U.S. patent application number 12/125606 was filed with the patent office on 2008-11-20 for methods and devices for the sustained release of multiple drugs.
This patent application is currently assigned to The General Hospital Corporation d/b/a Massachusetts General Hospital, The General Hospital Corporation d/b/a Massachusetts General Hospital. Invention is credited to William F. Crowley, JR., Robert S. Langer, Eyal S. Ron.
Application Number | 20080286339 12/125606 |
Document ID | / |
Family ID | 33423604 |
Filed Date | 2008-11-20 |
United States Patent
Application |
20080286339 |
Kind Code |
A1 |
Ron; Eyal S. ; et
al. |
November 20, 2008 |
METHODS AND DEVICES FOR THE SUSTAINED RELEASE OF MULTIPLE DRUGS
Abstract
The invention relates to an drug delivery device and a method
for delivering multiple drugs over a prolonged period of time. The
drug delivery device has two or more unitary segments comprising a
drug-permeable polymeric substance, wherein at least one of the
segments further comprises a pharmaceutically active agent. The
invention also relates to a method for the treatment of a benign
ovarian secretory disorder in a female mammal, a method of
contraception, and a method of relieving the symptoms associated
with menopausal, perimenopausal and post-menopausal periods in a
woman.
Inventors: |
Ron; Eyal S.; (Lexington,
MA) ; Langer; Robert S.; (Newton, MA) ;
Crowley, JR.; William F.; (Newtonville, MA) |
Correspondence
Address: |
NUTTER MCCLENNEN & FISH LLP
WORLD TRADE CENTER WEST, 155 SEAPORT BOULEVARD
BOSTON
MA
02210-2604
US
|
Assignee: |
The General Hospital Corporation
d/b/a Massachusetts General Hospital
Boston
MA
Massachusetts Institute of Technology
Cambridge
MA
|
Family ID: |
33423604 |
Appl. No.: |
12/125606 |
Filed: |
May 22, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10835414 |
Apr 29, 2004 |
|
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12125606 |
|
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|
|
60466318 |
Apr 29, 2003 |
|
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60473579 |
May 27, 2003 |
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Current U.S.
Class: |
424/432 ;
514/182 |
Current CPC
Class: |
A61K 31/565 20130101;
A61F 6/08 20130101; A61K 38/09 20130101; Y10S 514/843 20130101;
A61K 31/57 20130101; A61P 5/30 20180101; A61K 45/06 20130101; A61K
38/09 20130101; A61P 15/00 20180101; A61K 31/57 20130101; A61P
15/02 20180101; A61K 9/0056 20130101; A61P 5/24 20180101; A61K
31/565 20130101; A61F 6/142 20130101; A61K 9/0036 20130101; A61P
15/18 20180101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
424/432 ;
514/182 |
International
Class: |
A61F 6/14 20060101
A61F006/14; A61K 31/565 20060101 A61K031/565 |
Claims
1. A method of treating a decrease in estrogen secretion in a woman
exhibiting symptoms of a cessation of cyclical ovulation, which
method comprises: (a) providing a drug delivery device comprising a
first segment and a second segment, wherein said first segment
comprises a drug-permeable polymeric substance and a hormone
replacement steroid, and wherein said second segment comprises a
drug-permeable polymeric substance and progestational steroid; and
(b) inserting into the vagina of said woman the drug delivery
device of step (a) to release an effective amount of the hormone
replacement steroid to said woman.
2. The method of claim 1, wherein the hormone replacement steroid
is an estrogenic steroid.
3. The method of claim 2, wherein the estrogenic steroid is
selected from the group consisting of estradiol, estradiol
benzoate, estradiol cypionate, estradiol dipropionate, estradiol
enanthate, conjugated equine estrogen, estriol, estrone, estrone
sulfate, ethinyl estradiol, estrofurate, quinestrol and
mestranol.
4. The method of claim 2, wherein the estrogenic steroid is
selected from the group of selective estrogenic receptor modulators
consisting of tamoxifen, raloxifene, clomiphene, droloxifene,
idoxifene, toremifene, tibolone, ICI 182,780, ICI 164,384,
diethylstilbesterol, genistein, nafoxidine, moxestrol,
19-nor-progesterone derivatives, and 19-nor-testosterone
derivatives.
5. The method of claim 1, further comprising a third segment,
wherein said third segment comprises a drug-permeable polymeric
substance and an androgen or a selective androgen receptor
modulator (SARM).
Description
RELATED APPLICATION(S)
[0001] This application is a divisional application of U.S. patent
application Ser. No. 10/835,414, filed on Apr. 29, 2004, entitled
"Methods and Devices for the Sustained Release of Multiple Drugs,"
which claims the benefit of U.S. Provisional Application No.
60/466,318, filed on Apr. 29, 2003 and U.S. Provisional Application
No. 60/473,579, filed on May 27, 2003. The entire teachings of the
above applications are incorporated herein by reference.
FIELD
[0002] The invention relates to drug delivery devices for the
simultaneous release of multiple drugs in a substantially constant
ratio over a prolonged period of time. More specifically the
invention relates to intravaginal devices and methods for
contraception, hormone replacement therapy, and therapeutic methods
for the treatment of reproductive conditions and disorders, such as
benign ovarian secretory disorders.
BACKGROUND
[0003] The desirability of sustained release drug formulations has
long been a goal in the pharmaceutical industry. Sustained release
systems solve many of the problems associated with conventional
drug delivery systems, e.g., pills. For example in conventional
drug delivery systems administration of the drug is given
frequently and results in high variability in circulating drug
levels during the course of treatment. The concentration of the
drug increases to therapeutic concentrations after administration,
but in some instances the concentration rises above the minimal
therapeutic level reaching the toxic threshold. After a relatively
short period of the drug concentration decreases via metabolization
or excretion to levels that are no longer therapeutic.
[0004] In order to achieve constant levels of drugs and avoid the
inefficiencies of the drug concentration peaks and valleys the
drugs should be released from a delivery system at a rate that does
not change with time (so called zero-order release). Preferably,
the initial dose of a drug is the therapeutic dose, which is
maintained by the delivery system. Examples of a current sustained
drug delivery system include the reservoir systems which consist of
tubes, fibers, laminates, or microspheres. In these systems, a drug
reservoir is coated in a rate-controlling membrane. Drug diffusion
across the membrane is rate limiting and is constant (zero order)
as long as the membrane's permeability does not change and as long
as the concentration of drug in the reservoir is constant.
[0005] In matrix systems drugs are dispersed through a matrix and
are released as the drugs dissolve and diffuse through the matrix.
A drug is released from the outer surface of the matrix first, this
layer becomes depleted, and a drug that is released from further
within the core of the device must then diffuse through the
depleted matrix. The net result is that the release rate slows down
and thus it is very difficult to maintain constant and consistent
release. Other types of devices are polymeric devices that contain
a polymeric material that is permeable to the passage of the drug.
Although it is possible to choose from among a large variety of
polymeric materials, in practice only a small number of polymers
have been shown to function satisfactorily as a release-determining
outer layer of the reservoir. Sustained release systems that
release two or more active substances over a prolonged period of
time are extremely useful for certain applications, for example,
the in fields of contraception and hormone replacement therapy.
[0006] Ring-shaped vaginal drug delivery devices ("vaginal rings")
are well known in the art. Such devices are designed to deliver a
relatively constant dose of drug to the vagina, usually over a
period of weeks to months. Typically, they are made of a silicone
elastomer and contain a drug released by diffusion though the
elastomer. Vaginal rings have been developed for delivering
steroids to treat post-menopausal vaginal conditions, as well as
for contraception and hormone replacement therapy. Women generally
prefer vaginal rings to oral delivery for several reasons,
particularly their convenience, privacy, long-term delivery
capacity, and effectiveness. Vaginal rings provide a regulated dose
of drug with minimal involvement or attention by the user. They
also avoid the first pass of orally administered drugs through the
liver, where appreciable portions of the daily dosage of some
orally administered steroids are degraded.
[0007] U.S. Pat. No. 4,292,965 (Nash et al.) and U.S. Pat. No.
4,822,616 (Zimmermann et al.) disclose two-layered vaginal rings.
The rings comprise an inner drug-free supporting ring, a middle
layer comprising a drug, and an outer drug-free layer. All three
layers preferably comprise a silicone elastomer. However, the use
of silicone elastomers is now generally considered to be unsafe,
and is no longer the material of choice.
[0008] In addition to single drug delivery, vaginal rings have been
developed for simultaneous release of multiple drugs over a
prolonged period of time. For example, U.S. Pat. No. 3,995,633
(Gougeon) and U.S. Pat. No. 3,995,634 (Drobish) disclose vaginal
rings comprising separate reservoirs containing different active
substances, wherein the reservoirs are arranged in holders. U.S.
Pat. No. 4,237,885 (Wong et al.) also discloses a multi-reservoir
device, in which spacers are used to divide a tube or coil into
portions, wherein each portion is filled with a different active
substance in a silicone fluid and the two ends of the tube are
subsequently connected to form a ring. Patent Publication WO
97/02015 (Groenewegen et al.) discloses a two-compartment device,
wherein one compartment has a core, a medicated middle layer and a
non-medicated outer layer, and a second compartment having a
medicated core and a non-medicated outer layer. However, the active
substances in these multi-compartment or multi-reservoir devices
typically diffuse through the walls of the tubes, thus allowing
drug interactions, particularly during prolonged storage.
Interactions between the drugs often results in degradation or
inactivation of at least one of the drugs, and thus variations in
the pre-set fixed release ratio between the drugs over time.
[0009] The device described in U.S. Pat. No. 4,596,576 (de Nijs)
was designed to overcome the diffusion problem associated with
multi-compartment devices. de Nijs discloses a two-compartment
vaginal ring wherein each compartment comprises a reservoir filled
with a different active substance. However, to prevent diffusion
and maintain a constant release ratio between the various active
substances over time, the drug compartments are separated by
impermeable inert stoppers, formed of glass, gold or silver.
Although the stoppers effectively prevent diffusion of active
substance between reservoirs, the device is complicated and
expensive to manufacture.
[0010] The device described in U.S. Pat. No. 5,989,581
(Groenewegen) was also designed to overcome the diffusion problems
associated with existing delivery systems, as well as to provide a
less complicated and cheaper device for intravaginal delivery of
multiple active substances. The patent discloses a ring-shaped drug
delivery system for the simultaneous release of a progestogenic
steroid compound and an estrogenic steroid compound, reportedly in
a fixed ratio over a prolonged period of time. The drug delivery
system has a compartment comprising a thermoplastic polymer core
containing the mixture of the progestogenic and estrogenic
compounds and a thermoplastic polymer skin. However, like other
known vaginal devices, the Groenewegen device suffers from its own
inherent limitations. In general, the release per unit time of a
drug is determined by the solubility of the active substance in the
outer layer (wall) of polymeric material and by the diffusion
coefficient of the active substance in the wall. Thus, the choice
of the outer layer material of the reservoir largely determines the
release ratio of the active substances contained in the reservoir.
Unfortunately, only a few polymers are capable of functioning
satisfactorily as a release-determining outer layer of the
reservoir. Finding the appropriate polymer for a particular drug or
drug combination can be difficult. Moreover, the reservoir material
must be capable of taking up a large amount of the active substance
or substances in order to provide an adequate supply of the
substances to the outer wall. Meeting these challenges is
problematic, if not impossible, and must be addressed for each new
drug or drug combination.
[0011] An intravaginal drug delivery device which can release two
or more active substances in a substantially constant ratio to one
another over a lengthy period of time would be extremely useful for
certain applications. For example, in the field of contraception
and in the field of hormone replacement therapy, extensive use is
made of the simultaneous administration of an agent having a
progestogenic activity and an agent having an estrogenic activity,
preferably in a substantially constant ratio.
[0012] Drug delivery systems and methods for contraception and for
treating female reproductive disorders using combination therapy
have been developed. For example, U.S. Pat. No. 4,762,717 (Crowley,
Jr.) discloses a delivery system for the continuous delivery of
LHRH compositions in combination with sex steroid for use as a
contraceptive. U.S. Pat. No. 5,130,137 (Crowley, Jr.) discloses a
similar delivery system for the treatment of benign ovarian
secretory disorders.
[0013] Despite these significant advances in the field, a need
exists for an improved method for contraception and treatment of
female reproductive conditions and disorders, such as treatment of
benign ovarian secretory disorders and post-menopausal hormone
replacement therapy. In particular, a method that uses a hormone
replacement steroid and/or a LHRH and/or its analogues (either
agonists and/or antagonists), and that can be administered in a
safe, physiologic, and convenient manner, would be highly
desirable. Moreover, a need exists for an improved drug delivery
system for the simultaneous release of LHRH and sex steroids or sex
steroid modulators, particularly a system which releases the LHRH
and steroids in a substantially constant ratio over a prolonged
period of time, and which is easy and inexpensive to
manufacture.
[0014] Additionally, constant and reliable delivery of drugs or
combinations of drugs over long periods of time would be useful in
a wide variety of applications, including treatment or prevention
of AIDS/HIV, atherosclerosis, various cancers, cardiovascular
diseases, hypertension, toxemia of pregnancy, seizures,
degenerative neurological disorders, diabetes, hematological
disorders, addictions, and obesity and eating disorders, to name a
few. Unfortunately, in addition to not always providing
satisfactory release, release ratio, or release term in some cases,
all currently available intravaginal drug delivery devices suffer
from being relatively complicated, making them expensive to
manufacture. Thus, a need exists for an improved drug delivery
device for the simultaneous release of multiple drugs, particularly
a device which releases the drugs in a substantially constant ratio
over a prolonged period of time, and which is easy and inexpensive
to manufacture.
SUMMARY
[0015] It is an object of the present invention to provide a drug
delivery device for the sustained release of multiple drugs over a
prolonged period of time. Additionally, the present invention also
provides for a less expensive and easier to produce device than
currently available devices. It is also an object of the invention
to provide a method of treating disease with the device,
particularly benign ovarian secretory disorders. It is also an
object of the invention to administer multiple drugs for use in
contraception and hormone replacement therapy.
[0016] In a first aspect, the present invention relates to a drug
delivery device comprising two or more unitary segments. Each
segment comprises a drug-permeable polymeric substance, and at
least one segment comprises a mixture of the drug-permeable
polymeric substance and a drug. Two or more segments may each
contain a drug, preferably a different drug in each segment. The
drug-permeable polymeric substance may be a thermoplastic polymer,
such as an ethylene-vinyl acetate copolymer. At least one end of a
segment may be attached to the end of another unitary segment by a
coupling means, such as an adhesive material or by annealing the
ends of the segments to same or different thermoplastic polymers.
The drug delivery device may be in the shape of a ring, a wafer, or
a suppository, and may be suitable for use as a vaginal ring. The
drug delivery device may have an overall diameter of from 40 mm to
80 mm, and a cross-sectional diameter of from 2 mm to 12 mm. The
drug to be delivered may be a hormone replacement steroid or a
contraceptive agent, for example an estrogenic compound, a
progestational compound, and/or a gonadotropin releasing hormone or
its peptide or non-peptide agonists or antagonist analogues. The
drug may also be an interferon, anti-angiogenesis factors, growth
factors, hormones, enzymes, transferases, hydrolases, lysases,
isomerases, proteases, ligases and oxidoreductases, enzyme
inhibitors, steroids, anti-cancer drugs, antibiotics, growth
hormone, polysaccharides, antigens, and antibodies.
