Hair loss abstract
A method for treating hair loss in mammals uses compositions containing
prostaglandin F analogs. The compositions can be applied topically
to the skin. The compositions can arrest hair loss, reverse hair
loss, and promote hair growth.
Hair loss claims
What is claimed is:
1. A topical composition for treating hair loss comprising: A)
an active ingredient selected from the group consisting of a prostaglandin
F analog having the structure 9and pharmaceutically acceptable salts
and hydrates of the prostaglandin F analog; biohydrolyzable amides,
esters, and imides of the prostaglandin F analog; optical isomers,
diastereomers, and enantiomers of the prostaglandin F analog; and
combinations thereof; wherein R.sup.1 is selected from the group
consisting of CO.sub.2H, C(O)NHOH, CO.sub.2R.sup.5, CH.sub.2OH,
S(O).sub.2R.sup.5, C(O)NHR.sup.5, C(O)NHS(O).sub.2R.sup.5, and tetrazole;
R.sup.2 is selected from the group consisting of a hydrogen atom
and a lower monovalent hydrocarbon group; R.sup.3 and R.sup.4 are
each independently selected from the group consisting of H, CH.sub.3,
C.sub.2H.sub.5, OR.sup.10, SR.sup.10, and OH; with the proviso that
both R.sup.3 and R.sup.4 are not OH; R.sup.5 is selected from the
group consisting of monovalent hydrocarbon groups, substituted monovalent
hydrocarbon groups, aromatic groups, substituted aromatic groups,
carbocyclic groups, substituted carbocyclic groups, heterogeneous
groups, substituted heterogeneous groups, heterocyclic groups, substituted
heterocyclic groups, heteroaromatic groups, and substituted heteroaromatic
groups; X is selected from the group consisting of NR.sup.6R.sup.7,
OR.sup.8, SR.sup.9, S(O)R.sup.9, and S(O).sub.2R.sup.9; R.sup.6,
R.sup.7, and R.sup.8 are each independently selected from the group
consisting of hydrogen atoms, acyl groups, monovalent hydrocarbon
groups, substituted monovalent hydrocarbon groups, heterogeneous
groups, substituted heterogeneous groups, carbocyclic groups, substituted
carbocyclic groups, aromatic groups, substituted aromatic groups,
heteroaromatic groups, and substituted heteroaromatic groups; R.sup.9
is selected from the group consisting of monovalent hydrocarbon
groups, substituted monovalent hydrocarbon groups, heterogeneous
groups, substituted heterogeneous groups, carbocyclic groups, substituted
carbocyclic groups, heterocyclic groups, substituted heterocyclic
groups, aromatic groups, substituted aromatic groups, heteroaromatic
groups, and substituted heteroaromatic groups; R.sup.10 is selected
from the group consisting of a monovalent hydrocarbon group, a substituted
monovalent hydrocarbon group, a heterogeneous group, a substituted
heterogeneous group, a carbocyclic group, a substituted carbocyclic
group, an aromatic group, a substituted aromatic group, a heteroaromatic
group, and a substituted heteroaromatic group; with the proviso
that R.sup.10 has 1 to 8 member atoms; Y is selected from the group
consisting of an oxygen atom, a divalent hydrocarbon group, a sulfur-containing
moiety, and a nitrogen-containing group; and Z is selected from
the group consisting of a carbocyclic group, a substituted carbocyclic
group, a heterocyclic group, a substituted heterocyclic group, an
aromatic group, a substituted aromatic group, a heteroaromatic group,
and a substituted heteroaromatic group; and B) a carrier.
2. The composition of claim 1, wherein R.sup.1 is selected from
the group consisting of CO.sub.2H, CO.sub.2CH.sub.3, CO.sub.2C.sub.2H.sub.5,
CO.sub.2C.sub.3H.sub.7, CO.sub.2C.sub.4H.sub.9, CO.sub.2C.sub.3H.sub.7O.s-
ub.2, and C(O)NHS(O).sub.2R.sup.5.
3. The composition of claim 1, wherein R.sup.5 is selected from
the group consisting of CH.sub.3, C.sub.2H.sub.5, and C.sub.3H.sub.7.
4. The composition of claim 1, wherein R.sup.2 is selected from
the group consisting of a hydrogen atom and a methyl group.
5. The composition of claim 1, wherein R.sup.3 and R.sup.4 are
both hydrogen atoms.
6. The composition of claim 1, wherein X is selected from the group
consisting of NR.sup.6R.sup.7 and OR.sup.8.
7. The composition of claim 1, wherein R.sup.6 and R.sup.7 are
each independently selected from the group consisting of H, CH.sub.3,
and C.sub.2H.sub.5.
8. The composition of claim 1, wherein R.sup.8 is selected from
the group consisting of H, CH.sub.3, C.sub.2H.sub.5, and C.sub.3H.sub.7.
9. The composition of claim 1, wherein R.sup.9 is selected from
the group consisting of CH.sub.3, and C.sub.2H.sub.5.
10. The composition of claim 1, wherein Y is a divalent hydrocarbon
group having the formula (CH.sub.2).sub.n, wherein n is 1.
11. The composition of claim 1, wherein Y is selected from the
group consisting of a sulfur atom, an oxygen atom, S(O), and S(O).sub.2.
12. The composition of claim 1, wherein Y is a nitrogen-containing
group having the formula NR.sup.11; wherein R.sup.11 is selected
from the group consisting of a hydrogen atom, an acyl group, a monovalent
hydrocarbon group, a substituted monovalent hydrocarbon group, a
heterogeneous group, a substituted heterogeneous group, a carbocyclic
group, a substituted carbocyclic group, a heterocyclic group, a
substituted heterocyclic group, an aromatic group, a substituted
aromatic group, a heteroaromatic group, and a substituted heteroaromatic
group.
13. The composition of claim 1, wherein Z is selected from the
group consisting of a monocyclic carbocyclic group, a substituted
monocyclic carbocyclic group, a monocyclic heterocyclic group, a
substituted monocyclic heterocyclic group, a monocyclic aromatic
group, a substituted monocyclic aromatic group, a monocyclic heteroaromatic
group, and a substituted monocyclic heteroaromatic group.
14. The composition of claim 1, wherein component A) is added in
an amount of IC.sub.50.times.10.sup.-2.gtoreq.% of component A).gtoreq.IC.sub.50.times.10.sup.-3,
where IC.sub.50 of component A) is expressed in nanomolar units.
15. The composition of claim 1, wherein component C) is added to
the composition in an amount of 1 to 20%, and a sufficient amount
of component B) is added such that the amounts of components A),
B), and C) combined equal 100%.
16. The composition of claim 1, wherein component B) comprises
an ingredient selected from the group consisting of water, alcohols,
aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral
oil, propylene glycol, dimethyl isosorbide, polypropylene glycol-2
myristyl propionate, q) emollients, r) propellants, s) solvents,
t) humectants, u) thickeners, v) powders, w) fragrances, and combinations
thereof.
17. The composition of claim 16, wherein ingredient q) is selected
from the group consisting of stearyl alcohol, glyceryl monoricinoleate,
glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil,
cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate,
isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate,
decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate,
di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl
stearate, butyl stearate, polyethylene glycol, triethylene glycol,
lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated
lanolin alcohols, petrolatum, mineral oil, butyl myristate, isostearic
acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl
lactate, decyl oleate, myristyl myristate, and combinations thereof.
18. The composition of claim 16, wherein ingredient r) is selected
from the group consisting of propane, butane, isobutane, dimethyl
ether, carbon dioxide, nitrous oxide, and combinations thereof.
19. The composition of claim 16, wherein ingredient s) is selected
from the group consisting of water, ethyl alcohol, methylene chloride,
isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene
glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl
sulfoxide, dimethyl formamide, tetrahydrofuran, and combinations
thereof.
20. The composition of claim 16, wherein ingredient t) is selected
from the group consisting of glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate,
soluble collagen, dibutyl phthalate, gelatin, and combinations thereof.
21. The composition of claim 16, wherein ingredient v) is selected
from the group consisting of chalk, talc, fullers earth, kaolin,
starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra
alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically
modified magnesium aluminum silicate, organically modified montmorillonite
clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer,
sodium carboxymethyl cellulose, ethylene glycol monostearate, and
combinations thereof.
22. A method of treating hair loss comprising administering to
a mammal a composition comprising: A) an active ingredient selected
from the group consisting of a prostaglandin F analog having the
structure 10and pharmaceutically acceptable salts and hydrates of
the prostaglandin F analog; biohydrolyzable amides, esters, and
imides of the prostaglandin F analog; optical isomers, diastereomers,
and enantiomers of the prostaglandin F analog; and combinations
thereof; wherein R.sup.1 is selected from the group consisting of
CO.sub.2H, C(O)NHOH, CO.sub.2R.sup.5, CH.sub.2OH, S(O).sub.2R.sup.5,
C(O)NHR.sup.5, C(O)NHS(O).sub.2R.sup.5, and tetrazole; R.sup.2 is
selected from the group consisting of a hydrogen atom and a lower
monovalent hydrocarbon group; R.sup.3 and R.sup.4 are each independently
selected from the group consisting of H, CH.sub.3, C.sub.2H.sub.5,
OR.sup.10, SR.sup.10, and OH; with the proviso that both R.sup.3
and R.sup.4 are not OH; R.sup.5 is selected from the group consisting
of monovalent hydrocarbon groups, substituted monovalent hydrocarbon
groups, aromatic groups, substituted aromatic groups, carbocyclic
groups, substituted carbocyclic groups, heterogeneous groups, substituted
heterogeneous groups, heterocyclic groups, substituted heterocyclic
groups, heteroaromatic groups, and substituted heteroaromatic groups;
X is selected from the group consisting of NR.sup.6R.sup.7, OR.sup.8,
SR.sup.9, S(O)R.sup.9, and S(O).sub.2R.sup.9; R.sup.6, R.sup.7,
and R.sup.8 are each independently selected from the group consisting
of hydrogen atoms, acyl groups, monovalent hydrocarbon groups, substituted
monovalent hydrocarbon groups, heterogeneous groups, substituted
heterogeneous groups, carbocyclic groups, substituted carbocyclic
groups, aromatic groups, substituted aromatic groups, heteroaromatic
groups, and substituted heteroaromatic groups; R.sup.9 is selected
from the group consisting of monovalent hydrocarbon groups, substituted
monovalent hydrocarbon groups, heterogeneous groups, substituted
heterogeneous groups, carbocyclic groups, substituted carbocyclic
groups, heterocyclic groups, substituted heterocyclic groups, aromatic
groups, substituted aromatic groups, heteroaromatic groups, and
substituted heteroaromatic groups; R.sup.10 is selected from the
group consisting of a monovalent hydrocarbon group, a substituted
monovalent hydrocarbon group, a heterogeneous group, a substituted
heterogeneous group, a carbocyclic group, a substituted carbocyclic
group, an aromatic group, a substituted aromatic group, a heteroaromatic
group, and a substituted heteroaromatic group; with the proviso
that R.sup.10 has 1 to 8 member atoms; Y is selected from the group
consisting of an oxygen atom, a divalent hydrocarbon group, a sulfur-containing
moiety, and a nitrogen-containing group; and Z is selected from
the group consisting of a carbocyclic group, a substituted carbocyclic
group, a heterocyclic group, a substituted heterocyclic group, an
aromatic group, a substituted aromatic group, a heteroaromatic group,
and a substituted heteroaromatic group.
23. The method of claim 22, wherein R.sup.1 is selected from the
group consisting of CO.sub.2H, CO.sub.2CH.sub.3, CO.sub.2C.sub.2H.sub.5,
CO.sub.2C.sub.3H.sub.7, CO.sub.2C.sub.4H.sub.9, CO.sub.2C.sub.3H.sub.7O.s-
ub.2, and C(O)NHS(O).sub.2R.sup.5.
24. The method of claim 22, wherein R.sup.5 is selected from the
group consisting of CH.sub.3, C.sub.2H.sub.5, and C.sub.3H.sub.7.
25. The method of claim 22, wherein R.sup.2 is selected from the
group consisting of a hydrogen atom and a methyl group.
26. The method of claim 22, wherein R.sup.3 and R.sup.4 are both
hydrogen atoms.
27. The method of claim 22, wherein X is selected from the group
consisting of NR.sub.6R.sub.7 and OR.
28. The method of claim 22, wherein R.sup.6 and R.sup.7 are each
independently selected from the group consisting of H, CH.sub.3,
and C.sub.2H.sub.5.
