mixture was distributed into Tablet Triturate 200 mg mold and allowed to congeal at room temperature. The final product was protected from sunlight and stored in an air-tight container. The beyond use for troches prepared using the above protocol is estimated to be 180 days.

[0166] The starting dose was determined by the attending physician, taking into consideration the patient's age, weight, extent of hair loss, previous treatment responses and complications, and patient preferences. The mean dose of tofacitinib was 6mg daily (range 1-20). In the paediatric group the mean starting dose was 3mg daily (1-5mg), and mean overall treatment dose was 5mg (1-12.5mg). In the adult group the mean starting dose was 4.5mg daily (1-10mg), and mean overall treatment dose was 6mg (1- mg). The maximum treatment dose was 20mg daily, prescribed for one adult patient. Dosage was titrated in a non-standardized manner by the attending physician according to patient tolerability and response.

[0167] The mean dose of sublingual tofactinib during the study period was 4.64 mg daily (range 1-20 mg). The mean dose of orally administered tofacitinib during the study period was 5.22mg daily (range 2-12.5 mg).

[0168] Concomitant Treatments

[0169] For patients who were thought to beat risk of relapse with cessation of their current systemic therapy, tofacitinib was introduced alongside the existing therapies which were then tapered off. Seventy-one patients (56%) were on immunosuppressive co-therapy when tofacitinib was commenced. Sixty-six of these patients (93%) were receiving prednisolone at a mean maximum dose of 9mg (range 1.25-25). One patient was taking methotrexate, 3 patients were taking azathioprine and 17 patients were taking ciclosporin at baseline with or without prednisolone. Thirty-three of these patients (46%) successfully discontinued all other immunosuppressive treatment at some point after starting tofacitinib.

[0170] Oral or intralesional corticosteroids were introduced to 82 patients who were either slow to respond, partial responders, or who relapsed on tofacitinib therapy. Twenty-four of these patients (29%) were treated with oral prednisolone at a mean maximum dose of 16mg (range 5-25) for a mean period of 5 months (range 1-13). Seventy-four of these patients (58%) had intralesional triamcinolone acetonide (mean concentration 5mg/ml, range 2.5-20mg/ml; mean quantity 2ml, range 0.4-5ml) administered a mean of 4.5 times (range 1-11). Tofacitinib efficacy and time to response

[0171] Tofacitinib efficacy and time to response

[0172] Primary endpoint (table 3 and 4): After 3 months, 12% of patients achieved CR. At 12 months, 40% had achieved CR. At 18 months 80% had achieved CR.

Twenty-four patients remain in CR after six months of continued treatment, whilst another nine have remained in CR for >12 months. Dose reduction has commenced in 3 patients.

[0173] Secondary endpoints (Figure2): At 3 months the median score was +1 (IQR 0 to +2), the mean 0.84. At 12 months the median score was +2 (IQR +1 to +3), the mean 1.66. At 18 months the median score was +3 (IQR +3 to +3), the mean 2.33. An increase in hair growth of>+1 was experienced in 71 patients (56%) at 3 months, 43 (78%) at 12 months, and 9 (90%) at 18 months.

[0174] Early responders: Sixty-seven patients (53%) achieved >+1 score by 3 months of treatment. Of these, 40% achieved a +2, and 22% a +3. Ten patients (15%) were paediatric. The mean age of disease onset was 25.6 years (range 2-63) and mean duration of disease 9.8 years (range 1-40). Fifteen patients (22%) had AT/AU. Twenty two patients (32.8%) were able to cease concomitant immunosuppressant medication.

[0175] Late responders: Thirty-one patients (24%), achieved >+1 score after 6 months of treatment. At 6 months 8 had a score of 0, 17 a score of >+1, including 2 with CR. At 9 months 20 had a score of >+1 with 4 in CR. By 15 months all patients in this group were >+1 and 10 had achieved CR. The mean age of disease onset was 21 years (range 1-56) and mean duration of disease 9.3 years (range 1-37). Ten (32%) had AT/AU. Seven (22.5%) were able to cease concomitant immunosuppressant medication.

