Note: Descriptions are shown in the official language in which they were submitted.
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MEDICAMENTS COMPRISING RELAXIN AND THEIR USE
BACKGROUND ART
In humans, each hair follicle goes through repeated cyclical periods of
growth including an active growth stage (anagen), which can persist for
approximately 2 to 6 years; a transition phase (catagen), which lasts for only
a
week or two; and a resting period (telogen), which lasts 3 to 4 months. The
hair
is shed at the end of the telogen phase, and a new hair is grown as the cycle
repeats. In the human scalp, which contains approximately 100,000 hair
follicles, normally about 86% are in anagen, 1 % are in catagen and 13% are in
telogen. Therefore, in a normal human adult, approximately 100 hairs are shed
from the scalp per day.
Excessive hair loss, or alopecia, may be classified as being one of two
types, non-scarring alopecia and scarring alopecia, and can be caused by a
wide variety of factors. For example, non-scarring alopecia has been
attributed
to genetics and advanced age: administration of drugs such as anti-cancer
chemotherapeutic drugs and contraceptives; topical use of chemical
treatments, such as hair dyes, permanent wave solutions, and straighteners;
diseases, such as leprosy or syphilis; illness; allergy; and hair follicle
infection.
Scarring alopecia may be a consequence of burns (accidental or post surgical
from cryosurgery or laser surgery) or trauma, which often causes destruction
of
follicles.
The most common type of human hair loss is androgenetic alopecia
(also known as androgenic alopecia), which is a non-scarring hair loss of
telogen hairs caused by an excessive androgen effect in genetically
susceptible
men and women. Androgens trigger the miniaturization or atrophy of terminal
follicles that normally produce thick scalp hair and transforms them into
vellus-like follicles, eventually yielding fine, downy hair that is barely
perceptible. Androgenetic alopecia is expressed in males as baldness of the
vertex of the scalp and is commonly referred to as male pattern baldness. In
females, androgenetic alopecia appears as diffuse hair loss or thinning of the
frontoparietal areas. As alopecia progresses with age, hairs in these
predisposed areas miniaturize and appear to change from terminal hairs to
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resemble vellus hairs. In addition, as androgenetic alopecia continues, the
number of hairs in the active growth anagen phase decreases while there is an
increase the number of hairs in the telogen phase.
Androgenetic alopecia, which is sometimes referred to as "common
baldness" or "male pattern baldness," independent of its causes, is the
cutaneous aping of a particular zone (i.e., the scalp). Androgenetic alopecia
can
be defined, on one hand, as atrophy, sclerosis or minaturization of the hair
follicles. On the other hand, androgenetic alopecia can be defined as a
progressive shortening of the average duration of the anagen stage, which
results in vellus hair prior to complete disappearance.
Hair loss is an extremely common condition among healthy adult
males, and also occurs frequently in adult females. In fact, some degree of
alopecia on the vertex from puberty onwards is thought to be a universal
phenomenon in both men and women (R. P R. Dawber (1987) Dermatologica
175:23-28). Alopecia is also frequently observed in both pre- and post-
pubertal
patients as a side effect of anti-cancer chemotherapy, (A. M. Hussein, et al.
(1990) Science 249:1564-1566, B. W. Cline, (1984) Cancer Nursing, 7:221-
228; A. F: Hood (1986) Med. Clin. North Am. 70:187-209 ).
Despite the widespread occurrence of androgenetic alopecia, the need
for prevention and therapy still exists. The lack of a proven and effective
treatment for androgenetic alopecia has caused many afflicted individuals to
adopt the practice of wearing a wig or toupee. Another extreme measure used
to combat androgenetic alopecia, hair transplant surgery, is not available as
an
option in many cases (i.e., following chemotherapy) and offers, at best, only
a
partial remedy. At the same, the latter treatment suffers from
to a number of disadvantages, including the need for surgery.
