U.S. patent application number 13/044447 was filed with the patent office on 2011-08-11 for transdermal delivery systems for active agents.
This patent application is currently assigned to ANTARES PHARMA, IPL, AG. Invention is credited to Dario Norberto R. Carrara, Arnaud Grenier.
Application Number | 20110195114 13/044447 |
Document ID | / |
Family ID | 42631525 |
Filed Date | 2011-08-11 |
United States Patent
Application |
20110195114 |
Kind Code |
A1 |
Carrara; Dario Norberto R. ;
et al. |
August 11, 2011 |
TRANSDERMAL DELIVERY SYSTEMS FOR ACTIVE AGENTS
Abstract
A delivery vehicle for topical pharmaceutical formulations that
include a C2 to C4 alkanol, a polyalcohol, and a monoalkyl ether of
diethylene glycol present in relative amounts sufficient to provide
permeation enhancement of an active agent through mammalian dermal
or mucosal surfaces. Preferably, the delivery vehicle as well as
the formulations that contain it are substantially free of
long-chain fatty alcohols, long-chain fatty acids and long-chain
fatty esters in order to avoid potential undesirable odor and
irritation effects caused by such compounds during use of the
formulation. Without these additives, use of the formulations is
facilitated and patient compliance is greater
Inventors: |
Carrara; Dario Norberto R.;
(Oberwil, CH) ; Grenier; Arnaud; (Steinbrunn le
haut, FR) |
Assignee: |
ANTARES PHARMA, IPL, AG
|
Family ID: |
42631525 |
Appl. No.: |
13/044447 |
Filed: |
March 9, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12614216 |
Nov 6, 2009 |
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13044447 |
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10798111 |
Mar 10, 2004 |
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12614216 |
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11755923 |
May 31, 2007 |
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12614216 |
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11371042 |
Mar 7, 2006 |
7335379 |
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11755923 |
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PCT/EP2004/011175 |
Oct 6, 2004 |
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11371042 |
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11634005 |
Dec 4, 2006 |
7404965 |
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11755923 |
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10343570 |
May 19, 2003 |
7214381 |
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PCT/EP01/09007 |
Aug 3, 2001 |
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11634005 |
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60510613 |
Oct 10, 2003 |
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60453604 |
Mar 11, 2003 |
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60510613 |
Oct 10, 2003 |
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Current U.S.
Class: |
424/450 ;
514/179; 514/182; 514/772 |
Current CPC
Class: |
A61K 9/06 20130101; A61P
15/00 20180101; A61K 47/32 20130101; A61P 5/30 20180101; A61K 47/38
20130101; A61K 47/10 20130101; A61K 9/0014 20130101; A61P 25/00
20180101; A61P 5/26 20180101; A61K 31/216 20130101; A61P 21/00
20180101; A61P 31/04 20180101; A61K 31/56 20130101; A61P 19/10
20180101 |
Class at
Publication: |
424/450 ;
514/772; 514/179; 514/182 |
International
Class: |
A61K 9/127 20060101
A61K009/127; A61K 47/10 20060101 A61K047/10; A61K 31/568 20060101
A61K031/568; A61K 31/565 20060101 A61K031/565; A61P 5/26 20060101
A61P005/26; A61P 5/30 20060101 A61P005/30; A61P 15/00 20060101
A61P015/00; A61P 19/10 20060101 A61P019/10 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 3, 2000 |
EP |
PCT/EP00/07533 |
Claims
1. A delivery vehicle for a composition of an active agent that is
to be administered transdermally or transmucosally to a subject,
which comprises a C2 to C4 alkanol, a polyalcohol, a monoalkyl
ether of diethylene glycol, and water, present in relative amounts
sufficient to provide permeation enhancement of the active agent
through mammalian dermal or mucosal surfaces; wherein the delivery
system is substantially free of long-chain fatty alcohols,
long-chain fatty acids, and long-chain fatty esters in order to
avoid undesirable odor and irritation effects caused by such
compounds during use of the composition.
2. The delivery vehicle of claim 1, wherein the alkanol is selected
from the group consisting of ethanol, isopropanol, n-propanol, and
mixtures thereof; wherein the polyalcohol is selected from the
group consisting of propylene glycol and dipropylene glycol and
mixtures thereof; and wherein the monoalkyl ether of diethylene
glycol is selected from the group consisting of monomethyl ether of
diethylene glycol, monoethyl ether of diethylene glycol, and
mixtures thereof.
3. The delivery vehicle of claim 1, wherein the alkanol is present
in an amount between about 5 to 80% by weight, the polyalcohol is
present in an amount between about 1% to 30% by weight, and the
monoalkyl ether of diethylene glycol is present in an amount
between about 0.2 to 30% by weight so that the delivery vehicle
facilitates absorption of the active agent by the dermal or mucosal
surfaces so that transfer or removal of the formulation from such
surfaces is minimized.
4. The delivery vehicle of claim 3, wherein the alkanol is in
combination with water to form a hydroalcoholic mixture that is
present in an amount of between about 40 to about 98% by weight,
with the alkanol present in an amount of between about 5% to 80% by
weight of the mixture, and the water present in an amount of
between about 20% to 95% by weight of the mixture.
5. The delivery vehicle of claim 1, wherein the alkanol is present
in an amount between about 45 and 75% by weight; the polyalcohol is
present in an amount between about 1 to 30% by weight; and the
monoethyl ether of diethylene glycol is present in an amount
between about 1 to 15% by weight.
6. The delivery vehicle according claim 1, wherein the alkanol is
ethanol, isopropanol, or a mixture thereof present in an amount
between about 45 and 60% by weight; the polyalcohol is propylene
glycol present in an amount between about 1 to 20% by weight; and
the monoethyl ether of diethylene glycol is present in an amount
between about 1 to 10% by weight and further wherein the
polyalcohol and permeation enhancer are present in a weight ratio
of between 1:1 to 3:1.
7. The delivery system according to claim 6 consisting essentially
of the recited ingredients and amounts.
8. A non-occlusive formulation comprising the delivery vehicle
according claim 1 and an active agent or a pharmaceutically
acceptable salt thereof present in an amount of between about 1 to
20% by weight of the formulation; wherein the formulation is
substantially free of long-chain fatty alcohols, long-chain fatty
acids, and long-chain fatty esters in order to avoid undesirable
odor and irritation effects caused by such compounds during
use.
9. The formulation of claim 8, wherein the active agent is a
hormone,
10. The formulation of claim 8 wherein the active agent is selected
from the group consisting of an androgen, estrogen, progestin, or a
combination thereof; wherein the androgen is selected from the
group consisting of testosterone, 17-.beta.-hydroxyandrostenone,
testosterone esters, methyl testosterone, testolactone,
oxymetholone, fluoxymesterone, androsterone, androsterone acetate,
androsterone propionate, androsterone benzoate, androstenediol,
androstenediol-3-acetate, androstenediol-17-acetate,
androstenediol-3,17-diacetate, androstenediol-17-benzoate,
androstenediol-3-acetate-17-benzoate, androstenedione, sodium
dehydroepiandrosterone sulfate, 4-dihydrotestosterone, 5
adihydrotestosterone, dromostanolone, dromostanolone propionate,
ethylestrenol, nandrolone phenpropionate, nandrolone decanoate,
nandrolone furylpropionate, nandrolone cyclohexanepropionate,
nandrolone benzoate, nandrolone cyclohexanecarboxylate,
oxandrolone, and stanozolol or any combination thereof; the
estrogen is selected from the group consisting of 17
beta-estradiol, estradiol, estradiol benzoate, estradiol 17
beta-cypionate, estriol, estrone, ethynil estradiol, mestranol,
moxestrol, mytatrienediol, polyestradiol phosphate, quinestradiol,
and quinestrol or any combination thereof; and the progestin is
selected from the group consisting of allylestrenol, anagestone,
chlormadinone acetate, delmadinone acetate, demegestone,
desogestrel, dimethisterone, dydrogesterone, ethynilestrenol,
ethisterone, ethynodiol, ethynodiol diacetate, fluorogestone
acetate, gestodene, gestonorone caproate, haloprogesterone,
17-hydroxy-16-methylene-progesterone, 17 alpha-hydroxyprogesterone,
17 alpha-hydroxygesterone caproate, lynestrenol, medrogestone,
medroxyprogesterone, megestrol acetate, melengestrol,
16-methylene-17-alpha-acetoxy-19-nor-pregn-4-ene,3,20-dione,
norethindrone, norethindrone acetate, norethynodrel, norgesterone,
norgestimate, norgestrel, norgestrienone, 19-norprogesterone,
norvinisterone, pentagestrone, progesterone, natural progesterone,
promegestone, quingestrone, and trengestone or any combination
thereof; provided that the combination of estrogen and progestin is
not present.
10. The formulation of claim 8, wherein the pharmaceutically
acceptable salt of the active agent is selected from the group
consisting of acetate, bitartrate, citrate, edetate, edisylate,
estolate, esylate, fumarate, gluceptate, gluconate, glutamate,
hydrobromide, hydrochloride, lactate, malate, maleate, mandelate,
mesylate, methylnitrate, mucate, napsylate, nitrate, pamoate,
pantothenate, phosphate, salicylate, stearate, succinate, sulfate,
tannate and tartrate.
11. The formulation of claim 8, further comprising at least one
excipient selected from the group consisting of gelling agents,
solvents, cosolvents, antimicrobials, preservatives, antioxidants,
buffers, humectants, sequestering agents, moisturizers, emollients,
film-forming agents, or permeation enhancers.
12. The formulation of claim 8, in the form of a topical gel,
lotion, foam, cream, spray, aerosol, ointment, emulsion,
microemulsion, nanoemulsion, suspension, liposomal system, lacquer,
or non-occlusive dressing.
13. The formulation of claim 8, wherein the alkanol is ethanol or
isopropanol that is present in an amount between about 20 to 65% of
the formulation; the polyalcohol is propylene glycol that is
present in an amount between about 1% to 15% of the formulation;
the permeation enhancer is diethylene glycol monoethyl ether that
is present in an amount between about 1% to 15% of the formulation,
and further wherein the formulation comprises a gelling agent
present in an amount of between 0.05% to about 4% of the
formulation, a neutralizing agent present in an amount between
about 0.05% and 1% of the formulation, and water present in an
amount between about 20% to 65% of the formulation, and wherein the
active agent is either estradiol present in an amount between about
0.01% to about 2% of the formulation or testosterone in an amount
of about 0.01 to about 1% by weight.
14. A method for administering an active agent to a mammal in need
thereof which comprises topically or transdermally administering to
the skin or the mucosa of the mammal a formulation according to
claim 8.
15. The method of claim 14, wherein the active agent is present in
an amount of about 0.01 to about 5% of the composition and between
about 40 and about 250 mg of the composition is administered daily
upon the abdomen, shoulder, arm, or thigh of the mammal.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
12/614,216 filed Nov. 6, 2009, which is a continuation-in-part of
application Ser. No. 10/798,111 filed Mar. 10, 2004, which claims
the benefit of each of application Nos. 60/453,604 filed Mar. 11,
2003 and 60/510,613 filed Oct. 10, 2003. Application Ser. No.
12/614,216 is also a continuation-in-part of application Ser. No.
11/755,923 filed May 31, 2007, which is a continuation-in-part of
U.S. patent application Ser. No. 11/371,042 filed Mar. 7, 2006, now
U.S. Pat. No. 7,335,379, which is a continuation of International
application no. PCT/EP2004/011175 filed Oct. 6, 2004, which claims
the benefit of U.S. provisional patent application No. 60/510,613,
filed Oct. 10, 2003. Application Ser. No. 11/755,923 is also a
continuation-in-part of U.S. patent application Ser. No. 11/634,005
filed Dec. 4, 2006, now U.S. Pat. No. 7,404,965, which is a
continuation of application Ser. No. 10/343,570 filed May 19, 2003,
now U.S. Pat. No. 7,214,381, which is the U.S. national stage of
International application no. PCT/EP01/09007 filed Aug. 3, 2001
which claims priority to International application no.
PCT/EP00/07533 filed Aug. 3, 2000. Each prior application is
expressly incorporated herein in its entirety by reference
thereto.
TECHNICAL FIELD
[0002] The present invention relates to a novel transdermal or
transmucosal pharmaceutical formulation comprising at least one
active ingredient and a solvent system. The invention reveals a
pharmaceutical formulation that administers the active drug(s) at a
permeation rate that would ensure therapeutically effective
systemic concentration. The formulations of the present invention
contain defined amounts of chemicals that minimize the barrier
characteristics of the most uppermost layer of the epidermis and
provide sustained permeation rate. This invention relates generally
to a novel delivery vehicle and preferably one that is
substantially free of long chain fatty alcohols, long chain fatty
acids, and long-chain fatty esters.
BACKGROUND
[0003] The present invention relates to formulations and methods of
treatment using a wide variety of active agents. Of course, many
existing agents and treatments are currently known.
[0004] In the area of hormones, for example, reduced levels of
endogenous steroid hormones in humans often leads to a variety of
undesirable clinical symptoms. For example, men with low
testosterone levels (hypogonadism) may result in clinical symptoms
including impotence, lack of sex drive, muscle weakness, and
osteoporosis. Similarly, in women, reduced levels of testosterone
and/or estrogen may result in female sexual disorder, which include
clinical symptoms such as lack of sex drive, lack of arousal or
pleasure, low energy, reduced sense of well-being, and
osteoporosis. Moreover, reduced levels of estrogen and/or
progesterone in women, such as that due to menopause, often result
in clinical symptoms including hot flashes, night sweats, vaginal
atrophy, decreased libido, and osteoporosis.
[0005] In addition to reduced levels of endogenous steroid hormones
such as those described above, adrenal insufficiency leads to
reduced levels of dehydroepiandrosterone (DHEA) in men and women.
The adrenal glands are also involved in the production of many
hormones in the body, including DHEA and sex hormones such as
estrogen and testosterone. Consequently, adrenal insufficiency can
lead to reduced levels of DHEA and sex hormones which can lead to
the clinical symptoms described above.
[0006] Although steroid hormone concentrations may be restored to
normal or near-normal levels by hormone replacement therapy, the
current forms of treatment (i.e., oral, intramuscular,
subcutaneous, transdermal patches and topical formulations) have
several disadvantages. For example, orally administered
testosterone is largely degraded in the liver, and is therefore not
a viable option for hormone replacement since it does not allow
testosterone to reach systemic circulation. Further, analogues of
testosterone modified to reduce degradation (e.g.,
methyltestosterone and methandrostenolone) have been associated
with abnormalities to liver function, such as elevation of liver
enzymes and conjugated bilirubin. Injected testosterone produces
wide peak-to-trough variations in testosterone concentrations that
do not mimic the normal fluctuations of testosterone making
maintenance of physiological levels in the plasma difficult.
Testosterone injections are also associated with mood swings and
increased serum lipid levels. Injections require large needles for
intramuscular delivery, which leads to diminished patient
compliance due to discomfort. Commonly, estrogen is often
administered orally. This route of administration has been also
associated with complications related to hormone metabolism,
resulting in inadequate levels of circulating hormone. Further,
side-effects seen with the use of oral estrogen include gallstones
and blood clots. To overcome these problems, transdermal delivery
approaches have been developed to achieve therapeutic effects in a
more patient friendly manner.
[0007] The art recognizes that the transdermal and/or transmucosal
delivery of active agents provide a convenient, pain-free, and
non-invasive method of administering active agents to a subject.
Topical or transdermal delivery systems for the administration of
drugs are known to offer several advantages over oral delivery of
the same drugs. For example, the administration of active agents
through the skin or mucosal surface avoids the well-documented
problems associated with the "first pass effect" encountered by
oral administration of active agents.
[0008] Generally, the advantages of topical or transdermal delivery
of drugs relate to pharmacokinetics. More specifically, one common
problem associated with the oral delivery of drugs is the
occurrence of peaks in serum levels of the drug, which is followed
by a drop in serum levels of the drug due to its elimination and
possible metabolism. Thus, the serum level concentrations of orally
administered drugs have peaks and valleys after ingestion. These
highs and lows in serum level concentrations of drug often lead to
undesirable side effects.
[0009] In contrast, topical and transdermal delivery of drugs
provides a relatively slow and steady delivery of the drug.
Accordingly, unlike orally administered drugs, the serum
concentrations of topically or transdermally delivered drugs are
substantially sustained and do not have the peaks associated with
oral delivery.
[0010] Although the transdermal and/or transmucosal delivery of
active agents overcome some of the problems associated with oral
administration of the same agents, this route of administration is
not free of its own drawbacks. Transdermal patches very often cause
allergic reactions and skin irritations due to their occlusive
nature, or due to their composition (incompatibility reactions with
the polymers or adhesives that are used).
[0011] In addition to skin irritation and tolerance considerations,
another issue of transdermal drug delivery systems is that these
systems are typically restricted to low-molecular weight drugs and
those with structures having the proper lipophilic/hydrophilic
balance. High molecular weight drugs, or drugs with too high or too
low hydrophilic balance, often cannot be incorporated into current
transdermal systems in concentrations high enough to overcome their
impermeability through the stratum corneum. Efforts have been made
in the art to chemically modify the barrier properties of skin to
permit the penetration of certain agents (since diffusion is
primarily controlled through the stratum corneum), enhance the
effectiveness of the agent being delivered, enhance delivery times,
reduce the dosages delivered, reduce the side effects from various
delivery methods, reduce patient reactions, and so forth. In this
regard, penetration enhancers have been used to increase the
permeability of the dermal surface to drugs.
[0012] Efforts have been made in the art to chemically modify the
barrier properties of skin to permit the penetration of certain
agents (since diffusion is primarily controlled through the stratum
corneum), enhance the effectiveness of the agent being delivered,
enhance delivery times, reduce the dosages delivered, reduce the
side effects from various delivery methods, reduce patient
reactions, and so forth.
[0013] The most common penetration enhancers, however, are toxic,
irritating, oily, odiferous, or allergenic. Specifically, the
penetration enhancers used and thought to be necessary to
transdermally deliver hormones or other active agents such as
oxybutynin, namely, long-chain acids such as oleic acid or lauric
acid, long-chain alcohols such as lauryl or myristyl alcohol, and
long-chain esters such as triacetin (the glycerol trimester of
acetic acid), glycerol monolaurate or glycerol monooleate, tend to
include aliphatic groups that make the formulations oily and
malodorous.
[0014] For example, U.S. Pat. No. 5,891,462 teaches the use of
lauryl alcohol as a permeation enhancer for estradiol and
norethindrone acetate. Such formulations are not appealing to the
user nor to anyone else in close proximity to the user. Although
this particular patent discloses three examples of estradiol or
norethindrone acetate formulations having no lauryl alcohol
component, such formulations are comparative examples that are
intended to illustrate the long held position that long chain fatty
alcohols such as lauryl alcohol are necessary to transdermally
deliver norethindrone acetate in combination with estradiol to a
subject.
[0015] Additionally, for example, the known testosterone gel
formulations FORTIGEL.RTM. and TOSTRELLE.RTM. (Cellegy Pharma,
South San Francisco, Calif.), both include ethanol, propanol,
propylene glycol, carbomer, triethanolamine, purified water, and
oleic acid as a permeation enhancer, the latter being responsible
for the irritating and malodorous characteristics of these
formulations. Also, TESTIM.RTM. (Auxilium Pharmaceuticals,
Norristown, Pa.) is a 1% testosterone gel and includes
pentadecalactone, acrylates, glycerin, polyethylene glycol (PEG),
and pentadecalactone as a permeation enhancer. It is a very
odoriferous compound. Also, TESTIM.RTM. is not desirable because it
contains undesirable amounts of glycerin which are not well
tolerated by the skin.
[0016] For these reasons, other penetration enhancers have been
used to increase the permeability of the dermal surface to drugs.