29. The method of claim 22, wherein R.sup.8 is selected from the
group consisting of H, CH.sub.3, C.sub.2H.sub.5, and C.sub.3H.sub.7.
30. The method of claim 22, wherein R.sup.9 is selected from the
group consisting of CH.sub.3, and C.sub.2H.sub.5.
31. The method of claim 22, wherein Y is a divalent hydrocarbon
group having the formula (CH.sub.2).sub.n, wherein n is 1.
32. The method of claim 22, wherein Y is selected from the group
consisting of a sulfur atom, an oxygen atom, S(O), and S(O).sub.2.
33. The method of claim 22, wherein Y is a nitrogen-containing
group having the formula NR.sup.11; wherein R.sup.11 is selected
from the group consisting of a hydrogen atom, an acyl group, a monovalent
hydrocarbon group, a substituted monovalent hydrocarbon group, a
heterogeneous group, a substituted heterogeneous group, a carbocyclic
group, a substituted carbocyclic group, a heterocyclic group, a
substituted heterocyclic group, an aromatic group, a substituted
aromatic group, a heteroaromatic group, and a substituted heteroaromatic
group.
34. The method of claim 22, wherein Z is selected from the group
consisting of a monocyclic carbocyclic group, a substituted monocyclic
carbocyclic group, a monocyclic heterocyclic group, a substituted
monocyclic heterocyclic group, a monocyclic aromatic group, a substituted
monocyclic aromatic group, a monocyclic heteroaromatic group, and
a substituted monocyclic heteroaromatic group.
35. The method of claim 22, wherein the composition is administered
by a route selected from the group consisting of systemic and topical
routes.
36. The method of claim 35, wherein the composition is a topical
composition in a form selected from the group consisting of solutions,
oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out
hair conditioners, milks, cleansers, moisturizers, sprays, and skin
patches.
37. The method of claim 35, wherein the composition is a topical
composition further comprising B) a carrier comprising an ingredient
selected from the group consisting of water, alcohols, aloe vera
gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene
glycol, dimethyl isosorbide, polypropylene glycol-2 myristyl propionate,
q) emollients, r) propellants, s) solvents, t) humectants, u) I
thickeners, v) powders, w) fragrances, and combinations thereof.
38. The method of claim 35, wherein the composition further comprises
C) an activity enhancer selected from the group consisting of i)
a hair growth stimulant, ii) a penetration enhancer, and combinations
thereof.
39. The method of claim 38, wherein component i) is selected from
the group vasodilator, an antiandrogen, a cyclosporin, a cyclosporin
analog, an antimicrobial, an anti-inflammatory, a thyroid hormone,
a thyroid hormone derivative, and a thyroid hormone analog, a non-selective
prostaglandin agonist, a non-selective prostaglandin antagonist,
a retinoid, a triterpene, and combinations thereof.
40. The method of claim 35, wherein component ii) is selected from
the group consisting of 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate,
hexan-2,5-diol, polyoxyethylene(2) ethyl ether, di(2-hydroxypropyl)
ether, pentan-2,4-diol, acetone, polyoxyethylene(2) methyl ether,
2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1,4-dioxane,
tetrahydrofuran, butan-1,4-diol, propylene glycol dipelargonate,
polyoxypropylene 15 stearyl ether, octyl alcohol, polyoxyethylene
ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate,
dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate, dibutyl
sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate,
dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate,
dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate,
dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate,
ethyl salicylate, isopropyl palmitate, ethyl laurate, 2-ethyl-hexyl
pelargonate, isopropyl isostearate, butyl laurate, benzyl benzoate,
butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl
stearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hydroxyoctanoic
acid, dimethyl sulphoxide, N,N-dimethyl acetamide, N,N-dimethyl
formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,
1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides,
sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide,
1-dodecylazacyloheptan-2-one, and combinations thereof.
41. The method of claim 35, wherein the composition is a topical
composition locally administered on the skin once per day.
42. The method of claim 41, wherein the composition is administered
once per day for 6 to 12 weeks.
43. A mascara composition comprising: A) an active ingredient selected
from the group consisting of a prostaglandin F analog having the
structure 11and pharmaceutically acceptable salts and hydrates of
the prostaglandin F analog; biohydrolyzable amides, esters, and
imides of the prostaglandin F analog; optical isomers, diastereomers,
and enantiomers of the prostaglandin F analog; and combinations
thereof; wherein R.sup.1 is selected from the group consisting of
CO.sub.2H, C(O)NHOH, CO.sub.2R.sup.5, CH.sub.2OH, S(O).sub.2R.sup.5,
C(O)NHR.sup.5, C(O)NHS(O).sub.2R.sup.5, and tetrazole; R.sub.2 is
selected from the group consisting of a hydrogen atom and a lower
monovalent hydrocarbon group; R.sup.3 and R.sup.4 are each independently
selected from the group consisting of H, CH.sub.3, C.sub.2H.sub.5,
OR.sup.10, SR.sup.10, and OH; with the proviso that both R.sup.3
and R.sup.4 are not OH; R is selected from the group consisting
of monovalent hydrocarbon groups, substituted monovalent hydrocarbon
groups, aromatic groups, substituted aromatic groups, carbocyclic
groups, substituted carbocyclic groups, heterogeneous groups, substituted
heterogeneous groups, heterocyclic groups, substituted heterocyclic
groups, heteroaromatic groups, and substituted heteroaromatic groups;
X is selected from the group consisting of NR.sup.6R.sup.6, OR.sup.8,
SR.sup.8, S(O)R.sup.9, and S(O).sub.2R.sup.9; R.sup.6, R.sup.7,
and R.sup.8 are each independently selected from the group consisting
of hydrogen atoms, acyl groups, monovalent hydrocarbon groups, substituted
monovalent hydrocarbon groups, heterogeneous groups, substituted
heterogeneous groups, carbocyclic groups, substituted carbocyclic
groups, aromatic groups, substituted aromatic groups, heteroaromatic
groups, and substituted heteroaromatic groups; R.sup.9 is selected
from the group consisting of monovalent hydrocarbon groups, substituted
monovalent hydrocarbon groups, heterogeneous groups, substituted
heterogeneous groups, carbocyclic groups, substituted carbocyclic
groups, heterocyclic groups, substituted heterocyclic groups, aromatic
groups, substituted aromatic groups, heteroaromatic groups, and
substituted heteroaromatic groups; R.sub.10 is selected from the
group consisting of a monovalent hydrocarbon group, a substituted
monovalent hydrocarbon group, a heterogeneous group, a substituted
heterogeneous group, a carbocyclic group, a substituted carbocyclic
group, an aromatic group, a substituted aromatic group, a heteroaromatic
group, and a substituted heteroaromatic group; with the proviso
that R.sup.10 has 1 to 8 member atoms; Y is selected from the group
consisting of an oxygen atom, a divalent hydrocarbon group, a sulfur-containing
moiety, and a nitrogen-containing group; and Z is selected from
the group consisting of a carbocyclic group, a substituted carbocyclic
group, a heterocyclic group, a substituted heterocyclic group, an
aromatic group, a substituted aromatic group, a heteroaromatic group,
and a substituted heteroaromatic group, dd) a water-insoluble material,
ee) a water-soluble, film-forming polymer, ff) a wax; o) a surfactant;
gg) pigment; and s) a solvent.
44. A method for darkening and thickening hair comprising applying
to growing hair and skin a composition comprising: A) an active
ingredient selected from the group consisting of a prostaglandin
F analog having the structure 12 and pharmaceutically acceptable
salts and hydrates of the prostaglandin F analog; biohydrolyzable
amides, esters, and imides of the prostaglandin F analog; optical
isomers, diastereomers, and enantiomers of the prostaglandin F analog;
and combinations thereof; wherein R.sup.1 is selected from the group
consisting Of CO.sub.2H, C(O)NHOH, CO.sub.2R.sup.1, CH.sub.2OH,
S(O).sub.2R.sup.5, C(O)NHR.sup.5, C(O)NHS(O).sub.2R.sup.5, and tetrazole;
R.sup.2 is selected from the group consisting of a hydrogen atom
and a lower monovalent hydrocarbon group; R.sup.3and R.sup.4are
each independently selected from the group consisting of H, CH.sub.3,
C.sub.2H.sub.5, OR.sup.10, SR.sup.10, and OH; with the proviso that
both R.sup.3 and R.sup.4 are not OH; R.sup.5 is selected from the
group consisting of monovalent hydrocarbon groups, substituted monovalent
hydrocarbon groups, aromatic groups, substituted aromatic groups,
carbocyclic groups, substituted carbocyclic groups, heterogeneous
groups, substituted heterogeneous groups, heterocyclic groups, substituted
heterocyclic groups, heteroaromatic groups, and substituted heteroaromatic
groups; X is selected from the group consisting of NR.sup.6R.sup.7,
OR.sup.8, SR.sup.9, S(O)R.sup.9, and S(O).sub.2R.sup.9; R.sup.6,
R.sup.7, and R.sup.8 are each independently selected from the group
consisting of hydrogen atoms, acyl groups, monovalent hydrocarbon
groups, substituted monovalent hydrocarbon groups, heterogeneous
groups, substituted heterogeneous groups, carbocyclic groups, substituted
carbocyclic groups, aromatic groups, substituted aromatic groups,
heteroaromatic groups, and substituted heteroaromatic groups; R.sup.9
is selected from the group consisting of monovalent hydrocarbon
groups, substituted monovalent hydrocarbon groups, heterogeneous
groups, substituted heterogeneous groups, carbocyclic groups, substituted
carbocyclic groups, heterocyclic groups, substituted heterocyclic
groups, aromatic groups, substituted aromatic groups, heteroaromatic
groups, and substituted heteroaromatic groups; R.sup.10 is selected
from the group consisting of a monovalent hydrocarbon group, a substituted
monovalent hydrocarbon group, a heterogeneous group, a substituted
heterogeneous group, a carbocyclic group, a substituted carbocyclic
group, an aromatic group, a substituted aromatic group, a heteroaromatic
group, and a substituted heteroaromatic group; with the proviso
that R.sup.10 has 1 to 8 member atoms; Y is selected from the group
consisting of an oxygen atom, a divalent hydrocarbon group, a sulfur-containing
moiety, and a nitrogen-containing group; and Z is selected from
the group consisting of a carbocyclic group, a substituted carbocyclic
group, a heterocyclic group, a substituted heterocyclic group, an
aromatic group, a substituted aromatic group, a heteroaromatic group,
and a substituted heteroaromatic group; and B) a carrier.
Hair loss description
FIELD OF THE INVENTION
[0001] This invention relates to compositions and methods for treating
hair loss in mammals. More particularly, this invention relates
to compositions and methods for arresting or reversing hair loss,
or both, and promoting hair growth.
BACKGROUND OF THE INVENTION
[0002] Hair loss is a common problem which is, for example, naturally
occurring or chemically promoted through the use of certain therapeutic
drugs designed to alleviate conditions such as cancer. Often such
hair loss is accompanied by lack of hair re-growth which causes
partial or full baldness.
[0003] Hair growth on the scalp does not occur continuously, but
rather occurs by a cycle of activity involving alternating periods
of growth and rest. This cycle is divided into three main stages;
anagen, catagen, and telogen. Anagen is the growth phase of the
cycle and is characterized by penetration of the hair follicle deep
into the dermis with rapid proliferation of cells which are differentiating
to form hair. The next phase is catagen, which is a transitional
stage marked by the cessation of cell division, and during which
the hair follicle regresses through the dermis and hair growth ceases.
The next phase, telogen, is characterized as the resting stage during
which the regressed follicle contains a germ with tightly packed
dermal papilla cells. At telogen, the initiation of a new anagen
phase is caused by rapid cell proliferation in the germ, expansion
of the dermal papilla, and elaboration of basement membrane components.
When hair growth ceases, most of the hair follicles reside in telogen
and anagen is not engaged, thus causing the onset of full or partial
baldness.
[0004] Attempts to invoke the re-growth of hair have been made
by, for example, the promotion or prolongation of anagen. Currently,
there are two drugs approved by the United States Food and Drug
Administration for the treatment of male pattern baldness: topical
minoxidil (marketed as ROGAINE.RTM. by Pharmacia & Upjohn),
and oral finasteride (marketed as PROPECIA.RTM. by Merck & Co.,
Inc.). However, the search for efficacious hair growth inducers
is ongoing due to factors including safety concerns and limited
efficacy.
[0005] The thyroid hormone thyroxine ("T4") converts
to thyronine ("T3") in human skin by deiodinase I, a selenoprotein.
