Hair loss abstract
A method for treating hair loss in mammals uses compositions containing
prostaglandins 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 composition for treating hair loss comprising: A) an active
ingredient selected from the group consisting of oximyl- and hydroxylamino-prostaglandins
having the functionality 110wherein C is a carbon atom bonded within
a cyclopentyl ring and wherein the active ingredient selectively
activates FP receptors and does not activate any other receptors
that negate effects caused by activating the FP receptors, and wherein
R.sup.2 is hydrogen, and R.sup.3 is selected from the group consisting
of hydrogen and a lower monovalent hydrocarbon group, with the proviso
that alternatively, R.sup.2 and R.sup.3 may form a covalent bond,
and R.sup.4 is selected from the group consisting of a hydrogen
atom, a monovalent hydrocarbon group, a heterogeneous group, a carbocyclic
group, heterocyclic group, an aromatic group, a heteroaromatic group,
a substituted monovalent hydrocarbon group, a substituted heterogeneous
group, a substituted carbocyclic group, a substituted heterocyclic
group, a substituted aromatic group, and a substituted heteroaromatic
group; and B) a carrier.
2. The composition of claim 1, wherein R.sup.4 is selected from
the group consisting of a hydrogen atom and a monovalent hydrocarbon
group of 1 to 8 carbon atoms.
3. The composition of claim 1, wherein A) the active ingredient
has the structure: 111pharmaceutically acceptable salts and hydrates
of the structure above; biohydrolyzable amides, esters, and imides
of the structure above; and optical isomers, diastereomers, and
enantiomers of the structure above; and combinations thereof; wherein
W is selected from the group consisting of an oxygen atom, a sulfur
atom, NH, S(O), S(O).sub.2, and --(CH.sub.2).sub.m--, wherein m
is 0 to 3; X is selected from the group consisting of NHR.sup.8,
OR.sup.8, SR.sup.9, and S(O)R.sup.9; Y is selected from the group
consisting of a bond, an oxygen atom, a sulfur atom, NHR.sup.8,
S(O), and S(O).sub.2; with the proviso that when Y is NHR.sup.8,
no carbon atom in R.sup.8 is bonded to more than one heteroatom;
Z is selected from the group consisting of H, CH.sub.3, a carbocyclic
group, a heterocyclic group, a substituted carbocyclic group, a
substituted heterocyclic group, an aromatic group, a heteroaromatic
group, a substituted aromatic group, and a substituted heteroaromatic
group; R.sup.1 is selected from the group consisting of CO.sub.2H,
CO.sub.2R.sup.7, C(O)NHOH, S(O).sub.2R.sup.7, C(O)NHS(O).sub.2R.sup.7,
and tetrazole; each R.sup.5 is independently selected from the group
consisting of H, CH.sub.3, and C.sub.2H.sub.5; each R.sup.6 is independently
selected from the group consisting of H, CH.sub.3, C.sub.2H.sub.5,
OR.sup.8, and NHR.sup.8; R.sup.7 is selected from the group consisting
of monovalent hydrocarbon groups, heterogeneous groups, aromatic
groups, heteroaromatic groups, monocyclic carbocyclic groups, monocyclic
heterocyclic groups, substituted monovalent hydrocarbon groups,
substituted aromatic groups, and substituted heteroaromatic groups;
each R.sup.8 is independently 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, and heterocyclic group, a substituted heterocyclic
group, an aromatic group, a substituted aromatic group, a heteroaromatic
group, and a substituted heteroaromatic group; each R.sup.9 is independently
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, and heterocyclic group, a substituted heterocyclic
group, an aromatic group, a substituted aromatic group, a heteroaromatic
group, and a substituted heteroaromatic group; p is an integer with
a value of 0 to 6, q is an integer with a value of 0 to 5, with
the proviso that (p+q)=1 to 5, and bonds a, b, and c are each independently
selected from the group consisting of a single bond, a cis double
bond, and a trans double bond.
4. The composition of claim 3, wherein W is selected from the group
consisting of an oxygen atom and --(CH.sub.2).sub.m--.
5. The composition of claim 3, wherein X is OR.sup.8.
6. The composition of claim 3, wherein Y is selected from the group
consisting of a bond, an oxygen atom, and NHR.sup.8.
7. The composition of claim 3, wherein Z is selected from the group
consisting of aromatic, heteroaromatic, substituted aromatic, and
substituted heteroaromatic groups.
8. The composition of claim 3, wherein R.sup.1 is selected from
the group consisting of CO.sub.2H, C(O)NHOH, CO.sub.2R.sup.7, C(O)NHS(O).sub.2R.sup.7,
and tetrazole.
9. The composition of claim 3, wherein each R.sup.5 is independently
selected from the group consisting of H and CH.sub.3.
10. The composition of claim 3, wherein each R.sup.6 is independently
selected from the group consisting of H, CH.sub.3, C.sub.2H.sub.5,
and OR.sup.8.
11. The composition of claim 3, wherein R.sup.7 is selected from
the group consisting of methyl, ethyl, and isopropyl groups.
12. The composition of claim 3, wherein each R.sup.8 is a hydrogen
atom.
13. The composition of claim 3, wherein p is an integer with a
value 1 to 5.
14. The composition of claim 3, wherein bond a is selected from
the group consisting of a single bond and a cis double bond.
15. The composition of claim 3, wherein bond b is selected from
the group consisting of a single bond and a trans double bond.
16. The composition of claim 3, wherein Y is a bond, p is 0, and
q is 2 or 3.
17. The composition of claim 3, wherein Y is a bond, q is 0, and
component A) has the structure: 112wherein R.sup.1, W, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, X, R.sup.6, Z, p, and bonds a, b, and
c are as described above.
18. The composition of claim 3, wherein component A) is added in
an amount ofIC.sub.50.times.10.sup.-2.gtoreq.% of component A).gtoreq.IC.sub.50.tim-
es.10.sup.-3,where IC.sub.50 of component A) is expressed in nanomolar
units.
19. The composition of claim 18, wherein component C) an activity
enhancer 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%.
20. The composition of claim 3, wherein component B) comprises
an ingredient selected from the group consisting of q) emollients,
r) propellants, s) solvents, t) humectants, u) thickeners, v) powders,
w) fragrances, water, alcohols, aloe vera gel, allantoin, glycerin,
vitamin A and E oils, mineral oil, propylene glycol, polypropylene
glycol-2 myristyl propionate, dimethyl isosorbide, and combinations
thereof.
21. The composition of claim 20, 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, polydimethylsiloxane,
and combinations thereof.
22. The composition of claim 20, wherein ingredient r) is selected
from the group consisting of propane, butane, isobutane, dimethyl
ether, carbon dioxide, nitrous oxide, and combinations thereof.