Many of these are proton accepting solvents such as dimethyl
sulfoxide (DMSO) and dimethylacetamide. Other penetration enhancers
that have been studied and reported as effective include
2-pyrrolidine, N,N-diethyl-m-toluamide (Deet),
1-dodecal-azacycloheptane-2-one N,N-dimethylformamide,
N-methyl-2-pyrrolidine, calcium thioglycolate, hexanol, fatty acids
and esters, pyrrolidone derivatives, derivatives of 1,3-dioxanes
and 1,3-dioxolanes, 1-N-dodecyl-2-pyrrolidone-5-carboxylic acid,
2-pentyl-2-oxo-pyrrolidineacetic acid,
2-dodecyl-2-oxo-1-pyrrolidineacetic acid,
1-azacycloheptan-2-one-2-dodecylacetic acid, and aminoalcohol
derivatives, including derivatives of 1,3-dioxanes, among others.
Some of these permeation enhancers also present odor or even taste
disadvantages.
[0017] In addition, transdermal drug delivery systems are typically
restricted to low-molecular weight drugs and those with structures
having the proper lipophilic/hydrophilic balance. High molecular
weight drugs, or drugs with too high or low hydrophilic balance,
often cannot be incorporated into current transdermal systems in
concentrations high enough to overcome their impermeability through
the stratum corneum. Specifically, polar drugs tend to penetrate
the skin too slowly, and since most drugs are of a polar nature,
this limitation is significant.
[0018] Further, transdermal delivery from semi-solid formulations
faces antinomic requirements. The drug delivery system should
enable absorption of an extensive amount of active drug through the
skin within the shortest period of time in order to prevent
contamination of individuals, transfer to clothing or accidental
removing. The drug delivery system should also provide sustained
release of the active drug over 24 hours ideally, so that only
once-daily application is required. This drug delivery system
should also prevent drug crystallization at the application surface
area.
[0019] Drug delivery systems having such properties may be achieved
by combining various solvents. A volatile solvent may be defined as
a solvent that changes readily from solid or liquid to a vapor,
that evaporates readily at normal temperatures and pressures. Here
below is presented data for some usual solvents, where volatility
is reflected by the molar enthalpy of vaporization
.DELTA..sub.vapH, defined as the enthalpy change in the conversion
of one mole of liquid to gas at constant temperature. Values are
given, when available, both at the normal boiling point t.sub.b,
referred to a pressure of 101.325 kPa (760 mmHg), and at 25.degree.
C. (From "Handbook of Chemistry and Physics, David R. Lide,
79.sup.th edition (1998-1999)--Enthalpy of vaporization (6-100 to
6-115). Stanislaus et al. (U.S. Pat. No. 4,704,406 on Oct. 9, 2001)
defined as volatile solvent a solvent whose vapor pressure is above
35 mm Mg when the skin temperature is 32.degree. C., and as
non-volatile solvent a solvent whose vapor pressure is below 10 mm
Mg at 32.degree. C. skin temperature. Examples of non-volatile
solvents include, but are not limited to, propylene glycol,
glycerin, liquid polyethylene glycols, or polyoxyalkylene glycols.
Examples of volatile solvents include, but are not limited to,
ethanol, propanol, or isopropanol.
TABLE-US-00001 Enthalpy of vaporization of certain solvents t.sub.b
.DELTA..sub.vapH (t.sub.b) .DELTA..sub.vapH (25.degree. C.) Ethanol
78.3 38.6 42.3 Propan-2-ol (isopropanol) 82.3 39.9 45.4 Propanol
97.2 41.4 47.5 Butan-2-ol 99.5 40.8 49.7 Butan-1-ol 117.7 43.3 52.4
Ethylene glycol monomethyl ether 124.1 37.5 45.2 Ethylene glycol
monoethyl ether 135.0 39.2 48.2 Ethylene glycol monopropyl ether
149.8 41.4 52.1 1,2-Propylene glycol 187.6 52.4 Not available
Diethylene glycol monomethyl ether 193.0 46.6 Not available
Diethylene glycol monoethyl ether 196.0 47.5 Not available
1,3-Propylene glycol 214.4 57.9 Not available Glycerin 290.0 61.0
Not available
[0020] Numerous authors have investigated evaporation and
transdermal penetration from solvent systems. For Example, Spencer
et al. (Thomas S. Spencer, "Effect of volatile penetrants on in
vitro skin permeability", AAPS workshop held in Washington D.C. on
Oct. 31-Nov. 1, 1986) established that the relationship between
volatility and penetration is not absolute and depends on many
parameters such as for instance hydration of the tissue or the
solubility of the penetrant in the tissue. Stinchcomb et al.
reported that the initial uptake of a chemical (hydrocortisone,
flurbiprofen) from a volatile solvent system (acetone) is more
rapid than that from a non-volatile solvent system (aqueous
solution). With an aqueous solution, close to the saturation
solubility of the chemical, the driving force for uptake remains
more or less constant throughout the exposure period. Conversely,
for a volatile vehicle which begins evaporating from the moment of
application, the surface concentration of the chemical increases
with time up to the point at which the solvent has disappeared; one
is now left with a solid film of the chemical from which continued
uptake into the stratum corneum may be very slow and
dissolution-limited.
[0021] Risk assessment following dermal exposure to volatile
vehicles should pay particular attention, therefore, to the
duration of contact between the evaporating solvent and the skin
(Audra L. Stinchcomb, Fabrice Pirot, Gilles D. Touraille, Annette
L. Bunge, and Richard H. Guy, "Chemical uptake into human stratum
corneum in vivo from volatile and non-volatile solvents",
Pharmaceutical Research, Vol. 16, No 8, 1999). Kondo et al. studied
bioavailability of percutaneous nifedipine in rats from binary
(acetone and propylene glycol PG or isopropyl myristate IPM) or
ternary (acetone-PG-IPM) solvent systems, compared with the results
from simple PG or IPM solvent systems saturated with the drug.
(Kondo et al. S, Yamanaka C, Sugimoto I., "Enhancement of
transdermal delivery by superfluous thermodynamic potential. III.
Percutaneous absorption of nifedipine in rats", J Pharmaco Biodyn.
1987 December; 10(12):743-9).
[0022] U.S. Pat. No. 6,299,900 to Reed et al. discloses a
non-occlusive, percutaneous, or transdermal drug delivery
system-having active agent, safe and approved sunscreen as
penetration enhancer, and optional volatile liquid. The invention
describes a transdermal drug delivery system, which comprises at
least one physiologically active agent or prodrug thereof and at
least one penetration enhancer of low toxicity being a safe
skin-tolerant ester sunscreen. The composition comprises an
effective amount of at least one physiologically active agent, at
least one non-volatile dermal penetration enhancer; and at least
one volatile liquid.
[0023] U.S. Pat. No. 5,891,462 to Carrara discloses a
pharmaceutical formulation in the form of a gel suitable for the
transdermal administration of an active agent of the class of
estrogens or of progestin class or of a mixture of both, comprising
lauryl alcohol, diethylene glycol monoethyl ether and propylene
glycol as permeation enhancers.
[0024] Mura et al. describe the combination of diethylene glycol
monoethyl ether and propylene glycol as a transdermal permeation
enhancer composition for clonazepam (Mura P., Faucci M. T.,
Bramanti G., Corti P., "Evaluation of transcutol as a clonazepam
transdermal permeation enhancer from hydrophilic gel formulations",
Eur. J. Pharm. Sci., 2000 February; 9(4): 365-72)
[0025] Williams et al. reports the effects of diethylene glycol
monoethyl ether (TRANSCUTOL.TM.) in binary co-solvent systems with
water on the permeation of a model lipophilic drug across human
epidermal and silastic membranes (A. C. Williams, N. A. Megrab and
B. W. Barry, "Permeation of oestradiol through human epidermal and
silastic membranes from saturated TRANSCUTOL.RTM./water systems",
in Prediction of Percutaneous Penetration, Vol. 4B, 1996). Many
references may also illustrate the effect of TRANSCUTOL.TM. as an
intracutaneous drug depot builder well known to one skilled in the
art.
[0026] U.S. Pat. No. 5,658,587 to Santus et al. discloses
transdermal therapeutic systems for the delivery of alpha
adrenoceptor blocking agents using a solvent enhancer system
comprising diethylene glycol monoethyl ether and propylene
glycol.
[0027] U.S. Pat. No. 5,662,890 to Punto et al. discloses an
alcohol-free cosmetic compositions for artificially tanning the
skin containing a combination of diethylene glycol monoethyl ether
and dimethyl isosorbide as permeation enhancer.
[0028] U.S. Pat. No. 5,932,243 to Fricker et al. discloses a
pharmaceutical emulsion or microemulsion preconcentrate for oral
administration of macrolide containing a hydrophilic carrier medium
consisting of diethylene glycol monoethyl ether, glycofurol,
1,2-propylene glycol, or mixtures thereof.
[0029] U.S. Pat. Nos. 6,267,985 and 6,383,471 to Chen et al.
disclose pharmaceutical compositions and methods for improved
solubilization of triglycerides and improved delivery of
therapeutic agents containing diethylene glycol monoethyl ether and
propylene glycol as solubilizers of ionizable hydrophobic
therapeutic agents.
[0030] U.S. Pat. No. 6,426,078 to Bauer et al. discloses an oil-in
water microemulsion containing diethylene glycol monoethyl ether or
propylene glycol as co-emulsifier of lipophilic vitamins.
[0031] Many research experiments have been carried out on
diethylene glycol monoethyl ether (marketed under the trademark
TRANSCUTOL.TM. by Gattefosse) as an intracutaneous drug depot
builder. For example, Ritschel, W. A., Panchagnula, R., Stemmer,
K., Ashraf, M., "Development of an intracutaneous depot for drugs.
Binding, drug accumulation and retention studies, and mechanism
depot for drugs", Skin Pharmacol, 1991; 4: 235-245; Panchagnula, R.
and Ritschel, W. A., "Development and evaluation of an
intracutaneous depot formulation of corticosteroids using
TRANSCUTOL.RTM. as a cosolvent, in vitro, ex vivo and in-vivo rat
studies", J. Pharm. Pharmacology. 1991; 43: 609-614; Yazdanian, M.
and Chen, E., "The effect of diethylene glycol monoethyl ether as a
vehicle for topical delivery of ivermectin", Veternary Research
Com. 1995; 19: 309-319; Pavliv, L., Freebern, K., Wilke, T.,
Chiang, C-C., Shetty, B., Tyle, P., "Topical formulation
development of a novel thymidylate synthase inhibitor for the
treatment of psoriasis", Int. J. Pharm., 1994; 105: 227-233;
Ritschel, W. A., Hussain, A. S., "In vitro skin permeation of
griseofulvin in rat and human skin from an ointment dosage form",
Arzneimeittelforsch/Drug Res. 1988; 38: 1630-1632; Touitou, E.,
Levi-Schaffer, F., Shaco-Ezra, N., Ben-Yossef, R. and Fabin, B.,
"Enhanced permeation of theophylline through the skin and its
effect on fibroblast proliferation", Int. J. Pharm., 1991; 70:
159-166; Watkinson, A. C., Hadgraft, J. and Bye, A., "Enhanced
permeation of prostaglandin E.sub.2 through human skin in vitro",
Int. j. Pharm., 1991; 74: 229-236; Rojas, J., Falson, F., Courraze,
G., Francis, A., and Puisieux, F., "Optimization of binary and
ternary solvent systems in the percutaneous absorption of morphine
base", STP Pharma Sciences, 1991; 1: 71-75; Ritschel, W. A.,
Barkhaus, J K., "Use of absorption promoters to increase systemic
absorption of coumarin from transdermal drug delivery systems",
Arzneimeittelforsch/Drug Res. 1988; 38: 1774-1777.
[0032] Thus there remains a need to provide a pharmaceutically
acceptable transdermal or transmucosal pharmaceutical formulation
or drug delivery system that exhibits the advantages of both
occlusive systems (high thermodynamic activity) and non-occlusive
systems (low irritation and sensitization potential, and excellent
skin tolerance) while overcoming the disadvantages of these systems
such as low skin tolerability and unpleasant odors. The novel
transdermal or transmucosal pharmaceutical formulations of the
present invention satisfies this need.
SUMMARY OF INVENTION
[0033] The present invention relates to a delivery vehicle for
topical pharmaceutical formulations. The delivery vehicle comprises
a C2 to C4 alkanol, a polyalcohol, and a monoalkyl ether of
diethylene glycol present in relative amounts sufficient to provide
permeation enhancement of an active agent through mammalian dermal
or mucosal surfaces. Preferably, the delivery vehicle as well as
the formulations that contain it are substantially free of
long-chain fatty alcohols, long-chain fatty acids and long-chain
fatty esters in order to avoid potential undesirable odor and
irritation effects caused by such compounds during use of the
formulation. These preferred formulations advantageously do not
include the undesirable odor-causing and irritation-causing
permeation enhancers that were once thought to be necessary for
such transdermal or transmucosal formulations. Without these
additives, use of the formulations is facilitated and patient
compliance is greater.
[0034] Certain advantageous delivery system components and amounts
are disclosed herein. The alkanol may be selected from the group
consisting of ethanol, isopropanol, n-propanol, and mixtures
thereof; the polyalcohol from the group consisting of propylene
glycol and dipropylene glycol and mixtures thereof; and the
monoalkyl ether of diethylene glycol is selected from the group
consisting of monomethyl ether of diethylene glycol, monoethyl
ether of diethylene glycol, and mixtures thereof. The alkanol is
typically present in an amount between about 5 to 80% by weight,
the polyalcohol in an amount between about 1% to 30% by weight, and
the monoalkyl ether of diethylene glycol in an amount between about
0.2 to 30% by weight so that the delivery vehicle facilitates
absorption of the active agent by the dermal or mucosal surfaces so
that transfer or removal of the formulation from such surfaces is
minimized.
[0035] The invention also relates to a non-occlusive formulation
comprising a delivery vehicle as disclosed herein along with an
active agent or a pharmaceutically acceptable salt thereof present
in an amount of between about 1 to 20% by weight of the
formulation. Like the deliver system, the formulation is
substantially free of long-chain fatty alcohols, long-chain fatty
acids, and long-chain fatty esters in order to avoid undesirable
odor and irritation effects caused by such compounds during use. As
disclosed herein, a wide range of active agents can be delivered by
the formulations of the invention.
[0036] To facilitate application of the active agent, the
formulation may further comprise at least one excipient selected
from the group consisting of gelling agents, solvents, cosolvents,
antimicrobials, preservatives, antioxidants, buffers, humectants,
sequestering agents, moisturizers, emollients, film-forming agents,
or permeation enhancers. Thus, the formulation may be provided in
the form of a topical gel, lotion, foam, cream, spray, aerosol,
ointment, emulsion, microemulsion, nanoemulsion, suspension,
liposomal system, lacquer, or non-occlusive dressing.
[0037] The invention also relates to a method for administering an
active agent to a mammal in need thereof which comprises topically
or transdermally administering to the skin or the mucosa of the
mammal one of the formulations according to invention as disclosed
herein to deliver the active agent to the mammal. Preferably, the
active agent is present in an amount of about 0.01 to about 10% of
the composition and between about 40 and about 250 mg of the
composition is administered daily upon the abdomen, shoulder, arm,
or thigh of the mammal to effectuate the treatment.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] The features and benefits of the invention will now become
more clear from a review of the following detailed description of
illustrative embodiments and the accompanying drawings,
wherein:
[0039] FIG. 1 is a graph depicting drug flux over time for
testosterone in formulations including various amounts of lauryl
alcohol (LA) in an in vitro model using human excised skin and 10
mg testosterone/cm2 in the loading chamber (n=3-4.+-.SD).
[0040] FIG. 2 is a graph depicting drug flux over time for
testosterone in formulations including various amounts of lauryl
alcohol (LA) in an in vitro model using human excised skin and 50
mg testosterone/cm2 in the loading chamber (n=3-4.+-.SD).
[0041] FIGS. 3A, B & C are graphs depicting median total, free
and bioavailable testosterone serum concentrations following
administration of 1% T+0% LA gel in vivo over a sampling period on
days 1, 7, 14, and 21, respectively.
[0042] FIGS. 3D, E & F are graphs depicting mean bioavailable
and free testosterone serum concentrations after different dose
regimens and treatments with a 1% T+2% LA gel in vivo over a
sampling period on days 1, 7, 14, respectively.
[0043] FIG. 4A is a graph depicting mean serum concentrations of
estradiol (E2) following single dose administration of E2+0% LA gel
(a=0.75 mg E2; b=1.50 mg E2).
[0044] FIG. 4B is a graph depicting mean trough concentrations of
E2 over time following repeated administration of E2+0% LA gel
(a=0.75 mg E2; b=1.50 mg E2).
[0045] FIG. 4C is a graph depicting mean trough concentrations of
E2 over time following repeated administration of E2+0% LA gel in
one subject (2.5 g; .+-.SD; 240.0H-value out of scale (28.0
ng/dl)).
[0046] FIG. 4D is a graph depicting individual trough
concentrations of E2 over time following repeated administration of
E2+0% LA gel at both doses.
[0047] FIG. 4E is a graph depicting mean serum concentrations of E2
following multiple dose administration of E2+0% LA gel (a=0.75 mg
E2; b=1.50 mg E2).
[0048] FIG. 4F is a graph depicting mean serum concentrations of
estrone (E1) following single dose administration of E2+0% LA gel
(a=0.75 mg E2; b=1.50 mg E2).
[0049] FIG. 4G is a graph depicting mean trough concentrations of
E1 following repeated administration of E2+0% LA gel (a=0.75 mg E2;
b=1.50 mg E2).
[0050] FIG. 4H is a graph depicting mean serum concentrations of E1
following multiple dose administration of E2+0% LA gel (a=0.75 mg
E2; b=1.50 mg E2).
[0051] FIG. 4I is a graph depicting mean serum concentrations of
estrone-sulfate (E1-sulfate) following single dose administration
of E2+0% LA gel (a=0.75 mg E2; b=1.50 mg E2).
[0052] FIG. 4J is a graph depicting mean trough concentrations of
E1-sulfate following multiple dose administration of E2+0% LA gel
(a=0.75 mg E2; b=1.50 mg E2).
[0053] FIG. 4K is a graph depicting mean serum concentrations of
E1-sulfate following multiple dose administration of E2+0% LA gel
(a=0.75 mg E2; b=1.50 mg E2).
[0054] FIG. 5A is a graph depicting mean change from baseline in
daily moderate-to-severe hot flush rate after E2+0% LA gel at
various doses. (Intent-to-treat efficacy population ("ITT"); Method
of last observation carried forward for subjects who discontinued
early ("LOCF").
[0055] FIG. 5B is a graph depicting mean change from baseline in
daily moderate-to-severe hot flush rate after E2+0% LA gel at
various doses (Evaluable-LOCF).
[0056] FIG. 5C is a graph depicting mean change from baseline in
daily hot flush mean severity after E2+0% LA gel at various doses
(ITT-LOCF).
[0057] FIG. 6 is a graph illustrating the plasmatic concentrations
of oxybutynin in healthy volunteers during the pilot
pharmacokinetic study of an oxybutynin gel formulation of the
present invention.
[0058] FIG. 7 is a graph illustrating the plasmatic concentrations
of N-desethyloxybutynin in healthy volunteers during the pilot
pharmacokinetic study of an oxybutynin gel formulation of the
present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0059] The present invention relates generally to compositions or
formulations that contain an active agent for administration to
subjects in need thereof. The invention further relates to
preferred formulations for the transdermal or transmucosal
administration of such agents wherein the formulation is
substantially free of malodorous, and irritation-causing permeation
enhancers. Surprisingly, the formulations of the present invention
can achieve sufficient absorption to result in an effective dosage
of the active agent or its metabolites circulating in serum without
the inclusion of the malodorous and irritation-causing permeation
enhancers that have been used to date. In a preferred aspect of the
invention, the formulation is a clear, water-washable,
quick-drying, spreadable, non-greasy, non-occlusive topical gel
which is free of fatty permeation enhancers.
