U.S. patent application number 16/672125 was filed with the patent office on 2020-02-27 for formulations and methods for providing progestin-only contraception while minimizing adverse side effects associated therewith.
This patent application is currently assigned to ALLERGAN SALES, LLC. The applicant listed for this patent is ALLERGAN SALES, LLC. Invention is credited to Angela Anigbogu, Charles Ebert, Gary Hoel, Samir Roy.
Application Number | 20200061082 16/672125 |
Document ID | / |
Family ID | 37743291 |
Filed Date | 2020-02-27 |
United States Patent
Application |
20200061082 |
Kind Code |
A1 |
Ebert; Charles ; et
al. |
February 27, 2020 |
FORMULATIONS AND METHODS FOR PROVIDING PROGESTIN-ONLY CONTRACEPTION
WHILE MINIMIZING ADVERSE SIDE EFFECTS ASSOCIATED THEREWITH
Abstract
Formulations and methods for providing progestin-only
contraception to a woman including transdermally administering to a
woman a formulation having a contraceptively effective amount of
progestin-only hormonal agents as part of a contraceptive
regimen.
Inventors: |
Ebert; Charles; (Salt Lake
City, UT) ; Hoel; Gary; (Salt Lake City, UT) ;
Anigbogu; Angela; (Hauppauge, NY) ; Roy; Samir;
(Salt Lake City, UT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALLERGAN SALES, LLC |
IRVINE |
CA |
US |
|
|
Assignee: |
ALLERGAN SALES, LLC
IRVINE
CA
|
Family ID: |
37743291 |
Appl. No.: |
16/672125 |
Filed: |
November 1, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16162670 |
Oct 17, 2018 |
10500215 |
|
|
16672125 |
|
|
|
|
11205297 |
Aug 15, 2005 |
10137135 |
|
|
16162670 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/7061 20130101;
A61P 15/18 20180101; A61K 31/565 20130101; A61K 31/57 20130101 |
International
Class: |
A61K 31/57 20060101
A61K031/57; A61K 31/565 20060101 A61K031/565; A61K 9/70 20060101
A61K009/70 |
Claims
1. A method of providing progestin-only contraception to a woman
while minimizing adverse side effects associated with the
progestin-only contraception, comprising the steps of: a) applying
a transdermal patch to the outer skin surface of a woman and
allowing the patch to remain applied to the outer skin surface of
the woman for at least seven days; and b) removing the transdermal
patch from the outer skin surface after about seven days wherein
the transdermal patch comprises a drug formulation comprising (i)
norethindrone and/or norethindrone acetate as the only active
hormonal agents in an amount of from about 1% w/w to about 15% w/w
of the drug formulation and (ii) a permeation enhancer in an amount
from about 3% w/w to about 15% w/w of the drug formulation wherein
the permeation enhancer is selected from the group consisting of
isopropyl myristate as the sole permeation enhancer, a combination
of isopropyl myristate and sorbitan monooleate or a combination of
isopropyl myristate and dipropylene glycol; and the norethindrone
and/or norethindrone acetate are administered from the transdermal
patch at a rate and amount that provides a minimum norethindrone
serum level of at least 300 pg/ml from about 24 hours to about 168
hours following application of the patch to the outer skin surface
and a maximum norethindrone serum level of less than 1200 pg/ml
about 24 to 96 hours following application of the patch to the
outer skin surface.
2. The method described in claim 1 wherein the application step and
removal step are conducted once a week for 4 to 12 weeks.
3. The method described in claim 2 wherein the application step and
removal step are conducted once a week for 4 weeks.
4. The method described in claim 2 wherein the application step and
removal step are conducted once a week for 12 weeks.
5. The method described in claim 1 wherein at least 0.35 mg/day of
norethindrone and/or norethindrone acetate is delivered from the
transdermal patch.
6. The method as described in claim 1 wherein the minimum
norethindrone serum level is at least 350 pg/ml and is sustained
from about 24 hours to about 168 hours following application of the
transdermal patch to the outer skin surface.
7. The method as described in claim 1 wherein the maximum
norethindrone serum level is less than 1100 pg/ml and is obtained
about 24 to 96 hours following application of the transdermal patch
to the outer skin surface.
8. The method as described in claim 1 wherein the norethindrone
and/or norethindrone acetate is present in an amount of from about
2.5% w/w to about 12% w/w of the drug formulation.
9. The method as described in claim 1 wherein the adverse side
effect is selected from the group consisting of strokes, myocardial
infarctions, embolisms, breakthrough bleeding, and combinations
thereof.
10. The method as described in claim 1 wherein the drug formulation
further comprises diluents, emollients, plasticizers, skin
irritation reducing agents, or a mixture thereof.
11. The method as described in claim 10 wherein the drug
formulation includes a skin irritation reducing agent and wherein
the skin irritation reducing agent is glycerin.
12. The method as described in claim 1 wherein the only active
hormonal agent is a combination of norethindrone and norethindrone
acetate, which are present in an amount of from 2.5% to 12% w/w of
the drug formulation.
13. The method as described in claim 1 wherein the transdermal
patch is a matrix patch and the drug formulation further comprises
an acrylic polymer adhesive.
14. The method as described in claim 1 wherein the permeation
enhancer is isopropyl myristate as the sole permeation
enhancer.
15. The method as described in claim 1 wherein the permeation
enhancer is a combination of isopropyl myristate and sorbitan
monooleate.
16. The method as described in claim 1 wherein the permeation
enhancer is a combination of isopropyl myristate and dipropylene
glycol.
17. A method of providing progestin-only contraception to a woman
while minimizing adverse side effects associated with the
progestin-only contraception, comprising the steps of: a) applying
a transdermal patch to the outer skin surface of a woman and
allowing the patch to remain applied to the outer skin surface of
the woman for at least seven days; and b) removing the transdermal
patch from the outer skin surface after about seven days wherein
the transdermal patch is a matrix patch comprising a drug
formulation comprising (i) a combination of norethindrone and
norethindrone acetate as the only active hormonal agents in an
amount of from about 1% w/w to about 15% w/w of the drug
formulation; (ii) a permeation enhancer in an amount from about 3%
w/w to about 15% w/w of the drug formulation wherein the permeation
enhancer is selected from the group consisting of isopropyl
myristate as the sole permeation enhancer, a combination of
isopropyl myristate and sorbitan monooleate or a combination of
isopropyl myristate and dipropylene glycol; (iii) an acrylic
adhesive; (iv) one additional ingredient selected from the group
consisting of comprises diluents, emollients, plasticizers, skin
irritation reducing agents, or a mixture thereof; and the
norethindrone and/or norethindrone acetate are administered from
the transdermal patch at a rate and amount that provides a minimum
norethindrone serum level of at least 300 pg/ml from about 24 hours
to about 168 hours following application of the patch to the outer
skin surface and a maximum norethindrone serum level of less than
1200 pg/ml about 24 to 96 hours following application of the patch
to the outer skin surface.
18. The method as described in claim 17 wherein the permeation
enhancer is isopropyl myristate as the sole permeation
enhancer.
19. The method as described in claim 17 wherein the permeation
enhancer is a combination of isopropyl myristate and sorbitan
monooleate.
20. The method as described in claim 17 wherein the permeation
enhancer is a combination of isopropyl myristate and dipropylene
glycol.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/162,670 filed on Oct. 17, 2018 which is a
continuation of U.S. patent application Ser. No. 11/205,297 filed
on Aug. 15, 2005, now U.S. Pat. No. 10,137,135.
FIELD OF THE INVENTION
[0002] The present invention relates to formulations and methods
for effective contraception while minimizing or reducing adverse
side effects associated with progestin-only contraception, such as
breakthrough bleeding. Accordingly, this invention involves the
fields of pharmaceutical sciences, medicine, chemistry and other
health sciences.
BACKGROUND OF THE INVENTION
[0003] Progesterone is a primary progestational substance produced
by ovarian cells of the corpus luteum. Progestins, e.g.,
progesterone and its derivatives, transform the proliferative
endometrium into secretory endometrium. This change in the
endometrium is essential to the implantation of a fertilized ovum
and the development of a placenta during conception and the early
stages of pregnancy. Many of these changes require, however, the
presence of estrogen. Therefore, in the absence of estrogen,
progestins can exert an atrophic effect on the endometrium, as well
as various other contraceptive effects. Such contraceptive effects
may vary depending on the concentration and the nature of the
particular progestin involved.