23. The composition of claim 20, 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.
24. The composition of claim 20, 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.
25. The composition of claim 20, 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 s ilicate, fumed silica, carboxyvinyl polymer,
sodium carboxymethyl cellulose, ethylene glycol monostearate, and
combinations thereof.
26. A method of treating hair loss comprising administering to
a mammal a composition comprising: A) an active ingredient selected
from the group consisting of oximyl- and hydroxylamino-prostaglandins
having the functionality 113wherein C is a carbon atom bonded within
a cyclopentyl ring and wherein the active ingredient selectively
activates FP receptors and does not activate any other receptors
that negate effects caused by activating the FP receptors, and wherein
R.sup.2 is hydrogen, and R.sup.3 is selected from the group consisting
of hydrogen and a lower monovalent hydrocarbon group, with the proviso
that alternatively, R.sup.2 and R.sup.3 may form a covalent bond,
and R.sup.4 is selected from the group consisting of a hydrogen
atom, a monovalent hydrocarbon group, a heterogeneous group, a carbocyclic
group, heterocyclic group, an aromatic group, a heteroaromatic group,
a substituted monovalent hydrocarbon group, a substituted heterogeneous
group, a substituted carbocyclic group, a substituted heterocyclic
group, a substituted aromatic group, and a substituted heteroaromatic
group.
27. The method of claim 26, wherein component A) is selected from
the group consisting of oximyl- and hydroxylamino-prostaglandins
having the structure: 114pharmaceutically acceptable salts and hydrates
of the structure above; biohydrolyzable amides, esters, and imides
of the structure above; optical isomers, diastereomers, and enantiomers
of the structure above; and combinations thereof; wherein W is selected
from the group consisting of an oxygen atom, a sulfur atom, NH,
S(O), S(O).sub.2, and --(CH.sub.2).sub.m--, wherein m is 0 to 3;
X is selected from the group consisting of NHR.sup.8, OR.sup.8,
SR.sup.9, and S(O)R.sup.9; Y is selected from the group consisting
of a bond, an oxygen atom, a sulfur atom, NHR.sup.8, S(O), and S(O).sub.2;
with the proviso that when Y is NHR.sup.8, no carbon atom in R.sup.8
is bonded to more than one heteroatom; Z is selected from the group
consisting of H, CH.sub.3, a carbocyclic group, a heterocyclic group,
a substituted carbocyclic group, a substituted heterocyclic group,
an aromatic group, a heteroaromatic group, a substituted aromatic
group, and a substituted heteroaromatic group; R.sup.1 is selected
from the group consisting of CO.sub.2H, C(O)NHOH, S(O).sub.2R.sup.7,
C(O)NHS(O).sub.2R.sup.7, and tetrazole; each R.sup.5 is independently
selected from the group consisting of H, CH.sub.3, and C.sub.2H.sub.5;
each R.sup.6 is independently selected from the group consisting
of H, CH.sub.3, C.sub.2H.sub.5, OR.sup.8, and NHR.sup.8; R.sup.7
is selected from the group consisting of monovalent hydrocarbon
groups, heterogeneous groups, aromatic groups, heteroaromatic groups,
monocyclic carbocyclic groups, monocyclic heterocyclic groups, substituted
monovalent hydrocarbon groups, substituted aromatic groups, and
substituted heteroaromatic groups; each R.sup.8 is independently
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, and heterocyclic
group, a substituted heterocyclic group, an aromatic group, a substituted
aromatic group, a heteroaromatic group, and a substituted heteroaromatic
group; each R.sup.9 is independently 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, and heterocyclic
group, a substituted heterocyclic group, an aromatic group, a substituted
aromatic group, a heteroaromatic group, and a substituted heteroaromatic
group; p is an integer with a value of 0 to 6, q is an integer with
a value of 0 to 5, with the proviso that (p+q)=1 to 5, and bonds
a, b, and c are each independently selected from the group consisting
of a single bond, a cis double bond, and a trans double bond.
28. The method of claim 27, wherein W is selected from the group
consisting of an oxygen atom and --(CH.sub.2).sub.m--.
29. The method of claim 27, wherein X is OR.sup.8.
30. The method of claim 27, wherein Y is selected from the group
consisting of a bond, an oxygen atom, and NHR.sup.8.
31. The method of claim 27, wherein Z is selected from the group
consisting of aromatic, heteroaromatic, substituted aromatic, and
substituted heteroaromatic groups.
32. The method of claim 27, wherein R.sup.1 is selected from the
group consisting of CO.sub.2H, C(O)NHOH, CO.sub.2R.sup.7, C(O)NHS(O).sub.2R.sup.7,
and tetrazole.
33. The method of claim 27, wherein each R.sup.5 is independently
selected from the group consisting of H and CH.sub.3.
34. The method of claim 27, wherein each R.sup.6 is independently
selected from the group consisting of H, CH.sub.3, C.sub.2H.sub.5,
and OR.sup.8.
35. The method of claim 27, wherein R.sup.7 is selected from the
group consisting of methyl, ethyl, and isopropyl groups.
36. The method of claim 27, wherein each R.sup.8 is a hydrogen
atom.
37. The method of claim 27, wherein p is an integer with a value
1 to 5,
38. The method of claim 27, wherein bond a is selected from the
group consisting of a single bond and a cis double bond.
39. The method of claim 27, wherein bond b is selected from the
group consisting of a single bond and a trans double bond.
40. The method of claim 27, wherein Y is a bond, p is 0, and q
is 2 or 3.
41. The method of claim 27, wherein Y is a bond, q is 0, and component
A) has the structure: 115wherein R.sup.1, W, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, X, R.sup.6, Z, p, bonds a, b, and c are as described above.
42. The method of claim 27, wherein the composition is administered
by a route selected from the group consisting of systemic and topical
routes.
43. The method of claim 42, 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.
44. The method of claim 43, wherein the composition is a topical
composition further comprisinga topical carrier comprising an ingredient
selected from the group consisting of q) emollients, r) propellants,
s) solvents, t) humectants, u) thickeners, v) powders, w) fragrances,
water, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and
E oils, mineral oil, propylene glycol, polypropylene glycol-2 myristyl
propionate, dimethyl isosorbide, and combinations thereof.
45. The method of claim 43, 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.
46. The method of claim 45, 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.
47. The method of claim 43, 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, tetrahydrofurfuryl alcohol, urea, diethyl-m-toluamide,
1-dodecylazacyloheptan-2-one, and combinations thereof.
48. The method of claim 43, wherein the topical composition locally
administered on the skin once per day.