[0060] Advantageously, the substantial omission of the long-chain
fatty alcohols, long-chain fatty acids, and long-chain fatty esters
provides a formulation that does not have the unpleasant odor,
irritation, and/or greasy texture caused by formulations of the
prior art that include one or more of such compounds. Thus, the
formulation in accordance with the present invention will result in
greater patient compliance. The inventive formulations are
substantially free of such alcohols, acids, and esters so that the
odors associated with those compounds do not emanate from the
formulation. In this regard, "substantially free" means an amount
which does not impart a perceptible odor to the formulation at a
distance of one meter. Such formulations are also deemed to be
substantially odor-free. For the purpose of example and
illustration, a formulation comprising fatty alcohols, fatty acids
and/or fatty esters in an amount of less than about 0.1% by weight
of the formulation is substantially odor-free.
[0061] It is to be understood that the terminology used herein is
for the purpose of describing particular embodiments only, and is
not intended to be limiting. As used in this specification,
description of specific embodiments of the present invention, and
any appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to ""a compound" includes one or more
compounds, mixtures of compounds, and the like.
[0062] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the invention pertains. Although
other methods and materials similar, or equivalent, to those
described herein can be used in the practice of the present
invention, the preferred materials and methods are described
herein.
[0063] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0064] The term "dosage form" as used herein refers to a
pharmaceutical composition comprising an active agent and
optionally containing inactive ingredients, e.g., pharmaceutically
acceptable excipients such as suspending agents, surfactants,
disintegrants, binders, diluents, lubricants, stabilizers,
antioxidants, osmotic agents, colorants, plasticizers, coatings and
the like, that may be used to manufacture and deliver active
pharmaceutical agents.
[0065] The term "gel" as used herein refers to a semi-solid dosage
form that contains a gelling agent in, for example, an aqueous,
alcoholic, or hydroalcoholic vehicle and the gelling agent imparts
a three-dimensional cross-linked matrix ("gellified") to the
vehicle. ? The term "semi-solid" as used herein refers to a
heterogeneous system in which one solid phase is dispersed in a
second liquid phase.
[0066] The term "vehicle" as used herein refers to carrier
materials (other than the pharmaceutically active agent) suitable
for transdermal administration of a pharmaceutically active agent.
A vehicle may comprise, for example, solvents, cosolvents,
permeation enhancers, pH buffering agents, antioxidants, gelling
agents, additives, or the like, wherein components of the vehicle
are nontoxic and do not interact with other components of the total
composition in a deleterious manner.
[0067] The phrase "non-occlusive, transdermal drug delivery" as
used herein refers to transdermal delivery methods or systems that
do not occlude the skin or mucosal surface from contact with the
atmosphere by structural means, for example, by use of a patch
device, a fixed application chamber or reservoir, a backing layer
(for example, a structural component of a device that provides a
device with flexibility, drape, or occlusivity), a tape or bandage,
or the like that remains on the skin or mucosal surface for a
prolonged period of time. Non-occlusive, transdermal drug delivery
includes delivery of a drug to skin or mucosal surface using a
topical medium, for example, creams, ointments, sprays, solutions,
lotions, gels, and foams. Typically, non-occlusive, transdermal
drug delivery involves application of the drug (in a topical
medium) to skin or mucosal surface, wherein the skin or mucosal
surface to which the drug is applied is left open to the
atmosphere.
[0068] The term "transdermal" delivery, as used herein refers to
both transdermal (and "percutaneous") and transmucosal
administration, that is, systemic delivery by passage of a drug
through a skin or a mucosal tissue surface and ultimately into the
bloodstream.
[0069] The term "topical" delivery, as used herein refers to local
delivery of a drug into a skin surface or a mucosal tissue surface
with minimal passage into the bloodstream.
[0070] The phrase "therapeutically effective amount" as used herein
refers to a nontoxic but sufficient amount of a drug, agent, or
compound to provide a desired therapeutic effect
[0071] In accordance with the invention, the delivery vehicle of
the present invention preferably comprises a C2 to C4 short-chain
alkanol, a polyalcohol, and a monoalkyl ether of diethylene glycol
in an amount sufficient to provide permeation enhancement of the
oxybutynin through mammalian dermal or mucosal surfaces. For the
purpose of illustration and not limitation, the alkanol may be
ethanol, isopropanol, or n-propanol. The alkanol is preferably
ethanol. The alkanol is present in an amount between about 45 to
75% w/w, preferably between about 50% to 70%, and more preferably
between about 55% and 65% w/w. As known in the art, the amount of
the alkanol may be selected to maximize the diffusion of the active
agent through the skin while minimizing any negative impact on the
active agent itself or desirable properties of the formulation. The
alkanol can be present in a mixture with water.
[0072] The polyalcohol is preferably propylene glycol or
dipropylene glycol. The polyalcohol may also be a polyethylene
glycol having general formula
CH.sub.2OH(CH.sub.2OH).sub.nCH.sub.2OH wherein the number of
oxyethylene groups represented by n is between 4 to 200, propylene
glycol, dipropylene glycol, butylene glycol, hexylene glycol, and
mixtures thereof. The polyalcohol is advantageously present in an
amount between about 1% and 30% of the vehicle, preferably from
2.5% to 20% w/w, and more preferably from about 5% to 10% w/w.
[0073] The monoalkyl ether of diethylene glycol is preferably
selected from the group consisting of monomethyl ether of
diethylene glycol, monoethyl ether of diethylene glycol, and
mixtures thereof. It is present in an amount of about 1% and 15%,
preferably between about 2.5% to 10% w/w and more preferably
between about 2.5% to 5% w/w.
[0074] The formulation may further include a thickening agent or
gelling agent present in an amount sufficient to alter the
viscosity of the formulation. A gelling agent can be selected from
the group including: carbomer 980 or 940 NF, 981 or 941 NF, 1382 or
1342 NF, 5984 or 934 NF, ETD 2020, 2050, 934P NF, 971P NF, 974P NF,
Noveon AA-1 USP; cellulose derivatives such as ethylcellulose,
hydroxypropylmethylcellulose (HPMC), ethylhydroxyethylcellulose
(EHEC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC)
(Klucel grades), hydroxyethylcellulose (HEC) (Natrosol grades),
HPMCP 55, Methocel grades; natural gums such as arabic, xanthan,
guar gums, alginates; polyvinylpyrrolidone derivatives such as
Kollidon grades; polyoxyethylene polyoxypropylene copolymers such
as Lutrol F grades 68, 127. Other gelling agents include chitosan,
polyvinyl alcohols, pectins, veegum grades. A tertiary amine, such
as triethanolamine or trolamine, can be included to thicken and
neutralize the system. The amount and the type of the gelling agent
in the formulation may be selected by the man skilled in the art to
provide the desired product consistency and/or viscosity to
facilitate application to the skin. The gelling agent is present
from about 0.2 to about 30% w/w of the formulation depending on the
type of polymer. For example, the gelling agent is preferably
present in an amount between about 0.3% to 2% for carbomers, and
between about 1% to 5% for hydroxypropylcellulose derivatives.
[0075] In preferred embodiments, as noted, the composition is non
occlusive. The penetration enhancing system of the present
invention can also be used for mucosal delivery through the buccal,
sublingual, auricular, nasal, ophthalmic, rectal, or vaginal
mucosa.
[0076] The formulation may further include preservatives such as,
but not limited to, benzalkonium chloride and derivatives, benzoic
acid, benzyl alcohol and derivatives, bronopol, parabens,
centrimide, chlorhexidine, cresol and derivatives, imidurea,
phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric salts,
thimerosal, sorbic acid, derivatives thereof and the like. The
preservative is present from about 0.01 to about 10% w/w depending
on the type of compound.
[0077] The formulation may further include antioxidants such as but
not limited to, tocopherol, ascorbic acid, butylated
hydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid,
propyl gallate, sulfites, derivatives thereof and the like. The
antioxidant is present from about 0.001 to about 5.0% w/w of the
formulation depending on the type of compound.
[0078] The formulation may further include a buffer such as
carbonate buffers, citrate buffers, phosphate buffers, acetate
buffers, hydrochloric acid, lactic acid, tartric acid,
diethylamine, triethylamine, diisopropylamine, aminomethylamine.
Although other buffers as known in the art may be included. The
buffer may replace up to 100% of the water amount within the
formulation.
[0079] The formulation may further include a humectant. The
formulation may further include humectant, such as but not limited
to glycerin, propylene, glycol, sorbitol, triacetin. The humectant
is present from about 1 to 10% w/w of the formulation depending on
the type of compound.
[0080] The formulation may further include a sequestering agent
such as edetic acid. The sequestering agent is present from about
0.001 to about 5% w/w of the formulation depending on the type of
compound.
[0081] The formulation may further include anionic, non-ionic or
cationic surfactants. The surfactant is present from about 0.1% to
about 30% w/w of the formulation depending on the type of
compound.
[0082] The formulation may further include a pH regulator,
generally, a neutralizing agent, which can optionally have
cross-linking function. By way of example and not limitation, the
pH regulator may include a ternary amine such as monoethanolamine,
diethanolamine, triethanolamine, tromethamine,
tetrahydroxypropylethylendiamine, aminomethyl propanol,
diisopropanolamine, or an inorganic alkali such as NaOH solution,
KOH solution, or NH.sub.4OH solution. The pH regulator is present
in the formulations in variable amounts depending on the nature and
the relative strength of the pH regulator. The optimum pH may also
be determined and may depend on, for example, the nature of the
active agent and the degree of flux required.
[0083] For some lesser preferred embodiments, the delivery vehicle
may contain a saturated fatty alcohol or fatty acid, or mixtures
thereof in an amount of from about 0.4 to 10%, wherein the fatty
alcohol or fatty acid have the formula
CH.sub.3--(CH.sub.2).sub.n--CH.sub.2OH or
CH.sub.3--(CH.sub.2).sub.n--H.sub.2COOH, respectively, in which n
is an integer from 8 to 22; or an unsaturated fatty alcohol or
fatty acid, or mixtures thereof, wherein said unsaturated fatty
alcohol and/or fatty acid have the formula
CH.sub.3--(C.sub.nH.sub.2(n-x))--OH or
CH.sub.3--(C.sub.nH.sub.2(n-x))--COOH, respectively, in which n is
an integer from 8 to 22. Of these, lauryl alcohol or myristyl
alcohol present in an amount from 0.5 to 2% by weight of the total
formulation can be used.
[0084] Further, it has also been found that the glycol acts as a
modulator of the capability of the monoalkyl ether of diethylene
glycol to build a drug depot within the different layers of the
skin. Also, the significant reduction of unabsorbed active drug(s)
remaining at the application surface area results from the
simultaneous although independent inhibition of crystallization and
transdermal drug penetration, enhanced or not by additional
permeation enhancer(s).
[0085] Additional advantages of the present invention include the
discovery that the association of a monoalkyl ether of diethylene
glycol and the preferred propylene glycol component at specified
ratios exhibits a synergic effect and inhibits crystallization of
the active ingredient(s) in transdermal semi-solid formulations. In
addition, it has been discovered that a totally unexpected control
of the active drug(s) distribution in the different layers of the
skin is achieved when modifying the range of the monoalkyl
ether:glycol ratio, simultaneously but independently from the
crystallization inhibitor effect above mentioned.
[0086] The monoalkyl ether of diethylene glycol and the glycol are
generally present in a weight ratio of 10:1 to 1:10 and preferably
in a ratio ranging from 10:1 to 2:1 or 1:2 to 1:10, although ratios
between 3:1 and 1:1 or 2:1 to 1:1 are preferred.
[0087] It has been surprisingly discovered that it is possible to
achieve a therapeutically effective, sustained and controlled
penetration rate of diverse active substances into the skin with
the aid of the inventive delivery system. It has also been
discovered surprisingly that the formulations compositions
disclosed herein exert higher permeation rates when compared with
compositions that do not contain the delivery system of the
invention.
[0088] It also has been surprisingly discovered also that by
utilizing the combination of diethylene glycol monoethyl ether and
propylene glycol as permeation enhancers in the delivery system of
the invention herein disclosed, an adequate penetration enhancement
factor and a sustained flux of the active agent is attained,
thereafter reflected in achieving therapeutic effective, controlled
and sustained levels of the active drugs by only once-a-day
application of the formulation. Thus, the present invention relates
to a method for administering topically or systemically different
active substance(s).
[0089] The delivery vehicle may further include moisturizers and
emollients to soften and smoothen the skin or to hold and retain
moisture. By way of example and not limitation, moisturizers and
emollients may include cholesterol, lecithin, light mineral oil,
petrolatum, and urea.
[0090] The present formulations advantageously (a) inhibits
crystallization of the at least one active ingredient on a skin or
mucosal surface of a mammal, (b) reduces or prevents transfer of
the formulation to clothing or to another being, (c) modulates
biodistribution of the at least one active agent within different
layers of skin, (d) facilitates absorption of the at least one
active agent by a skin or a mucosal surface of a mammal, or (e)
provides a combination of one or more of (a) through (d).
[0091] For any particular formulation, the active agent, delivery
vehicle and other ingredients may be selected to achieve the
desired drug delivery profile and the desired penetration.
[0092] In accordance with the invention, the active agent may be
present in an amount between about 0.1% to 20% by weight of the
delivery vehicle. The active agent may be present in the form of a
pharmaceutically acceptable salt thereof. Examples of such salts
comprise, but are not limited to, acetate, bitartrate, citrate,
edetate, edisylate, estolate, esylate, fumarate, gluceptate,
gluconate, glutamate, hydrobromide, hydrochloride, lactate, malate,
maleate, mandelate, mesylate, methylnitrate, mucate, napsylate,
nitrate, pamoate, pantothenate, phosphate, salicylate, stearate,
succinate, sulfate, tannate and tartrate. The invention is
applicable to combinations of active agents, where a primary active
agent is present in combination with a secondary active agent for
concurrent administration to the subject.
[0093] The active agent may be a hormone selected from the group
consisting of an androgen, estrogen, progestin, or a combination
thereof. The androgen may be selected from the group consisting of
testosterone, 17-.beta.-hydroxyandrostenone, testosterone esters,
methyl testosterone, testolactone, oxymetholone, fluoxymesterone,
androsterone, androsterone acetate, androsterone propionate,
androsterone benzoate, androstenediol, androstenediol-3-acetate,
androstenediol-17-acetate, androstenediol-3,17-diacetate,
androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate,
androstenedione, sodium dehydroepiandrosterone sulfate,
4-dihydrotestosterone, 5 adihydrotestosterone, dromostanolone,
dromostanolone propionate, ethylestrenol, nandrolone
phenpropionate, nandrolone decanoate, nandrolone furylpropionate,
nandrolone cyclohexanepropionate, nandrolone benzoate, nandrolone
cyclohexanecarboxylate, oxandrolone, and stanozolol or any
combination thereof. The estrogen may be selected from the group
consisting of 17 beta-estradiol, estradiol, estradiol benzoate,
estradiol 17 beta-cypionate, estriol, estrone, ethynil estradiol,
mestranol, moxestrol, mytatrienediol, polyestradiol phosphate,
quinestradiol, and quinestrol or any combination thereof. The
progestin may be selected from the group consisting of
allylestrenol, anagestone, chlormadinone acetate, delmadinone
acetate, demegestone, desogestrel, dimethisterone, dydrogesterone,
ethynilestrenol, ethisterone, ethynodiol, ethynodiol diacetate,
fluorogestone acetate, gestodene, gestonorone caproate,
haloprogesterone, 17-hydroxy-16-methylene-progesterone, 17
alpha-hydroxyprogesterone, 17 alpha-hydroxygesterone caproate,
lynestrenol, medrogestone, medroxyprogesterone, megestrol acetate,
melengestrol,
16-methylene-17-alpha-acetoxy-19-nor-pregn-4-ene,3,20-dione,
norethindrone, norethindrone acetate, norethynodrel, norgesterone,
norgestimate, norgestrel, norgestrienone, 19-norprogesterone,
norvinisterone, pentagestrone, progesterone, natural progesterone,
promegestone, quingestrone, and trengestone or any combination
thereof. Preferably, the combination of estrogen and progestin is
not present in the formulation.
[0094] The active agent may also be any of the following: drugs to
treat Parkinson disease; drugs to treat Alzheimer disease and
senile dementia; Attention Deficit and Hyperactivity Disorders
(ADHD) drugs; drugs to treat narcolepsy; anti-anxiety drugs;
anti-depression drugs; drugs to treat epilepsy; drugs to treat
insomnia; drugs to treat motor neurone diseases; drugs to treat
multiple sclerosis; anti-nausea and anti-vomiting drugs;
anti-psychotic drugs; hypnotics; anti-depressants; tranquilizers;
drugs to treat Restless Legs Syndrome (RLS); drugs to treat alcohol
addiction, nicotine addiction, drug addiction, or food addiction;
central analgesics; drugs to treat central metabolism disorders; or
a combination of one of the previously mentioned drugs with another
drug.
[0095] The active agent may also be an anti-Parkinson drug selected
from the group consisting of amantadine, benserazide, carbidopa,
levodopa, benztropine, biperiden, benzhexyl, procyclidine,
bornaprine, budipine, entacapone, ethopropazine, lazabemide,
memantine, orphenadrine, selegiline, tolcapone, trihexyphenidyl,
modafinil, talampanel, altinicline, brasofensine, safinamide,
droxidopa, rasagline, bromocriptine, cabergoline, pergolide,
piribedil, pramipexole, quinagolide, terguride, rotigotine,
riluzole, talipexole, piroheptine, bifeprunox, spheramine,
lisuride, sumanirole, ropinirole, rotigotine, and pharmaceutically
acceptable salts, isomers, and mixtures thereof; an anti-Alzheimer
drug selected from the group consisting of tacrine, donepezil,
rivastigmine, galantamine, amantadine, memantine, rimantadine, and
pharmaceutically acceptable salts, isomers, and mixtures thereof;
or an analgesic drug selected from the group consisting of
alfentanil, buprenorphine, butorphanol, codeine, dextromoramide,
dextropropoxyphene, dezocine, diamorphine, dihydrocodeine,
fentanyl, flupirtine, hydrocodone, hydromorphone, ketobemidone,
levomethadyl, mepiridine, meptazinol, methadone, morphine,
nalbuphine, oxycodone, oxymorphone, papavereturn, pentazocine,
pethidine, phenoperidine, piritramide, remifentanil, tilidine,
tramadol, sufentanil and pharmaceutically acceptable salts,
isomers, and mixtures thereof.
[0096] The active agent may also be an anti-addiction drug selected
from the group consisting of nicotine, buprenorphine, naloxone, and
pharmaceutically acceptable salts, isomers, and mixtures thereof;
or an anti-psychotic drug selected from the group consisting of
chlorpromazine, fluphenazine, perphenazine, prochlorperazine,
thioridazine, trifluoperazine, butyrophenones, haloperidol,
droperidol, pimozide, clozapine, olanzapine, mirtanzapine,
tinaeptine, bupropion, risperidone, quetiapine, ziprasidone,
amisulpride, melperone, paliperidone, aripiprazole, and
pharmaceutically acceptable salts, isomers, and mixtures thereof;
or an anti-anxiety drug selected from the group consisting of
alprazolam, bromazepam, diazepam, lorazepam, clonazepam, temazepam,
oxazepam, flunitrazepam, triazolam, chlordiazepoxide, flurazepam,
estazolam, nitrazepam, and pharmaceutically acceptable salts,
isomers, and mixtures thereof; or even an anti-depressant drug
selected from the group consisting of citalopram, escitalopram
oxalate, fluoxetine, fluvoxamine, paroxetine, sertraline,
dapoxetine; venlafaxine and duloxetine; harmaline, iproniazid,
isocarboxazid, nialamide, pargyline, phenelzine, selegiline,
toloxatone, tranylcypromine, brofaromine, moclobemide;
amitriptyline, amoxapine, butriptyline, clomipramine, desipramine,
dibenzepin, dothiepin, doxepin, imipramine, iprindole, lofepramine,
melitracen, nortriptyline, opipramol, protriptyline, trimipramine;
maprotiline, mianserin, nefazodone, trazodone, and pharmaceutically
acceptable salts, isomers, and mixtures thereof.