Selenium deficiency causes a decrease in T3 levels due to a decrease
in deiodinase I activity; this reduction in T3 levels is strongly
associated with hair loss. Consistent with this observation, hair
growth is a reported side effect of administration of T4. See, e.g.,
Berman, "Peripheral Effects of L-Thyroxine on Hair Growth and
Coloration in Cattle", Journal of Endocrinology, Vol. 20, pp.
.sup.282-292 (1960); and Gunaratnam, "The Effects of Thyroxine
on Hair Growth in the Dog", J. Small Anim. Pract., Vol. 27,
pp. 17-29 (1986). Furthermore, T3 and T4 have been the subject of
several patent publications relating to treatment of hair loss.
See, e.g., Fischer et al., DE 1,617,477, published Jan. 8, 1970;
Mortimer, GB 2,138,286, published Oct. 24, 1984; and Lindenbaum,
WO 96/25943, assigned to Life Medical Sciences, Inc., published
Aug. 29, 1996.
[0006] Unfortunately, however, administration of T3 or T4, or both,
to treat hair loss is often not practicable because these thyroid
hormones can induce significant cardiotoxicity. See, e.g., Walker
et al., U.S. Pat. No. 5,284,971, assigned to Syntex, issued Feb.
8, 1994 and Emmett et al., U.S. Pat. No. 5,061,798, assigned to
Smith Kline & French Laboratories, issued Oct. 29, 1991.
[0007] In an alternative approach, prostaglandins have been proposed
to promote hair growth because prostaglandins may have a similar
benefit to thyroid hormones, i.e., increasing hair length and changing
pigmentation. Naturally occurring prostaglandins (e.g., PGA.sub.2,
PGB.sub.2, PGE.sub.1, PGF.sub.2.alpha., and PGI.sub.2) are C-20
unsaturated fatty acids. PGF.sub.2.alpha., the naturally occurring
Prostaglandin F analog in humans, is characterized by hydroxyl groups
at the C9 and C11 positions on the alicyclic ring, a cis-double
bond between C5 and C6, and a trans-double bond between C 13 and
C 14. PGF.sub.2.alpha.has the formula: 1
[0008] Analogs of naturally occurring Prostaglandin F are known
in the art. For example, see U.S. Pat. No. 4,024,179 issued to Bindra
and Johnson on May 17, 1977; German Patent No. DT-002,460,990 issued
to Beck, Lerch, Seeger, and Teufel published on Jul. 1, 1976; U.S.
Pat. No. 4,128,720 issued to Hayashi, Kori, and Miyake on Dec. 5,
1978; U.S. Pat. No. 4,011,262 issued to Hess, Johnson, Bindra, and
Schaaf on Mar. 8, 1977; U.S. Pat. No. 3,776,938 issued to Bergstrom
and Sjovall on Dec. 4, 1973; P. W. Collins and S. W. Djuric, "Synthesis
of Therapeutically Useful Prostaglandin and Prostacyclin Analogs",
Chem. Rev., Vol. 93, pp. 1533-1564 (1993); G. L. Bundy and F. H.
Lincoln, "Synthesis of 17-Phenyl-18,19,20-Trinorprostaglandins:
I. The PG.sub.1 Series", Prostaglandin, Vol. 9 No. 1, pp. 1-4
(1975); W. Bartman, G. Beck, U. Lerch, H. Teufel, and B. Scholkens,
"Luteolytic Prostaglandin: Synthesis and Biological Activity",
Prostaglandin, Vol. 17 No. 2, pp. 301-311 (1979); C. Iiljebris,
G. Selen, B. Resul, J. Sternschantz, and U. Hacksell, "Derivatives
of 17-Phenyl-18, 19,20-trinorprostaglandin F.sub.2.alpha.. Isopropyl
Ester: Potential Antiglaucoma Agents", Journal of Medicinal
Chemistry, Vol. 38, No. 2, pp. 289-304, (1995).
[0009] Prostaglandins in general have a wide range of biological
activities. For example, PGE.sub.2 has the following properties:
a) regulator of cell proliferation, b) regulator of cytokine synthesis,
c) regulator of immune responses and d) inducer of vasodilatation.
Vasodilatation is thought to be one of the mechanisms of how minoxidil
provides a hair growth benefit. In vitro results in the literature
also indicate some anti-inflammatory properties of the prostaglandins.
c.f.; Tanaka, H., Br J. Pharm., 116, 2298, (1995).
[0010] However, previous attempts at using prostaglandins to promote
hair growth have been unsuccessful. Different prostaglandin analogs
can bind to multiple receptors at various concentrations with a
biphasic effect. Furthermore, administration of naturally occurring
prostaglandins can cause side effects such as inflammation, surface
irritation, smooth muscle contraction, pain, and bronchoconstriction.
Therefore, it is an object of this invention to provide methods
for using prostaglandin analogs to grow hair and to provide compositions
that promote hair growth in humans and lower animals. It is a further
object of this invention to provide a selection of appropriate prostaglandin
analogs that will promote hair growth and that do not cause significant
undesirable side effects.
SUMMARY OF THE INVENTION
[0011] This invention relates to compositions and methods for treating
hair loss. The methods comprise administering the compositions comprising
specific prostaglandin F analogs that interact strongly with hair-selective
receptors, such as the FP receptor. The choice of prostaglandin
F analog is important because it must selectively activate the FP
receptor and not activate any other receptors that would negate
the effect of activating the FP receptor. The compositions comprise:
component A) the prostaglandin F analog, component B) a carrier,
and optionally component C) an activity enhancer.
[0012] Suitable prostaglandin F analogs ("PGF's") for
this invention have the general formula: 2
[0013] wherein R.sup.1 is preferably CO.sub.2H or CO.sub.2CH.sub.3;
R.sup.2 is preferably H; R.sup.3 and R.sup.4 are preferably H or
CH.sub.3; X is preferably OH; Y is selected from the group consisting
of a divalent hydrocarbon group, O, S, S(O), S(O).sub.2, and NR.sup.11,
wherein R.sup.11 is preferably a hydrogen atom or a methyl group;
and Z is preferably thienyl or phenyl. Other suitable PGF's are
pharmaceutically acceptable salts, hydrates, and biohydrolyzable
amides, esters, and imides of the general formula above. Optical
isomers, diastereomers, and enantiomers of the structure described
above are also suitable for this invention. At all stereocenters
where stereochemistry is not defined (i.e., C11, C12, C15, and C16),
both epimers are envisioned with the epimer that corresponds to
the naturally-occurring one being preferred.
DETAILED DESCRIPTION OF THE INVENTION
[0014] This invention relates to compositions comprising prostaglandin
F analogs ("PGF's") to treat hair loss in mammals. "Treating
hair loss" includes arresting hair loss or reversing hair loss,
or both, and promoting hair growth.
[0015] Publications and patents are referred to throughout this
disclosure. All U.S. patents cited herein are hereby incorporated
by reference.
[0016] All percentages, ratios, and proportions used herein are
by weight unless otherwise specified.
Definition and Usage of Terms
[0017] The following is a list of definitions for terms, as used
herein:
[0018] "Activate" means binding and signal transduction
of a receptor.
[0019] "Acyl group" means a monovalent group suitable
for acylating a nitrogen atom to form an amide or carbamate, an
alcohol to form a carbonate, or an oxygen atom to form an ester
group. Preferred acyl groups include benzoyl, acetyl, tert-butyl
acetyl, para-phenyl benzoyl, and trifluoroacetyl. More preferred
acyl groups include acetyl and benzoyl. The most preferred acyl
group is acetyl.
[0020] "Aromatic group" means a monovalent group having
a monocyclic ring structure or fused bicyclic ring structure. Monocyclic
aromatic groups contain 5 to 10 carbon atoms, preferably 5 to 7
carbon atoms, and more preferably 5 to 6 carbon atoms in the ring.
Bicyclic aromatic groups contain 8 to 12 carbon atoms, preferably
9 or 10 carbon atoms in the ring. Aromatic groups are unsubstituted.
The most preferred aromatic group is phenyl.
[0021] "Carbocyclic group" means a monovalent saturated
or unsaturated hydrocarbon ring. Carbocyclic groups are monocyclic,
or are fused, spiro, or bridged bicyclic ring systems. Monocyclic
carbocyclic groups contain 4 to 10 carbon atoms, preferably 4 to
7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring.
Bicyclic carbocyclic groups contain 8 to 12 carbon atoms, preferably
9 to 10 carbon atoms in the ring. Carbocyclic groups are unsubstituted.
Preferred carbocyclic groups include cyclopentyl, cyclohexyl, cyclohexenyl,
cycloheptyl, and cyclooctyl. More preferred carbocyclic groups include
cyclohexyl, cycloheptyl, and cyclooctyl. The most preferred carbocyclic
group is cycloheptyl. Carbocyclic groups are not aromatic.
[0022] "Cyano group" means a group containing a nitrile
functionality.
[0023] "FP agonist" means a compound that activates the
FP receptor.
[0024] "FP receptor" means known human FP receptors,
their splice variants, and undescribed receptors that have similar
binding and activation profiles as the known human FP receptors.
"FP" means the receptor is of the class which has the
highest affinity for PGF.sub.2.alpha.of all the naturally occurring
prostaglandins. FP refers to a known protein.
[0025] "Halogen atom" means F, Cl, Br, or I. Preferably,
the halogen atom is F, Cl, or Br; more preferably Cl or F; and most
preferably F.
[0026] "Halogenated heterogenous group" means a substituted
heterogenous group or a substituted heterocyclic group, wherein
at least one substituent is a halogen atom. Halogenated heterogenous
groups can have a straight, branched, or cyclic structure. Preferred
halogenated heterogenous groups have 1 to 12 carbon atoms, more
preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon
atoms. Preferred halogen atom substituents are Cl and F.
[0027] "Halogenated hydrocarbon group" means a substituted
monovalent hydrocarbon group or a substituted carbocyclic group,
wherein at least one substituent is a halogen atom. Halogenated
hydrocarbon groups can have a straight, branched, or cyclic structure.
Preferred halogenated hydrocarbon groups have 1 to 12 carbon atoms,
more preferably 1 to 6 carbon atoms, and most preferably 1 to 3
carbon atoms. Preferred halogen atom substituents are Cl and F.
The most preferred halogenated hydrocarbon group is trifluoromethyl.
[0028] "Heteroaromatic group" means an aromatic ring
containing carbon and 1 to 4 heteroatoms in the ring. Heteroaromatic
groups are monocyclic or fused bicyclic rings. Monocyclic heteroaromatic
groups contain 5 to 10 member atoms (i.e., carbon and heteroatoms),
preferably 5 to 7, and more preferably 5 to 6 in the ring. Bicyclic
heteroaromatic rings contain 8 to 12 member atoms, preferably 9
or 10 in the ring. Heteroaromatic groups are unsubstituted. Preferred
heteroaromatic groups include thienyl, thiazolyl, purinyl, pyrimidyl,
pyridyl, and furanyl. More preferred heteroaromatic groups include
thienyl, furanyl, and pyridyl. The most preferred heteroaromatic
group is thienyl.
[0029] "Heteroatom" means an atom other than carbon in
the ring of a heterocyclic group or the chain of a heterogeneous
group. Preferably, heteroatoms are selected from the group consisting
of nitrogen, sulfur, and oxygen atoms. Groups containing more than
one heteroatom may contain different heteroatoms.
[0030] "Heterocyclic group" means a saturated or unsaturated
ring structure containing carbon and 1 to 4 heteroatoms in the ring.
No two heteroatoms are adjacent in the ring. Heterocyclic groups
are not aromatic. Heterocyclic groups are monocyclic, or are fused
or bridged bicyclic ring systems. Monocyclic heterocyclic groups
contain 4 to 10 member atoms (i.e., including both carbon atoms
and at least 1 heteroatom), preferably 4 to 7, and more preferably
5 to 6 in the ring. Bicyclic heterocyclic groups contain 8 to 12
member atoms, preferably 9 or 10 in the ring. Heterocyclic groups
are unsubstituted. Preferred heterocyclic groups include piperzyl,
morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and piperdyl.
[0031] "Heterogeneous group" means a saturated or unsaturated
chain containing 1 to 18 member atoms (i.e., including both carbon
and at least one heteroatom). No two heteroatoms are adjacent. Preferably,
the chain contains 1 to 12 member atoms, more preferably 1 to 6,
and most preferably 1 to 4. The chain may be straight or branched.
Preferred branched heterogeneous groups have one or two branches,
preferably one branch. Preferred heterogeneous groups are saturated.
Unsaturated heterogeneous groups have one or more double bonds,
one or more triple bonds, or both. Preferred unsaturated heterogeneous
groups have one or two double bonds or one triple bond. More preferably,
the unsaturated heterogeneous group has one double bond. Heterogeneous
groups are unsubstituted.