[0017] In another aspect, the invention relates to a drug delivery
system for the simultaneous release of two or more drugs. The drug
delivery system comprises two or more unitary segments, wherein at
least two of the segments comprise a mixture of a drug-permeable
polymeric substance and a drug. Moreover, at least two of the
segments may comprise a different drug, and the drug-permeable
polymeric substance may be a thermoplastic polymer, such has an
ethylene-vinyl acetate copolymer. The drug may be a hormone
replacement steroid or a contraceptive agent, for example an
estrogenic compound, a progestational compound, and/or a
gonadotropin releasing hormone or its agonistic or antagonistic
analogues. The drug may also be an interferon, anti-angiogenesis
factors, growth factors, hormones, enzymes, transferases,
hydrolases, lysases, isomerases, proteases, ligases and
oxidoreductases, enzyme inhibitors, steroids, anti-cancer drugs,
antibiotics, growth hormone, polysaccharides, antigens, and
antibodies.
[0018] In still a further aspect, the invention relates to a method
for delivering a drug to a female mammal. The method comprises
preparing a drug delivery device comprising two or more unitary
segments, wherein each segment comprises a drug-permeable polymeric
substance, and wherein at least one segment comprises a mixture of
the drug-permeable polymeric substance and a drug. The drug
delivery device is then positioned in the vaginal tract of the
female mammal, and maintained in the vaginal tract for a period of
time sufficient to deliver an effective amount of the drug to the
female mammal. The drug-permeable polymeric substance may be a
thermoplastic polymer, such as an ethylene-vinyl acetate copolymer.
The drug may be a hormone replacement steroid or a contraceptive
agent, for example an estrogenic compound, a progestational
compound, and/or a gonadotropin releasing hormone. The drug may
also be interferon, anti-angiogenesis factors, growth factors,
hormones, enzymes, transferases, hydrolases, lysases, isomerases,
proteases, ligases and oxidoreductases, enzyme inhibitors,
steroids, anti-cancer drugs, antibiotics, growth hormone,
polysaccharides, antigens, and antibodies. In yet another aspect,
the invention relates to a method of making a ring-shaped drug
delivery device. The method comprises mixing a first drug-permeable
polymeric substance with a first drug to form a first polymeric
mixture, molding the first polymeric mixture to form a first ring,
and cutting the first ring to form two or more first unitary
segments. The method is then repeated with a second drug-permeable
polymeric substance and a second drug to form a second unitary
segment. The first and second drug-permeable polymeric substances
may be the same or different. An end of a first segment is then
connected to an end of a second segment to form a ring-shaped drug
delivery device. The first and second drug-permeable polymeric
substances may be a thermoplastic polymer, such as an
ethylene-vinyl acetate copolymer. The foregoing method may be
repeated with a third drug-permeable polymeric substance and a
third drug to form a third unitary segment. Additional segments may
be prepared by the same method. The connection of the segments may
be performed using an adhesive material or by annealing the ends of
the segments with the same or a different thermoplastic polymer. In
an alternate embodiment, the ring-shaped drug delivery device is
formed by preparing individual segments, instead of rings, and
connecting the ends of the segments to form the ring-shaped drug
delivery device.
[0019] In another aspect the invention relates a method of making a
ring-shaped drug delivery device. The method comprises mixing a
first drug-permeable polymeric substance with a first drug to form
a first polymeric mixture, injecting the first polymeric mixture
into a mold to form a first unitary segment. The method is then
repeated with a second drug-permeable polymeric substance and a
second drug to form a second unitary segment and thus forming the
drug delivery device. The first and second drug-permeable polymeric
substances may be the same or different. The first and second
drug-permeable polymeric substances may be a thermoplastic polymer,
such as an ethylene-vinyl acetate copolymer. The foregoing method
may be repeated with a third drug-permeable polymeric substance and
a third drug to form a third unitary segment. Additional segments
may be prepared by the same method.
[0020] In another aspect, the present invention relates to a method
for the treatment of a benign ovarian secretory disorder in a
female mammal, such as polycystic ovarian disease (PCOD). The
method comprises providing a drug delivery device comprising at
least two segments, wherein the first segment comprises a
drug-permeable polymeric substance and a luteinizing hormone
releasing hormone (LHRH) or one of its agonistic or antagonistic
analogues or a small molecular weight mimic that either binds to
the GnRH receptor or blocks its subsequent mechanism of action, and
wherein the second segment comprises the drug-permeable polymeric
substance and an estrogenic steroid. The drug delivery device is
then inserted into the vagina of the female mammal to release a
therapeutically effective amount of the LHRH and an effective
amount of the estrogenic steroid or estrogen receptor modulator (to
avoid the metabolic consequences of the castrational state induced
by the LHRH). The drug delivery device may further comprise a third
segment, which comprises the drug-permeable polymeric substance and
a progestational steroid or a progestin receptor modulator, and
which releases an effective amount of the progestational steroid.
The drug-permeable polymeric substance may be a thermoplastic
polymer, such as an ethylene-vinyl acetate copolymer. The drug
delivery device may be in the shape of a ring, a wafer, or a
suppository, preferably a ring shape. The benign ovarian secretory
disorder may be polycystic ovarian disease. The benign ovarian
secretory disorder may be characterized by excessive ovarian
androgen secretion, excessive ovarian estrogen secretion,
hyperthecosis, hirsutism, dysfunctional uterine bleeding,
amenorrhea, or anestrus. The female mammal may be a human female.
The estrogen steroid may be estradiol, estradiol benzoate,
estradiol cypionate, estradiol dipropionate, estradiol enanthate,
conjugated equine estrogen, estriol, estrone, estrone sulfate,
ethinyl estradiol, estrofurate, quinestrol or mestranol. The
estrogen steroid may also be a selective estrogen receptor
modulators such as tamoxifen, raloxifene, clomiphene, droloxifene,
idoxifene, toremifene, tibolone, ICI 182,780, ICI 164,384,
diethylstilbesterol, genistein, nafoxidine, moxestrol,
19-nor-progesterone derivatives, or 19-nor-testosterone
derivatives. The progestation steroid may be progesterone,
17-hydroxy progesterone derivatives, 19-nor-testosterone
derivatives, 19-nor-progesterone derivatives norethindrone,
norethindrone acetate, norethynodrel, norgestrel, norgestimate,
ethynodiol diacetate, allylestrenol, lynoestrenol, fuingestanol
acetate, medrogestone, norgestrienone, dimethiderome, ethisterone,
cyproterone levo-norgestrel, di-norgestrel, cyproterone acetate,
gestodene, desogestrol, dydrogesterone, ethynodiol diacetate,
medroxyprogesterone acetate, megestrol acetate, phytoprogestins, or
an animal-derived progestin or metabolic derivatives thereof. The
progestational steroid may also be a selective progestin receptor
modulator such as RU486, CDB2914, a 19-nor-progesterone derivative,
a 19-nor-testosterone derivative, a
6-aryl-1,2-dihydro-2,2,4-trimethylquinoline derivative, a
5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinoline derivative, a
5-alkyl 1,2-dihydrochomeno[3,4-f]quinoline derivative, or a
6-thiophenehydroquinoline derivative.
[0021] In another aspect, the invention relates to preventing
pregnancy in a female mammal. The method comprises providing a drug
delivery device comprising: (1) a first segment comprising a
drug-permeable polymeric substance and a luteinizing hormone
releasing hormone (LHRH) or one of its agonistic or antagonistic
analogues or a small molecular weight mimic that either binds to
the GnRH receptor or blocks its subsequent mechanism of action, (2)
a second segment comprising the drug-permeable polymeric substance
and an estrogenic steroid or selective estrogen receptor modulator
(SERM), and (3) a third segment comprising the drug-permeable
polymeric substance and a progestational steroid or selective
progestin receptor modulator (SPRM). The drug delivery device is
then inserted into the vagina of the mammal to release a
therapeutically effective amount of the LHRH, an effective amount
of the estrogenic steroid or selective estrogen receptor modulator
(SERM), and an effective amount of the progestational steroid or
SPRM to the female mammal. The drug-permeable polymeric substance
may be a thermoplastic polymer, such as an ethylene-vinyl acetate
copolymer. The drug delivery device may be in the shape of a ring,
a wafer, or a suppository, preferably a ring shape.
[0022] In yet another aspect, the invention relates to a method of
treating a decrease in estrogen secretion in a woman exhibiting
symptoms of a cessation of cyclical ovulation and/or the
peri-menopause. In one embodiment, the method comprises providing a
drug delivery device comprising: (1) a first segment comprising a
drug-permeable polymeric substance and a luteinizing hormone
releasing hormone (LHRH) or one of its agonistic or antagonistic
analogues or a small molecular weight mimic that either binds to
the GnRH receptor or blocks its subsequent mechanism of action, (2)
a second segment comprising the drug-permeable polymeric substance
and a hormone replacement steroid, such as an estrogenic steroid or
selective estrogen receptor modulator (SERM), and (3) a third
segment comprising the drug-permeable polymeric substance and a
progestational steroid or selective progestin receptor modulator
(SPRM). In an optional embodiment, the drug delivery device further
comprises a fourth segment, which comprises a drug-permeable
polymeric substance and an androgen or a selective androgen
receptor modulator (SARM). The drug delivery device is then
inserted into the vagina of the woman to release effective amounts
of the LHRH, sex steroids and/or sex steroid modulators. The
estrogen component of the hormone replacement steroid may be an
estrogenic steroid, such as a naturally occurring estrogen or a
synthetic estrogen. The estrogenic steroid may be estradiol,
estradiol benzoate, estradiol cypionate, estradiol dipropionate,
estradiol enanthate, conjugated equine estrogen, estriol, estrone,
estrone sulfate, ethinyl estradiol, estrofurate, quinestrol or
mestranol or other estrogenic steroids.
[0023] In still another aspect, the invention relates to a method
of treating a decrease in estrogen secretion in a woman exhibiting
symptoms of a cessation of cyclical ovulation and/or the menopause.
The method comprises providing a drug delivery device comprising at
least two segments, wherein the first segment comprises a
drug-permeable polymeric substance and a hormone replacement
steroid, such as an estrogenic steroid or selective estrogen
receptor modulator (SERM), and wherein the second segment comprises
a drug-permeable polymeric substance and a progestational steroid
or a selective progestin receptor modulator (SPRM). In an optional
embodiment, the drug delivery device further comprises a third
segment, which comprises a drug-permeable polymeric substance and
an androgen or a selective androgen receptor modulator (SARM). The
drug delivery device is then inserted into the vagina of the woman
to release an effective amount of the hormone replacement steroid.
The estrogen component of the hormone replacement steroid may be an
estrogenic steroid, such as a naturally occurring estrogen or a
synthetic estrogen, such as those described above.
[0024] In still a further aspect, the invention relates to a method
for relieving the symptoms and signs associated with menopausal,
perimenopausal and post-menopausal periods in a woman having these
periods and in need of estrogen therapy. The method comprises
providing a drug delivery device having a first segment and a
second segment, wherein the first segment comprises a
drug-permeable polymeric substance and an estrogenic steroid. The
drug delivery device in then inserted into the vagina of the woman
to release an effective amount of the estrogenic steroid. The
drug-permeable polymeric substance may be a thermoplastic polymer,
such as an ethylene-vinyl acetate copolymer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 shows a ring-shaped intravaginal drug delivery device
consisting of two segments 12 and 13, which are connected to each
other by a coupling means;
[0026] FIG. 2 illustrates the serum level (ng/ml) of gonadotropin
releasing hormone (GnRH) in Rhesus monkeys following vaginal
administration of a composition comprising GnRH and a commercially
available hydrogel (Replenz.RTM.);
[0027] FIG. 3 illustrates the in vitro zero order release kinetics
of estradiol (circles) and progesterone (squares) from an EVA-based
intravaginal delivery device of the invention;
[0028] FIG. 4 illustrates the in vitro zero order release kinetics
of natural GnRH from an EVA-based intravaginal delivery device of
the invention;
[0029] FIG. 5 illustrates the bi-phasic release kinetics of
estradiol (circles) and progesterone (squares) from EVA-based
delivery devices;
[0030] FIG. 6 illustrates the effect of cellulosics on the release
kinetics of progesterone from an EVA-based delivery device, where
high concentrations of ethocel are represented by diamonds and low
concentrations of ethocel are represented by squares;
[0031] FIG. 7 illustrates the bi-phasic release kinetics of
estradiol (circles) and progesterone (squares) from a single
EVA-based delivery device;
[0032] FIG. 8 illustrates the pharmacokinetics of intravaginally
administered GnRH in Rhesus monkeys and the corresponding effect on
endogenous levels of luteinizing hormone (LH, diamonds); and
[0033] FIG. 9 shows a ring-shaped multiple port mold consisting of
a Portal No. 1, Portal No. 2, Portal No. 3, and Portal No. 4.
DETAILED DESCRIPTION
[0034] The present invention relates to a drug delivery device, a
method for delivering a drug to a female mammal, a method of making
a ring-shaped drug delivery device, methods for the treatment of a
benign ovarian secretory disorder, methods of contraception and
methods for hormone replacement therapy.
[0035] The drug delivery device, which comprises a drug-permeable
polymeric substance, has at least two unitary segments. The
segments are preferably joined end to end to form a ring shape. At
least one of the segments comprises a mixture of the drug-permeable
polymeric substance and a drug, wherein the drug is substantially
uniformly dispersed throughout the segment. The invention further
relates to a drug delivery system for the simultaneous release of a
plurality of drugs, wherein the system releases the drugs in a
substantially constant ratio over a prolonged period of time. The
method of delivering the drug or combination of drugs to the female
mammal comprises the steps of preparing a drug delivery device
having two or more unitary segments, positioning the device in the
vaginal tract of the female mammal, and maintaining the device in
the vaginal tract for a period of time sufficient to deliver a
pharmaceutically effective amount of the drug(s) to the female
mammal.
[0036] As stated above, the drug delivery device, which comprises a
drug-permeable polymeric substance, has at least two unitary
segments. The device may be in any physiologically acceptable
shape, such as a ring, a wafer, or a suppository. In one
embodiment, the segments are joined end to end to form a ring
shape. At least one of the segments comprises a mixture of the
drug-permeable polymeric substance and a drug, wherein the drug is
substantially uniformly dispersed throughout the segment. Because
of its unique design, the drug delivery device of the present
invention provides simultaneous release of a plurality of drugs, in
a substantially constant ratio over a prolonged period of time.
[0037] The drug delivery device can be easily manufactured, and
provides for the reliable and predictable release of the drug or
drug combination. In contrast to known intravaginal drug delivery
devices comprising a drug-containing fluid core or reservoir, the
solid thermoplastic devices used in the methods of the present
invention are not susceptible to rupture and the consequent leakage
of drug-containing fluid. Moreover, unlike existing devices
comprising multiple layers or compartments, the devices described
herein can be easily and cheaply manufactured using conventional
extrusion technology.