49. The method of claim 48, wherein the topical composition is
administered once per day for 6 to 12 weeks.
50. A mascara composition comprising: A) an active ingredient selected
from the group consisting of oximyl- and hydroxylamino-prostaglandins
having the functionality 116wherein C is a carbon atom bonded within
a cyclopentyl ring and wherein the active ingredient selectively
activates FP receptors and does not activate any other receptors
that negate effects caused by activating the FP receptors, and wherein
R.sup.2 is hydrogen, and R.sup.3 is selected from the group consisting
of hydrogen and a lower monovalent hydrocarbon group, with the proviso
that alternatively, R.sup.2 and R.sup.3 may form a covalent bond,
and R.sup.4 is selected from the group consisting of a hydrogen
atom, a monovalent hydrocarbon group, a heterogeneous group, a carbocyclic
group, heterocyclic group, an aromatic group, a heteroaromatic group,
a substituted monovalent hydrocarbon group, a substituted heterogeneous
group, a substituted carbocyclic group, a substituted heterocyclic
group, a substituted aromatic 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.
51. A method for darkening and thickening hair, wherein the method
comprises applying to growing hair and skin a composition comprising:
A) an active ingredient selected from the group consisting of oximyl-
and hydroxylamino-prostaglandins having the functionality 117wherein
in each functionality C is a carbon atom bonded within a cyclopentyl
ring and wherein the active ingredient selectively activates FP
receptors and does not activate any other receptors that negate
effects caused by activating the FP receptors, and wherein R.sup.2
is hydrogen, and R.sup.3 is selected from the group consisting of
hydrogen and a lower monovalent hydrocarbon group, with the proviso
that alternatively, R.sup.2 and R.sup.3 may form a covalent bond,
and R.sup.4 is selected from the group consisting of a hydrogen
atom, a monovalent hydrocarbon group, a heterogeneous group, a carbocyclic
group, heterocyclic group, an aromatic group, a heteroaromatic group,
a substituted monovalent hydrocarbon group, a substituted heterogeneous
group, a substituted carbocyclic group, a substituted heterocyclic
group, a substituted aromatic 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.
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,
G B 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 C13 and
C14. 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 (1993), pp. 1533-1564; 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 (1975),
pp. 1-4; W. Bartman, G. Beck, U. Lerch, H. Teufel, and B. Scholkens,
"Luteolytic Prostaglandin: Synthesis and Biological Activity",
Prostaglandin, Vol. 17 No. 2 (1979), pp. 301-311; C. liljebris,
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 (1995), pp. 289-304.
[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. (1995) 116, 2298.
[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 a composition comprising
a specific prostaglandin that interacts strongly with hair-selective
receptors, such as the FP receptor. The choice of prostaglandin
is important because the prostaglandin 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, component B) a carrier,
and optionally component C) an activity enhancer.
[0012] Suitable prostaglandins are selected from the group consisting
of oximyl-prostaglandins and hydroxylamino-prostaglandins. These
oximyl- and hydroxylamino-prostaglandins have the general formula:
2
[0013] Preferably, W is an oxygen atom or an alkyl group; X is
OR.sup.8; Y is a bond or an oxygen atom; Z is thienyl or phenyl;
R.sup.1 is CO.sub.2H, CO.sub.2R.sup.7, or C(O)NHOH; R.sup.2 and
R.sup.3 form a covalent bond; R.sup.4 is a lower monovalent hydrocarbon
group; R.sup.5 H or CH.sub.3; R.sup.6 is H or CH.sub.3; R.sup.7
is a methyl, ethyl, or isopropyl group; and R.sup.5 is preferably
a hydrogen atom. Preferably, p is an integer with a value of 1 to
5, and q is an integer with a value of 0 to 5. Preferably, bond
a is a single bond, a cis double bond, or a trans double bond, bond
b is a single bond or a trans double bond, and bond c is a cis double
bond or a trans double bond.
DETAILED DESCRIPTION OF THE INVENTION
[0014] This invention relates to compositions and methods using
oximyl- and hydroxylamino-prostaglandins 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] "Alkoxy group" means a monovalent group having
the structure --O(C.sub.xH.sub.2x+1) wherein x is 1 to 12.
[0021] "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 7 to 17 carbon atoms, preferably
7 to 14 carbon atoms, and more preferably 9 or 10 carbon atoms in
the ring. Aromatic groups are unsubstituted. The most preferred
aromatic group is phenyl.
[0022] "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 7 to 17 carbon atoms, preferably
7 to 14 carbon atoms, and more 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.
[0023] "Cyano group" means a group containing a nitrile
functionality.
[0024] "FP agonist" means a compound that activates the
FP receptor.
[0025] "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.
[0026] "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.
[0027] "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. "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 7 to 17 member atoms, preferably 7
to 14, and more 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 ring 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 7 to 17
member atoms, preferably 7 to 14, and more preferably 9 or 10 in
the ring. Heterocyclic groups are unsubstituted. Preferred heterocyclic
groups include piperzyl, morpholinyl, tetrahydrofuranyl, 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. Preferred lower
monovalent hydrocarbon groups include alkyl groups such as methyl,
ethyl, propyl, and butyl. Monovalent hydrocarbon groups may have
a straight chain or branched chain structure. Preferred branched
monovalent hydrocarbon groups have one or two branches, preferably
1 branch. Monovalent hydrocarbon groups may be saturated or unsaturated.
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. Preferred monovalent hydrocarbon groups include
alkyl groups.
[0033] "Pharmaceutically acceptable" means suitable for
use in a human or other mammal.
[0034] "Prostaglandin" means a fatty acid derivative
which has a variety of potent biological activities of a hormonal
or regulatory nature.
[0035] "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.
[0036] "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).
[0037] "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.
[0038] "Subject" means a living, vertebrate, hair- or
fur-bearing animal such as a mammal (preferably human) in need of
treatment.
[0039] "Substituted aromatic group" means an aromatic
group wherein at least 1 (preferably 1 to 4) of the hydrogen atoms
bonded to a carbon atom in the ring has been replaced with another
substituent. 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.
[0040] "Substituted carbocyclic group" means a carbocyclic
group wherein at least 1 (preferably 1 to 4) of the hydrogen atoms
bonded to a carbon atom in the ring has been replaced with another
substituent. 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.
[0041] "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.
[0042] "Substituted heterocyclic group" means heterocyclic
group wherein at least 1 (preferably 1 to 4) of the hydrogen atoms
bonded to a carbon atom in the ring has been replaced with another
substituent. 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,
aromatic groups, substituted aromatic groups, heteroaromatic groups,
substituted heteroaromatic groups, phenoxy groups, or any combination
thereof. More preferred substituents include halogen atoms and halogenated
hydrocarbon groups. Substituted heterocyclic groups are not aromatic.
