U.S. patent application number 09/774558 was filed with the patent office on 2002-01-31 for cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives.
Invention is credited to DeLong, Mitchell Anthony, McIver, John McMillan, Youngquist, Robert Scott.
Application Number | 20020013294 09/774558 |
Document ID | / |
Family ID | 22715254 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013294 |
Kind Code |
A1 |
DeLong, Mitchell Anthony ;
et al. |
January 31, 2002 |
Cosmetic and pharmaceutical compositions and methods using
2-decarboxy-2-phosphinico derivatives
Abstract
A method for treating hair loss in mammals uses compositions
containing 2-decarboxy-2-phosphinico prostaglandin derivatives. The
compositions can be applied topically to the skin. The compositions
can arrest hair loss, reverse hair loss, and promote hair growth.
Compositions containing 2-decarboxy-2-phosphinico prostaglandin
derivatives can also be used to lower intraocular pressure and
treat bone disorders.
Inventors: |
DeLong, Mitchell Anthony;
(West Chester, OH) ; McIver, John McMillan;
(Cincinnati, OH) ; Youngquist, Robert Scott;
(Mason, OH) |
Correspondence
Address: |
THE PROCTER & GAMBLE COMPANY
PATENT DIVISION
IVORYDALE TECHNICAL CENTER - BOX 474
5299 SPRING GROVE AVENUE
CINCINNATI
OH
45217
US
|
Family ID: |
22715254 |
Appl. No.: |
09/774558 |
Filed: |
January 31, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60193845 |
Mar 31, 2000 |
|
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|
Current U.S.
Class: |
514/79 ; 514/114;
514/140; 558/190; 558/194 |
Current CPC
Class: |
A61K 8/64 20130101; A61K
45/06 20130101; A61P 17/14 20180101; A61Q 1/10 20130101; A61P 27/02
20180101; A61K 31/662 20130101; A61K 2800/596 20130101; C07F 9/304
20130101; A61Q 5/02 20130101; C07F 9/302 20130101; A61K 2800/74
20130101; A61P 19/10 20180101; A61K 8/55 20130101; A61Q 7/00
20130101; A61Q 5/065 20130101 |
Class at
Publication: |
514/79 ; 514/114;
514/140; 558/190; 558/194 |
International
Class: |
A61K 031/675; A61K
031/661; C07F 009/38 |
Claims
What is claimed is:
1. A 2-decarboxy-2-phosphinico prostaglandin analog having the
structure: 50R.sup.1 is selected from the group consisting of a
hydrogen atom, lower monovalent hydrocarbon groups, and lower
heterogeneous groups; R.sup.2 is selected from the group consisting
of a hydrogen atom, a monovalent hydrocarbon group, a substituted
monovalent hydrocarbon group, a heterogeneous group, a substituted
heterogeneous group, a carbocyclic group, a substituted carbocyclic
group, a heterocyclic group, a substituted heterocyclic group, an
aromatic group, a substituted aromatic group, a heteroaromatic
group, and a substituted heteroaromatic group; R.sup.3 is selected
from the group consisting of an oxygen atom, a sulfur atom, and NH;
R.sup.4 is selected from the group consisting of an oxygen atom and
a sulfur atom; R.sup.5 is a divalent group selected from the group
consisting of a hydrocarbon group, a substituted hydrocarbon group,
a heterogeneous group, and a substituted heterogeneous group; bond
a is selected from the group consisting of a single bond, a trans
double bond, and a triple bond; R.sup.6 is a divalent group
selected from the group consisting of --C(O)--and
--C(R.sup.9)(0R.sup.9)--; R.sup.7 is selected from the group
consisting of a divalent group having the formula
--(CR.sup.9(R.sup.9)).sub.p--X--(CR.sup.9(R.sup.9)).sub.q, wherein
p is an integer from 0 to 3 and q is an integer from 0 to 3, and
wherein X is selected from the group consisting of an oxygen atom,
a divalent hydrocarbon group, a sulfur atom, SO, SO.sub.2, and
NR.sup.9; R.sup.8 is selected from the group consisting of a methyl
group or a carbocyclic group, a substituted carbocyclic group, a
heterocyclic group, a substituted heterocyclic group, aromatic
group, a substituted aromatic group, a heteroaromatic group, a
substituted heteroaromatic group; R.sup.9 is selected from the
group consisting of a hydrogen atom and a lower monovalent
hydrocarbon group; and R.sup.10 is a lower monovalent hydrocarbon
group.
2. A composition for treating hair loss comprising: A) an active
ingredient selected from the group consisting of
2-decarboxy-2-phosphinic- o derivatives of prostaglandins; optical
isomers, diastereomers, and enantiomers of the
2-decarboxy-2-phosphinico derivatives; pharmaceutically-acceptable
salts of the 2-decarboxy-2-phosphinico derivatives; biohydrolyzable
amides, esters, and imides of the 2-decarboxy-2-phosphinico
derivatives; and combinations thereof; and B) a carrier.
3. The composition of claim 2, wherein the
2-decarboxy-2-phosphinico derivative has a structure selected from
the group consisting of: 51wherein R.sup.1 is selected from the
group consisting of a hydrogen atom, and lower monovalent
hydrocarbon groups, and lower heterogeneous groups; R.sup.2 is
selected from the group consisting of a hydrogen atom, a monovalent
hydrocarbon group, a substituted monovalent hydrocarbon group, a
heterogeneous group, a substituted heterogeneous group, a
carbocyclic group, a substituted carbocyclic group, a heterocyclic
group, a substituted heterocyclic group, an aromatic group, a
substituted aromatic group, a heteroaromatic group, and a
substituted heteroaromatic group; R.sup.3 is selected from the
group consisting of an oxygen atom, a sulfur atom, and NH; R.sup.4
is selected from the group consisting of an oxygen atom and a
sulfur atom; R.sup.5 is a divalent group selected from the group
consisting of a hydrocarbon group, a substituted hydrocarbon group,
a heterogeneous group, and a substituted heterogeneous group; with
the proviso that when R.sup.5 is a heterogeneous group, R.sup.5 has
only one heteroatom, which is selected from the group consisting of
oxygen, sulfur, and nitrogen; bond a is selected from the group
consisting of a single bond, a trans double bond, and a triple
bond; R.sup.6 is a divalent group selected from the group
consisting of --C(O)-- and --C(R.sup.9)(OR.sup.9)--; R.sup.7 is
selected from the group consisting of a divalent group having the
formula --(CR.sup.9(R.sup.9)).sub.p--X--(C-
R.sup.9(R.sup.9)).sub.q, wherein p is an integer from 0 to 3 and q
is an integer from 0 to 3, and wherein X is selected from the group
consisting of an oxygen atom, a divalent hydrocarbon group, a
sulfur atom, SO, SO.sub.2, and NR.sup.9; R.sup.8 is selected from
the group consisting of a methyl group, a carbocyclic group, a
substituted carbocyclic group, a heterocyclic group, a substituted
heterocyclic group, an aromatic group, a substituted aromatic
group, a heteroaromatic group, a substituted heteroaromatic group;
R.sup.9 is selected from the group consisting of a hydrogen atom
and a lower monovalent hydrocarbon group; and R.sup.10 is selected
from the group consisting of a hydrogen atom and a lower monovalent
hydrocarbon group.
4. The composition of claim 3, wherein R.sup.1 is selected from the
group consisting of a hydrogen atom, an alkyl group, a halogenated
hydrocarbon group, CH.sub.2CH.sub.2OH, and
CH.sub.2CH.sub.2CH.sub.2OH.
5. The composition of claim 3, wherein R is selected from the group
consisting of H, CH.sub.2CO.sub.2H, CH.sub.2C(O)NHOH, methyl,
CF.sub.3, ethyl, n-propyl, isopropyl, CH.sub.2CH.sub.2OH,
CH.sub.2CH(OH)CH.sub.2OH, benzyl, and t-butyl.
6. The composition of claim 3, wherein R.sup.3 is selected from the
group consisting of an oxygen atom and NH.
7. The composition of claim 3, wherein R.sup.4 is an oxygen
atom.
8. The composition of claim 3, wherein R.sup.5 has 1 to 5 member
atoms.
9. The composition of claim 3, wherein R.sup.6 is --C(H)(OH)--.
10. The composition of claim 3, wherein X is selected from the
group consisting of a single bond, a trans double bond, a triple
bond, an oxygen atom, a sulfur atom, and NR.sup.9.
11. The composition of claim 3, wherein R.sup.8 is selected from
the group consisting of a monocyclic carbocyclic group, a
substituted monocyclic carbocyclic group, a monocyclic heterocyclic
group, a substituted monocyclic heterocyclic group, aromatic group,
a substituted aromatic group, a heteroaromatic group, and a
substituted heteroaromatic group.
12. The composition of claim 3, wherein R.sup.9 is a hydrogen
atom.
13. The composition of claim 3, wherein R.sup.10 is a hydrogen
atom.
14. The composition of claim 3, wherein the
2-decarboxy-2-phosphinico derivative has the structure: 52wherein,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.9, and bond a are as described above.
15. The composition of claim 2, 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.
16. The composition of claim 2, further comprising component C) an
activity enhancer selected from the group consisting of i) a hair
growth stimulant, ii) a penetration enhancer, and combinations
thereof.