[0004] Accordingly, various progestins have been utilized as
contraceptive drugs due to their convenient nature coupled with
their fairly predictable ovulatory and progestational effects. One
specific progestin that has received much attention is
norethindrone (NE) and its prodrug norethindrone acetate (NEA).
Both compounds have been orally and transdermally administered as
part of a number of specific formulations. Though the actions of
these and other progestins can vary, many exert effects on the
ovaries, the endometrium, and the cervix. For example, certain long
acting injectable progestins in appropriate doses can cause
endometrial atrophy. Oral preparations can vary according to the
drug and the dose. Some permitting a normal endometrium and others
causing regression. Progestins can also inhibit ovulation by
suppressing the ovarian response to gonadotropins. This may cause a
failure to ovulate or, if ovulation does occur, a smaller
hyposecreting corpus luteum. Particularly high doses of progestins
tend to suppress the pituitary release of lutenizing hormone and
the hypothalamic release of gonadotropin releasing hormone (GnRH),
which can act to prevent ovulation through decreased gonadotropin
output. Progestins also tend to increase the viscosity of cervical
mucous secretions and therefore impede the mobility of sperm. These
and other actions of progestins can act in combination to provide
effective contraception.
[0005] One undesirable issue with the use of oral progestin-only
contraception is the need for consistent dosing at the same time
each day. The onset of cervical mucus thickening typically occurs
within about 2 hours of dosing and lasts for about 16 to 19 hours.
By about 24 hours post dose, the cervical mucus returns to
substantially normal viscosity. Since thickening of cervical mucus
is such an important factor in attaining the progestin-induced
contraceptive effect, it is extremely important that dosing take
place substantially 24 hours apart in order to maintain the
elevated mucus viscosity. Of course, such a stringent dosing
regimen is inconvenient and runs a high risk of non-compliance.
[0006] Additionally, progestin-only contraception tends to induce
certain adverse side effects. One of the most inconvenient of such
side effects is spotting and breakthrough bleeding. Such bleeding
can be unpredictable or irregular in onset, and in some cases
bleeding can be more voluminous than in regular menstruation. Such
effects can often weigh heavily against the supposed convenience of
this form of birth control.
[0007] Therefore, formulations and methods for progestin-only
contraception which minimize the incidence of adverse side effects,
particularly spotting and breakthrough bleeding, continue to be
sought.
SUMMARY OF THE INVENTION
[0008] Accordingly, the present invention discloses methods of
providing effective progestin-only contraception to a woman while
minimizing adverse side effects that are normally associated with
progestin-only contraception. Such adverse side effects include,
without limitation, strokes, myocardial infarctions, embolisms,
breakthrough bleeding, etc. In one aspect, such a method can
include transdermally administering a formulation having a
contraceptively effective amount of a single progestin as the sole
active hormonal agent to the woman.
[0009] A variety of progestins may be used as the active agent in
the formulations and methods of the present invention. Specific
examples of progestins may include without limitation,
progesterone, hydroxyprogesterone, megestrol acetate,
dimethisterone, norgestrel, levonorgestrel, medroxyprogesterone
acetate, desogestrel, norgestimate, ethynodiol diacetate,
norethindrone, norethindrone acetate, and norethynodrel, including
their active metabolites and derivatives. In one specific aspect,
the progestin can be or consist of progesterone. In another aspect,
the progestin can include or consist of norethindrone. In another
aspect, the progestin can include or consist of norethindrone
acetate. In yet another aspect, the progestin can include or
consist of norethynodrel.
[0010] The formulations of the present invention may include
various dosages of progestins to achieve a therapeutic effect. For
example, in one aspect the progestin may be either norethindrone or
norethindrone acetate administered at a rate and an amount that
provides a minimum norethindrone serum level of at least about 160
pg/ml in order to cause and sustain physiologic events in the woman
resulting in contraception, while at the same time providing a
maximum norethindrone serum level of less than about 2400 pg/ml in
order to avoid a significant incidence of adverse side effects. In
another aspect, the maximum norethindrone serum level may be from
about 240 pg/ml to about 1920 pg/ml. In yet another aspect, the
maximum norethindrone serum level may be from about 300 pg/ml to
about 1200 pg/ml. In a further aspect, the maximum norethindrone
serum level can be from about 400 pg/ml to about 1100 pg/ml. In one
aspect, the minimum norethindrone serum level can be at least about
300 pg/ml. In yet another aspect, the minimum norethindrone serum
level can be at least about 350 pg/ml.
[0011] Various physiologic events resulting from the administration
of a progestin are believed to contribute to contraception. Such
physiologic events may include, without limitation, suppression of
ovulation, a thickening of cervical mucus, and combinations
thereof. Contraceptive physiologic events can be sustained for
varying amounts of time following the initial administration,
depending on the dosage form, the nature of any penetration
enhancer present, the amount of progestin in the formulation, etc.
In one aspect, physiologic events may be sustained for a period of
up to at least 168 hours. In another aspect, physiologic events
associated with contraception may be sustained for a period from
about 24 hours to about 168 hours. In yet another aspect,
contraception may be sustained for a period of from about 24 hours
to about 96 hours. In a further aspect, contraception may be
sustained for a period of from about 48 hours to about 168
hours.
[0012] As such, either norethindrone or norethindrone acetate may
also be administered at a rate and an amount that provides a
minimum norethindrone serum level sufficient to cause and sustain
contraception for a period of from about 24 hours to about 168
hours and which avoids a significant incidence of adverse side
effects by attaining a maximum norethindrone serum level that is
less than about 2400 pg/ml.
[0013] In addition to the progestin, the transdermal formulations
of the present invention may optionally include various additional
additives of a non-hormonal nature. For example, delivery of the
progestin may be improved by utilizing one or more permeation
enhancers. As such, the formulations can include a permeation
enhancer. In one aspect, the permeation enhancer can include, or
consist of a sorbitan ester-type enhancer. One example of a
sorbitan ester-type enhancer is, without limitation, sorbitan
monooleate. In another aspect, the permeation enhancer can include
a lauryl-type enhancer. Examples of lauryl type enhancers may
include, without limitation, lauryl alcohol,
1-lauryl-2-pyrrolidone, and mixtures thereof. In yet another
aspect, the permeation enhancer may include a combination of lauryl
alcohol an isopropyl myristate. In a further aspect, the permeation
enhancer may include a polyol-type enhancer, such as dipropylene
glycerol. While the amount of penetration enhancer used may vary
depending on a number of criteria, such as the type of enhancer
selected, the material of the carrier, etc., in one aspect, the
enhancer amount may be from about 0.01% w/w to about 50% w/w of the
transdermal composition. In another aspect, the enhancer amount may
be from about 3% w/w to about 15% w/w of the transdermal
composition.
[0014] In one specific aspect of the present invention, a method of
providing progestin-only contraception to a woman while minimizing
adverse side effects associated with progestin-only contraception
is provided. The method may include transdermally administering a
formulation having norethindrone acetate as the sole active
hormonal ingredient in an amount of from about 5% w/w to about 25%
w/w of the transdermal formulation and a permeation enhancer in an
amount from about 0.01% w/w to about 50% w/w of the transdermal
formulation. The formulation may be administered at a rate and an
amount that provides a minimum norethindrone serum level of at
least 200 pg/ml in order to cause and sustain physiologic events in
the woman resulting in contraception for a period of from about 24
to about 168 hours, and also provide a maximum norethindrone serum
level of less than about 2400 pg/ml in order to avoid a significant
incidence of adverse side effects. The maximum norethindrone serum
level may be obtained from about 24 to about 96 hours following
administration.