[0038] The thermoplastic polymer used in the manufacture of the
device may be any thermoplastic polymer or elastomer material
suitable for pharmaceutical use, such as polysiloxanes,
polyurethane, polyethylene, ethylene-vinyl acetate copolymers,
cellulose, copolymers of polystyrene, polyacrylates and various
types of polyamides and polyesters. The ethylene-vinyl acetate
copolymer (EVA) is highly preferred due to its excellent mechanical
and physical properties (e.g., solubility of the drug in the
material). The EVA material can be any commercially available
ethylene-vinyl acetate copolymer, such as the products available
under the names Elvax.RTM., Evatane.RTM., Lupolen.RTM.,
Movriton.RTM., Ultrathene.RTM. and Vestypar.RTM..
[0039] The intravaginal drug delivery device used in the methods of
the present invention can be manufactured in any size as required.
In the case of human use, the ring-shaped device has an outer
diameter from about 40 mm to about 80 mm, and preferably between 50
mm and 60 mm; the cross-sectional diameter is preferably between
about 1 mm and about 12 mm, and preferably between 2 and 6 mm.
[0040] The present invention also relates to methods for the
treatment of a benign ovarian secretory disorder and for preventing
pregnancy in a female mammal, as well as methods for treating a
decrease in estrogen secretion in a woman exhibiting symptoms of a
cessation of cyclical ovulation and for relieving the symptoms and
signs associated with menopausal, perimenopausal and
post-menopausal periods in a woman. The methods comprise providing
a drug delivery device having two or more unitary segments, wherein
at least one of the segments comprises a drug-permeable polymeric
substance and a drug. The choice of drug(s) will depend on the
particular application or indication being treated. For example,
for contraceptive uses and the treatment of a benign ovarian
secretory disorder, the drugs are a luteinizing hormone releasing
hormone (LHRH) and an estrogenic steroid and sequential
progesterone/progestine; for contraceptive purposes, the drugs are
LHRH, an estrogenic steroid, and progestational steroid; and, for
treating a decrease in estrogen secretion, the drug is a hormone
replacement steroid, such as an estrogenic steroid. An estrogenic
steroid is also the drug used in methods for relieving the symptoms
and signs associated with menopause. Similarly, progesterone can be
used in methods for relieving the symptoms and signs associated
with menopause. The drug delivery device is then inserted into the
vagina of the female mammal, such as a human female, to release an
effective amount(s) of the drug(s). The drug-permeable polymeric
substance may be a thermoplastic polymer, such as an ethylene-vinyl
acetate copolymer. The drug delivery device may be in the shape of
a ring, a wafer, or a suppository, preferably a ring shape.
[0041] The following detailed description discloses how to practice
the methods of the present invention. It also describes how to make
and use the intravaginal drug delivery device to deliver a
pharmaceutically effective amount of a drug to a female mammal.
I. Definitions
[0042] For convenience, the meaning of certain terms and phrases
used in the specification, examples, and appended claims are
provided below.
[0043] As used herein, the terms "unitary segment" or "segment"
refer to a solid material having a substantially uniform or
homogenous composition throughout. The terms "segment" and "unitary
segment" specifically exclude vaginal rings or portions thereof
comprising a core or reservoir and an inner and/or outer layer of
material, such as a skin, wall, membrane, coating, or polymeric
layer or layers.
[0044] As used herein, the terms "unitary cylindrical segment" and
"unitary cylindrical rod" refer to a solid cylinder or rod-shaped
material having a substantially uniform or homogenous composition
throughout. The terms "segment" and "unitary cylindrical rod"
specifically exclude vaginal rings or portions thereof comprising a
core or reservoir and an inner and/or outer layer of material, such
as a skin, wall, membrane, coating, or polymeric layer or
layers.
[0045] As used herein, the term "drug-permeable" refers to a
polymeric material through which a drug can diffuse and thus be
absorbed for local and/or systemic effects in a mammal. The term
"non-absorbable" means there is no absorption of the polymeric
material in the vaginal tract of the female mammal being treated.
The term "non-erodible" means that the polymeric material does not
erode in the vaginal tract of the female mammal. The term
"non-degradable" means that the polymeric material does not degrade
or break down in vivo. The term "compatible" means compatible both
with the environment of the vaginal tract in that there is no
breakdown of the tensile nature or structural integrity of the
device due to the contents of the vagina. Likewise there is no
deleterious action on the sensitive tissue in the area of placement
in the vaginal tract. Widely varying types of polymeric material
are suitable in providing these non-toxic, drug-permeable
properties, for example polysiloxanes, polyurethane, polyethylene,
ethylene-vinyl acetate copolymers, cellulose, copolymers of
polystyrene, polyacrylates and various types of polyamides and
polyesters. The above-mentioned polymers can be used in a porous or
microporous form. The term "thermoplastic polymer" refers to a
polymeric material which is capable of being softened by heating
and hardened by cooling through a temperature range characteristic
of the polymer, and in the softened state can be shaped by flow
into devices by molding or extrusion.
[0046] As used herein, the term "coupling means" refers to a
method, mechanism, material or device for joining or connecting the
ends of two unitary segments or unitary cylindrical rods to each
other. The term "adhesive material," as used herein refers to an
inert bonding agent, glue, or other substance having sufficient
adhesive properties to bind the ends of the segments. The adhesive
material can be, for example, a medical grade silicone
adhesive.
[0047] As used herein, the terms "patient" and "female mammal" are
used interchangeably to refer to a human or other animal in which
it is desired to provide a medical treatment or contraceptive
agent.
[0048] By "simulating or inducing the follicular or luteal phase of
the menstrual cycle" is meant to simulate or induce the sex steroid
hormone milieu in the patient so as to provide such patient with
levels of sex steroid hormones that approximate the endocrine
environment of a normal follicular or luteal phase.
[0049] As used herein, "benign ovarian secretory disorders" refers
to any of a variety of benign conditions in which suppression of
ovarian function is important. These conditions largely center
around benign secretory disorders of the ovaries such as (a)
polycystic ovarian disease and hyperandrogenic hirsutism, and/or
(b) excessive ovarian sex steroid secretion of androgens, estrogens
or progestins. Benign ovarian secretory disorders may be
characterized, for example, by hyperthecosis, hirsutism,
dysfunctional uterine bleeding, amenorrhea, anestrus, or
oligomenorrhea.
[0050] By "excessive" ovarian sex steroid secretion of androgens,
estrogens or progestins is meant secretion of androgens, estrogens
or progestins in amounts such that the ratios of the androgens,
estrogens or progestins in the serum of a patient are abnormal when
compared to normal levels of such androgens, estrogens or
progestins for the female mammal. Therefore, "excessive" estrogen
secretion is meant to encompass conditions wherein the ovaries
secrete estrogen levels that do not conform to the normal levels
encountered in female reproduction physiology such as the normal
menstrual cycle; "excessive" progestin secretion is meant to
encompass conditions wherein the ovaries secrete too much
progestin, e.g., levels excessive or inappropriate for normal
physiologic levels in normal women; and, "excessive" androgen
secretion is meant to encompass conditions wherein the ovaries
secrete too much androgen, e.g., levels above those encountered in
normal female physiology.
[0051] As used herein, "LHRH" and "LHRH composition" refer to
luteinizing hormone releasing hormone (LHRH), LHRH analogues, LHRH
agonists and LHRH antagonists analogues (peptide and/or non-peptide
in nature), and/or any compound (peptide or non-peptide) that can
bind to the LHRH receptor and/or can produce hypogonadotropic
hypogonadism in a mammal, such as a human. The LHRH that may be
used in this invention are physiologically active peptides or
non-peptide analogues capable of binding to the LHRH receptor and
are gonadotropin secretory inhibitors or
gonadotropin-receptor-effect blockers. LHRH is characterized as a
decapeptide having the following structure:
p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2 SEQ ID NO: 1
[0052] As used herein, the terms "LHRH agonist" and "LHRH
antagonist" refer to such physiologically active peptides or
non-peptide analogues which respectively enhance or inhibit the
biological activity of LHRH. For example, LHRH agonists useful in
the methods of the invention include, but are not limited to,
Cystorelin (Hoechst), Gonadorelin (Ayerst), Zoladex.TM. (ICI),
Buserelin (Boechst), Leuprolide (Abbott/Takeda), Decapeptyl
(Debiopharm, Ipsen/Beaufour), Nafarelin (Syntex), Lutrelin (Wyeth)
and Histrelin (Ortho). LHRH, LHRH analogues, LHRH agonists and LHRH
antagonists are well known in the art and are described in numerous
patents, including the following patents: U.S. Pat. Nos. 4,705,778,
4,690,916, 4,530,920; 4,481,190; 4,419,347; 4,341,767; 4,318,905;
4,234,571; 4,386,074; 4,244,946; 4,218,439; 4,215,038; 4,072,668;
4,431,635; 4,317,815; 4,010,125; 4,504,414; 4,493,934; 4,377,515;
4,504,414; 4,338,305; 4,089,946; 4,111,923; 4,512,923; 4,008,209;
and 4,010,149, all incorporated herein by reference. The LHRH
compositions described in the above patents may be used in the
methods of this invention.
[0053] As used herein, the terms "estrogenic steroid" and
"estrogen" are used interchangeably to refer to an agent, natural
or synthetic, that exerts biological effects characteristic of
estrogenic hormones such as estradiol. As used herein, the terms
"estrogenic steroid" and "estrogen" also encompasses "conjugated
estrogens," which are an amorphous preparation of naturally
occurring, water-soluble, conjugated forms of mixed estrogens that
typically are obtained from the urine of pregnant mares (e.g.,
sodium estrone sulfate). Also included are "esterified estrogens,"
which are a mixture of the sodium salts of sulfate esters or
glucanoride of sulfate conjugates of estrogenic substances.
Examples of suitable estrogens include, without limitation,
estradiol valerate, estradiol benzoate, 17-.beta. estradiol,
estradiol cypionate, estrone, piperazine estrone sulfate, estriol,
ethyl estradiol, polyestradiol phosphate, estrone potassium
sulfate, benzestrol, chlorotrianisene, methallenestril, dienestrol,
diethylstilbestrol diphosphate, mestranol, diethylstilbestrol
(DES), quinestranol, phytoestrogens, animal-derived estrogens
(e.g., equine estrogens), and metabolic derivatives of
animal-derived estrogens. These also include any steroid or
non-steroidal compound that binds either to the known estrogen
receptors that exist within cells or to estrogen receptors that
bind to extracellular membranes and cause biologic effects that
mimic those of estradiol or other estrogenic compounds.
[0054] As used herein, the terms "progestational steroid" and
"progestin" are used interchangeably to refer to an agent, natural
or synthetic, that effects some or all of the biological changes
produced by progesterone, which is a hormone of the corpus luteum.
For example, a progestin can induce secretory changes in the
endometrium. Examples of progestins include, without limitation,
progesterone, 17-hydroxy progesterone derivatives,
19-nor-testosterone derivatives, 19-nor-progesterone derivatives
norethindrone, norethindrone acetate, norethynodrel, norgestrel,
norgestimate, ethynodiol diacetate, allylestrenol, lynoestrenol,
fuingestanol acetate, medrogestone, norgestrienone, dimethiderome,
ethisterone, cyproterone levo-norgestrel, dl-norgestrel,
cyproterone acetate, gestodene, desogestrol, dydrogesterone,
ethynodiol diacetate, medroxyprogesterone acetate, megestrol
acetate, phytoprogestins, animal-derived progestins, and metabolic
derivatives of animal-derived progestins. These compounds also
include any steroidal or non-steroidal compounds that bind to the
cytoplasmic or membrance bound progesterone and mimic any of the
biologic effects of progesterone or progestins.
[0055] As used herein, the terms "androgenic steroid" and
"androgen" are used interchangeably to refer to a natural or
synthetic agent that stimulates activity of the accessory male sex
organs and/or muscle development and/or encourages development of
male sex characteristics. Examples of suitable androgens include,
without limitation, testosterone, methyltestosterone,
fluoxymesterone, testosterone cypionate, testosterone enanthate,
testosterone propionate, oxymetholone, ethylestrenol, oxandrolone,
nandrolone phenpropionate, nandrolone decanoate, testosterone
buccilate, stanozolol, dromostanolone propionate, androstenedione,
dehydropepiandrosterone, dehydroepiandrosterone sulfate (DHEAS),
dihydrotestosterone, phytoandrogens, animal-derived androgens, and
metabolic derivatives of animal-derived androgens. This also
included any steroidal or non-steroidal compounds that bind to
either the cytoplasmic or membrane bound androgen receptor and
produce biologic effects that mimic testosterone or other
androgenic compounds.
[0056] A "selective estrogen receptor modulator" ("SERM") is a
compound that is an estrogen analog and which exerts
tissue-selective effects. Such compounds can function as estrogen
antagonists or partial agonists. Examples of suitable SERMs include
tamoxifen, raloxifene, clomiphene, droloxifene, idoxifene,
toremifene, tibolone, ICI 182,780, ICI 164,384,
diethylstilbesterol, genistein, nafoxidine, moxestrol,
19-nor-progesterone derivatives, and 19-nor-testosterone
derivatives.
[0057] A "selective androgen receptor modulator" ("SARM") is a
compound that is an androgen analog and which exerts
tissue-selective effects. Such compounds can function as androgen
antagonists or partial agonists. Examples of suitable SARMs include
cyproterone acetate, hydroxyflutamide, bicalutamide,
spironolactone,
4-(trifluoromethyl)-2(1H)-pyrrolidino[3,2-g]quinolinone
derivatives, 1,2-dihydropyridono[5,6-g]quinoline derivatives, and
piperidino[3,2-g]quinolinone derivatives.
[0058] A "selective progestin receptor modulator" ("SPRM") is a
compound that is an progesterone analog and which exerts
tissue-selective effects. Such compounds can function as
progesterone antagonists or partial agonists. Examples of suitable
SPRMs include RU486, CDB2914, 19-nor-progesterone derivatives,
19-nor-testosterone derivatives,
6-aryl-1,2-dihydro-2,2,4-trimethylquinoline derivatives,
5-aryl-1,2-dihydro-51-1-chromeno[3,4-f]quinoline derivatives,
5-alkyl 1,2-dihydrochomeno[3,4-f]quinoline derivatives, and
6-thiophenehydroquinoline derivatives.
[0059] Unless indicated otherwise, the hormonal steroids used in
the methods of the present invention (e.g., estrogenic steroids,
progestational steroids, and androgenic steroids) include the
respective sex steroids (both natural and synthetic, including
derivatives and analogues thereof), as well as their respective
hormone receptor modulator compounds (e.g., SERMs, SPRMs, and
SARMs). Hormonal steroids are well known in the art and are
described, for example, in Remington's Pharmaceutical Sciences
(16th edition, 1980) at pages 925-939.
[0060] A "postmenopausal" woman is one who in the absence of
hormone replacement therapy or other medication would experience at
least 12 months of amenorrhea or levels of serum
follicle-stimulating hormone greater than 30 mIU/ml.
[0061] A "perimenopausal" woman is one who in the absence of
hormone replacement therapy or other medication would experience a
change in her intermenstrual cycle interval and have associated
symptoms of estrogen deficiency, such as vasomotor flushes, vaginal
dryness, and worsening premenstrual syndrome. Also included are
women who in the absence of hormone replacement therapy or other
medication would experience less than 12 months of amenorrhea.
[0062] As used herein, the term "drug" means any physiologically or
pharmacologically active substance that produces a local and/or
systemic effect in a mammal, such as a human.