[0043] "Substituted heterogeneous group" means a heterogeneous
group, wherein at least 1 of the hydrogen atoms bonded to a carbon
atom in the chain has been replaced with another substituent. 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 halophenyl), 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).
[0044] "Substituted monovalent hydrocarbon group" means
a monovalent hydrocarbon group wherein at least 1 of the hydrogen
atoms bonded to a carbon atom in the chain has been replaced with
another substituent. Preferably 1 to 4, more preferably 1 to 3,
of the hydrogen atoms bonded to a carbon atom have been replaced
with other substituents. Preferred substituents include halogen
atoms; substituted monovalent hydrocarbon groups; lower monovalent
hydrocarbon groups such as 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); aryl groups (e.g., phenyl, tolyl,
alkoxyphenyl, alkoxycarbonylphenyl, and halophenyl); heterocyclic
groups; heteroaromatic groups; carbocyclic groups, heterocyclic
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).
Prostaglandins Used in the Invention
[0045] This invention relates to the use of prostaglandins to treat
hair loss. The prostaglandin is selected from the group consisting
of oximyl- and hydroxylamino-prostaglandins having the structure:
3
[0046] and pharmaceutically acceptable salts and hydrates of the
structure above; biohydrolyzable amides, esters, and imides of the
structure above; optical isomers, diastereomers, and enantiomers
of the structure above; and combinations thereof.
[0047] W is selected from the group consisting of O, NH, S, S(O),
S(O).sub.2, and --(CH.sub.2).sub.m--, wherein m is 0 to 3. Preferably,
W is selected from the group consisting of O and --(CH.sub.2).sub.m--,
and more preferably, W is --CH.sub.2--.
[0048] X is selected from the group consisting of NHR.sup.8, OR.sup.8,
SR.sup.9, and S(O)R.sup.9. Preferably, X is OR.sup.8.
[0049] Y is selected from the group consisting of a bond, an oxygen
atom, a sulfur atom, NHR.sup.8, S(O), and S(O).sub.2; with the proviso
that when Y is NHR.sup.8, no carbon atom in R.sup.8 is bonded to
more than one heteroatom. Preferably, Y is selected from the group
consisting of a bond, an oxygen atom, and NHR.sup.5 More preferably,
Y is a bond or an oxygen atom.
[0050] Z is selected from the group consisting of H, CH.sub.3,
a carbocyclic group, a heterocyclic group, a substituted carbocyclic
group, a substituted heterocyclic group, an aromatic group, a heteroaromatic
group, a substituted aromatic group, and a substituted heteroaromatic
group. Z is preferably selected from the group consisting of aromatic,
heteroaromatic, substituted aromatic, and substituted heteroaromatic
groups. More preferably, the aromatic, heteroaromatic, substituted
aromatic, and substituted heteroaromatic groups are monocyclic and
have 6 member atoms in the ring. Still more preferably, Z is selected
from the group consisting of thienyl and phenyl. Preferably, when
Y is S, S(O), or S(O).sub.2 and Z is H, q is at least 1.
[0051] R.sup.1 is selected from the group consisting of CO.sub.2H,
CO.sub.2R.sup.7, C(O)NHOH, S(O).sub.2R.sup.7, C(O)NHS(O).sub.2R.sup.7,
and tetrazole. Preferably, R.sup.1 is selected from the group consisting
of CO.sub.2H, C(O)NHOH, CO.sub.2R.sup.7, C(O)NHS(O).sub.2R.sup.7,
and tetrazole, More preferably, R.sup.1 is selected from the group
consisting of CO.sub.2H, CO.sub.2R.sup.7, and C(O)NHOH.
[0052] R.sup.2 is hydrogen, and R.sup.3 is hydrogen or a lower
monovalent hydrocarbon group, with the proviso that alternatively,
R.sup.2 and R.sup.3 may form a covalent bond (i.e., the oximyl structure).
[0053] R.sup.4 is a hydrogen atom, a monovalent hydrocarbon group,
a heterogeneous group, a carbocyclic group, heterocyclic group,
an aromatic group, a heteroaromatic group, a substituted monovalent
hydrocarbon group, a substituted heterogeneous group, a substituted
carbocyclic group, a substituted heterocyclic group, a substituted
aromatic group, or a substituted heteroaromatic group. Preferably,
R.sup.4 is selected from the group consisting of a hydrogen atom
and a monovalent hydrocarbon group of 1 to 8 carbon atoms. More
preferably, R.sup.4 is a hydrogen atom or a lower monovalent hydrocarbon
group. Still more preferably, R.sup.4 is a hydrogen atom or a methyl
group. Most preferably, R.sup.4 is a hydrogen atom.
[0054] Each R.sup.5 is independently selected from the group consisting
of H, CH.sub.3, and C.sub.2H.sub.5. Preferably, R.sup.5 is selected
from the group consisting of H and CH.sub.3; more preferably, R.sup.5
is H.
[0055] Each R.sup.6 is independently selected from the group consisting
of H, CH.sub.3, C.sub.2H.sub.5, OR.sup.8, and NHR.sup.8. Preferably,
R.sup.6 is selected from the group consisting of H, CH.sub.3, C.sub.2H.sub.5,
and OR.sup.8. More preferably, R.sup.6 is H or CH.sub.3.
[0056] R.sup.7 is selected from the group consisting of monovalent
hydrocarbon groups, heterogeneous groups, aromatic groups, heteroaromatic
groups, monocyclic carbocyclic groups, monocyclic heterocyclic groups,
substituted monovalent hydrocarbon groups, substituted aromatic
groups, and substituted heteroaromatic groups. R.sup.7 preferably
contains 1 to 8 carbon atoms. R.sup.7 is more preferably selected
from the group consisting of methyl, ethyl, and isopropyl groups.
[0057] Each R.sup.8 is independently 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, and heterocyclic group, a substituted heterocyclic
group, an aromatic group, a substituted aromatic group, a heteroaromatic
group, and a substituted heteroaromatic group. R.sup.8 is preferably
a hydrogen atom.
[0058] Each R.sup.9 is independently 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, and heterocyclic
group, a substituted heterocyclic group, an aromatic group, a substituted
aromatic group, a heteroaromatic group, and a substituted heteroaromatic
group.
[0059] The subscript p is an integer with a value of 0 to 6, preferably
1 to 5, and the subscript q is an integer with a value of 0 to 5,
with the proviso that (p+q)=1 to 5. When Y is a bond and p is 0,
q is preferably 2 or 3.