17. The composition of claim 16, wherein component A) is present in
the composition in an amount of: IC.sub.50.times.10.sup.-2.gtoreq.%
of component A) .gtoreq.IC.sub.50.times.10.sup.-3, where IC.sub.50
is expressed in nanomolar units; component C) is present in an
amount of 1 to 20% component C), and a sufficient amount of
component B) is present such that the amounts of components A), B),
and C), combined equal 100%.
18. The composition of claim 2, wherein component A) is present in
the composition in an amount of: IC.sub.50.times.10.sup.-2.gtoreq.%
of component A) .gtoreq.IC.sub.50.times.10.sup.-3, where IC.sub.50
is expressed in nanomolar units.
19. A method for treating hair loss comprising administering to a
mammal suffering from hair loss, a composition comprising: A) an
active ingredient selected from the group consisting of
2-decarboxy-2-phosphinic- o derivatives of prostaglandins; optical
isomers, diastereomers, and enantiomers of the
2-decarboxy-2-phosphinico derivatives; pharmaceutically-acceptable
salts of the 2-decarboxy-2-phosphinico derivatives; biohydrolyzable
amides, esters, and imides of the 2-decarboxy-2-phosphinico
derivatives; and combinations thereof.
20. The method of claim 19, wherein the of
2-decarboxy-2-phosphinico derivative has a structure selected from
the group consisting of: 53wherein R.sup.1 is selected from the
group consisting of a hydrogen atom, and lower monovalent
hydrocarbon groups, and lower heterogeneous groups; R.sup.2 is
selected from the group consisting of a hydrogen atom, a monovalent
hydrocarbon group, a substituted monovalent hydrocarbon group, a
heterogeneous group, a substituted heterogeneous group, a
carbocyclic group, a substituted carbocyclic group, a heterocyclic
group, a substituted heterocyclic group, an aromatic group, a
substituted aromatic group, a heteroaromatic group, and a
substituted heteroaromatic group; R.sup.3 is selected from the
group consisting of an oxygen atom, a sulfur atom, and NH; R.sup.4
is selected from the group consisting of an oxygen atom and a
sulfur atom; R.sup.5 is a divalent group selected from the group
consisting of a hydrocarbon group, a substituted hydrocarbon group,
a heterogeneous group, and a substituted heterogeneous group; with
the proviso that when R.sup.5 is a heterogeneous group, R.sup.5 has
only one heteroatom, which is selected from the group consisting of
oxygen, sulfur, and nitrogen; bond a is selected from the group
consisting of a single bond, a trans double bond, and a triple
bond; R.sup.6 is a divalent group selected from the group
consisting of --C(O)-- and --C(R.sup.9)(OR.sup.9)--; R.sup.7 is
selected from the group consisting of a divalent group having the
formula --(CR.sup.9(R.sup.9)).sub.p--X--(C-
R.sup.9(R.sup.9)).sub.q, wherein p is an integer from 0 to 3 and q
is an integer from 0 to 3, and wherein X is selected from the group
consisting of an oxygen atom, a divalent hydrocarbon group, a
sulfur atom, SO, SO.sub.2, and NR.sup.9; R.sup.8 is selected from
the group consisting of a methyl group, a carbocyclic group, a
substituted carbocyclic group, a heterocyclic group, a substituted
heterocyclic group, aromatic group, a substituted aromatic group, a
heteroaromatic group, a substituted heteroaromatic group; R.sup.9
is selected from the group consisting of a hydrogen atom and a
lower monovalent hydrocarbon group; and R.sup.10 is selected from
the group consisting of a hydrogen atom and a lower monovalent
hydrocarbon group.
21. The method of claim 19, wherein the composition is administered
by a route selected from the group consisting of systemic and
topical routes.
22. The method of claim 21, 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.
23. The method of claim 22, wherein the composition is a topical
composition further comprising B) a topical carrier, wherein the
topical carrier 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, dimethyl isosorbide, polypropylene
glycol-2 myristyl propionate, and combinations thereof.
24. The method of claim 19, 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.
25. The method of claim 24, 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.
26. The method of claim 24, 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-l-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, tetrahydrofurfural alcohol, urea,
diethyl-m-toluamide, 1-dodecylazacyloheptan-2-one, and combinations
thereof.
27. The method of claim 21, wherein the composition is a topical
composition locally administered on the skin once per day.
28. The method of claim 27, wherein the composition is administered
once per day for 6 to 12 weeks.
29. A mascara composition comprising: A) an active ingredient
selected from the group consisting of 2-decarboxy-2-phosphinico
derivatives of prostaglandins; optical isomers, diastereomers, and
enantiomers of the 2-decarboxy-2-phosphinico derivatives;
pharmaceutically-acceptable salts of the 2-decarboxy-2-phosphinico
derivatives; biohydrolyzable amides, esters, and imides of the
2-decarboxy-2-phosphinico derivatives; and combinations thereof,
dd) a water-insoluble material, ee) a water-soluble, film-forming
polymer, ff) a wax; o) a surfactant; gg) pigment; and s) a
solvent.
30. A method for darkening and thickening hair comprising applying
to growing hair and skin, a composition comprising: A) an active
ingredient selected from the group consisting of
2-decarboxy-2-phosphinico derivatives of prostaglandins; optical
isomers, diastereomers, and enantiomers of the
2-decarboxy-2-phosphinico derivatives; pharmaceutically-acceptable
salts of the 2-decarboxy-2-phosphinico derivatives; biohydrolyzable
amides, esters, and imides of the 2-decarboxy-2-phosphinico
derivatives; and combinations thereof; and B) a carrier.
Description
FIELD OF THE INVENTION
[0001] This invention relates to compositions and methods for using
2-decarboxy-2-phosphinico derivatives of prostaglandins. More
particularly, this invention relates to the use of
2-decarboxy-2-phosphinico derivatives of prostaglandins for
treating hair loss in mammals. This invention further relates to
the use of 2-decarboxy-2-phosphinico derivatives of prostaglandins
for lowering intraocular pressure and treating bone disorders in
mammals.
BACKGROUND OF THE INVENTION
Hair Loss--Cosmetic Treatment
[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 ROGAIN.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, GB
2,138,286, published Oct. 24, 1984; and Lindenbaum, WO 96/25943,
assigned to Life Medical Sciences, Inc., published Aug. 29,
1996.
[0006] Unfortunately, however, administration of T3 or T4, or both,
to treat hair loss is often not practicable because these thyroid
hormones can induce significant cardiotoxicity. See, e.g., Walker
et al., U.S. Pat. No. 5,284,971, assigned to Syntex, issued Feb. 8,
1994 and Emmett et al., U.S. Pat. No. 5,061,798, assigned to Smith
Kline & French Laboratories, issued Oct. 29, 1991.
[0007] In an alternative approach, prostaglandins have been
proposed to promote hair growth because prostaglandins may have a
similar benefit to thyroid hormones, i.e., increasing hair length
and changing pigmentation. Naturally occurring prostaglandins
(e.g., PGA.sub.2, PGB.sub.2, PGE.sub.1, PGF.sub.2.alpha., and
PGI.sub.2) are C-20 unsaturated fatty acids. PGF.sub.2.alpha., the
naturally occurring Prostaglandin F analog in humans, is
characterized by hydroxyl groups at the C9 and C11 positions on the
alicyclic ring, a cis-double bond between C5 and C6, and a
trans-double bond between 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,, pp. 1533-1564 (1993);
G. L. Bundy and F. H. Lincoln, "Synthesis of
17-Phenyl-18,19,20-Trinorprostaglandins: I. The PG.sub.1 Series",
Prostaglandin, Vol. 9, No. 1, pp. 1-4 (1975); W. Bartman, G. Beck,
U. Lerch, H. Teufel, and B. Scholkens, "Luteolytic Prostaglandin:
Synthesis and Biological Activity", Prostaglandin, Vol. 17, No. 2,
pp. 301-311 (1979).
[0009] Prostaglandins in general have a wide range of biological
activities. For example, PGE.sub.2 has the following properties: a)
regulator of cell proliferation, b) regulator of cytokine
synthesis, c) regulator of immune responses and d) inducer of
vasodilatation. Vasodilatation is thought to be one of the
mechanisms of how minoxidil provides a hair growth benefit. In
vitro results in the literature also indicate some
anti-inflammatory properties of the prostaglandins. c.f.; Tanaka,
H., Br J. Pharm., 116, 2298, (1995).
[0010] However, previous attempts at using prostaglandins to
promote hair growth have been unsuccessful. Different
prostaglandins can bind to multiple receptors at various
concentrations with a biphasic effect. Therefore, it is an object
of this invention to provide methods for using prostaglandins to
grow hair and to provide compositions that promote hair growth. It
is a further object of this invention to provide a selection of
appropriate prostaglandins that will promote hair growth in humans
and lower animals.
Bone Disorders--Pharmaceutical Treatment
[0011] In addition to the biological activities discussed above,
prostaglandins are also known to affect bone. Therefore, it is a
further object of this invention to provide compositions and
methods for using prostaglandins to treat bone disorders.