[0097] The active agent may also be a drug for treating ADHD
selected from the group consisting of methylphenidate, and
pharmaceutically acceptable salts, isomers, and mixtures thereof;
or an anti-insomnia drug selected from the group consisting of
zolpidem, zopiclone, and pharmaceutically acceptable salts,
isomers, and mixtures thereof; or a 5-alpha-reductase inhibitor
such as the azasteroid compounds, namely, finasteride or
dutasteride.
[0098] Also in accordance with the invention, the pharmaceutical
active agent may include anti-gout drugs such as colchicine and
derivatives, sulfinpyrazone, probenecid, benzbromarone,
allopurinol; local anaesthetics such as benzocaine, procaine,
tetracaine, lidocaine, etidocaine, prilocalne, mepivacaine,
bupivacaine, butanilicaine, articaine, fomocaine; general
anaesthetics such as methohexital, thiamylal, thiopenthal,
ketamine, etomidate, propofol, midazolam, flumazenil, droperidol,
fentanyl, alfentanil, sufentanil; muscle relaxant drugs such as
curare derivatives, hexacarbacholine, dantrolene, tetrazepam,
carisoprodol, chlorzoxazone, baclofen, memantine, tizandine;
diuretics such as hydrochlorothiazide and derivatives,
chlortalidone, indapamide, furosemide, bumetanide, piretanide,
azosemide, etozolin, ethacrynic acid, amiloride, triamterene,
spironolactone; angiotensin converting enzyme inhibitors such as
captopril, enalapril, trandolapril, lisinopril, perindopril,
benazepril, cilazepril, fosinopril, moexipril, quinapril, ramipril;
calcium-channel blockers such as bepridil, diltiazem, felodipine,
flunarizine, isradipine, nicardipine, nitrendipine, nifedipine,
nimodipine, verapamil, amlodipine, lacidipine, buflomedil;
anti-arythmics such as quinidine, ajmaline, procainamide,
disopyramide, propafenone, tocamide, phenyloin, aprindine,
mexiletine, flecamide, lorcamide, propafenone, sotalol, amiodarone,
verapamil, diltiazem; anti-angina drugs such as nitrate
derivatives, molsidomine; anti-migraine drugs such as, pizotifene,
oxetorone, methysergide sumatriptan, zolmitriptan, naratriptan,
eletriptan, almotriptan, rizatriptan; antiemetic drugs such as
chlorphenoxamine, dimenhydramine, meclozine, triethylperazine,
triflupromazine, metoclopramide, bromopride, domperidone,
granisetron, ondansetron, tropisetron, dolasetron, alosteron,
tegaserod; anti-histaminic and anti-asthma drugs such as
cromoglycate, nedocromil, tritoqualine, ketotifene, lodoxamide,
salbutamol, terbutaline, pirbuterol, salmeterol, formoterol,
bambuterol, montelukast, pranlukast, theophylline, ipratropium,
oxitropium, beclometasone, dexamethasone, fluticasone, budesonide,
flunisolide; thrombolytics such as alteplase and derivatives,
streptokinase, urokinase; analgesics such as morphine, codeine,
diamorphine, dihydrocodeine, hydromorphone, hydrocodone, oxycodone,
oxymorphone, levorphanol, pethidine, levomethadone, fenpipramine,
piritramide, clofedanol, pentazocine, buprenorphine, butorphanol,
nalbuphine, tilidine, tramadol, nefopam, salicylic acid and
derivatives, salsalate, diflunisal, acetaminophen, benorylate,
mefenamic acid, flufenamic acid, niflumic acid, metamizole,
phenazone, phenylbutyazone, aminophenazone, oxyphenbutazone,
azapropazone, indometacin, diclofenac, sulindac, felbinac,
ibuprofen, naproxen, fenoprofen, flurbiprofen, ketoprofen,
tiaprofenic acid, nabumetone, piroxicam, tenoxicam, meloxicam,
antitussive agents such as codeine and derivatives, clobutinol,
isoaminile, pentoxyverine, butamirate, oxeladine, pipazetate;
tricyclic antidepressants such as imipramine, desipramine,
trimipramine, lofepramine, clomipramine, opipramol, amitriptyline,
amitriptylinoxide, nortriptyline, dibenzepin, doxepin, melitracen;
tetracyclic antidepressants such as maprotiline, mianserin;
atypical antidepressants such as fluvoxamine, trazodone, viloxacin,
fluoxetine; monoamine oxidase inhibitors such as tranylcipromine;
serotonin precursors such as oxitriptan; lithium salts;
tranquilizers such as meprobamate, hydroxyzine, chlordiazepoxide,
temazepam, flurazepam, lormetazepam, nitrazepam, flunitrazepam,
diazepam, prazepam, oxazepam, lorazepam, clonazepam, bromazepam,
clotiazepam, alprazolam, triazolam, oxazolam, midazolam, ketazolam,
brotizolam, clobazam, clorazepate, buspirone; amphetamines and
related compounds such as amfetamine, metamfetamine, fenetylline,
methylphenidate, prolintane; anorectics such as cathine,
amfepramone, mefenorex, propylhexedrine, fenfluramine;
psychodysleptics such as N-dimethyltryptamine, psilocin,
psilocybin, bufotenin, lysergide, mescaline, tetrahydrocannabinol;
nootropics such as pyritinol, piracetam, meclofenoxate; hypnotics
such as carbromal, bromisoval, vinylbital, aprobarbital,
secbutabarbital, pentobarbital, cyclobarbital, phenobarbital,
glutethimide, methyprylon, methaqualone; analeptics such as
doxapram; tricyclic neuroleptics such as chlorpromazine, promazine,
triflupromazine, alimemazine, levomepromazine, chlorprothixene,
pecazine, thioridazine, perphenazine, trifluoperazine periciazine,
perazine, fluphenazine, dixyrazine, clopenthixol, dixyrazine,
prothipendyl, thithixene, chlorprothixene, clopenthixol,
flupentixol; butyrophenones and diphenylbutylpiperidines
neuroleptics such as haloperidol, bromperidol, droperidol,
trifluperidol, pipamperone, melperone, benperidol, pimozide,
fluspirilene; benzamide neuroleptics such as sulpiride;
anti-psychotic drugs such as clozapine, haloperidol, olanzapine,
quetiapine, risperidone; anti-convulsive drugs such as
carbamazepine, valproic acid and its derivatives, primidone,
phenyloin, ethosuximide, trimethadione, sultiame,
hypothalamo-hypophysis regulators such as gonadoreline,
triptoreline, leupropreline, busereline, gosereline, nafareline,
gonadotrophins, follitropins, danazol, clomifene, quinagoline,
bromocriptine, lisuride; anti hypo- and anti hyperthyroidy drugs
such as thyreotropin releasing hormone, thyreostimuline hormone,
triiodothyronine, thyroxine, tiratricol, benzylthiouracile,
clotrimazole, corticosteroids; glucocorticoids and
mineralocorticoids; glycemia regulators such as insuline,
glipizide, glibenclamide, glibornuride, gliclazide, carbutamide,
glimepiride, repaglinide, metformine, acarbose, miglitol, glucagon,
diazoxide; hypolipidemia drugs such as orlistat, simvastatine,
pravastatine, fluvastatine, atorvastatine, tiadenol,
cholestyramine, fenofibrate, ciprofibrate, bezafibrate,
gemfibrozil, ursodiol; phosphocalcic metabolism regulators such as
ergocalciferol, cholecalciferol calcitriol, alfacalcidol,
calcifediol, calcipotriol, tacalcitol; anti-inflammatory drugs such
as nabumetone, meloxicam, nimesulide, etodolac, alminoprofene,
sulfasalazine, mefasalazine, olsalazine, rofecoxib, celecoxib,
valdecoxib, nefopam; antisecretive gastric drugs such as
omeprazole, lansoprazole, pantoprazole, rabeprazole, misoprostol;
laxatives; gastric mucosa protectors such as cimetidine,
famotidine, ranitidine, nizatidine, gastric motricity modulators;
bile salts adsorbants; chelators; gall stone dissolvants;
anti-anemia drugs; cutaneous diseases drugs; alpha antagonist drugs
such as urapidil and derivatives, prazosine and derivatives,
nicergoline, moxisylyte, anti parasitic drugs such as albendazole,
atovaquone, chloroquine, dehydroemetine, diloxanide, furazolidone,
halofantrine, iodoquinol, ivermectin, mebendazole, mefloquine,
metronidazole, nifurtimox, primaquine, pyrantel, pyrimethamine,
quinine, quinidine, penicillins; cephalosporins; aminosids;
polypeptides; sulfamides; diaminopyrimidines; tetracyclins;
chloramphenicol; thiamphenicol; macrolides; vancomycin;
teicoplanin; rifampicin; fusidic acid; 5-nitro-imidazoles;
lincosamides; quinolones; isoniazide, ethambutol; antineoplasic
drugs such as chlormethine, chlorambucil, melphalan,
cyclophosphamide, ifosfamide, estramustine, carnustine, lomustine,
fotemustine, carbazine derivatives, cisplatine and derivatives,
thiothepa, daunorubicine and derivatives, mitoxantrone,
5-fluorouracil, capecitabine, cytarabine, gemcitabine,
mercaptiopurine azathioprine, fludarabine, thioguanine,
pentostatine, cladribine, raltitrexed; anti virus drugs such as
zidovudine and derivatives, aciclovir and derivatives, foscarnet,
ritonavir and derivatives; antifungus drugs such as nystatine,
terbinafine, micanazole, ketoconazole, fluconazole, itraconazole,
bifonazole, econazole, omoconazole, sulconazole, tioconazole,
isoconazole, fenticonazole, sertaconazole.
[0099] The active agent may also be oxybutynin or another
anticholinergic drug. Although oxybutynin is the preferred
anti-cholinergic agent that is disclosed herein, other such agents,
among which those having an antimuscarinic activity are preferred,
can be used in place of oxybutynin. Preferred anti-cholinergic
drugs with antimuscarinic activity include, without limitation,
tolterodine, trospium, propiverine, flavoxate, emepronium,
propantheline, darifenacin, and solifenacin. These can be used, for
example, in the treatment of hyperactivity of the detrusor muscle
(over activity of the bladder muscle) with frequent urge to
urinate, increased urination during the night, urgent urination,
involuntary urination with or without the urge to urinate
(incontinence), painful or difficult urination.
[0100] Preferably, the formulations of the invention provides
therapeutic levels of the active agent or metabolite for at least
24 hours. More preferably, the method provides sustained
therapeutic levels for at least 48 hours. Most preferably, the
method provides sustained therapeutic levels for at least 72 hours.
Thus, the formulations of the invention only need to be
administrated every once a day, every other day, every third day or
twice per week.
[0101] The present invention further provides various treatment
methods for administering the active agent to a subject in need
thereof via the topical or transdermal formulations disclosed
herein. For example, methods for treating hormonal diseases,
disorders, or conditions in a subject are disclosed. These methods
generally comprise administering to the subject a formulation
comprising an effective dosage of at least one active agent of a
hormone and the delivery vehicle.
[0102] The subject in need of treatment may be male or female.
Thus, the type of active agents selected for the formulation and
method of treatment, and the effective dosages of the active agents
is in part dependent on the sex of the subject to be treated, and
the type of hormonal disorder being treated.
[0103] For the purpose of illustration and not limitation, and in
accordance with the invention, for example, a woman undergoing
treatment may be of childbearing age or older, in whom ovarian
estrogen, progesterone and/or androgen production has been
interrupted either because of natural menopause, surgical
procedures, radiation, chemical ovarian ablation or extirpation, or
premature ovarian failure. In addition to natural menopause and
aging, a decline in total circulating androgens leading to
testosterone deficiency can be attributed to conditions that
suppress adrenal androgen secretion (i.e., acute stress, anorexia
nervosa, Cushing's syndrome, and pituitary renal insufficiency),
conditions that can decrease ovarian androgen secretion (i.e.,
ovarian failure and the use of pharmacologic doses of
glucocorticoids), and chronic illness such as muscle-wasting
diseases like Acquired Immune Deficiency Syndrome (AIDS). Thus, the
term "hormonal disorder" as used herein means any condition that
causes a suppression or reduction of hormonal secretions in a
subject.
[0104] In addition to treating female subjects for female
menopausal symptoms due to aging and other factors as discussed
above, reduced levels of androgens (and estrogens) in women may
lead to female sexual dysfunction (FSD) resulting in clinical
symptoms such as lack of sex drive, arousal or pleasure; low
energy, reduced sense of well-being and osteoporosis. Preferred
results of using the formulations of the invention to treat FSD in
women may include one or more of the following: increased energy,
increased sense of well-being, decreased loss of calcium from bone,
and increased sexual activity and desires.
[0105] In pre-menopausal women, total plasma testosterone
concentrations generally range from 15-65 ng/dL (free testosterone
in pre-menopausal women is approximately 1.5 to 7 pg/ml) and
fluctuate during the menstrual cycle, with peaks of androgen
concentration corresponding to those of plasma estrogens at the
pre-ovulatory and luteal phases of the cycle. In the years leading
to postmenopausal transition, levels of circulating androgens begin
to decline as a result of age-related reductions of both ovarian
and adrenal secretion. There are reports in studies that 24-hour
mean plasma testosterone levels in normal pre-menopausal women in
their 40's are half that of women in their early 20's. It has been
generally accepted, however, that women with androgen deficiency
have total testosterone levels <25 ng/dL (<50-years-old) or
<20 ng/dL (.gtoreq.50-years-old) while oophorectomized women can
have total testosterone levels <10 ng/dL.
[0106] In this regard, the method may include administering to the
female subject a therapeutically effective dosage of testosterone
from about 1 mg to about 3 mg each 24 hours. Therefore, the
formulation preferably provides the subject with a total serum
concentration of testosterone from at least about (>30 ng/dL) 15
to about 55 ng/dL, or a free serum concentration of testosterone
from about 2 to about 7 pg/mL.
[0107] Moreover, studies have shown that testosterone replacement
combined with estrogen replacement therapy ("ERT") improves
parameters of sexual function and well-being versus ERT alone. A
decline in rates of sexual intercourse and fewer sexual thoughts
and fantasies has been associated with significant decreases in
estradiol and testosterone. A decrease in testosterone has also
been associated with decreased frequency of coitus. Although
estradiol treatment alone in oophorectomized women improved
vasomotor symptoms, vaginal dryness, and general well-being, little
improvement in libido has been observed. Increased sexual drive,
arousal, and frequency of sexual fantasies were observed in
hysterectomized and oophorectomized women with
testosterone-enanthate injections over and above those observed
with ERT alone. Therefore, in accordance with the method of the
invention, treating female subjects comprising administration of
formulations comprising active agents including both an androgen,
preferably testosterone, and an estrogen, as well as treating
female subjects comprising administering formulations comprising
estradiol alone as the active agent.
[0108] Another study in women who were naturally or surgically
menopausal with inadequate ERT for .gtoreq.4 months showed
significant improvements in sexual sensation and desire after 4 and
8 weeks of androgen/estrogen treatment vs. placebo or estrogen
treatment alone. Sexual desire, arousal, well-being, and energy
levels were enhanced with androgen/estrogen therapy in studies in
surgically menopausal women. Results of improved libido with
subcutaneous testosterone implants in combination with subcutaneous
estrogen implants in postmenopausal women have also been reported.
In women who have undergone oophorectomy and hysterectomy,
transdermal testosterone improved sexual function and psychological
well-being. To achieve good response in terms of libido, plasma
testosterone levels need to be restored to near the upper end of
the normal physiologic range observed in young ovulating women.
[0109] Therefore, treatment with a separate or the same composition
including estrogen may be desirable to achieve at least the
preferred results described above. A pre-menopausal female subject
generally has a serum concentration of estradiol from about 30 to
100 pg/mL, whereas normal post-menopausal levels are below 20
pg/mL.
[0110] Further, reduced levels of estrogens (and progestin) in
women, such as due to aging, leads to menopause resulting in
clinical symptoms such as hot flashes and night sweats, vaginal
atrophy, decreased libido, increased risk of heart disease and
osteoporosis. Preferred results of using a composition of the
present invention may include one or more of the following:
decreased incidence and severity of hot flashes and night sweats,
decreased loss of calcium from bone, decreased risk of death from
ischemic heart disease, increased vascularity and health of the
vaginal mucosa and urinary tract are and increased sexual activity
and desires. Thus, in another preferred embodiment, the method
include administering to a female subject in need of treatment, a
formulation comprising both an estrogen in combination with a
progestin as active agents.
[0111] As stated above, the methods include treating male subjects
for hormonal disorders. For example, the male is treated for
hypogonadism (low testosterone levels). Hypogonadism in men may
result in clinical symptoms including impotence, lack of sex drive,
muscle weakness and osteoporosis. Preferred results of using the
compositions of the invention to treat hypogonadism in men may
include one or more of the following: decreased incidence and
severity of impotence, decreased loss of calcium from bone,
increased muscle strength, and increased sexual activity and
desires.
[0112] A normal male subject generally has a total serum
concentration of testosterone from about 300 to 1050 ng/dL, whereas
hypogonadal men have levels below 300 ng/dL. Therefore, the
composition of the invention may be used to provide the subject
with a therapeutically effective dosage of testosterone of about 50
mg/day. Therefore, in use the composition preferably provides the
subject with a free serum concentration of testosterone from at
least about 300 to 1000 ng/dL.
[0113] The invention also relates to a method for administering
oxybutynin or other anticholinergic agent to a mammal in need
thereof comprising topically or transdermally administering to the
skin or the mucosa of a mammal one of the compositions disclosed
herein. Preferably, the mammal is a human. For example, the
treatments methods include treating hyperactivity of the detrusor
muscle with frequent urge to urinate, increased urination during
the night, urgent urination, involuntary urination with or without
the urge to urinate, painful or difficult urination, detrusor
hyperreflexia and detrusor instability. Typically, not more than
200 mg of the active agent is administered per day, with a daily
dose of between about 40 and about 100 mg being preferred. The
composition is advantageously administered upon the abdomen,
shoulder, arm, or thigh of the subject.
[0114] The preferred formulations for these treatments include the
following:
TABLE-US-00002 TABLE 1 Estradiol 0.01%-2% Carbomer 0.05%-4%
Triethanolamine (adjust to pH 5.9) 0.05%-1% Alcohol 20%-65%
Propylene glycol 1%-15% Diethylene glycol monoethyl ether 1%-15%
Ion Exchange Purified Water q. ad. 20%-65%
TABLE-US-00003 TABLE 2 Testosterone 0.01%-10% Carbomer 0.05%-4%
Triethanolamine (adjust to pH 5.9) 0.05%-1% Alcohol 20%-65%
Propylene glycol 1%-15% Diethylene glycol monoethyl ether 1%-15%
Ion Exchange Purified Water q. ad. 20%-65%
TABLE-US-00004 TABLE 3 Estradiol 0.01%-1% Carbomer 940 1.2%
Triethanolamine (adjust to pH 5.9) 0.4% Alcohol 46.28% Propylene
glycol 6% Diethylene glycol monoethyl ether 5% Disodium EDTA 0.06%
Ion Exchange Purified Water q. ad. 100%
TABLE-US-00005 TABLE 4 Testosterone 0.01%-10% Carbomer 980 1.2%
Triethanolamine (adjust to pH 5.9) 0.4% Alcohol 46.28% Propylene
glycol 6% Diethylene glycol monoethyl ether 5% Disodium EDTA 0.06%
Ion Exchange Purified Water q. ad. 100%
TABLE-US-00006 TABLE 5 Testosterone 1% Carbomer 980 1.2%
Triethanolamine (adjust to pH 5.9) 0.4% Ethanol 47.5% Propylene
glycol 6% Diethylene glycol monoethyl ether 5% Disodium EDTA 0.06%
Ion Exchange Purified Water q. ad. 100%
[0115] The preferred formulations of the present invention are
advantageous at least for the following reasons. First, the
formulations of the present invention are substantially free of
long-chain fatty alcohols, long-chain fatty acids, and long-chain
fatty esters. Surprisingly, the formulations exhibit skin
penetration sufficient to deliver an effective dosage of the active
agent to the user. This is an unexpected advantage that those of
ordinary skill in the art would not have readily discovered since
it had been generally understood that permeation enhancers, and
more particularly long-chain fatty alcohols, long-chain fatty
acids, and long chain fatty esters, would be required to enhance
skin penetration of certain active agents such as oxybutynin to
permit an effective dose to penetrate the skin. Second, because the
formulation does not include aliphatic acid groups, such as fatty
acids, that are commonly included in topical gels, it does not have
the odor or oily texture which is associated with that ingredient
as in presently-available gels. Numerous studies acknowledge the
irritation-causing potential of unsaturated fatty acids such as
oleic acid. See, Tanojo H. Boelsma E, Junginger H E, Ponec M, Bodde
H E, "In vivo human skin barrier modulation by topical application
of fatty acids," Skin Pharmacol Appl. Skin Physiol. 1998 March
April; 11 (2) 87 97. Third, the absence of long-chain fatty
alcohols, long-chain fatty acids, and long-chain fatty esters means
that the irritation potential is lower and that there is less
chance for the components to interact, reducing the need for
stabilizers in the formulation. It is to be understood, however,
that if such stabilizers are desired, the invention encompasses
formulations which include antioxidants, chelators or
preservatives. The reduction in the number of ingredients is
advantageous at least in reducing manufacturing costs, possible
skin irritation.