[0060] Bonds a, b, and c are each independently selected from the
group consisting of a single bond, a cis double bond, and a trans
double bond. Preferably, bond a is a single bond or a cis double
bond. Preferably, bond b is a single bond or a trans double bond.
Preferably, bond c is a single bond.
[0061] Examples of prostaglandins having the formula above are
shown in Table 1.
1TABLE 1 Examples of Prostaglandins Suitable for Component A 4
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49
50 51
[0062] Of the prostaglandins in Table 1, 11-oximyl-16-((3-trifluoromethyl)-
phenoxy)-16-tetranor PGD.sub.2 methyl ester, 11-oximyl-13,14-dihydro-16-ph-
enoxy-16-tetranor 5,6-dihydro-4,5-dehydro PGD.sub.2 isopropyl ester,
and 11-oximyl-16-phenoxy-16-tetranor PGD.sub.2 are preferred.
[0063] When Y is a bond and q is 0, the prostaglandin will have
the formula: 52
[0064] wherein R.sup.1, W, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
X, R.sup.6, Z, p, bond a, and bond b are as described above. Examples
of suitable prostaglandins having this formula are shown in Table
2.
2TABLE 2 Examples of Prostaglandins Suitable for Component A 53
54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75
76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97
98 99 100
[0065] (In the table above, Me represents a methyl group, and Et
represents an ethyl group.)
[0066] Of the compounds in Table 2, 11 -oximyl-PGD.sub.2 and 11-hydroxylamino-15-S-methyl-PGF.sub.2.alpha.
are preferred.
[0067] Even though the some of the prostaglandins having the structures
above are more structurally similar to PGD analogs than PGF analogs,
the above prostaglandins selectively activate the FP receptor and
do not activate the DP receptor. Without wishing to be bound by
theory, it is believed that the functionality (shown below) at the
C11 position in the structures above imparts the selectivity to
bind with the FP receptor. 101
[0068] Therefore, any FP agonist containing this functionality,
wherein C* is one of the carbon atoms in the cyclopentyl ring, that
selectively activates the FP receptor is also suitable to use in
this invention. Preferably, C* is the carbon atom at the C11 position.
[0069] Prostaglandins suitable for use in this invention can be
made using conventional organic syntheses. Preferred syntheses are
exemplified by the following two general reaction schemes: 102
[0070] In Scheme 1, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, X, Y, p, q, and Z are as defined above. Q.sup.1 is a silyl-functional
protecting group. Q.sup.2 is a protecting group. The methyl 7(3-(R)-hydroxy-5-oxo-1-cyclopent-1-yl)
heptanoate (S1a) depicted as starting material for Scheme 1 is commercially
available (such as from Sumitomo Chemical or Cayman Chemical).
[0071] In the above Scheme 1, methyl 7-(3-(R)-hydroxy-5-oxo-1-cyclopent-1--
yl) heptanoate (S1a) is reacted with a silylating agent and base
in a solvent that will allow the silylation to proceed. Preferred
silylating agents include tert-butyldimethylsilyl chloride and tert-butyldimethylsilyl
trifluoromethanesulfonate. The most preferred silylating agent is
tert-butyldimethylsilyl trifluoromethanesulphonate. Preferred bases
include triethylamine, trimethylamine, and 2,6-lutidine. More preferred
bases include triethylamine and 2,6-lutidine. The most preferred
base is 2,6-lutidine. Preferred solvents include halogenated hydrocarbon
solvents with dichloromethane being the most preferred solvent.
The reaction is allowed to proceed at a temperature preferably of
-100.degree. C. to 100.degree. C., more preferably -80.degree. C.
to 80.degree. C., and most preferably -70.degree. C. to 23.degree.
C.
[0072] The resulting silylated compound is isolated by methods
known to those of ordinary skill in the art. Such methods include
extraction, solvent evaporation, distillation, and crystallization.
Preferably, the silyl ether is purified after isolation by distillation
under vacuum.
[0073] The silylated compound is then reacted with the cuprate
generated via Grignard formation of the appropriate alkenyl bromide
as disclosed, for example, in the following references: H. O. House
et. al., "The Chemistry of Carbanions: A Convenient Precursor
for the Generation of Lithium Organocuprates", J. Org. Chem.
Vol. 40 (1975) pp. 1460-69, and P. Knochel et. al., "Zinc and
Copper Carbenoids as Efficient and Selective a'/d' Multicoupling
Reagents", J. Amer. Chem. Soc. Vol. 111 (1989) p. 6474-76.
Preferred alkenyl bromides include 4-bromo-1-butene, 4-bromo-1-butyne,
4-bromo-2-methyl-1-butene, and 4-bromo-2-ethyl-1-butene- . The most
preferred alkenyl bromide is 4-bromo-1-butene. Preferred solvents
include ethereal solvents, of which diethyl ether and tetrahydrofuran
are preferred. The most preferred solvent is tetrahydrofuran. The
Grignard reagent is allowed to form at a temperature of 80.degree.
C. to 23.degree. C., more preferably 80.degree. C. to 30.degree.
C., and most preferably 75.degree. C. to 65.degree. C. The reaction
time is preferably 1 hour to 6 hours, more preferably 2 to 5 hours,
and most preferably 3 to 4 hours.
[0074] Once the Grignard reagent is formed, the cuprate is generated
from the alkenyl magnesium species. The temperature range for cuprate
formation is -100.degree. C. to 0.degree. C., preferably -80.degree.
C. to -20.degree. C., and more preferably -75.degree. C. to -50.degree.
C. The preferred reaction time is 30 to and 6 hours, more preferably
45 minutes to 3 hours, and most preferably 1 to 1.5 hours.
[0075] The compound depicted as S1b is isolated by methods known
to one of ordinary skill in the art. Such methods include extraction,
solvent evaporation, distillation, and crystallization. Preferably,
S1b is purified by flash chromatography on silica gel (Merck, 230-400
mesh) using 10% EtOAc/hexanes as the eluent.
[0076] S1b is then reacted with a hydride reducing agent and a
polar, protic solvent to give the C.sub.9 alcohol. Preferred reducing
agents include lithium aluminum hydride, sodium borohydride, and
L-selectride. More preferred reducing agents include sodium borohydride,
and L-selectride. The most preferred reducing agent is sodium borohydride.
Preferred solvents include methanol, ethanol, and butanol. The most
preferred solvent is methanol. The reduction is carried out at a
temperature of -100.degree. C. to 23.degree. C., preferably -60.degree.
C. to 0.degree. C., and most preferably -45.degree. C. to -20.degree.
C.
[0077] The resulting alcohol of S1b is isolated by methods known
to one of ordinary skill in the art. Such methods include extraction,
solvent evaporation, distillation, and crystallization. Preferably,
the alcohol is purified by flash chromatography on silica gel (Merck,
230-400 mesh) using 20% EtOAc/hexanes as the eluent.