[0012] Accelerated bone loss may result from drug administration,
such as corticosteroids, prolonged bed rest, disuse of a limb, and
microgravity. In osteoporotics, an imbalance in the bone remodeling
process develops in which bone is resorbed at a rate faster than it
is being made. Although this imbalance occurs to some extent in
most individuals, male and female, as they age, it is more severe
and occurs at a younger age in osteoporotics, particularly those
who develop the post menopausal form of the condition. Bone loss
due to the above conditions can result in complete removal of
trabeculae and a deterioration of bone architecture such that the
strength of the remaining bone decreases disproportionately.
[0013] To completely return the bone to normal strength, new
trabeculae should be formed to restore architecture and increase
bone mass. When restoration of normal architecture is associated
with an increase in strength and return to normal stiffness and
shock absorbing capability, the bone is less likely to fracture.
Subjects suffering from other bone disorders, such as
osteoarthritis, Paget's disease, periodontal disease, and fractures
may also benefit from treatments that restore normal architecture
and bone mass.
[0014] Various agents have been tried in attempts to treat bone
disorders by slowing bone loss or increasing bone mass. Agents for
slowing bone loss and reestablishing bone density are exemplified
by antiresorptive agents such as bisphosphonates.
[0015] Prostaglandin E analogs are potent stimulators of bone
resorption and formation. Anabolic agents such as some
prostaglandin E analogs may be detrimental to one suffering from
bone disorders such as osteoporosis because increased resorption
may cause perforation and loss of trabeculae or may weaken the
exsting trabecular structure. Increased resorption may also occur
in cortical bone, which may increase the incidence of fracture at
some sites.
[0016] Anabolic agents such as fluoride and other prostaglandin E
analogs have been used to increase bone mass. However, such agents
have failed to build bone that is structurally and architecturally
similar to the type of bone lost.
[0017] Naturally occurring PGF.sub.2.alpha., shown above, is also
known to affect bone resorption. However, naturally occurring
prostaglandins have several drawbacks that limit their desirability
for systemic administration. Naturally occurring prostaglandins are
characterized by their activity at a certain prostagladin receptor,
however, their activity is not limited to any one receptor.
Therefore, systemic administration of naturally occurring
prostaglandins can cause side effects such as inflammation, surface
irritation, smooth muscle contraction, pain, and
bronchoconstriction.
[0018] Therefore, it is an object of this invention to provide
compositions and methods using prostaglandins to treat bone
disorders without significant undesirable side effects. It is a
further object of this invention to provide a selection of
appropriate prostaglandins that will promote bone growth in humans
and lower animals.
Intraocular Pressure--Pharmaceutical Treatment
[0019] In addition to the pharmacological properties discussed
above, naturally occurring prostaglandins are also known to reduce
intraocular pressure. Reduction of intraocular pressure is
effective to treat disorders such as glaucoma. See C. Iiljebris, G.
Selen, B. Resul, J. Sternschantz, and U. Hacksell, "Derivatives of
17-Phenyl-18, 19,20-trinorprostaglandin F.sub.2.alpha.. Isopropyl
Ester: Potential Antiglaucoma Agents", Journal of Medicinal
Chemistry, Vol. 38, No. 2, pp. 289-304 (1995). However, as
discussed above, the naturally occurring prostaglandins generally
are not specific for any one prostaglandin receptor, and thus are
known to cause side effects.
[0020] Therefore, it is an object of this invention to provide
compositions and methods using prostaglandins to lower intraocular
pressure without significant undesirable side effects. It is a
further object of this invention to provide a selection of
appropriate prostaglandins that will lower intraocular pressure in
humans and lower animals.
SUMMARY OF THE INVENTION
[0021] This invention relates to compositions and methods for
treating hair loss. The methods comprise administering the
compositions comprising specific prostaglandins that interact
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 or that would cause significant undesirable side effects.
The prostaglandins used in this invention are
.sup.2-decarboxy-2-phosphinico derivatives of prostaglandins. This
invention further relates to the use of 2-decarboxy-2-phosphinico
derivatives of prostaglandins to prepare compositions for treating
hair loss. The compositions comprise: component A) the
2-decarboxy-2-phosphini- co derivative of a prostaglandin,
component B) a carrier, and optionally component C) an activity
enhancer.
[0022] This invention further relates to compositions and methods
for treating bone disorders. The methods comprise administering, to
subjects suffering from bone disorders such as osteoporosis,
compositions comprising 2-decarboxy-2-phosphinico derivatives of
prostaglandins. This invention further relates to the use of
2-decarboxy-2-phosphinico derivatives of prostaglandins to prepare
compositions for treating bone disorders.
[0023] This invention further relates to compositions and methods
for lowering intraocular pressure. The methods comprise
administering, to subjects suffering from conditions such as
glaucoma, compositions comprising 2-decarboxy-2-phosphinico
derivatives of prostaglandins. This invention further relates to
the use of 2-decarboxy-2-phosphinico derivatives of prostaglandins
to prepare compositions for lowering intraocular pressure.
DETAILED DESCRIPTION OF THE INVENTION
[0024] In one aspect, this invention relates to compositions for
treating hair loss in mammals. "Treating hair loss" includes
arresting hair loss or reversing hair loss, or both, and promoting
hair growth.
[0025] Publications and patents are referred to throughout this
disclosure. All U.S. Patents cited herein are hereby incorporated
by reference.
[0026] All percentages, ratios, and proportions used herein are by
weight unless otherwise specified.
Definition and Usage of Terms
[0027] The following is a list of definitions for terms, as used
herein:
[0028] "Activate" means binding and signal transduction of a
receptor.
[0029] "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.
[0030] "Aromatic group" means a monovalent group having a
monocyclic ring structure or fused bicyclic ring structure.
Monocyclic aromatic groups contain 5 to 10 carbon atoms, preferably
5 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms in the
ring. Bicyclic aromatic groups contain 8 to 12 carbon atoms,
preferably 9 or 10 carbon atoms in the ring. Aromatic groups are
unsubstituted. The most preferred aromatic group is phenyl.
[0031] "Carbocyclic group" means a monovalent saturated or
unsaturated hydrocarbon ring. Carbocyclic groups are monocyclic, or
are fused, spiro, or bridged bicyclic ring systems. Monocyclic
carbocyclic groups contain 4 to 10 carbon atoms, preferably 4 to 7
carbon atoms, and more preferably 5 to 6 carbon atoms in the ring.
Bicyclic carbocyclic groups contain 8 to 12 carbon atoms,
preferably 9 to 10 carbon atoms in the ring. Carbocyclic groups are
unsubstituted. Preferred carbocyclic groups include cyclopentyl,
cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. More
preferred carbocyclic groups include cyclohexyl, cycloheptyl, and
cyclooctyl. The most preferred carbocyclic group is cycloheptyl.
Carbocyclic groups are not aromatic.
[0032] "Cyano group" means a group containing a nitrile
functionality.
[0033] "FP agonist" means a compound that activates the FP
receptor.
[0034] "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.
[0035] "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.
[0036] "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.
[0037] "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.
[0038] "Heteroaromatic group" means an aromatic ring containing
carbon and 1 to 4 heteroatoms in the ring. Heteroaromatic groups
are monocyclic or fused bicyclic rings. Monocyclic heteroaromatic
groups contain 5 to 10 member atoms (i.e., carbon and heteroatoms),
preferably 5 to 7, and more preferably 5 to 6 in the ring. Bicyclic
heteroaromatic rings contain 8 to 12 member atoms, preferably 9 or
10 in the ring. Heteroaromatic groups are unsubstituted. Preferred
heteroaromatic groups include thienyl, thiazolyl, purinyl,
pyrimidyl, pyridyl, and furanyl. More preferred heteroaromatic
groups include thienyl, furanyl, and pyridyl. The most preferred
heteroaromatic group is thienyl.
[0039] "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. "Heterocyclic group"
means a saturated or unsaturated ring structure containing carbon
and 1 to 4 heteroatoms in the ring. No two heteroatoms are adjacent
in the ring. Heterocyclic groups are not aromatic. Heterocyclic
groups are monocyclic, or are fused or bridged bicyclic ring
systems. Monocyclic heterocyclic groups contain 4 to 10 member
atoms (i.e., including both carbon atoms and at least 1
heteroatom), preferably 4 to 7, and more preferably 5 to 6 in the
ring. Bicyclic heterocyclic groups contain 8 to 12 member atoms,
preferably 9 or 10 in the ring. Heterocyclic groups are
unsubstituted. Preferred heterocyclic groups include piperzyl,
morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and
piperdyl.
[0040] "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.
[0041] "Monovalent hydrocarbon group" means a chain of 1 to 18
carbon atoms, preferably 1 to 12 carbon atoms. "Lower monovalent
hydrocarbon group" means a monovalent hydrocarbon group having 1 to
6, preferably 1 to 4 carbon atoms. Monovalent hydrocarbon groups
may have a straight chain or branched chain structure. Preferred
monovalent hydrocarbon groups have one or two branches, preferably
1 branch. Preferred monovalent hydrocarbon groups are saturated.
Unsaturated monovalent hydrocarbon groups have one or more double
bonds, one or more triple bonds, or combinations thereof. Preferred
unsaturated monovalent hydrocarbon groups have one or two double
bonds or one triple bond; more preferred unsaturated monovalent
hydrocarbon groups have one double bond.
[0042] "Pharmaceutically acceptable" means suitable for use in a
human or other mammal.
[0043] "Prostaglandin" means a fatty acid derivative which has a
variety of potent biological activities of a hormonal or regulatory
nature.
