Title: Treatment of conditions
relating to hormone deficiencies by administration of progestins
United States Patent: 7,427,609
Issued: September 23, 2008
Inventors: Leonard; Thomas
W. (Wilmington, NC)
Laboratories, Inc. (Woodcliffe Lake, NJ)
Appl. No.: 10/678,828
Filed: October 3, 2003
Pharm Bus Intell
& Healthcare Studies
The present invention includes methods
for preventing endometrial hyperplasia associated with estrogen therapy
through the administration of a progestin agent. The methods presented may
include starting the administration of a progestin agent at a high dose,
and then lowering the dose.
Description of the
SUMMARY OF THE INVENTION
The present invention relates to a method for treating conditions related to
hormone deficiencies comprising continuously administering at least one
estrogen and at least one progestin wherein the amount of estrogen is
substantially constant and the amount of progestin is decreased in at least
one step from an amount sufficient to establish a nonproliferative
endometrium to an amount that maintains the nonproliferative endometrium.
The present invention particularly relates to methods for treating physical
conditions related to vasomotor symptoms, brought about by the onset of
menopause. The method of the invention provides a method of treating a
subject by administering a therapeutically effective amount of two or more
dosage levels of progestin wherein the dosage levels of progestin decrease
stepwise during the treatment period. The conditions treated include
vasomotor symptoms, atrophic vaginitis, and osteoporosis, among: others.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described with reference to the embodiments set
forth herein. These embodiments are intended to illustrate the invention and
are not meant to limit the scope of the invention.
In one aspect, the invention relates to a method of administering a
pharmaceutical composition. The pharmaceutical composition comprises a
therapeutically effective amount of a progestin agent and a pharmaceutically
acceptable carrier. Additionally, the composition may contain an estrogenic
compound. The composition also may contain an androgenic compound.
A "therapeutically effective" amount as used herein is an amount of an
estrogenic compound that is sufficient to ameliorate symptoms exhibited by a
subject. The therapeutically effective amount will vary with the age and
physical condition of the patient, the severity of the condition of the
patient being treated, the duration of the treatment, the nature of any
concurrent treatment, the pharmaceutically acceptable carrier used and like
factors within the knowledge and expertise of those skilled in the art.
Pharmaceutically acceptable carriers are preferably solid dosage forms such
as tablets or capsules. Liquid preparations for oral administration also may
be used and may be prepared in the form of syrups or suspensions, e.g.,
solutions containing an active ingredient, sugar, and a mixture of ethanol,
water, glycerol, and propylene glycol. If desired, such liquid preparations
may include one or more of following: coloring agents, flavoring agents, and
saccharin Additionally, thickening agents such as carboxymethylcellulose
also may be used as well as other acceptable carriers, the selection of
which are known in the art.
A progestin agent may be used in combination with the estrogenic compound.
Examples of progestin agents are set forth in U.S. Pat. No. Re. 36,247 to
Plunkett et al. Examples include, but are not limited to, dl-norgestrel,
norethindrone (norethisterone), norethindrone (norethisterone) acetate,
ethynodiol diacetate, dydrogesterone, medroxyprogesterone acetate,
norethynodrel, allylestrenol, lynoestrenol, quingestanol acetate,
medrogestone, norgestrienone, dimethisterone, ethisterone, cyproterone
acetate, desogestrel, levonorgestrel, hydroxyprogesterone caproate,
19-nortestosterone, chlormadinone acetate, megestrol acetate, norgestimate,
norgestrel, trimegestone, gestodene, normegestrel acetate, progesterone,
5.alpha.-pregnan-3.beta., 20.beta.-diol sulfate,
As stated above, an estrogenic compound may be combined with the progestin
agent. Estrogen levels are related to the general physiological health of
menopausal, perimenopausal, and postmenopausal women. They exert positive
central nervous system (CNS) effects on hot flashes, and improve nerve
transmission, which is believed to delay various types of dementia. They
have positive cardiovascular effects by improving lipid levels and promoting
vasodilation and relaxation. They also contribute to health of the vagina,
provide local vasodilation effects and stimulate mucous production. Suitable
estrogenic compounds include estrone, 17.alpha.-estradiol,
17.beta.-estradiol, equilin, 17.alpha.-dihydroequilin,
17.beta.-dihydroequilin, equilenin, 17.alpha.-dihydroequilenin,
17.beta.-dihydroequilenin, .DELTA..sup.8,9-dehydroestrone, 17.alpha.