[0063] As used herein, "pharmacologically effective amount,"
"therapeutically effective amount" or simply "effective amount"
refers to that amount of a drug effective to produce the intended
pharmacological, therapeutic or preventive result. For example, if
a given clinical treatment is considered effective when there is at
least a 25% reduction in a measurable parameter associated with a
disease or disorder, a therapeutically effective amount of a drug
for the treatment of that disease or disorder is the amount
necessary to effect at least a 25% reduction in that parameter.
II. Drug Delivery Device
[0064] By way of example, FIG. 1 shows one embodiment of the
present invention. The drug delivery device shown in this figure is
offered for illustration only, and is not to be construed as
limiting the invention. As one of skill in the art will appreciate,
the drug delivery device can be manufactured in a variety of
shapes, sizes, and dimensions, depending upon the particular mammal
to be treated, as well as the nature and severity of the condition
to be treated. In FIG. 1, drug delivery device 10 comprises a body
11 sized, shaped and adapted for placement in the vaginal tract of
a human. The drug delivery device 10 comprises a body 11 formed of
a polymer that releases a drug(s) by diffusion into the vaginal
tract of the patient. The drug delivery device 10 shown in FIG. 1
comprises two unitary cylindrical segments 12 and 13, which are
connected to each other by a coupling means 14. Although FIG. 1
depicts unitary cylindrical segments one of skill in the art will
appreciate the segments can be manufactured in a variety of shapes,
sizes, and dimensions. The two segments can also be directly fused
without the need for a coupling means. Such a formulation is
contemplated by the multiple port mold of Example 9. Although the
illustrated device comprises two segments, the drug delivery device
of the present invention can comprise three, four, five, six, or
more segments. The number and size of the segments used for a
particular application will depend, inter alia, on the number of
drugs to be delivered the dosages of the drugs, and the need for a
placebo segment(s) to prevent diffusion and interaction of the
drugs within the device.
[0065] The drug delivery device of the present invention is formed
of a drug-permeable polymeric material. Suitable polymers include,
for example, olefin and vinyl-type polymers, carbohydrate-type
polymers, condensation-type polymers, rubber-type polymers, and
organosilicon polymers. In a presently preferred embodiment, the
polymer is a non-absorbable thermoplastic polymer. Polymers that
can be used for manufacturing the drug delivery device include,
without limitation, poly(ethylene-vinyl acetate),
poly(methylacrylate), poly(butylmethacrylate), plasticized
poly(vinylchloride), plasticized nylon, plasticized soft nylon,
plasticized poly(ethylene terephthalate), poly(ethylene),
poly(acrylonitrile), poly(trifluorochloroethylene),
poly(4,4'-isopropylene-diphenylene carbonate), poly(ethylenevinyl
esters), poly(vinyl chloridediethyl fumarate), poly(esters of
acrylic and methacrylic), cellulose acetate, cellulose acylates,
partially hydrolyzed poly(vinyl acetate), poly(vinyl butyral),
poly(amides), poly(vinyl carbonate), poly(urethane), poly(olefins),
and the like. These polymers and their physical properties are
known to the art and can be synthesized according to the procedures
disclosed, for example, in Encyclopedia of Polymer Science and
Technology (Interscience Publishers, Inc., New York, 1971) Vol. 15,
pp. 508-530; Polymers (1976), Vol. 17, 938-956; Technical Bulletin
SCR-159, 1965, Shell Corp., New York; and references cited therein;
and in Handbook of Common Polymers, Scott and Roff (CRC Press,
Cleveland, Ohio, 1971).
[0066] In a preferred embodiment, the thermoplastic polymer is an
ethylene-vinyl acetate (EVA) copolymer. EVA copolymers, which are
well known and commercially available materials, are particularly
useful for the controlled release of drugs by diffusion. Very
suitable EVA polymers include, for example, the EVA material
manufactured by Aldrich Chemical Co. (Cat. No. 34,050-2);
Evatane.RTM. with the designations 28-150, 28-399, and 28-400,
supplied by ICI and 28.420, and in particular 28.25 and 33.25
supplied by Atochem; and Elvax.RTM. with the designations 310, 250,
230, 220, and 210, supplied by Du Pont de Nemours.
[0067] The release of the drug by a drug delivery device comprising
EVA is determined to a large extent by the vinyl acetate content of
the material. In its broadest aspects, the present invention
contemplates use of EVA copolymers having a vinyl acetate content
of about 4 to 80% by weight of the total, and a melt index of about
0.1 to 1000 grams per ten minutes. Melt index is the number of
grams of polymer which can be forced through a standard cylindrical
orifice under a standard pressure at a standard temperature, and
thus is inversely related to the molecular weight of the polymer.
Preferably, the EVA has a vinyl acetate content of about 4 to 50%
by weight and a melt index of about 0.5 to 250 grams per ten
minutes. In general, the rate of passage of a drug through the
polymer is dependent on the molecular weight and solubility of the
drug therein, as well as on the vinyl acetate content of the
polymer. This means that selection of particular EVA compositions
will depend on the particular drug to be delivered. By varying the
composition and properties of the EVA, the dosage rate per area of
the device can be controlled. Thus, devices of the same surface
area can provide different dosage of a drug by varying the
characteristics of the EVA copolymer. The release of the drug by a
drug delivery device comprising EVA is also controlled by the
surface area of the segment. For example, in order to increase the
rate of release of the drug one could increase the length and/or
circumference of the segment.
[0068] In addition to varying the percentage of vinyl acetate in
the copolymer and the melt index or molecular weight, the
properties of the copolymer can be changed by selectively
hydrolyzing its acetate groups to alcohol groups. By converting a
portion of the vinyl acetate units of the polymer to vinyl alcohol
units, the polymer is rendered more hydrophilic and the rate of
passage of relatively hydrophilic drugs is increased. The
percentage of vinyl acetate units hydrolyzed to vinyl alcohol units
can vary widely but typically from about 20 to 60% are converted.
This partial hydrolysis is a well known procedure and can be
accomplished under standard conditions well known in the art.
Exemplary hydrolysis procedures are described in U.S. Pat. Nos.
3,386,978 and 3,494,908, both of which are incorporated by
reference herein.
[0069] The rate of diffusion of a drug from the drug delivery
device is broadly determined by measuring the rate of the drug
transferred from one chamber through a sintered glass filter of
known pore size and thickness into another chamber and calculating
from the obtained data the drug transfer rate. The procedure is
well known in the art, and described, for example, in Proc. Roy.
Sci. London, Ser. A, 148:1935; J. Pharm. Sci. (1966) 55:1224-1229;
and references cited therein. The diffusion coefficient of a drug
can also be experimentally determined by using the same or similar
apparatus. Methods for determining the diffusion coefficient are
described in Diffusion in Solids, Liquids and Gases, by W. Jost
(Rev. Ed., Academic Press Inc. NY; 1960), Chapter XI, pp. 436-488.
Preferably, the drug(s) to be delivered has a molecular weight of
between 50 and 2000, more preferably between 200 and 1300.
[0070] The solubility of a drug in an EVA copolymer is determined
by preparing a saturated solution of the drug and ascertaining, by
analysis, the amount present in a defined area of the copolymer
material. For example, the solubility of the drug in the EVA
copolymer is determined by first equilibrating the polymer material
with a saturated solution of the drug at a known temperature, for
example 37.degree. C., or with a pure liquid drug, if the drug is a
liquid at 37.degree. C. Next, the drug is desorbed from the
saturated polymer material with a suitable solvent for the drug.
The resultant solution is then analyzed by standard techniques such
as ultraviolet, visible spectrophotometry, refractive index,
polarography, electrical conductivity and the like, to calculate
the concentration or solubility of the drug in the material.
[0071] The solubility of a drug in a polymeric material can be
determined by various art known techniques. Typical methods used
for the measurement of solubility are chemical analysis,
measurement of density, refractive index, electrical conductivity,
and the like. Details of various methods for determining
solubilities are described in U.S. Public Health Service Bulletin
No. 67 of the Hygienic Laboratory; Encyclopedia of Science and
Technology (McGraw-Hill, Inc.; 1971) 12:542-556; and Encyclopaedic
Dictionary of Physics (Pergamon Press, Inc; 1962) 6:545-557. Also,
according to Fick's Law, the rate of drug solution is directly
proportional to the area (A) of the drug, A in cm.sup.2, as exposed
to polymeric material and inversely proportional to the length of
the path through which the dissolved drug must diffuse (see
Remington Pharmaceutical Science (Mack Publishing Company, 14th
Ed., 1970), pp. 246-269.
[0072] In a preferred embodiment, the drug delivery device of the
invention provides "zero order kinetic" drug administration, in
which a drug is released in a steady state, thus providing a
corresponding predictable absorption and metabolism of the drug in
the body tissues. In this manner, the delivery of drugs may be
"targeted" to the specific body organ, where the intended
therapeutic effect is desired; other organs such as liver, in which
unintended effects may occur, may be bypassed. Thus, the efficient
metabolic and therapeutic use of a drug or drug combination may be
enhanced, and the development of adverse metabolic side effects may
be reduced. "Zero order kinetic" drug administration is well known
in the art. Other methods for the controlled timed release of
predetermined amounts of pharmacologically active compositions at a
target site are also known. Methods for achieving targeted delivery
of drugs include, for example, the use of micellar structures, such
as liposomes, capsids, capsoids, polymeric nanocapsules, and
polymeric microcapsules. Liposomal suspensions (including liposomes
targeted to cells with monoclonal antibodies to specific viral
antigens) are particularly useful for practicing the methods of the
present invention. Liposomal formulations can be prepared according
to methods known to those skilled in the art, for example, as
described in U.S. Pat. No. 4,522,811; PCT publication WO 91/06309;
and European patent publication EP-A-43075, which are incorporated
by reference herein. The use of highly hydrophobic formulations,
such as liposomes, also increases the absorption rate of the drug
through the vaginal epithelium.
[0073] In another embodiment, the polymeric matrix is capable of
being degraded by ultrasonic energy such that the incorporated drug
is released at a rate within a desired release range, or, in the
case of nondegradable polymers, release is enhanced presumably due
to the effects of cavitation or other mechanical effects.
Representative suitable polymers for this embodiment include
polyanhydrides having the formula described in U.S. Pat. No.
4,657,543 (Langer et al.), which is incorporated by reference in
its entirety herein. The monomers in the copolymer can be
distributed regularly or at random. Since the anhydride linkage is
highly reactive toward hydrolysis, it is preferable that the
polymer backbone be hydrophobic in order to attain the
heterogeneous erosion of the encapsulated composition.
Hydrophobicity can be regulated easily, for example, by regulating
the concentration of aromatic moities in the linking backbone, or
by monitoring the monomer ratio in the copolymer. A particularly
suitable backbone comprises the acid such as 1-phenylamine,
tryptophan, tyrosine or glycine. Other suitable polymers include
ethylene-vinyl acetate, polylactic acid, polyglutamic acid,
polycaprolactone, lactic/glycolic acid copolymers, polyorthoesters,
polyamides or the like. Non-degradable polymers include
ethylene-vinyl acetate, silicone, hydrogels such as
polyhydroxyethylmethacrylate, polyvinyl alcohol, and the like.
[0074] In addition to providing excellent release properties, the
preferred compatible, non-absorbable, non-toxic polymeric materials
used in the manufacture of the inventive drug delivery device
(e.g., EVA copolymer, organopolysiloxane, or other rubbery-type
resilient material) do not induce a significant tissue reaction at
the site of placement in the vaginal tract of the female mammal. As
a result, the drug delivery device of the present invention is
useful in a wide variety of applications, such as those described
in sections III-VI.
[0075] The dosage unit amount for conventional beneficial drugs as
described herein is well known in the art (see, e.g., Remington's
Pharmaceutical Science (Fourteenth ed., Part IV, Mack Publishing
Co., Easton, Pa., 1970)). The amount of drug incorporated in the
drug delivery device varies depending on the particular drug, the
desired therapeutic effect, and the time span for which the device
provides therapy. Since the inventive device is intended to provide
dosage regimes for therapy for a variety of applications and
indications, there is no critical upper limit on the amount of drug
incorporated in the device. Similarly, the lower limit will depend
on the activity of the drug and the time span of its release from
the device. Thus, it is not practical to define a range for the
therapeutically effective amount of drug to be incorporated in or
released by the device.
[0076] The relative amount(s) of the drug(s) to be released can be
modified over a wide range depending upon the drug to be
administered or the desired effect. Generally, the drug can be
present in an amount which will be released over controlled periods
of time, according to predetermined desired rates, which rates are
dependent upon the initial concentration of the active substance in
the polymeric matrix. In the second embodiment described above, the
rate will also depend upon the level of ultrasonic energy to which
it is subjected. This necessarily implies a quantity of active
substance greater than the standard single dosage. Proportions
suitable for the purposes of this invention can range from about
0.01 to 50 parts by weight of the active substance to between about
99.99 and about 50 parts by weight of the polymeric matrix,
preferably between about 10 and about 30 parts by weight in the
case of a drug to be implanted to give 100 parts per weight of the
final system. The polymeric matrix in the composition to be
released can be admixed in any convenient manner, for example by
mixing the components as powders and subsequently forming the
mixture into a desired shape such as by thermal forming at a
temperature less than that which the composition will become
degraded and at which the polymer has desired morphological
properties. Such procedures are described in detail in the examples
provided herein.
[0077] The polymeric mixture utilized in the drug delivery device
used in the methods of the present invention can be manufactured by
standard techniques provided that such manufacture includes process
steps such as blending, mixing or the equivalent thereof for
structurally defining the system comprising the drug(s) to be
released and the polymeric matrix. For example, one suitable method
for making the inventive devices comprises mixing the polymer and
an appropriate solvent, thereby to form a casting solution, mixing
a known amount of the drug to be released in the casting solution,
charging the solution into a mold and then drying the mold,
optionally under vacuum, causing the polymer to precipitate in
forming the matrix with the drug to be released therein.
Alternatively, the polymer in the form of a powder can be admixed
with the drug to be released in the form of a powder and then
molded under adequate temperature and pressure to the desired
shape, through injection, compression, or extrusion. When two or
more drugs are to be delivered, the foregoing steps of manufacture
are repeated for each individual drug, thus forming a separate
molded polymeric mixture for each drug. The individual molded
polymeric mixtures, each preferably containing a different drug,
are then cut into pieces of the required length using conventional
cutting techniques, thus producing a plurality of uniform segments.
The drug delivery device or system for simultaneous delivery of
multiple drugs is then assembled by joining together, directly or
indirectly, at least one segment of the molded polymeric mixture
for each drug to be delivered. Preferably, the uniform segments are
assembled to form a ring shape, which has a thickness between about
1 mm and about 5 mm. The drug delivery devices of this invention
can be manufactured in a wide range of shapes, sizes and forms for
delivering the drug(s) to different environments of use.
[0078] Alternatively, when two or more drugs are to be delivered,
each drug:polymer mix can be molded together under adequate
temperature and pressure to the desired shape, through injection,
compression, or extrusion such that the two drug mixtures form one
solid unit and do not require a coupling means. In one embodiment,
the drug mixtures are injected, preferably sequentially, into a
mold comprising a single port. In an alternative embodiment, as
exemplified in Example 8, herein below, the drug mixtures are
injected simultaneously or sequentially into a mold having multiple
ports. Multiple port moldings are well known and commercially
available in the art. Such molding may be modified or customized
for a particular application as will be appreciated by those of
skill in the art.