[0044] "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.
[0045] "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).
[0046] "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.
[0047] "Subject" means a living vertebrate animal such as a mammal
(preferably human) in need of treatment.
[0048] "Substituted aromatic group" means an aromatic group wherein
1 to 4 of the hydrogen atoms bonded to carbon atoms in the ring
have been replaced with other substituents. Preferred substituents
include: halogen atoms, cyano groups, monovalent hydrocarbon
groups, substituted monovalent hydrocarbon groups, heterogeneous
groups, aromatic groups, substituted aromatic groups, or any
combination thereof. More preferred substituents include halogen
atoms, monovalent hydrocarbon groups, and substituted monovalent
hydrocarbon groups. Preferred substituted aromatic groups include
naphthyl. The substituents may be substituted at the ortho, meta,
or para position on the ring, or any combination thereof. The
preferred substitution pattern on the ring is ortho or meta. The
most preferred substitution pattern is ortho.
[0049] "Substituted carbocyclic group" means a carbocyclic group
wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the ring
have been replaced with other substituents. Preferred substituents
include: halogen atoms, cyano groups, monovalent hydrocarbon
groups, monovalent heterogeneous groups, substituted monovalent
hydrocarbon groups, aromatic groups, substituted aromatic groups,
or any combination thereof. More preferred substituents include
halogen atoms and substituted monovalent hydrocarbon groups.
Carbocyclic group does not include aromatic rings.
[0050] "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.
[0051] "Substituted heterocyclic group" means a heterocyclic group
wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the ring
have been replaced with other substituents. Preferred substituents
include: halogen atoms, cyano groups, monovalent hydrocarbon
groups, substituted monovalent hydrocarbon groups, heterogeneous
groups, substituted heterogeneous groups, halogenated hydrocarbon
groups, halogenated heterogenous groups, phenyl groups, phenoxy
groups, or any combination thereof. More preferred substituents
include halogen atoms and halogenated hydrocarbon groups.
Substituted heterocyclic groups are not aromatic.
[0052] "Substituted heterogeneous group" means a heterogeneous
group, wherein 1 to 4 of the hydrogen atoms bonded to carbon atoms
in the chain have been replaced with other substituents. Preferred
substituents include halogen atoms, hydroxy groups, alkoxy groups
(e.g., methoxy, ethoxy, propoxy, butoxy, and pentoxy), aryloxy
groups (e.g., phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy,
benzyloxy, alkyloxycarbonylphenoxy, and acyloxyphenoxy), acyloxy
groups (e.g., propionyloxy, benzoyloxy, and acetoxy), carbamoyloxy
groups, carboxy groups, mercapto groups, alkylthio groups, acylthio
groups, arylthio groups (e.g., phenylthio, chlorophenylthio,
alkylphenylthio, alkoxyphenylthio, benzylthio, and
alkyloxycarbonylphenylthio), aromatic groups (e.g., phenyl and
tolyl), substituted aromatic groups (e.g., alkoxphenyl,
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).
[0053] "Substituted monovalent hydrocarbon group" means a
monovalent hydrocarbon group wherein 1 to 4 of the hydrogen atoms
bonded to carbon atoms in the chain have been replaced with other
substituents. Preferred substituents include halogen atoms;
halogenated hydrocarbon groups; halogenated heterogenous groups;
alkyl groups (e.g., methyl, ethyl, propyl, and butyl); hydroxy
groups; alkoxy groups (e.g., methoxy, ethoxy, propoxy, butoxy, and
pentoxy); aryloxy groups (e.g., phenoxy, chlorophenoxy, tolyloxy,
methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy, and
acyloxyphenoxy); acyloxy groups (e.g., propionyloxy, benzoyloxy,
and acetoxy); carbamoyloxy groups; carboxy groups; mercapto groups;
alkylthio groups; acylthio groups; arylthio groups (e.g.,
phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio,
benzylthio, and alkyloxycarbonylphenylthio); aryl groups (e.g.,
phenyl, tolyl, alkoxyphenyl, alkoxycarbonylphenyl, and halophenyl);
heterocyclyl groups; heteroaryl groups; and amino groups (e.g.,
amino, mono- and di-alkanylamino groups of 1 to 3 carbon atoms,
methylphenylamino, methylbenzylamino, alkanylamido groups of 1 to 3
carbon atoms, carbamamido, ureido, and guanidino).
Prostaglandins Used in the Invention
[0054] The prostaglandins suitable for use in this invention are
selected from the group consisting of 2-decarboxy-2-phosphinico
derivatives of prostaglandins; optical isomers, diastereomers, and
enantiomers of the 2-decarboxy-2-phosphinico derivatives;
pharmaceutically-acceptable salts of the 2-decarboxy-2-phosphinico
derivatives; and biohydrolyzable amides, esters, and imides of the
2-decarboxy-2-phosphinico derivatives.
[0055] Suitable 2-decarboxy-2-phosphinico derivatives can have a
formula selected from the group consisting of: 2
[0056] R.sup.1 is selected from the group consisting of a hydrogen
atom, lower monovalent hydrocarbon groups, lower substituted
monovalent hydrocarbon groups, and lower heterogeneous groups.
R.sup.1 is preferably selected from the group consisting of a
hydrogen atom; an alkyl group such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, and t-butyl; a halogenated
hydrocarbon group such as trifluoromethyl or
CH.sub.2CH.sub.2CF.sub.3; CH.sub.2CH.sub.2OH, and
CH.sub.2CH.sub.2CH.sub.- 2OH. More preferably, R.sup.1 is a
hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, t-butyl, trifluoromethyl, CH.sub.2CH.sub.2CF.sub.3,
CH.sub.2CH.sub.2OH, or CH.sub.2CH.sub.2CH.sub.2- OH. Most
preferably, R.sup.1 is a hydrogen atom, methyl, ethyl, n-propyl,
isopropyl, or CH.sub.2CH.sub.20H.
[0057] R2 is selected from the group consisting of a hydrogen atom,
a monovalent hydrocarbon group, a substituted monovalent
hydrocarbon group, a heterogeneous group, a substituted
heterogeneous group, a carbocyclic group, a substituted carbocyclic
group, a heterocyclic group, a substituted heterocyclic group, an
aromatic group, a substituted aromatic group, a heteroaromatic
group, and a substituted heteroaromatic group. Preferably R.sup.2
is H, CH.sub.2CO.sub.2H, CH.sub.2C(O)NHOH, methyl, CF.sub.3, ethyl,
n-propyl, isopropyl, CH.sub.2CH.sub.2OH, CH.sub.2CH(OH)CH.sub.2OH,
benzyl, or t-butyl. More preferably, R.sup.2 is H, methyl,
CF.sub.3, ethyl, n-propyl, isopropyl, CH.sub.2CH.sub.2OH,
CH.sub.2C(O)NHOH, and benzyl. Most preferably, R.sup.2 is H,
methyl, CF.sub.3, ethyl, n-propyl, isopropyl, or
CH.sub.2CH.sub.2OH.
[0058] R.sup.3is selected from the group consisting of an oxygen
atom, a sulfur atom, and NH. Preferably, R.sup.3 is an oxygen atom
or NH; more preferably, R.sup.3is an oxygen atom.
[0059] R.sup.4 is selected from the group consisting of an oxygen
atom and a sulfur atom. Preferably, R.sup.4 is an oxygen atom.
[0060] R.sup.5is a divalent group. R.sup.5 is selected from the
group consisting of a hydrocarbon group, a substituted hydrocarbon
group, a heterogeneous group, and a substituted heterogeneous
group. R.sup.5 may be saturated or unsaturated, i.e., R.sup.5 may
contain one or more single bond, double bond, triple bond, or
combinations thereof. When R.sup.5 is a heterogeneous group, R5 has
only one heteroatom, which is selected from the group consisting of
oxygen, sulfur, and nitrogen. The preferred heteroatom is oxygen.
R.sup.5 preferably has 1 to 5 member atoms, more preferably 3 to 5
member atoms.
[0061] Bond a is selected from the group consisting of a single
bond, a trans double bond, and a triple bond.
[0062] R.sup.6 is a divalent group selected from the group
consisting of --C(O)-- and --C(R.sup.9)(OR.sup.9)--.
[0063] R.sup.7 is selected from the group consisting of a divalent
group having the formula
--(CR.sup.9(R.sup.9)).sub.p--X--(CR.sup.9(R.sup.9)).su- b.q,
wherein p is an integer from 0 to 3 and q is an integer from 0 to
3, and wherein X is selected from the group consisting of an oxygen
atom, a divalent hydrocarbon group, a sulfur atom, SO, SO.sub.2,
and NR.sup.9. Preferably, X is selected from the group consisting
of a single bond, a trans double bond, a triple bond, an oxygen
atom, a sulfur atom, and NR.sup.9.
[0064] R.sup.8 is selected from the group consisting of a methyl
group, a carbocyclic group, a substituted carbocyclic group, a
heterocyclic group, a substituted heterocyclic group, aromatic
group, a substituted aromatic group, a heteroaromatic group, a
substituted heteroaromatic group. When R.sup.8 is a monocyclic
group, it has 5 to 10 member atoms. When R.sup.8 is a bicyclic
group, it has 8 to 12 member atoms. Preferably, R.sup.8 is selected
from the group consisting of a monocyclic carbocyclic group, a
substituted monocyclic carbocyclic group, a monocyclic heterocyclic
group, a substituted monocyclic heterocyclic group, aromatic group,
a substituted aromatic group, a heteroaromatic group, and a
substituted heteroaromatic group.