[0032] "Monovalent hydrocarbon group" means a chain of
1 to 18 carbon atoms, preferably 1 to 12 carbon atoms. "Lower
monovalent hydrocarbon group" means a monovalent hydrocarbon
group having 1 to 6, preferably 1 to 4 carbon atoms. Monovalent
hydrocarbon groups may have a straight chain or branched chain structure.
Preferred monovalent hydrocarbon groups have one or two branches,
preferably 1 branch. Preferred monovalent hydrocarbon groups are
saturated. Unsaturated monovalent hydrocarbon groups have one or
more double bonds, one or more triple bonds, or combinations thereof.
Preferred unsaturated monovalent hydrocarbon groups have one or
two double bonds or one triple bond; more preferred unsaturated
monovalent hydrocarbon groups have one double bond.
[0033] "Pharmaceutically acceptable" means suitable for
use in a human or other mammal.
[0034] "PGF" means a prostaglandin F analog.
[0035] "Prostaglandin" means a fatty acid derivative
which has a variety of potent biological activities of a hormonal
or regulatory nature.
[0036] "Protecting group" is a group that replaces the
active hydrogen of a hydroxyl moiety thus preventing undesired side
reaction at the hydroxyl moiety. Use of protecting groups in organic
synthesis is well known in the art. Examples of protecting groups
are found in Chapter 2 Protecting Groups in Organic Synthesis by
Greene, T. W. and Wuts, P. G. M., 2.sup.nd ed., Wiley & Sons,
Inc., 1991. Preferred protecting groups include silyl ethers, alkoxymethyl
ethers, tetrahydropyranyl, tetrahydrofuranyl, esters, and substituted
or unsubstituted benzyl ethers.
[0037] "Safe and effective amount" means a quantity of
a prostaglandin high enough to provide a significant positive modification
of the subject's condition to be treated, but low enough to avoid
serious side effects (at a reasonable benefit/risk ratio).
[0038] "Selective" means having a binding or activation
preference for a specific receptor over other receptors which can
be quantitated based upon receptor binding or activation assays.
[0039] "Subject" means a living, vertebrate, hair- or
fur-bearing animal such as a mammal (preferably human) in need of
treatment.
[0040] "Substituted aromatic group" means an aromatic
group wherein 1 to 4 of the hydrogen atoms bonded to carbon atoms
in the ring have been replaced with other substituents. Preferred
substituents include: halogen atoms, cyano groups, monovalent hydrocarbon
groups, substituted monovalent hydrocarbon groups, heterogeneous
groups, aromatic groups, substituted aromatic groups, or any combination
thereof. More preferred substituents include halogen atoms, monovalent
hydrocarbon groups, and substituted monovalent hydrocarbon groups.
Preferred substituted aromatic groups include naphthyl. The substituents
may be substituted at the ortho, meta, or para position on the ring,
or any combination thereof. The preferred substitution pattern on
the ring is ortho or meta. The most preferred substitution pattern
is ortho.
[0041] "Substituted carbocyclic group" means a carbocyclic
group wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the
ring have been replaced with other substituents. Preferred substituents
include: halogen atoms, cyano groups, monovalent hydrocarbon groups,
monovalent heterogeneous groups, substituted monovalent hydrocarbon
groups, aromatic groups, substituted aromatic groups, or any combination
thereof. More preferred substituents include halogen atoms and substituted
monovalent hydrocarbon groups. Carbocyclic group does not include
aromatic rings.
[0042] "Substituted heteroaromatic group" means a heteroaromatic
group wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the
ring have been replaced with other substituents. Preferred substituents
include: halogen atoms, cyano groups, monovalent hydrocarbon groups,
substituted monovalent hydrocarbon groups, heterogeneous groups,
substituted heterogeneous groups, phenyl groups, phenoxy groups,
or any combination thereof. More preferred substituents include
halogen atoms, halogenated hydrocarbon groups, halogenated heterogenous
groups, monovalent hydrocarbon groups, and phenyl groups.
[0043] "Substituted heterocyclic group" means a heterocyclic
group wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the
ring have been replaced with other substituents. Preferred substituents
include: halogen atoms, cyano groups, monovalent hydrocarbon groups,
substituted monovalent hydrocarbon groups, heterogeneous groups,
substituted heterogeneous groups, halogenated hydrocarbon groups,
halogenated heterogenous groups, phenyl groups, phenoxy groups,
or any combination thereof. More preferred substituents include
halogen atoms and halogenated hydrocarbon groups. Substituted heterocyclic
groups are not aromatic.
[0044] "Substituted heterogeneous group" means a heterogeneous
group, wherein 1 to 4 of the hydrogen atoms bonded to carbon atoms
in the chain have been replaced with other substituents. Preferred
substituents include halogen atoms, hydroxy groups, alkoxy groups
(e.g., methoxy, ethoxy, propoxy, butoxy, and pentoxy), aryloxy groups
(e.g., phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxy,
alkyloxycarbonylphenoxy, and acyloxyphenoxy), acyloxy groups (e.g.,
propionyloxy, benzoyloxy, and acetoxy), carbamoyloxy groups, carboxy
groups, mercapto groups, alkylthio groups, acylthio groups, arylthio
groups (e.g., phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio,
benzylthio, and alkyloxycarbonylphenylthio), aromatic groups (e.g.,
phenyl and tolyl), substituted aromatic groups (e.g., alkoxyphenyl,
alkoxycarbonylphenyl, and halogenated phenyl), heterocyclic groups,
heteroaromatic groups, and amino groups (e.g., amino, mono- and
di-alkylamino having 1 to 3 carbon atoms, methylphenylamino, methylbenzylamino,
alkanylamido groups of 1 to 3 carbon atoms, carbamamido, ureido,
and guanidino).
[0045] "Substituted monovalent hydrocarbon group" means
a monovalent hydrocarbon group wherein 1 to 4 of the hydrogen atoms
bonded to carbon atoms in the chain have been replaced with other
substituents. Preferred substituents include halogen atoms; halogenated
hydrocarbon groups; halogenated heterogneous groups; alkyl groups
(e.g., methyl, ethyl, propyl, and butyl); hydroxy groups; alkoxy
groups (e.g., methoxy, ethoxy, propoxy, butoxy, and pentoxy); aryloxy
groups (e.g., phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy,
benzyloxy, alkyloxycarbonylphenoxy, and acyloxyphenoxy); acyloxy
groups (e.g., propionyloxy, benzoyloxy, and acetoxy); carbamoyloxy
groups; carboxy groups; mercapto groups; alkylthio groups; acylthio
groups; arylthio groups (e.g., phenylthio, chlorophenylthio, alkylphenylthio,
alkoxyphenylthio, benzylthio, and alkyloxycarbonylphenylthio); aromartic
groups (e.g., phenyl and tolyl); susbstituted aromatic groups (e.g.,
alkoxyphenyl, alkoxycarbonylphenyl, and halogenated phenyl); heterocyclic
groups; heteroaryl groups; and amino groups (e.g., amino, mono-
and di-alkanylamino groups of 1 to 3 carbon atoms, methylphenylamino,
methylbenzylamino, alkanylamido groups of 1 to 3 carbon atoms, carbamamido,
ureido, and guanidino).
Prostaglandin F Analogs Used in the Invention
[0046] This invention relates to the use of prostaglandin F analogs
(PGFs) to treat hair loss. "Treating hair loss" means
arresting hair loss, reversing hair loss, or both, and promoting
hair growth. Suitable PGFs for use in this invention are selected
from the group consisting of PGFs having the structure: 3
[0047] and pharmaceutically acceptable salts, hydrates, and biohydrolyzable
amides, esters, and imides thereof.
[0048] R.sup.1 is selected from the group consisting of CO.sub.2H,
C(O)NHOH, CO.sub.2R.sup.5, CH.sub.2OH, S(O).sub.2R.sup.5, C(O)NHR.sup.5,
C(O)NHS(O).sub.2R.sup.5, and tetrazole. R.sup.5 is selected from
the group consisting of monovalent hydrocarbon groups, substituted
monovalent hydrocarbon groups, aromatic groups, substituted aromatic
groups, carbocyclic groups, substituted carbocyclic groups, heterogeneous
groups, substituted heterogeneous groups, heterocyclic groups, substituted
heterocyclic groups, heteroaromatic groups, and substituted heteroaromatic
groups. Preferably, R.sup.5 is selected from the group consisting
of CH.sub.3, C.sub.2H.sub.5, and C.sub.3H.sub.7. Preferably, R.sup.1
is selected from the group consisting of CO.sub.2H, CO.sub.2CH.sub.3,
CO.sub.2C.sub.2H.sub.5, CO.sub.2C.sub.3H.sub.7, CO.sub.2C.sub.4H.sub.9,
CO.sub.2C.sub.3H.sub.7O.sub.2, and C(O)NHS(O).sub.2R.sup.5. More
preferably, R.sup.1 is selected from the group consisting of CO.sub.2H,
CO.sub.2CH.sub.3, CO.sub.2C.sub.2H.sub.5, and CO.sub.2C.sub.3H.sub.7.
Most preferably, R.sup.1 is selected from the group consisting of
CO.sub.2H, CO.sub.2CH.sub.3, and CO.sub.2C.sub.3H.sub.7.
[0049] R.sup.2 is a hydrogen atom or a lower monovalent hydrocarbon
group. R.sup.2 is preferably a hydrogen atom or a methyl group.
[0050] R.sup.3 and R.sup.4 are each independently selected from
the group consisting of H, CH.sub.3, C.sub.2H.sub.5, OR.sup.10,
SR.sup.10, and OH; with the proviso that both R.sup.3 and R.sup.4
are not OH. R.sup.10 is selected from the group consisting of a
monovalent hydrocarbon group, a substituted monovalent hydrocarbon
group, a heterogeneous group, a substituted heterogeneous group,
a carbocyclic group, a substituted carbocyclic group, an aromatic
group, a substituted aromatic group, a heteroaromatic group, and
a substituted heteroaromatic group; with the proviso that R.sub.10
has 1 to 8 member atoms. Preferably, R.sup.3 and R.sup.4 are both
hydrogen atoms.
[0051] X is selected from the group consisting of NR.sup.6R.sup.7,
OR.sup.8, SR.sup.9, S(O)R.sup.9, and S(O).sub.2R.sup.9. Preferably,
X is selected from the group consisting of NR.sup.6R.sup.7 and OR.sup.8.
More preferably, X is OH.
[0052] R.sup.6, R.sup.7, and R.sup.8 are each independently selected
from the group consisting of hydrogen atoms, acyl groups, monovalent
hydrocarbon groups, substituted monovalent hydrocarbon groups, heterogeneous
groups, substituted heterogeneous groups, carbocyclic groups, substituted
carbocyclic groups, aromatic groups, substituted aromatic groups,
heteroaromatic groups, and substituted heteroaromatic groups. Preferably,
R.sup.6 and R.sup.7 are selected from the group consisting of H,
CH.sub.3, and C.sub.2H.sub.5. Preferably, R.sup.8 is selected from
the group consisting of H, CH.sub.3, C.sub.2H.sub.5, and C.sub.3H.sub.7.
[0053] R.sup.9 is selected from the group consisting of monovalent
hydrocarbon groups, substituted monovalent hydrocarbon groups, heterogeneous
groups, substituted heterogeneous groups, carbocyclic groups, substituted
carbocyclic groups, heterocyclic groups, substituted heterocyclic
groups, aromatic groups, substituted aromatic groups, heteroaromatic
groups, and substituted heteroaromatic groups. Preferably, R.sup.9
is selected from the group consisting of CH.sub.3, and C.sub.2H.sub.5.
[0054] Y is selected from the group consisting of an oxygen atom,
a divalent hydrocarbon group, a sulfur-containing moiety, and a
nitrogen-containing group. The divalent hydrocarbon group has the
formula (CH.sub.2).sub.n, wherein n is an integer with a value of
0 to 3. Preferably, n is 0, 1, or 2; more preferably, n is 1.
[0055] The sulfur-containing moiety for Y is selected from the
group consisting of a sulfur atom, S(O), and S(O).sub.2. When Y
is a sulfur-containing moiety, it preferably is a sulfur atom.
[0056] The nitrogen-containing group for Y has the formula NR.sup.11.
R.sup.11 is selected from the group consisting of a hydrogen atom,
an acyl group, a monovalent hydrocarbon group, a substituted monovalent
hydrocarbon group, a heterogeneous group, a substituted heterogeneous
group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic
group, a substituted heterocyclic group, an aromatic group, a substituted
aromatic group, a heteroaromatic group, and a substituted heteroaromatic
group. Preferably R.sup.11 is H or CH.sub.3.