.DELTA..sup.8,9-dehydroestradiol, 17.beta. .DELTA..sup.8,9-dehydroestradiol,
6-OH equilenin, 6-OH 17.alpha.-dihydroequilenin, ethinyl estradiol,
estradiol valerate, 6-OH 17.beta.-dihydroequilenin, and mixtures, conjugates
and salts thereof, and the estrogen ketones and their corresponding
17.alpha.- and 17.beta.-hydroxy derivatives.
The estrogenic compounds also may be present as conjugated estrogens.
Approximately 1.0 mg of 17.beta.-estradiol is equivalent to 0.625 mg of
conjugated estrogens. The conjugates may be various conjugates understood by
those skilled in the art, including, but not limited to, sulfate and
glucuronide. The most preferred estrogen conjugates are estrogen sulfates.
The estrogenic compounds also may be present as salts of estrogens
conjugates. The salts may be various salts understood by those skilled in
the art, including, but not limited to, sodium salts, calcium salts,
magnesium salts, lithium salts, and piperazine salt. The most preferred
salts are sodium salts. The estrogenic compounds can be derived from natural
and synthetic sources. Preferably, the therapeutically effective amount of
estrogenic compound is about 0.05 to about 3 mg, and preferably about 0.5 to
about 2 mg based on oral dose equivalents of estradiol.
The amount of estrogen utilized preferably will remain substantially
constant throughout the treatment period. In one aspect of the invention,
the amount of estrogen will be an amount equivalent to from about 0.05 to
about 5 mg conjugated estrogens. In a preferred aspect of the invention, the
amount of estrogen will be an amount equivalent to from about 0.15 to about
1.25 mg conjugated estrogens for solid doses and 0.01 to 1 mg for topical
and transdermal doses. In a more preferred aspect of the invention, the
amount of estrogen will be at either an oral dosing strength of an
equivalent of about 0.45 mg conjugated estrogens or an equivalent of about
0.625 mg conjugated estrogens.
The therapeutically effective dosage of any specific compound, the use of
which is in the scope of present invention, will vary from compound to
compound and patient to patient and condition to condition, and will depend
upon factors such as the age, weight, and condition of the patient and the
route of delivery. As a general proposition, a dosage from about 0.001 or
0.1 mg/kg to about 50, 100 or 500 mg/kg may have therapeutic efficacy, with
all weights being calculated based upon the weight of the active compound,
including the cases where a salt is employed.
Androgenic compounds may be combined with the progestin agents and
estrogenic compounds. Suitable androgenic compounds include both aromatizing
and non-aromatizing compounds. Acceptable compounds include, but are not
limited to, methyltestosterone, androsterone, androsterone acetate,
androsterone propionate, androsterone benzoate, androsteronediol,
androsteronediol-3-acetate, androsteronediol-17-acetate, androsteronediol
3-17-diacetate, androsteronediol-17-benzoate, androsteronedione,
androstenedione, androstenediol, dehydroepiandrosterone, sodium
dehydroepiandrosterone sulfate, dromostanolone, dromostanolone propionate,
ethylestrenol, fluoxymesterone, nandrolone phenpropionate, nandrolone
decanoate, nandrolone furylpropionate, nandrolone cyclohexane-propionate,
nandrolone benzoate, nandrolone cyclohexanecarboxylate,
androsteronediol-3-acetate-17-benzoate, oxandrolone, oxymetholone,
stanozolol, testosterone, testosterone decanoate, 4-dihydrotestosterone,
17.alpha.-methyl-19-nortestosterone, xandrolone, oxymetholone, stanozolone,
danazol, and pharmaceutically acceptable esters and salts thereof, as well
as combinations of any of the foregoing. Preferably, the therapeutically
effective amount of the androgenic compound is about 0.15 to about 10 mg.
For women suffering from androgen deficiency the oral dosage equivalents of
oxandrolone is about 0.5 to 5 mg of an androgenic compound per day.
Additionally, preferably the therapeutically effective amount of the
androgenic compound is equivalent to oral doses of about 0.15 to about 2.5
mg of methyl testosterone.