[0079] In one embodiment, discussed briefly above, the ends of the
segments are joined together to form a drug delivery device using a
coupling means. The coupling means can be any method, mechanism,
device or material known in the art for bonding materials or
structures together. Exemplary coupling means include solvent
bonding, adhesive joining, heat fusing, heat bonding, pressure, and
the like. When a solvent is used, the ends of the segments are
moistened with an organic solvent that causes the surfaces to feel
tacky, and when placed in contact the surfaces then bond and adhere
in a fluid tight union. The ends of the segments can be adhesively
united to form a ring-shaped delivery device by applying an
adhesive to at least one end of a segment, and then contacting the
adhesive coated end or ends. For the above procedures, the solvents
include organic solvents such as methylene chloride, ethylene
dichloride, trichlorobenzene, dioxan, isophorone, tetrahydrofuran,
aromatic and chlorinated hydrocarbons, mixed solvents such as 50/50
ethylene dichloride/diacetone alcohol; 40/60 alcohol/toluene; 30/70
alcohol/carbon tetrachloride, and the like. Suitable adhesives
include natural adhesives and synthetic adhesives, such as animal,
nitrocellulosic, polyamide, phenolic, amino, epoxy, isocyanate,
acrylic, silicate, organic adhesives of polymers, and the like.
Adhesives are well known to the art (see, e.g., The Encyclopedia of
Chemistry (Second ed.; G. L. Clark and G. G. Hawley, editors;
VanNostrand Reinhold Co., Cincinnati, Ohio; 1966)), as well as
solvents (see, e.g., Encyclopedia of Chemical Technology
(Kirk-Othmer, Sec. Ed., Vol. 16, Interscience, Publishers Inc., New
York, 1969)).
[0080] The lengths of the segments of the drug delivery device or
system are chosen to give the required performance. Ratios of the
lengths of the segments will depend upon the particular therapeutic
application, including the desired ratio and dosages of each drug
to be delivered. Ratios of the lengths of the segments are
contemplated to be between 30:1 and 1:30, preferably between 15:1
and 1:1. When placebo segments are required to prevent drug
diffusion and interactions, the lengths of the placebo segments are
long enough to prevent excessive mixing of the drugs. The length of
the placebo segment depends on the nature of the polymeric
substance and its capacity to prevent permeation of the drugs.
Preferably, the placebo segment completely prevents mixing of the
drugs, since mixing may disturb the release pattern. However,
depending upon the drugs, some minor mixing is generally permitted,
provided it does affect the release of the drugs in such a manner
that plasma levels of the drugs get outside the required values.
Placebo segments may also be used to close or complete the
ring-shaped structure.
[0081] In an alternate embodiment, the drug delivery device is
manufactured by preparing unitary rods, rather then segments, then
joining the ends of the rods to form a ring-shaped drug delivery
device for the simultaneous release of multiple drugs. In this
embodiment, the unitary rods are prepared essentially as described
above for the segments, except that the polymeric mixture is molded
into the shape of a rod rather than a ring. In the case of vaginal
rings, the polymeric substance must be sufficiently pliable when
dry to allow the rods to be bent and formed into the final
ring-shaped device. Thus, the step of cutting the ring into
segments may be avoided, provided that the molded rods meet the
specifications (e.g., length, diameter, etc.) to deliver the
required dosages of drugs. Alternatively, the polymeric mixture may
be molded into over-sized cylindrical rods, which are then cut into
shorter rods having the required dimensions. Rods of the proper
size are then joined end-to-end, as described above for the
segments, to form a ring-shaped drug delivery device.
[0082] As previously mentioned, the drug delivery device can be
manufactured in any size as required. For human use, however, the
outer ring diameter will generally be between 40 mm and 80 mm,
preferably between 45 mm and 70 mm, and more preferably between 50
and 60 mm. Similarly, the cross sectional diameter will typically
be between 0.5 mm and 12 mm, preferably between 0.5 mm and 10 mm,
more preferably between 1 mm and 8 mm, even more preferably between
1 and 6 mm, and most preferably between 1 and 5 mm.
III. Administration
[0083] In another aspect, the invention relates to a method for
delivering a drug to a female mammal. The method involves preparing
a drug delivery device, as described above. The device is then
positioned in the vaginal tract of the female mammal to be treated,
where it is maintained for a period of time sufficient to deliver
an effective amount of the drug to the female mammal. Although the
present invention is described in terms of an intravaginal drug
delivery device, the invention contemplates making and using a
device for administering a drug to a male mammal. In this case, the
device is manufactured in a shape and size appropriate for use in a
male mammal, for example as a subdermal implant or rectal
suppository. The male drug delivery device may comprise any
suitable active substance for use in a wide variety of applications
and for treating a variety of diseases and medical conditions, such
as those described below, and particularly male-specific diseases
such as prostate cancer.
[0084] Because of its convenience, safety, and excellent release
properties, the drug delivery device of the present invention is
useful in a wide variety of applications, and can be used to treat
numerous conditions and disorders. Examples of applications and
therapeutic uses for the device include, without limitation,
contraception, hormone replacement therapy, polycystic ovarian
disease, addiction, imaging, AIDS/HIV, immunology, alcohol-related
disorders, infectious diseases, allergy, leukemia/lymphoma,
Alzheimer's disease, lung cancer, anesthesiology, metabolic
disorders, anti-infectives, neonatology, anti-inflammatory agents,
neurological disorders, arthritis, neuromuscular disorders, asthma,
nuclear medicine, atherosclerosis, obesity, eating disorders, bone
diseases, orthopedic, breast cancer, colon cancer, prostate cancer,
cancer, parasitic diseases, cardiovascular diseases, hypertension,
toxemia of pregnancy, seizures perinatal disorders, child health,
pregnancy, preventative medicine, congenital defects, decision
analysis, psychiatric disorders, degenerative neurologic disorders,
pulmonary disorders, dementia, radiology, dermatology, renal
disorders, diabetes mellitus, reproduction, diagnostics, Rheumatic
diseases, stroke, drug discovery/screen, surgical, endocrine
disorders, transplantation, ENT, vaccines, epidemiology, vascular
medicine, eye diseases, wound healing, fetal and maternal medicine,
women's health, gastrointestinal disorders, gene therapy, genetic
diagnostics, genetics, genitourinary disorders, geriatric medicine,
growth and development, hearing, hematologic disorders,
hepatobiliary disorders, and hypertension.
[0085] Any pharmaceutically active agent used to treat the body,
and which is capable of diffusing through the polymer and being
absorbed by the lining of the vaginal tract, is useful in the
present invention. Preferably, though not necessarily, the drug is
one that has already been deemed safe and effective for use by the
appropriate governmental agency or body. For example, drugs for
human use listed by the FDA under 21 C.F.R. 330.5, 331 through 361;
440-460; drugs for veterinary use listed by the FDA under 21 C.F.R.
500-582, incorporated herein by reference, are all considered
acceptable for use in the present novel polymer networks. Examples
of suitable active substances (drugs) include, without limitation,
interferon, anti-angiogenesis factors, antibodies, antigens,
polysaccharides, growth factors, hormones including insulin,
glucogen, parathyroid and pituitary hormones, calcitonin,
vasopressin, renin, prolactin, thyroid stimulating hormone,
corticotrophin, follicle stimulating hormone, luteinizing hormone
and chorionic gonadotropins; enzymes including soybean, tyrpsin
inhibitor, lysozyme, catalase, tumor angiogenesis factor, cartilage
factor, transferases, hydrolases, lysases, isomerases, proteases,
ligases and oxidoreductases such as esterases, phosphatases,
glysidases, and peptidases; enzyme inhibitors such as leupeptin,
antipain, chrymostatin and pepstatin; and drugs such as steroids,
anti-cancer drugs or antibiotics. Suitable pharmaceuticals for
parenteral administration are well known as is exemplified by the
Handbook on Injectable Drugs, 6th edition, by Lawrence A. Trissel,
American Society of Hospital Pharmacists, Bethesda, Md., 1990
(hereby incorporated by reference).
[0086] Additional examples of drugs which may be delivered by drug
delivery devices according to this invention include, without
limitation, prochlorperzine edisylate, ferrous sulfate,
aminocaproic acid, mecamylamine hydrochloride, procainamide
hydrochloride, amphetamine sulfate, methamphetamine hydrochloride,
benzamphetamine hydrochloride, isoproterenol sulfate, phenmetrazine
hydrochloride, bethanechol chloride, methacholine chloride,
pilocarpine hydrochloride, atropine sulfate, scopolamine bromide,
isopropaimide iodide, tridihexethyl chloride, phenformin
hydrochloride, methylphenidate hydrochloride, theophylline
cholinate, cephalexin hydrochloride, diphenidol, meclizine
hydrochloride, prochlorperazine maleate, phenoxybenzamine,
thiethylperzine maleate, anisindone, diphenadione erythrityl
tetranitrate, digoxin, isofluorophate, acetazolamide,
methazolamide, bendroflumethiazide, chloropromaide, tolazamide,
chlormadinone acetate, phenaglycodol, allopurinol, aluminum
aspirin, methotrexate, acetyl sulfisoxazole, erythromycin,
hydrocortisone, hydrocorticosterone acetate, cortisone acetate,
dexamethasone and its derivatives such as betamethasone,
triamcinolone, methyltestosterone, 17-S-estradiol, ethinyl
estradiol, ethinyl estradiol 3-methyl ether, prednisolone,
17.varies.-hydroxyprogesterone acetate, 19-nor-progesterone,
norgestrel, norethindrone, norethisterone, norethiederone,
progesterone, norgesterone, norethynodrel, aspirin, indomethacin,
naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin,
isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol,
cimetidine, clonidine, imipramine, levodopa, chlorpromazine,
methyldopa, dihydroxyphenylalanine, theophylline, calcium
gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin,
haloperidol, zomepirac, ferrous lactate, vincamine, diazepam,
phenoxybenzamine, diltiazem, milrinone, capropril, mandol,
quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenufen,
fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuinal,
nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine,
lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine,
lisinolpril, enalapril, enalaprilat, captopril, ramipril,
famotidine, nizatidine, sucralfate, etintidine, tetratolol,
minoxidil, chlordiazepoxide, diazepam, amitriptyline, and
imipramine.
[0087] The compositions of the invention include a safe and
effective amount of a pharmaceutically active agent. "Safe and
effective" as it is used herein, means an amount high enough to
significantly positively modify the condition to be treated or the
pharmaceutic effect to be obtained, but low enough to avoid serious
side effects. As is mentioned herein above, compositions of the
invention are considered to include both pharmaceutical agents
which treat the source or symptom of a disease or physical disorder
and personal care or cosmetic agents which promote bodily
attractiveness or mask the physical manifestations of a disorder or
disease.
[0088] Any conventional pharmaceutical permeation enhancer that
does not interfere with performance of the pharmaceutically active
agent can be used in the preparations according to the present
invention. A "permeation enhancer" is any compound that increases
the uptake of the pharmaceutically active agent. Examples of
permeation enhancers which may be used with the drug delivery
devices according to this invention include, without limitation,
alcohols, short- and long-chain alcohols, polyalcohols, amines and
amides, urea, amino acids and their esters, amides, azone or
pyrrolidone and its derivatives, terpenes, fatty acids and their
esters, macrocyclic compounds, sulfoxides, tensides,
benzyldimethylammonium chloride, cetyl trimethyl ammonium bromide,
cineole, cocamidopropyl betaine, cocamidopropyl hydroxysultaine,
dodecyl pyridinium chloride, dodecylamine, hexadecyl
trimethylammoniopropane sulfonate, isopropyl myristate, limonene,
linoleic acid (OA), linolenic acid (LA), menthol, methyl laurate,
methylpyrolidone, N-decyl-2-pyrrolidone, NLS, nicotine sulfate,
nonyl-1,3-dioxolane, octyl trimethylammonium bromide, oleyl
betaine, PP, polyethyleneglycol dodecyl ether, polyoxyethelene
sorbitan monolaurate (TWEEN20), SLA, sodium oleate, sodium lauryl
sulfate, sodium octyl sulfate (SOS), sorbitan monolaurate (S20),
TWEEN20, tetracaine, and Triton X-100. Additional examples of
permeation enhancers can be found in Sayani and Chien, Crit. Rev.
Ther. Drug Carrier Syst. 13:85-184 (1996); Karande et al. Nature
Biotechnology, 22, (2), 192-197, (2004); Pfister et al., Med Device
Technol. November-December 1990; 1(6):28-33; Mitragotri, Pharm Res.
November 2000; 17(1):1354-9; and Hadgraf Int J Pharm. Jul. 5, 1999;
184(1):1-6, and references cited therein.
[0089] The drug delivery devices of the present invention are
constructed in such a way that they are retained in the vagina for
periods of a day up to several months and can be readily inserted
and removed, for example, in the case of the human female patient.
The device, due to its unique shape and size, does not obstruct the
cervix, as do diaphragms. In an optional embodiment, a locally
effective antimicrobial agent, for example an antibiotic such as
neomycin, nystatin and polymyxin can be included within the
polymeric material. The improved device of this invention possesses
numerous advantages over, for example, the intravaginal devices
comprising multiple reservoirs or layers. Such advantages include
controlled, simultaneous release of multiple drugs, release of
drugs in a substantially constant ratio over a prolonged period of
time, and ease and low cost of manufacture. The drug or combination
of drugs can be incorporated into the device in sufficient amounts
to bring about the desired local and/or systemic effect. The drug
delivery device of the present invention provides more immediate
effects, as compared to existing devices, as well as more uniform
and constant serum levels of drug during the predetermined period
of time for which the beneficial physiologic effects are desired.
This is in marked contrast to fluctuations that occur with known
intravaginal devices, for example the delayed release associated
with most layered devices, the inconsistent and unreliable release
frequently observed with multi-compartment or multi-reservoir
devices, and the variations in the pre-set fixed release ratio
commonly associated with drug delivery devices for administering
multiple drugs.
IV. Methods for Treating Benign Ovarian Secretory Disorders
[0090] In one embodiment, the invention relates to a method for
treating benign ovarian secretory disorders in female mammals
(patients) using a drug delivery device to deliver an effective
amount of an LHRH composition (i.e., luteinizing hormone releasing
hormone (LHRH), LHRH analogues, LHRH agonists and/or LHRH
antagonists, and/or their non-peptide analogues capable of binding
to the LHRH receptor), an effective amount of an estrogenic steroid
and/or its receptor modulators, and an effective amount of a
progestational steroid and/or its receptor modulators. Preferably,
the device is administered to the patient during an induced
follicular phase of the menstrual cycle, beginning, if possible, at
the onset of menses. In patients whose benign ovarian secretory
disorder is characterized by amenorrhea, the methods of the
invention may be initiated at any time following the determination
of a non-pregnant status. The continuous delivery of LHRH
compositions in combination with sex steroid delivery for use in
treating benign ovarian secretory disorders is described in detail
in U.S. Pat. No. 5,130,137 (Crowley, Jr.), which is incorporated by
reference in its entirety herein.