[0057] Z is selected from the group consisting of a carbocyclic
group, a substituted carbocyclic group, a heterocyclic group, a
substituted heterocyclic group, an aromatic group, a substituted
aromatic group, a heteroaromatic group, and a substituted heteroaromatic
group. Preferably Z is selected from the group consisting of a monocyclic
carbocyclic group, a substituted monocyclic carbocyclic group, a
monocyclic heterocyclic group, a substituted monocyclic heterocyclic
group, a monocyclic aromatic group, a substituted monocyclic aromatic
group, a monocyclic heteroaromatic group, and a substituted monocyclic
heteroaromatic group. More preferably, Z is selected from the group
consisting of a monocyclic aromatic group, a substituted monocyclic
aromatic group, a monocyclic heteroaromatic group, and a substituted
monocyclic heteroaromatic group. Most preferably, Z is thienyl or
phenyl.
[0058] Optical isomers, diastereomers, and enantiomers of the structure
described above are also suitable for use in this invention. At
all stereocenters where stereochemistry is not defined (i.e., C11,
C12, C15, and C16), both epimers are envisioned.
[0059] Examples of suitable PGF's having the formula above wherein
Y is selected from the group consisting of NR.sup.11, S, S(O), and
S(O).sub.2 include:
[0060] 13,14-dihydro-16-(3-methylphenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha. methyl ester;
[0061] 13,14-dihydro-16-(3-methylphenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha.;
[0062] 3,14-dihydro-16-(3-fluorophenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha.;
[0063] 13,14-dihydro-16-(3-fluorophenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha. methyl ester;
[0064] 13,14-dihydro-16-(3-fluorophenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha. isopropyl ester;
[0065] 13,14-dihydro-16-(2,6-difluorophenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha. methyl ester;
[0066] 13,14-dihydro-16-(3,5-difluorophenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha.;
[0067] 13,14-dihydro-16-(2-methylphenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha. methyl ester;
[0068] 13,14-dihydro-16-(4-methylphenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha. methyl ester;
[0069] 13,14-dihydro-16-(4-methylphenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha.;
[0070] 13,14-dihydro-16-(2-fluorophenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha. methyl ester;
[0071] 13,14-dihydro-16-(2-fluorophenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha.;
[0072] 13,14-dihydro-15-methyl-16-(3-fluorophenylthio)-16-tetranor
Prostaglandin F.sub.1.alpha. methyl ester;
[0073] 13,14-dihydro-15-methyl-16-(3-fluorophenylthio)-16-tetranor
Prostaglandin F.sub.1.alpha.;
[0074] 13,14-dihydro-15-methyl-16-(2-methylphenylthio)-16tetranor
Prostaglandin F.sub.1.alpha. methyl ester;
[0075] 13,14-dihydro-15-methyl-16-(2-methylphenylthio)-16-tetranor
Prostaglandin F.sub.1.alpha.;
[0076] 13,14-dihydro-16-(3-fluorophenylsulfonyl)-16-tetranor Prostaglan
din F.sub.1.alpha.;
[0077] 13,14-dihydro-16-(3-methylphenylatino)-16-tetranor prostaglandin
F.sub.1.alpha. methyl ester;
[0078] 13,14-dihydro-16-(3-methylphenylamino)-16-tetranor prostaglandin
F.sub.1.alpha.;
[0079] 13,14-dihydro-16-(2-methylphenylamino)-16-tetranor prostaglandin
F.sub.1.alpha. methyl ester;
[0080] 13,14-dihydro-16-(2-methylphenylamino)-16-tetranor prostaglandin
F.sub.1.alpha.;
[0081] 13,14-dihydro-16-(2-fluorophenylthio)-16-tetranor prostaglandin
F.sub.1.alpha. 1-hydroxamic acid;
[0082] 13,14-dihydro-16-(3-chlorophenylamino)-16-tetranor prostaglandin
F.sub.1.alpha. 1-hydroxamic acid;
[0083] 13,14-dihydro-16-(3-trifluoromethylphenylthio)-16-tetranor
Prostaglandin F.sub.1.alpha. methyl ester;
[0084] 13,14-dihydro-16-(3-trifluoromethylphenylthio)-16-tetranor
Prostaglandin F.sub.1.alpha.;
[0085] 13,14-dihydro-16-(3-trifluoromethylphenylthio)-16-tetranor
prostaglandin F.sub.1.alpha. 1-hydroxamic acid;
[0086] 13,14-dihydro-16-(phenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha. methyl ester;
[0087] 13,14-dihydro-16-(phenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha. isopropyl ester;
[0088] 13,14-dihydro-15-methyl-16-(phenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha. methyl ester;
[0089] 13,14-dihydro-15-methyl-16-(phenylthio)-16-tetranor Prostaglandin
F.sub.1.alpha.;
[0090] 13,14-dihydro-16-(phenylamino)-16-tetranor prostaglandin
F.sub.1.alpha. methyl ester;
[0091] 13,14-dihydro-16-(phenylamino)-16-tetranor prostaglandin
F.sub.1.alpha.;
[0092] 13,14-dihydro-16-(2-thienylthio)-16-tetranor prostaglandin
F.sub.1.alpha. methyl ester;
[0093] 13,14-dihydro-16-(2-thienylthio)-16-tetranor prostaglandin
F.sub.1.alpha.;
[0094] 13,14-dihydro-16-(1-napthylthio)-16-tetranor Prostaglandin
F.sub.1.alpha. isopropyl ester;
[0095] 13,14-dihydro-16-(1-napthylthio)-16-tetranor Prostaglandin
F.sub.1.alpha.; and
[0096] 13,14-dihydro-15-butoxy-15-dehydroxy-16-(phenylthio)-16-tetranor
prostaglandin F.sub.1.alpha. methyl ester.
[0097] Examples of suitable PGF's having the formula above wherein
Y is a divalent hydrocarbon group include:
[0098] 13,14-dihydro-17-(2,4-difluorophenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester;
[0099] 13,14-dihydro-17-(2,4-difluorophenyl)-17-trinor prostaglandin
F.sub.1.alpha.;
[0100] 13,14-dihydro-17-(2-fluorophenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester;
[0101] 13,14-dihydro-17-(2-fluorophenyl)-17-trinor prostaglandin
F.sub.1.alpha.;
[0102] 13,14-dihydro-1 7-(3-fluorophenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester;
[0103] 13,14-dihydro-17-(3-fluorophenyl)-17-trinor prostaglandin
F.sub.1.alpha.;
[0104] 13,14-dihydro-17-(4-fluorophenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester;
[0105] 13,14-dihydro-17-(4-fluorophenyl)-17-trinor prostaglandin
F.sub.1.alpha.;
[0106] 13,14-dihydro-17-(2-methoxyphenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester;
[0107] 13,14-dihydro-17-(2-methoxyphenyl)-17-trinor prostaglandin
F.sub.1.alpha.;
[0108] 13,14-dihydro-17-(3-methoxyphenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester;
[0109] 13,14-dihydro-17-(3-methoxyphenyl)-17-trinor prostaglandin
F.sub.1.alpha.;
[0110] 13,14-dihydro-17-(4-methoxyphenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester;
[0111] 13,14-dihydro-1 7-(4-methoxyphenyl)-17-trinor prostaglandin
F.sub.1.alpha.;
[0112] 13,14-dihydro-17-(3,5-difluorophenyl)-17-trinor prostaglandin
F.sub.1.alpha. isopropyl ester;
[0113] 13,14-dihydro-18-(2-thienyl)-18-dinor prostaglandin F.sub.1.alpha.
methyl ester;
[0114] 13,14-dihydro-18-(2-thienyl)-18-dinor prostaglandin F.sub.1.alpha.
isopropyl ester;
[0115] 13,14-dihydro-17-((2-trifluoromethyl)phenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester;
[0116] 13,14-dihydro-17-((2-trifluoromethyl)phenyl)-17-trinor prostaglandin
F.sub.1.alpha.;
[0117] 13,14-dihydro-17-((3-trifluoromethyl)phenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester;
[0118] 13,14-dihydro-17-((3-trifluoromethyl)phenyl)-17-trinor prostaglandin
F.sub.1.alpha.;
[0119] 13,14-dihydro-17-((4-trifluoromethyl)phenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester;
[0120] 13,14-dihydro-17-((4-trifluoromethyl)phenyl)-17-trinor prostaglandin
F.sub.1.alpha.;
[0121] 13,14-dihydro-17-(2-methylphenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester;
[0122] 13,14-dihydro-17-(2-methylphenyl)-17-trinor prostaglandin
F.sub.1.alpha.;
[0123] 13,14-dihydro-17-(3-methylphenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester;
[0124] 13,14-dihydro-17-(3-methylphenyl)-17-trinor prostaglandin
F.sub.1.alpha.;
[0125] 13,14-dihydro-17-(4-methylphenyl)-17-trinor prostaglandin
F.sub.1.alpha. methyl ester; and
[0126] 13,14-dihydro-17-(4-methylphenyl)-17-trinor prostaglandin
F.sub.1.alpha..
[0127] Examples of suitable PGF's having the formula above wherein
Y is an oxygen atom include:
[0128] 13,14-dihydro-16,16-dimethyl-16-(2-fluorophenoxy)-16-tetranor
prostaglandin F.sub.1.alpha.;
[0129] 13,14-dihydro-16,16-dimethyl-16-(2-methylphenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha.;
[0130] 13,14-dihydro-16,16-dimethyl-16-(2,3 difluorophenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha.;
[0131] 13,14-dihydro-16-(2,5 difluorophenoxy)-16-tetranor Prostaglandin
F.sub.1.alpha.;
[0132] 13,14-dihydro-16-(3-fluoro-5-trifluoromethyl phenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha. isopropyl ester;
[0133] 13,14-dihydro-16,16-dimethyl-16-(4-chlorophenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha.;
[0134] 13,14-dihydro-16-methyl-16-(3-chlorophenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha. isopropyl ester;
[0135] 13,14-dihydro-1.sup.6-isopropyl-16-(2-fluorophenoxy)-16-tetranor
prostaglandin F.sub.1.alpha.;
[0136] 13,14-dihydro-16-ethyl-1 6-(2-methylphenoxy)-1 6-tetranor
Prostaglandin F.sub.1.alpha. isopropyl ester;
[0137] 13,14-dihydro-16-(hydroxymethyl)-16-phenoxy-16-tetranor
Prostaglandin F.sub.1.alpha.;
[0138] 13,14-dihydro-16-methyl-16-(4-ethylphenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha.;
[0139] 13,14-dihydro-16-methyl-16-(3-chlorophenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha. methyl ester;
[0140] 13,14-dihydro-16-methyl-16-(4-phenylphenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha. isopropy ester;
[0141] 13,14-dihydro-16,16-dimethyl-16-(4-phenoxyphenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha. isopropyl ester;
[0142] 13,14-dihydro-16,16-dimethyl-16-(2-fluorophenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha. hydroxamic acid;
[0143] 13,14-dihydro-16-methyl-16-(3-chlorophenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha. 1-hydroxamic acid;
[0144] 13,14-dihydro-16-methoxymethyl-16-(2,3-difluorophenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha. 1-hydroxamic acid;
[0145] 13,14-dihydro-16-phenoxy-16-tetranor Prostaglandin F.sub.1.alpha.
methanesulfonamide;
[0146] 13,14-dihydro-15-fluoro-16-(2-fluorophenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha. methyl ester;
[0147] 13,14-dihydro-15-methyl-16,16-dimethyl-16-(2-fluorophenoxy)-16-tetr-
anor Prostaglandin F.sub.1.alpha.;
[0148] 13,14-dihydro-15-fluoro-16-(2,3-difluorophenoxy)-16-tetranor
Prostaglandin F.sub.1.alpha. 1-hydroxamic acid;
[0149] 13,14-dihydro-15-methylthio-15-dehydroxy-16-(2-methylphenoxy)-16-te-
tranor Prostaglandin F.sub.1.alpha.;
[0150] 13,14-dihydro-15-methylthio-15-dehydroxy-16-methyl-16-(2-methylphen-
oxy) 16-tetranor Prostaglandin Floe 1-hydroxamic acid;
[0151] 13,14-dihydro-15-methoxy-16,16-dimethyl-16-(2-fluorophenoxy)-16-tet-
ranor Prostaglandin F.sub.1.alpha. 1-hydroxamic acid;
[0152] 13,14-dihydro-15-ethoxy-15-dehydroxy-16-phenoxy-16-tetranor
Prostaglandin F.sub.1.alpha. isopropyl ester;
[0153] 13,14-dihydro-15-sulfonylmethyl-15-dehydroxy-16-methyl-16-(2-methyl-
phenoxy)-16-tetranor Prostaglandin F.sub.1.alpha. methyl ester;
[0154] 13,14-dihydro-15-sulfoxylmethyl-15-dehydroxy-16-methyl-16-(2-methyl-
phenoxy)-16-tetranor Prostaglandin F.sub.1.alpha. methyl ester;
[0155] 13,14-dihydro-15-methyl-15-methylamino-15-dehydroxy-16,16-dimethyl--
16-(2-fluorophenoxy)-16-tetranor Prostaglandin F.sub.1.alpha. methyl
ester;
[0156] 13,14-dihydro-15-methyl-15-methylamino-15-dehydroxy-16-methyl-16-(2-
-methylphenoxy)-16-tetranor Prostaglandin F.sub.1.alpha. 1-hydroxamic
acid;
[0157] 13,14-dihydro-15-methyl-15-(N,N-dimethylamino)-16-ethyl-16-(2-fluor-
ophenoxy)-16-tetranor Prostaglandin F.sub.1.alpha. isopropyl ester;
and
[0158] 13,14-dihydro-16(2,6-difluorophenoxy)-16-tetranor Prostaglandin
F.sub.1.alpha. glyceryl ester.