[0065] R.sup.9 is a hydrogen atom or a lower monovalent hydrocarbon
group. Preferably, R.sup.9 is a hydrogen atom.
[0066] R.sup.10 is a hydrogen atom or a lower monovalent
hydrocarbon group. Preferably, R.sup.10 is a hydrogen atom.
[0067] Component A) may also be any optical isomer, diastereomer,
and enantiomer of any of the above structures; or any
pharmaceutically-accept- able salts of any of the above structures;
or any biohydrolyzable amides, esters, and imides of any of the
above structures; or combinations thereof.
[0068] The prostaglandin used in this invention preferably has the
formula: 3
[0069] wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, and bond a are as described
above. More preferably, R.sup.9 is a hydrogen atom.
[0070] Suitable prostaglandins for component A) can be prepared by
conventional organic syntheses. Examples of suitable prostaglandins
for component A) can be prepared by the following reaction scheme.
4
[0071] In the reaction scheme above, R.sup.1, R.sup.2, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, and bond a are as described
above, X is a halogen atom, and Q and Q.sup.2 are protecting
groups. The Corey Lactone (S1a) starting material is commercially
available (from Aldrich Chemical Company or Cayman Chemical
Company). Known Wadsworth-Horner-Emmons chemistry is used to attach
the bottom chain of the desired prostaglandin to the Corey Lactone,
creating compounds of the type S1b. There follows standard
prostaglandin omega chain manipulation and functional group
protection, including optional alkene reduction, which creates
compounds of type S1c. At this point, the standard course of
prostaglandin synthesis is altered; the omega-functionalized Wittig
reagent depicted is used to create 2-decarboxy prostaglandin
derivatives of the type S1d. When the carboxycyclic acid containing
prostaglandin is available, compounds of the type S1d are also
obtained by a one-carbon degradation using a modification of the
Hunsdiecker reaction.
[0072] Compounds depicted by S1e are available from compounds of
the type S1d via a phosphinite coupling reaction with an alkyl
diethyloxyphosphinite, which is obtained, as shown, from the
chlorodiethyloxyphosphine reagent, which is commercially available.
Compounds depicted by Formula III are available from compounds of
the type S1e via optional removal of the alkene and subsequent
removal of the protecting groups Q and Q.sup.2 of S1e.
[0073] Alternatively, compounds of the type S1f can be prepared
from intermediate S1e, where the protecting groups Q and Q.sup.2
are judiciously selected from a variety available to those skilled
in the art (see, for example: Protecting Groups in Organic
Synthesis by Greene, T. W. and Wuts, P. G. M., 2.sup.nd ed., Wiley
& Sons, Inc., 1991). Subsequent removal of Q at C11, followed
by oxidation would give the ketone precursor to S1f. Compounds of
the type S1f can then be obtained by final deprotection.
[0074] Compounds of Formula I can be prepared from compounds of
formula S1f by condensation with hydroxyl amine. Compounds of
Formula II can be reduced to prepare compounds of Formula I by
treatment with sodium cyanoborohydride in THF:acetic acid (1:1) and
thereafter quenching with HCl. Using conventional organic synthesis
techniques, one skilled in the art could prepare prostaglandins
suitable for use in this invention.
[0075] Examples of suitable prostaglandins of Formula I include
Formula 1A. Formula 1A is
1TABLE 1A Substituents in Formula 1A 5 R.sup.9 R.sup.1 R.sup.7
R.sup.8 H CH.sub.3 CH.sub.2S 6 H CH.sub.2CH.sub.3 CH.sub.2S 7 H
CH.sub.3 CH.sub.2O 8 H CH.sub.3 CH.sub.2CH.sub.2CH.sub.2CH.sub.2
CH.sub.3 H CH.sub.3 CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2
CH.sub.3 H CH.sub.3 CH.sub.2O 9 H CH.sub.3 CH.sub.2NH 10 CH.sub.3
CH.sub.3 CH.sub.2CH.sub.2CH.sub.2CH.sub.2 CH.sub.3 H
CH.sub.2CH.sub.3 CH.sub.2S 11 H CH.sub.2CH.sub.2CH.sub.2CH.sub.3 12
13
[0076] Examples of suitable prostaglandins of Formula II include
Formula 2A. Formula 2A is
2TABLE 2A Substituents in Formula 2A 14 b a R.sup.1 R.sup.7-R.sup.8
cis trans CH.sub.3 15 single single CH.sub.3 16 single single
CH.sub.2CH.sub.3 17 single single CH.sub.2CH.sub.3 18 cis trans
CH.sub.2CH.sub.3 19 single single CH(CH.sub.3).sub.2 20
[0077] Examples of suitable prostaglandins of Formula III include
Formulae 3A and 3B. Formula 3A is
3TABLE 3A Substituents in Formula 3A 21 R.sup.1 R.sup.7 R.sup.8
CH.sub.3 CH.sub.2CH.sub.2 22 CH.sub.3 CH.sub.2S 23 CH.sub.3
CH.sub.2O 24 CH.sub.2CH.sub.3 CH.sub.2O 25 CH.sub.2CH.sub.3
CH.sub.2O 26 CH.sub.2CH.sub.2CH.sub.3 CH.sub.2CH.sub.2 27 CH.sub.3
CH.sub.2NH 28 CH.sub.3 CH.sub.2NH 29 CH.sub.3
CH.sub.2CH.sub.2CH.sub.2CH.sub.2 CH.sub.3 CH.sub.2CH.sub.3 CH.sub.2
30 CH.sub.3 CH.sub.2O 31 CH.sub.3 CH.sub.2CH.dbd.CHCH.sub.2
CH.sub.3 CH.sub.3 CH.sub.2O 32 CH.sub.2CH.sub.2CH.sub.3
CH.sub.2CH.sub.2 33 CH.sub.3 CH.sub.2 34 CH.sub.2CH.sub.3 CH.sub.2O
35
[0078]
4TABLE 3B Substituents in Formula 3B 36 R.sup.1 R.sup.7 R.sup.8
CH.sub.3 CH.sub.2S 37 CH.sub.2CH.sub.3 CH.dbd.CH 38 CH.sub.3 39 40
CH.sub.3 --CH.dbd.C.dbd.CH-- 41 CH.sub.3 CH.sub.2S 42 CH.sub.3
CH.sub.2O 43 CH.sub.2CH.sub.3 CH.sub.2O 44 CH.sub.3 CH.sub.2NH 45
CH.sub.3 CH.sub.2NH 46 H CH.sub.2CH.sub.2 47
Compositions of the Invention
Hair Loss
[0079] This invention further relates to a composition for treating
hair loss. "Treating hair loss" means arresting hair loss,
reversing hair loss, or both, and promoting hair growth. The
composition comprises A) the PGF described above and B) a carrier.
The composition may further comprise C) one or more optional
activity enhancers.
[0080] 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).
[0081] 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, depending on the intended use as
described herein.
[0082] The choice of carrier for component B) depends on the route
by which A) the prostaglandin 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.
[0083] 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.
[0084] 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; sorbitol; and maltodextrin.
[0085] 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.
[0086] 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,
ethylcellulose, methylcellulose, microcrystalline cellulose, and
hydroxypropylmethylcellu- lose; carbomer; providone; acacia; guar
gum; and xanthan gum.
[0087] 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.
[0088] Ingredient e) is a colorant such as an FD&C dye.
[0089] Ingredient f) is a flavor such as menthol, peppermint, and
fruit flavors.
[0090] Ingredient g) is a sweetener such as saccharin and
aspartame.
[0091] Ingredient h) is an antioxidant such as butylated
hydroxyanisole, butylated hydroxytoluene, and vitamin E.
[0092] Ingredient j) is a preservative such as phenol, alkyl esters
of parahydroxybenzoic acid, benzoic acid and the salts thereof,
boric acid and the salts thereof, sorbic acid and the salts
thereof, chorbutanol, benzyl alcohol, thimerosal, phenylmercuric
acetate and nitrate, nitromersol, benzalkonium chloride,
cetylpyridinium chloride, methyl paraben, and propyl paraben.
Particularly preferred are the salts of benzoic acid,
cetylpyridinium chloride, methyl paraben and propyl paraben, and
sodium benzoate.
[0093] Ingredient k) is a glidant such as silicon dioxide.
[0094] Ingredient m) is a solvent, such as water, isotonic saline,
ethyl oleate, alcohols such as ethanol, glycerin, glycols (e.g.,
polypropylene glycol and polyethylene glycol), and buffer solutions
(e.g., phosphate, potassium acetate, boric carbonic, phosphoric,
succinic, malic, tartaric, citric, acetic, benzoic, lactic,
glyceric, gluconic, glutaric, and glutamic).
[0095] Ingredient n) is a suspending agent. Suitable suspending
agents include AVICEL.RTM. RC-591 from FMC Corporation of
Philadelphia, Pennsylvania and sodium alginate.