[0176] ProlongedDisease Duration: Thirty-eight patients were included whose current AA episode had persisted for >10 years. The mean disease duration was 19.9 years (range 10-40). Fourteen had AT/AU and 5 were paediatric cases. Eleven achieved a CR with tofacitinib, 21 were early responders, 10 were late responders, 2 relapsed and 6 never responded. Seven ceased concomitant immunosuppressant medication, 5 started prednisolone and 18 were given intralesional triamcinolone.

[0177] Relapses: Twenty-eight patients (22%) experienced a relapse. Fifteen were early responders, 9 were late responders. Nine relapsed after having initially achieved CR that had been sustained for 3-12 months. The relapse was salvaged in 23 patients with continued treatment but 5 were unable to regain disease control and were considered secondary treatment failures. Five had AT/AU. Ten were paediatric patients. All but eight had a dose escalation. Five had a short course of oral prednisolone and 3 stopped treatment.

[0178] Treatmentfailures

[0179] Primary: Twenty-four patients (19%) failed to respond to treatment. The mean age of disease onset was 25 years (range 2-60) and the mean duration of disease 9 years (range 2-39). Four were paediatric. Ten (42%) had AT/AU. At the time of writing this application, 17 remain on treatment. Three have had continuous treatment out to months with no evidence of hair regrowth and 3 have ceased concomitant immunosuppressant medications. Seven ceased treatment without achieving regrowth.

[0180] Secondary: Five patients out of 28 who experienced a relapse while on treatment failed to respond and were considered a secondary failure. The mean age of disease onset was 9 years (range 3-13) and mean disease duration 18.6 years (4-31). None had AT/AU. Two were paediatric. None stopped treatment and 1 ceased concomitant immunosuppressant medications. Three reached 15 months and 1 reached 18 months. Only 1 patient reached CR. Rescue therapy included dose escalation, intralesional triamcinolone and oral prednisolone. Of these, 2 had deteriorated, 1 was unchanged and 2 had slightly improved from baseline.

[0181] Comparison ofsublingual versus orally administeredtofacitinib

[0182] Abreak-down of subjects treated with sublingual minoxidil compared to those treated with orally administered tofacitinib is provided in Tables 6 and 7. The mean dose of tofacitinib sublingually (4.64 mg) was lower than orally administered (5.22 mg) tofacitinib. Comparable efficacy at a lower dose was observed with sublingual minoxidil compared to orally administered minoxidil without the requirement for additional drugs administered with orally administered tofacitinib to reduce hepatic metabolism of tofacitinb.

[0183] Tofacitinibmonotherapy

[0184] Fifty-six patients (44%) were not taking any other immunosuppressant medications when they started tofacitinib. There were 34 females and 22 males, 10 were pediatric, the mean age was 36 years (range 11-68), with a mean age of onset of disease of 25 years (range 2-63) and a mean duration of disease of 10.5 years (range 1 ). Twenty-nine of these patients had patchy disease, whilst 27 had AT/AU. Eighteen of these patients achieved a CR. Twenty-nine (51.7%) were considered early responders, 11 (19.6%) were late responders, 15 were primary failures (26.7%), and 1 was a secondary failure. Fifteen (26.7%) of these patients were given rescue oral prednisolone at some point with a mean daily dose of 16.8mg (range 10-25) for a mean period of 5.5 months (range 2-11). Twenty-one (37.5%) of these patients were given intralesional steroid injections at some point with a mean of 4 injections (range 1-8).

[0185] Table 3 - Percentage of responders with orally administered tofacitinib

Time point MeanDosemg Score+1 Score+2 Score+3 Total Total non (Range) Tablet responders responders 3 months (n=39) 4.19(1- 10) 7 8 7(18%) 22(56%) 17(44%) 6 months (n=36) 4.96(2- 15) 4 7 10(27%) 21(58%) 15(42%) 9 months (n=25) 5.58(2- 15) 3 4 12 (48%) 19 (76%) 6(24%) 12 months (n=21) 5.63 (2-15) 1 5 11 (52%) 17 (81%) 4(19%) 15 months (n=16) 6.90 (1.25 - 20) 1 2 9(56%) 12(75%) 4(25%) 18 months (n=7) 6.07(5- 10) 0 1 5(71%) 6(86%) 1(14%)