[0015] In another aspect of the present invention, a method of
providing progestin-only contraception to a woman while minimizing
adverse side effects associated with the progestin-only
contraception is provided. The method may include transdermally
administering a formulation having either norethindrone or
norethindrone acetate as the sole active hormonal agent to the
woman, at a rate and an amount that provides a minimum
norethindrone serum level sufficient to cause and sustain
contraception for a period of from about 24 to about 168 hours and
which maintains a maximum norethindrone serum level that may be up
to about 15 times greater than the minimum norethindrone serum
level. In yet another aspect, the maximum norethindrone serum level
may be up to about 8 times greater than the minimum norethindrone
serum level. In a further aspect, the maximum norethindrone serum
level may be up to about 4 times greater than the minimum
norethindrone serum level. In yet another aspect, the maximum
norethindrone serum level may be up to about 2.75 times greater
than the minimum norethindrone serum level.
[0016] The present invention additionally encompasses various kits,
formulations, and articles of manufacture to be used in providing
progestin-only contraception to a woman while minimizing adverse
side effects, such as breakthrough bleeding, associated with
progestin-only contraception. In one aspect, such a kit may include
a transdermally administrable formulation including norethindrone
acetate as the sole active agent in an amount of from about 5% w/w
to about 25% w/w of the transdermal formulation and a permeation
enhancer in an amount of from about 0.01% w/w to about 50% w/w of
the transdermal formulation. The formulation may be administered at
a rate and an amount that provides a minimum norethindrone serum
level of at least 160 pg/ml in order to cause and sustain
physiologic events in the woman resulting in contraception for a
period of from about 24 hours to about 168 hours, and also may
provide a maximum norethindrone serum level of less than about 2400
pg/ml, which is obtained from about 24 to about 96 hours following
administration, in order to avoid a significant incidence of
adverse side effects. The kit may also include a set of
instructions describing a method of using the transdermally
administrable formulation.
[0017] Numerous transdermal dosage forms are contemplated for use
with the present invention. For example, in one aspect the kit can
contain a formulation having a dosage form selected from the group
consisting of transdermal patches, ointments, lotions, gels,
pastes, mousses, aerosols, creams, gels, and combinations thereof.
In one aspect, the formulation may be in a transdermal patch dosage
form, and the kit may include at least three patches to be
administered for up to about 168 hours. The kit may also contain a
placebo patch.
[0018] There has thus been outlined, rather broadly, the more
important features of the invention so that the detailed
description thereof that follows may be better understood, and so
that the present contribution to the art may be better appreciated.
Other features of the present invention will become clearer from
the following detailed description of the invention, taken with the
accompanying claims, or may be learned by the practice of the
invention.
DETAILED DESCRIPTION
A. Definitions
[0019] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set forth below.
[0020] The singular forms "a," "an," and, "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "an adhesive" includes reference to one or
more of such adhesives, and reference to "an excipient" includes
reference to one or more of such excipients.
[0021] The terms "progestin" or "progestogen" refer to any natural
or synthetic progestational substance that mimics some or all of
the actions of progesterone. "Progestin" and "progestogen" may also
refer to any natural or synthetic substance that exerts a
biological or pharmacological action primarily by binding to
progestin receptors. Examples include, but are not limited to,
progesterone, medroxyprogesterone acetate, hydroxyprogesterone,
megestrol acetate, dimethisterone, norgestrel, levonorgestrel,
desogestrel, norgestimate, ethynodiol diacetate, norethynodrel,
norethindrone, and norethindrone acetate, esters, derivatives,
prodrugs, active metabolites, and isomers thereof. Progestins have
been administered to women in order to provide effective
contraception. While the amount of a progestin required to achieve
this effect vary from woman to woman, methods for determining
appropriate or effective amounts for the purpose of contraception
are well known to those of ordinary skill in the art. Progestins
themselves are well known in the art, a partial description of
which can be found on pgs. 1386-1388 of Remington: The Science and
Practice of Pharmacy (20.sup.th ed. 2000), which is incorporated
herein by reference.
[0022] As used herein in, "norethindrone," or "NE" refers to a
compound having the general chemical structure:
##STR00001##
Norethindrone is well known in the art, and is listed as monograph
6790 on pg. 1149 of the Merck Index (12.sup.th ed. 1996), which is
incorporated herein by reference.
[0023] As used herein, "norethindrone acetate," or "NEA" refers to
a compound having the general chemical structure:
##STR00002##
Norethindrone acetate is well known in the art as an ester type
prodrug of norethindrone and is described on pg. 1096 of Remington:
The Science and Practice of Pharmacy (19'' ed. 1995), which is
incorporated herein by reference.
[0024] The terms "breakthrough bleeding" and "intermenstral
bleeding" can be used interchangeably, and are defined as any
vaginal bleeding occurring during the menstrual cycle of a woman on
hormonal contraceptives, excluding contiguous bleeding with menses.
Breakthrough bleeding can include any discernable vaginal bleeding,
including spotting.
[0025] As used herein, "subject" refers to a mammal that may
benefit from the administration of a drug composition or method of
this invention. Examples of subjects include humans, especially
females, and may also include other animals such as horses, pigs,
cattle, dogs, cats, rabbits, and aquatic mammals.
[0026] As used herein, the terms "formulation" and "composition"
are used interchangeably and refer to a mixture of two or more
compounds, elements, or molecules. In some aspects the terms
"formulation" and "composition" may be used to refer to a mixture
of an active agent with a carrier or other excipients. The terms
"drug," "pharmaceutical," "active agent," and "bioactive agent" are
also used interchangeably to refer to a pharmacologically active
substance or composition. These terms of art are well-known in the
pharmaceutical and medicinal arts.
[0027] As used herein, "transdermal" refers to the route of
administration taken by a drug that is applied to and absorbed
through an area of skin. In some aspects, the skin may be
substantially unbroken. Thus the terms "transdermal formulation"
and "transdermal composition" can be used interchangeably, and
refer to formulations or compositions that are applied to a surface
of the skin and transdermally absorbed. Examples of transdermal
formulations include but are not limited to, ointments, creams,
gels, transdermal patches, sprays, lotions, mousses, aerosols,
nasal delivery systems, pulmonary delivery systems, buccal and
sublingual delivery systems, vaginal rings, and pastes. The term
"transdermal administration" thus refers to the transdermal
application of a formulation or composition. Transdermal
administration can be accomplished by applying, pasting, rolling,
attaching, pouring, pressing, rubbing, spraying, etc., of a
transdermal preparation or formulation onto a skin surface. These
and additional methods of administration are well known in the
art.
[0028] The terms "transdermal delivery system," "transdermal
patches" or simply "patches" refer to a matrix or liquid reservoir
type of transdermal delivery device which is used to transdermally
deliver defined doses of a substance, over a specific application
period.
[0029] By the term "matrix", "matrix system", or "matrix patch" is
meant a composition comprising an effective amount of a drug
dissolved or dispersed in a polymeric phase, often a pressure
sensitive adhesive, which may also contain other ingredients, such
as permeation enhancers, skin irritation reducing agents,
excipients, plasticizers, emollients, and other optional
ingredients. This definition is meant to include embodiments
wherein such polymeric phase is laminated to a pressure sensitive
adhesive or used within an overlay adhesive.
[0030] One example of a transdermal patch for administering a
progestin in accordance with this invention is a matrix-type patch
which comprises an occlusive backing that is impermeable to the
progestin and defines the face or top surface of the patch and a
solid or semisolid matrix layer comprised of a homogeneous blend of
the hormone, a polymeric pressure sensitive adhesive carrier, and
optionally one or more skin permeation enhancers. Matrix patches
are known in the art of transdermal drug delivery. Examples without
limitation, of adhesive matrix transdermal patches are those
described or referred to in U.S. Pat. Nos. 5,985,317, 5,783,208,
5,626,866, 5,227,169, 5,122,383, and 5,460,820 which are
incorporated by reference in their entirety.
[0031] Another example of a transdermal patch for administering a
progestin in accordance with this invention is a liquid reservoir
system (LRS) type patch which comprises progestin and other
optional ingredients, such as a permeation enhancer, in a carrier
vehicle. The carrier vehicle comprises a fluid of desired
viscosity, such as a gel or ointment, which is formulated for
confinement in a reservoir having an impermeable backing and a skin
contacting permeable membrane, or membrane adhesive laminate
providing diffusional contact between the reservoir contents and
the skin. For application, a peelable release liner is removed and
the patch is attached to the skin surface. LRS patches are known in
the art of transdermal drug delivery. Examples without limitation,
of LRS transdermal patches are those described or referred to in
U.S. Pat. Nos. 4,849,224, 4,983,395, which are incorporated by
reference in their entirety.