[0091] In addition, patients with disorders such that their ovaries
malfunction for any of a variety of reasons such that their ovaries
secrete excessive sex steroids, i.e., estrogens, progestins, and/or
androgens, the consequences of which are recurrent irregular
menstrual periods, and/or hirsutism would be included in the
methods of the invention. The methods of the invention are
especially useful in treating polycystic ovarian disease, and
ovarian diseases characterized by dysfunctional uterine bleeding,
amenorrhea, and especially hyper-, normo-, or hypo-gonadotropic
amenorrhea, and hyperthecosis.
[0092] The methods of the invention for treating benign ovarian
secretory disorders are characterized in that they provide a
continuous hormonal replacement therapy which simulates a normal
sex steroid hormone pattern in the patient that is similar to those
levels and/or patterns of sex steroid secretion encountered in
normal women during their ovulatory menstrual cycles.
[0093] Progesterone and estradiol are well characterized in the
art. Table 1 lists current estradiol and progesterone products in
human use with relevant properties. The following publications are
referenced in Table 1: (1) Levy et al. Hum Reprod. March 1999;
14(3):606-10; (2) Mircuioiu et al. Eur J Drug Metab Pharmacokinet.
July-September 1998; 23(3):391-6; and (3) Archer et al. Am J Obstet
Gynecol. August 1995; 173(2):471-7; discussion 477-8, all of which
are herein incorporated by reference.
TABLE-US-00001 TABLE 1 Steady State Amount/ Serum Name Steroid
Device Rate/day Concentration T.sub.max Normal Menstrual Cycle Sex
Estradiol 50-700 ug 50-500 pg/ml Midcycle Steroid Secretion
Progesterone 2-6 ng/ml Midluteal Vaginal Estring Estradiol 2 mg 22
ug 8 pg/ml 1 h Rings Intravaginal Estrace Estradiol 0.1 mg Gels
VagiFem 25 ug 25 ug Crinone Progesterone 45 & 90 mg 45/90 mg 7
ng/ml 5.6-6.8 h Transdermal Alora Estradiol 1.5, 2.3, 50, 75, and
60-100 pg/ml 18-24 h and 3.0 100 ug mg Climara 2.0, 3.8, 25, 50, 75
22-106 pg/ml 18-24 h 5.7 or or 100 ug 7.6 mg Vivelle 0.39, 25,
37.5, 34-104 pg/ml 1 h 0.585, 50, 75, or 0.78, 100 ug 1.17, or 1.56
mg Oral ORTHO- Estradiol 1 mg 1 mg/day 7 h PREFEST 0.5, 1 &
0.5, 1 & Estrace 2 mg 2 mg/day PROMETRIUM Progesterone 100/200
mg 100/200 mg ~3 ng/ml 1.5/2.3 h Vaginal Academic Progesterone
50/100 mg 50/100 mg 6-7 ng/ml 6.1/6.4 h Tablets/ Research
Suppository 100/200 mg 100/200 mg 6-10 ng/mL 4 h 100/200 mg 100/200
mg 10-14 ng/mL Our Target WHI Estradiol 3 mg 100 ug 100 pg/mL
Progesterone 630 mg 45 mg 6 ng/mL D-Trp6- 5 mg 4 ug/Kg/day 10-100
pg/mL Pro9-Net- GnRH Name C.sub.max T.sub.1/2 Indication Normal
Menstrual Cycle Sex 500 pg/ml Steroid Secretion 35 ng/ml 12 h --
Vaginal Estring 63 pg/ml Rx. of urogenital Sx. Rings in menopause
Intravaginal Estrace Rx of vulval and Gels vaginal atrophy VagiFem
50 pg/ml Rx of atrophic vaginitis Crinone 14 ng/ml 34-55 h
progesterone supplementation or replacement as part of an IVF
Transdermal Alora 92-144 pg/ml 2 h Rx of vaso- motor Sx. in
menopause Climara 32-174 pg/ml 4 h Rx of vulvar and vaginal atrophy
Vivelle 46-145 pg/ml 5.9-7.7 h Oral ORTHO- 27.4 pg/ml 16 h Rx. of
vasomotor PREFEST symptoms in the Estrace menopause PROMETRIUM
17/28 ng/ml Prevention of endometrial hyperplasia in non-
hysterectomized postmenopausal women Rx'd with estrogens Vaginal
Academic 20/31 nmol/l 13.2/13.7 h .sup.1 Tablets/ Research
Suppository 10-15 ng/mL 9-14 h .sup.2 5.7-20.9 ng/mL .sup.3 Our
Target WHI
[0094] The methods of the invention for treating benign ovarian
secretory disorders comprise providing a drug delivery device
having two or more segments, wherein a first segment comprising a
drug-permeable polymeric substance and a LHRH, and a second segment
comprising an effective amount of an estrogenic steroid or
selective estrogen receptor modulator (SERM). The drug delivery
device is then inserted into the vagina of the female mammal, such
as a human female, to release effective amounts of the hormones.
The drug-permeable polymeric substance may be a thermoplastic
polymer, such as an ethylene-vinyl acetate copolymer. The drug
delivery device may be in the shape of a ring, a wafer, or a
suppository. In a preferred embodiment, the drug delivery device is
a ring-shaped device such as the one described above in Section
II.
[0095] Estrogenic steroids which can be used according to this
aspect of the invention include natural estrogenic hormones and
congeners, including, but not limited to, estradiol, estradiol
benzoate, estradiol cypionate, estradiol valerate, estrone,
piperazine, estrone sulfate, ethinyl estradiol, polyestradiol
phosphate, estriol, and estrone potassium sulfate. Synthetic
estrogens can be used in the invention, including, but not limited
to, benzestrol, chlorotrianisene, dienestrol, diethystilbestrol,
diethylstilbestrol diphosphate, and mestranol. In the preferred
embodiment of this invention, natural estrogenic hormones are used.
Also included are estrogens developed for veterinary use, including
equine estrogens such as equilelinin, equilelinin sulfate and
estetrol.
[0096] In addition to the above-described estrogenic compounds,
estrogenic steroids useful in accordance with this aspect of the
invention include selective estrogen receptor modulators (SERMs),
which are estrogen analogues having tissue-selective effects.
Examples of suitable SERMs include tamoxifen, raloxifene,
clomiphene, droloxifene, idoxifene, toremifene, tibolone, ICI
182,780, ICI 164,384, diethylstilbesterol, genistein, nafoxidine,
moxestrol, 19-nor-progesterone derivatives, and 19-nor-testosterone
derivatives.
[0097] Typical dose ranges for estrogenic steroids will depend upon
the estrogenic steroid compounds chosen for use in the methods of
the invention and the female mammal patient. As an example, for
estradiol, for the human adult female, typical dose ranges will be
administered such that the serum level of estradiol will be from
about 20 to about 200 pg/ml. Preferably the serum level of
estradiol is from about 50 to about 150 pg/ml; more preferably from
about 80 to about 120 pg/ml. Levels of the synthetic estrogens
which are the physiological equivalents of these ranges of
estradiol can be used according to the methods of the
invention.
[0098] Plasma estradiol can be measured by a variety of means well
known in the art, e.g. ELISA. For example plasma estradiol levels
can be measured by a microparticle enzyme immunoassay (MEIA)
technology utilizing the AxSYM immunoassay system (Abbott) with the
Estradiol reagent pack (Abbott, Cat.#7A63-20) according to
manufacturer's protocol.
[0099] Progestational steroids which can be used according to the
invention described herein include, but are not limited to,
dydrogesterone, ethynodiol diacetate, hydroxyprogesterone caproate,
medroxyprogesterone acetate, norethindrone, norethindrone acetate,
norethynodrel, norgestrel, progesterone, and megestrol acetate.
[0100] Veterinarian progestational steroids can also be used in
this invention, including acetoxyprogesterone, chlormadinone
acetate, delmadinone acetate, proligesterone, melengestrol acetate,
and megestrol acetate.
[0101] Other progestational steroids useful in accordance with this
aspect of the invention include selective progestin receptor
modulators (SPRMs). Examples of suitable SPRMs include RU486,
CDB2914, 19-nor-progesterone derivatives, 19-nor-testosterone
derivatives, 6-aryl-1,2-dihydro-2,2,4-trimethylquinoline
derivatives, 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinoline
derivatives, 5-alkyl 1,2-dihydrochomeno[3,4-f]quinoline
derivatives, and 6-thiophenehydroquinoline derivatives.
[0102] Typical dose ranges for progestational steroids will also
depend upon the progestational steroid chosen for use in this
invention and upon the female mammal patient. For a human adult
female, typical dose ranges will be an amount which can be
administered such that the patient's serum levels of progesterone
will be from about 1 to about 20 ng/ml. Preferably the serum level
of progesterone is from about 1 to about 15 ng/ml; more preferably
from about 2 to about 10 ng/ml.
[0103] Plasma progesterone can be measured by a variety of methods
well known in the art, e.g., ELISA. For example, Levy et al. Human
Reproduction, 14:606-610 (1999), which is herein incorporated by
reference teaches that plasma progesterone may be measured by the
IMMULITE chemiluminescent immunoassay (Diagnostic Products
Corporation, Los Angeles, Calif.).
[0104] In the combined administration of an effective dose of LHRH
composition, the dose range will depend upon the particular LHRH
composition used, but will be in an amount sufficient to suppress
LH and FSH secretion by the action of the LHRH composition on the
pituitary membrane LHRH receptor and/or block its subsequent
biological action. As will be understood by one of skill in the
art, the effective dose ranges will be compound specific and will
depend upon patient characteristics, such as species, age and
weight. An effective dose range of LHRH composition may be
determined by routine testing by one of skill in the art, without
undue experimentation. Further, the LHRH composition may comprise
one LHRH composition or may comprise two or more LHRH compositions.
In general, it is expedient to administer the active LHRH
composition in amounts between about 0.01 to 10 mg/kg of body
weight per day. It will be understood in the art that this range
will vary depending upon whether a LHRH antagonistic analogue or a
LHRH agonistic analogue, or a combination of the two, is
administered.
[0105] It well known in the art how to measure FSH and LH levels in
plasma. For example FSH and LH can both be measured by ELISA. Levy
et al. teaches that leutinizing hormone and FSH can be measured by
Enzyme test kit (Boehringer Mannheim Immunodiagnostics, Sussex,
UK).
[0106] As is known in the art, menstrual cycles are characteristic
of humans and primates and do not occur in other vertebrate groups.
Other mammals have estrous cycles. Both menstrual cycles and
estrous cycles are regulated by the same interaction of the
hypothalamic, pituitary and ovarian hormones, and the effects of
the ovarian hormones on the reproductive tract are comparable. The
menstrual cycle is generally divided into two phases: the
follicular phase and the luteal phase. The follicular phase extends
from the onset of menstruation to ovulation (approximately 14 days
in the humans). The luteal phase extends from ovulation to the
beginning of menstruation (approximately another 14 days in
humans).
[0107] The estrous cycle is generally divided into four phases: the
estrus phase, the metestrus phase, the diestrus phase, and the
proestrus phase. Ovulation typically occurs during the estrus phase
and thus the estrus and metestrus phases roughly correspond to the
luteal phase. The diestrus phase and proestrus phase roughly
correspond to the follicular phase. As used herein, these phases
are all referred to as "follicular" and "luteal phases" of the
menstrual cycle, although it is to be understood that the invention
described herein also applies to mammals with estrous cycles.
Appropriate dose ranges can be determined for mammals with estrous
cycles by one of skill in the art through routine testing, without
undue experimentation. In mammals with estrous cycles, it may also
be desirable to control estrous behavior. The dose range
administered for prevention of pregnancy and reduction of estrous
behavior can also be determined by one of skill in the art by
routine testing. The methods would be especially useful in
treating, for example, female animals diagnosed with cystic ovarian
disease (COD) and especially when such cysts manifest themselves as
nymphomania, continuous estrus, irregular estrus, first estrus
postpartum, anestrus since calving, anestrus after estrus,
persistant corpus luteum or anestrus after insemination.
[0108] The methods of this invention may be administered to mammals
including but not limited to humans, primates, equines, canines,
felines, bovines, ovines, ursines, and fowl.
[0109] LHRH compositions are absorbed very well across a wide
variety of surfaces. Thus oral, subcutaneous, intramuscular,
intravenous, vaginal, nasal, transdermal and aural routes of
administration have all proven to be effective. In a preferred
embodiment of this invention, administration of the delivery system
is made via the vaginal route. Approximately 1-10% or greater of
the LHRH composition is absorbed through the vaginal epithelium.
Thus, the LHRH composition is administered via a vaginal delivery
system using a matrix which permits transvaginal absorption. In
this same first vaginal delivery system, an effective dosage of
physiological amounts of an estrogenic steroid is also delivered.
This delivery system allows complete suppression of gonadotropins,
removal of reproductive function of the ovaries, total suppression
of ovarian steroidogenesis, and yet still effects a physiological
replacement of sufficient levels of estrogen to thwart the long
term side effects of the estrogen deficiency that occurs during
LHRH administration. This vaginal delivery device is preferably
administered during the follicular phase of the menstrual cycle,
beginning at the onset of menses.
[0110] The methods of the invention would also be useful to induce
breeding. In seasonal breeding animals, such as sheep, sequential
application of an induced follicular phase of variable length
followed by an induced luteal phase would induce subsequent
estrous. Such induced estrous provides a more timely and
experimentally controllable breeding. The methods of the invention
would also serve to induce breeding at a higher frequency, for
example, to induce breeding more than once or twice a year.
V. Methods for Preventing Pregnancy in Mammals
[0111] In another embodiment, the invention relates to a method for
preventing pregnancy in a mammal. The method comprises
administering an effective amount of an LHRH composition (i.e.,
luteinizing hormone releasing hormone (LHRH), LHRH analogues, LHRH
agonists and/or LHRH antagonists, and/or their non-peptide
analogues capable of binding to the LHRH receptor) and an effective
amount of an estrogenic steroid and/or a selective estrogen
receptor modulator (SERM) during the follicular phase of the
menstrual cycle, beginning at the onset of normal menses. Next,
during the luteal phase of the menstrual cycle, the method
comprises administering an effective amount of a LHRH composition,
an effective amount of an estrogenic steroid and/or SERM, and an
effective amount of a progestational steroid and/or a selective
progestin receptor modulator (SPRM). Following the luteal phase,
the LHRH composition and an effective amount of an estrogenic
steroid and/or SERM are administered, at which time menstruation
would typically occur. The continuous delivery of LHRH compositions
in combination with sex steroid delivery for use as a contraceptive
is described in detail in U.S. Pat. No. 4,762,717 (Crowley, Jr.),
which is incorporated by reference in its entirety herein.
[0112] The LHRH composition (i.e., luteinizing hormone releasing
hormone (LHRH), LHRH analogues, LHRH agonists and/or LHRH
antagonists, and/or their peptide or non-peptide analogues capable
of binding to the LHRH receptor), estrogenic steroid and/or SERM,
and progestational steroid or non-steroidal analogues and/or SPRM,
which are useful in accordance with this aspect of the invention,
are described above.
[0113] Typical dose ranges for estrogenic steroids and SERMs will
depend upon the estrogenic steroid compound chosen for use in this
invention and the female mammal patient. For a human adult female,
typical dose ranges will be administered such that the serum level
of estradiol will be from about 50 to about 140 pg/ml. Preferably
the serum level of estradiol is from about 20 to about 150 pg/ml;
more preferably from about 80 to about 120 pg/ml. Serum estrogenic
steroid levels can be measured as described in Section IV.
