US20090269418A1 - Compositions and Methods for Inducing Hair Growth - Google Patents

Compositions and Methods for Inducing Hair Growth Download PDF

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US20090269418A1
US20090269418A1 US11/662,743 US66274305A US2009269418A1 US 20090269418 A1 US20090269418 A1 US 20090269418A1 US 66274305 A US66274305 A US 66274305A US 2009269418 A1 US2009269418 A1 US 2009269418A1
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alopecia
tellurium
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pharmaceutical composition
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Michael Albeck
Benjamin Sredni
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Biomas Ltd
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Definitions

  • the present invention relates to novel therapeutic methods and pharmaceutical compositions for inducing hair growth and, more particularly, to compositions comprising and methods utilizing tellurium-containing compounds for inducing hair growth and thus for the treatment of various types of alopecia and other conditions associated with hair loss.
  • Alopecia is the most common hair growth disorder in humans. Hair loss most commonly occurs from the scalp. However, any hair-bearing area can be affected, including eyebrows, eyelashes, beard and body areas.
  • Hair is composed of keratin, a strong structural protein.
  • Each strand of hair consists of three layers:
  • the outermost layer known as the cuticle, which is thin and colorless and serves as a protector of the cortex.
  • the hair follicle is a dynamic structure that generates hair through complex and extraordinarly regulated cycles of growth and remodeling. It represents an ectodermal-mesenchymal interaction unit that displays unique life-long, cyclic transformations between stages of rapid growth and production of a pigmented hair shaft (anagen), apoptosis-driven regression (catagen), and relative resting (telogen).
  • Every phase in the hair cycle is characterized by defined, tightly coordinated programs of tissue proliferation, differentiation, and apoptosis, that are controlled by the local balance of numerous growth-stimulatory and growth-inhibitory signals [1, 2].
  • Growth and development of hair follicles is influenced by a variety of growth factors and cytokines, such as epidermal growth factor [3], transforming growth factor [4], hepatocyte growth factor [5], interleukin-1 [6], Glial cell line-derived neurotrophic factor [7], parathyroid hormone-related protein [8], bone morphogenetic protein-4, and several members of the fibroblast growth factor family (FGF) [3]. It has been previously proposed that one member of this family, FGF-7, known as the keratinocyte growth factor (KGF), is an important endogenous mediator of normal hair growth and development [9].
  • KGF-7 keratinocyte growth factor
  • the dermal papilla At the base of the hair follicle is the dermal papilla, which is fed by the bloodstream, which carries nourishment to produce new hair.
  • the dermal papilla contains receptors for male hormones and androgens. Androgens regulate hair growth and may cause the hair follicle to get progressively smaller and the hairs to become finer in individuals who are genetically predisposed to this type of hair loss.
  • Alopecia can be divided into disorders in which the hair follicle is normal but the cycling of hair growth is abnormal, and disorders in which the hair follicle is damaged.
  • Six major types of alopecia are known: adrogenetic alopecia, alopecia greata, anagen effluvium, self-induced hair loss, telogen effluvium and scarring alopecia.
  • Androgenetic alopecia includes male pattern baldness and female pattern baldness. Androgenetic alopecia accounts for 95% of all hair loss. This genetically determined disorder is progressive through the gradual conversion of large, thick, pigmented, terminal hairs into thinner, shorter, indeterminate hairs and finally to short, wispy, non-pigmented, vellus hairs. Patients have a reduction in the terminal-to-vellus hair ratio, normally at least 2:1. Following miniaturization of the follicles, fibrous tracts remain. Patients with this disorder usually have a typical distribution of hair loss.
  • DHT The male hormone dihydrotestosterone
  • testosterone by the enzyme 5-alpha-reductase
  • DHT causes a gradual reduction of scalp hair follicle size and reduced time in the anagen stage of the growth cycle, leading to more hair follicles in the telogen stage.
  • Proven treatments for androgenetic alopecia include topical application of minoxidil and oral administration of finestidine.
  • Minoxidil (marketed under the name RogaineTM), as described in U.S. Pat. No. 4,139,619, appears to work by stimulating the conversion of vellus hair to terminal hair, as well as increasing the rate of growth of terminal hair. This has the effect of gradually enlarging and lengthening hair follicles which have been gradually shrinking due to androgenetic alopecia, and extending the growth phase, giving the hairs an opportunity to reach a longer length before they fall out.
  • the two main disadvantages associated with minoxidil are its high cost, and the need for its continuous application in order to maintain the results achieved.
  • Finasteride (PropeciaTM), as described in EP 155096B1 to Merck, is a 4-aza-steroid compound that is a specific inhibitor of type 2 5-alpha-reductase.
  • Reported side effects include breast enlargement and tenderness, skin rashes, and swelling of the lips, abdominal pain, back pain, decreased libido, diarrhea, dizziness, headache, impotence, and decreased volume of ejaculate.
  • Treatment for androgenetic alopecia include retin-A; ketoconazole; azelaic acid; zinc; Saw Palmetto extract; gamma linoleic acid; vitamin B6; and polysorbate 80.
  • Treatments for female pattern baldness include use of cimetidine, cyproterone acetate, or spironolactone, all of which block the binding of DHT dihydrotestosterone to its receptors; and ketaconazole, which can cause a reduction in the production of testosterone and other androgens by the adrenal gland and by the male and female reproductive organs; or of a combined treatment of cyproterone acetate with ethinyloestradiol, which blocks the peripheral action of male hormones commonly present in the female body.
  • Propecia has been found to be ineffective in treating women suffering from androgenetic alopecia.
  • Alopecia greata is thought to be an autoimmune disease in which T-lymphocytes attack the hair follicles, causing the hair to stop growing and enter into the telogen phase. At the end of the telogen phase, the hair falls out.
  • Alopecia areata affects both men and women equally and is often experienced first in childhood.
  • Oral zinc has been shown to be of occasional benefit in alopecia greata and appears to possess an immunomodulatory effect as well as an anti-androgenetic effect. However very high doses are needed for it to be effective and this may result in side effects, which can include vomiting and diarrhea.
  • PUVA treatment which involves use of a psoralen, which is a light sensitive drug, followed by a short period of exposure to long-wave ultraviolet light; application of irritants or allergens to the scalp, which cause an allergic reaction, drawing the T-lymphocytes away from the hair follicle, thus allowing the hair a chance to start regrowing; and use of immunosuppressive drugs.
  • Possible side effects of oral cortisone include fluid retention and weight increase, osteoporosis, hypertension, sugar diabetes, indigestion or worsening of a peptic ulcer, mood changes, impaired healing of cuts, increased growth of facial hair, increased risk of infection, muscle weakness, joint pain and cataract of the eye.