[0096] Ingredient o) is a surfactant such as lecithin, polysorbate
80, sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid
esters, polyoxyethylene monoalkyl ethers, sucrose monoesters,
lanolin esters, and lanolin ethers. Suitable surfactants are known
in the art and commercially available, e.g., the TWEENS.RTM. from
Atlas Powder Company of Wilmington, Del.
[0097] 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.
[0098] 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%.
[0099] 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 sucrose. Preferred binders
include starch, and gelatin. 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.
[0100] 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.
[0101] 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.
[0102] 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, acrylic
resins such as EUDRAGIT.RTM. coatings (available from Rohm &
Haas G.M.B.H. of Darmstadt, Germany), waxes, shellac,
polyvinylpyrrolidone, and other commercially available film-coating
preparations such as Dri-Klear, manufactured by Crompton &
Knowles Corp., Mahwah, N.J. or OPADRY.RTM. manufactured by
Colorcon, Inc., of West Point, Pa.
[0103] 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.
[0104] 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.
[0105] The compositions for treating hair loss may further comprise
component C) an optional activity enhancer. Component C) is
preferably selected from the group consisting of i) hair growth
stimulants (other than the prostaglandin) and ii) penetration
enhancers.
[0106] Component i) is an optional hair growth stimulant. Component
i) is exemplified by vasodilators, antiandrogens, cyclosporins,
cyclosporin analogs, antimicrobials, antiinflammatories, 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.
[0107] 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.
[0108] Examples of suitable antiandrogens include
5-.alpha.-reductase inhibitors such as finasteride and those
described in U.S. Pat. No. 5,516,779, and in Nane et al., Cancer
Research 58, "Effects of Some Novel Inhibitors of C17,20-Lyase and
5.alpha.-Reductase in vitro and in vivo and Their Potential Role in
the Treatment of Prostate Cancer," as well as cyproterone acetate,
azelaic acid and its derivatives and those compounds described in
U.S. Pat. No. 5,480,913, flutamide, and those compounds described
in U.S. Pat. Nos. 5,411,981, 5,565,467, and 4,910,226.
[0109] 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.
[0110] 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.
[0111] 3,5,3'-Triiodothyronine is an example of a suitable thyroid
hormone.
[0112] 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.
[0113] Suitable retinoids include isotretinoin, acitretin, and
tazarotene.
[0114] 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 interleukin1
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.
[0115] Other additional hair growth stimulants are described in JP
09-157,139 to Tsuji et al., published Jun. 17, 1997; EP 0277455 A1
to Mirabeau, published Aug. 10, 1988; WO 97/05887 to Cabo Soler et
al., published Feb. 20, 1997; WO 92/16186 to Bonte et al.,
published Mar. 13, 1992; JP 62-93215 to Okazaki et al., published
Apr. 28, 1987; U.S. Pat. No. 4,987,150 to Kurono et al., issued
Jan. 22, 1991; JP 290811 to Ohba et al., published Oct. 15, 1992;
JP 05-286,835 to Tanaka et al., published Nov. 2, 1993, FR
2,723,313 to Greff, published Aug. 2, 1994, U.S. Pat. No. 5,015,470
to Gibson, issued May 14, 1991, U.S. Pat. No. 5,559,092, issued
Sep. 24, 1996, U.S. Pat. No. 5,536,75 1, 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.
[0116] The most preferred activity enhancers are minoxidil and
finasteride, most preferably minoxidil. 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-ethylhexyl 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-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine
oxides, sugar esters, tetrahydrofurfural alcohol, urea,
diethyl-m-toluamide, 1-dodecylazacyloheptan-2-one, omega three
fatty acids and fish oils, and combinations thereof.
[0117] 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. Topical compositions preferably further comprise C) one
or more of the optional activity enhancers described above.
[0118] The exact amounts of each component in the topical
composition for treating hair loss depend on various factors. The
amount of component A) depends on the IC.sub.50 of the
prostaglandin selected. "IC.sub.50" means inhibitory concentration
50th percentile. The amount of component A) added to the topical
composition is:
IC.sub.50.times.10.sup.-2.gtoreq.% of component A)
IC.sub.50.times.10.sup.- -3,
[0119] where IC.sub.50 is expressed in nanomolar units. 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.
[0120] The topical composition preferably further comprises 1 to
20% component C), and a sufficient amount of component B) such that
the amounts of components A), B), and C), combined equal 100%. The
amount of B) the carrier employed in conjunction with the
prostaglandin is sufficient to provide a practical quantity of
composition for administration per unit dose of the compound.
Techniques and compositions for making dosage forms useful in the
methods of this invention are described in the following
references: Modern Pharmaceutics, Chapters 9 and 10, Banker &
Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms:
Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage
Forms, 2.sup.nd Ed., (1976).
[0121] 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.
[0122] 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.
[0123] 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.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] Ingredient u) is a thickener. The amount of ingredient u) in
the topical composition is typically 0 to 95%.
[0128] 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.
[0129] 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%.
[0130] 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).
[0131] In an alternative embodiment of the invention, the topical
composition may be applied to growing hair and skin in the locus of
the growing hair to darken to darken hair, reverse hair graying,
and thicken the hair. 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.
[0132] 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.
[0133] 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.
[0134] 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.
[0135] 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).
[0136] 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.
[0137] 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.
[0138] 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.
[0139] Ingredient s) is a solvent described above, preferably
water.
[0140] The amount of A) the prostaglandin added to the mascara is
as described above for topical compositions.
[0141] 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).
[0142] 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 lontotherapeutic Delivery Devices for Transdermal
Delivery of Peptide/Protein Drugs", Pharm. Res., Vol. 10 (5), pp.
697-702 (1993); Ferry, "Theoretical Model of Iontophoresis Utilized
in Transdermal Drug Delivery", Pharmaceutical Acta Helvetiae, Vol
70, pp. 279-287 (1995); Gangarosa et al., "Modern Iontophoresis for
Local Drug Delivery", Int. J. Pharm., Vol. 123, pp. 159-171 (1995);
Green et al., "Iontophoretic Delivery of a Series of Tripeptides
Across the Skin in vitro", Pharm. Res., Vol 8, pp. 1121-1127
(1991); Jadoul et al., "Quantification and Localization of Fentanyl
and TRH Delivered by Iontophoresis in the Skin", Int. J. Pharm.,
Vol. 120, pp. 221-8 (1995); O'Brien et al., "An Updated Review of
its Antiviral Activity, Pharmacokinetic Properties and Therapeutic
Efficacy", Drugs, Vol. 37, pp. 233-309 (1989); Parry et al.,
"Acyclovir Biovailability in Human Skin", J. Invest. Dermatol.,
Vol. 98 (6), pp. 856-63 (1992); Santi et al., "Drug Reservoir
Composition and Transport of Salmon Calcitonin in Transdermal
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. 1869-1873 (1995);
Thysman et al., "Human Calcitonin Delivery in Rats by
Iontophoresis", J. Pharm. Pharmacol., Vol. 46, pp. 725-730 (1994);
and Volpato et al., "Iontophoresis Enhances the Transport of
Acyclovir through Nude Mouse Skin by Electrorepulsion and
Electroosmosis", Pharm. Res., Vol. 12 (11), pp. 1623-1627
(1995).
[0143] The prostaglandins may be included in kits comprising a
prostaglandin, a systemic or topical composition described above,
or both; and information, instructions, or both that use of the kit
will provide treatment for hair loss in mammals (particularly
humans). The information and instructions may be in the form of
words, pictures, or both, and the like. In addition or in the
alternative, the kit may comprise a prostaglandin, a composition,
or both; and information, instructions, or both, regarding methods
of application of the prostaglandin or composition, preferably with
the benefit of treating hair loss in mammals.
Bone Disorders
[0144] In addition to benefits in treating hair loss, the
prostaglandins of this invention may also be useful to treat bone
disorders. Without wishing to be bound by theory, it is believed
that the prostaglandins are useful in increasing bone volume and
trabecular number through formation of new trabeculae, formation of
bone mass while maintaining a normalized bone turnover rate, and
formation at the endosteal surface without removing bone from the
existing cortex.
[0145] This invention further relates to compositions for treating
bone disorders. Compositions for treating bone disorders can be
prepared by standard pharmaceutical formulation techniques, such as
those disclosed in Remington's Pharmaceutical Sciences, Mack
Publishing Company, Easton, Pa. (1990), using the ingredients
described above. The preferred routes of administration for
treating bone disorders are transdermal, intranasal, rectal,
sublingual, and oral.
[0146] Suitable oral compositions for treating bone disorders
typically comprise A) a prostaglandin described above and B) a
carrier. A typical tablet composition comprises 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
sucrose. Preferred lubricants include magnesium stearate, stearic
acid, and talc. Preferred binders include microcrystalline
cellulose, starch, and gelatin. Preferred disintegrants include
sodium starch glycolate, alginic acid, and croscarmelose.
[0147] Typical parenteral pharmaceutical compositions for treating
bone disorders comprise A) the prostaglandin and B) a carrier
comprising ingredients selected from the group consisting of j)
preservatives and m) solvents. Preferred preservatives include
methyl paraben and ethyl paraben. Preferred solvents include
isotonic saline. One skilled in the art can optimize ingredients
for the compositions to treat bone disorders without undue
experimentation.
[0148] The prostaglandins can optionally be used in combination
with other ingredients which have a beneficial effect on bone loss.