[0114] Typical dose ranges for progestational steroids and SPRMs
will also depend upon the progestational steroid chosen for use in
this invention and upon the female mammal patient. For a human
adult female, typical dose ranges will be an amount which can be
administered such that the patient's serum levels of progesterone
will be from about 1 to about 20 ng/ml. Preferably the serum level
of progesterone is from about 1 to about 15 ng/ml; more preferably
from about 2 to about 10 ng/ml. Serum progesterone levels can be
measured as described in Section IV.
[0115] In the combined administration of an effective dose of LHRH
composition, the dose range will depend upon the particular LHRH
composition used, but will be in an amount sufficient to suppress
LH and FSH secretion by the action of the LHRH composition on the
pituitary membrane receptor and block its subsequent actions. As
will be understood by one of skill in the art, the effective dose
ranges will be compound specific and will depend upon patient
characteristics, such as age and weight. An effective dose range of
LHRH composition may be determined by routine testing by one of
skill in the art, without undue experimentation. Further, the LHRH
composition may comprise one LHRH composition or may comprise two
or more LHRH compositions. In general, it is expedient to
administer the active LHRH composition in amounts between about
0.01 to 10 mg/kg of body weight per day. It will be understood in
the art that this range will vary depending upon whether a LHRH
antagonistic analogue or a LHRH agonistic analogue, or a
combination of the two, is administered. Serum LH and FSH levels
can be measured as described in Section IV.
[0116] As is known in the art, menstrual cycles are characteristic
of humans and primates and do not occur in other vertebrate groups.
Other mammals have estrous cycles. Both menstrual cycles and
estrous cycles are regulated by the same interaction of the
hypothalmic, pituitary and ovarian hormones, and the effects of the
ovarian hormones on the reproductive tract are comparable. The
menstrual cycle is generally divided into two phases: the
follicular phase and the luteal phase. The follicular phase extends
from the onset of menstruation to ovulation (approximately 14 days
in humans). The luteal phase extends from ovulation to the
beginning of menstruation (approximately another 14 days in
humans).
[0117] The estrous cycle is generally divided into four phases: the
estrus phase, the metestrus phase, the diestrus phase, and the
proestrus phase. Ovulation typically occurs during the estrus phase
and thus the estrus and metestrus phases roughly correspond to the
luteal phase. The diestrus phase and proestrus phase roughly
correspond to the follicular phase. As used herein, these phases
are all referred to as follicular and luteal phases of the
menstrual cycle, although it is to be understood that the
inventions described herein also apply to mammals with estrous
cycles. Appropriate dose ranges can be determined for mammals with
estrous cycles by one of skill in the art through routine testing,
without undue experimentation. In mammals with estrous cycles, it
may also be desirable to control estrous behavior. The dose range
administered for prevention of pregnancy and reduction of estrous
behavior can also be determined by one of skill in the art by
routine testing.
[0118] The method of this invention may be administered to mammals
including but not limited to humans, primates, equines, canines,
felines, bovines, and ursines.
[0119] The methods of the invention for preventing pregnancy in a
mammal comprise providing a drug delivery device having two or more
segments, wherein a first segments comprising a drug-permeable
polymeric substance and a LHRH, and a second segment comprising an
effective amount of an estrogenic steroid or SERM. The drug
delivery device is then inserted into the vagina of the female
mammal, such as a human female, to release effective amounts of the
hormones. The drug-permeable polymeric substance may be a
thermoplastic polymer, such as an ethylene-vinyl acetate copolymer.
The drug delivery device may be in the shape of a ring, a wafer, or
a suppository. In a preferred embodiment, the drug delivery device
is a ring-shaped device such as the one described below in Section
V.
[0120] In one embodiment of this aspect of the invention, the
device described above is removed following maintenance of the
LHRH/estrogenic steroid deliver, system during the follicular phase
(typically fourteen days in humans), and replaced by a second
vaginal delivery system which has the LHRH/estrogenic steroid
combination and the effective physiological amount of a
progestational steroid or SPRM. This second delivery system is
administered during the luteal phase of the menstrual cycle
(typically fourteen days in humans), until the onset of normal
menses. This second delivery system provides an artificial luteal
phase to the female.
[0121] Following the second vaginal delivery system, and
readministration of the first vaginal delivery system, menstruation
occurs, reassuring the patient of lack of conception. Further, the
administration of a progestational steroid in the second delivery
system permitting menstruation, also avoids endometrial
hyperplasia.
[0122] In an alternate embodiment of this aspect of the invention,
the two formulations described above (the LHRH/estrogenic steroid
formulation and LHRH/estrogenic/progestational steroid formulation)
are combined in one drug delivery device, which is designed to
remain in the vagina of the female for the entire menstrual cycle.
In this embodiment, the drug delivery device comprises at least one
cylindrical unitary segment per hormonal formulation, or,
alternatively, at least one cylindrical unitary segment per active
ingredient (i.e., LHRH, sex steroid, or sex steroid modulator). The
choice of polymeric material and the ratio of polymeric material to
LHRH/sex steroid/sex steroid modulator are preselected for each
segment to provide the appropriate release kinetics for the
individual steroids and/or steroidal formulations. By selecting the
polymeric material based on its release properties and adjusting
the ratio of polymeric material to drug, the method of the present
invention provides the pre-set timed delivery of LHRH, estrogenic
steroid, and progestational steroid at the appropriate phase of the
menstrual cycle to achieve the desired contraceptive effect. For
example, this "combined" device would release LHRH and/or its
agonists or antagonists continuously for 30 days in combination
with an estrogenic compound. After approximately two weeks of such
therapy, the device would release progesterone or a progestational
steroid or non-steroidal compound for the last 14 days of the cycle
following which its declining levels would induce a menstrual bleed
due to decreasing progesterone support exactly as occurs in the
normal female menstrual cycle. In one embodiment, the two
formulations described above (the LHRH/estrogenic steroid
formulation and LHRH/estrogenic/progestational steroid formulation)
would exhibit the characteristics described in Table II.
TABLE-US-00002 TABLE II Drug Drug Circulation Release from the
Loading for 21 Drug Level Ring per day days of Release Ring A
Estradiol 100 pg/mL 100 .mu.g 2.1 mg D-Trp6-Pro9-Net- 10-100 pg/mL
4 .mu.g/Kg 5 mg GnRH Ring B Estradiol 100 pg/mL 100 .mu.g 2.1 mg
Progesterone 6 ng/mL 45 mg 630 mg D-Trp6-Pro9-Net- 10-100 pg/mL 4
.mu.g/Kg 5 mg GnRH
VI. Hormone Replacement Therapy
[0123] In another aspect, the invention relates to a method for
treating perimenopausal or postmenopausal women, including women of
all ages having premature ovarian failure (e.g., young women who
have had an ablation of ovarian function due to surgery, radiation,
or chemotherapy). In this aspect, the invention provides methods
for treating a decrease in estrogen secretion as well as relieving
the symptoms and signs associated with menopausal, perimenopausal,
and post-menopausal periods in women. In one embodiment, the method
involves providing a drug delivery device, as described in Section
V below, comprising a drug-permeable polymeric substance and (i) an
androgen or a selective androgen receptor modulator (SARM), (ii) an
estrogen or a selective estrogen receptor modulator (SERM), and
(iii) a progestin or a selective progestin receptor modulator
(SPRM) or any combination of the above depending upon the
individual patient's needs. The drug delivery device is inserted
into the vagina of the woman to release an effective amount of the
sex steroids or sex steroid modulators to the woman. The continuous
delivery of replacement hormones for treating perimenopausal or
postmenopausal women is described in detail in U.S. Ser. No.
09/585,935, filed Jun. 2, 2000 (K. A. Martin et al.), which is
incorporated by reference in its entirety herein.
[0124] In another embodiment, the method of the present invention
involves providing a drug delivery device, as described below,
comprising a drug-permeable polymeric substance and (i) a SERM and
(ii) an androgen or a SARM. Optionally, the drug delivery device
also includes (iii) a progestin or a SPRM. The drug delivery device
is inserted into the vagina of the woman, where it releases a
therapeutically effective amount of the active agents (SERM, an
androgen or SARM, and optionally a progestin or SPRM), thereby
relieving the symptoms and signs associated with the menopausal,
perimenopausal and postmenopausal periods.
[0125] In yet another embodiment, the method of the present
invention involves the use of a drug delivery device comprising (i)
a SERM and (ii) an estrogen, and optionally (iii) a progestin or
SPRM. The drug delivery device is inserted into the vagina of the
woman, where it releases a therapeutically effective amount of the
active agents (SERM, estrogen, and optionally progestin or SPRM),
thereby relieving the symptoms and signs associated with the
menopausal, perimenopausal and postmenopausal periods.
[0126] In another variation of the above, the drug delivery device
contains (i) a SERM, (ii) an estrogen, and (ii) an androgen or
SARM, and optionally (iv) a progestin or SPRM. The drug delivery
device is inserted into the vagina of the woman, where it releases
a therapeutically effective amount of the active agents (SERM,
estrogen, androgen or SARM, and optionally progestin or SPRM),
thereby relieving the symptoms and signs associated with the
menopausal, perimenopausal and postmenopausal periods.
[0127] Virtually all postmenopausal and perimenopausal women can be
treated with the methods of the invention with or without the
addition of LHRH or one of its peptide or non-peptide analogues. If
desired, such a woman can be identified as being in need of hormone
replacement therapy (using standard criteria, as described, for
example, by the American College of Physicians Guidelines, which is
incorporated herein by reference) prior to treatment of the woman
with the methods of the invention. A variety of therapeutic
regimens are suitable for use in the invention, and practitioners
of ordinary skill in the art can readily optimize a particular
regimen for a particular woman by monitoring the woman for signs
and symptoms of hormone deficiency, and increasing or decreasing
the dosage and/or frequency of treatment as desired.
[0128] In this embodiment of the invention, the androgen is
administered at a daily dosage of 0.01 .mu.g to 5 mg/kg of body
weight (e.g., 1 .mu.g/kg to 5 mg/kg), the estrogen typically is
administered at a dosage of 0.01 .mu.g/kg to 4 mg/kg (e.g., 0.2
.mu.g/kg to 100 .mu.g/kg), and the progestin typically is
administered at a dosage of 0.02 mg/kg to 200 mg/kg (e.g., 2
.mu.g/kg to 10 mg/kg). A SARM typically is administered at a daily
dosage of 0.01 .mu.g/kg to 100 mg/kg of body weight (e.g., 1
.mu.g/kg to 4 mg/kg), a SERM typically is administered at a dosage
of 0.01 .mu.g/kg to 100 .mu.g/kg (e.g., 1 .mu.g/kg to 2 mg/kg), and
a SPRM typically is administered at a dosage of 0.01 .mu.g/kg to
100 mg/kg (e.g., 1 .mu.g/kg to 30 mg/kg). Typically, the woman will
be treated over the course of several months or years, or even
life-long to ameliorate the signs and symptoms resulting from
natural or induced impairment of ovarian function.
[0129] In one example of a suitable method of treating
perimenopausal women, the therapeutic regimen entails administering
to the woman a drug delivery device comprising each of (i) an
androgen or SARM, (ii) an estrogen or SERM, and (iii) a progestin
or SPRM for 13 to 14 days, followed by administering each of (i) an
estrogen or SERM and (ii) an androgen or SARM for 13 to 14 days.
The dosages listed above are suitable. In this embodiment, the drug
delivery device is removed following the initial 13-14 day period
(the follicular phase), and replaced by a second drug delivery
device containing the estrogen or SERM and androgen or SARM
combination. Alternatively, the two formulations (the
androgen/SARM, estrogen/SERM and progestin/SPRM formulation; and
the estrogen/SERM and androgen/SARM formulation) are combined in a
single drug delivery device, which is designed to remain in the
vaginal tract of the female for the entire menstrual cycle, as
described above in Section III in the context of contraception.
[0130] In one example of a suitable method of treating menopausal
women, the therapeutic regimen entails administering to the woman a
drug delivery device comprising each of (i) an androgen or SARM,
(ii) an estrogen or SERM, and (iii) a progestin or SPRM. The
dosages listed above are suitable. In this embodiment, the drug
delivery device is designed to remain in the vaginal tract of the
patient for at least 30 days, preferably several months (e.g., 2-4
months).
[0131] In another method, the woman is treated with a drug delivery
device containing each of (i) a SERM, (ii) an androgen or SARM,
and, optionally, (iii) a progestin or SPRM. In a typical
therapeutic regimen, the device remains in the vaginal tract of the
woman for at least 30 days, delivering a daily dose of active
agents at the dosages listed above. Usually, the woman will be
treated over the course of several months or years, or even
life-long to relieve her of the signs and symptoms resulting from
natural or induced impairment of ovarian function.
[0132] Alternatively, the woman can be treated with a drug delivery
device containing each of (i) a SERM and (ii) an estrogen, and,
optionally, (iii) a progestin or SPRM. In a typical therapeutic
regimen, this combination of steroids is administered to the woman
for at least 30 days at the daily dosages listed above. Usually,
the woman will be treated over the course of several months or
years, or even life-long to relieve her of the signs and symptoms
resulting from natural or induced impairment of ovarian
function.
[0133] In still an alternative method, the woman can be treated
with a drug delivery device containing each of (i) a SERM, (ii) an
estrogen, (iii) an androgen or SARM, and, optionally, (iv) a
progestin or SPRM. In a typical therapeutic regimen, this
combination of steroids is administered to the woman for at least
30 days at the daily dosages listed above. Usually, the woman will
be treated over the course of several months or years, or even
life-long to relieve her of the signs and symptoms resulting from
natural or induced impairment of ovarian function.
[0134] For long-term delivery of replacement hormones, the device
will typically contain sufficient quantities of the sex steroids or
sex steroid modulators to provide a 1 to 48 month supply, a 1 to 36
month supply, a 1 to 24 month supply, preferably a 1 to 12 month
supply, and most preferably a 1 to 6 month supply of replacement
hormones.
[0135] The following examples are merely illustrative of the
present invention and they should not be considered as limiting the
scope of the invention in any way, as these examples and other
equivalents thereof will become apparent to those versed in the art
in the light of the present disclosure, drawings and the
accompanying claims. For example, the following examples illustrate
the practice of the invention for controlled release of
progesterone, estradiol, and LHRH or gonadotropin releasing hormone
(GnRH). As described elsewhere herein, the invention is useful in a
wide variety of applications and for treating numerous conditions
and disorders. Thus, as will be appreciated by those skilled in the
art, drug delivery devices according to the invention can be
manufactured to contain any number of segments or rods, comprising
any suitable drug or drug combination, and may be used to treat a
variety of indications, in both male and female mammals.