A common non-surgical treatment for stimulating hair growth is
minoxidil (The Upjohn Company, Kalamazoo. Mich.). A solution of minoxidil as
active ingredient is known as Rogaine® As stated in the Rogaine®
Patient Information Booklet (The Upjohn Company, Kalamazoo, Mich., revised
June, 1992) minoxidil is a vasodilatory drug which has serious side effects
when administered orally for the treatment of hypertension. At the same time,
topical application of minoxidil for the treatment of androgenetic alopecia is
only partially effective and suffers from a number of disadvantages. For
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example, minoxidil is only recommended for treatment of male pattern
alopecia of the vertex (i.e., frontal recession), has to be applied twice
daily for
at least four months, and requires a normal scalp with no local abrasions,
dermatitis or sunburn - conditions that can increase absorption into the blood
stream and the concomitant risk of side effects. Further, minoxidil is of
limited
effectiveness. For example, there is no significant increase in terminal hair
regrowth between minoxidil and placebo treatment groups after four months of
treatment (refer to the Rogaine® Patient Information Booklet, The Upjohn
Company, Kalamazoo. Mich., revised June, 1992 ). In patients who do respond
to minoxidil treatment, the new hair is likely to be shed within a few months
after stopping treatment.
Androgens are responsible for many physiological functions in both
males and females. Androgen action is mediated by specific intracellular
hormone receptors expressed in androgen responsive cells. Testosterone, the
major circulating androgen, is secreted by Leydig cells of the testes under
the
stimulation of pituitary-derived luteinizing hormone (LH). However, reduction
of
the 4, 5 double bond of testosterone to dihydrotestosterone (DHT) is required
in some target tissues, such as prostate and skin, for androgen action.
Steroid
5.alpha.-reductases in target tissues catalyze conversion of testosterone to
DHT.
The requirement for DHT to act as an agonist in these target tissues has
been highlighted by studies of steroid 5.alpha.-reductase deficient
individuals
who have vestigial prostate glands and do not suffer from male pattern
baldness (see McGinley. J. et al., The New England J. of Medicine, 300, 1233
(1979)). Thus, inhibition of the conversion of testosterone to DHT in these
target tissues is anticipated to be useful in the treatment of a variety of
androgen responsive diseases (i.e., benign prostatic hyperplasia, prostate
cancer, acne, male pattern baldness and hirsutism).
Additionally, it has been discovered that two isozymes of
5.alpha.-reductase exist in humans which differ in their tissue distribution,
affinity for testosterone, pH profile and sensitivity to inhibitors (see
Russell, D.
W. et al., J. Clin. Invest., 89, 293 (1992): Russell, D. W. et al., Nature,
354, 159
(1991)). The steroid 5.alpha.-reductase deficient individuals studied by
Imperato-McGinley are deficient in the type 2,5.alpha.-reductase enzyme
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(Russell, D. W. et al.. J. Clin. Invest., 90, 799 (1992 ); Russell, D. W. et
al., New
England J. Med., 327, 1216 (1992)), which is the predominant isozyme present
in the prostate, while the type 1
isozyme is predominant in the skin. The relative value of isozyme specific and
dual inhibitors of the two isozymes of 5.alpha.-reductase will depend upon the
type of disease treated (benign prostatic hyperplasia, prostate cancer, acne,
male pattern baldness or hirsutism) as well as the stage of the disease
(prevention versus treatment) and the anticipated side-effects in the intended
patients (for example treatment of acne vulgaris in pubescent males).
Because of their valuable therapeutic potential, testosterone 5.alpha.-
reductase inhibitors have been the subject of active research worldwide. For
example, see: Hsia, S. and Voight, W., J. Invest. Derm., 62, 324 (1973);
Robaire, B. et W., J. Steroid Biochem., 8. 307 (1977); Petrow, V. et al.,
Steroids, 38, 121 (1981); Liang. T. et al. J. Steroid Biochem., 19, 385
(1983);
Holt, D. et al., J. Med. Chem., 33, 937 (1990): U.S. Pat. No. 4.377,584, U.S.
Pat. No. 4,760,071 and U.S. Pat. No. 5,017,568. Several particularly
promising 5.alpha.-reductase inhibitors are: (1) MK-906 (Merck), known by the
generic name, finasteride, and marketed under the trademark, Proscar; (2)
SKF-105657 (SmithKline Beecham); and (3) cyproterone acetate.