[0032] The terms "skin," "skin surface," "derma," "epidermis," and
similar terms are used interchangeably herein, and refer to not
only the outer skin of a subject comprising the epidermis, but also
to mucosal surfaces to which a drug composition may be
administered. Examples of mucosal surfaces include the mucosal of
the respiratory (including nasal and pulmonary), oral (mouth and
buccal), vaginal, introital, labial, and rectal surfaces. Hence the
terms "transdermal" encompasses "transmucosal" as well.
[0033] As used herein, "enhancement," "penetration enhancement," or
"permeation enhancement," refer to an increase in the permeability
of the skin to a drug, so as to increase the rate at which the drug
permeates through the skin. Thus, "permeation enhancer,"
"penetration enhancer," or simply "enhancer" refers to an agent, or
mixture of agents that achieves such permeation enhancement.
Several compounds have been investigated for use as penetration
enhancers. See, for example, U.S. Pat. Nos. 5,601,839; 5,006,342;
4,973,468; 4,820,720; 4,006,218; 3,551,154; and 3,472,931. An index
of permeation enhancers is disclosed by David W. Osborne and Jill
J. Henke, in their publication entitled "Skin Penetration Enhancers
Cited in the Technical Literature." published in Pharmaceutical
Technology (June 1998), which is incorporated by reference
herein.
[0034] As used herein, "effective amount of an enhancer refers to
an amount sufficient to increase the penetration of a drug through
the skin. Methods for assaying the characteristics of permeation
enhancers are well-known in the art. See, for example, Merritt et
al., "Diffusion Apparatus for Skin Penetration. J. of Controlled
Release 61 (1984), incorporated herein by reference in its
entirety. Thus, an "effective amount" or a "therapeutically
effective amount" of a drug refers to a non-toxic, but sufficient
amount of the drug, to achieve therapeutic results in treating a
condition for which the drug is known to be effective. It is
understood that various biological factors may affect the ability
of a substance to perform its intended task, and that an "effective
amount" or a "therapeutically effective amount" may be dependent in
some instances on such biological factors. Further, while the
achievement of therapeutic effects may be measured by a physician
or other qualified medical personnel using evaluations known in the
art, it is recognized that individual variation and response to
treatments may make the achievement of therapeutic effects a
somewhat subjective decision. Generally speaking, the determination
of an effective amount is well within the ordinary skill in the art
of pharmaceutical sciences and medicine. See, for example, Meiner
and Tonascia, "Clinical Trials: Design, Conduct, and Analysis."
Monographs in Epidemiology and Biostatistics, Vol. 8 (1986),
incorporated herein by reference.
[0035] A "contraceptively effective amount" refers to the minimum
amount of drug sufficient to produce a contraceptive effect in a
subject. The determination of a contraceptively effective amount of
a drug is well-within the ordinary skill in the art of
pharmaceutical and medical sciences.
[0036] As used herein, "serum level" refers to the level of a drug
in the blood of a subject. A therapeutically effective serum level
may vary depending on the therapeutic benefit desired, as well as
other variables such as the subject's age, weight, metabolism,
physiological conditions such as gastrointestinal motility, renal
clearance, etc. Therapeutically effective serum levels may be
achieved in one or more administrations, applications or dosages.
As used herein, "serum level" is used interchangeably with terms
such as blood concentration, plasma level, plasma concentration,
blood level, serum concentration, serum blood level, serum blood
concentration, etc.
[0037] As used herein, "pharmaceutically acceptable carrier," and
"carrier" may be used interchangeably, and refer to any inert and
pharmaceutically acceptable material that has substantially no
biological activity, and makes up a substantial part of the
formulation. The carrier may be polymeric, such as an adhesive, or
non-polymeric and is generally admixed with other components of the
composition (e.g., drug, binders, fillers, penetration enhancers,
anti-irritants, emollients, lubricants, etc., as needed) to
comprise the formulation.
[0038] The term "admixed" means that a drug and/or enhancer can be
dissolved, dispersed, suspended, or otherwise combined with a
carrier.
[0039] As used herein, a plurality of items, structural elements,
compositional elements, and/or materials may be presented in a
common list for convenience. However, these lists should be
construed as though each member of the list is individually
identified as a separate and unique member. Thus, no individual
member of such list should be construed as a de facto equivalent of
any other member of the same list solely based on their
presentation in a common group without indications to the
contrary.
[0040] Concentrations, amounts, and other numerical data may be
expressed or presented herein in a range format. It is to be
understood that such a range format is used merely for convenience
and brevity and thus should be interpreted flexibly to include not
only the numerical values explicitly recited as the limits of the
range, but also to include all the individual numerical values or
sub-ranges encompassed within that range as if each numerical value
and sub-range is explicitly recited. As an illustration, a
numerical range of "about 1 micron to about 5 microns" should be
interpreted to include not only the explicitly recited values of
about 1 micron to about 5 microns, but also include individual
values and sub-ranges within the indicated range. Thus, included in
this numerical range are individual values such as 2, 3, and 4 and
sub-ranges such as from 1-3, from 2-4, and from 3-5, etc.
[0041] This same principle applies to ranges reciting only one
numerical value. Furthermore, such an interpretation should apply
regardless of the breadth of the range or the characteristics being
described.
B. The Invention
[0042] The present invention involves methods and formulations for
effecting progestin-only contraception in a woman in a manner that
reduces or minimizes various adverse side effects known as
problematic to progestin-only contraception and further increases
the convenience of the contraceptive regimen and decreases the risk
of pregnancy through dosing non-compliance. Specifically, the
Applicants have discovered a surprising relationship between
contraceptive effectiveness, side effects, and the dosage form of
the progestin formulation. They have found that when serum levels
sufficient to provide a contraceptive effect are obtained by
transdermal administration of a progestin that various adverse side
effects such as breakthrough bleeding are minimized, especially as
compared to an equivalent amount of the same progestin administered
orally. Further, Applicants have discovered that transdermal
administration of progestins for contraceptive purposes virtually
eliminates the risk of day-to-day dosing non-compliance, which is
significant with oral progestin-only contraception as each pill
must be taken at the same time each day.
[0043] In practice, transdermal progestin administration is able to
provide a minimum drug serum level and reduce or avoid serum
concentration "peaks" or "spikes" typically associated with oral
progestin therapies. It is believed that peaks may significantly
contribute to the incidence of side effects such as break through
bleeding, and that by avoiding these peaks through the transdermal
administration of a progestin, side effects may be minimized.
Additionally, unlike oral therapies, peak drug serum levels can be
reduced while minimum drug serum levels are maintained above a
threshold level in order to ensure a contraceptive effect in the
subject. A similar reduction in peak drug serum levels in oral
therapies typically also facilitates a concomitant reduction in
minimum drug serum levels thus posing a risk of
noneffectiveness.
[0044] Accordingly, various transdermal formulations and
compositions that contain a contraceptively effective amount of a
progestin to be administered to a woman as part of a progestin-only
contraceptive regimen are disclosed and described herein. Various
progestin-only formulations and articles of manufacture, including
kits containing such, are thus contemplated, and are considered to
be within the scope of the present invention. Furthermore, methods
of minimizing adverse side effects known to be associated with
progestin-only contraception by utilizing such formulations are
also disclosed and described. Such adverse side effects include,
without limitation, strokes, myocardial infarctions, embolisms,
breakthrough bleeding, and combinations thereof.
[0045] A wide variety of contraceptively effective progestins known
to those of ordinary skill in the art can be utilized as the
contraceptively active agent in the transdermal formulations of the
present invention. Examples of such progestins can include, without
limitation, progesterone, hydroxyprogesterone, megestrol acetate,
dimethisterone, norgestrel, levonorgestrel, medroxyprogesterone
acetate, desogestrel, norgestimate, ethynodiol diacetate,
norethindrone, norethindrone acetate, norethynodrel and derivatives
thereof. In one aspect, the progestin is progesterone. In another
aspect, the progestin is norethindrone. In another aspect, the
progestin is norethindrone acetate. In yet another aspect, the
progestin is norethynodrel. As the formulation is for
progestin-only contraception, other non-progestin type steroids or
active agents that contribute to contraception will generally not
be included with the selected progestin in the transdermal
formulation. Further, most often only a single progestin will be
used in the formulation. However, in some circumstances two or more
progestins, especially progestins of different type, may be
combined in order to achieve a specific formulation.