The estrogen formulations of the present invention may be, for example, in
the form of tablets; effervescent tablets; pills; powders; elixirs;
suspensions; emulsions; solutions; syrups; soft and hard gelatin capsules;
transdermal patches; topical gels, creams and the like; vaginal
suppositories such as gels and creams and the like; sterile injectable
solutions; and sterile packaged powders, sublingual tablets, buccal tablets
and buccal adhesive systems.
In certain embodiments, the drug product is present in a solid
pharmaceutical composition that may be suitable for oral administration. A
solid composition of matter according to the present invention may be formed
and may be mixed with and/or diluted by an excipient. The solid composition
of matter also may be enclosed within a carrier, which may be, for example,
in the form of a capsule, sachet, tablet, paper, or other container. When
the excipient serves as a diluent, it may be a solid, semi-solid, or liquid
material which acts as a vehicle, carrier, or medium for the composition of
Various suitable excipients will be understood by those skilled in the art
and may be found in the National Formulary, 19: 2404-2406 (2000), the
disclosure of pages 2404 to 2406 being incorporated herein in their
entirety. Examples of suitable excipients include, but are not limited to,
starches, gum arabic, calcium silicate, microcrystalline cellulose,
methacrylates, shellac, polyvinylpyrrolidone, cellulose, water, syrup, and
methylcellulose. The drug product formulations additionally can include
lubricating agents such as, for example, talc, magnesium stearate and
mineral oil; wetting agents; emulsifying and suspending agents; preserving
agents such as methyl- and propyl hydroxybenzoates; sweetening agents; or
flavoring agents. Polyols, buffers, and inert fillers also may be used.
Examples of polyols include, but are not limited to, mannitol, sorbitol,
xylitol, sucrose, maltose, glucose, lactose, dextrose, and the like.
Suitable buffers include, but are not limited to, phosphate, citrate,
tartarate, succinate, and the like. Other inert fillers that may be used
include those that are known in the art and are useful in the manufacture of
various dosage forms. If desired, the solid formulations may include other
components such as bulking agents and/or granulating agents, and the like.
The drug products of the invention may be formulated so as to provide quick,
sustained, or delayed release of the active ingredient after administration
to the patient by employing procedures well known in the art.
To form tablets for oral administration, the composition of matter of the
present invention may be made by a direct compression process. In this
process, the active drug ingredients may be mixed with a solid, pulverant
carrier such as, for example, lactose, saccharose, sorbitol, mannitol,
starch, amylopectin, cellulose derivatives or gelatin, and mixtures thereof,
as well as with an antifriction agent such as, for example, magnesium
stearate, calcium stearate, and polyethylene glycol waxes. The mixture may
then be pressed into tablets using a machine with the appropriate punches
and dies to obtain the desired tablet size. The operating parameters of the
machine may be selected by the skilled artisan. Alternatively, tablets for
oral administration may be formed by a wet granulation process. Active drug
ingredients may be mixed with excipients and/or diluents. The solid
substances may be ground or sieved to a desired particle size. A binding
agent may be added to the drug. The binding agent may be suspended and
homogenized in a suitable solvent. The active ingredient and auxiliary
agents also may be mixed with the binding agent solution. The resulting dry
mixture is moistened with the solution uniformly. The moistening typically
causes the particles to aggregate slightly, and the resulting mass is
pressed through a stainless steel sieve having a desired size. The mixture
is then dried in controlled drying units for the determined length of time
necessary to achieve a desired particle size and consistency. The granules
of the dried mixture are sieved to remove any powder. To this mixture,
disintegrating, antifriction, and/or anti-adhesive agents may be added.
Finally, the mixture is pressed into tablets using a machine with the
appropriate punches and dies to obtain the desired tablet size. The
operating parameters of the machine may be selected by the skilled artisan.
If coated tablets are desired, the above prepared core may be coated with a
concentrated solution of sugar or cellulosic polymers, which may contain gum
arabic, gelatin, talc, titanium dioxide, or with a lacquer dissolved in a
volatile organic solvent or a mixture of solvents. To this coating various
dyes may be added in order to distinguish among tablets with different
active compounds or with different amounts of the active compound present.