  • Side-effects of immuno-suppressive drugs include lowered resistance to infection.
  • Anagen effluvium is the sudden hair loss, which occurs as a result of exposure to chemicals or radiation, such as the hair loss that results during certain types of chemotherapy or radiation treatment, or as a result of exposure to toxic chemicals such as thallium and arsenic.
  • the hair does not enter a resting stage.
  • the hair loss is usually sudden occurring 1 to 3 weeks after expose to the chemicals or radiation has occurred. In most cases hair growth will return to normal once treatment is finished.
  • the drugs which are most likely to cause hair loss include amsacrine; cisplatinum; cytosine arabinoside; cyclophosphamide; doxorubicin; epirubicin; etoposide ifosfamide; and vincristine. It has been found that agents which protect against alopecia induced by a particular drug may be ineffective in protecting against a different drug. For example, a composition obtained from the bacteria Serratia marcescens has been used to protect against the alopecia which is associated with the use of cytosine araginoside and doxorubicin. This composition had no effect on alopecia which was induced by cyclophosphamide.
  • Self-induced hair loss may be inflicted consciously or unconsciously.
  • the two main types of self-induced hair loss are trichotillomania and traction alopecia.
  • Trichotillomania is self-induced hair loss which results from the continuous pulling or plucking of the hair. It occurs most commonly among young children, adolescents and women and affects twice as many females as males. The hair is often pulled out in distinct patches on the scalp. However some individuals also pull out eyebrows and eyelashes.
  • the treatment for trichotillomania often involves counseling or psychiatric help, whereby in some cases an antidepressant is prescribed.
  • Traction alopecia is usually caused by continuous and excessive pulling on the hair due to various types of hairstyling, which gradually results in hair loss that may become permanent. Generally, however, a change in hairstyle that reduces the traction on the hair and hair follicle is sufficient to reverse the hair loss in this case.
  • Telogen effluvium is sudden or severe stress related hair loss, which appears as thinning throughout the whole scalp.
  • a sudden or stressful event can cause the hair follicles to prematurely stop growing and enter into a resting phase.
  • the hair will then stay in the resting phase for about 3 months after which time a large amount of hair will be shed.
  • the hair loss is temporary and the hair soon recovers. However in some cases the hair loss continues until the underlying cause is removed.
  • telogen effluvium include childbirth; termination of pregnancy; starting or stopping birth control pills; use of various medications; and severe emotional stress.
  • birth control pills affect the hormone levels within the body and these hormone levels can affect hair growth.
  • hair thinning may occur due to the male hormones present is some types of contraceptive pills, resulting in hair loss similar to that of androgenetic alopecia.
  • Discontinuation of the pill can result in hair loss similar to that which occurs after childbirth, due to the drop in hormone levels.
  • Drugs which may cause hair loss as a side effect include anti-gout agents such as alloppurinol; blood thinners such as heparin and coumarin; and cholesterol lowering drugs such as clofibrate and gemfibrozil.
  • Telogen effluvium may also occur after a traumatic event such as the death of a loved one, an accident, abuse or any other severely traumatic event. These events may trigger hair follicles to enter the resting phase prematurely in which case an increase in the amount of hair shed will be noticed about 3 months after the event.
  • telogen effluvium causes of telogen effluvium include thyroid gland malfunction (hypothyroidism or hyprethyroidism, which occurs when the thyroid gland produces too little or too much, respectively, of the thyroid hormone, thyroxin); diabetes; anaemia; and the autoimmune disease, systemic lupus erythematosis.
  • Scarring alopecia occurs as a result of inflammation of the hair follicles due to infection.
  • Scarring alopecia may be caused by discoid lupus erythematosus, a diffuse connective tissue disease; lichenplanus, which is an inflammatory disease that strikes primarily the skin and mucous membranes; Pseudopelade of Brocq, a rare scarring alopecia which has no potential for regrowth; aplasia cutis congenita, a rare disorder that often results as a small blistered atrophied area usually in the midline of the scalp and present from birth; or congenital ctrichia.
  • hair loss include syphilitic alopecia, a secondary manifestation of syphilis; scleroderma; and tinea capitis (ringworm).
  • U.S. Pat. No. 5,262,149 teaches a method for treatment or prevention of alopecia which is induced by an antineoplastic agent, by administration of a tellurium-containing compound prior to the administration of the antineoplastic agent.
  • U.S. Pat. No. 6,552,089 teaches a method for treatment or prevention of male pattern baldness by administration of a tellurium-containing compound.
  • the preferred tellurium-containing compounds utilized in the methods taught by these patents are widely described in, for example, U.S. Pat. Nos. 4,752,614; 4,761,490; 4,764,461 and 4,929,739, which are all incorporated by reference as if fully set forth herein.
  • AS101 ammonium trichloro(dioxyethylene-O,O′)tellurate, which is also referred to herein and in the art as AS101.
  • AS101 as a representative example of the family of tellurium-containing compound discussed hereinabove, has been found to have act as an immunomodulator which stimulates the innate and acquired arms of the immune system, and is a potent inducer of interferon (IFN) in mice and in humans.
  • IFN interferon
  • U.S. Pat. Nos. 5,262,149 and 6,522,089 fail to demonstrate the efficacy of these tellurium-containing compounds in treating types of alopecia other than male pattern baldness and alopecia induced by an antineoplastic agent.
  • U.S. Pat. No. 5 6,522,089 refers to non-scarring alopecia as including toxic alopecia, alopecia greata and trichotillomania, and teaches that non-scarring alopecia may be avoided or reduced by administration of an effective amount of an effective tellurium compound
  • this patent fails to provide enabling examples with regard to forms of alopecia other than alopecia induced by chemotherapeutic agents. This document therefore merely provides an invitation to try to find forms of alopecia which are treatable by tellurium compounds, without any disclosure as to which particular forms, other than alopecia induced by an antineoplastic agent, are suitable for such treatment.
  • AS101 In human clinical studies ( FASEB J 18: 400-402, 2004), AS101 exhibited the ability to protect cancer patients from both bone marrow toxicity and alopecia induced by chemotherapy. AS101 has been found to induce hair growth in nude mice, normal mice, and in humans. In nude mice, AS101 exerts this effect when applied systemically, orally or topically. AS101 possesses the dual ability to both induce anagen and retard spontaneous catagen in the C57BL/6 mouse model.
  • Anagen induced by AS101 is mediated by keratinocyte growth factor (KGF) since it is abrogated both in nude mice co-treated with AS101 and neutralizing anti-KGF antibodies, and in AS101-treated transgenic mice expressing a dominant negative KGF receptor transgene in basal keratinocytes.