[0046] The amount of progestin to be administered may be measured
according to several different parameters. In one aspect, the rate
or amount of progestin administered may be a rate or an amount
sufficient to achieve a contraceptive effect. The amount required
to obtain a contraceptive effect may vary depending on a number of
factors, including the activity or potency of the specific
progestin selected, as well as physiological variations among women
as to drug tolerance and general metabolic issues. In one aspect,
ovulation, or a lack thereof, can provide some measure of
contraceptive effectiveness. In some cases, serum levels of
progesterone .ltoreq.3.0 ng/ml are considered to indicate a lack of
ovulation. It should be noted, however, that ovulation is highly
variable among different subjects, and as such, the .ltoreq.3.0
ng/ml level may not be indicative of ovulation in all women. It has
been demonstrated that progestins are contraceptively effective
even though a large proportion of women ovulate while taking them.
In another aspects, inter alia, thickening of the cervical mucus,
suppression of lutenizing hormone (LH) and follicle stimulating
hormone (FSH) peaks, reduction of ciliary activity in the fallopian
tubes, and certain alterations of the endometrium may also be
indicators of contraceptive effectiveness. As such, it is well
within the knowledge of those skilled in the art to determine
contraceptive effectiveness. In one aspect, at least about 0.35
mg/day of a progestin such as norethindrone or norethindrone
acetate can be administered to achieve contraceptive effectiveness.
In another aspect, at least about 0.30 mg/day can be administered.
In yet another aspect, at least about 0.25 mg/day can be
administered. In yet another aspect, from about 0.25 mg/day to
about 4.0 mg/day can be administered.
[0047] The rate or amount of a progestin to be delivered can also
be measured according to serum levels. In one embodiment, the
progestin may be either norethindrone or norethindrone acetate
administered at a rate and an amount that provides a minimum
norethindrone serum level that is sufficient to cause and sustain
physiologic events in the woman resulting in contraception, while
at the same time providing a maximum norethindrone serum level that
avoids a significant incidence of adverse side effects. Various
maximum norethindrone serum levels are contemplated that may avoid
such adverse side effects. In one aspect, the maximum norethindrone
serum level may be less than about 2400 pg/ml. In another aspect,
the maximum norethindrone serum level may be from about 240 pg/ml
to about 1920 pg/ml. In yet another aspect, the maximum
norethindrone serum level may be from about 300 pg/ml to about 1200
pg/ml. In a further aspect, the maximum norethindrone serum level
can be from about 400 pg/ml to about 1100 pg/ml. Additionally,
various minimum norethindrone serum levels are contemplated that
may be sufficient to cause and sustain physiologic events in the
woman resulting in contraception. In one aspect, the minimum
norethindrone serum level can be at least about 160 pg/ml. In
another aspect, the minimum norethindrone serum level can be at
least about 300 pg/ml. In yet another aspect, the minimum
norethindrone serum level can be at least about 350 pg/ml.
[0048] Serum levels can also be expressed in terms of a
relationship between the maximum and minimum values. For example,
in one aspect the maximum norethindrone serum level that may be up
to about 15 times greater than the minimum norethindrone serum
level. In another aspect, the maximum norethindrone serum level may
be up to about 8 times greater than the minimum norethindrone serum
level. In yet another aspect, the maximum norethindrone serum level
may be up to about 4 times greater than the minimum norethindrone
serum level. In a further aspect, the maximum norethindrone serum
level may be up to about 2.75 times greater than the minimum
norethindrone serum level.
[0049] Contraceptive physiologic events can be sustained for
varying amounts of time following progestin administration,
depending on the dosage form, the nature of any penetration
enhancer present, the amount of progestin in the formulation, etc.
In one aspect, physiologic events may be sustained for a period of
up to at least 168 hours. In another aspect, physiologic events
associated with contraception may be sustained for a period from
about 24 hours to about 168 hours. In yet another aspect,
contraception may be sustained for a period of from about 24 hours
to about 96 hours. In a further aspect, contraception may be
sustained for a period of from about 48 hours to about 168
hours.
[0050] In accordance with another aspect of the invention, other
progestins may be administered according to their additional
potencies in amounts that are sufficient to provide a therapeutic
effect equivalent to that of norethindrone. Those of ordinary skill
in the art will readily recognize a number of mechanisms for
determining the correct amount of a given progestin to
substantially match the potency of a specific amount of
norethindrone.
[0051] The exact amount of progestin to be included in the
transdermal formulations of the present invention to achieve a
contraceptively effective amount is also considered to be within
the knowledge of those skilled in the art. Such a determination may
depend again on the activity or potency of the specific progestin
selected and physiological variations among women as to drug
tolerance and general metabolic issues. Further, considerations for
drug load may also be made in view of specifically desired
properties for the transdermal formulation, such as size, delivery
rate, and duration of administration, and may range from
subsaturated to supersaturated concentrations. However, in one
aspect, the amount of progestin may be from about 0.01% w/w to
about 50% w/w of the formulation. In a further aspect, the amount
of progestin may be from about 0.3% w/w to about 30% w/w of the
formulation. In another aspect, the amount of progestin may be from
about 1% w/w to about 15% w/w. In yet another aspect, the amount of
progestin may be from about 2.5% w/w to about 12% w/w. In a further
aspect, the amount of progestin may be about 5% w/w to about 10%
w/w of the formulation. In an additional aspect, the progestin
amount may be about 10% w/w of the formulation.
[0052] A number of pharmaceutically acceptable transdermal
formulations and methods for administering progestin may be used
for achieving the desired aspects of the present invention. The
transdermal drug delivery system for the progestin may take a
variety of well-known delivery formulations, including but not
limited to transdermal patches such as adhesive matrix patches,
liquid reservoir system (LRS) patches, transmucosal patches or
tablets, and topical formulations, such as creams, lotions,
ointments, gels, pastes, mousses, aerosols, sprays, suppositories,
etc. In one general aspect, the transdermal drug delivery system
can comprise a pharmaceutically acceptable carrier and a progestin
for transdermal delivery.
[0053] When presented in the form of a transdermal patch, the
transdermal drug delivery system of the present invention may
include structural components, as known in the art. For example, in
the case of an adhesive matrix patch, a distal backing can be
laminated to a polymer layer. Such a distal backing defines the
side of the matrix patch that faces the environment, i.e., distal
to the skin or mucosa. The backing layer functions to protect the
matrix polymer layer and the transdermal formulation, and to
provide a layer that prevents loss of progestin to the environment.
Thus, the material chosen for the backing should be compatible with
the polymer layer, progestin, and any optional ingredient such as
an enhancer, and should be minimally permeable to any components of
the matrix patch. In one aspect, the backing can be opaque to
protect components of the matrix patch from degradation from
exposure to ultraviolet light. In another aspect, the backing can
be transparent. Furthermore, the backing should be capable of
binding to and supporting the polymer layer, yet should be pliable
enough to accommodate the movements of a person using the matrix
patch.
[0054] Suitable materials for the backing include, but are not
limited to: metal foils, metalized polyfoils, composite foils or
films containing polyester such as polyester terephthalate,
polyester or aluminized polyester, polytetrafluoroethylene,
polyether block amide copolymers, polyethylene methyl methacrylate
block copolymers, polyurethanes, polyvinylidene chloride, nylon,
silicone elastomers, rubber based polyisobutylene, styrene,
styrene-butadiene and styrene-isoprene copolymers, polyethylene,
and polypropylene. Additionally, the backing may include various
foams, such as closed cell foams. Examples may include, without
limitation, polyolefin foams, polyvinyl chloride foams,
polyurethane foams, polyethylene foams, etc. In one aspect of the
invention, the backing layer may have a thickness of about 0.0005
to 0.1 inch.