[0159] Suitable PGF's are known in the art. Examples of suitable
PGF's and methods for their preparation are disclosed in International
Published Patent Application Numbers WO 99/12895A1, WO 99/12896A1,
and WO 99/12899A1, and in U.S. Pat. No. 5,977,173.
Compositions of the Invention
[0160] This invention further relates to a composition for treating
hair loss. The composition comprises A) the PGF described above
and B) a carrier. The composition may further comprise C) one or
more optional activity enhancers. The composition can be a pharmaceutical
or cosmetic composition, administered for treatment or prophylaxis
of hair loss. Standard pharmaceutical formulation techniques are
used, such as those disclosed in Remington's Pharmaceutical Sciences,
Mack Publishing Company, Easton, Pa. (1990).
[0161] The composition further comprises component B) a carrier.
"Carrier" means one or more compatible substances that
are suitable for administration to a mammal. Carrier includes solid
or liquid diluents, hydrotopes, surface-active agents, and encapsulating
substances. "Compatible" means that the components of
the composition are capable of being commingled with the PGF's,
and with each other, in a manner such that there is no interaction
which would substantially reduce the efficacy of the composition
under ordinary use situations. Carriers must be of sufficiently
high purity and sufficiently low toxicity to render them suitable
for administration to the mammal being treated. The carrier can
be inert, or it can possess pharmaceutical benefits, cosmetic benefits,
or both.
[0162] The choice of carrier for component B) depends on the route
by which A) the PGF will be administered and the form of the composition.
The composition may be in a variety of forms, suitable, for example,
for systemic administration (e.g., oral, rectal, nasal, sublingual,
buccal, or parenteral) or topical administration directly to the
locus of desired hair growth (e.g., local application on the skin,
ocular, liposome delivery systems, or iontophoresis). Topical administration
is preferred.
[0163] Carriers for systemic administration typically comprise
one or more ingredients selected from the group consisting of a)
diluents, b) lubricants, c) binders, d) disintegrants, e) colorants,
f) flavors, g) sweeteners, h) antioxidants, j) preservatives, k)
glidants, m) solvents, n) suspending agents, o) surfactants, combinations
thereof, and others.
[0164] Ingredient a) is a diluent. Suitable diluents include sugars
such as glucose, lactose, dextrose, and sucrose; polyols such as
propylene glycol; calcium carbonate; sodium carbonate; glycerin;
mannitol; and sorbitol.
[0165] Ingredient b) is a lubricant. Suitable lubricants are exemplified
by solid lubricants including silica, talc, stearic acid and its
magnesium salts and calcium salts, calcium sulfate; and liquid lubricants
such as polyethylene glycol and vegetable oils such as peanut oil,
cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma.
[0166] Ingredient c) is a binder. Suitable binders include polyvinylpyrrolidone;
magnesium aluminum silicate; starches such as corn starch and potato
starch; gelatin; tragacanth; and cellulose and its derivatives,
such as ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose,
microcrystalline cellulose, and sodium carboxymethylcellulose; carbomer;
providone; acacia; guar gum; and xanthan gum.
[0167] Ingredient d) is a disintegrant. Suitable disintegrants
include agar, alginic acid and the sodium salt thereof, effervescent
mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch,
sodium starch glycolate, clays, and ion exchange resins.
[0168] Ingredient e) is a colorant such as an FD&C dye.
[0169] Ingredient f) is a flavor such as menthol, peppermint, and
fruit flavors.
[0170] Ingredient g) is a sweetener such as aspartame and saccharin.
[0171] Ingredient h) is an antioxidant such as butylated hydroxyanisole,
butylated hydroxytoluene, and vitamin E.
[0172] Ingredient j) is a preservative such as phenol, alkyl esters
of parahydroxybenzoic acid, benzoic acid and the salts thereof,
boric acid and the salts thereof, sorbic acid and the salts thereof,
chorbutanol, benzyl alcohol, thimerosal, phenylmercuric acetate
and nitrate, nitromersol, benzalkonium chloride, cetylpyridinium
chloride, methyl paraben, and propyl paraben. Particularly preferred
are the salts of benzoic acid, cetylpyridinium chloride, methyl
paraben and propyl paraben, and sodium benzoate.
[0173] Ingredient k) is a glidant such as silicon dioxide.
[0174] Ingredient m) is a solvent, such as water, isotonic saline,
ethyl oleate, alcohols such as ethanol, glycerin, glycols (e.g.,
polypropylene glycol and polyethylene glycol), and buffer solutions
(e.g., phosphate, potassium acetate, boric carbonic, phosphoric,
succinic, malic, tartaric, citric, acetic, benzoic, lactic, glyceric,
gluconic, glutaric and glutamic).
[0175] Ingredient n) is a suspending agent. Suitable suspending
agents include AVICEL.RTM. RC-591 from FMC Corporation of Philadelphia,
Pa. and sodium alginate.
[0176] Ingredient o) lecithin, polysorbate 80, sodium lauryl sulfate,
polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monoalkyl
ethers, sucrose monoesters, lanolin esters, and lanolin ethers.
Suitable surfactants are known in the art and commercially available,
e.g., the TWEENS.RTM. from Atlas Powder Company of Wilmington, Del.
[0177] Compositions for parenteral administration typically comprise
A) 0.1 to 10% of a PGF and B) 90 to 99.9% of a carrier comprising
a) a diluent and m) a solvent. Preferably, component a) is propylene
glycol and m) is ethanol or ethyl oleate.
[0178] Compositions for oral administration can have various dosage
forms. For example, solid forms include tablets, capsules, granules,
and bulk powders. These oral dosage forms comprise a safe and effective
amount, usually at least 5%, and preferably from 25% to 50%, of
A) the PGF. The oral dosage compositions further comprise B) 50
to 95% of a carrier, preferably 50 to 75%.
[0179] Tablets can be compressed, tablet triturates, enteric-coated,
sugar-coated, film-coated, or multiple-compressed. Tablets typically
comprise A) the PGF, and B) a carrier comprising ingredients selected
from the group consisting of a) diluents, b) lubricants, c) binders,
d) disintegrants, e) colorants, f) flavors, g) sweeteners, k) glidants,
and combinations thereof. Preferred diluents include calcium carbonate,
sodium carbonate, mannitol, lactose and cellulose. Preferred binders
include starch, gelatin, and sucrose. Preferred disintegrants include
alginic acid, and croscarmelose. Preferred lubricants include magnesium
stearate, stearic acid, and talc. Preferred colorants are the FD&C
dyes, which can be added for appearance. Chewable tablets preferably
contain g) sweeteners such as aspartame and saccharin, or f) flavors
such as menthol, peppermint, and fruit flavors.
[0180] Capsules (including time release and sustained release formulations)
typically comprise A) the PGF, and B) a carrier comprising one or
more a) diluents disclosed above in a capsule comprising gelatin.
Granules typically comprise A) the PGF, and preferably further comprise
k) glidants such as silicon dioxide to improve flow characteristics.
[0181] The selection of ingredients in the carrier for oral compositions
depends on secondary considerations like taste, cost, and shelf
stability, which are not critical for the purposes of this invention.
One skilled in the art can optimize appropriate ingredients without
undue experimentation.
[0182] The solid compositions may also be coated by conventional
methods, typically with pH or time-dependent coatings, such that
A) the PGF is released in the gastrointestinal tract at various
times to extend the desired action. The coatings typically comprise
one or more components selected from the group consisting of cellulose
acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl
cellulose phthalate, ethyl cellulose, EUDRAGIT.RTM. coatings (available
from Rohm & Haas G.M.B.H. of Darmstadt, Germany), waxes and
shellac.
[0183] Compositions for oral administration can also have liquid
forms. For example, suitable liquid forms include aqueous solutions,
emulsions, suspensions, solutions reconstituted from non-effervescent
granules, suspensions reconstituted from non-effervescent granules,
effervescent preparations reconstituted from effervescent granules,
elixirs, tinctures, syrups, and the like. Liquid orally administered
compositions typically comprise A) the PGF and B) a carrier comprising
ingredients selected from the group consisting of a) diluents, e)
colorants, and f) flavors, g) sweeteners, j) preservatives, m) solvents,
n) suspending agents, and o) surfactants. Peroral liquid compositions
preferably comprise one or more ingredients selected from the group
consisting of e) colorants, f) flavors, and g) sweeteners.
[0184] Other compositions useful for attaining systemic delivery
of the subject compounds include sublingual, buccal and nasal dosage
forms. Such compositions typically comprise one or more of soluble
filler substances such as a) diluents including sucrose, sorbitol
and mannitol; and c) binders such as acacia, microcrystalline cellulose,
carboxymethyl cellulose, and hydroxypropyl methyl cellulose. Such
compositions may further comprise b) lubricants, e) colorants, f)
flavors, g) sweeteners, h) antioxidants, and k) glidants.
[0185] The compositions may further comprise component C) an optional
activity enhancer. Component C) is preferably selected from the
group consisting of i) hair growth stimulants (other than the PGF)
and ii) penetration enhancers.
[0186] Component i) is an optional hair growth stimulant. Component
i) is exemplified by vasodilators, antiandrogens, cyclosporins,
cyclosporin analogs, antimicrobials, anti-inflammatories, thyroid
hormones, thyroid hormone derivatives, and thyroid hormone analogs,
non-selective prostaglandin agonists or antagonists, retinoids,
triterpenes, combinations thereof, and others. "Non-selective
prostaglandin" agonists and antagonists differ from component
A) in that they do not selectively activate the FP receptor, and
they may activate other receptors.
[0187] Vasodilators such as potassium channel agonists including
minoxidil and minoxidil derivatives such as aminexil and those described
in U.S. Pat. Nos. 3,382,247, 5,756,092, 5,772,990, 5,760,043, 5,466,694,
5,438,058, 4,973,474, and cromakalin and diazoxide can be used as
optional hair growth stimulants in the composition.
[0188] Examples of suitable antiandrogens include 5-.alpha.-reductase
inhibitors such as finasteride and those described in U.S. Pat.
No. 5,516,779, and in Nane et al., Cancer Research 58, "Effects
of Some Novel Inhibitors of C17,20-Lyase and 5.alpha.-Reductase
in vitro and in vivo and Their Potential Role in the Treatment of
Prostate Cancer," as well as cyproterone acetate, azelaic acid
and its derivatives and those compounds described in U.S. Pat. No.
5,480,913, flutamide, and those compounds described in U.S. Pat.
Nos. 5,411,981, 5,565,467, and 4,910,226. Antimicrobials include
selenium sulfide, ketoconazole, triclocarbon, triclosan, zinc pyrithione,
itraconazole, asiatic acid, hinokitiol, mipirocin and those described
in EPA 0,680,745, clinacycin hydrochloride, benzoyl peroxide, benzyl
peroxide and minocyclin.
[0189] Examples of suitable anti-inflammatories include glucocorticoids
such as hydrocortisone, mometasone furoate and prednisolone, nonsteroidal
anti-inflammatories including cyclooxygenase or lipoxygenase inhibitors
such as those described in U.S. Pat. No. 5,756,092, and benzydamine,
salicylic acid, and those compounds described in EPA 0,770,399,
published May 2, 1997, WO 94/06434, published Mar. 31, 1994, and
FR 2,268,523, published Nov. 21, 1975.