  • KGF keratinocyte growth factor
  • AS101 upregulates KGF expression by interacting with the Cys118 residue in p21 ras and activating the ras signalling pathway in cultured fibroblasts.
  • AS101-induced delayed catagen is associated with inhibition of terminal differentiation marker expression in epidermal follicular keratinocytes and in cultures of primary mouse follicular keratinocytes induced to differentiate both in nude and C57BL/6 mice.
  • a method of treating or preventing alopecia, excluding male pattern baldness and alopecia induced by antineoplastic agents comprising administration to a subject in need thereof a therapeutically effective amount of a compound having at least one tellurium dioxide moiety.
  • At least one tellurium-containing compound having at least one tellurium dioxide moiety in treating or preventing alopecia, excluding male pattern baldness and alopecia induced by antineoplastic agents.
  • compositions identified for use in the treatment or prevention of alopecia, excluding male pattern baldness and alopecia induced by antineoplastic agents, the composition comprising at least one tellurium-containing compound having at least one tellurium dioxide moiety.
  • the tellurium dioxide moiety is optionally and preferably at least one of tellurium dioxide (TeO 2 ) per se, an organic complex of TeO 2 (as detailed hereinbelow), a compound having general Formula I:
  • each of t, u and v is independently 0 or 1;
  • each of m and n is independently an integer from 0 to 3;
  • Y is selected from the group consisting of ammonium, phosphonium, potassium, sodium and lithium;
  • X is a halogen atom
  • each of R 1 -R 14 is independently selected from the group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate and sulfonamido.
  • each of R 1 , R 8 , R 9 and R 10 is hydrogen; more preferably X is a halogen atom, most preferably the halogen atom is chloro. More preferably, Y is ammonium.
  • the preferred compound according to this embodiment is referred to hereinafter as AS101.
  • the method may optionally further comprise administering a therapeutically effective amount of an additional active agent for treating alopecia.
  • administration of the tellurium-containing compound may be effected by the intraperitoneal, parenteral, oral, topical, rectal, transmucosal, intestinal, intrathecal, direct intraventricular, intravenous, intranasal, or intraocular route.
  • a therapeutically effective amount administered intraperitoneally preferably ranges from about 0.025 to about 0.8 mg/kg of body weight.
  • a therapeutically effective amount for parenteral administration preferably ranges from about 0.025 to about 2.5 mg/kg of body weight.
  • a therapeutically effective amount for oral administration preferably ranges from about 0.025 to about 7.5 mg/kg of body weight.
  • administering is effected topically, preferably by applying a therapeutically effective amount of a tellurium-containing compound onto a treated skin area.
  • administering is preferably effected according to a regime that ranges from twice daily to once weekly. In one preferred embodiment, administering is effected on a daily basis.
  • administering is effected for a time period that ranges from 1 day to 90 days and more preferably from 7 days to 90 days.
  • the tellurium-containing compound of the method or use of the present invention forms a part of a pharmaceutical composition, further comprising a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated as a gel, a cream, an ointment, a paste, a lotion, a milk, a suspension, an aerosol, a spray, a foam, a serum, a swab, a pledglet, a pad or a patch.
  • a concentration of tellurium-containing compound of formula I, II or III in the carrier ranges from about 0.01 weight percent to about 50 weight percents, more preferably from about 0.01 weight percent to about 20 weight percents of the total weight of the composition.
  • the composition of the present invention may optionally further comprise at least one additional active agent for treating alopecia.
  • the additional active agent of the method, use or composition of the present invention may be, for example, minoxidil, finasteride, retin-A; ketoconazole; azelaic acid; zinc; Saw Palmetto extract; gamma linoic acid; vitamin B6; polysorbate 80; cyproterone acetate; ethinyloestradiol; cimetidine; spironolactone; ketaconazole, a corticosteroid; dithranol; an immunosuppressive drug or an irritant.
  • the additional active agent is minoxidil, finasteride or a combination thereof.
  • the alopecia treated or prevented by the method, use or pharmaceutical composition of the present invention may optionally comprise alopecia induced by an autoimmune disease (such as alopecia greata); female pattern baldness; self-induced alopecia; traction alopecia; tellogen effluvium; and scarring alopecia (such as that caused by discoid lupus erythmatosus, lichen planus, aplasia cutis congenital or congenital atrichia).
  • an autoimmune disease such as alopecia greata
  • female pattern baldness self-induced alopecia
  • traction alopecia such as that caused by discoid lupus erythmatosus, lichen planus, aplasia cutis congenital or congenital atrichia.
  • tellogen effluvium treated or prevented by the method, use or pharmaceutical composition of the present invention may be, for example, that associated with administration of a drug, such as a contraceptive pill, an anti-gout agent, a blood thinner, or a cholesterol lowering agent, including, but not limited to allopurinol, heparin, coumarin, clofibrate and gemfibrozil.
  • a drug such as a contraceptive pill, an anti-gout agent, a blood thinner, or a cholesterol lowering agent, including, but not limited to allopurinol, heparin, coumarin, clofibrate and gemfibrozil.
  • the tellogen effluvium may be due to a condition such as, for example, thyroid gland malfunction, diabetes, anemia or systemic lupus erythematosis.
  • a method of inducing hair growth and/or reducing or preventing hair loss comprising administering to a subject in need thereof a therapeutically effective amount of at least one tellurium-containing compound having general Formula IV:
  • each of m and n is independently an integer from 0 to 3;
  • each of R 15 -R 22 is independently selected from the group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate and sulfoneamido.
  • composition identified for use in inducing hair growth and/or reducing or preventing hair loss in a subject in need thereof, the composition comprising a therapeutically effective amount of at least one tellurium-containing compound having general Formula IV, as defined above.
  • n and m of the compound of general Formula IV are each 0. More preferably, each of R 15 , R 18 , R 19 and R 22 is hydrogen.
  • the preferred compound according to this embodiment is referred to hereinafter as SAS.
  • the method of the present invention further comprises administering a therapeutically effective amount of an additional active agent for inducing hair growth and/or reducing or preventing hair loss.
  • the tellurium-containing compound is used in combination with at least one additional active agent for inducing hair growth and/or reducing or preventing hair loss.
  • the additional active agent of the method, use or composition of the present invention may be, for example, minoxidil, finasteride, retin-A; ketoconazole; azelaic acid; zinc; Saw Palmetto extract; gamma linoic acid; vitamin B6; polysorbate 80; cyproterone acetate; ethinyloestradiol; cimetidine; spironolactone; ketaconazole, a corticosteroid; dithranol; an immunosuppressive drug or an irritant.