Finasteride (l7.beta.-(N-tert-butylcarbamoyl
-4-aza5.alpha.-androst-I-ene-3-one). which is marketed by Merck & Co., Inc.
under the tradename PROSCAR®. is an inhibitor of 5. alpha.-reductase 2
and is known to be useful for the treatment of hyperandrogenetic conditions.
See e.g., U.S. Pat. No. 4,760,071. Finasteride is currently marketed in the
United States and worldwide for the treatment of benign prostatic hyperplasia.
Finasteride's utility in the treatment of androgenetic alopecia is also
disclosed
in the following documents: EP 0 285,382. published Oct. 5, 1988; EP 0 285
383, published Oct. 5, 1988; Canadian Patent no. 1,302,277; and Canadian
Patent no. 1,302.276.
Androgens are the most obvious regulators of human hair growth in
both sexes. Androgens have pradoxically contrasting effects on follicles
depending on their location in the body. Androgens stimulate hair growth in
many locations (i.e., beard, axilla) while inhibiting scalp hair growth in
genetically predisposed individuals. Androgens act on the hair follicles via
the
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dermal papilla, presumably by altering the production of regulatory factors
effecting the dermal papilla cells. Cultured dermal papilla cells secrete
soluble,
proteinaceous factors which are mitogenic for other dermal papilla cells,
outer
root sheath cells, epidermal keratinocytes and endothelial cells. Androgen
sensitive cells from beard or balding scalp reflect their in vivo androgenetic
responses by responding to testosterone, by increasing (i.e., beard) or
decreasing (i.e.. balding) their mitogenic ability.
The dermal papilla is a connective tissue structure situated at the base
of hair follicles. The dermal papilla is composed of specialized fibroblast
cells
which demonstrate major changes in terms of cell morphology, vascularization,
composition and volume of extracellular matrix. During anagen the dermal
papilla cells show intracellular structures indicating on going protein
synthesis
and there is an active vascularization process, whereas during the telogen it
is
quiescent and non vascularized.
The dermal papilla extracellular matrix contains collagen laminin
fibronectin and haparin sulfate proteoglycan. During the transition form
anagen
to catagen the extracellular matrix diminishes in volume and in the telogen
phase it is almost nonexistent. Also in the telogen phase fibronectin, laminin
and proteoglicans dirninwhile the collagen content is increased in the
interfollicular dermis and in the dermal papilla. There is some evidence
indicating proteoglicans involvement in the hair growth process in addition to
the
above mentioned changed pattern of expression during the hair growth cycle.
Injection of glycosamonoglycans in to skin of rabbits stimulated hair growth.
The accumulation of proteoglycans in the skin, like in pretibial myxedema is
associated with hypertrichosis.
The present invention relates to the use of Relaxin, in the manufacture
of medicaments having a novel application, to a method of use in which relaxin
is utilized for the treatment and prevention of certain conditions and to
pharmaceutical compositions comprising relaxin. Relaxin otherwise known as
Cervilaxitl, and formerly referred to as Releasin, is a polypeptide hormone
secreted by the corpora lutes of many mamalian species during pregnancy.
As described in U.S. Pat. No. 3,096,246. the contents of which are
incorporated herein by reference, relaxin is present in the ovaries of animals
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and may be extracted therefrom. It is believed to be a hormone of pregancy
and has aroused great interest in the field of medical research. For example,
it
has been known to cause uterine cervix relaxation in cows; to increase the
dilatability of uterine cervix in ovariectomized estrogen-primed hogs; to
cause
definite milk let-down in sheep, and, to a lesser extent, in cows, and to
cause
marked lobulo-alveolar growth of the mammary gland in rats; and, in the
clinic,
it has been found to cause dilation of the uterine cervix in near-term
pregnant
women who fail to dilate after injections of pitocin, and to stop premature
labor
in certain female patients, allowing them to go through to term.