EXAMPLES
Example 1
Preparation of a Vaginal Ring for Controlled Release of
Progesterone, Estradiol and Gonadotropin Releasing Hormone
(GnRH)
[0136] The intravaginal drug delivery device illustrated in FIG. 1
was prepared using poly(ethyl-co-vinyl acetate) (EVA) manufactured
by Aldrich Chemical Co. (Cat. No. 34,050-2; Lot No. 07322DR). 630
(milligrams) mg of progesterone (Sigma Corp.; Cat. No. P-3972) or
2.8 mg of estradiol (Sigma Corp.; Cat. no. E-1072) were each
dissolved separately in approximately 5 mL of dichloromethane
(Fluka Chem. Co.; Cat. No. 66740; Lot No. 404915/1 62800) in
separate scintillation vials. Next, polymeric mixtures were
prepared by adding 1400 mg of EVA to the progesterone solution and
1800 mg of EVA to the estradiol solution, and mixing the EVA/drug
compositions using a rotary shaker. The resulting mixtures were
then solvent cast in dry ice using ethanol as the solvent (Pharmco;
Cat. No. 111 USP 200 CSGL; Lot No. M8241). The solvent was allowed
to evaporate overnight, and the dry EVA/drug mixtures were then
ground into powders. The EVA/drug powders were placed in an
injection molding unit (DSM, Geleen, Holland). The injector was
heated to approximately 80.degree. C. The molten EVA/drug
compositions were extruded into stainless steel mold (the mold is
at 10.degree. C.), creating a 1800 mg ring with an outer diameter
of 50 mm and a cross section of 4 mm.
[0137] Similarly, a polymeric ring comprising GnRH agonist
(D-Trp6-Pro9-Net-GnRH) was prepared by dissolving 10 mg of GnRH
agonist and 450 mg of methyl cellulose in approximately 5 mL
methylene chloride. 1800 mg EVA was added. The EVA/drug mixture was
dried and the resulting powder was placed in an injection molding
unit (DSM, Geleen, Holland). The injector was heated to
approximately 80.degree. C. The molten EVA/GnRH/cellulose
compositions was extruded into stainless steel mold (the mold is at
10.degree. C.), creating a 1800 mg EVA ring with an outer diameter
of 50 mm and a cross section of 4 mm.
[0138] The EVA rings containing estradiol, progesterone, and GnRH
were each aseptically cut into unitary cylindrical segments of the
appropriate lengths, i.e., lengths that contain sufficient
quantities of drug to provide therapeutically effective amounts of
each drug. The pieces of the EVA loaded drug were placed back in
the mold and neat EVA was injected to the mold to connect the
pieces together. If needed, a fourth (placebo) segment of EVA may
be used to complete the ring structure.
[0139] The vaginal ring described herein was designed to deliver
21-day dosages of each drug, i.e., 100 micrograms (.mu.g) per day
of estradiol, 6 milligrams (mg) per day of progesterone, and 240
.mu.g per day of GnRH.
Example 2
Intravaginal Administration of GnRH to Rhesus Monkeys
[0140] Compositions comprising GnRH were prepared using an
over-the-counter hydrogel sold under the name Replens.RTM.
(Columbia Laboratories, Inc., Livingston, N.J.). Compositions
comprising GnRH were prepared by mixing 10 mg of GnRH with 2 g of
Replens.RTM.. 2 g of the GnRH/Replens.RTM. mixture was then placed
in the vaginal tracts of five Rhesus monkeys and allowed to remain
there for 9 hours. Blood samples were obtained at one hour
intervals for the full 9 hour course. The blood samples had the
serum separated from the clot by centrifugation and samples were
subjected to an RIA assay to measure GnRH. GnRH levels were
determined based on a traditional double antibody RIA for GnRH
(this protocol can be modified to also measure GnRH agonists, or
GnRH antagonists by varying the antibody).
[0141] Briefly, anti-GnRH was added to standard and test samples
and incubated at room temperature for 20-24 hours. The 1-125
labeled GnRH were diluted to 21,000-22,5000 CPM/100 .mu.l solutions
and added to each tube of the assay and to total count tubes and
incubated at room temperature for 20-24 hours. 100 .mu.l of sheep
anti-rabbit gamma globulin (SARGG) and 100 .mu.l of 16% PEG
(Fisher, Cat. #P156-500) was added to each tube and incubated at
4.degree. C. for 1 hour. Samples were washed with 2 ml of distilled
water and centrifuged at 3000 rpm for 20 minutes. Supernatants were
decanted and pellets were counted for one minute in a gamma
counter. FIG. 2 shows the serum levels of GnRH in three monkeys as
a function of time.
[0142] This example shows that GnRH (molecular weight of
approximately 1,100) can traverse the vaginal epithelium in
primates in sufficient quantities to achieve therapeutic serum
levels of the hormone.
Example 3
Simultaneous Release of Estradiol, Progesterone, GNRH from an EVA
Ring
[0143] Intravaginal drug delivery devices comprising estradiol,
progesterone, and GnRH were prepared as described in Example 1.
Estradiol, progesterone and GnRH rings were placed in 100 ml of
release media (70:30 PBS:EtOH, pH=6) at 37.degree. C. on as rotary
shaker (100 RPM). At the indicated time points media was collected
and measured by HPLC on an Agilent 1100 Series HPLC (Agilent,
Forest City, Calif.). Estradiol and progesterone were detected by
UV at 230 nm while GnRH was measured at 215 nm. Results were
calculated based on the area under the curve compared to a 5 point
calibration curve. Results were expressed as the cumulative release
in .mu.g released over the course of the experiment.
[0144] FIG. 3 shows the in vitro zero order kinetic release of
estradiol and progesterone over a 21-day period. FIG. 4 shows the
in vitro zero order kinetic release of GnRH during this same
period.
[0145] This example demonstrates stable zero order release kinetics
for estradiol, progesterone, and GnRH over a 14 to 21 day period,
without drug interactions or interference. The example also shows
that vaginal rings produced in accordance with the present
invention have sufficient capacity to sustain at least 21 days of
adequate flux rates of GnRH (i.e., delivery rates capable of
producing a serum level of 3-6 ng/ml in the circulation) to
completely silence ovarian production of sex steroids, thereby
totally suppressing ovulation. The vaginal rings also have
sufficient capacity to deliver therapeutically effective amounts of
the naturally secreted ovarian hormones, estradiol and
progesterone, to restore both normal levels and patterns of each
and to produce a normal, monthly menstrual flow. Natural estradiol
should be administered at a rate of 100 .mu.g/day, whereas
progesterone should be delivered at approximately 45 mg/day, i.e.,
rates that have been demonstrated to produce serum levels of
approximately 100 pg/ml of estradiol and 6,000 .mu.g/ml/day of
progesterone.
Example 4
Release Kinetics of Estradiol and Progesterone from an EVA
Matrix
[0146] EVA mixtures containing estradiol and progesterone where
prepared as described in Example 1 above, except that the EVA/drug
mixtures were not further processed by injection molding or
extrusion to form rings. After drying, the compositions (discs)
were evaluated for their release kinetics. Estradiol and
progesterone were placed in 100 ml of release media (70:30
PBS:EtOH, pH=6) at 37.degree. C. on a rotary shaker (100 RPM). At
the indicated time points, media was collected and measured by HPLC
on an Agilent 1100 Series HPLC (Agilent, Forest City, Calif.).
Estradiol and progesterone were detected by UV at 230 nm. Results
were calculated based on the area under the curve compared to a 5
point calibration curve. Results are shown in FIG. 5.
[0147] As shown in FIG. 5, the dry EVA/drug mixtures provide
bi-phasic release kinetics with a total recovery of 70% over a
21-day period.
Example 5
Effect of Cellulosics on Release Kinetics
[0148] EVA mixtures containing progesterone and estradiol where
prepared as described in Example 1 above, except that the EVA/drug
mixtures were not further processed by injection molding or
extrusion. Also, varying amounts of a commercially available
cellulosic, Methocel.RTM. (Dow Chemicals, Co., Midland, Mich.) were
incorporated into the mixtures to evaluate the effect of
cellulosics on release kinetics. Briefly, estradiol and
progesterone were each dissolved in two separate vials of ethanol,
and a low concentration (5% by weight) and a high concentration
(25% by weight) of Methocel.RTM. was added to the estradiol and
progesterone vials. The solutions were slowly emulsified into a
methylene chloride solution containing EVA. The resulting emulsions
were solvent-casted into a mold, which was then cooled on dry ice.
Following sublimation, the solvents were cut into 1 cm.times.1 cm
samples, and placed in scintillation vials, to which 0.1 M
phosphate buffered saline (pH 6.10) and ethanol were added in a
70:30 ratio. The vials were placed in a 37.degree. C. incubator on
a shaker rotating at 100 RPM. The buffer solution was replaced at
predetermined time points. The released amount of estradiol and
progesterone was determined by UV/VIS spectrophotometry at 280 nm
or 250 nm, respectively. Next, the release kinetics were determined
by plotting the cumulative release amounts as a function of time.
As shown in FIG. 6, the addition of Methocel.RTM. results in pseudo
zero order release kinetics. Also, the higher the ratio of
cellulosics to progesterone, the greater the release rate of
progesterone. This example demonstrates that the release rate of a
drug from the drug delivery device can be manipulated through the
use of excipients, such as cellulosics.
Example 6
Release Kinetics of Estradiol and Progesterone from an EVA
Matrix
[0149] EVA mixtures containing estradiol and progesterone were
prepared as described in Example 1 above, except that the EVA/drug
mixtures were not further processed by injection molding or
extrusion. Also, the EVA/drug mixtures were combined to form a
double-sided disc, comprising estradiol on one side and
progesterone on the other. After drying, the discs were evaluated
for their release kinetics. Briefly, Estradiol and progesterone
were placed in 100 ml of release media (70:30 PBS:EtOH, pH=6) at
37.degree. C. on as rotary shaker (100 RPM). At the indicated time
points, 100% of the media was collected for measurement and 100 ml
of release media was replaced. The media was measured by an Agilent
1100 Series HPLC (Agilent). Estradiol and progesterone were
detected by UV at 230 nm. Results were calculated based on the area
under the curve compared to a 5 point calibration curve and
depicted in FIG. 7 as the cumulative percent released. As shown in
FIG. 7, estradiol and progesterone have independent bi-phasic
release kinetics.
Example 7
Intravaginal Administration of GnRH to Rhesus Monkeys
[0150] Polymeric mixtures comprising GnRH and a polyacrylic
(polycarbophyl) based hydrogel, sold under the tradename
Replens.RTM. (LDS Consumer Products, Cedar Rapids, Iowa), were
prepared by mixing 10 mg of GnRH with 2 g of hydrogel (0.5% wt/wt;
pH 7). 2 g aliquots of the GnRH/hydrogel mixture were then placed
in the vaginal tracts of five Rhesus monkeys and allowed to remain
there for 48 hours. Blood samples were taken at the specified
intervals of time an assayed for GnRH and LH levels.
[0151] Briefly, anti-GnRH was added to standard and test samples
and incubated at room temperature for 20-24 hours. The I-125
labeled GnRH were diluted to 21,000-22,5000 CPM/100 ul solutions
and added to each tube of the assay and to total count tubes and
incubated at room temperature for 20-24 hours. 100 ul of sheep
anti-rabbit gamma globulin (SARGG) and 100 ul of 16% PEG (Fisher,
Cat. #P156-500) was added to each tube and incubated at 4.degree.
C. for 1 hour. Samples were washed with 2 ml of distilled water and
centrifuged at 3000 rpm for 20 minutes. Supernatants were decanted
and pellets were counted for one minute in a gamma counter. Results
were expressed as ng/ml of GnRH and LH. FIG. 8 shows the serum
levels of GnRH (mean level in diamonds) in the monkeys as a
function of time, as well as the corresponding serum levels of
endogenous luteinizing hormone (LH) (mean level in squares).
[0152] This example demonstrates sufficient transvaginal absorption
of GnRH to provide ng/mL quantities of GnRH in the serum. As
expected, the release of exogenous GnRH produces elevated levels of
endogenous LH, thus demonstrating the biological activity of the
GnRH.
Example 8
Formation of a Multi-Linked Ring
[0153] The multi-linked intravaginal drug delivery device
illustrated in FIG. 9 can be prepared using poly(ethyl-co-vinyl
acetate) (EVA) manufactured by Aldrich Chemical Co. (Cat. No.
34,050-2; Lot No. 07322DR). 630 (milligrams) mg of progesterone
(Sigma Corp.; Cat. No. P-3972), and 3.0 mg of estradiol (Sigma
Corp.; Cat. no. E-1072) can be dissolved separately in
approximately 5 mL of dichloromethane (Fluka Chem. Co.; Cat. No.
66740; Lot No. 404915/1 62800) in separate scintillation vials.
Next, polymeric mixtures can be prepared by adding 1000 mg of EVA
to the progesterone solution and 300 mg of EVA to the estradiol
solution, and mixing the EVA/drug compositions using a rotary
shaker. Similarly, a mixture comprising GnRH agonist (2.5 mg
(D-Trp6-Pro9-Net-GnRH), 110 mg of methyl cellulose and 50 mg of
EVA) can be prepared by dissolving the mixture in 5 mL methylene
chloride.
[0154] The resulting mixtures can then be individually solvent cast
in dry ice using ethanol as the solvent (Pharmco; Cat. No. 111 USP
200 CSGL; Lot No. M8241). The solvent can be evaporated overnight,
and the dry EVA/drug mixtures can be ground into powders. The
EVA/drug powders can be placed in individual injection molding
units (DSM, Geleen, Holland) and injected at 80.degree. C. into the
multiport molding of FIG. 9. For example, the Portal No. 1 can be
injected with the mixture of GnRH agonist (2.5 mg GnRH agonist, 110
mg methyl cellulose and 50 mg EVA), the Portal No. 2 can be
injected with the mixture of estradiol (3 mg of estradiol and 300
mg of EVA), the Portal No. 3 can be injected with the progesterone
mix (630 mg of progesterone and 1 g of EVA) and the Portal No. 4
can be injected with 500 mg of EVA (neat).
Example 9
Delayed Release Ring
[0155] The rate of hydration of the intravaginal device depends on
many factors, including the rate of water penetration into the
polymer. The rate of water penetration can be modulated by the
osmotic pressure within the polymer. The osmotic pressure can be
modulated by adding salt (NaCl, KCl, etc) to the formulation of the
drug.
[0156] Estradiol and GnRH can be formulated as described herein.
Yet, additional salt is added (300 mmol). These two drugs can form
2 segments of the ring and be designed to be release over 28 days
(Table III). A third segment can incorporate Progesterone without
salt (Table IV).
TABLE-US-00003 TABLE III Drug Drug Circulation Release from the
Loading for 28 Drug Level Ring per day days of Release Estradiol
100 pg/Ml 100 .mu.g 3 mg D-Trp6-Pro9-Net- 10-100 pg/Ml 4 .mu.g/Kg =
6.8 mg GnRH 240 .mu.g/day
TABLE-US-00004 TABLE IV Release from the Drug Loading for 14 Drug
Circulation Ring per day days of Release Progesterone 6 ng/mL 45 mg
630 mg
[0157] As a result of the additional salt in the Estradiol and the
GnRH agonist segments, these drugs will rehydrate sooner and
immediately start their release which will continue over 28 days.
However, the segment containing progesterone will begin the release
after 14 days and continue for 4 days. Thus, a single ring may be
used as birth control for about one month with an early phase of 2
weeks with a zero order release of just estradiol ("E2") and GnRH
agonist, followed by 14 days of a zero order release of E2, GnRH
agonist and progesterone.
[0158] All patents, patent applications, and published references
cited herein are hereby incorporated by reference in their
entireties. While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
Sequence CWU 1
1
1110PRTUnknownSynthetic Peptide Sequence 1Glu His Trp Ser Tyr Gly
Leu Arg Pro Gly1 5 10
* * * * *