Thus, other actives such as vitamin D analogs, hormones, calcium
supplements, diphosphonate compounds such as those extensively
described in the literature of the Procter & Gamble Company,
combinations thereof, and the like may also be administered to
patients in need of such treatment in conjunction with the
prostaglandins. Dosage levels and means of administration include
pulsed-dosing, and are as described in the literature.
Intraocular Pressure
[0149] The prostaglandins used in this invention are also useful in
decreasing intraocular pressure. Thus, these prostaglandins are
useful in the treatment of glaucoma. This invention further relates
to compositions for lowering intraocular pressure. The preferred
route of administration for lowering intraocular pressure is
topical. 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.
[0150] Examples of z) cellulose derivatives suitable for use in the
topical pharmaceutical composition for ocular administration
include sodium carboxymethyl cellulose, ethyl cellulose, methyl
cellulose, and hydroxypropylmethylcellulose.
Hydroxypropylmethylcellulose is preferred.
[0151] 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.
[0152] 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.
Methods of the Invention
Hair Loss
[0153] This invention further relates to a method for treating hair
loss in mammals. The method comprises administering to a mammal
(preferably a human) suffering from hair loss, a prostaglandin
described above. For example, a mammal diagnosed with alopecia
including male pattern baldness and female pattern baldness can be
treated by the methods of this invention. Preferably, a systemic or
topical composition comprising A) the prostaglandin and B) a
carrier is administered to the mammal. More preferably, the
composition is a topical composition comprising A) the
prostaglandin, B) the carrier, and C) an optional activity
enhancer.
[0154] The dosage of the prostaglandin administered to treat hair
loss depends on the method of administration. For systemic
administration, (e.g., oral, rectal, nasal, sublingual, buccal, or
parenteral), typically, 0.5 mg to 300 mg, preferably 0.5 mg to 100
mg, more preferably 0.1 mg to 10 mg, of a prostaglandin described
above is administered per day. These dosage ranges are merely
exemplary, and daily administration can be adjusted depending on
various factors. The specific dosage of the prostaglandin to be
administered, as well as the duration of treatment, and whether the
treatment is topical or systemic are interdependent. The dosage and
treatment regimen will also depend upon such factors as the
specific prostaglandin used, the treatment indication, the efficacy
of the compound, the personal attributes of the subject (such as,
for example, weight, age, sex, and medical condition of the
subject), compliance with the treatment regimen, and the presence
and severity of any side effects of the treatment.
[0155] For topical administration (e.g., local application on the
skin, liposome delivery systems, or iontophoresis), the topical
composition is typically administered once per day. The topical
compositions are administered daily for a relatively short amount
of time (i.e., on the order of weeks). Generally, 6 to 12 weeks is
sufficient. The topical compositions are preferably leave-on
compositions. In general, the topical composition should not be
removed for at least several hours after administration.
[0156] In addition to the benefits in treating hair loss, the
inventors have found that the prostaglandins in the compositions
and methods of this invention also darken and thicken hair and may
reverse hair graying. 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. In a
preferred embodiment of the invention, the topical composition,
such as the mascara composition described above, is applied to
eyelashes.
Bone Disorders
[0157] This invention further relates to methods for treating bone
disorders sing the prostaglandins described above. The method
comprises administering to a mammal (preferably a human) suffering
from a bone disorder, a prostaglandin described above. For example,
a mammal diagnosed with osteoporosis can be treated by the methods
of this invention. Preferably, a systemic composition comprising A)
the prostaglandin and B) a carrier is administered to the mammal.
The preferred routes of administration for treating bone disorders
are transdermal, intranasal, rectal, sublingual, and oral.
[0158] The dosage range of the prostaglandin for systemic
administration to treat bone disorders is from about 0.01 to about
1000 .mu.g/kg body weight, preferably from about 0.1 to about 100
.mu.g per body weight, most preferably form about 1 to about 50
.mu.g/kg body weight per day. The transdermal dosages will be
designed to attain similar serum or plasma levels, based upon
techniques known to those skilled in the art of pharmacokinetics
and transdermal formulations. Plasma levels for systemic
administration are expected to be in the range of 0.01 to 100
nanograms/ml, more preferably from 0.05 to 50 ng/ml, and most
preferably from 0.1 to 10 ng/ml. While these dosages are based upon
a daily administration rate, weekly or monthly accumulated dosages
may also be used to calculate the clinical requirements.
[0159] Dosages may be varied based on the patient being treated,
the condition being treated, the severity of the condition being
treated, the route of administration, etc. to achieve the desired
effect.
Intraocular Pressure
[0160] The prostaglandins of the present invention are also useful
in decreasing intraocular pressure. Thus, these prostaglandins are
useful in the treatment of glaucoma. This invention further relates
to a method for lowering intraocular pressure in mammals. The
method comprises administering to a mammal (preferably a human) a
prostaglandin described above. For example, a mammal diagnosed with
glaucoma can be treated by the methods of this invention. The
preferred route of administration for treating glaucoma is topical.
Preferably, a topical composition for ocular administration
described above is administered to the mammal. The topical
composition for ocular administration is typically administered
once per day. The topical compositions are administered daily for a
relatively short amount of time (i.e., on the order of weeks).
Generally, 6 to 12 weeks is sufficient.
EXAMPLES
[0161] These examples are intended to illustrate the invention to
those skilled in the art and should not be interpreted as limiting
the scope of the invention set forth in the claims.
Reference Example 1
Radioligand Binding Assay
[0162] IC.sub.50 of a prostaglandin can be determined relative to
PGF.sub.2.alpha. using the Radioligand Binding Assay. As a control,
the IC.sub.50 for PGF.sub.2.alpha. itself should be no lower than
1.0 nM and no higher than 5.0 nM.
[0163] In this assay, COS-7 cells are transiently transfected with
the hFP recombinant plasmid using LipofectAMINE Reagent.
Forty-eight hours later, the tranfected cells are washed with
Hank's Balanced Salt Solution (HBSS, without CaCl.sub.2,
MgCl.sub.2, MgSO.sub.4, or phenol red). The cells are detached with
versene, and HBSS is added. The mixture is centrifuged at 200 g for
10 minutes, at 4.degree. C. to pellet the cells. The pellet is
resuspended in Phosphate-Buffered Saline-EDTA buffer (PBS; 1 mM
EDTA; pH 7.4; 4.degree. C.). The cells are disrupted by nitrogen
cavitation (Parr model 4639), at 800 psi, for 15 minutes at
4.degree. C. The mixture is centrifuged at 1000 g for 10 minutes at
4.degree. C. The supernatant is centrifuged at 100,000 g for 60
minutes at 4.degree. C. The pellet is resuspended to 1 mg
protein/mL TME buffer (50 mM Tris; 10 mM MgCl2; 1 mM EDTA; pH 6.0;
4.degree. C.) based on protein levels measured using the Pierce BCA
Protein Assay kit. The homogenate is mixed for 10 seconds using a
Kinematica POLYTRON .RTM. (available from KINEMATICA AG,
Luzemerstrassel47A CH-6014 Littau, Switzerland). The membrane
preparations are then stored at -80.degree. C., until thawed for
assay use.
[0164] The receptor competition binding assays are developed in a
96 well format. Each well contains 100 g of hFP membrane, 5 nM (3H)
PGF2.alpha., and the various competing compounds in a total volume
of 200 L. The plates are incubated at 23.degree. C. for 1 hour. The
incubation is terminated by rapid filtration using the Packard
Filtermate 196 harvester through Packard UNILTER.RTM. GF/B filters
(available from Packard Instrument Co., Inc. of Downers Grove
Illinois) pre-wetted with TME buffer. The filter is washed four
times with TME buffer. Packard Microscint 20, a high efficiency
liquid scintillation cocktail, is added to the filter plate wells
and the plates remain at room temperature for three hours prior to
counting. The plates are read on a Packard TOPCOUNT.RTM. Microplate
Scintillation Counter (also available from Packard Instrument Co.,
Inc.)
Reference Example 2
Telogen Conversion Assay
[0165] Prostaglandins are tested for their potential to grow hair
using the Telogen Conversion Assay. The Telogen Conversion Assay
measures the potential of a prostaglandin to convert mice in the
resting stage of the hair growth cycle ("telogen"), to the growth
stage of the hair growth cycle ("anagen").
[0166] Without intending to be limited by theory, there are three
principal phases of the hair growth cycle: anagen, catagen, and
telogen. It is believed that there is a longer telogen period in
C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, Ind.) from
approximately 40 days of age until about 75 days of age, when hair
growth is synchronized. It is believed that after 75 days of age,
hair growth is no longer synchronized. Wherein about 40 day-old
mice with dark fur (brown or black) are used in hair growth
experiments, melanogenesis occurs along with hair (fur) growth
wherein the topical application of hair growth inducers are
evaluated. The Telogen Conversion Assay herein is used to screen
prostaglandins for potential hair growth by measuring
melanogenesis.
[0167] Three groups of 44 day-old C3H mice are used: a vehicle
control group, a positive control group, and a test prostaglandin
group, wherein the test prostaglandin group is administered a
prostaglandin used in the method of this invention. The length of
the assay is 24 days with 15 treatment days (wherein the treatment
days occur Mondays through Fridays). Day 1 is the first day of
treatment. A typical study design is shown in Table 4 below.