[0137] Table 4 - Percentage of responders with sublingually administered tofacitinib

Time point Mean Dose mg Score Score Score +3 Total Total non (Range) +1 +2 responder responder Sublingual s s 3 months (n=88) 3.73(2- 5) 21 20 8(9%) 49(53%) 41 (46.5%) 6 months (n=74) 4.48 (2.5 - 10) 18 17 15(20%) 50(68%) 24(32%) 9 months (n=53) 4.71 (2.5 -10) 13 12 14(26%) 39(74%) 14 (26%) 12 months (n=34) 6.25 (2.5 - 12.5) 8 11 11(32%) 29(85%) 5(15%) 15 months (n=15) 6.81 (2.5 - 10) 3 5 6(40%) 14(93%) 1(7%) 18 months (n=3) 5.00 (2.5 - 7.5) 0 0 3(100%) 3(100%) 0

[0186] Discussion

[0187] Tofacitinib (dose range 1-20mg) was well tolerated, arrested hair loss and stimulated regrowth in the overwhelming majority of patients. Response to treatment was noted as early as 3 months. Most had a partial response at 6 months and a CR by 18 months. Relapse was seen in 28 patients (22%). Ten patients went on to respond and three ceased treatment. Primary failure was seen in 24 patients (19%) and 7 of these ceased treatment with tofacitinib.

[0188] Our study included both children and adults, as well as patients with prolonged disease duration (up to 40 years). AA that remains active after 12 months follows a relapsing and remitting course and it is therefore difficult to ascertain with certainty when exactly the disease process has completely arrested. Patients often return with new disease long after they have achieved what appears to be complete remission. In light of this clinical experience, we decided to record the disease duration from the first date of reported disease rather than from the current episode as we feel this reflects better the true clinical course of the disease. Thirty-eight of our patients (30%) had disease duration of>10 years. Of these, 11 achieved a CR, 21 were early responders, and 10 were late responders. Therefore 81.6% of these patients had regrowth with tofacitinib. Likewise, 25 patients (71%) with AT/AU achieved a response and 13 (37%) achieved a CR.

[0189] Tofacitinib is not reimbursed for alopecia areata in Australia and the cost to patients for sixty 5mg tablets is approximately AUD $1342. For some patients, the distress associated with alopecia areata would justify this expense, but for many patients this is simple unaffordable. The sublingual composition as described herein provides a more cost effective option of treating and prevent hair loss conditions such as alopecia areata.

[0190] Side effects were infrequent and mild. One patient developed asymptomatic hepatic transaminitis that failed to improve with dose reduction and led to eventual treatment discontinuation. The patient was later diagnosed with nonalcoholic steatohepatitis.

[0191] Conclusion

[0192] Tofacitinib was well tolerated and highly effective although prolonged treatment may be required. The relatively high number of late responders seen in our cohort indicate that tofacitinib treatment should not be deemed to have failed until at least 12 months of continued treatment. Tofacitinib can be administered sublingually with comparable efficiency to orally administered doses administered with other components to reduce tofacitinib hepatic metabolism

[0193] References

Amin et al (2015) Oral film technology: Challenges and future scope for pharmaceutical industry 3(3): 183-203. Bittencourt et al (2014) Clin Exp Dermatol 39:868-73. Dey and Maiti (2010) J Nat Sci Biol Med l(l):2-5. Gad et al (2008) Pharmaceutical manufacturing handbook: Production and processes. Published by Wiley-Interscience. Irfan et al (2016) Saudi Pharmacutical Journal 245:537-546. Jamr6z et al (2017) Int J Pharm. S0378-5173(17)30464-7. Messenger and Sinclair (2006) Br J Dermatol 155: 926-930. Messenger et al (2010) Eighth Edition. Blackwell Publishing. Oxford. 63.1-63.100. Nagaraju et al (2013) Curr Drug Delivery 10(1):96-108. Narang et al (2001) International Journal of Pharmacy and Pharmaceutical Sciences. 3(2):18-22. Olsen et al (1997) Australas J Dermatol 38(20). Olsen et al (1999) Journal of the American Academy of Dermatology.1999;40(2 Pt 1):242-6. Olsen et al (2004) Journal of the American Academy of Dermatology 51(3): p. 440-7. Olsen et al (2016) Journal of the American Academy of Dermatology 75(6): p. 1268 1270. Rowe et al (2009) Published by the Pharmaceutical Press and the American Pharmaceuticals Association. Sayeed et al (2014) Pharamceutical Technology. Volume 38, Issue 11. Singh et al (2012) Journal of Drug Delivery 4:407-417. Pfizer (2005) Medical Review application number: NDA 21-812 Minoxidil, Men's Rogaine extra strength 5% Topical foam. Johnson & Johnson (2014) Product Monograph Submission control number: 1732017 Rogain Topical 2% solution. USP/NP. Physical Tests: Disintegration (701) 22/17 ed. Rockville, MD: United States Pharmacopoeial Convention Inc; 1990