[0116] Additionally, the reduced number of ingredients increases
the storage stability of the formulation by decreasing the chance
that the ingredients will interact prior to being delivered to the
patient in need thereof. This does not, however, imply that
additional ingredients cannot be included in the formulation for
particular aesthetic and/or functional effects. For example, the
formulation may optionally include one or more moisturizers for
hydrating the skin or emollients for softening and smoothing the
skin. Glycerin is an example of such a suitable moisturizing
additive.
[0117] The formulation may be applied once daily, or multiple times
per day depending upon the condition of the patient. The
formulation of the invention may be applied topically to any body
part, such as the thigh, abdomen, shoulder, and upper arm. In one
embodiment, up to 10 grams of a formulation in the form of a gel is
applied to an area of skin. In a preferred embodiment of the
invention, not more than 5 grams of a formulation in the form of a
gel is applied to about an area of skin for about 1 g of gel. In a
most preferred embodiment of the invention, about 1 to 3 grams of a
formulation in the form of a gel is applied to about a 100
square-centimeter to a 1000 square-centimeter area of skin.
Formulation of the present invention may be applied on alternate
areas of the body as applications alternate. For example, the gel
may be applied to the abdomen for the first application, the upper
arm for the second application, and back to the abdomen for the
third application. This may be advantageous in alleviating any
sensitivity of the skin to repeated exposure to components of the
formulation. Alternatively, the formulation of the present
invention may be applied always on the same area of the body.
[0118] The invention includes the use of the formulations described
above to treat subjects to increase circulating levels of the
active agent or a metabolite thereof within the patient. Preferred
dosage units are capable of delivering an effective amount of the
active agent or metabolite over a period of about 24 hours. By an
"effective" or "therapeutically effective" amount of the active
agent or metabolite means a nontoxic, but sufficient amount to
provide the desired effect. However, it will be appreciated by
those skilled in the art that the desired dose will depend on the
specific form of the active agent or metabolite as well as on other
factors. The formulation is preferably applied on a regularly-timed
basis so that administration of the active agent or metabolite is
substantially continuous.
[0119] The composition may be applied directly or indirectly to the
skin or mucosal surfaces. Preferably, the composition is non
occlusive. The phrase "non-occlusive" as used herein refers to a
system that does not trap nor segregate the skin from the
atmosphere.
[0120] The composition of the invention can be in a variety of
forms suitable for transdermal or transmucosal administration. For
purpose of illustration and not limitation, the various possible
forms for the present composition include gels, ointments, creams,
lotions, microspheres, liposomes, micelles, foams, lacquers, and
non-occlusive transdermal patches, bandages, or dressings, or
combinations thereof. Alternatively, the composition may be in the
form of a spray, aerosol, solution, emulsion, nanosphere,
microcapsule, nanocapsule, as well as other topical or transdermal
forms known in the art. In a preferred embodiment, the invention is
a gel, a lotion, or a cream. In a most preferred embodiment, the
invention is a non-occlusive gel. Gels are semisolid,
suspension-type systems. Single-phase gels comprise macromolecules
(polymers) distributed substantially uniformly throughout the
carrier liquid, which is typically aqueous. However, gels
preferably comprise alcohol and, optionally, oil. Preferred
polymers, also known as gelling agents, are crosslinked acrylic
acid polymers, polyethylene oxides,
polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol;
cellulosic polymers (hydroxypropyl cellulose, hydroxyethyl
cellulose, hydroxypropyl methylcellulose, hydroxypropyl
methylcellulose phthalate, methyl cellulose); gums such as
tragacanth and xanthan gum; sodium alginate; and gelatin. In order
to prepare a uniform gel, dispersing agents such as alcohol or
glycerin can be added, or the gelling agent can be dispersed by
trituration, mechanical mixing or stirring, or combinations
thereof.
[0121] The compositions of the present invention may be
manufactured by conventional techniques of drug formulation,
particularly topical and transdermal drug formulation, which are
within the skill of the art. Such techniques are disclosed in
"Encyclopedia of Pharmaceutical Technology, 2.sup.nd Ed., edited by
J. Swarbrick and J. C. Boylan, Marcel Dekker, Inc., 2002, the
content of which is incorporated herein by reference.
EXAMPLES
[0122] 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 skilled in the
art in light of the present disclosure and the accompanying
claims.
Example 1
[0123] One embodiment of the formulation according to the invention
is a topical gel having Testosterone 1.25% w/w, propylene glycol
5.95% w/w, Ethyl alcohol 45.46% w/w, Distilled water 45.67% w/w,
Carbomer (Carbopol 980 NF) 1.21% w/w, Triethanolamine 0.39% w/w,
Disodium EDTA 0.06% w/w.
Example 2
[0124] One embodiment of the formulation according to the invention
is a gel composed by testosterone 1.00% w/w, diethylene glycol
monoethyl ether 5.00% w/w, propylene glycol 6.00% w/w, ethanol
47.52% w/w, purified water 38.87% w/w, carbomer (CARBOPOL.TM. 980
NF) 1.20% w/w, triethanolamine 0.35% w/w, and disodium EDTA 0.06%
w/w.
Example 3
[0125] One embodiment of a formulation according to the invention
is a topical hydroalcoholic gel formulation with 1% testosterone as
the active ingredient. The formulation has been studied in one
Phase I/II multiple dose, dose escalating clinical study in women.
The study was conducted to determine the effectiveness of the
formulation for the treatment of hypoactive sexual desire disorder
("HSDD"), in subjects including surgically menopausal women with
low testosterone levels.
[0126] This study showed that the testosterone gel dosing between
about 0.22 g to about 0.88 g formulation (2.2 to 8.8 mg/day
testosterone) daily for 7 days resulted in average total and free
testosterone serum concentrations within the normal range or
somewhat above the normal range for pre-menopausal women.
Example 4
[0127] In vitro studies were conducted to determine the
permeability profile of testosterone in human surgically excised
skin using the testosterone formulation of Table 5 above
(containing no lauryl alcohol, "1% T+0% LA"), as compared with
other testosterone formulations containing 1% and 2% lauryl alcohol
("1% T+1% or 2% LA"). The results of these studies are presented
below in Tables 6, 7 and 8.
[0128] In the first study pieces of excised human skin were mounted
in Franz Vertical Diffusion Cells (Hansen Research Inc.).
Approximately 10 mg of testosterone/cm.sup.2 (1% T+0, 1 or 2% LA),
were loaded in the loading chamber over the skin, which was
maintained at 35.degree. C. Sampling of the receptor solution was
performed at selected intervals after loading. The testosterone
flux and cumulative amount in the permeability study are shown
below in Table 6.
TABLE-US-00007 TABLE 6 Cum. Flux (.mu.g/h cm.sup.2)
(.mu.g/cm.sup.2) Amt. (SD) Time (h) 0% LA 1% LA 2% LA 0% LA 1% LA
2% LA 3 0.043 0.159 0.101 0.129 0.478 0.303 6 0.093 0.468 0.307
0.410 1.884 1.225 9 0.062 0.329 0.172 0.595 2.871 1.740 12 0.051
0.165 0.121 0.748 3.368 2.104 18 0.027 0.049 0.047 0.911 3.664
2.388 24 0.026 0.036 0.052 1.070 3.883 2.699
[0129] The testosterone flux and cumulative amount for the gel
comprising approximately 1.25% testosterone, 5.00% Transcutol,
5.95% propylene glycol, 43.09% ethyl alcohol, 43.07% distilled
water, 1.20% Carbopol 980NF, 0.38% triethanolamine, 0.059% EDTA are
represented below in Tables 7 and 8.
TABLE-US-00008 TABLE 7 Testosterone In vitro flux (.mu.g/h *
cm.sup.2)* Mean +/- S.D. Example 1 described above 1.12 +/- 0.36
*(Slope of cumulative amount of permeated drug vs. time between 12
and 24 h)
TABLE-US-00009 TABLE 8 Testosterone Cumulative Amount
(.mu.g/cm.sup.2) Mean +/- S.D. Time (h) Example 1 described above 0
0 6 10.25 +/- 4.97 12 20.40 +/- 6.75 18 27.84 +/- 8.70 24 33.80 +/-
10.45
[0130] FIG. 1 is a graph depicting drug flux over time for
testosterone in formulations including various amounts of lauryl
alcohol (LA) in an in vitro model using human excised skin and 10
mg testosterone/cm.sup.2 in the loading chamber (n=3-4.+-.SD). The
profile of 1% T+0% LA is different than the formulations containing
lauryl alcohol. The profile is about 4 times lower at 6 hours than
the 2% LA formulation, but overall more consistent. All profiles
showed a decrease in testosterone flux after 6 hours of permeation,
possibly due to drug depletion.
[0131] Another permeation study was conducted using the method
described above, except that approximately 50 mg of
testosterone/cm.sup.2 were loaded in the loading chamber over the
skin. Sampling of the receptor solution was performed at selected
intervals hours after loading. The testosterone flux and cumulative
amount in the permeability study are shown below.
TABLE-US-00010 TABLE 9 Flux .mu.g/(h cm.sup.2) Cum. .mu.g/cm.sup.2
Amt. (SD) Time (h) 0% LA 1% LA 2% LA 0% LA 1% LA 2% LA 3.0 0.448
0.872 0.900 1.345 2.617 2.700 6.0 0.521 1.216 1.336 2.908 5.732
6.709 9.0 0.504 0.914 0.801 4.421 8.473 9.112
[0132] FIG. 2 is a graph depicting drug flux over time for
testosterone in formulations including various amounts of lauryl
alcohol (LA) in an in vitro model using human excised skin and 50
mg testosterone/cm.sup.2 in the loading chamber (n=3-4.+-.SD). This
study shows that the 1% T+0% LA has a lower permeation rate.
However, the permeation profile was less variable making it
potentially more desirable for use in women since testosterone
levels must be titrated within a narrow range. Thus, these in vitro
studies would lead one of ordinary skill in the art to believe that
the inclusion of lauryl alcohol in the formulation is required in
the formulation in order to achieve suitable circulating levels of
hormones. However, Applicants have unexpectedly found that the
inclusion of lauryl alcohol is not required in topical formulations
to achieve an effective dose of circulating active agent
penetration. This is especially true for Female Sexual Dysfunction
where required testosterone plasmatic levels are lower than
testosterone therapeutic plasmatic levels observed to treat
hypogonadism.
Example 5
[0133] Experience with gel formulations and transdermal patches
generally show low rates of mild dermal toxicity with the gels and
extensive skin reactions with the patches, probably related to the
adhesive used or the occlusive nature of the patch. For instance,
with a topical gel formulation of testosterone, a few patients had
skin reactions, none of which required treatment or discontinuation
of drug. In contrast, transient mild to moderate erythema was
observed in the majority of patients treated with a transdermal
patch, and some patients had more severe reactions including
blistering, necrosis, and ulceration. See for example, Gelas B,
Thebault J, Roux I, Herbrecht F, Zartarian M., "Comparative study
of the acceptability of a new estradiol Tx 11323 (A) gel and a
transdermal matrix system," Contraception, fertilite, sexualite
1997 June; 25 (6):470-474).
Example 6
[0134] The objective of this study was to evaluate the safety and
pharmacokinetic profiles of multiple doses of a 1% T+0% LA
hydroalcoholic gel, in postmenopausal women. During the first 7
days of the study, the subjects received daily topical applications
of 0.22 g of a formulation including 1% T+0% LA (2.2 mg/day
testosterone). On Days 8-14, the subjects received 0.44 g of a
formulation including 1% T+0% LA (4.4 mg/day testosterone), and on
Days 15-21, the subjects received 0.88 g of a formulation including
1% T+0% LA (8.8 mg/day testosterone). There was no washout period,
prior to each dose escalation. The pharmacokinetic results for
total, free and bioavailable testosterone are shown below.
TABLE-US-00011 TABLE 10 Total Testosterone Parameter Day 1 Day 7
Day 14 Day 31 Daily Dose 2.2 mg 2.2 mg 4.4 mg 8.8 mg N 7 7 7 7
C.sub.o (ng/dL) 21.00 (6.0) 42.43 (14.8) 68.71 (35.6) 87.00 (41.6)
C.sub.avg (ng/dL) 38.49 (17.0) 56.03 (24.5) 91.99 (51.2) 141.49
(72.0) C.sub.max (ng/dL) 69.86 (33.0) 113.57 (92.9) 165.57 (113.8)
203.86 (128.3) C.sub.min (ng/Dl) 19.00 (6.2) 31.14 (15.6) 43.14
(20.6) 77.57 (27.9) T.sub.max* (hr) 20 (20-24) 16 (1-24) 16 (1-24)
20 (3-24) T.sub.min* (hr) 1 (0-6) 6 (0-20) 6 (0-12) 0 (0-12) AUC
(ng hr/dL) 923.79 (408.3) 1344.71 (588.5) 2207.79 (1228.1) 3395.64
(1728.8) AR (ratio) -- 1.59 (0.7) 2.32 (0.5) 3.59 (0.6) Parameter
Day 1 Day 7 Day 14 Day 21 Free Testosterone Daily Dose 2.2 mg 2.2
mg 4.4 mg 8.8 mg N 7 7 7 7 C.sub.o (pg/mL) 2.64 (1.0) 5.24 (1.8)
7.87 (3.2) 10.80 (7.4) C.sub.avg (pg/mL) 4.81 (1.8) 6.96 (1.9)
11.13 (5.4) 16.69 (7.3) C.sub.max (pg/mL) 8.84 (3.6) 15.79 (14.3)
21.31 (19.5) 25.80 (16.0) C.sub.min (pg/mL) 2.26 (0.9) 3.67 (1.3)
5.53 (2.2) 9.23 (4.9) T.sub.max* (hr) 20 (20-24) 20 (3-24) 16
(1-24) 20 (3-24) T.sub.min* (hr) 1 (0-12) 9 (0-20) 9 (0-12) 0 (0-6)
AUC (pg hr/mL) -- 1.57 (0.6) 2.28 (0.5) 3.43 (0.8) Bioavailable
Testosterone Daily Dose 2.2 mg 2.2 mg 4.4 mg 8.8 mg N 7 7 7 7
C.sub.o (ng/dL) 4.01 (2.1) 7.94 (3.7) 12.56 (5.8) 16.27 (12.1)
C.sub.avg (ng/dL) 7.48 (3.4) 10.81 (3.6) 16.47 (8.1) 25.04 (11.5)
C.sub.max (ng/dL) 13.33 (6.7) 25.57 (28.5) 32.14 (29.4) 39.13
(27.1) C.sub.min (ng/dL) 3.69 (1.7) 5.84 (2.7) 8.43 (3.6) 13.84
(7.7) T.sub.max* (hr) 20 (20-24) 16 (1-24) 16 (9-24) 20 (3-24) AUC
(ng hr/dL) 179.4 (81.4) 259.52 (87.1) 395.23 (195.0) 600.94 (276.2)
AR (ratio) -- 1.59 (0.7) 2.26 (0.7) 3.48 (1.2)
[0135] FIGS. 3A-C are graphs depicting median total, free and
bioavailable testosterone serum concentrations following
administration of 1% T+0% LA in vivo over a sampling period on days
1, 7, 14, and 21, respectively.
[0136] The average baseline total testosterone and free
testosterone concentrations were 21.0 ng/dL and 2.6 pg/mL,
respectively. After one week of 0.22 g daily doses of 1% T+0% LA,
the average total testosterone and free testosterone concentrations
were 56.0 ng/dL and 7.0 pg/mL, respectively. One week of daily 0.44
g doses of 1% T+0% LA increased the average total testosterone and
free testosterone concentrations to 92.0 ng/dL and 11.1 pg/mL,
respectively. Daily doses of 0.88 g 1% T+0% LA for 7 days increased
the average testosterone and free testosterone concentrations to
141.5 ng/dL and 16.7 pg/mL in the 7 subjects.
[0137] FIGS. 3D-F are graphs depicting mean bioavailable and free
testosterone serum concentrations after different dose regimens and
treatments with 1% T+2% LA in vivo over a sampling period on days
1, 7, 14, respectively. When like testosterone dosages are
compared, this data shows that in vivo testosterone levels are not
substantially changed by the inclusion of lauryl alcohol.
Therefore, contrary to the in vitro findings, lauryl alcohol was
not necessary to achieve effective serum levels in vivo.
[0138] This study demonstrated that 1% T 0% LA has the potential to
elevate free testosterone concentrations in women with low
endogenous testosterone production. The 0.22 g dose, corresponding
to 2.2 mg testosterone, resulted in average free testosterone
concentrations towards the upper limit of normal. For the 0.44 g
dose, average free testosterone concentrations were 1.6 times the
upper limit of normal while average free testosterone
concentrations for the 0.88 g dose were approximately 2.4 times the
upper limit of normal.
[0139] Further, the 1% T+0% LA formulation has been administered in
daily testosterone doses of 2.2, 4.4, and 8.8 mg (doses of 0.22
g/day, 0.44 g/day, and 0.88 g/day, each applied for 7 days,
respectively) in one Phase I/II study. The formulation was well
tolerated in this study. No serious or significant adverse events
were reported. No significant changes in clinical laboratory
variables, vital signs, ECG parameters or physical findings were
detected in any of the treatment groups.
Example 7
[0140] The primary objectives of this study were to evaluate the
safety, tolerability, and pharmacokinetic profile of two different,
multiple topical doses of an estradiol gel including in terms of
the PK variables AUC and C.sub.max with and without corrections for
endogenous estradiol concentrations in postmenopausal female
subjects. Each subject received one of two estradiol treatments for
14 consecutive days; either 1.25 g estradiol gel 0.06% (0.75 mg
estradiol/day) or 2.5 g estradiol gel 0.06% (1.5 mg
estradiol/day).
[0141] Multiple doses of 0.75 mg E2/day maintained average
concentrations (=AUC.tau./24) of 2.4 ng/dl (24 pg/ml). The double
dose of 1.5 mg E2/day resulted in an average concentration of 5.3
ng/dl (53 pg/ml). The values correspond very well to those observed
after transdermal patches such as Estraderm.RTM.. When using a
patch with a nominal delivery rate of 25 .mu.g/day, an average
maintenance concentration of 23 pg/ml has been reported. For
patches with a delivery rates of 50 .mu.g/day or 100 .mu.g/day,
average concentrations of 40 pg/ml and 75 pg/ml have been reported,
respectively. Estraderm.RTM. has been registered in the European
Community and in the United States as being efficacious for
postmenopausal disorders including reduction in hot flashes, and
for osteoporosis prophylaxis. Therefore, it is predicted that the
E2 gel formulation will be safe and effective for treatment of
menopausal symptoms including reduction of hot flashes, and for
osteoporosis prophylaxis.
[0142] Estradiol Concentration Time Data (0-24 hours) Following a
Single Dose (Day 1). FIG. 4A is a graph depicting mean serum
concentrations of estradiol (E2) following single dose
administration of E2+0% LA gel (a=0.75 mg E2; b=1.50 mg E2).