EP 08664g, the contents of which are incorporated herein by reference,
relates to the molecular cloning and characterization of the gene sequence
coding for porcine relaxin. Thus, recombinant DNA techniques for the
preparation of porcine relaxin were described more than ten years ago.
However, before the advent of the present invention, application of relaxin
has
been restricted essentially to pregnancy- and gynecologically-related uses.
DISCLOSURE OF THE INVENTION
It has now been found in accordance with the present invention that
relaxin and relaxin analog compounds in combination with anti-androgenic
agents (i.e., relaxin plus finasteride, SKL-105657, estrogen, Cyproterone
acetate, spironolactor, Flutamide, topical minoxidil 2 Jo, topical minoxidil
5%,
or RU58841.) can be used to treat and prevent androgenetic alopecia and
related conditions, and thus to encourage hair growth and to prevent hair
loss.
Furthermore, it has been found that relaxin and relaxin analog compounds in
combination with estrogenic hormones prevents hair loss in females.
The term "relaxiri" means human relaxin, including full length relaxin or
a portion of the relaxin molecule that retains biological activity [as
described in
U.S. Pat. No. 5,023,321, preferably recombinant human relaxin (H2)] and
other active agents with relaxin-like activity, such as agents that
competitively
displace bound relaxin from a receptor. Relaxin can be made by any method
known to those skilled in the art, preferably as described in U.S. Pat. No.
4,835,251 or U.S. Pat. No. 5,811,395 issued to Schwabe. The terns "relaxin
analog, " unless stated otherwise, refers to the Asb(B14) analog and
derivatives
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thereof, including full length Asp(B 14) relaxin or a portion of the Asp(B 14)
relaxin molecule that retains biological activity [as described in U.S. Pat.
No.
5,023,321, preferably recombinant human relaxin (H2)] and other active
agents with relaxin-like activity, such as agents that competitively displace
bound relaxin from a receptor.
In one aspect, the invention provides use of relaxin and relaxin analog
compounds in combination with antiandrogenetic agents in the manufacture of
a medicament for the treatment and prevention of androgenetic alopecia and
related conditions (such as atrophy, sclerosis and miniaturization of the hair
and hair follicles). The medicament may comprise the relaxin or relaxin analog
compounds/ anitandrogenetic agent combination in a pharmaceutically
acceptable (i.e., topically acceptable) carrier, and may be used, for example,
for prolonging the duration of the anagen stage of hair growth.
In another aspect of the invention, the invention provides a method for
the treatment and prevention of androgenetic alopecia and related conditions,
which comprises administering to a human in which said treatment or
prevention is desired, an effective amount of relaxin or relaxin compounds. In
this method, relaxin or relaxin compounds may be administered in combination
with a pharmaceutically acceptable (i.e., a topically acceptable) carrier. The
method may thus be used, for example, for the treatement and prevention of a
condition selected from atrophy, sclerosis and miniaturization of the hair and
hair follicles, or for prolonging the duration of the anagen stage of hair
growth.
BEST MODE FOR CARRYING OUT THE INVENTION
As is known in the art, cyclic activity of the hair is divided into three
stages: a period of active growth known as antigen, a short transition phase
called catagen, and a resting period which ends in hair loss, called telogen.
It is also an accepted fact that the percentage of follicles in antigen
rises steeply during pregnancy, when as many as ninety-five percent (95 Jo) of
the follicles are active. Two to four months after parturition, the proportion
falls
to less than seventy percent (70d/o). Therefore, it appears that the hormonal
conditions of late pregnancy prolong antigen. and follicles are consequently
precipitated into telogen via catagen after parturition.
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In hair follicles there are two important enzymes which have a key role
in androgen metabolis; these are (1) 5.alpha.-reductase, and (2) aromatase.
The object of the present invention is to decrease the activity of 5.alpha.-
reductase and increase the activity of aromatase.
The clearest example of systematic influence on the human hair growth
cycle is pregnancy. During pregnancy there is a marked increase in the
proportion of follicles in the anagen phase. After termination of the
pregnancy,
whether by birth or otherwise, large numbers of follicles enter telogen,
thereby
causing shedding (i.e., postpartum telogen effluvium). These changes are
related to the hormonal changes during pregnancy. One of the specific
problems of women with androgenetic alopeciti is polycystic ovary disease, in
which there is an inadequate function or absence of the corpus luteum. It is
the
corpus luteum that is the main source of relaxin.