  • the additional active agent is minoxidil, finasteride, or combinations thereof.
  • administration of the tellurium-containing compound may be effected by the intraperitoneal, parenteral, oral, topical, rectal, transmucosal, intestinal, intrathecal, direct intraventricular, intravenous, intranasal, or intraocular route.
  • a therapeutically effective amount of the compound of formula IV administered intraperitoneally preferably ranges from about 0.04 to about 1.3 mg/kg of body weight.
  • a therapeutically effective amount of the compound of formula IV for parenteral administration preferably ranges from about 0.04 to about 4.2 mg/kg of body weight.
  • a therapeutically effective amount of the compound of formula IV for oral administration preferably ranges from about 0.04 to about 12.7 mg/kg of body weight.
  • administration is effected topically by applying onto a treated skin or mucosal membrane area a therapeutically effective amount of the at least one tellurium-containing compound described above.
  • administering is preferably effected according to a regime that ranges from twice daily to once weekly, more preferably for a time period that ranges from 1 day to 90 days and more preferably from 7 days to 90.
  • the method, use or pharmaceutical composition of the present invention may preferably be used for treating a condition in which inducing hair growth and/or preventing hair loss is beneficial, such as, for example, adrogenetic alopecia, alopecia greata, anagen effluvium (such as induced by an antineoplastic agent), self-induced hair loss, telogen effluvium and scarring alopecia (such as caused by discoid lupus erythmatosus, lichen planus, aplasia cutis congenital and congenital atrichia).
  • a condition in which inducing hair growth and/or preventing hair loss is beneficial such as, for example, adrogenetic alopecia, alopecia greata, anagen effluvium (such as induced by an antineoplastic agent), self-induced hair loss, telogen effluvium and scarring alopecia (such as caused by discoid lupus erythmato
  • the tellogen effluvium treated or prevented by the method, use or pharmaceutical composition of this aspect of the present invention may be due to a drug such as a contraceptive pill, an anti-gout agent, a blood thinner, or a cholesterol lowering agent, such as, for example, allopurinol, heparin, coumarin, clofibrate and gemfibrozil, which may optionally be co-administered together with the tellurium-containing compound.
  • the tellogen effluvium may optionally be due thyroid gland malfunction, diabetes, anemia or systemic lupus erythematosis.
  • tellurium-containing compound of the method or use or pharmaceutical composition of the present invention may optionally form a part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier, more preferably the composition is formulated as a gel, a cream, an ointment, a paste, a lotion, a milk, a suspension, an aerosol, a spray, a foam, a serum, a swab, a pledglet, a pad or a patch.
  • a concentration of tellurium-containing compound of formula IV in the carrier ranges from about 0.1 weight percent to about 85 weight percents, more preferably from about 0.1 weight percents to about 40 weight percents of the total weight of the composition.
  • the present invention successfully addresses the shortcomings of the presently known configurations by providing methods, uses and compositions for treatment or prevention of alopecia other than male pattern baldness and alopecia caused by antineoplastic agents, and further provides methods, uses and compositions for inducing hair growth and/or reducing or preventing hair loss.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
  • treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
  • composition or method may include additional ingredients and/or steps, but only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • terapéuticaally effective amount denotes that dose of an active ingredient or a composition comprising the active ingredient that will provide the therapeutic effect for which the active ingredient is indicated.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range.
  • the phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
  • FIG. 1 is an example of the analysis of results obtained in the present study using the TrichoScan system
  • FIGS. 2 a and 2 b present graphical representation of results obtained in the study described in Example 1 for a representative female subject aged 39 ( FIG. 2 a ) and a representative male subject aged 29 ( FIG. 2 b );
  • FIG. 3 shows results obtained by a specific patient with twice daily administration of AS101.
  • the present invention is of the use of tellurium-containing compounds for treating and/or preventing alopecia.
  • the present invention provides methods utilizing tellurium-containing compound having at least one tellurium dioxide moiety, to treat or prevent alopecia, excluding male pattern baldness and alopecia induced by antineoplastic agents.
  • the present invention further provides other tellurium-containing compounds, which can be used for inducing hair growth and/or reducing or preventing hair loss.
  • tellurium-containing compound encompasses any compound that includes one or more tellurium atoms and exhibits immunomodulating properties.
  • the tellurium-containing compounds include one or more tellurium dioxide moiety.
  • alopecia differ in their underlying causes, which take effect according to various mechanisms of actions. Furthermore, as further described hereinabove, a composition obtained from the bacteria Serratia marcescens which was found to protect against the alopecia which is associated with the use of cytosine araginoside and doxorubicin had no effect on alopecia which was induced by cyclophosphamide. Hence, it is apparent that the various types of alopecia may respond differently to a particular compound for treatment of alopecia.
  • alopecia greata which is an autoimmune disease
  • U.S. Pat. No. 5,262,149 teaches use of a tellurium containing compound of general formula I, II or III, preferably AS101, for treatment or prevention of alopecia which is induced by an antineoplastic agent, and U.S. Pat. No. 6,552,089 teaches use of these compounds for treatment or prevention of male pattern baldness.
  • the background art does not teach or suggest the efficacy of these tellurium-containing compounds in treating types of alopecia other than male pattern baldness and alopecia induced by an antineoplastic agent.
  • U.S. Provisional Patent Application No. 60/610,660 discloses a novel family of tellurium-containing compounds, (which are collectively represented by general formula IV herein), use of which has not been suggested nor practiced for inducing hair growth and/or reducing or preventing hair loss.
  • AS101 as well as other tellurium-containing immunomodulators, stimulate the innate and acquired arm of the immune response.
  • AS101 is a potent activator of interferon (IFN) (IFN) in mice ( J. Natl. Cancer Inst. 88(18):1276-84, 1996) and humans ( Nat. Immun. Cell Growth Regul. 9(3):182-90, 1990 ; Immunology 70(4):473-7, 1990 ; J. Natl. Cancer Inst. 88(18):1276-84, 1996.)
  • IFN interferon
  • AS101 as well as other tellurium-containing immunomodulators, induce the secretion of a spectrum of cytokines, such as IL-1, IL-6 and TNF- ⁇ , and that macrophages are one main target for AS101 ( Exp. Hematol. 23(13):1358-66, 1995) and it was found to inhibit IL-10 at the m-RNA level, and this inhibition may cause an increase in IL-12 ( Cell Immunol. 176(2):180-5, 1997); J. Natl. Cancer Inst. 88(18):1276-84, 1996).