[0078] The alcohol can be protected as described above. The protected
or unprotected alcohol is then treated with meta-chloroperbenzoic
acid in a halocarbon solvent to provide the novel epoxide intermediate
depicted as S1c. Preferred halocarbon solvents include dichloromethane,
dichloroethane, and chloroform. More preferred halocarbon solvents
are dichloromethane and dichloroethane. The most preferred halocarbon
solvent is dichloromethane.
[0079] The compound depicted as S1c is isolated by methods known
to one of ordinary skill in the art. Such methods include extraction,
solvent evaporation, distillation, and crystallization. Preferably,
S1c is purified by flash chromatography on silica gel (Merck, 230-400
mesh) using 20% EtOAc/hexanes as the eluent.
[0080] The intermediate epoxide depicted as S1c can be reacted
with a variety of oxygen, sulfur and nitrogen containing nucleophiles
as disclosed, for example, in J. G. Smith, "Synthetically Useful
Reactants of Epoxides", Synthesis (1984) p. 629-656, to provide
the C.sub.11-protected 13,14-dihydro-15-substituted-16-tetranor
prostaglandin F.sub.1.alpha. derivatives.
[0081] With sulfur nucleophiles, the reaction is carried out at
a temperature of preferably 80.degree. C. to 0.degree. C., more
preferably 80.degree. C. to 20.degree. C., and most preferably 80.degree.
C. to 50.degree. C. Preferred bases for the reaction include triethylamine,
N,N diisopropylethylamine, and trimethylamine. The most preferred
base is triethylamine. Preferred solvents for the reaction are aromatic
hydrocarbon solvents. Preferred solvents include xylenes, toluene,
and benzene. The most preferred solvent is benzene. With nitrogen
and oxygen nucleophiles, preferred solvents include ethereal solvents
and polar, protic solvents. More preferred ethereal solvents include
diethyl ether, dibutyl ether and tetrahydrofuran. The most preferred
ethereal solvent is tetrahydrofuran. More preferred polar, protic
solvents include ethyl alcohol, methyl alcohol, and tert-butyl alcohol.
The most preferred polar, protic solvent is ethyl alcohol.
[0082] The ring-opening process with nitrogen and oxygen nucleophiles
can be catalyzed with Lewis acids. Preferred Lewis acids include
magnesium perchlorate, trimethylsilyl trifluoromethanesulphonate,
and trimethylaluminum. The most preferred Lewis acid is magnesium
perchlorate. The reaction is carried out at a temperature of 80.degree.
C. to 23.degree. C., preferably 80.degree. C. to 40.degree. C.,
and more preferably 80.degree. C. to 70.degree. C.
[0083] The selective protection of C-9 and C-15 can be accomplished
by methods known to one of ordinary skill in the art. Preferred
protecting groups include, but are not limited to acylating agents,
alkylating agent, and carbonate forming agents. The most preferred
protecting group is acetyl. Preferred solvents include halohydrocarbon
and amine solvents. The most preferred is pyridine. Preferred reagents
include acetyl halides and acetic anhydride. The most preferred
is acetic anhydride. The temperature range for the reaction is -100.degree.
C. to 100.degree. C., preferably -10.degree. C. to 40.degree. C.,
and more preferably -5.degree. C. to 40.degree. C. The preferred
reaction time is 1 to 48 hours, preferably 6 to 24 hours.
[0084] The compound depicted as S1d is isolated by methods known
to one of ordinary skill in the art. Such methods include extraction,
solvent evaporation, distillation, and crystallization. Preferably,
S1d is purified by flash chromatography on silica gel (Merck, 230-400
mesh) using 10% EtOAc/hexanes as the eluent.
[0085] The resulting C-11 ether on compound S1d is deprotected
using using a fluoride or its equivalent. The deprotection reagents
include tetrabutyl ammonium fluoride, hydrogen fluoride in pyridine,
potassium fluoride, and treatment with strong acid. Preferred is
HF/pyridine. The temperature range is -100.degree. C. to 50.degree.
C. The preferred temperature range is -50.degree. C. to 30.degree.
C. The most preferred is -20.degree. C. to 10.degree. C. The preferred
solvents are THF, acetonitrile, and Et.sub.2O. Most preferred is
acetonitrile. The compound is isolated by methods known to one of
ordinary skill in the art. Such methods include extraction, solvent
evaporation, distillation, and crystallization. Preferably the compound
is purified by flash chromatography on silica gel (Merck, 230-400
mesh) using 20% EtOAc/hexanes as the eluent.
[0086] Compound S1e is produced by the oxidation of the C11 alcohol
to give the ketone. The oxidation can be accomplished by, for example,
Swern, Jones, PCC, PDC. The most preferred is PCC. The most preferred
solvent is dichloromethane. The preferred reaction temperature is
-30.degree. C. to 100.degree. C. The most preferred is 0.degree.
C. to 50.degree. C. Compound S1e is isolated by methods known to
one of ordinary skill in the art. Such methods include extraction,
solvent evaporation, distillation, and crystallization. Preferably
the compound is purified by filtering through FLUORISLTM or silica
gel and solvent evaporation.
[0087] Compound S1f is formed by the reaction of NH.sub.2OR.sub.4
in buffered solution of solvents. The preferred buffer is sodium
acetate. The preferred solvent ratio is 3:1:1 (methanol:dioxane:water).
The preferred temperature range is -20.degree. C. to 100.degree.
C. The compound depicted as S1f is isolated by methods known to
one of ordinary skill in the art. Such methods include extraction,
solvent evaporation, distillation, and crystallization. Preferably,
S1f is purified by flash chromatography on silica gel (Merck, 230-400
mesh) using 10% EtOAc/hexanes as the eluent.
[0088] Deprotection of S1f is accomplished by methods known to
one of ordinary skill in the art and yields compounds of Formula
I.
[0089] Reduction of the oxime of S1f gives the compound S1h as
the hydroxyl amine. The reduction is accomplished by treatment with
sodium cyanoborohydride. The preferred solvent is methanol. The
preferred temperature range is -100.degree. C. to 100.degree. C.
Deprotection of S1h is accomplished by methods known to one of ordinary
skill in the art and yields compounds of Formula II.