[0190] 3,5,3'-Triiodothyronine is an example of a suitable thyroid
hormone.
[0191] Examples of suitable non-selective prostaglandin agonists
and antagonists include compounds such as those described in WO
98/33497, Johnstone, published Aug. 6, 1998, WO 95/11003, Stjernschantz,
published Apr. 27, 1995, JP 97-100091, Ueno and JP 96-134242, Nakamura.
[0192] Suitable retinoids include isotretinoin, acitretin, and
tazarotene.
[0193] Other optional hair growth stimulants for component i) include
benzalkonium chloride, benzethonium chloride, phenol, estradiol,
chlorpheniramine maleate, chlorophyllin derivatives, cholesterol,
salicylic acid, cysteine, methionine, red pepper tincture, benzyl
nicotinate, D,L-menthol, peppermint oil, calcium pantothenate, panthenol,
castor oil, prednisolone, resorcinol, chemical activators of protein
kinase C, glycosaminoglycan chain cellular uptake inhibitors, inhibitors
of glycosidase activity, glycosaminoglycanase inhibitors, esters
of pyroglutamic acid, hexosaccharic acids or acylated hexosaccharic
acids, aryl-substituted ethylenes, N-acylated amino acids, flavinoids,
ascomycin derivatives and analogs, histamine antagonists such as
diphenhydramine hydrochloride, triterpenes such as oleanolic acid
and ursolic acid and those described in U.S. Pat. Nos. 5,529,769,
5,468,888, 5,631,282, and 5,679,705, JP 10017431, WO 95/35103, JP
09067253, WO 92/09262, JP 62093215, and JP 08193094; saponins such
as those described in EP 0,558,509 to Bonte et al., published Sep.
8, 1993 and WO 97/01346 to Bonte et al, published Jan. 16, 1997,
proteoglycanase or glycosaminoglycanase inhibitors such as those
described in U.S. Pat. Nos. 5,015,470, 5,300,284, and 5,185,325,
estrogen agonists and antagonists, pseudoterins, cytokine and growth
factor promoters, analogs or inhibitors such as interleukin 1 inhibitors,
interleukin-6 inhibitors, interleukin-10 promoters, and tumor necrosis
factor inhibitors, vitamins such as vitamin D analogs and parathyroid
hormone antagonists, Vitamin B12 analogs and panthenol, interferon
agonists and antagonists, hydroxyacids such as those described in
U.S. Pat. No. 5,550,158, benzophenones, and hydantoin anticonvulsants
such as phenytoin, and combinations thereof.
[0194] Other additional hair growth stimulants are described in
JP 09-157,139 to Tsuji et al., published Jun. 17, 1997; EP 0277455
A1 to Mirabeau, published Aug. 10, 1988; WO 97/05887 to Cabo Soler
et al., published Feb. 20, 1997; WO 92/16186 to Bonte et al., published
Mar. 13, 1992; JP 62-93215 to Okazaki et al., published Apr. 28,
1987; U.S. Pat. No. 4,987,150 to Kurono et al., issued Jan. 22,
1991; JP 290811 to Ohba et al., published Oct. 15, 1992; JP 05-286,835
to Tanaka et al., published Nov. 2, 1993, FR 2,723,313 to Greff,
published Aug. 2, 1994, U.S. Pat. No. 5,015,470 to Gibson, issued
May 14, 1991, U.S. Pat. No. 5,559,092, issued Sep. 24, 1996, U.S.
Pat. No. 5,536,751, issued Jul. 16, 1996, U.S. Pat. No. 5,714,515,
issued Feb. 3, 1998, EPA 0,319,991, published Jun. 14, 1989, EPA
0,357,630, published Oct. 6, 1988, EPA 0,573,253, published Dec.
8, 1993, JP 61-260010, published Nov. 18, 1986, U.S. Pat. No. 5,772,990,
issued Jun. 30, 1998, U.S. Pat. No. 5,053, 410, issued Oct. 1, 1991,
and U.S. Pat. No. 4,761,401, issued Aug. 2, 1988.
[0195] The most preferred activity enhancers are minoxidil and
finasteride, most preferably minoxidil.
[0196] Component ii) is a penetration enhancer that can be added
to all of the compositions for systemic administration. The amount
of component ii), when present in the composition, is typically
1 to 5%. Examples of penetration enhancers include 2-methyl propan-2-ol,
propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, polyoxyethylene(2)
ethyl ether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone,
polyoxyethylene(2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic
acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran, butan-1,4-diol,
propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether,
octyl alcohol, polyoxyethylene ester of oleyl alcohol, oleyl alcohol,
lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl
adipate, di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate,
dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate,
dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate,
dimethyl azelate, butyl myristate, dibutyl succinate, didecyl phthalate,
decyl oleate, ethyl caproate, ethyl salicylate, isopropyl palmitate,
ethyl laurate, 2-ethyl-hexyl pelargonate, isopropyl isostearate,
butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl
caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hydroxypropanoic
acid, 2-hydroxyoctanoic acid, dimethyl sulphoxide, N,N-dimethyl
acetamide, N,N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolid(one,
5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone,
phosphine oxides, sugar esters, tetrahydrofurfural alcohol, urea,
diethyl-m-toluamide, 1-dodecylazacyloheptan-2-one, omega three fatty
acids and fish oils, and combinations thereof.
[0197] In a preferred embodiment of the invention, the PGF's are
topically administered. Topical compositions that can be applied
locally to the skin may be in any form including solutions, oils,
creams, ointments, gels, lotions, shampoos, leave-on and rinse-out
hair conditioners, milks, cleansers, moisturizers, sprays, skin
patches, and the like. Topical compositions comprise: component
A) the PGF described above and component B) a carrier. The carrier
of the topical composition preferably aids penetration of the PGF's
into the skin to reach the environment of the hair follicle. Component
B) may further comprise one or more optional components. Topical
compositions preferably further comprise C) one or more of the optional
activity enhancers described above.
[0198] The exact amounts of each component in the topical composition
depend on various factors. The amount of component A) depends on
the IC.sub.50 of the PGF selected. "IC.sub.50" means inhibitory
concentration 50.sup.th percentile. The amount of component A) added
to the topical composition is:
IC.sub.50.times.10.sup.-2.gtoreq.% of component A).gtoreq.IC.sub.50.times.-
10.sup.-3,
[0199] where IC.sub.50 is expressed in nanomolar units. For example,
if the IC.sub.50 of the PGF is 1 nM, the amount of component A)
will be 0.001 to 0.01%. If the IC.sub.50 of the PGF is 10 nM, the
amount of component A) will be 0.01 to 0.1%. If the IC.sub.50 of
the PGF is 100 nM, the amount of component A) will be 0.1 to 1.0%.
If the IC.sub.50 of the PGF is 1000 nM, the amount of component
A) will be 1.0 to 10%, preferably 1.0 to 5%. If the amount of component
A) is outside the ranges specified above (i.e., either higher or
lower), efficacy of the treatment may be reduced. IC.sub.50 can
be calculated according to the method in Reference Example 1, below.
One skilled in the art can calculate IC.sub.50 without undue experimentation.
[0200] The topical composition preferably further comprises 1 to
20% component C), and a sufficient amount of component B) such that
the amounts of components A), B), and C), combined equal 100%. The
amount of B) the carrier employed in conjunction with the PGF is
sufficient to provide a practical quantity of material for administration
per unit dose of the compound. Techniques and compositions for making
dosage forms useful in the methods of this invention are described
in the following references: Modern Pharmaceutics, Chapters 9 and
10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical
Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical
Dosage Forms, 2.sup.nd Ed., (1976).
[0201] Component B) the carrier may comprise a single ingredient
or a combination of two or more ingredients. In the topical compositions,
component B) is a topical carrier. Preferred topical carriers comprise
one or more ingredients selected from the group consisting of water,
alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils,
mineral oil, propylene glycol, polypropylene glycol-2 myristyl propionate,
dimethyl isosorbide, combinations thereof, and the like. More preferred
carriers include propylene glycol, dimethyl isosorbide, and water.
[0202] The topical carrier may comprise one or more ingredients
selected from the group consisting of q) emollients, r) propellants,
s) solvents, t) humectants, u) thickeners, v) powders, and w) fragrances
in addition to, or instead of, the preferred topical carrier ingredients
listed above. One skilled in the art would be able to optimize carrier
ingredients for the topical compositions without undue experimentation.
[0203] Ingredient q) is an emollient. The amount of ingredient
q) in the topical composition is typically 5 to 95%. Suitable emollients
include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate,
propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl
isostearate, stearic acid, isobutyl palmitate, isocetyl stearate,
oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol,
isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl
myristate, isopropyl palmitate, isopropyl stearate, butyl stearate,
polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut
oil, arachis oil, castor oil, acetylated lanolin alcohols, petrolatum,
mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl
linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl
myristate, polydimethylsiloxane, and combinations thereof. Preferred
emollients include stearyl alcohol and polydimethylsiloxane.
[0204] Ingredient r) is a propellant. The amount of ingredient
r) in the topical composition is typically 5 to 95%. Suitable propellants
include propane, butane, isobutane, dimethyl ether, carbon dioxide,
nitrous oxide, and combinations thereof. Ingredient s) is a solvent.
The amount of ingredient s) in the topical composition is typically
5 to 95%. Suitable solvents include water, ethyl alcohol, methylene
chloride, isopropanol, castor oil, ethylene glycol monoethyl ether,
diethylene glycol monobutyl ether, diethylene glycol monoethyl ether,
dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations
thereof. Preferred solvents include ethyl alcohol.
[0205] Ingredient t) is a humectant. The amount of ingredient t)
in the topical composition is typically 5 to 95%. Suitable humectants
include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate,
soluble collagen, dibutyl phthalate, gelatin, and combinations thereof.
Preferred humectants include glycerin.
[0206] Ingredient u) is a thickener. The amount of ingredient u)
in the topical composition is typically 0 to 95%.
[0207] Ingredient v) is a powder. The amount of ingredient v) in
the topical composition is typically 0 to 95%. Suitable powders
include chalk, talc, fullers earth, kaolin, starch, gums, colloidal
silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites,
trialkyl aryl ammonium smectites, chemically modified magnesium
aluminum silicate, organically modified montmorillonite clay, hydrated
aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl
cellulose, ethylene glycol monostearate, and combinations thereof.
[0208] Ingredient w) is a fragrance. The amount of ingredient w)
in the topical composition is typically 0.001 to 0.5%, preferably
0.001 to 0.1%.
[0209] Component C) the optional activity enhancer is as described
above. Any of the i) hair growth stimulants and ii) penetration
enhancers may be added to the topical compositions. Preferably,
the topical composition comprises 0.01 to 15% of component i) the
optional hair growth stimulant. More preferably, the composition
comprises 0.1 to 10%, and most preferably 0.5 to 5% of component
i). Preferably, the topical composition comprises 1 to 5% of component
ii).
[0210] In an alternative embodiment of the invention, topical pharmaceutical
compositions for ocular administration are prepared by conventional
methods. Topical pharmaceutical compositions for ocular administration
typically comprise A) a PGF, B) a carrier, such as purified water,
and one or more ingredients selected from the group consisting of
y) sugars such as dextrans, particularly dextran 70, z) cellulose
or a derivative thereof, aa) a salt, bb) disodium EDTA (Edetate
disodium), and cc) a pH adjusting additive.
[0211] Examples of z) cellulose derivatives suitable for use in
the topical pharmaceutical composition for ocular administration
include sodium carboxymethyl cellulose, ethyl cellulose, methyl
cellulose, and hydroxypropylmethylcellulose. Hydroxypropylmethylcellulose
is preferred.
[0212] Examples of aa) salts suitable for use in the for use in
the topical pharmaceutical composition for ocular administration
include sodium chloride, potassium chloride, and combinations thereof.
[0213] Examples of cc) pH adjusting additives include HCl or NaOH
in amounts sufficient to adjust the pH of the topical pharmaceutical
composition for ocular administration to 7.2-7.5.
[0214] This invention further relates to a method for darkening
hair, thickening hair, and reversing hair graying. The method comprises
applying the topical composition for treating hair loss to hair,
to skin in the locus of hair, or both. For example, the topical
composition may be applied to hair growing on the scalp or eyelashes.