  • cytokines such as IL-1, IL-6 and TNF- ⁇
  • macrophages are one main target for AS101 ( Exp. Hematol. 23(13):1358-66, 1995) and it was found to inhibit IL-10 at the m-RNA level, and this inhibition may cause an increase in IL-12 ( Cell Immunol. 176(2):180-5, 1997); J. Natl. Cancer Inst. 88
  • the process of hair follicle development consists of a series of dermal-epidermal signaling events that culminate with the mesenchymal cells of the dermal papilla inducing epithelial cells of the hair plug to grow and differentiate into a follicle. It follows from this that substances that mediate intercellular signaling events, that in turn affect intracellular control mechanisms inside follicular keratinocytes, would enhance the maintenance of normal hair growth.
  • growth and development of hair follicles is known to be influenced by growth factors and cytokines, such as epidermal growth factor [3], transforming growth factor [4], hepatocyte growth factor [5], interleukin-1 [6], Glial cell line-derived neurotrophic factor [7], parathyroid hormone-related protein [8], bone morphogenetic protein-4, and several members of the fibroblast growth factor family (FGF) [3].
  • growth factors and cytokines such as epidermal growth factor [3], transforming growth factor [4], hepatocyte growth factor [5], interleukin-1 [6], Glial cell line-derived neurotrophic factor [7], parathyroid hormone-related protein [8], bone morphogenetic protein-4, and several members of the fibroblast growth factor family (FGF) [3].
  • the present inventors have postulated that the immunomodulatory effect of the tellurium containing compound AS101 can be harnessed to treat alopecia other than male pattern baldness and alopecia caused by antineoplastic agents, and also to induce hair growth and/or reduce or prevent hair loss.
  • alopecia which includes male pattern baldness and female pattern baldness, is known to be caused by the hormone dihydrotestosterone; alopecia greata is believed to be an auto-immune disease in which T-lymphocytes attack the hair follicles; anagen effluvium occurs during certain types of chemotherapy or radiation treatment, or as a result of exposure to toxic chemicals, such that the hair is prevented from entering the resting stage; self-induced hair loss is related to an underlying psychological factor; traction alopecia is caused by physical strain exerted on the hair, such as pulling due to a specific hairstyle; telogen effluvium is caused by sudden or stressful event, which may be an emotional trauma, or a hormone-induced stress, such as that following childbirth; and scarring alopecia occurs as a result of inflammation of the hair follicles due to infection.
  • tellurium-containing compounds which are known to be effective in treating alopecia due to antineoplastic agents and male pattern baldness, could not be anticipated to be effective in treating other types of alopecia.
  • AS101 and related tellurium-containing compounds are effective in treatment or prevention of many types of alopecia, in addition to those described in the background art.
  • compounds of the general formula IV can be effective in generally inducing hair growth and/or reducing or preventing hair loss.
  • the present invention therefore provides a method of treating or preventing alopecia, excluding male pattern baldness and alopecia induced by antineoplastic agents, by administration of a therapeutically effective amount of at least one tellurium-containing compound having at least one tellurium dioxide moiety, and optionally and preferably selected from the group consisting of tellurium dioxide (TeO 2 ) per se, an organic complex of TeO 2 (as detailed hereinbelow), a compound having general Formula I:
  • each of t, u and v is independently 0 or 1;
  • each of m and n is independently an integer from 0 to 3;
  • Y is selected from the group consisting of ammonium, phosphonium, potassium, sodium and lithium;
  • X is a halogen atom
  • each of R 1 -R 14 is independently selected from the group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate and sulfonamido.
  • each of R 1 , R 8 , R 9 and R 10 is hydrogen; more preferably X is a halogen atom, most preferably the halogen atom is chloro. More preferably, Y is ammonium.
  • the preferred compound according to this embodiment is referred to hereinafter as AS101.
  • the present invention further provides a method of inducing hair growth and/or reducing or preventing hair loss, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one tellurium-containing compound having general Formula IV:
  • each of m and n is independently an integer from 0 to 3;
  • each of R 15 -R 22 is independently selected from the group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate and sulfoneamido.
  • n and m are each 0. More preferably, each of R 15 , R 18 , R 18 and R 22 is hydrogen.
  • the hair loss treated or prevented may be alopecia.
  • alkyl refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 1 to 20 carbon atoms. Whenever a numerical range; e.g., “1-20”, is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. More preferably, the alkyl is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkyl is a lower alkyl having 1 to 5 carbon atoms. The alkyl group may be substituted or unsubstituted.
  • the substituent group can be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfate, cyano, nitro, sulfonamide, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate, amido, sulfonamido, and amino, as these terms are defined herein.
  • hydroxyalkyl refers to an alkyl, as this term is defined herein, substituted by a hydroxy group, as defined herein, and includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxy-n-butyl.
  • haloalkyl refers to an alkyl, as this term is defined herein, substituted by a halogen, as defined herein, and includes, for example, chloromethyl, 2-iodoethyl, 4-bromo-n-butyl, iodoethyl, 4-bromo-n-pentyl and the like.
  • alkanoyloxy refers to a carbonyl group, as define herein and includes, for example, acetyl, propionyl, butanoyl and the like.
  • carboxyalkyl refers to an alkyl, as this term is defined herein, substituted by a carboxy group, as defined herein, and includes, for example, carboxymethyl, carboxyethyl, ethylenecarboxy and the like.
  • alkylcarbonylalkyl refers to an alkyl, as this term is defined herein, substituted by a carbonyl group, as defined herein, and includes, for example, methanoylmethyl, ethanoylethyl and the like.
  • amidoalkyl refers to an alkyl, as this term is defined herein, substituted by an amide group, as defined herein, and includes, for example, —CH 2 CONH 2 ; —CH 2 CH 2 CONH 2 ; —CH 2 CH 2 CH 2 CONH 2 and the like.
  • cyanoalkyl refers to an alkyl, as this term is defined herein, substituted by an cyano group, as defined herein, and includes, for example, —CH 2 CN; —CH 2 CH 2 CN; —CH 2 CH 2 CH 2 CN and the like.
  • N-monoalkylamidoalkyl refers to an alkyl, as this term is defined herein, substituted by an amide group, as defined herein, in which one of R′ and R′′ is an alkyl, and includes, for example, —CH 2 CH 2 CONHCH 3 , and —CH— 2 CONHCH 2 CH 3 .
  • N,N-dialkylamidoalkyl refers to an alkyl, as this term is defined herein, substituted by an amide group, as defined herein, in which both R′ and R′′ are alkyl, and includes, for example, —CH 2 CON(CH 3 ) 2 ; CH 2 CH 2 CON(CH 2 —CH 3 ) 2 and the like.
  • a “cycloalkyl” group refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein one of more of the rings does not have a completely conjugated pi-electron system.
  • examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene, and adamantane.
  • a cycloalkyl group may be substituted or unsubstituted.
  • the substituent group can be, for example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro, phosphonyl, phosphinyl, carbonyl, thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate, amido, sulfonamido, and amino, as these terms are defined herein.
  • alkenyl refers to an alkyl group which consists of at least two carbon atoms and at least one carbon-carbon double bond.
  • alkynyl group refers to an alkyl group which consists of at least two carbon atoms and at least one carbon-carbon triple bond.
  • aryl group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group may be substituted or unsubstituted.
  • the substituent group can be, for example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfate, cyano, nitro, phosphonyl, phosphinyl, phosphonium, carbonyl, thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate, amido, sulfonamido, and amino, as these terms are defined herein.
  • heteroaryl group refers to a monocyclic or fused ring (i.e., rings which to share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system.
  • heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine.
  • the heteroaryl group may be substituted or unsubstituted.
  • the substituent group can be, for example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfate, cyano, nitro, phosphonyl, phosphinyl, phosphonium, carbonyl, thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate, amido, sulfonamido, and amino, as these terms are defined herein.
  • a “heteroalicyclic” group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur.
  • the rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system.
  • the heteroalicyclic may be substituted or unsubstituted.
  • the substituted group can be, for example, lone pair electrons, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfate, cyano, nitro, phosphonyl, phosphinyl, phosphonium, carbonyl, thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate, amido, sulfonamido, and amino, as these terms are defined herein.
  • Representative examples are piperidine, piperazine, tetrahydro furane, tetrahydropyrane, morpholino and the like.
  • a “hydroxy” group refers to an —OH group.
  • alkoxy refers to both an —O-alkyl and an —O-cycloalkyl group, as defined herein.
  • aryloxy refers to both an —O-aryl and an —O-heteroaryl group, as defined herein.
  • a “thiohydroxy” group refers to a —SH group.
  • a “thioalkoxy” group refers to both an —S-alkyl group, and an —S-cycloalkyl group, as defined herein.
  • a “thioaryloxy” group refers to both an —S-aryl and an —S-heteroaryl group, as defined herein.
  • a “carbonyl” group refers to a —C( ⁇ O)—R′ group, where R′ is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) or heteroalicyclic (bonded through a ring carbon) as defined herein.
  • a “thiocarbonyl” group refers to a —C( ⁇ S)—R′ group, where R′ is as defined herein for R′.
  • a “carboxy” group refers to a —C( ⁇ O)—O—R′ or a —O—C( ⁇ O)—R′ group, where R′ is as defined herein.
  • a “sulfinyl” group refers to an —S( ⁇ O)—R′ group, where R′ is as defined herein.
  • a “sulfonyl” group refers to an —S( ⁇ O) 2 —R′ group, where R′ is as defined herein.
  • a “sulfate” group refers to a —O—S( ⁇ O) 2 —OR′ group, where R′ is as defined herein.
  • a “sulfonamido” group refers to a —S( ⁇ O) 2 —NR′R′′ group or a R′S( ⁇ O) 2 —NR′′, with R′ is as defined herein and R′′ is as defined for R′.
  • a “carbamyl” or “carbamate” group refers to an —OC( ⁇ O)—NR′R′′ group or a R′′OC( ⁇ O)—NR′— group, where R′ and R′′ are as defined herein.
  • a “thiocarbamyl” or “thiocarbamate” group refers to an —OC( ⁇ S)—NR′R′′ group or an R′′OC( ⁇ S)NR′— group, where R′ and R′′ are as defined herein.
  • amino refers to an —NR′R′′ group where R′ and R′′ are as defined herein.
  • An “amido” group refers to a —C( ⁇ O)—NR′R′′ group or a R′C( ⁇ O)—NR′′ group, where R′ and R′′ are as defined herein.
  • a “nitro” group refers to an —NO 2 group.
  • a “cyano” group refers to a —C ⁇ N group.
  • phosphonyl describes a —O—P( ⁇ O)(OR′)(OR′′) group, with R′ and R′′ as defined hereinabove.
  • phosphinyl describes a —PR′R′′ group, with R′ and R′′ as defined hereinabove.
  • the compounds in this category are salts of organic tellurium-containing compounds.
  • the salts can be, for example, ammonium salts, phosphonium salts and alkaline salts such as potassium salts, sodium salts, lithium salts and the like.
  • Y in Formula I above can be a phosphonium group, as defined herein, an ammonium group, as defined herein, potassium (K + ), sodium (Na + ) or lithium (Li + ).
  • phosphonium describes a —P+R′R′′R′′′ group, with R′ and R′′ as defined herein and R′′′ is as defined for R′.
  • phosphonium as used herein, further refers to a —P + R 6 group, wherein each of the six R substituents is independently as defined herein for R′, R′′ and R′′′.
  • ammonium describes a —N+R′R′′R′′′ group, with R′, R′′ and R′′′ as defined herein.
  • More preferred compounds in this category include compounds having the general Formula I described above, in which Y is ammonium or phosphonium, t, u and v are each 0, and each of R 1 , R 8 , R 9 and R 10 is independently hydrogen or alkyl. These compounds can be represented by the following structure:
  • each of R 1 , R 8 , R 9 and R 10 is independently hydrogen or alkyl, preferably methyl, and X is halogen, preferably chloro.
  • the presently most preferred compound for use in the context of the present invention has the following structure:
  • This compound is ammonium trichloro(dioxyethylene-O,O′)tellurate, which is also referred to herein and in the art as AS101.
  • the bidentate cyclic moiety is preferably a di-oxo ligand having two oxygen atoms attached to the tellurium atom.
  • the bidentate cyclic moiety can be a di-thio ligand, in which two sulfur atoms are attached to the tellurium atom.
  • More preferred compounds are those in which t, u, and v are each 0, and X is chloro, such as, but not limited to, the compound having the following structure:
  • the above compound is also known and referred to herein as AS103.
  • organic tellurium-containing compounds having Formulae I and II can be readily prepared by reacting tetrahalotelluride such as TeCl 4 with a dihydroxy compound, as is described in detail in U.S. Pat. Nos. 4,752,614, 4,761,490, 4,764,461 and 4,929,739, which are incorporated by reference as if fully set forth herein.
  • each of the cyclic moieties is a di-oxo moiety.
  • one or more of the cyclic moieties is a di-thio moiety.
  • each of R 11 -R 14 is independently selected from the group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, alkoxy, carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate and sulfoneamido, as these terms are defined herein.
  • the most preferred compound in this category is a compound in which each of R 11 -R 14 is hydrogen. This compound is also known as AS102.