5.alpha.-reductase converts testosterone to dihydrotestosterone. The
presence of dihydrotestosterone must be limited, in so far as possible.
Limiting
dihydrotestosterone is accomplished by inhibiting the activity of 5.alpha.-
reductase.
Increased activity of aromatase will convert testosterone to estrogens,
such as estrone and estradiol, which is desirable. Aromatase is located
specifically in the outer root sheath in active follicles in quantities 2-5
times
higher in women than in men.
Cytokines are small proteins involved in cell to cell communication.
They include peptide growth factors (i.e., EGF, IGF-1, FGF's, NGF) and
interlukins (i.e., ILI, IL2, TNF's). They have an important role in cell
growth
regulation and differentiation of many cell types, including skin fibroblast
and
keratinocytes. They act through specific cell surface receptors and they have
fast, potent and local action. There are over 50 or more known complex
biological control systems.
Cytokines act as (1) inhibitors of hair growth in vitro (i.e., TGF-BETA, ILI
-ALPHA. ILI-BETA, TNF-ALPHA) and (2) modulators of catagen (i.e., KGF FGF).
There is no single hair growth factor. Hair growth is an interaction
between several different cytokines, however, two cytokines stand out from the
rest in terms of importance: these are IGF-1 and TGF-BETA. IGF-1 maintains
hair follicles in the anagen phase. The follicles enter catagen if IGF-1 is
absent.
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IGF-I and IGF-I-R gene expression declines. TGF-BETA triggers the catagen
phase. It is a potent inhibitor of hair growth in vitro. Relaxin increases IGF-
1
and decreases TGF-BETA therefore it has the desired effect on hair growth and
prevention of hair loss.
It is also known that localized hypertrichosis is associated with an
increase in the cutaneous blood flow and the increase of perfusion caused by
vasodilator may contribute to hair growth: relaxin influences vasodialation
through its influence to increase the nitric oxide level and its activity in
increasing VGF-1 and VGF
From relevant histology we learn that those afflicted with androgenetic
alopecia demonstrate: (1) an increase of 5 alpha.-reductase activity: (2) an
increase in the production of dihydrotestosterone-, (3) lower aromatase
activity:
and (4) reduced production of estradiol. Those afflicted with androgenetic
alopecia also demonstrate inflammation, follicular streamers, dermal and
perifollicular fibrosis, atrophy and sclerosis with net results of
miniturization of
the hair follicle. Moreover, androgenetic alopecia is characterized by a
progressive shortening of the average duration of the anagen phase with net
results of terminal hair transformation into
vellus hair before complete disappearance.
In order to prevent androgenetic alopecia one must look for a substance
that: ( I )will have anti androgenetic effect, such as cyproterone acetate,
spironolactor, Flutamide, all of which are useful for females, and topical
minoxidil 2°~o and SaJo, and all blockers of androgenetic receptors,
such as
RU58841 and blocker of 5.alpha.-reductase such as Finasteride (only for
treatement of males), which are useful for both males and females; (2) will
prolong the duration of the anagen phase and prevent the transfer to the
catagen phase; (3) control the production and the non-production of cytokines;
(4) cause remodelling of the collagen matrix and increase the concentration of
various extracellular components (i.e., proteoglicans and fibronectin
laminin);
and (5) will have a vasodilatory effect on capillary loops of the dermal
papilla,
such as nitric oxide, which is increased in the presence of Relaxin.