Typical dosage concentrations are set forth in Table 3, however the
skilled artisan will readily understand that such concentrations
may be modified.
5TABLE 4 Assay Parameters Group Animal Concen- Application Length #
# Compound tration volume of Study 1 1-10 Test 0.01% in 400 .mu.L
topical 26 days Compound vehicle** 2 11-20 Positive 0.01% in 400
.mu.L topical 26 days Control vehicle** (T3)* 3 21-30 Vehicle** N/A
400 .mu.L topical 26 days *T3 is 3,5,3'-triiodothyronine. **The
vehicle is 60% ethanol, 20% propylene glycol, and 20% dimethyl
isosorbide
[0168] (commercially available from Sigma Chemical Co., St. Louis,
Mo.).
[0169] The mice are treated topically Monday through Friday on
their lower back (base of tail to the lower rib). A pipettor and
tip are used to deliver 400 .mu.L to each mouse's back. The 400
.mu.L application is applied slowly while moving hair on the mouse
to allow the application to reach the skin.
[0170] While each treatment is being applied to the mouse
topically, a visual grade of from 0 to 4 will be given to the skin
color in the application area of each animal. As a mouse converts
from telogen to anagen, its skin color will become more
bluish-black. As indicated in Table 5, the grades 0 to 4 represent
the following visual observations as the skin progresses from white
to bluish-black.
6TABLE 5 Evaluation Criteria Visual Observation Grade Whitish Skin
Color 0 Skin is light gray (indication of initiation of anagen) 1
Appearance of Blue Spots 2 Blue Spots are aggregating to form one
large blue area 3 Skin is dark blue (almost black) with color
covering majority of 4 treatment area (indication of mouse in full
anagen)
Reference Example 3
Ovariectomized Rat Assay
[0171] Bone activity of the prostaglandins can be conveniently
demonstrated using an assay designed to test the ability of the
prostaglandins to increase bone volume, mass, or density. An
example of such assays is the ovariectomized rat assay.
[0172] In the ovariectomized rat assay, six-month old rats are
ovariectomized, aged 2 months, and then dosed once a day
subcutaneously with a prostaglandin. Upon completion of the study,
bone mass and/or density can be measured by dual energy x-ray
absorptometry (DXA) or peripheral quantitative computed tomography
(pQCT), or micro computed tomography (mCT). Alternatively, static
and dynamic histomorphometry can be used to measure the increase in
bone volume or formation.
Reference Example 4
Pharmacological Activity for Glaucoma Assay
[0173] Pharmacological activity for glaucoma can be demonstrated
using assays designed to test the ability of the subject compounds
to decrease intraocular pressure. Examples of such assays are
described in the following reference, incorporated herein: C.
Iiljebris, G.
[0174] 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.
Example 1
[0175] Compositions for topical administration are made,
comprising:
7 Component 1-1 1-2 Prostaglandin (wt %) 0.42 1.14 IC.sub.50 the
PGF (nM) 42 114 Ethanol (wt %) 59.74 59.32 Propylene Glycol (wt %)
19.92 19.77 Dimethyl Isosorbide (wt %) 19.92 19.77
[0176] The prostaglandins in the topical compositions are as
follows:
8 Example Prostaglandin 1-1 48 1-2 49
[0177] A human male subject suffering from male pattern baldness is
treated by a method of this invention. Specifically, for 6 weeks,
one of the above compositions is daily administered topically to
the subject to induce hair growth.
Example 2
[0178] A composition for topical administration is made according
to the method of 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), using a PGF in lieu of cyclosporin A and using
the NOVASOME.RTM. 1 (available from Micro-Pak, Inc. of Wilmington,
Del.) for the non-ionic liposomal formulation.
[0179] A human male subject suffering from male pattern baldness is
treated each day with the above composition. Specifically, for 6
weeks, the above composition is administered topically to the
subject.
Example 3
[0180] Shampoos are made, comprising:
9 Component Ex. 3-1 Ex. 3-2 Ex. 3-3 Ex. 3-4 Ammonium Lauryl Sulfate
11.5% 11.5% 9.5% 7.5% Ammonium Laureth Sulfate 4% 3% 2% 2% Cocamide
MEA 2% 2% 2% 2% Ethylene Glycol Distearate 2% 2% 2% 2% Cetyl
Alcohol 2% 2% 2% 2% Stearl Alcohol 1.2% 1.2% 1.2% 1.2% Glycerin 1%
1% 1% 1% Polyquaternium 10 0.5% 0.25% -- -- Polyquaternium 24 -- --
0.5% 0.25% Sodium Chloride 0.1% 0.1% 0.1% 0.1% Sucrose Polyesters
of Cottonate 3% 3% -- -- Fatty Acid Sucrose Polyesters of Behenate
2% 3% -- -- Fatty Acid Polydimethyl Siloxane -- -- 3% 2%
Cocaminopropyl Betaine -- 1% 3% 3% Lauryl Dimethyl Amine Oxide 1.5%
1.5% 1.5% 1.5% Decyl Polyglucose -- -- 1% 1% DMDM Hydantoin 0.15%
0.15% 0.15% 0.15% PGF having IC.sub.50 of 42 nM -- 0.42% 0.42% --
PGF having IC.sub.50 of 114 nM 0.11% -- -- 0.11% Minoxidil 3% 2%
Phenoxyethanol 0.5% 0.5% 0.5% 0.5% Fragrance 0.5% 0.5% 0.5% 0.5%
Water q.s. q.s. q.s. q.s.
[0181] The prostaglandins are the same as in Example 1.
[0182] A human subject suffering from male pattern baldness is
treated by a method of this invention. Specifically, for 12 weeks,
a shampoo described above is used daily by the subject.
Example 4
[0183] A mascara composition is prepared. The composition
comprises:
10 Component % W/W WATER, DEIONIZED, USP q.s. BLACK 1080 MICRONIZED
TYPE 10.000 GLYCERYL MONOSTEARATE (2400 TYPE) 8.500 C18-36 ACID
TRIGLYCERIDE 5.500 STEARIC ACID, TRIPLE PRESSED, LIQUID 4.000 ETHYL
ALCOHOL SD 40-B, 190 PROOF/SERIAL #: 4.000 BEESWAX WHITE, FLAKES
3.250 SHELLAC, NF 3.000 LECITHIN, GRANULAR (TYPE 6450) 2.500
TRIETHANOLAMINE 99% - TANK 2.470 PARAFFIN WAX 2.250 PARAFFIN WAX
118/125 2.250 CARNAUBA WAX, NF 2.000 POTASSIUM CETYL PHOSPHATE
1.000 PHENOXYETHANOL 0.800 OLEIC ACID NF 0.750 DL-PANTHENOL 0.350
PVP/VA COPOLYMER 0.250 METHYLPARABEN, NF 0.200 DIAZOLIDINYL UREA
0.200 SIMETHICONE 0.200 ETHYLPARABEN NF 0.150 PENTAERYTHRITYL
HYDROGENATED ROSINATE 0.150 PROPYLPARABEN, NF 0.100 TRISODIUM EDTA
0.100 PROSTAGLANDIN having IC.sub.50 of 114 nM 0.114
[0184] The prostaglandin is the same as in Example 1-2.
[0185] A human female subject applies the composition each day.
Specifically, for 6 weeks, the above composition is administered
topically to the subject to darken and thicken eyelashes.
Example 5
[0186] A pharmaceutical composition in the form of a tablet is
prepared by conventional methods, such as mixing and direct
compaction, formulated as follows:
11 Ingredient Quantity (mg per tablet) Prostaglandin 5
Microcrystalline Cellulose 100 Sodium Starch Glycollate 30
Magnesium Stearate 3
[0187] The prostaglandin is the same as in Example 1-2.
[0188] When administered orally once daily, the above composition
substantially increases bone volume in a patient suffering from
osteoporosis.
Example 6
[0189] A pharmaceutical compositions in liquid form is prepared by
conventional methods, formulated as follows:
12 Ingredient Quantity Prostaglandin 1 mg Phosphate buffered
physiological saline 10 ml Methyl Paraben 0.05 ml
[0190] The prostaglandin used is the same as in Example 1-2.
[0191] When 1.0 ml of the above composition is administered
subcutaneously once daily, the above composition substantially
increases bone volume in a patient suffering from osteoporosis.
Example 7
[0192] A topical pharmaceutical composition for lowering
intraocular pressure are prepared by conventional methods and
formulated as follows:
13 Ingredient Amount (wt %) Prostaglandin 0.004 Dextran 70 0.1
Hydroxypropyl methylcellulose 0.3 Sodium Chloride 0.77 Potassium
chloride 0.12 Disodium EDTA (Edetate disodium) 0.05 Benzalkonium
chloride 0.01 HCl and/or NaOH pH 7.2-7.5 Purified water q.s. to
100%
[0193] The prostaglandin is the same as in Example 1-2.
[0194] When the above composition is administered once daily for 6
to 12 weeks, it lowers intraocular pressure in a patient suffering
from glaucoma.
Effects of the Invention
[0195] The compositions and methods herein provide a cosmetic
benefit with respect to hair growth and appearance in subjects
desiring such treatment. The compositions and methods herein also
provide pharmaceutical benefits with respect to treating bone
disorders and lowering intraocular pressure in subjects needing
such treatment.
* * * * *
References