[0055] Further, a release liner may be temporarily provided upon
the proximal side (side to adhere to the skin) of the adhesive
layer. Such a liner provides many of the same functions as the
backing layer, prior to adhesion of the patch to the skin. In use,
the release liner is peeled from the adhesive layer just prior to
application and discarded. The release liner can be made of the
same materials as the backing layer, or other suitable films coated
with an appropriate release surface.
[0056] In addition to containing the progestin, transdermal
formulations of the present invention may also include one or more
of a number of other additives, such as diluents, excipients,
emollients, plasticizers, skin irritation reducing agents, or a
mixture thereof. Such materials are pharmaceutically acceptable in
that they are nontoxic, do not hinder drug delivery, and are not
for any other reasons biologically or otherwise undesirable.
Examples of such additional materials include water, mineral oils,
silicone, inorganic gels, aqueous emulsions, liquid sugars, waxes,
petroleum jellies, plasticizers, low molecular weight polymers, and
a variety of other oils and polymeric materials. These types of
components, as well as others not specifically recited, are well
known in the art for inclusion in various transdermal formulations,
and may be added as desired to the transdermal drug delivery system
of the present invention in specific types and amounts in order to
achieve a desired result. Additionally, many transdermal drug
delivery formulations have a tendency to cause skin irritation
after prolonged exposure to the skin, thus addition of a skin
irritation reducing agent aids in achieving a composition that is
better tolerated by the skin. In one aspect, the skin irritation
reducing agent may be glycerin, as disclosed in U.S. Pat. No.
4,855,294, which is incorporated by reference in its entirety.
[0057] As described herein, the transdermal formulations of the
present invention may also optionally include a permeation
enhancer, or mixture of permeation enhancers. Useful permeation
enhancers may include, without limitation, fatty acids, fatty acid
esters, fatty alcohols, fatty acid esters of lactic acid or
glycolic acid, glycerol tri-, di-, and monoesters, triacetin, short
chain alcohols, and mixtures thereof. Specific species or
combinations or species may be selected from the above listed
classes of compounds by one skilled in the art, in order to
optimize enhancement of the particular progestin employed. As more
fully enumerated below, it has been found that sorbitan ester-type,
lauryl-type, and polyol-type agents provide a significant
penetration enhancing effect on norethindrone and norethindrone
acetate. One skilled in the art would, however, understand that
many other enhancers could be utilized in these formulations, and
would thus be included within the scope of the present
invention.
[0058] In one aspect of the present invention, the permeation
enhancer is a sorbitan ester-type enhancer. Sorbitan ester-type
enhancers are discussed in U.S. Pat. Nos. 5,227,169 and 5,212,199,
which are incorporated by reference in their entireties. Exemplary
sorbitan esters can be, without limitation, longchain sorbitan
monoesters such as sorbitan monooleate and sorbitan
monolaurate.
[0059] In another aspect, the permeation enhancer included in the
transdermal formulation may be a lauryl-type enhancer. A variety of
lauryl-type enhancers may be suitable for use in the present
invention. However, in one aspect the lauryl-type enhancer used may
include without limitation, lauryl alcohol, 1-lauryl-2-pyrrolidone,
and mixtures thereof. In another aspect, the enhancer may be a
mixture of lauryl alcohol in an amount of about 5% w/w and
1-lauryl-2-pyrrolidone in an amount of about 3% w/w. In yet another
aspect, the permeation enhancer may be a polyol-type enhancer.
Further, a variety of polyol-type enhancers may be suitable for use
in the present invention. However, in one aspect, the polyol-type
enhancer used may be dipropylene glycol.
[0060] The specific sorbitan ester-, lauryl-, or polyol-type
enhancer, and the amount thereof, may be selected by one of
ordinary skill in the art depending on a specific result to be
achieved. However, as a general matter, the amount of enhancer
included in the transdermal formulation may be from about 0.01% w/w
to about 50% w/w of the formulation. In a more detailed aspect, the
amount of enhancer may be from about 3% w/w to about 15% w/w of the
formulation. In a further aspect, the amount of enhancer may be
about 10% w/w of the formulation. In an additional aspect, the
amount of enhancer may be about 5% w/w of the formulation.
[0061] In yet another aspect, the permeation enhancer in the
transdermal formulation may be isopropyl myristate (IPM). IPM can
be included as the sole enhancer, or the transdermal formulation
can include IPM and at least one other enhancer, such as, without
limitation, lauryl alcohol, sorbitan monooleate, or dipropylene
glycol. In one particular aspect of the invention, the enhancer may
be a combination of lauryl alcohol and isopropyl myristate. A more
detailed discussion of permeation enhancer combinations of lauryl
alcohol and isopropyl myristate can be found in Applicant's
copending U.S. Patent Application No. 60/705,289 filed on Aug. 3,
2005 entitled "Formulations and Methods for Enhancing the
Transdermal Penetration of a Drug," which is incorporated herein by
reference.
[0062] In one general aspect, the transdermal drug delivery system
of the present invention can comprise a pharmaceutically acceptable
carrier intended to contain the progestin and other optional
components. A number of pharmaceutically acceptable carriers are
known to those of ordinary skill in the art and may be used in
connection with the present invention.
[0063] The pharmaceutically acceptable carrier of an LRS patch may
be of any suitable viscous material known to those skilled in the
art of transdermal drug delivery. Such carriers are typically a
fluid of desired viscosity, such as a gel or ointment, which is
formulated for confinement in a reservoir having an impermeable
backing and a skin contacting permeable membrane, or membrane
adhesive laminate providing diffusional contact between the
reservoir contents and the skin. Such a viscous carrier may contain
both the progestin to be transdermally delivered as well as other
optional components of the transdermal formulation. LRS patches are
those described or referred to in U.S. Pat. Nos. 4,849,224, and
4,983,395, which are hereby incorporated by reference in their
entirety.
[0064] The present invention contemplates various structural types
of transdermal matrix patches. For example, monolithic systems
where the progestin is contained directly in a single pressure
sensitive adhesive layer, as well as systems containing one or more
polymeric reservoirs in addition to the pressure sensitive adhesive
layer may be utilized. In aspects comprising systems having
multiple layers/laminates, a rate controlling member may be
included. Generally, a rate controlling member is located between a
reservoir layer and the skin. In those aspects including a delivery
layer and a reservoir layer, the rate controlling member may be
adhered between a proximal side of the reservoir layer, and a
distal side of the delivery layer. The rate controlling member is
provided for the purpose of metering, or controlling, the rate at
which drug and/or permeation enhancer migrates from the storage
layer into the delivery layer. As noted herein, in one aspect of
the present invention, a permeation enhancer may be used to
increase the delivery rate of the drug, and thus may also be used
to vary other parameters, such as patch size, etc.
[0065] In one aspect, the pressure-sensitive adhesive of the
pharmaceutically acceptable carrier can be suitable for long-term
(e.g., greater than 1 day, may be about 3-4 days, or longer such as
1-4 weeks) contact with the skin. In another aspect, the
pressure-sensitive adhesive of the carrier is suitable for a
short-term administration (e.g., for a few minutes to a few hours,
less than or equal to 1 day). Such adhesives must be physically and
chemically compatible with the progestin and any optional enhancer
present, and with any carriers and/or vehicles or other additives
incorporated into the formulation. In one aspect of the invention,
the adhesives of the pharmaceutically acceptable carrier can
include polymeric adhesives. Example of such adhesives can include
without limitation, acrylic adhesives including cross-linked and
uncross-linked acrylic copolymers; vinyl acetate adhesives; natural
and synthetic rubbers including polyisobutylenes, neoprenes,
polybutadienes, and polyisoprenes; ethylenevinylacetate copolymers;
polysiloxanes; polyacrylates; polyurethanes; plasticized weight
polyether block amide copolymers, and plasticized styrene-rubber
block copolymers or mixtures thereof. In yet another aspect of the
invention, contact adhesives for use in the pharmaceutically
acceptable carrier layer are acrylic adhesives, such as DUROTAK.TM.