Relaxin is a small polypeptide member of the protein hormone family, which
also includes insulin and insulin like growth factors IGF-I and IGF-2. Relaxin
is
expressed during pregnancy and research demonstrates that relaxin: (1) exerts
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a stimulatory synergistic effect on aromatase activity (anti-androgenetic
effect)
in human endometrial stromal cells: (2) promotes growth of porcine granulosa
cells by stimulation of IGF-I; (3) is a potent collagen down regulatory agent
which interrupts collagen expression pretransitionally and at a point in the
collagen induction pathway common to both TGF-BETA and ILI-BETA (two
stimulators of collagen expression); (4) influences molecules of the
extracellular matrix of connective tissue increasing the content of
proteoglycans
in rat uterus and cervix; (5) promotes synthesis of laminin in endothermal
stromal cells in mice; (6) assists in the partial degradation of the fetal
membrane extracellular matrix and causes activation of an enzyme cascade
resulting in remodeling and changes in the structure of this complex matrix;
(7)
exerts a vasodilator effect through stimulation of nitric oxide production in
its
target cells; (8) blocks absorption of calcium by cytoplasmic membranes of the
smooth muscle cells of blood vessel walls; (9) binds with specificity to the
skin,
particularly to the stratum granulosum and the malpighian layer (i.e., strata
spinosum and germinativum) of the epidermis and the outer root of the hair
follicles of pregnant pigs; and (10) prolongs the duration of the anagen phase
and prevents the transfer to the catagen phase.
The patterns of relaxin and relaxin binding cells indicates that in the
hair follicles these patterns may act not only directly as mitogen on the
germinative cells and on the outer root sheath, but also indirectly on the
dermal papilla stimulating the production of growth factors. The binding cells
of relaxin in the outer root sheath indicate that relaxin may play a role in
regulating terminal differentiation.
Relaxin influences the fibroblasts and fibroblast-like cells of the
pilosebacious unit. Relaxin treatment, either topically or systemically, will
result in preventing atrophy, sclerosis and minaturization of the hair, by
prolonging the duration of the anagen stage, or otherwise. It will remodulate
the cutaneous aging process in general and in particular it will remodulate
androgenetic alopecia in both males and females.
According to the present invention, there is provided a composition
which can be applied topically in the form of lotion, ointment, gel or cream,
or
systemically for internal or parenteral use, in the form of capsules, tablets
or
ampules, for treatement of androgenetic alopecia and related conditions such
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as alopecia areata, anagen effluvium, telogen effuvium and post-partum telogen
alopecia, diffuse alopecia, and alopecia androgenetica.
Said compositions can be in the form of lotions, ointments, gels or
creams, prepared for use in any conventional manner, in admixture with one or
more physiologically acceptable carriers and diluents.
The compositions may take such forms as suspensions, solutions, or
emulsions in oily or aqueous vehicles, and may contain agents such as
emulsifying, suspending, stabilizing, gelling and/or dispersing agents.
Alternatively, the active ingredients may be in powder form for constitution
with
a suitable vehicle (i.e., sterile, pyrogen-free water) before use and may
compounded into tablet, powder or capsule form using techniques well known
to those skilled in the formulary art.
While it is possible for the active ingredient combination to be
administered alone, it is preferable to present them as pharmaceutical
formulations. The formulations of the present invention comprise at least one
active ingredient, as above defined, together with one or more acceptable
carriers therefor and optionally other therapeutic ingredients. The carriers)
must be acceptable in the sense of being compatible with the other ingredients
of the formulation and not deleterious to the recipient thereof.
The formulations may conveniently be presented in unit dosage form
and may be prepared by any of the methods well known in the art of pharmacy.
Such methods include the step of bringing into association the active
ingredient
with the carrier, which constitutes one or more accessory ingredients. In
general, the formulations are prepared by uniformly and intimately bringing
into association the active ingredient with liquid carriers or finely divided
solid
carriers, or both, and then, if necessary, shaping the product.
The formulations are preferably applied as a topical lotion, ointment,
gel or cream, containing the active ingredient in a concentration of, for
example, 0.005 to 10.0 percent, preferably 0.01 to 5.0 percent w/w and most
preferably 0.05 to 2.0 percent w/w. When formulated in cream, the active
ingredients may be employed with an oil-in-water cream base.