  • organic tellurium-containing compounds that are suitable for use in the context of the present invention include the recently disclosed bis-tellurium compounds having general Formula IV:
  • each of R 15 -R 22 is independently selected from the group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, alkoxy, carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate and sulfoneamido, as these terms are defined herein; and
  • n are each an integer from 0 to 3.
  • Preferred compounds in this category are those in which m and n are each 0.
  • the presently most preferred compound in this family is a compound in which R 15 , R 18 , R 19 and R 22 are all hydrogen, referred to hereinafter as SAS, and which has the following structure:
  • Compounds having the general Formula IV can be readily prepared by reacting substantially equimolar amounts of a tellurium tetralkoxide and a polycarboxylic acid. These materials are combined in the presence of a water free organic solvent such as dried ethanol, dimethyl sulfoxide, i-propanol and the like. Generally the reaction may take place at ambient conditions but if desired higher or lower temperatures and higher or lower pressures may be utilized.
  • Exemplary tellurium tetraalkoxide compounds that are usable in the preparation of the compounds having general Formula IV above include, without limitation, tetramethoxide, tetraethoxide, tetrapropoxide, tetraisopropoxide, tetrabutoxide, and tetrapentoxide tellerium compounds.
  • Useful polycarboxylic acids include also polyhydroxy polycarboxylic and hydroxy polycarboxylic acids.
  • Exemplary polycarboxylic acids that are usable in the preparation of the compounds having general Formula IV above include, without limitation, tartaric acid, glutaric acid, succinic acid, malonic acid, gluconic acid and the like.
  • Any of the tellurium-containing compounds of the present invention may be provided as a pharmaceutical composition, further comprising a pharmaceutically acceptable carrier.
  • a “pharmaceutical composition” refers to a preparation of one or more of the active with other chemical components such as physiologically suitable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound or a mixture of compounds to the subject treated.
  • physiologically acceptable carrier and “pharmaceutically acceptable carrier” which may be interchangeably used refer to a carrier or a diluent that does not cause significant irritation to the subject and does not abrogate the biological activity and properties of the administered compound.
  • compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
  • suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin.
  • Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
  • the formulation should be suitable for the mode of administration.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • Suitable pharmaceutical excipients include without limitation, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, sodium stearate, glycerol monostearate, talc, sodium chloride, glycerol, propyleneglycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • compositions herein described may also comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes, utilizing a tellurium-containing compound as described herein.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the pharmaceutical composition is formulated as a gel, a cream, an ointment, a paste, a lotion, a milk, a suspension, an aerosol, a spray, a foam, a serum, a swab, a pledglet, a pad or a patch.
  • a concentration of tellurium-containing compound of formula I, II or III in the carrier ranges from about 0.01 weight percent to about 50 weight percents, more preferably from about 0.01 weight percent to about 20 weight percents, of the total weight of the composition.
  • a concentration of tellurium-containing compound of formula IV in the carrier ranges from about 0.02 weight percent to about 85 weight percents, more preferably from about 0.02 weight percents to about 40 weight percents of the total weight of the composition.
  • the concentration of the tellurium-containing compound of formula I, II or II can be, for example, 0.01 weight percent, 0.05 weight percent, 0.1 weight percent, 0.5 weight percent, 1 weight percent, 2 weight percents, 3 weight percents, 4 weight percents, 5 weight percents, 10 weight percents, 15 weight percents, 20 weight percents, 30 weight percents, 40 weight percents and up to 50 weight percents of the total weight of the composition.
  • the concentration of the tellurium-containing compound of formula IV can be for example, 0.02 weight percent, 0.05 weight percent, 0.1 weight percent, 0.5 weight percent, 1 weight percent, 2 weight percents, 5 weight percents, 10 weight percents, 20 weight percents, 30 weight percents, 40 weight percents, 50 weight percents, 60 weight percents, 70 weight percents, 80 weight percents, and up to 85 weight percents of the total weight of the composition.
  • the pharmaceutical composition is preferably identified for use in the treatment or prevention of alopecia, excluding male pattern baldness and alopecia induced by antineoplastic agents.
  • the composition of the present invention may optionally further comprise at least one additional active agent for treating alopecia, such as minoxidil, finasteride, retin-A; ketoconazole; azelaic acid; zinc; Saw Palmetto extract; gamma linoic acid; vitamin B6; polysorbate 80; cyproterone acetate; ethinyloestradiol; cimetidine; spironolactone; ketaconazole, a corticosteroid; dithranol; an immunosuppressive drug or an irritant.
  • the additional active agent is minoxidil, finasteride, or a combination thereof.
  • the alopecia treated may include that induced by an autoimmune disease (such as alopecia greata); female pattern baldness; self-induced alopecia; traction alopecia; tellogen effluvium; and scarring alopecia (such as that caused by discoid lupus erythmatosus, lichen planus, aplasia cutis congenital or congenital atrichia).
  • Tellogen may be, for example, that associated with administration of a drug, such as a contraceptive pill, an anti-gout agent, a blood thinner, or a cholesterol lowering agent, including, but not limited to allopurinol, heparin, coumarin, clofibrate and gemfibrozil.
  • the tellogen effluvium may be due to a condition such as, for example, thyroid gland malfunction, diabetes, anemia or systemic lupus erythematosis.
  • Administration of the tellurium-containing compounds may be effected by the intraperitoneal, parenteral, oral, topical, rectal, transmucosal, intestinal, intrathecal, direct intraventricular, intravenous, intranasal, or intraocular route.
  • an effective therapeutic amount of any of the compounds of formulae I-III preferably ranges from about 0.025 to about 0.8 mg/kg of body weight.
  • an effective therapeutic amount of the compound of formulae IV for parenteral administration preferably ranges from about 0.4 to about 1.3 mg/kg of body weight.
  • compositions described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
  • the compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes.
  • Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.
  • An effective therapeutic amount of any of the compounds of formulae I-III for parenteral administration preferably ranges from about 0.025 to about 2.5 mg/kg of body weight.
  • An effective therapeutic amount of the compound of formula IV for parenteral administration preferably ranges from about 0.04 to about 4.2 mg/kg of body weight.
  • Formulations for oral delivery can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Such carriers enable the active ingredients of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • compositions which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
  • an effective therapeutic amount of any of the compounds of formulae I-III for oral administration preferably ranges from about 0.025 to about 7.5 mg/kg of body weight.
  • An effective therapeutic amount of the compound of formula IV for oral administration preferably ranges from about 0.04 to about 12.7 mg/kg of body weight.