The topical composition can be, for example, a cosmetic composition
prepared as described above. An example of a composition that may
be applied to eyelashes is a mascara. The prostaglandin may be added
to mascara compositions known in the art, such as the mascara described
in U.S. Pat. No. 5,874,072, which is hereby incorporated by reference.
The mascara comprises dd) a water-insoluble material, ee) a water-soluble,
film-forming polymer, ff) a wax, o) a surfactant, gg) a pigment,
and s) a solvent.
[0215] Ingredient dd) is a water-insoluble material selected from
the group consisting of acrylate copolymers; styrene/acrylate/methacrylate
copolymers; acrylic latex; styrene/acrylic ester copolymer latex;
polyvinylacetate latex; vinyl acetate/ethylene copolymer latex;
styrene/butadiene copolymer latex; polyurethane latex; butadiene/acrylonitrile
copolymer latex; styrene/acrylate/acrylonitrile copolymer latex;
and mixtures thereof, wherein the acrylate copolymers, and the styrene/acrylate/methacrylate
copolymers additionally comprise ammonia, propylene glycol, a preservative
and a surfactant.
[0216] Ingredient ee) is a water-soluble, film-forming polymer.
Ingredient ee) is selected from the group consisting of vinyl alcohol/poly(alkyleneoxy)acrylate,
vinyl alcohol/vinyl acetate/poly-(alkyleneoxy)acrylate, polyethylene
oxide, polypropylene oxide, acrylates/octyl-acrylamide copolymers
and mixtures thereof.
[0217] Ingredient ff) is a wax. "Wax" means a lower-melting
organic mixture or compound of high molecular weight, solid at room
temperature and generally similar in composition to fats and oils
except that they contain no glycerides. Some are hydrocarbons, others
are esters of fatty acids and alcohols. Waxes useful in this invention
are selected from the group consisting of animal waxes, vegetable
waxes, mineral waxes, various fractions of natural waxes, synthetic
waxes, petroleum waxes, ethylenic polymers, hydrocarbon types such
as Fischer-Tropsch waxes, silicone waxes, and mixtures thereof wherein
the waxes have a melting point between 55 and 100.degree. C.
[0218] Ingredient o) is surfactant, as described above. Ingredient
o) in the mascara is preferably a surfactant having an HLB from
3 to 15. Suitable surfactants include those disclosed in the C.T.F.A.
Cosmetic Ingredient Handbook, pp.587-592 (1992); Remington's Pharmaceutical
Sciences, 15th Ed. pp. 335-337 (1975); and McCutcheon's Volume 1,
Emulsifiers & Detergents, North American Edition, pp. 236-239
(1994).
[0219] Ingredient gg) is a pigment. Suitable pigments include inorganic
pigments, organic lake pigments, pearlescent pigments, and mixtures
thereof. Inorganic pigments useful in this invention include those
selected from the group consisting of rutile or anatase titanium
dioxide, coded in the Color Index under the reference CI 77,891;
black, yellow, red and brown iron oxides, coded under references
CI 77,499, 77,492 and, 77,491; manganese violet (CI 77,742); ultramarine
blue (CI 77,007); chromium oxide (CI 77,288); chromium hydrate (CI
77,289); and ferric blue (CI 77,510) and mixtures thereof.
[0220] The organic pigments and lakes useful in this invention
include those selected from the group consisting of D&C Red
No. 19 (CI 45,170), D&C Red No. 9 (CI 15,585), D&C Red No.
21 (CI 45,380), D&C Orange No. 4 (CI 15,510), D&C Orange
No. 5 (CI 45,370), D&C Red No. 27 (CI 45,410), D&C Red No.
13 (CI 15,630), D&C Red No. 7 (CI 15,850), D&C Red No. 6
(CI 15,850), D&C Yellow No. 5 (CI 19,140), D&C Red No. 36
(CI 12,085), D&C Orange No. 10 (CI 45,425), D&C Yellow No.
6 (CI 15,985), D&C Red No. 30 (CI 73,360), D&C Red No. 3
(CI 45,430) and the dye or lakes based on Cochineal Carmine (Cl
75,570) and mixtures thereof.
[0221] The pearlescent pigments useful in this invention include
those selected from the group consisting of the white pearlescent
pigments such as mica coated with titanium oxide, bismuth oxychloride,
colored pearlescent pigments such as titanium mica with iron oxides,
titanium mica with ferric blue, chromium oxide and the like, titanium
mica with an organic pigment of the above-mentioned type as well
as those based on bismuth oxychloride and mixtures thereof.
[0222] Ingredient s) is a solvent described above, preferably water.
[0223] The amount of A) the PGF added to the mascara is as described
above for topical compositions.
[0224] The PGF's may also be administered in the form of liposome
delivery systems, such as small unilamellar vesicles, large unilamellar
vesicles, and multilamellar vesicles. Liposomes can be formed from
a variety of phospholipids, such as cholesterol, stearylamine or
phosphatidylcholines. A preferred formulation for topical delivery
of the present compounds uses liposomes as described in Dowton et
al., "Influence of Liposomal Composition on Topical Delivery
of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless
Mouse Skin", S.T.P. Pharma Sciences, Vol. 3, pp. 404-407 (1993);
Wallach and Philippot, "New Type of Lipid Vesicle: Novasome.RTM.",
Liposome Technology, Vol. 1, pp. 141-156 (1993); Wallach, U.S. Pat.
No. 4,911,928, assigned to Micro-Pak, Inc., issued Mar. 27, 1990;
and Weiner et al., U.S. Pat. No. 5,834,014, assigned to The University
of Michigan and Micro-Pak, Inc., issued November 10, 1998 (with
respect to Weiner et al., with a compound as described herein administered
in lieu of, or in addition to, minoxidil).
[0225] The PGF's may also be administered by iontophoresis. See,
e.g., Internet site www.unipr.it/arpa/dipfarm/erasmus/erasm14.html;
Banga et al., "Hydrogel-based lontotherapeutic Delivery Devices
for Transdermal Delivery of Peptide/Protein Drugs", Pharm.
Res., Vol. 10 (5), pp. 697-702 (1993); Ferry, "Theoretical
Model of Iontophoresis Utilized in Transdermal Drug Delivery",
Pharmaceutical Acta Helvetiae, Vol 70, pp. 279-287 (1995); Gangarosa
et al., "Modern Iontophoresis for Local Drug Delivery",
Int. J. Pharm, Vol. 123, pp. 159-171 (1995); Green et al., "Iontophoretic
Delivery of a Series of Tripeptides Across the Skin in vitro",
Pharm. Res., Vol 8, pp. 1121-1127 (1991); Jadoul et al., "Quantification
and Localization of Fentanyl and TRH Delivered by Iontophoresis
in the Skin", Int. J. Pharm., Vol. 120, pp. 221-8 (1995); O'Brien
et al., "An Updated Review of its Antiviral Activity, Pharmacokinetic
Properties and Therapeutic Efficacy", Drugs, Vol. 37, pp. 233-309
(1989); Parry et al., "Acyclovir Biovailability in Human Skin",
J. Invest. Dermatol., Vol. 98 (6), pp. 856-63 (1992); Santi et al.,
"Drug Reservoir Composition and Transport of Salmon Calcitonin
in Transdermal lontophoresis", Pharm. Res., Vol 14 (1), pp.
63-66 (1997); Santi et al., "Reverse Iontophoresis--Parameters
Determining Electroosmotic Flow: I. pH and Ionic Strength",
J. Control. Release, Vol. 38, pp. 159-165 (1996); Santi et al.,
"Reverse Iontophoresis--Parameters Determining Electroosmotic
Flow: II. Electrode Chamber Formulation", J. Control. Release,
Vol. 42, pp. 29-36 (1996); Rao et al., "Reverse lontophoresis:
Noninvasive Glucose Monitoring in vivo in Humans", Pharm. Res.,
Vol. 12 (12), pp. 1869-1873 (1995); Thysman et al., "Human
Calcitonin Delivery in Rats by lontophoresis", J. Pharm. Pharmacol.,
Vol. 46, pp. 725-730 (1994); and Volpato et al., "Iontophoresis
Enhances the Transport of Acyclovir through Nude Mouse Skin by Electrorepulsion
and Electroosmosis", Pharm. Res., Vol. 12 (11), pp. 1623-1627
(1995).
[0226] The PGF's may be included in kits comprising a PGF, a systemic
or topical composition described above, or both; and information,
instructions, or both that use of the kit will provide treatment
for hair loss in mammals (particularly humans). The information
and instructions may be in the form of words, pictures, or both,
and the like. In addition or in the alternative, the kit may comprise
a PGF, a composition, or both; and information, instructions, or
both, regarding methods of application of the PGF or composition,
preferably with the benefit of treating hair loss in mammals.
[0227] In all of the foregoing compositions, and for all routes
of administration, the PGF's can be used alone or in combinations
of two or more PGF's. The compositions may further comprise additional
drugs or excipients as appropriate for the indication.
Methods of the Invention
[0228] This invention further relates to a method for treating
hair loss in mammals. The method comprises administering to a mammal
(preferably a human) suffering from hair loss, a PGF described above.
For example, a mammal diagnosed with alopecia including male pattern
baldness and female pattern baldness can be treated by the methods
of this invention. Preferably, a systemic or topical composition
comprising A) the PGF and B) a carrier is administered to the mammal.
More preferably, the composition is a topical composition comprising
A) the PGF, B) the carrier, and C) an optional activity enhancer.
[0229] The dosage of the PGF administered depends on the method
of administration. For systemic administration, (e.g., oral, rectal,
nasal, sublingual, buccal, or parenteral), typically, 0.5 mg to
300 mg, preferably 0.5 mg to 100 mg, more preferably 0.1 mg to 10
mg, of a PGF described above is administered per day. These dosage
ranges are merely exemplary, and daily administration can be adjusted
depending on various factors. The specific dosage of the PGF to
be administered, as well as the duration of treatment, and whether
the treatment is topical or systemic are interdependent. The dosage
and treatment regimen will also depend upon such factors as the
specific PGF used, the treatment indication, the efficacy of the
compound, the personal attributes of the subject (such as, for example,
weight, age, sex, and medical condition of the subject), compliance
with the treatment regimen, and the presence and severity of any
side effects of the treatment.
[0230] For topical administration (e.g., local application on the
skin, ocular, liposome delivery systems, or iontophoresis), the
topical composition is typically administered once per day. The
topical compositions are administered daily for a relatively short
amount of time (i.e., on the order of weeks). Generally, 6 to 12
weeks is sufficient. The topical compositions are preferably leave-on
compositions. In general, the topical composition should not be
removed for at least several hours after administration.
[0231] In addition to the benefits in treating hair loss, the inventors
have surprisingly found that the PGF's in the compositions and methods
of this invention also darken and thicken hair and may reverse hair
graying.
EXAMPLES
[0232] These examples are intended to illustrate the invention
to those skilled in the art and should not be interpreted as limiting
the scope of the invention set forth in the claims.
Reference Example 1
Radioligand Binding Assay
[0233] IC.sub.50 of a PGF can be determined relative to PGF.sub.2.alpha.
using the Radioligand Binding Assay. As a control, the IC.sub.50
for PGF.sub.2.alpha. itself should be no lower than 1.0 nM and no
higher than 5.0 nM.
[0234] In this assay, COS-7 cells are transiently transfected with
the hFP recombinant plasmid using LipofectAlNE Reagent. Forty-eight
hours later, the tranfected cells are washed with Hank's Balanced
Salt Solution (HBSS, without CaCl.sub.2, MgCl.sub.2, MgSO.sub.4,
or phenol red). The cells are detached with versene, and HBSS is
added. The mixture is centrifuged at 200g for 10 minutes, at 4.degree.
C. to pellet the cells. The pellet is resuspended in Phosphate-Buffered
Saline-EDTA buffer (PBS; 1 mM EDTA; pH 7.4; 4.degree. C.). The cells
are disrupted by nitrogen cavitation (Parr model 4639), at 800 psi,
for 15 minutes at 4.degree. C. The mixture is centrifuged at 1000
g for 10 minutes at 4.degree. C. The supernatant is centrifuged
at 100,000 g for 60 minutes at 4.degree. C. The pellet is resuspended
to 1 mg protein/mL TME buffer (50 mM Tris; 10 mM MgCl2; 1 mM EDTA;
pH 6.0; 4.degree. C.) based on protein levels measured using the
Pierce BCA Protein Assay kit. The homogenate is mixed for 10 seconds
using a Kinematica POLYTRON.RTM. (available from KINEMATICA AG,
Luzernerstrassel47A CH-6014 Littau, Switzerland). The membrane preparations
are then stored at -80.degree. C., until thawed for assay use.
[0235] The receptor competition binding assays are developed in
a |