If desired, the aqueous phase of the cream base may include, for
example, at least thirty percent ( 30°0 ) w/w of a polyhydric alcohol
(i.e., an
alcohol having two or more hydroxyl groups such as propylene glycol, butane-
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1,3-diol. Mannitol, sorbitol, glycerol and polyethylene glycol and mixtures
thereof. The topical formulations many desirably include a compound which
enhances absorption or penetration of the active ingredient through the skin
or
other affected areas. Examples of such dermal penetration enhancers include
dimethylsulphoxide and related analogues.
The oily phase of the emulsions of this invention may be constituted
from known ingredients in a known manner. The oil phase may comprise
merely an emulsifier it desirably comprises a mixture of at least one
emulsifier
with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic
emulsifier is included together with a lipophilic emulsifier, which acts as a
stabilizer. It is also preferred to include both an oil and a fat. Together,
the
emulsifier(s), with or without stabilizers(s), make up the so-called
emulsifying
wax, and the wax, together with the oil and/or fat, make up the so-called
emulsifying ointment base, which forms the oily dispersed phase of the cream
formulations.
Emulgents and emulsion stabilizers suitable for use in the formulation
of the present invention include Tween 60. Span 80, cetostearyl alcohol,
myristyl alcohol, glycerl monostearate and sodium lauryl sulphate.
The choice of suitable oils or fats for the formulation is based on
achieving the desired cosmetic properties, because the solubility of the
active
compound in most oils likely to be used in pharmaceutical emulsion
formulations is very low. Therefore, the cream should preferably be a
non-greasy, non-staining and washable product with suitable consistency to
avoid leakage from tubes or other containers. Straight or branched chain,
mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate,
propylene
glycol diester or coconut fatty acids, isopropyl myristate, decyl oleate, iso-
propyl palmitate, butyl stearate, 3-ethylhexyl palmitate, or a
blend of branched chain esters known as Crodamol CAP may be used, the last
three being preferred esters. These may be used alone or in combination,
depending on the properties required. Alternatively, high melting-point
lipids,
such as white soft paraffin and/or liquid paraffin, or other mineral oils, can
be
used.
While the invention will now be described in connection with certain
preferred embodiments in the following examples so that aspects thereof may
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be more fully understood and appreciated, it is not intended to limit the
invention to these particular embodiments. On the contrary, it is intended to
cover all alternatives, modifications and equivalents as may be included
within
the scope of the invention as defined by the appended claims. Thus, the
following examples, which include preferred embodiments, will serve to
illustrate the practice of this invention, it being understood that the
particulars
shown are by way of example and for purposes of illustrative discussion of
preferred embodiments of the present invention only and are presented in the
cause
of providing what is believed to be the most useful and readily understood
description of formulation procedures as well as of the principles and
conceptual aspects of the invention.
EXAMPLE 1
Lotion
Relaxin 100 mg
cyproterone acetate100 mg
Deionizcd water 850 ml
Ethanol 150 ml
The Relaxin and anti-adnogenetic agent were dissolved in the mixture of
solvents.
EXAMPLE 2
Gel
Relaxin 20 mg
Flutamide 10 mg
Deionized water 49.0 g
Ethanol 49.0 g
Carbomer 934 P 0.5 g
Triethanolamine 0.5 g
The Relaxin was dissolved in the water/alcohol mixture. The carbomer was
dispersed in the solution and the triethanolainine was added while agitating
constantly.
EXAMPLE 3
Gel
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Relaxin 5.0 mg
Spironolactor 5.0 mg
Deionizcd water 83.9 g
Ethanol 75.0 g
Carborner 934 P 0.25 g
HPMC 4000 cps 0.6 g
Triethanolaminc 0.25 g
The Relaxin and HPMC were dissolved in the water and the alcohol was added.
The carbomer was dispersed in the solution and triethanolamine was added
while agitating.
EXAMPLE 3a
Gel
Relaxin 5.0 mg
Minoxidil 1.0 mg
Deionized water 83.9 g
Ethanol 75.0 g
Carbomer 934 P 0.25 g
HPMC 4000 cps 0.6 g
Triethanolamine 0.25 g
The Relaxin and minoxidil and HPMC were dissolved in the water and the
alcohol was added. The carbomer was dispersed in the solution and the
triethanolamine was added while agitating.