Following administration of the lower dose (treatment a), the
concentration-time profile demonstrates that an increase in E2
concentrations was observed. On average, E2 concentrations
increased from a baseline value of 0.4 ng/dl E2 at 0 H to 2.1 ng/dl
E2 at 24 H. Following application of the higher dose, (treatment b)
an increase from 0.5 ng/dl E2 at baseline at 0 H to 3.0 ng/dl E2 at
24 H was observed.
[0143] Estradiol Trough Concentration Data (Days 1-20). FIG. 4B is
a graph depicting mean trough concentrations of E2 over time
following repeated administration of E2+0% LA gel. On average, the
trough concentrations increased until approximately 24 H after
application (Day 2, predose). Thereafter a plateau in
concentrations was observed and levels fluctuated between 2.1 ng/dl
at 24 H and 2.4 ng/dl E2 on the day after the last dose was applied
(336 H=Day 15, 0 H). Within this sampling interval, the trough
concentrations were variable and fluctuated between a minimum of
1.3 ng/dl E2 observed at 48 H (Day 3 predose) to a maximum of 2.4
ng/dl at 336 H (Day 15, 0 H). Following the last administration,
average E2 concentrations declined to 0.8 ng/dl and were near
predose baseline levels (0.6 ng/dl) at 456 H (Day 20, 0 H; 5 days
after discontinuation of drug application).
[0144] FIG. 4D is a graph depicting individual trough
concentrations of E2 over time following repeated administration of
E2+0% LA gel at both doses. On average, E2 concentrations continued
to increase until approximately 240 H (Day 11 predose).
Concentrations increased from 0.5 ng/dl at baseline (0 H) to 8.7
ng/dl at 240 H.
[0145] The median trough values were also examined and these
reached a plateau of approximately 5.1 ng/dl E2 at 96 H (Day 5
predose) after application. Thereafter, the trough concentrations
were variable and fluctuated between a minimum of 4.2 ng/dl E2
(median at 288 H, Day 13 predose) to a maximum of 5.3 ng/dl at 336
H (Day 15, 0 H). Following the last administration, average E2
concentrations declined to 0.8 ng/dl and were near predose baseline
levels (0.5 ng/dl) at 456 H (Day 20, 0 H; 5 days after
discontinuation of drug application). Examination of median trough
concentrations indicate that steady state E2 concentrations are
reached by 4 and 5 days for the E2 gel 1.25 g and 2.5 g doses,
respectively.
[0146] Estradiol Concentration Time Data (0-24 hours) Following 14
Doses (Day 14). FIG. 4E is a graph depicting mean serum
concentrations of E2 following multiple dose administration of
E2+0% LA gel. The profiles on Day 14 demonstrate that steady state
E2 concentrations were reached by Day 14 (312 H). The mean E2
concentrations at the beginning of this interval (treatment a: 2.0
ng/dl E2, treatment b: 5.0 ng/dl E2) and at the end of this
sampling interval (treatment a: 2.4 ng/dl E2, treatment b: 5.5
ng/dl E2) were comparable. Average maximum E2 concentrations were
3.7 ng/dl and 8.8 ng/dl, respectively (Day 14 data).
[0147] Estradiol Pharmacokinetic Parameters on Day 1 and Day 14.
The pharmacokinetic parameters for E2 following single and multiple
applications of Bio-E-Gel at 1.25 g and 2.5 g are presented in
Table 10a. A descriptive summary of the pharmacokinetic parameters,
uncorrected and baseline-adjusted, are presented in Table 10c and
10d, respectively.
TABLE-US-00012 TABLE 10a E2 - PK Variables by Dose Regimens 1.25 g
1.25 g 2.5 g 2.5 g Bio-E- Bio-E- Bio-E- Bio-E- Gel, Gel, Gel, Gel,
Single Multiple Single Multiple Variable Statistic Dose Dose Dose
Dose AUC.sub..tau. N 6 6 6 6 [ng/dl * H] Mean 27.5 57.0 49.7 128.2
SD 17.2 29.9 48.1 50.0 GeoM 19.2 51.9 38.4 117.6 G_CV 173.5 48.0
79.0 53.1 C.sub.max N 6 6 6 6 [ng/dl] Mean 2.3 3.7 3.7 8.8 SD 1.8
2.3 2.7 4.8 GeoM 1.7 3.2 3.1 7.6 G_CV 110.1 54.2 75.9 67.0
t.sub.max N 6 6 6 6 [H] Mean 17.67 327.83 18.00 330.33 SD 8.62 9.85
4.90 8.62 Min 2.00 313.00 12.00 314.00 Med 20.00 332.00 16.00
334.00 Max 24.00 336.00 24.00 336.00 Baseline, N 6 6 6 6 C.sub.0
Mean 0.5 0.5 0.4 0.4 [ng/dl] SD 0.4 0.4 0.3 0.3 Min 0.0 0.0 0.0 0.0
Med 0.5 0.5 0.4 0.4 Max 1.3 1.3 0.8 0.8
[0148] Following a single application of 1.25 g of E2 gel, maximum
concentrations (C.sub.max) on Day 1 were 2.3 ng/dl. On average, the
time to maximum concentrations, t.sub.max, was achieved by 17.67H.
The exposure to E2, as measured by AUC.tau. was 27.5 ng/dl*H.
Following multiple applications, C.sub.max concentrations increased
to 3.7 ng/dl on Day 14. The t.sub.max estimates were approximately
16 H on Day 14 and were comparable to those observed on Day 1. The
exposure to E2 was 57.0 ng/dl*H on Day 14 and was higher than that
observed on Day 1, demonstrating the accumulation of E2 in the
serum following repeated applications.
[0149] Following a single application of 2.5 g of E2 gel, maximum
concentrations (C.sub.max) on Day 1 were 3.7 ng/dl. On average, the
time to maximum concentrations, t.sub.max, was achieved by 18 H.
The exposure to E2, as measured by AUC.tau. was 49.7 ng/dl*H.
Following multiple application, C.sub.max concentrations increased
to 8.8 ng/dl on Day 14. The t.sub.max estimates were approximately
18 H on Day 14 and were comparable to those observed on Day 1. The
exposure to E2 was 128.2 ng/dl*H on Day 14 and was higher than that
observed on Day 1, demonstrating the accumulation of E2 in the
serum following repeated applications.
[0150] The ratio of geometric means of E2 gel 2.5 g/1.25 g was used
to assess the dose proportionality of E2 following the two doses of
E2 gel. After single dose application, the mean AUC ratio (E2 gel
2.5 g/1.25 g) was 38.4/19.2=2.0 and after multiple doses it was
117.6/51.9=2.3, indicating dose proportionality.
[0151] Baseline Adjusted Estradiol Pharmacokinetic Parameters on
Day 1 and Day 14. Baseline concentrations of E2 were similar for
both groups and were calculated as 0.5 ng/dl and 0.4 ng/dl for the
1.25 g and 2.5 g E2 gel, respectively. In order to correct for
endogenous E2 concentrations, the baseline E2 concentration (E2 gel
1.25 g: 0.5 ng/dl and 2.5 g: 0.4 ng/dl) was subtracted from the
total concentration measured after application and the AUC.tau. and
C.sub.max were recalculated based on the baseline-adjusted
concentration. The results of the baseline-adjusted pharmacokinetic
variables are summarized in Table 10b. The baseline-adjusted
C.sub.max estimates were 1.8 ng/dl and 3.4 ng/dl following single
applications of the 1.25 g and 2.5 g E2 gel, respectively. For
AUC.tau., the baseline-adjusted values were 14.9 ng/dL*H and 41.4
ng/dl*H for the 1.25 g and 2.5 g E2 gel, respectively. Following
repeated applications, C.sub.max estimates increased to 3.1 ng/dl
and 8.4 ng/dl and AUC.tau. estimates increased to 44.2 ng/dl*H and
119.6 ng/dl*H for 1.25 g and 2.5 g E2 gel, respectively. These
increases reflect the accumulation of drug in the serum following
repeated application of the gel.
[0152] The terminal elimination half-life (t1/2) of E2 was
calculated from the baseline-adjusted concentrations following the
last dose (at 312 H, Day 14 predose) by log-linear regression from
the linear portion of the logarithmic transformed
concentration-time plot. The individual and mean estimates of
half-life following the application of 1.25 g and 2.5 g E2 gel are
presented in Table 10d. The median half-life was 22.15 .mu.l
(range: 13.11-76.71) for E2 gel 1.25 g and 35.58 .mu.l (range:
26.60-51.59) for 2.5 g. The half-life estimates for both treatment
groups were comparable.
TABLE-US-00013 TABLE 10b E2 - PK Variables, Baseline Adjusted 1.25
g, 2.5 g, 2.5 g, Single 1.25 g, Single Multiple Variable Statistic
Dose Multiple Dose Dose Dose .delta.AUC.sub..tau. N [ng/dl * H]
Mean 14.9 44.2 41.4 119.6 SD 13.3 22.2 51.1 51.2 GeoM 9.8 39.7 25.2
108.9 G_CV 147.3 56.1 139.6 53.5 .delta.C.sub.max N 6 6 6 6 [ng/dl]
Mean 1.8 3.1 3.4 8.4 SD 1.8 2.0 2.9 4.7 GeoM 1.2 2.7 2.4 7.3 G_CV
132.8 56.4 118.5 68.5 t.sub.1/2 N 4 4 [H] Mean 33.53 37.34 SD 29.16
12.41 Min 13.11 26.60 Med 22.15 35.58 Max 76.71 51.59
[0153] Estrone Concentration Time Data (0-24 hours) Following a
Single Dose (Day 1). FIG. 4F is a graph depicting mean serum
concentrations of estrone (E1) following single dose administration
of E2+0% LA gel. On average, E1 concentrations increased from a
baseline value of 2.4 ng/dl E1 at 0 H to 3.4 ng/dl E1 at 24 H.
Following application of the higher dose, (treatment b) an increase
from 2.4 ng/dl E1 at baseline (0 H) to 4.0 ng/dl E1 at 24 H was
observed.
[0154] Estrone Trough Concentration Data (Days 1-20). FIG. 4G is a
graph depicting mean trough concentrations of E1 following repeated
administration of E2+0% LA gel. On average, the trough
concentrations increased to approximately 72 H (Day 4 predose)
after application. Thereafter a plateau in concentrations was
observed and levels fluctuated between 4.3 ng/dl at 72 H and 5.2
ng/dl E1 on the day after the last dose was applied (336 H=Day 15,
0 H). Within this sampling interval, the trough concentrations were
variable and fluctuated between a minimum of 4.1 ng/dl E1 observed
at 96 H (Day 5 predose) to a maximum of 5.3 ng/dl at 288 H (Day 13
predose). Following the last administration, average E1
concentrations declined to 3.0 ng/dl and were near predose baseline
levels (2.4 ng/dl) at 456 H (Day 20, 0 H; 5 days after
discontinuation of drug application).
[0155] The mean E1 trough concentrations following repeated
administration of Bio-E-Gel 2.5 g are also presented in FIG. 4G. On
average, E1 concentrations continued to increase until
approximately 240 H (Day 11 predose). Concentrations increased from
2.4 ng/dl at baseline (0 H) to 10.4 ng/dl at 240 H. Thereafter, the
trough concentrations were variable and fluctuated between 9.1
ng/dl E1 (at 288 H=Day 13 predose) to 7.8 ng/dl at 336 H (Day 15, 0
H). Following the last administration, average E1 concentrations
declined to 3.1 ng/dl and were near predose baseline levels (4.0
ng/dl) at 456 H (Day 20, 0 H; 5 days after discontinuation of drug
application). Examination of mean trough concentrations indicate
that steady state E1 concentrations are reached by 11 and 13 days
for the Bio-E-Gel 2.5 g and 1.25 g doses, respectively.
[0156] Estrone Concentration Time Data (0-24 hours) Following 14
Doses (Day 14). FIG. 4H is a graph depicting mean serum
concentrations of E1 following multiple dose administration of
E2+0% LA gel. The profiles on Day 14 demonstrate that steady state
E1 concentrations were reached by Day 14 (312 H). The E1
concentrations at the beginning of this interval (treatment a: 4.8
ng/dl, treatment b: 8.2 ng/dl) and at the end of this sampling
interval (treatment a: 5.2 ng/dl, treatment b: 7.8 ng/dl) were
comparable. Average maximum E1 concentrations on Day 14 (312 to 336
H) were 6.0 ng/dl and 9.2 ng/dl, respectively.
[0157] Estrone Pharmacokinetic Parameters on Day 1 and Day 14.
Following a single application of 1.25 g of E2 gel, maximum
concentrations (C.sub.max) on Day 1 were 3.6 ng/dl. On average, the
time to maximum concentrations, t.sub.max, was achieved by 12.67H.
The exposure to E1, as measured by AUC.tau. was 56.2 ng/dl*H.
Following multiple applications, Cmax concentrations increased to
6.0 ng/dl on Day 14. The t.sub.max estimates were approximately 11H
on Day 14 and were comparable to those observed on Day 1. The
exposure to E1 was 111.4 ng/dl*H on Day 14 and was higher than that
observed on Day 1, demonstrating the accumulation of E1 in the
serum following repeated applications.
[0158] Following a single application of 2.5 g of E2 gel, maximum
concentrations (C.sub.max) on Day 1 were 4.1 ng/dl. On average, the
time to maximum concentrations, t.sub.max, was achieved by 21H. The
exposure to E1, as measured by AUC.tau. was 62.2 ng/dl*H. Following
multiple application, Cmax concentrations increased to 9.2 ng/dl on
Day 14. The t.sub.max estimates were approximately 2 H on Day 14
and were lower than those observed on Day 1. The exposure to E1 was
179.7 ng/dl*H on Day 14 and was higher than that observed on Day 1,
demonstrating the accumulation of E1 in the serum following
repeated applications.
TABLE-US-00014 TABLE 10c E1 - PK Variables by Dose Regimens 1.25 g,
2.5 g, 2.5 g, Single 1.25 g, Single Multiple Variable Statistic
Dose Multiple Dose Dose Dose AUC.sub..tau. N 6 6 6 6 [ng/dl * H]
Mean 56.2 111.4 62.2 179.7 SD 31.2 54.2 30.0 67.6 GeoM 49.6 100.8
56.2 167.1 G_CV 59.2 51.9 53.2 46.3 C.sub.max N 6 6 6 6 [ng/dl]
Mean 3.6 6.0 4.1 9.2 SD 1.6 2.7 0.6 3.1 GeoM 3.2 5.6 4.0 8.7 G_CV
56.3 45.0 13.2 40.5 t.sub.max N 6 6 6 6 [H] Mean 12.67 323.33 21.01
314.33 SD 12.42 9.93 7.33 1.51 Min 1.00 312.00 6.05 312.00 Med
13.00 322.00 24.00 314.00 Max 24.00 336.00 24.00 316.00 Baseline, N
6 6 6 6 C.sub.0 Mean 1.8 1.8 2.0 2.0 [ng/dl] SD 1.4 1.4 0.9 0.9 Min
0.5 0.5 1.1 1.1 Med 1.5 1.5 1.8 1.8 Max 4.4 4.4 3.2 3.2
[0159] Baseline Adjusted Estrone Pharmacokinetic Parameters on Day
1 and Day 14. Baseline concentrations of E1 were similar for both
groups and were calculated as 1.8 ng/dl and 2.0 ng/dl for the 1.25
g and 2.5 g E2 gel, respectively. In order to correct for
endogenous E1 concentrations, the baseline E1 concentration (E2 gel
1.25 g: 1.8 ng/dl and E2 gel 2.5 g: 2.0 ng/dl) was subtracted from
the total concentration measured after application and the AUC.tau.
and C.sub.max were recalculated based on the baseline-adjusted
concentration. The results of the baseline-adjusted pharmacokinetic
variables are summarized in Table 10d. The baseline-adjusted
C.sub.max estimates were 1.8 ng/dl and 2.0 ng/dl following single
applications of the 1.25 g and 2.5 g E2 gel respectively. For
AUC.tau., the baseline-adjusted values were 14.5 ng/dL*H and 17.9
ng/dl*H for the 1.25 g and 2.5 g E2 gel, respectively. Following
repeated applications, C.sub.max estimates increased to 4.2 ng/dl
and 7.2 ng/dl and AUC.tau. estimates increased to 67.1 ng/dl*H and
131.2 ng/dl*H for 1.25 g and 2.5 g E2 gel, respectively. These
increases reflect the accumulation of drug in the serum following
repeated application of the gel.
TABLE-US-00015 TABLE 10d E1 - PK Variables, Baseline Adjusted 1.25
g 1.25 g 2.5 g 2.5 g Single Multiple Single Multiple Variable
Statistic Dose Dose Dose Dose .delta.AUC.sub..tau. N 6 6 6 6 [ng/dl
* H] Mean 14.5 67.1 17.9 131.2 SD 5.6 27.1 6.0 68.4 Med 14.6 63.9
16.2 139.6 GeoM 13.6 63.0 17.2 113.8 G_CV 42.1 39.9 31.3 68.0
.delta.C.sub.max N 6 6 6 6 [ng/dl] Mean 1.8 4.2 2.0 7.2 SD 0.8 1.7
0.5 3.2 Med 1.7 3.6 2.0 8.0 GeoM 1.6 4.0 2.0 6.4 G_CV 47.2 34.7
30.6 57.5
[0160] Estrone-Sulfate Concentration Time Data (0-24 hours)
Following a Single Dose (Day 1). FIG. 4I is a graph depicting mean
serum concentrations of estrone-sulfate (E1-sulfate) following
single dose administration of E2+0% LA gel (a=0.75 mg E2; b=1.50 mg
E2). On average, E1-S concentrations increased from a baseline
value of 45.8 ng/dl E1 at 0 H to 79.0 ng/dl E1-S at 24 H. Following
application of the higher dose, (treatment b) an increase from 34.7
ng/dl E1-S at baseline at 0 H to 70.7 ng/dl E1-S at 24 H was
observed.
[0161] Estrone-Sulfate Trough Concentration Data (Days 1-20). FIG.
4J is a graph depicting mean trough concentrations of E1-sulfate
following multiple dose administration of E2+0% LA gel (a=0.75 mg
E2; b=1.50 mg E2). On average, the trough concentrations continued
to increase with repeated applications although the mean plot
suggested a change in the rate of increase by approximately 192 H
(Day 9 predose). E1-S serum concentrations fluctuated between 133.8
ng/dl at 192 H and 117.8 ng/dl E1-S on the day after the last dose
was applied (336 H; Day 15, 0 H). Following the last
administration, average E1-S concentrations declined to 77.0 ng/dl
and were higher than predose baseline levels (45.8 ng/dl) at 456 H
(Day 20, 0 H; 5 days after discontinuation of drug
application).
[0162] On average, E1-S concentrations continued to increase until
approximately 312 H (Day 14 predose) although a change in the rate
of increase was evident at approximately 240 H (Day 11 predose).
Concentrations increased from 34.7 ng/dl at baseline (0 H) to 193.5
ng/dl at 240 H. Thereafter, the trough concentrations were variable
and fluctuated between 193.5 ng/dl E1 (at 240 H) to 155.7 ng/dl at
336 H (Day 15, 0 H). Following the last administration, average
E1-S concentrations declined to 60.3 ng/dl and were higher than
predose baseline levels (34.7 ng/dl) at 456 H (Day 20, 0 H; 5 days
after discontinuation of drug application). Examination of mean
trough concentrations indicate that steady state E1-sulfate
concentrations are reached by 13 and 14 days for the E2 gel 1.25 g
and 2.5 g doses, respectively.
[0163] Estrone-Sulfate Concentration Time Data (0-24 hours)
Following 14 Doses (Day 14). FIG. 4K is a graph depicting mean
serum concentrations of E1-sulfate following multiple dose
administration of E2+0% LA gel. The profiles on Day 14 demonstrate
that steady state E1-S concentrations were essentially reached by
Day 14 (312 H). The mean E1-S concentrations at the beginning of
this interval (treatment a: 130.7 ng/dl, treatment b: 200.3 ng/dl)
and at the end of this sampling interval (treatment a: 117.8 ng/dl,
treatment b: 155.7 ng/dl) were slightly different. However, the
range of the values overlapped thereby suggesting the comparability
of the results. Average maximum E1-S concentrations on Day 14 were
163.5 ng/dl E1-S for E2 gel 1.25 g and 253.8 ng/dl E1-S for E2 gel
2.5 g.