In a particular embodiment, the active ingredient may be present in a core
surrounded by one or more layers including enteric coating layers.
Soft gelatin capsules may be prepared in which capsules contain a mixture of
the active ingredient and vegetable oil. Hard gelatin capsules may contain
granules of the active ingredient in combination with a solid, pulverulent
carrier, such as, for example, lactose, saccharose, sorbitol, mannitol,
potato starch, corn starch, amylopectin, cellulose derivatives, and/or
In one preferred embodiment, the formulation is in the form of
orally-administered tablets that contain the composition of matter of the
present invention as set forth herein along with the following inactive
ingredients: calcium phosphate tribasic, calcium sulfate, carnauba wax,
cellulose, glyceryl monooleate, lactose, magnesium stearate, methylcellulose,
pharmaceutical glaze, polyethylene glycol, stearic acid, sucrose, and
titanium dioxide. Such ingredients may be present in amounts similar to
those present in Premarin.RTM. (conjugated estrogens tablets, USP) made
commercially available by Wyeth-Ayerst Laboratories of Philadelphia, Pa.
Tablets employing the active ingredients of the invention may contain
excipients similar to those contained in the 0.3 mg, 0.625 mg, and 1.25 mg
tablets of Premarin.RTM. (conjugated estrogens tablets, USP).
Liquid preparations for oral administration may be prepared in the form of
syrups or suspensions, e.g., solutions containing an active ingredient
sugar, and a mixture of ethanol, water, glycerol, and propylene glycol. If
desired, such liquid preparations may comprise one or more of following:
coloring agents, flavoring agents, and saccharin. Thickening agents such as
carboxymethylcellulose also may be used.
In the event that the above pharmaceuticals are to be used for parenteral
administration, such a formulation may comprise sterile aqueous injection
solutions, non-aqueous injection solutions, or both, comprising the
composition of matter of the present invention. When aqueous injection
solutions are prepared, the composition of matter may be present as a water
soluble pharmaceutically acceptable salt. Parenteral preparations may
contain anti-oxidants, buffers, bacteriostats, and solutes which render the
formulation isotonic with the blood of the intended recipient. Aqueous and
non-aqueous sterile suspensions may comprise suspending agents and
thickening agents. The formulations may be presented in unit-dose or
multi-dose containers, for example sealed ampules and vials. Extemporaneous
injection solutions and suspensions may be prepared from sterile powders,
granules and tablets of the kind previously described.
In a preferred embodiment, the drug product of the present invention is in
the form of an injectable solution containing a predetermined amount (e.g.,
25 mg) of the composition of matter in a sterile lyophilized cake that also
contains lactose, sodium citrate, and simethicone. The pH of a solution
containing the above ingredients may be adjusted using a suitable buffer
(e.g., sodium hydroxide or hydrochloric acid). Reconstitution may be carried
out according to known methods, e.g., using a sterile diluent (5 mL)
containing 2 percent by volume benzyl alcohol in sterile water. A preferred
injectable solution is similar to Premarin.RTM. Intravenous made
commercially available by Wyeth-Ayerst Laboratories.
The composition of matter also may be formulated such that it may be
suitable for topical administration (e.g., vaginal cream). These
formulations may contain various excipients known to those skilled in the
art. Suitable excipients may include, but are not limited to, cetyl esters
wax, cetyl alcohol, white wax, glyceryl monostearate, propylene glycol,
monostearate, methyl stearate, benzyl alcohol, sodium lauryl sulfate,
glycerin, mineral oil, water, carbomer, ethyl alcohol, acrylate adhesives,
polyisobutylene adhesives, and silicone adhesives.
The drug product may be in the form of a vaginal cream containing the
composition of matter as set forth herein present in a nonliquefiing base.
The nonliquefying base may contain various inactive ingredients such as, for
example, cetyl esters wax, cetyl alcohol, white wax, glyceryl monostearate,
propylene glycol monostearate, methyl stearate, benzyl alcohol, sodium
lauryl sulfate, glycerin, propylene glycol and mineral oil. Such composition
may be formulated similar to Premarin.RTM. Vaginal Cream made commercially
available by Wyeth-Ayerst Laboratories.