[0090] Alternatively, the prostaglandins used in this invention
can be prepared according to reaction schemes 2-1, 2-2, 2-3, and
2-4. In schemes 2-1 through 2-4, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6 W, X, and Z are as defined above. Q.sup.1 and Q.sup.2
are protecting groups. 103
[0091] In scheme 2-1, intermediate S2f is prepared. The Corey Aldehyde
(S2a) depicted as starting material for Scheme 2-1 is commercially
available (such as from Aldrich Chemical or Cayman Chemical). The
Corey Aldehyde (S2a) is commercially-available with a protecting
group Q.sup.1 attached to the alcohol. Q.sup.1 can be either a silyl
group or an ester group. The preferred protecting groups for Q.sup.1
include tert-butyldimethylsilyl, acetate, benzoate, and para-phenyl
benzoate. The most preferred protecting group for Q.sup.1 is tert-butyldimethylsilyl.
[0092] The Corey aldehyde (S2a) is first reacted with an aldehyde
protecting group to make a ketal or acetal. Examples of this type
of protection are found in Greene and Wuts, Protecting Groups in
Organic Synthesis, 2d ed., Wiley & Sons, N.Y. 1991. In this
case, especially preferred are cyclic ketals and acetals. The aldehyde
(S2a) is reacted with the appropriate 1,2-diol and a suitable acidic
catalyst. The solvent can be the diol, and an anhydrous solvent,
such as ether or dichloromethane. Particularly useful is 1,2-bis-TMS
ethylene glycol to effect this transformation in ether at room temperature.
[0093] The ketal-protected S2a may then undergo a routine of protection
or deprotection if desired, to exchange the Q.sup.1 group for a
more suitable one, using procedures known in the art. Particularly
useful is the exchange of a silyl group for an acyl group, and vice
versa. Also useful is the exchange of a silyl or acyl group for
an o-bromo-benzyl ether group.
[0094] The compound (S2b) is then subjected to a DIBAL reduction
to make the hemiacetal. This intermediate is not isolated but reacted
as soon as possible with a Wittig salt to form an alkene (S2c).
Particularly preferred Wittig salts are derived from omega bromo-
four to five carbon straight chain carboxcyclic acids and 3-oxo-carboxcyclic
acids. These are conveniently combined with triphenylphosphine in
a suitable solvent to form the reactive Wittig salts. Other preferred
reagents include straight chain omega-bromo tetrazoles and primary
nitriles.
[0095] The compound (S2c) is not isolated, but reacted crude with
diazomethane in diethyl ether or, preferably, with TMS diazomethane
in methanol to give S2d. In addition, a suitable protecting group
Q.sup.2 may be placed on the C.sub.9 alcohol at this time. The compound
S2d is isolated by methods known to one of ordinary skill in the
art. Such methods include extraction, solvent evaporation, distillation,
and crystallization. Preferably, it is purified by flash chromatography
on silica gel (Merck, 230-400 mesh) using 10% EtOAc/hexanes as the
eluent.
[0096] The compound (S2d) is then optionally reduced at C-5,6 to
give the saturated alpha chain of the prostaglandin, if desired,
or taken on without reduction. The cyclic ketal is removed with
acid or acidic ion exchange resin in a suitable solvent to give
the free aldehyde. Preferred solvents include tetrahydrofuran/water
mixtures.
[0097] The resulting aldehyde (S2e) is not isolated but reacted
with ketone-stabilized phosphonium salts. These are generally referred
to as "Wadsworth-Horner-Emmons" reagents. This reaction
requires a mild base. Examples of suitable bases include sodium
carbonate or triethyl arnine. The ketone (intermediate S2f) is purified
by methods known to one of ordinary skill in the art. Such methods
include extraction, solvent evaporation, distillation, and crystallization.
Preferably, the ketone (intermediate S2f) is purified by flash chromatography
on silica gel (Merck, 230-400 mesh) using 20% EtOAc/hexanes as the
eluent.
[0098] The ketone (intermediate S2f) can be reacted in three ways
as shown in schemes 2-2, 2-3, and 2-4. 104
[0099] In scheme 2-2, reduction of the ketone with a reducing agent
such as the Luche reagent, effects an alcohol at C-15, as illustrated
by S2g. At this point, the alcohols of S2g at C-9 and C-15 may be
protected, if needed or desired. If so, the alcohols can be protected
as described previously herein. The S2g compound containing protected
or unprotected alcohols is then treated with a deprotecting agent
to release selectively Q.sup.1 on C-11. Examples of such selective
deprotection reactions are given in Greene and Wuts.
[0100] Alternatively, when Q.sup.1 is the o-bromobenzyl ether,
reduction of the bromine with a radical reducing agent such as (n-butyl).sub.3SnH
will cause the radical-induced oxidation of C-11 to the ketone without
needing protection.
[0101] Compounds of the type S2h can be converted into compounds
of Formula III and Formula IV.
[0102] Compounds of Formula IX can be made from sulfonation or
hydroxylamination of compounds of Formula III. In Formula IX, R.sup.1
is a sulfonamide group or a hydroxamic acid group.
[0103] These compounds are isolated by methods known to one of
ordinary skill in the art. Such methods include extraction, solvent
evaporation, distillation, and crystallization. 105
[0104] The ketone (S2f) can also be converted into compounds of
the type S21. This occurs by the addition of suitable nucleophile
to the ketone (S2f). Examples of nucleophiles include methyl magnesium
bromide. Using substantially the same techniques described above,
the compounds of the type S21 can be converted into compounds of
Formula V, and compounds of Formula V can be converted into compounds
of Formula VI. 106
[0105] Compounds of the type S2f can also be reacted to give compounds
of the type S2m by reacting the ketone at C-15 with an active amine.
Examples of reactive amines include methyl amine and ethyl amine.
The products can be reduced or can react with nucleophiles using
standard techniques, and the reduction can also extend to reduce
the alkenes, if desired, using a reagent such as hydrogen gas over
palladium on carbon. Alternatively, sodium cyanoborohydride will
selectivity reduce the imine without disrupting the alkenes. Finally,
a suitable nucleophile, preferably such as a methyl cerium reagent,
can add to the imine. Addition of the methylcerium nucleophile (.about.1.5
equiv.) is described in T. Imamoto, et al., "Carbon-Carbon
Bond Forming Reactions Using Cerium Metal or Organocerium (III)
Reagents", J. Org. Chem. Vol. 49 (1984) p. 3904-12; T. Imamoto,
et al., "Reactions of Carbonyl Compounds with Grignard Reagents
in the Presence of Cerium Chloride", J. Am. Chem. Soc. Vol.
111 (1989) p. 4392-98; and references cited therein, gives the aminomethyl
derivative. In that case, R.sup.5 in compound S1n would be a methyl
group.
[0106] Using the reactions disclosed above for compounds of the
type S2h, compounds of Formula VII can be made from S2n.
Compositions of the Invention
[0107] This invention further relates to a composition for treating
hair loss. The composition comprises A) the prostaglandin described
above and B) a carrier. The composition may further comprise C)
one or more optional activity enhancers.