EXAMPLE 3b
Gel
Relaxin 5.0 mg
Dihydrotestosterone3.0 mg
Deionized water 83.9 g
Ethanol 75.0 g
Carborner 934 P 0.25 g
HPMC 4000 cps 0.60 g
Triethanolamine 0.25 g
The active ingredients were dissolved in the water and the alcohol was added.
The carbomer was dispersed in the solution and triethanolamine was added
while agitating.
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EXAMPLE 4
Cream
Relaxin 1.0 g
Estrogen 200 mg
Cetylester wax 2.0 g
Polysorbate 60 1.0 g
Paraffin oil 10.0 g
Carbomer 934 P 1.0 g
Glycerol 5.0 g
Potassium sorbate 0.2 g
Ammonia 25aJo 0.7 g
Deionized water to 100 g
The Relaxin, potassium sorbate, and glycerol were dissolved in water and the
carbomer was dispersed in the solution, at room temperature. The cetylester
wax, polysorbate and paraffin oil were heated to dissolve, and were mixed with
the aqueous portion at room temperature. Ammonia was added to gel the
carbomer.
EXAMPLE 5
Ta blets
Quantities per tablet
Relaxin 100 mg
Minoxidil 50 mg
Lactose 180 mg
Polyvinylpyrrolidone 10 mg
Sodium starch glycollate75 mg
Magnesium stearate 125 mg
The Relaxin and the polyvinylpytrolidone were dissolved in a quantity of
deionized water and the lactose and sodium starch glycollate were granulated
in accordance with normal procedure. The granulation was dried and the
magnesium stearate added. The mixture was compressed into tablets.
EXAMPLE 6
Capsules
Quantities per capsule:
Relaxin 20 mg
Minoxidil 20 mg
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Microcrystalline cellulose 100 mg
Colloidal silicon dioxide 3 mg
The ingredients were thoroughly blended and filled into hard gelatin capsules.
Capsules with 25 to 200 mg of dihydrotestosterone in addition to relaxin can
be compounded as well.
EXAMPLE 7
Ampoules or Multidose Ampoules
- Relaxin analog 50 mg
Flutamide 25 mg
Benzyl alcohol 20 mg
Water for injection to I ml
The ingredients were dissolved in the water for injection and the solution
sterilized by filtration. The ampoules were filled and sealed under aseptic
conditions
EXAMPLE 8
Implant
Relaxin 200 mg
Progesterone 150 mg
In a suitable non-toxic medium (i.e., silicon polymer) to act as an embedding
agent.
EXAMPLE 9
Slow Release Patch
This is spread onto a polyester layer with an adhesive such as poly-
isobutylene,
and covered with a siliconized polyester release liner.
EXAMPLE 10
Shampoo
- Relaxin analog 1.0
g
Spimnolactor 0.5
g
Sodium lauryl ether suphate 30
g
Dicthanolamine of coconut oil 6 g
fatty acids
Water 62
g
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It will he evident to those skilled in the art that the invention is not
limited to the details of the foregoing illustrative examples and that the
present
invention may be embodied in other specific forms without departing from the
essential attributes thereof, and it is therefore desired that the present
embodiments and examples be considered in all respects as illustrative and not
restrictive, reference being made to the appended claims, rather than to the
foregoing description, and all changes which come within the meaning and
range of equivalency of the claims are therefore intended to be embraced
therein.
Further Examples of Mixtures of Active Components
Below are specific active component mixtures that will be useful in the
practice of the invention:
Example A1
Cyproterone acetate 2 mg
Relaxin 2 mg
Ethinylestadiol 0.035 mg
Examel_e A2
Gestodene 0.075 mg
Relaxin 2 mg
Example A3
Gestodene 75 mcg
Ethinylestadiol 20 mcg
Relaxin 1750 mcg
Exam~l_e A4
Ethinylestadiol 0.020 mg
Desorgestel 0.150 mg
Relaxin 0.70 mg
Exam .ale A5
Finasteride 1.0 mg
Relaxin 2.0 mg
17