87-2888 adhesive (National Starch & Chemical Co., Bridgewater,
N.J.); and polyisobutylene adhesives such as ARCARE.RTM. MA-24
(Adhesives Research, Glen Rock, Pa.) and ethylene vinyl acetate
copolymer adhesives. Those of ordinary skill in the art will
appreciate that the specific type and amount of adhesive polymer
used may be selected depending upon the desired specific
characteristics of the final product. However, in one aspect, the
amount of adhesive polymer in the adhesive matrix layer may be at
least about 50% w/w of the adhesive layer. In another aspect, the
amount may be at least about 60% w/w of the adhesive layer. In yet
another aspect, the amount may be at least about 85% w/w of the
adhesive layer. In a further aspect, the amount may be at least
about 90% w/w of the adhesive layer. In an additional aspect, the
amount may be from about 50% w/w to about 95% w/w of the adhesive
layer.
[0066] In one aspect of the present invention, the carrier can be a
biocompatible polymer. In another aspect, the carrier is an
adhesive such as a polymeric adhesive matrix. In yet another
aspect, the polymeric adhesive may be an acrylic polymer, such as
an acrylic pressure sensitive adhesive. The carrier, in some
aspects, may contain both the progestin to be transdermally
delivered, and a permeation enhancer or other optional
components.
[0067] The transdermal formulations of the present invention can
also be provided with pharmaceutical carriers that improve the
stability of progestins during long-term storage. Such compositions
may comprise ethylhexylacrylate polymers, or other carriers that do
not contain or form acid functional groups upon storage, as
described in U.S. Pat. No. 5,780,050, which is incorporated by
reference herein. Methods for providing such hormones to females,
as well as males, are also well known. See, U.S. Pat. Nos.
5,460,820, 5,152,997, and 5,783,208, which are incorporated by
reference herein. It is appreciated that using the disclosure of
the present invention, one skilled in the art can readily
accomplish the objective of the above-referenced patents.
[0068] The formulations of the present invention can include
sustained release formulations that administer therapeutically
effective amounts of a progestin over an extended period of time.
However, in one aspect, the sustained delivery period of the
progestin may be for at least about 7 days. In another aspect, the
sustained delivery period may be at least about 5 days. In a
further aspect, the sustained delivery period may be at least about
3 days. In yet another aspect, the period may be about 24
hours.
[0069] In addition to the methods of providing progestin only
contraception to minimize breakthrough bleeding side effects
associated with progestin-only contraception, the present invention
includes a kit for providing the progestin only contraception
according to the methods disclosed herein. The kit can comprise a
transdermally administrable formulation having a contraceptively
effective amount of a single progestin as the sole active hormonal
agent, and instructions describing a method of using the
transdermally administrable formulation. The transdermal
formulation can utilize the progestins, optional enhancers, dosage
forms, and other transdermal components described herein.
EXAMPLES
[0070] The following examples of progestin-only contraceptive
formulations are provided to promote a more clear understanding of
certain embodiments of the present invention, and are in no way
meant as a limitation thereon.
Example 1
[0071] Transdermal matrix systems containing norethindrone acetate
can be made as follows. The solids contents of an acrylic adhesive
solution, (DUROTAK.TM. 87-2888, National Starch) are determined by
placing small amounts into pre-weighed aluminum dishes which are
then put in a convection oven (Model A4718-Q, Blue M) at 75.degree.
C. overnight. Following evaporation of the solvents, the weight of
the dry adhesive is obtained and the solids content calculated as a
ratio of the dry to wet weight.
[0072] The adhesive 87-2888 contains approximately 32-35% solids
and is used undiluted. Known quantities of the adhesive are weighed
into glass bottles based on previously determined solids content.
An appropriate quantity of norethindrone acetate (NEA) is added to
the liquid adhesive in each bottle to give about a 5% w/w NEA
concentration upon drying. The bottles are capped and sealed with
parafilm and rotated until all the NEA is dissolved. An appropriate
amount of sorbitan monooleate (SMO) enhancer is added to the
bottles containing the NEA in adhesive to give the desired
compositions having about 10% w/w SMO enhancer upon drying. Each
bottle is again tightly capped, sealed with parafilm and rotated
overnight during which time the NEA and the enhancer dissolve to
yield a clear solution.
[0073] An appropriate amount of the composition (about 10 g) is
then placed onto the high release side of a silicone release-coated
3 Mil thick polyester (PET) liner (Loparex Inc., 10393S) and
manually cast with a 10 Mil gap casting knife. Each cast is placed
in a convection oven (Model A4718-Q, Blue M) at 75.degree. C. for
15 minutes. After drying, each cast is then laminated with a 3 Mil
polyethylene (PET) monolayer backing film (3M, COTRAN.TM. 9720).
The cast and backing film can then be cut to provide a proper
delivery dosage, namely 22 cm.sup.2 for 0.2 mg/day and 33 cm.sup.2
for 0.3 mg/day patches.
Example 2
[0074] Transdermal matrix systems containing norethindrone acetate
can also be made as follows. The solids contents of an acrylic
adhesive solution, (DUROTAK.TM. 87-900A) are determined by placing
small amounts into pre-weighed aluminum dishes which are then put
in a convection oven (Model A4718-Q, Blue M) at 75.degree. C.
overnight. Following evaporation of the solvents, the weight of the
dry adhesive is obtained and the solids content calculated as a
ratio of the dry to wet weight.
[0075] The adhesive 87-900A contains approximately 40-44% solids
and is used undiluted. Lauryl alcohol is a solid at room
temperature and has to be melted by heating a small quantity held
in a glass jar in a water bath prior to use. For each casting
solution being prepared, the appropriate amount of soluble
polyvinylpyrrolidone (PVP) K-12 to yield 10% w/w in the dried film
is weighed directly into a jar and the minimum amount of absolute
ethanol calculated to completely dissolve the PVP is added to the
jar. After dissolving the PVP based on the previously determined
solids content, a known volume of the adhesive is weighed into the
jar and, appropriate amounts of norethindrone acetate (NEA), lauryl
alcohol (LA), isopropyl myristate (IPM) (with the appropriate
overages) are added to provide the desired compositions upon drying
10% w/w NEA, 5% w/w LA, 5% w/w IPM and 10% w/w PVP-K12. The bottles
are tightly capped, sealed with parafilm and rotated over night
during which time all the ingredients dissolve to yield a
translucent solution.
[0076] A small amount of the formulation (about 10 g) is placed
onto a fluoropolymer coated 3 Mil thick polyester (PET) liner (3M,
SCOTCHPAK.TM., 1022) and manually cast with a 10 mil gap casting
knife. The cast is placed in a convection oven (Model A4718-Q, Blue
M) at 75.degree. C. for 15 minutes. After drying, the cast is
laminated with the polyester side of a 2 Mil (PET/EVA) laminate
backing film (3M, SCOTCHPAK.TM., 9739). The cast and backing film
can then be cut to appropriate sizes to provide a proper delivery
dosage, 0.2 mg/day and 0.3 mg/day patches.
Example 3
[0077] A clinical trial using the transdermal formulation of
Example 1 was conducted for the purposes of comparing such
formulations with oral progestin-only contraceptive tablets (NOR
QD.RTM., Watson Pharmaceuticals, Inc.) Volunteer subjects were
subjected to a screening and baseline period consisting of a 4-week
washout of previous contraceptive treatment, if necessary, followed
by approximately a one month baseline evaluation period (cycle 1)
which consisted of one full menses cycle to determine eligibility
for participating in the study. Eligibility was based on whether a
subject ovulated (serum progesterone >3 ng/ml) and had a
favorable cervical mucus score (.gtoreq.10) during cycle 1.
Subjects who qualified for entry into the study were randomized
into two 12-week study groups: [0078] once weekly application to
the abdomen of 0.3 mg/day formulation of Example 1 for 12
consecutive weeks starting on the first day of bleeding of the
first menstrual cycle following randomization; and [0079] once
daily oral administration of 0.35 mg NOR QD.RTM.
(norethindrone-only formulation) for 12 consecutive weeks starting
on the first day of bleeding of the first menstrual cycle following
randomization.