[0108] 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).
[0109] 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 prostaglandins,
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.
[0110] The choice of carrier for component B) depends on the route
by which component A) 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 (e.g., local application
on the skin, ocular, liposome delivery systems, or iontophoresis).
Topical administration directly to the locus of desired hair growth
is preferred.
[0111] 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.
[0112] 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.
[0113] 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.
[0114] 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 sodium carboxymethylcellulose, ethyl cellulose, methylcellulose,
microcrystalline cellulose and sodium carboxymethylcellulose.
[0115] 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.
[0116] Ingredient e) is a colorant such as an FD&C dye.
[0117] Ingredient f) is a flavor such as menthol, peppermint, and
fruit flavors.
[0118] Ingredient g) is a sweetener such as aspartame and saccharin.
[0119] Ingredient h) is an antioxidant such as butylated hydroxyanisole,
butylated hydroxytoluene, and vitamin E.
[0120] Ingredient j) is a preservative such as methyl paraben and
sodium benzoate.
[0121] Ingredient k) is a glidant such as silicon dioxide.
[0122] Ingredient m) is a solvent, such as water, isotonic saline,
ethyl oleate, alcohols such as ethanol, and phosphate buffer solutions.
[0123] Ingredient n) is a suspending agent. Suitable suspending
agents include AVICEL.RTM. RC-591 from FMC Corporation of Philadelphia,
Pa. and sodium alginate.
[0124] Ingredient o) is a surfactant such as the TWEENS.RTM. from
Atlas Powder Company of Wilmington, Del., lecithin, polysorbate
80, and sodium lauryl sulfate.
[0125] Compositions for parenteral administration typically comprise
A) 0.1 to 10% of a prostaglandin 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.
[0126] 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 prostaglandin. The oral dosage compositions further comprise
B) 50 to 95% of a carrier, preferably 50 to 75%.
[0127] Tablets can be compressed, tablet triturates, enteric-coated,
sugar-coated, film-coated, or multiple-compressed. Tablets typically
comprise A) the prostaglandin, 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.
[0128] Capsules (including time release and sustained release formulations)
typically comprise A) the prostaglandin, and B) a carrier comprising
one or more a) diluents disclosed above in a capsule comprising
gelatin. Granules typically comprise A) the prostaglandin, and preferably
further comprise k) glidants such as silicon dioxide to improve
flow characteristics.
[0129] 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.
[0130] The solid compositions may also be coated by conventional
methods, typically with pH or time-dependent coatings, such that
A) the prostaglandin 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.
[0131] 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 prostaglandin 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.
[0132] 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,
carboxymethylcellulose, and hydroxypropylmethylcellulose. Such compositions
may further comprise b) lubricants, e) colorants, f) flavors, g)
sweeteners, h) antioxidants, and k) glidants.
[0133] 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 component
A) and ii) penetration enhancers.
[0134] 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.
[0135] 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.
[0136] 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 CT7,20-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.
[0137] 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.
[0138] 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.
[0139] 3,5,3'-Triiodothyronine is an example of a suitable thyroid
hormone.
[0140] Examples of suitable non-selective prostaglandins agonists
and antagonists include compounds such as those described in WO
98/33497, Johnstone, published Aug. 6, 1998, WO 95/11003, Stjemschantz,
published Apr. 27, 1995, JP 97-100091, Ueno and JP 96-134242, Nakamura.
[0141] Suitable retinoids include isotretinoin, acitretin, and
tazarotene.
[0142] 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.
[0143] Other additional hair growth stimulants are described in
JP 09-157,139 to Tsuji et al., published Jun. 17, 1997; EP 0277455
Al 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.
[0144] The most preferred activity enhancers are minoxidil and
finasteride, most preferably minoxidil.
[0145] 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 sulfoxide, N,N-dimethyl acetamide,
N,N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,
1,5-dimethyl-2-pyrrolidon- e, 1-ethyl-2-pyrrolidone, phosphine oxides,
sugar esters, tetrahydrofurfuryl alcohol, urea, diethyl-m-toluamide,
1-dodecylazacyloheptan-2-one, omega three fatty acids and fish oils,
and combinations thereof.
[0146] In a preferred embodiment of the invention, the prostaglandins
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 prostaglandin described above and component B) a carrier.
The carrier of the topical composition preferably aids penetration
of the prostaglandins 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.
[0147] The exact amounts of each component in the topical composition
depend on various factors. 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,
[0148] where IC.sub.50 of component A) is expressed in nanomolar
units. "IC.sub.50" means inhibitory concentration 50.sup.th
percentile. For example, if the IC.sub.50 of the prostaglandin is
1 nM, the amount of component A) will be 0.001 to 0.01%. If the
IC.sub.50 of the prostaglandin is 10 nM, the amount of component
A) will be 0.01 to 0.1%. If the IC.sub.50 of the prostaglandin is
100 nM, the amount of component A) will be 0.1 to 1.0%. If the IC.sub.50
of the prostaglandin 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.
[0149] 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 component
A) is sufficient to provide a practical quantity of composition
for administration per unit dose of the prostaglandin. 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).
[0150] 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.
[0151] 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] Ingredient u) is a thickener. The amount of ingredient u)
in the topical composition is typically 0 to 95%.
[0157] 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.
[0158] 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%.
[0159] 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).
[0160] 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 prostaglandin 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.
[0161] Examples of z) cellulose derivatives suitable for use in
the topical pharmaceutical composition for ocular administration
include sodium carboxymethylcellulose, ethylcellulose, methylcellulose,
and hydroxypropylmethylcellulose. Hydroxypropylmethylcellulose is
preferred.
[0162] 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.
[0163] 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.
[0164] 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.
[0165] 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.
[0166] 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.
[0167] 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.
[0168] 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).
[0169] 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.
[0170] 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 (CI
75,570), and mixtures thereof.
[0171] 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.
[0172] Ingredient s) is a solvent described above, preferably water.
[0173] The amount of A) the prostaglandin added to the mascara
is as described above for topical compositions.
[0174] The prostaglandins 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 Nov. 10,
1998 (with respect to Weiner et al., with a compound as described
herein administered in lieu of, or in addition to, minoxidil).
[0175] The prostaglandins may also be administered by iontophoresis.
See, e.g., Internet site www.unipr.it/arpa/dipfarm/erasmus/erasm14.html;
Banga et al., "Hydrogel-based Iontotherapeutic 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. 1121-11.sup.27 (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 Iontophoresis", 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 Iontophoresis:
Noninvasive Glucose Monitoring in vivo in Humans", Pharm. Res.,
Vol. 12 (12), pp |