Dosage units for vaginal or rectal administration may be prepared in the
form of suppositories that may contain the composition of matter in a
mixture with a neutral fat base, polyethylene glycol, or they may be
prepared in the form of gelatin-rectal capsules that contain the active
substance in a mixture with a vegetable oil or paraffin oil.
In the treatment of conditions relating to hormone deficiencies such as in
the treatment of menopausal symptoms or in hormone replacement therapy, one
issue of relative importance includes the absence of spotting or
breakthrough bleeding when a subject takes a progestin agent. The methods
and preparations of the present invention may be useful in alleviating
menopausal symptoms and in providing long-term benefits and protection for
women with decreasing hormone levels. The present invention also may provide
a long-term solution to spotting and bleeding problems manifested with other
treatment regimens. The present invention includes methods that may solve
problems with spotting and bleeding during an estrogen treatment period. A
reduction in bleeding may occur by initiating therapy with a progestin dose
higher than that required to maintain therapy. The methods of the present
invention also may maintain a substantially atrophic endometrium. Although
traditional therapies utilized low progestin dosages, the present invention
discloses that by providing a higher dose of progestin during a first
portion of the treatment period and then lowering the dose of progestin to a
maintenance dose, a reduction in spotting and bleeding problems may occur.
The higher dose initiation period may extend from about seven days to about
two months and may be stepped down gradually to a maintenance dose, or can
be stepped down in one, two or more stages, as is known in the art.
In one embodiment, the first phase or initiation step of the treatment
period may assist in controlling or inhibiting the estrogen induced
proliferation of the endometrium of the uterus during the initiation of
hormone replacement therapy and facilitate development of an atrophic
endometrium. Once the controlling or inhibiting has been achieved, the step
down in dosage of progestin may help maintain a substantially atrophic
endometrium. Additionally, an initial dose of up to at least 400 mg of a
progestin agent, based on dose equivalents to orally administered megestrol
acetate may be administered to achieve a substantially atrophic endometrium.
The methods, preparations and pharmaceutical products of the present
invention may provide for at least two or more dosage strengths over the
course of the treatment period such that the dosages, when administered as
provided herein, may result in an acceptable bleeding pattern. The initial
dosing of the progestin may be relatively high to assist in inducing or
establishing a nonproliferative endometrium. Typically, this effect may be
evidenced by an absence of substantive mitotic activity. The dosing may be
used to enhance the formation of nonproliferative endometrium and results in
a reduction of random bleeding during the remainder of the treatment period.
This dosage strength typically is administered for about 7 to about 120
days. This time period may be less than 7 days depending on the dosage.
Administration of a high dosage may allow for a shorter initial period. The
dosage amount of progestin is then either gradually reduced in a series of
steps or is reduced in one step to a maintenance amount that is less than
the initiation amount. The maintenance dose preferably is at least about 25%
less than the initial dose and, most preferably, the maintenance amount is
about half of the initiation dosage. More preferably the second dose is at
least a 50% reduction than the initial dose of progestins. Subsequent doses
may be greater than 50%, i.e., administering 400 mg in the first dose and
dropping the dose all the way to 2 mg. At this point in the treatment
period, the dosage amount is such that the nonproliferative or atrophic
endometrium is maintained or continued. This dosage amount of progestin
inhibits or decreases the potential for breakthrough bleeding and spotting,
typical problems in traditional therapies. This dosage strength is typically
administered for about two to four weeks for short-term therapies or may be
administered indefinitely for longer therapies. The treatment period ends
upon cessation of administration of the estrogen and progestin therapy.
In one embodiment of the invention, the amount of progestin is provided in
an initiation step of the treatment period in an amount exhibiting progestin
activity equivalent to above 10.0 mg of megestrol acetate and is provided in
a maintenance step during the treatment period in an amount exhibiting
progestin activity equivalent to below about 10.0 mg of megestrol acetate.
Preferably, the amount of progestin activity is reduced by at least 25%;
most preferably the amount of progestin is 50% the amount in the maintenance
step as the amount in the initiation step. In another aspect of the
invention, the amount of progestin preferably is decreased in a series of
steps to the maintenance step wherein the progestin activity is about half
the amount administered in the initiation dosage.