[0164] Estrone-Sulfate Pharmacokinetic Parameters on Day 1 and Day
14. The pharmacokinetic parameters for E1-S following single and
multiple applications of E2 gel at 1.25 g and 2.5 g are presented
in Table 10e. A descriptive summary of the pharmacokinetic
parameters, uncorrected and baseline-adjusted, are presented in
Table 10c and 10d, respectively.
[0165] Following a single application of 1.25 g of E2 gel, maximum
concentrations (C.sub.max) on Day 1 were 80.2 ng/dl. On average,
the time to maximum concentrations, t.sub.max, was achieved by
20.67H. The exposure to E1-S, as measured by AUC.tau. was 1359.2
ng/dl*H.
[0166] Following multiple applications, Cmaxconcentrations
increased to 163.5 ng/dl on Day 14. The t.sub.max estimates were
approximately 5 H on Day 14 and were lower than those observed on
Day 1. The exposure to E1-S was 2834.1 ng/dl*H on Day 14 and was
higher than that observed on Day 1, demonstrating the accumulation
of E1-S in the serum following repeated applications.
[0167] Following a single application of 2.5 g of E2 gel, maximum
concentrations (Cmax) on Day 1 were 74.7 ng/dl. On average, the
time to maximum concentrations, t.sub.max, was achieved by 20H. The
exposure to E1-S, as measured by AUC.tau. was 1207.4 ng/dl*H.
Following multiple applications, Cmax concentrations increased to
253.8 ng/dl on Day 14. The t.sub.max estimates were approximately 3
H on Day 14 and were lower than those observed on Day 1. The
exposure to E1-S was 4079.2 ng/dl*H on Day 14 and was higher than
that observed on Day 1, demonstrating the accumulation of E1-S in
the serum following repeated applications.
TABLE-US-00016 TABLE 10e E1-Sulfate - PK Variables by Dose Regimens
1.25 g, 2.5 g, 2.5 g, Single 1.25 g, Single Multiple Variable
Statistic Dose Multiple Dose Dose Dose AUC.sub..tau. N 6 6 6 6
[ng/dl * H] Mean 1359.2 2834.1 1207.4 4079.2 SD 407.8 1219.0 243.6
1674.5 GeoM 1302.6 2611.1 1184.3 3798.7 G_CV 33.9 47.2 22.6 43.4
C.sub.max N 6 6 6 6 [ng/dl] Mean 80.2 163.5 74.7 253.8 SD 30.5 75.5
12.1 124.2 GeoM 75.2 148.2 73.8 231.3 G_CV 41.5 52.6 17.0 49.0
t.sub.max N 6 6 6 6 [H] Mean 20.67 316.67 20.00 315.33 SD 8.16 3.93
6.20 4.46 Min 4.00 314.00 12.00 312.00 Med 24.00 315.00 24.00
313.50 Max 24.00 324.00 24.00 324.00 Baseline, N 6 6 6 6 C.sub.0
Mean 51.3 51.3 36.9 36.9 [ng/dl] SD 17.9 17.9 10.7 10.7 Min 23.3
23.3 23.3 23.3 Med 55.5 55.5 38.0 38.0 Max 71.0 71.0 53.0 53.0
[0168] Baseline Adjusted Estrone-Sulfate Pharmacokinetic Parameters
on Day 1 and Day 14. Baseline concentrations of E1-S were similar
for both groups and were measured as 51.3 ng/dl and 36.9 ng/dl for
the 1.25 g and 2.5 g E2 gel, respectively. In order to correct for
endogenous E1-S concentrations, the baseline E1-S concentration (E2
gel 1.25 g: 51.3 ng/dl and Bio-E-Gel 2.5 g: 36.9 ng/dl) was
subtracted from the total concentration measured after application
and the AUC.tau. and C.sub.max were recalculated based on the
baseline-adjusted concentration. The baseline-adjusted
Cmaxestimates were 28.8 ng/dl and 37.7 ng/dl following single
applications of the 1.25 g and 2.5 g E2 gel, respectively. For
AUC.tau., the baseline-adjusted values were 165.7 ng/dL*H and 325.5
ng/dl*H for the 1.25 g and 2.5 g E2 gel, respectively. Following
repeated applications, C.sub.max estimates increased to 112.2 ng/dl
and 216.9 ng/dl and AUC.tau. estimates increased to 1602.1 ng/dl*H
and 3192.5 ng/dl*H for 1.25 g and 2.5 g E2 gel, respectively. These
increases reflect the accumulation of drug in the serum following
repeated application of the gel.
TABLE-US-00017 TABLE 10f E1-Sulfate - PK Variables, Baseline
Adjusted 1.25 g 1.25 g 2.5 g 2.5 g Single Multiple Single Multiple
Variable Statistic Dose Dose Dose Dose .delta.AUC.sub..tau. N 6 6 6
6 [ng/dl * H] Mean 165.7 1602.1 325.5 3192.5 SD 63.7 878.6 267.1
1543.4 GeoM 153.9 1403.2 256.1 2893.6 G_CV 46.4 61.9 87.6 51.8
.delta.C.sub.max N 6 6 6 6 [ng/dl] Mean 28.8 112.2 37.7 216.9 SD
19.3 61.0 16.0 120.4 GeoM 24.1 97.0 33.7 192.9 G_CV 71.7 67.2 63.6
55.7
[0169] Sex Hormone Binding Globulin (SHBG). The SHBG concentrations
in the subsequent table were determined in addition to the study
protocol, specially in order enable the interpretation of the
unexpected accumulation of E2 in Subject 04. The data are tabulated
in Table 10 g. Generally the mean SHBG concentrations increased
with time, after E2 gel 1.25 g from mean 72.5 nmol/l at 0 H over
80.17 nmol/l to 84.00 nmol/l and after E2 gel 2.5 g from mean 72.5
nmol/l at 0 H over 77.83 nmol/l to 88.83 nmol/l. Subject 04 who
received E2 gel 2.5 g showed a similar pattern. The pre-treatment
SHBG-concentrations were 58 nmol/l and 53 nmol/l, respectively. 192
H (Day 9 predose) after the first application the SHBG
concentration was 58 nmol/l and after 360 H (Day 16, 0 H) it was
increase to 71 nmol/l. Subject 04 thus did not appear to differ
from the other subjects and the SHBG concentration do not explain
the excessive E2 concentrations in this subject.
TABLE-US-00018 TABLE 10g SHBG [nMol/l] Scheduled time relative to
first application Treatment Statistic -16 -10 192 360 E2 gel, 1.25
N 6 6 6 6 Mean 72.33 72.50 80.17 84.00 SD 23.73 24.83 28.53 29.18
GeoM 69.12 69.02 75.94 79.73 G_CV 34.09 35.54 37.59 36.85 E2 gel,
2.5 g N 6 6 6 6 Mean 74.00 72.50 77.83 88.83 SD 29.64 30.34 32.17
38.97 GeoM 68.91 67.20 72.20 81.17 G_CV 43.88 45.10 45.01 50.71
[0170] Pharmacokinetics Conclusions. The pharmacokinetic
characteristics were calculated as surrogates for the evaluation of
the efficacy. It could be shown that multiple doses of 0.75 mg and
1.5 mg E2 gel resulted in average serum concentrations of about 2.4
ng/dl E2 and 5.3 ng/dl E2, respectively. These values are of a
magnitude which are obtained after transdermal patches with a
delivery rate of 25 and 50 .mu.g E2 per day and are approved for
postmenopausal disorders, including reduction of hot flashes.
[0171] Safety Conclusions. Eight adverse events were observed; 7 of
them were classified as (possibly) related to the study treatments:
3 and 4 events after the administration of 1.25 g and 2.5 g E2 gel,
respectively. Both treatments regimens showed excellent skin
tolerability. No severe, serious, or significant adverse events
occurred. No drop outs were observed. There were no significant
changes in vital signs, ECG, clinical laboratory variables or
physical findings. The study medication was well tolerated. There
were no relevant differences in safety profile of the two
treatments investigated.
[0172] Conclusions. The mean and individual serum
concentration-time profiles for E2, E1 and E1-S from 1.25 g and 2.5
g E2 gel showed that the two treatments provided drug
concentrations that were above the measured baseline levels. The
pharmacokinetics of the gel product demonstrate that upon repeated
administration a plateau in drug levels is generally reached. In
addition, once drug is discontinued, drug levels return to or are
near baseline levels within 5 days. The pharmacokinetics of E2, E1
and E1-S suggested dose proportionality for the 1.25 and 2.5 g gel
products. Mean parameter estimates in the 2.5 g treatment group
were approximately double the estimates in the 1.25 g treatment
group on Days 1 and 14.
[0173] Estimates of t.sub.max were variable in both treatment
groups. At steady-state on Day 14, some estimates of t.sub.max
occurred at the beginning of the dosing interval. In these cases,
it is possible that serum concentrations continued to rise
immediately after a dose due to continued presence of drug from the
previously administered dose. The time to maximum concentration
following administration of both treatments occurred within 16-20 H
after the first application.
[0174] The achievement of steady-state was assessed primarily by
graphical methods. Mean trough concentrations for E2 in both
treatment groups were highly variable but showed no significant
increasing trend over the study period. The median trough
concentration plots suggested that steady-state was reached for E2
by Day 5 in both treatment groups. Based upon the estimates of t1/2
for E2 obtained in this study (approximately 33 H), steady-state
would be achieved after approximately 9 to 10 days of dosing, a
finding which is consistent with the results of the graphical
analysis. Thus, the pharmacokinetic measurements conducted on Day
14 of treatment should be representative of steady-state. Similar
results were observed for E1 and E1-S although concentrations did
appear to be more variable and to fluctuate more for these two
analytes.
[0175] The pharmacokinetic characteristics were calculated as
surrogates for the evaluation of the efficacy. It could be shown
that multiple doses of 0.75 mg and 1.5 mg E2 gel resulted in
average serum concentrations of about 2.4 ng/dl E2 and 5.3 ng/dl
E2, respectively. These values are of a magnitude, which are
obtained after transdermal patches with a delivery rate of 25 and
50 .mu.g E2 per day and are approved for postmenopausal disorders,
including reduction of hot flashes and osteoporosis. Therefore, it
is predicted that E2 gel will be proven safe and effective for
treatment of menopausal symptoms including reduction of hot flashes
and osteoporosis.
Example 8
[0176] Study of the Safety and Efficacy of Topical E2 Gel Versus
Placebo for Treatment of Vasomotor Symptoms in Postmenopausal
Females. The objectives of this study were to evaluate the safety
and efficacy, and determine the lowest effective dose of E2 gel,
administered as a daily regimen, as compared to that of placebo gel
in the treatment of vasomotor symptoms in postmenopausal women.
Eligible subjects were equally randomized to one of four treatment
arms: E2 gel 0.625/day (0.375 mg estradiol), E2 gel 1.25 g/day
(0.75 mg estradiol), E2 gel 2.5 g/day (1.5 mg estradiol) or
matching placebo gel. Eligible subjects were healthy postmenopausal
women, with an estradiol level <20 pg/mL, who exhibited
.gtoreq.7 moderate to severe hot flushes each day or .gtoreq.60
moderate to severe hot flushes total during 7 days of
screening.
[0177] E2 gel consisted of 0.06% estradiol in a hydroalcoholic gel
formulation supplied in single-dose sachets: E2 gel 0.625 g/day
(0.375 mg/day E2), E2 gel 1.25 g/day (0.75 mg/day E2), or E2 gel
2.5 g/day (1.5 mg/day E2). Daily topical applications of E2 gel was
administered by the subject on the thigh.
[0178] Parameters were evaluated including: hot flush occurrence
rates and severity. Adverse events, safety laboratory tests, vitals
signs, weight, physical examinations, breast examinations, skin
irritation were assessed.
[0179] Results of the primary analyses of the co-primary efficacy
endpoints indicate that the lowest effective dose of E2 gel in the
treatment of vasomotor symptoms in postmenopausal women is E2 gel
2.5 g/day (1.5 mg/day E2). In the E2 gel 2.5 g/day treatment group,
the difference from placebo of 2.7 in mean change from baseline in
the moderate-to-severe hot flush rate at Week 4 was clinically
meaningful (i.e., .gtoreq.2.0), with a complimentary superiority to
placebo in mean change from baseline in daily hot flush mean
severity (placebo -0.6; E2 gel 2.5 g/day, -0.9). The analogous
differences from placebo in daily hot flush rate for the other E2
gel dose groups were not clinically meaningful (E2 gel 0.625 g/day,
0.7; E2 gel 1.25 g/day, 0.0).
TABLE-US-00019 TABLE 11 Daily Moderate-to-Severe Hot Flush Rates:
Mean Change from Baseline.sup.a E2 Gel E2 Gel E2 Gel Placebo 0.625
g/day 1.25 g/day 2.5 g/day Evaluation (N = 42) (N = 41) (N = 39) (N
= 38) Baseline 16.0 .+-. 9.88 12.5 .+-. 5.60 12.3 .+-. 7.26 13.0
.+-. 5.97 (Mean .+-. SD).sup.b Week -1 -5.3 -3.9 -4.7 -5.0 (Placebo
Lead-In) Week 1 -7.3 -5.8 -5.9 -7.5 Week 2 -7.9 -7.5 -7.2 -9.4 Week
3 -8.5 -8.5 -7.4 -10.5 Week 4 -8.5 -9.2 -8.5 -11.2 .sup.aFor Week
-1 through Week 4, means are least squares means derived from the
ANCOVA model with factors for treatment, site, and
treatment-by-site interaction, with baseline hot flush rate as the
covariate. .sup.bUnadjusted means and standard deviations. Baseline
based on the first 7 days of the Screening Period.
[0180] As in the primary efficacy analyses, comparison of treatment
groups with respect to the proportion of subjects with a
.gtoreq.90% reduction in daily moderate-to-severe hot flush rate at
Week 4 indicates effectiveness in the E2 gel 2.5 g/day group (55%
of subjects), while the other E2 gel dose groups performed similar
to placebo (27% to 35%). Furthermore, the median estradiol
concentration at Week 4 for the E2 gel 2.5 g/day dose group (33
pg/mL) is in the low end of the expected therapeutic range, with
the median concentrations falling below the range for the other E2
gel dose groups (E2 gel 0.625 g/day, 12 pg/mL; E2 gel 1.25 g/day,
23 pg/mL).
[0181] Analyses of Efficacy. The primary efficacy evaluation of the
clinical effectiveness of E2 gel 0.625 g/day (0.375 mg E2), E2 gel
1.25 g/day (0.75 mg E2), and E2 gel 2.5 g/day (1.5 mg E2) as
compared to placebo was determined with respect to change from
baseline in daily (moderate-to-severe) hot flush rate at Week 4 and
change from baseline in daily hot flush mean severity at Week 4
evaluated in the ITT LOCF Data Set. The baseline measures used in
these analyses are based on data obtained during the Screening
Period analyses with baseline measures based on data obtained
during the Placebo Lead In Period were not included.
[0182] The primary analysis of change from baseline in daily hot
flush mean severity was based on unadjusted means from the one-way
ANOVA model with treatment as the factor. However, in consideration
of dissimilarity across treatment groups with respect to mean
baseline daily hot flush rates, as well as an apparent
treatment-by-site interaction, the primary analysis of change from
baseline in daily hot flush rate was based on least-squares means
derived from the ANCOVA model with factors for treatment, site, and
treatment-by-site interaction, with baseline hot flush rate as the
covariate. Only these primary analysis results are discussed.
[0183] As secondary efficacy analyses, the analyses of the 2
co-primary endpoints described above were performed on the
Evaluable Subject LOCF Data Set. Additional analyses included the
proportions of subjects who had a .gtoreq.50%, .gtoreq.60%,
.gtoreq.70%, .gtoreq.80%, .gtoreq.90%, .gtoreq.95% or 100%
reduction from baseline in daily moderate-to-severe hot flush rate
at Week 4, conducted for the ITT LOCF and the Evaluable Subject
LOCF Data Sets. For the ITT Data Set, the results of these
proportion analyses are presented in a text table.
[0184] Descriptive analyses of the 2 co-primary endpoints were
performed for the ITT Observed-Case Data Set and the Evaluable
Subject Observed-Case Data Set at Week 1, Week 2, Week 3, and Week
4. Since only 4 subjects discontinued treatment prematurely, the
results of the observed-case analyses on these data sets are nearly
identical to those from the LOCF analyses and are therefore not
discussed explicitly in this report.
[0185] Mean Change from Baseline in Daily Moderate-to-Severe Hot
Flush Rates. Intent-to-Treat Data Set--LOCF Analyses. In the LOCF
analyses of the ITT Data Set, mean reductions from baseline in
daily moderate-to-severe hot flush rates were observed for all four
treatment groups, with a more pronounced reduction observed in the
E2 gel 2.5 g/day dose group (see Table 11a and FIG. 5a).
[0186] A clinically significant difference (i.e., .gtoreq.2.0) was
observed between the E2 gel 2.5 g/day group and placebo in the mean
reduction of daily hot flush rate at Week 4 (difference between
groups=-2.7), while the two lower doses of E2 gel did not show a
clinically meaningful difference from placebo. Therefore, the two
lower E2 gel doses are non-effective and the E2 gel 2.5 g/day dose
is demonstrated to be the lowest effective dose for the treatment
of moderate-to-severe hot flushes.
[0187] FIG. 5A is a graph depicting mean change from baseline in
daily moderate-to-severe hot flush rate after estradiol at various
doses (ITT-LOCF).
TABLE-US-00020 TABLE 11a Mean Change from Baseline in Daily
Moderate-to-Severe Hot Flush Rate (ITT-LOCF) Mean Change from
Baseline E2 Gel E2 Gel E2 Gel Placebo 0.625 g/day 1.25 g/day 2.5
g/day Evaluation (N = 42) (N = 41) (N = 39).sup.b (N = 38).sup.c
Baseline 16.0 .+-. 9.88 12.5 .+-. 5.60 12.3 .+-. 7.26 13.0 .+-.
5.97 (Mean .+-. SD).sup.d Week -1 -5.3 -3.9 -4.7 -5.0 (Placebo
Lead-In) Week 1 -7.3 -5.8 -5.9 -7.5 Week 2 -7.9 -7.5 -7.2 -9.4 Week
3 -8.5 -8.5 -7.4 -10.5 Week 4 -8.5 -9.2 -8.5 -11.2 .sup.aFor Week
-1 through Week 4, means are least squares means derived from the
ANCOVA model with factors for treatment, site, and
treatment-by-site interaction, with baseline hot flush rate as the
covariate. .sup.bThough 40 subjects are in the ITT Bio-E-Gel 1.25
g/day treatment group, Subject 102 is not included in the hot flush
analyses due to intractable baseline data. .sup.cFor the evaluation
at Week 1, N = 37 for the E2 gel 2.5 g/day treatment group since
the hot flush diary for Subject 187 for that week was lost.
.sup.dUnadjusted means and standard deviations. Baseline based on
the first 7 days of the Screening Period.
[0188] Evaluable Subject Dataset--LOCF Analyses. In the LOCF
analyses of the Evaluable Subject Data Set, mean reductions from
baseline in daily moderate-to-severe hot flush rates were observed
for all 4 treatment groups, with a more pronounced reduction
observed in the E2 gel 2.5 g/day dose group (see Table 11b and FIG.
5b). A clinically significant difference (i.e., .gtoreq.2.0) was
observed between the E2 gel 2.5 g/day dose group and placebo in the
mean reduction of daily hot flush rate at Week 4 (difference
between groups=-3.2), while the two lower doses of E2 gel did not
show a clinically meaningful difference from placebo.