Claims

CLAIMS:

1. A method of treating autoimmune hair loss or excessive hair shedding in a subject by administering to a subject an effective dose of a tofacitinib that is predominantly absorbed through the oral mucosa.

2. The method of claim 1, wherein the oral mucosa is the sublingual mucosa.

3. The method of any one of claims 1 to 2, wherein the dose comprises a sublingual adhesion agent.

4. The method of any one of claims 1 to 3, wherein tofacitinib is in the range of from about 0.1 mg to 20 mg, or from about 0.1 mg to 18 mg, or from about 0.1 mg to mg, or from about 0.2 mg to 12.5 mg, or from about 0.2 mg to 10 mg, or from about 0.5 mg to 8 mg, or from about 1 mg to 6 mg, or from about 1 mg to 5 mg, or from about 1 mg to 4 mg, or from about 1 mg to 3 mg, or from about 1 mg to 2 mg, or is about 5 mg, or is about 4 mg, or is about 3 mg, or is about 2 mg, or is about 1 mg, or is about 0.5 mg daily.

5. The method of any one of claims 1 to 4, wherein the dose is administered at least every 3 days, at least every 2 days, or daily.

6. The method of any one of claims 1 to 5, wherein the dose is in a form selected from a: strip, wafer, pellet, film, troche, tablet, lipid matrix tablet, capsule, pill, granule, pellet, powder, drop, spray and lozenge.

7. The method of any one of claims 1 to 6, which further comprises administering one or more of a: (i) further JAK inhibitor, (ii) vasodilator, (iii) aldosterone antagonist, (iv) 5a-reductase inhibitor, (v) non-steroidal antiandrogen drug, (vi) steroidal antiandrogen, (vii) prostaglandin D2 receptor antagonist, (viii) immunosuppressant, and (ix) glucocorticoid.

8. The method of any one of claims 1 to 7, which further comprises administering one or more of: (i) a further JAK inhibitor in the range of from about 0.1 mg to 20 mg; (ii) minoxidil in the range of from about 0.1 mg to 20 mg; (iii) spironolactone in the range of from about 10 mg to 500 mg; (iv) finasteride in the range of from about 0.1 mg to 1 mg; (v) dutasteride in the range of from about 0.01 mg to 1 mg; (vi) flutamide in the range of from about 10 mg to 500 mg; (vii) cyproterone acetate in the range of from about 1 mg to 100 mg; (viii) bicalutamide in the range of from about 1 mg to 100 mg; (ix) enzalutamide in the range of from about 1 mg to 100 mg; (x) nilutamide in the range of from about 1 mg to 100 mg; (xi) drosperidone in the range of from about 0.1 mg to 10 mg; (xii) apalutamide in the range of from about 1 mg to 100 mg; (xiii) buseralin in the range of from about 0.1 mg to 10 mg; (xiv) setipiprant in the range of from about 50 mg to 4000 mg; (xv) fevipiprant in the range of from about 50 mg to 1000 mg; (xvi) cyclosporin in the range of from about 10 mg to 600 mg; (xvii)methotrexate in the range of from about 2.5 mg to 40 mg; (xviii) azathioprine in the range of from about 25 mg to 200 mg; (xix) prednisolone in the range of from about 0.1 mg to 40 mg; and (xx) dexamethasone in the range of from about 0.1 mg to 5 mg.