In another embodiment of the invention, the progestin is provided in an
initiation step of the treatment in an amount exhibiting progestin activity
equivalent to an oral dose of about 1 mg to about 40 mg of megestrol acetate
and is provided in a maintenance step during the treatment period in an
amount exhibiting progestin activity equivalent to an oral dose of about 0.5
to about 10 mg of megestrol acetate; provided, however, that the amount of
progestin activity is reduced in the maintenance step by at least 25%; most
preferably the amount of progestin is 50% the amount in the maintenance step
as the amount in the initiation step. A third step is most preferably
reduced by an additional 50% from the second step.
In another embodiment of the present invention, the amount of progestin when
the amount of estrogen is about 0.625 mg, may be either about 6 mg or about
12 mg in the initiation step and about 3 mg or about 6 mg, respectively, in
the remaining or maintenance step of the treatment period. When the amount
of estrogen is about 0.45 mg, the amount of progestin is preferably 5 mg or
10 mg, respectively, in the initiation step of the treatment period and
approximately 2.5 mg or 5 mg in the remaining step or maintenance step of
the treatment period. All amounts of progestin are in terms of biological
equivalence to oral doses of megestrol acetate and all amounts of estrogen
are in terms of biological equivalence to oral doses of conjugated
estrogens. One skilled in the art will be able to compare the dose
equivalency tables should they choose a progestin outside of megestrol
Thus, the methods used in the present invention may include reducing the
amount of a progestin given to a subject by starting out administering a
high dose of a progestin agent to a subject and then gradually lowering the
dose once therapy has been effectively established. One skilled in the art
will be able to use a number of permutations in that the dosage of the
progestin agent may be lowered. Additionally, once therapy has been
effectively established it may be possible to continue the step-down therapy
as disclosed above by decreasing the amount of progestin agent in a third or
fourth dose. One skilled in the art will be able to choose additional
regimens based upon this information.
The first dose may be administered daily, continuously and uninterruptedly
for an effective time period until such time that therapy has been
effectively established, preferably one week to two months, more preferably
two to six weeks.
The initiation dosage amount of progestin may be sufficient to enhance
formation of or may help establish a nonproliferative or atrophic
endometrium. The treatment may further substantially induce bleeding and
then obviate or reduce random bleeding. The maintenance dosage amount is
sufficient and effective for continuing or maintaining the nonproliferative
endometrium established by the initiation dosage of progestin. The
maintenance dosage amount further inhibits and decreases breakthrough
bleeding and spotting observed in traditional therapies.
The methods may be used for a number of treatments such as, but not limited
to, vasomotor symptoms; atrophic vaginitis; osteoporosis; hypoestrogenism
due to hypogonadism, castration, or other primary ovarian failure, among
others. The administration of estrogen and progestin according to the
present invention may be continuous for a short-term, for example, to treat
vasomotor symptoms, or may be continuous for a long-term, for example for
osteoporosis. One example of long-term use would be from the onset of
menopause until death.
The pharmaceutical product of the invention may be provided in a variety of
forms, such that the sequential dosage units may be easily accessible by a
subject. For example, the pharmaceutical product may be provided as a
pharmaceutical package containing the sequential dosages in an arrangement
suitable for daily administration of the appropriate dosages of estrogen and
progestin. The number of dosages in each package may depend on the therapy
and whether it is a long-term therapy for hormone deficiencies, or a
short-term therapy. Typically, the pharmaceutical product may include a kit
or package with daily dosages arranged for proper sequential administration.
The sequence or arrangement of the dosage units will correspond to the
stages of daily administration.
The present invention is primarily concerned with the treatment of human
subjects, but the invention also may be carried out on animal subjects,
particularly mammalian subjects such as mice, rats, dogs, cats, livestock
and horses for veterinary purposes, and for drug screening and drug
Claim 1 of 14 Claims
1. A method of treating vasomotor
symptoms comprising: administering continuously and uninterruptedly a dose
of a therapeutic amount of an estrogenic compound to a subject;
administering continuously and uninterruptedly a dose of a therapeutic
amount of a progestin agent to a subject for about 7 to about 120 days;
and administering continuously and uninterruptedly a second dose of a
therapeutic amount of a progestin agent at a later time period to the
subject for at least about two weeks, said second dose comprising a lower
dosage of said therapeutic amount of a progestin agent than said first
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