[0080] A third study group was also established, the results of
which are not included herein. A treatment period consisted of
12-week study divided into three cycles, namely cycles 2-4. Each
cycle was approximately 4 weeks in duration, beginning on the first
day of menstrual bleeding for a give cycle.
Example 4
[0081] Plasma norethindrone (NE) concentration measurements were
performed on the study groups of Example 3 to determine the peak
and trough levels of NE during the third month of treatment, Cycle
4. For the oral 0.35 mg NOR QD.RTM. group, trough NE plasma
concentration levels were collected prior to the subjects taking
their morning dose, and peak NE plasma concentration levels were
collected one hour following dosing. For the 0.3 mg/day NOR TD.TM.
group, peak and trough NE plasma concentration values were
determined by comparing the date/time of the concentration to the
date/time of the last transdermal patch application. For example,
blood NE samples were considered peak concentration levels if the
blood was collected >24 hours and <96 hours from the time of
the last transdermal patch application. If however, the difference
between when the blood NE sample was collected and the time of the
last transdermal patch application was <24 hours or was between
96 and 168 hours, the concentration level was considered trough.
Plasma NE concentrations are summarized for each treatment group in
Table 1.
TABLE-US-00001 TABLE 1 Plasma NE concentrations summarized for each
treatment group Plasma NE concentrations (pg/mL) 0.3 mg/day 0.35 mg
NOR TD .TM.* NOR QD .RTM.** Peak 549.8 2721.9 Trough 367.6 551.2
*80 subjects **79 subjects
[0082] The mean peak NE levels for the 0.3 mg/day NOR TD.TM. dose
group is similar to levels (600 pg/mL) that are thought to be
required to consistently inhibit ovulation when using subdermal
implants of NEA. As can be seen in Table 1, daily ingestion of an
oral NE formulation produces significantly higher plasma NE
concentrations than the transdermal NE formulation. Moreover, the
difference between peak and trough associated with the transdermal
formulation is much less than the difference associated with the
oral formulation.
Example 5
[0083] The portion of each group that did not ovulate was during
the treatment is shown in Table 2. A direct quantitative assessment
was obtained by measuring serum progesterone levels. Non-ovulation
was defined as serum progesterone levels of .ltoreq.3 ng/mL.
TABLE-US-00002 TABLE 2 The proportion of subjects who did not
ovulate Ovulation 0.3 mg/day 0.35 mg NOR TD .TM.* NOR QD .RTM.**
Ovulated 55% 49% Did not ovulate 45% 51% *80 subjects **79
subjects
[0084] The 95% confidence interval lower limit for the 0.3 mg/day
NOR TD.TM. treatment group was -18.6%, and is therefore within a
20% equivalence bound indicating that the two treatment groups are
considered equivalent.
Example 6
[0085] Cervical mucus samples were collected between Days 11 and 17
of Cycle 4 and scored according to WHO Laboratory Manual for the
Examination of Human Semen and Sperm-Cervical Mucus Interaction,
(4.sup.th ed., Cambridge University Press, 1999), which is
incorporated herein by reference. Variables evaluated included
volume, spinnbarkeit, consistency, cellularity, and ferning. The
scale for each variable ranged from 0 to 3, allowing a maximum
total score of 15. The score for each variable was totaled to
produce the cervical mucus score, which could range from 0 to 15.
Using the scoring system from the WHO lab manual, a score
.gtoreq.10 was used to indicate cervical mucus conditions favorable
for sperm penetration and a score <10 was used to indicate
unfavorable mucus conditions for sperm penetration. The results of
this evaluation are shown in Table 3.
TABLE-US-00003 TABLE 3 A comparison of cervical mucus status
Cervical Mucus Status (Cycle 4) 0.3 mg/day 0.35 mg NOR TD .TM.* NOR
QD .RTM.** % Favorable 11% 8% % Unfavorable 89% 92% *80 subjects
**79 subjects
[0086] The 95% confidence interval lower limit for the 0.3 mg/day
NOR TD.TM. treatment group was -12.1%, and is therefore within a
20% equivalence bound indicating that the two treatment groups are
considered equivalent.
Example 7
[0087] Subjects in the treatment groups of Example 3 were evaluated
for any breakthrough bleeding that occurred during the three
cycles. A number of subjects were included in this evaluation that
were disqualified prior to the evaluations in Examples 4-6.
Breakthrough bleeding or intermenstrual bleeding was defined as any
bleeding or spotting occurring during the menstrual cycle,
excluding contiguous bleeding with menses. Breakthrough bleeding
was categorized using the following criteria: [0088] none [0089]
spotting (.ltoreq.1 sanitary pad/tampon used) [0090] bleeding
(.gtoreq.2 sanitary pad/tampons used)
[0091] Results from the breakthrough bleeding studies are contained
in Tables 4 and 5.
TABLE-US-00004 TABLE 4 A comparison of the percentage of women that
experienced breakthrough bleeding (spotting) Breakthrough Bleeding:
Spotting Cycle 2 Cycle 3 Cycle 4 0.3 mg/day 13.6% 17.8% 18.4% NOR
TD .TM.* 0.35 mg 17.9% 18.4% 21.9% NOR QD .RTM.** *112 subjects
**113 subjects
TABLE-US-00005 TABLE 5 A comparison of the percentage of women that
experienced breakthrough bleeding (bleeding) Breakthrough Bleeding:
Spotting Cycle 2 Cycle 3 Cycle 4 0.3 mg/day 20.0% 23.4% 20.4% NOR
TD .TM.* 0.35 mg 14.3% 27.2% 34.4% NOR QD .RTM.** *112 subjects
**113 subjects
[0092] As can be seen from these data, the incidence of
breakthrough bleeding was lower in the 0.3 mg/day NOR TD.TM. group
than the oral 0.35 mg NOR QD.RTM. group, particularly for bleeding
during cycle 4.
[0093] Examples 5 and 6 demonstrate that the 0.3 mg/day NOR TD.TM.
and the 0.35 mg NOR QD.RTM. formulations may be therapeutically
equivalent because they appear to provide equivalent levels of
contraceptive protection as demonstrated by the similarities
observed in the study populations regarding ovulation and cervical
mucus status.
[0094] Given this apparent dose equivalence and similar
contraceptive effect between the 0.30 mg/day transdermal and the
0.35 mg oral formulations, a surprising relationship appears
between the progestin dosage form and the incidence of breakthrough
bleeding in the study populations shown in Example 7. Specifically,
transdermal delivery of the NEA-only formulation caused overall
fewer incidents of breakthrough bleeding than the oral NE-only
formulation. It is possible that the higher incidence of
breakthrough bleeding in the group taking the 0.35 mg NOR QD.RTM.
oral formulation may be a result of the significantly higher peak
NE serum levels observed as compared to the 0.3 mg/day NOR TD.TM.
transdermal formulation, as shown in Example 4. Thus the higher
peak serum level of NE as a result of taking an oral NE formulation
may be associated with the higher incidence of side effects.
Moreover, as shown in Table 1, the difference between peak and
trough associated with the transdermal formulation is much less
than the difference associated with the oral formulation. As such,
NE serum level rise and fall rapidly throughout a 24 hour period.
This rapid change may also account for the differences in
breakthrough bleeding side effects observed between the oral and
transdermal formulations.
[0095] Regardless of the method of action, however, it is apparent
from these data that the transdermal NEA-only formulation is
superior to the oral NE-only formulation because, while both attain
substantially similar contraceptive effects, the transdermal
formulation further minimizes side effects such as breakthrough
bleeding and reduce the risk of dosage non-compliance, and
therefore increases the overall efficacy of the contraceptive
regimen.
[0096] It is to be understood that the above-described compositions
and modes of application are only illustrative of preferred
embodiments of the present invention. Numerous modifications and
alternative arrangements may be devised by those skilled in the art
without departing from the spirit and scope of the present
invention and the appended claims are intended to cover such
modifications and arrangements.
[0097] Thus, while the present invention has been described above
with particularity and detail in connection with what is presently
deemed to be the most practical and preferred embodiments of the
invention, it will be apparent to those of ordinary skill in the
art that numerous modifications, including, but not limited to,
variations in size, materials, shape, form, function and manner of
operation, assembly and use may be made without departing from the
principles and concepts set forth herein.
* * * * *