  • the ingredients for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Topical administration is preferably affected by applying a therapeutically effective amount of a tellurium-
  • a pharmaceutical composition as described herein, formulated for topical application is applied onto the treated area.
  • the amount applied and the concentration of the compound in the composition depend on the composition form, and the area and condition being treated.
  • Administering is preferably effected according to a regime that ranges from twice daily to once weekly. In a preferred embodiment, administering is effected on a daily basis.
  • administering is effected from 1 day to 90 days and more preferably from 7 days to 90 days.
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen individually.
  • compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA (the U.S. Food and Drug Administration) approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may, for example, comprise glass, plastic foil, such as, but not limited to a blister pack or a pressurized container.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • Compositions according to the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for use in immunization.
  • tellurium-containing compound encompasses any compound that includes one or more tellurium atoms and exhibits immunomodulating properties.
  • the sample group consisted of 36 patients, of which 6 withdrew due to non-compliance. Data from a further 14 patients was considered to be unsuitable for analysis with the TrichoScan system, for example, due to untraceable tattoos. 16 patients were therefore available for evaluation.
  • a designated area of the scalp (about 0.7 cm 2 ) was shaved. Three days later, the area was tattooed using red ink, and photographed (Nikon digital camera). Patients were provided with a topical spray composition comprising 0.01% AS101 in 20% propylene glycol, 20% water and 60% ethyl alcohol, and were instructed to apply about 2 ml of the composition on the designated area on a daily basis for the first week, and once a day, twice a week thereafter. Patients were examined upon enrollment, and then after about 2 months, after about 3 months, and after about 6 months. Hair density, terminal hair density, and vellus hair density were analyzed, using the DatInf R Image DB image archiving system, and TichoScan software.
  • FIG. 1 shows micrographs obtained in this study from an individual patient using the above-described archiving TrichoScan system.
  • Results were calculated in terms of hair density, terminal hair density, and vellus hair density.
  • FIGS. 2 a and 2 b present the data obtained for the hair density, terminal hair density and vellus hair density, each per cm 2 , with two representative individuals of the study. The above parameters were measured at commencement of the study, after about 1 month, after about 3 months, and after about 6 months. All results were obtained using the DatInf R Image DB image archiving system, and TichoScan software.
  • a patient suffering from alopecia induced by an autoimmune disease applies a spray containing 0.01% AS101 in 20% propylene glycol, 20% water and 60% ethyl alcohol twice daily.
  • the results are monitored at commencement of the study, after about 1 month, after about 3 months, and after about 6 months. Hair density, terminal hair density, and vellus hair density are analyzed, using the DatInf R Image DB image archiving system, and TichoScan software.
  • a patient suffering from self-induced alopecia applies a spray containing 0.01% AS101 in 20% propylene glycol, 20% water and 60% ethyl alcohol twice daily. The results are monitored at commencement of the study, after about 1 month, after about 3 months, and after about 6 months. Hair density, terminal hair density, and vellus hair density are analyzed, using the DatInf R Image DB image archiving system, and TichoScan software.
  • a patient suffering from traction alopecia applies a spray containing 0.01% AS101 in 20% propylene glycol, 20% water and 60% ethyl alcohol twice daily. The results are monitored at commencement of the study, after about 1 month, after about 3 months, and after about 6 months. Hair density, terminal hair density, and vellus hair density are analyzed, using the DatInf R Image DB image archiving system, and TichoScan software.
  • a patient suffering from tellogen effluvium applies a spray containing 0.01% AS101 in 20% propylene glycol, 20% water and 60% ethyl alcohol twice daily.
  • the results are monitored at commencement of the study, after about 1 month, after about 3 months, and after about 6 months. Hair density, terminal hair density, and vellus hair density are analyzed, using the DatInf R Image DB image archiving system, and TichoScan software.
  • a patient suffering from scarring alopecia applies a spray containing 0.01% AS101 in 20% propylene glycol, 20% water and 60% ethyl alcohol twice daily.
  • the results are monitored at commencement of the study, after about 1 month, after about 3 months, and after about 6 months. Hair density, terminal hair density, and vellus hair density are analyzed, using the DatInf R Image DB image archiving system, and TichoScan software.
  • a patient suffering from hair loss applies a spray containing 0.017% SAS in 20% propylene glycol, 20% water and 60% ethyl alcohol twice daily.
  • the results are monitored at commencement of the study, after about 1 month, after about 3 months, and after about 6 months. Hair density, terminal hair density, and vellus hair density are analyzed, using the DatInf R Image DB image archiving system, and TichoScan software.

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US11207511B2 (en) 2010-12-06 2021-12-28 Follica, Inc. Methods for treating baldness and promoting hair growth
US11312714B2 (en) 2017-06-30 2022-04-26 The Regents Of The University Of California Compositions and methods for modulating hair growth
US11472804B2 (en) 2017-06-30 2022-10-18 The Regents Of The University Of California Compositions and methods for modulating hair growth
US11787804B2 (en) 2017-06-30 2023-10-17 The Regents Of The University Of California Compositions and methods for modulating hair growth
CN111295188A (zh) * 2017-09-29 2020-06-16 加利福尼亚大学董事会 调节毛发生长的组合物和方法
EP3687528A4 (fr) * 2017-09-29 2021-07-21 The Regents of the University of California Compositions et procédés de modulation de la pousse des cheveux

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CA2580642C (fr) 2014-09-02
US7652065B2 (en) 2010-01-26
EP1802292A2 (fr) 2007-07-04
EP1791535B1 (fr) 2008-07-30
US8623908B2 (en) 2014-01-07
WO2006030437A2 (fr) 2006-03-23
US20100081623A1 (en) 2010-04-01
CA2580643A1 (fr) 2006-03-23
CA2580804A1 (fr) 2006-03-23
WO2006030437A3 (fr) 2006-06-22
CA2580642A1 (fr) 2006-03-23
HK1103355A1 (en) 2007-12-21
DE602005008622D1 (de) 2008-09-11
WO2006030438A3 (fr) 2006-05-04
US20080015175A1 (en) 2008-01-17
WO2006030438A2 (fr) 2006-03-23
US7709524B2 (en) 2010-05-04
CA2580643C (fr) 2018-06-12
ES2614113T3 (es) 2017-05-29
PT1796660T (pt) 2017-02-13
ES2312012T3 (es) 2009-02-16
EP1796660A4 (fr) 2008-01-16
AU2005283719A1 (en) 2006-03-23
EP1802292A4 (fr) 2008-02-13
WO2006030439A2 (fr) 2006-03-23
WO2006030439A3 (fr) 2007-05-18
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EP1796660B1 (fr) 2016-11-23
EP1791535A2 (fr) 2007-06-06

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