9. The method of claim 7 or claim 8, wherein thefurther JAK inhibitor is selected from baracitinib and ruxolitinib.

10. The method of any one of claims 1 to 9, wherein the autoimmune hair loss or excessive hair shedding is the result of one or more of the following autoimmune conditions; alopecia areata, alopecia totalis, alopecia universalis, androgenetic alopecia, telogen effluvium, anagen effluvium, , male pattern baldness, female pattern baldness, monilethrix, , polycystic ovary syndrome, cicatricial alopecia (lichen planopilaris, discoid lupus erythematosus, folliculitis decalvans), , loose anagen hair syndrome,

11. An oral composition when used to treat autoimmune hair loss or excessive hair shedding in a subject comprising an effective amount of tofacitinib predominantly absorbed through the oral mucosa.

12. The composition of claim 11, wherein the oral composition is a sublingual composition predominantly absorbed in the sublingual mucosa.

13. The composition of claim 11 of claim 12, wherein tofacitinib is in the range of from about 0.1 mg to 20 mg, or from about 0.1 mg to 18 mg, or from about 0.1 mg to mg, or from about 0.2 mg to 12.5 mg, or from about 0.2 mg to 10 mg, or from about 0.5 mg to 8 mg, or from about 1 mg to 6 mg, or from about 1 mg to 5 mg, or from about 1 mg to 4 mg, or from about 1 mg to 3 mg, or from about 1 mg to 2 mg, or is about 5 mg, or is about 4 mg, or is about 3 mg, or is about 2 mg, or is about 1 mg, or is about 0.5 mg daily.

14. The composition of any one of claims 11 to 13, which additionally comprises one or more of: (i) a further JAK inhibitor in the range of from about 0.1 mg to 20 mg; (ii) minoxidil in the range of from about 0.1 mg to 20 mg; (iii) spironolactone in the range of from about 10 mg to 500 mg; (iv) finasteride in the range of from about 0.1 mg to 1 mg; (v) dutasteride in the range of from about 0.01 mg to 1 mg; (vi) flutamide in the range of from about 10 mg to 500 mg; (vii) cyproterone acetate in the range of from about 1 mg to 100 mg; (viii) bicalutamide in the range of from about 1 mg to 100 mg; (ix) enzalutamide in the range of from about 1 mg to 100 mg; (x) nilutamide in the range of from about 1 mg to 100 mg; (xi) drosperidone in the range of from about 0.1 mg to 10 mg; (xii) apalutamide in the range of from about 1 mg to 100 mg;

(xiii) buseralin in the range of from about 0.1 mg to 10 mg; (xiv) setipiprant in the range of from about 50 mg to 4000 mg; (xv) fevipiprant in the range of from about 50 mg to 1000 mg; (xvi) cyclosporin in the range of from about 10 mg to 600 mg; (xvii)methotrexate in the range of from about 2.5 mg to 40 mg; (xviii) azathioprine in the range of from about 25 mg to 200 mg; (xix) prednisolone in the range of from about 0.1 mg to 40 mg; and (xx) dexamethasone in the range of from about 0.1 mg to 5 mg.

15. The composition of any one of claims 11 to 13, wherein the further JAK inhibitor is selected from baracitinib and ruxolitinib.

16. The composition of any one of claims 11 to 15, wherein the composition comprises one or more of: a sublingual adhesion agent, a disintegration agent which aids disintegration of the composition in the presence of saliva, and a taste modifying agent.

17. The composition of any one of claims 11 to 16, wherein the composition is in a form selected from a: strip, wafer, pellet, film, troche, tablet, lipid matrix tablet, capsule, pill, granule, pellet, powder, drop, spray and lozenge.

18. The composition of claim 17, wherein the composition is in a form selected from a: strip, wafer, and film.

19. Use of tofacitinib in the preparation of a medicament for the treatment of autoimmune hair loss or excessive hair shedding in a subject by administering to a subject an effective dose of tofacitinib through the oral mucosa.

20. Use of tofacitinib in the preparation of a medicament for the treatment of autoimmune hair loss or excessive hair shedding in a subject by administering to a subject an effective dose of tofacitinib through the sublingual mucosa.

Figure 1 1/2

Figure 2 2/2