[0189] FIG. 5B is a graph depicting mean change from baseline in
daily moderate-to-severe hot flush rate after estradiol at various
doses (Evaluable-LOCF).
TABLE-US-00021 TABLE 11b Mean Change from Baseline in Daily
Moderate-to-Severe Hot Flush Rate (Evaluable-LOCF) Mean Change from
Baseline.sup.a E2 Gel E2 Gel E2 Gel Placebo 0.625 g/day 1.25 g/day
2.5 g/day Evaluation (N = 28) (N = 38) (N = 33) (N = 30) Baseline
15.3 .+-. 9.35 12.3 .+-. 5.11 12.8 .+-. 7.73 13.4 .+-. 5.91 (Mean
.+-. SD).sup.b Week -1 -4.8 -3.7 -5.0 -4.8 (Placebo Lead-In) Week 1
-6.7 -5.9 -6.0 -7.6 Week 2 -7.1 -7.6 -7.3 -9.4 Week 3 -7.9 -8.5
-7.6 -10.6 Week 4 -8.0 -9.1 -9.0 -11.2 .sup.aFor Week -1 through
Week 4, means are least squares means derived from the ANCOVA model
with factors for treatment, site, and treatment-by-site
interaction, with baseline hot flush rate as the covariate.
.sup.bUnadjusted means and standard deviations. Baseline based on
the first 7 days of the Screening Period.
[0190] Proportion of Subjects with .gtoreq.90% or 100% Percent
Reductions in Daily Moderate-to-Severe Hot Flush Rates at Week 4.
Intent-to-Treat Data Set--LOCF Analyses. In the LOCF analyses of
the ITT Data Set, the majority (55%, 21/38) of subjects in the E2
gel 2.5 g/day dose group experienced a .gtoreq.90% reduction in
daily moderate-to-severe hot flush rate at Week 4, compared to
approximately a third of subjects in placebo and the two lower E2
gel dose groups (see Table 11c). Twenty-four percent (24%) of
subjects in the E2 gel 2.5 g/day dose group had a 100% reduction
(i.e., no moderate-to-severe hot flushes) at Week 4.
TABLE-US-00022 TABLE 11c Number and Proportion of Subjects with a
.gtoreq.50% to a 100% Reduction in Daily Moderate-to-Severe Hot
Flush Rates at Week 4 (ITT-LOCF) Number (%) of Subjects E2 Gel E2
Gel E2 Gel Placebo 0.625 g/day 1.25 g/day 2.5 g/day Evaluation (N =
42) (N = 41) (N = 39).sup.a (N = 38) .gtoreq.50% Reduction 32 (76%)
31 (76%) 32 (82%) 33 (87%) .gtoreq.60% Reduction 29 (69%) 29 (71%)
28 (72%) 32 (84%) .gtoreq.70% Reduction 24 (57%) 21 (51%) 23 (59%)
29 (76%) .gtoreq.80% Reduction 19 (45%) 15 (37%) 17 (44%) 24 (63%)
.gtoreq.90% Reduction 13 (31%) 11 (27%) 14 (36%) 21 (55%)
.gtoreq.95% Reduction 8 (19%) 7 (17%) 12 (31%) 19 (50%) 100%
Reduction 4 (10%) 4 (10%) 8 (21%) 9 (24%) .sup.aThough 40 subjects
are in the ITT E2 Gel 1.25 g/day treatment group, Subject 102 is
not included in the hot flush analyses due to intractable baseline
data.
[0191] Mean Change from Baseline Severity of Hot Flushes.
Intent-to-Treat Data Set--LOCF Analyses. In the LOCF analyses of
the ITT Data Set, mean reductions from baseline daily hot flush
mean severity were observed for all four treatment groups, with a
more pronounced reduction observed in the E2 gel 2.5 g/day dose
group, and to a lesser degree, in the E2 gel 1.25 g/day dose group
(see Table 11d and FIG. 5c). The decrease in daily hot flush mean
severity over time in the E2 gel 2.5 g/day dose group is
complimentary to the clinically meaningful difference from placebo
seen at Week 4 in mean reduction of daily hot flush rate.
[0192] FIG. 5C is a graph depicting mean change from baseline in
daily hot flush mean severity after estradiol at various doses
(ITT-LOCF).
TABLE-US-00023 TABLE 11d Mean Change from Baseline in Daily Hot
Flush Mean Severity (ITT-LOCF) Mean Change from Baseline.sup.a E2
Gel E2 Gel E2 Gel Placebo 0.625 g/day 1.25 g/day 2.5 g/day
Evaluation (N = 42) (N = 41) (N = 39).sup.b (N = 38).sup.c Baseline
2.3 .+-. 0.31 2.2 .+-. 0.30 2.3 .+-. 0.33 2.2 .+-. 0.33 (Mean .+-.
SD).sup.d Week -1 -0.2 -0.2 -0.2 -0.1 (Placebo Lead-In) Week 1 -0.5
-0.2 -0.3 -0.3 Week 2 -0.6 -0.3 -0.5 -0.6 Week 3 -0.6 -0.4 -0.6
-0.7 Week 4 -0.6 -0.6 -0.8 -0.9 .sup.aSeverity scale: 1 = mild, 2 =
moderate, 3 = severe. .sup.bThough 40 subjects are in the ITT
Bio-E-Gel 1.25 g/day treatment group, Subject 102 is not included
in the hot flush analyses due to intractable baseline data.
.sup.cFor the evaluation at Week 1, N = 37 for the Bio-E-Gel 2.5
g/day treatment group since the hot flush diary for Subject 187 for
that week was lost. .sup.dUnadjusted means and standard deviations.
Baseline based on the first 7 days of the Screening Period.
[0193] Drug Dose, Drug Concentration, and Relationships to
Response. Estradiol, Estrone, and Estrone Sulfate. Trough serum
samples were obtained prior to dosing on Day 1 and upon study
completion for determination of estradiol, estrone, and estrone
sulfate concentrations. For summarization, all assay results below
the detection limit of 5 pg/mL were set equal to the limit (i.e.,
assigned a value of 5 pg/mL). Trough concentrations of estradiol,
estrone, and estrone sulfate at Day 1 and Week 4 were highly
variable within treatment groups (see Table 11e). In consideration
of the variability and the moderate sample sizes, median values
will be discussed.
[0194] Across all treatment groups, median values at Day 1 for
estradiol (5 pg/mL), estrone (18.5 to 22.0 pg/mL), and the
estradiol-to-estrone ratio (0.29 to 0.42) were consistent with a
postmenopausal profile (see Table 11e). However, note that some
subjects who met the inclusion criterion of <20 pg/mL estradiol
at screening failed to meet this criterion at Day 1. Apart from
variability inherent to the assay, speculative reasons for this are
instability of hormone levels for subjects with menopause onset
within the prior year, hysterectomy without oopherectomy in
subjects <50 years of age, or possible unreported noncompliance
regarding use of an estrogen product during the Screening
Period.
[0195] After therapy with E2 gel, median estradiol, estrone, and
estrone sulfate concentrations at Week 4 showed separation between
treatment groups in accord with E2 gel dose administration (see
Table 11e). The median estradiol values at Week 4 were 12 pg/mL, 23
pg/mL, and 33 pg/mL, respectively, for the E2 gel 0.625 g/day, 1.25
g/day, and 2.5 g/day dose groups.
TABLE-US-00024 TABLE 11e Trough Estradiol, Estrone, and Estrone
Sulfate at Day 1 and Week 4 (ITT) E2 Gel E2 Gel E2 Gel Hormone
Evaluation Placebo 0.625 g/day 1.25 g/day 2.5 g/day E2 (pg/mL) Day
1 (N = 41) (N = 41) (N = 39) (N = 38) Mean .+-. SD 12.2 .+-. 18.5
15.3 .+-. 24.5 10.3 .+-. 13.5 12.3 .+-. 20.3 Median 5 5 5 5 Range
5-110 5-120 5-64 5-110 Week 4 (N = 40) (N = 41) (N = 37) (N = 37)
Mean .+-. SD 11.4 .+-. 15.4 24.1 .+-. 41.6 34.8 .+-. 33.0 46.8 .+-.
44.6 Median 5 12 23 33 Range 5-85 5-240 5-170 5-250 E1 (pg/mL) Day
1 (N = 41) (N = 41) (N = 39) (N = 38) Mean .+-. SD 22.3 .+-. 13.9
29.9 .+-. 28.1 24.3 .+-. 15.8 22.4 .+-. 13.9 Median 19.0 22.0 22.0
18.5 Range 5-65 6-160 5-93 5-67 Week 4 (N = 40) (N = 41) (N = 37)
(N = 36) Mean .+-. SD 21.6 .+-. 15.3 36.3 .+-. 15.7 51.9 .+-. 29.1
72.3 .+-. 43.8 Median 19.5 35.0 44.0 60.5 Range 5-82 5-78 13-130
17-200 E2/E1 Ratio Day 1 (N = 41) (N = 41) (N = 39) (N = 38) Mean
.+-. SD 0.55 .+-. 0.52 0.49 .+-. 0.36 0.43 .+-. 0.29 0.47 .+-. 0.33
Median 0.42 0.31 0.29 0.39 Range 0.2-2.9 0.0-1.6 0.1-1.2 0.2-2.0
Week 4 (N = 40) (N = 41) (N = 37) (N = 36) Mean .+-. SD 0.59 .+-.
0.59 0.55 .+-. 0.56 0.67 .+-. 0.59 0.64 .+-. 0.33 Median 0.37 0.35
0.51 0.54 Range 0.2-3.2 0.2-3.3 0.2-3.8 0.2-1.7 E1-S (pg/mL) Day 1
(N = 41) (N = 41) (N = 39) (N = 38) Mean .+-. SD 532.4 .+-. 350.2
691.0 .+-. 815.5 457.4 .+-. 193.9 523.2 .+-. 443.5 Median 410.0
480.0 430 430.0 Range 150-2100 170-4760 190-940 180-2650 Week 4 (N
= 40) (N = 40) (N = 38) (N = 36) Mean .+-. SD 573 .+-. 616.6 944.4
.+-. 579.1 1562 .+-. 1610 2283 .+-. 1884 Median 400.0 740.0 995.0
1765 Range 110-4020 300-2870 280-8020 330-7040
[0196] Safety Conclusions. Daily application of 0.625-2.5 g E2 gel
(0.375-1.5 mg estradiol) for approximately 4 weeks was safe and
well-tolerated in this population of postmenopausal females. The
overall incidence of treatment-emergent adverse events among the E2
gel groups was not increased with dose level (approximately 50% in
each dose group), and compared well to the incidence in the placebo
group (40%). Adverse events associated with reproductive system and
breast disorders were reported more frequently in the E2 gel groups
(10%, 18%, and 13% in the 0.625 g/day, 1.25 g/day, and 2.5 g/day E2
gel groups, respectively) versus placebo (5%), as would be expected
in this class of drugs. These events reported in 2 or more E2 gel
subjects included: breast tenderness, metrorrhagia (vaginal
spotting), nipple pain, uterine spasm, and vaginal discharge. No
relationship was apparent between the incidence of these events and
E2 gel dose or estradiol level. No subjects discontinued the study
due to these events.
[0197] Breast examination indicated no effect of E2 gel at final
evaluation for all but one subject; the change observed for this
subject (E2 gel 2.5 g/day) corresponded to one of the reported
adverse events of mild breast tenderness, which resolved one week
after final study drug administration.
[0198] No deaths or serious adverse events occurred during the
study. Two (2) subjects (both E2 gel 1.25 g/day) discontinued
double-blind treatment due to an adverse event, only one of which
(dizziness) was considered possibly related; both subjects
recovered.
[0199] No clinically meaningful effects of E2 gel on clinical
laboratory results were observed in analyses of mean change from
baseline to Week 4 evaluations. Comparisons of proportions of
subjects with shifts from normal baselines to abnormal levels at
Week 4 indicated a higher incidence of shifts to above normal
cholesterol levels in E2 gel groups, and an apparent E2 gel
dose-related increased incidence of shifts to above normal BUN
levels; however, only about 10 subjects per group were included in
the cholesterol comparison (since most subjects had above normal
baseline cholesterol levels), and the BUN shifts were not
associated with corresponding shifts in other renal function
indicators or clinical manifestations of renal insufficiency.
[0200] No clinically important effects of E2 gel were observed for
vital signs, body weight, physical examinations, or skin irritation
assessment.
[0201] Conclusion. Transdermal ET delivers estradiol directly into
the systemic circulation via the skin, thus avoiding the first-pass
hepatic metabolism that occurs with oral ET and avoiding the
effects on the hepatobiliary system seen with oral ET. No
statistically significant or clinically meaningful changes noted in
the mean change from baseline to Week 4 evaluation were observed
for any liver function parameters. One subject in the E2 gel 0.625
g/day dose group experienced an increased AST that the investigator
felt was clinically significant; also this subject had an elevated
ALT (44 u/L) at baseline that increased to 70 u/L at final
evaluation. No subjects were observed to have clinically
significant increases in liver function tests in the E2 gel 1.25
g/day or E2 gel 2.5 g/day dose groups.
[0202] Adverse events associated with the topical application of
the study gel were minimal and were more frequently reported in the
E2 gel 1.25 g/day dose group. Dry skin at the application site was
the most frequently reported event associated with the application
of study drug, occurring in two subjects. These events were
considered mild, with the onset greater than 2 weeks on study drug,
and the events lasted no longer than 7 days. Other skin related
events reported included burning or itching at the application
site, occurring in one subject for each event. No
treatment-emergent erythema at application site occurred.
[0203] Oral ET has been shown to produce an increase in the biliary
cholesterol saturation index, and is associated with an increased
risk of gallstones disease; however, this effect does not appear to
be evident in transdermal ET. No subjects in the E2 gel dose groups
were noted to have clinically significant changes in bilirubin
levels, and no adverse events related to increased cholesterol,
bilirubinemia, or gallstones were reported.
[0204] While it was initially thought that the use of transdermal
ET would avoid the increases in serum lipids and lipoproteins seen
with oral ET, studies have shown that changes in serum lipids and
lipoproteins do occur, but with onset and progression that is
slower than with oral ET. In this 4 week study, clinically
meaningful mean changes were not observed in these parameters,
though overall changes would not be expected in just a 4-week
duration of treatment. One subject in the E2 gel 2.5 g/day dose
group had a clinically significant change from baseline in
triglycerides; however, the subject's final laboratory blood draw
was non-fasting. Incidentally, this subject's baseline cholesterol
was 287 mg/dL and LDL was 172 mg/dL.
[0205] The results of this study demonstrate that E2 gel
administered daily in doses of 0.625-2.5 g/day for 4 weeks is safe
and well-tolerated.
[0206] In accordance with the invention, the formulation may be
provided in a kit including the formulations described above, as
well as instructions for use of the same. The kit generally
includes a container that retains the formulation and has a
dispenser for releasing or applying a predetermined dosage or
predetermined volume of the formulation upon demand. The dispenser
can also automatically release the predetermined dosage or volume
of the composition upon activation by the user.
[0207] The kit of the present may include the formulations in a
pouch, tube, bottle, or any other appropriate container. The kit
may include a single doses of the formulation packaged in
individual sachets, such that each day a user opens and applies the
amount of the composition included in the sachet as the dosage of
the active ingredient. The kit may also include multiple doses of
the composition packaged in a container. During use, the subject
may be instructed to dispense a given amount of the composition
from the container for application to the skin (such as a
"dime-sized amount", or the like). Storage of the compositions
according to this invention may be in aluminum tubes at about
25.degree. C. and 60% relative humidity as well as 40.degree. C.
and 75% relative humidity at least for about 6 weeks.
[0208] The container may include a metered dispenser, such that a
known volume or dosage of the formulation is dispensed by the user
at each activation of the dispenser. In one example, the
formulation may be supplied in a metered dose pump bottle. The
formulation provided may be in a concentration such that a certain
weight or volume (such as 0.87 g) may be dispensed from each
depression on the pump, and multiple activations of the pump, such
as three times, may dispense the desired dosage of the formulation
for the application by the subject. In one example, the kit
includes a gel formulation included within a container such as an
Orion metered dose pump bottle. Although containers other than pump
bottle type container may be used, e.g., stick, or roll-on
containers, and the like.
Example 9
[0209] Pilot pharmacokinetic study of an oxybutynin gel formulation
of the present invention in healthy volunteers
[0210] In vivo study was conducted by a qualified investigator to
determine the pharmacokinetics of oxybutynin in healthy human
volunteers. The study was a single-center, multiple-dose,
open-label study during which the following oxybutynin gel
formulation was tested. This gel included oxybutynin free base 3%
w/w, ethanol 96% v/w .about.55% w/w, diethylene glycol monoethyl
ether 2.5 w/w, propylene glycol 20% w/w, hydroxypropylcellulose
(KLUCEL.TM. HF Pharm) 1.5 w/w, butylhydroxytoluene (BHT) 0.05% w/w,
hydrochloric acid HCl q. ad. for pH 7 to 8, and purified water q.
ad. for 100% w/w, and was prepared by dissolving the oxybutynin
free base in the ethanol/propylene glycol/diethylene glycol
monoethyl ether mixture. Purified water was then added and pH
adjusted to the target with hydrochloric acid solution.
Hydroxypropylcellulose was then thoroughly dispersed in the
hydro-alcoholic solution under mechanical stirring at room
temperature at a suitable speed ensuring good homogenization of the
formulation while avoiding lumps formation and air entrapment until
complete swelling. The BHT was added to the ethanol/propylene
glycol/diethylene glycol monoethyl ether mixture.
[0211] This study was planned and performed in accordance with the
Declaration of Helsinki in its version of Somerset West, 1996, and
in accordance with the EU Clinical Trial Directive 2001/20/EC and
relevant guidances ("Note for Guidance on Good Clinical Practice",
CPMP/ICH/135/95 of Jan. 17, 1997; "Note for Guidance on the
Investigation of Bioavailability and Bioequivalence",
CPMP/EWP/QWP/1401/98; "Note for Guidance on modified release oral
and transdermal dosage forms: Section II", CPMP/EWP/280/96).
Treatment consisted in multiple doses of 2.8 g of gel per day
(corresponding to 84 mg oxybutynin per day) administered each
morning for 7 consecutive days. The gel was distributed over a skin
area of 700 cm.sup.2 on the abdomen. 58 non-smoking males and
females (including 25-40 women), aged 18 to 55, white, physically
and mentally healthy as confirmed by an interview, medical history,
clinical examination and having given written informed consent,
enrolled in this study. Summary data on study population are
presented in Table 12 herein. 54 subjects completed the study.
Blood sampling was performed on Day 1 at initiation of the study
(H0), and then on Day 7 (H0+144; H0+146; H0+148; H0+152; H0+156),
Day 8 (H0+160; H0+164; H0+168), Day 9 (H0+192), Day 10 (H0+216),
Day 11 (H0+240) and Day 12 (H0+264). Blood samples were then
processed and analyzed by LC-MS-MS method (LLOQ set to 50 ng/ml).
Criteria considered for evaluation were Pharmacokinetics
(oxybutynin and N-desethyloxybutynin), area under the
concentration-time curve (AUC.sub..tau.), highest concentration
determined in the measuring interval (C.sub.max), and adverse
events and vital signs. Summary results of this study are presented
in Table 13 and in Table 14 herein.
TABLE-US-00025 TABLE 12 Pilot pharmacokinetic study of an
oxybutynin gel formulation of the present invention in healthy
volunteers: demographic data, safety population Body Ethnic Age
weight Height BMI Sex origin Stat. [years] [kg] [cm] [kg/m.sup.2]
female white, N = 58 N 58 58 58 58 and male Mean 36.1 72.9 174.8
23.74 SD 8.3 11.9 9.2 2.38 CV 23.1 16.3 5.3 10.02 Minimum 22 48 156
19.2 Median 34.0 74.0 176.0 24.15 Maximum 52 100 199 27.0 female, N
= 32 white, N = 32 N 32 32 32 32 Mean 34.5 65.4 168.5 22.99 SD 8.9
9.2 6.2 2.54 CV 25.9 14.1 3.7 11.04 Minimum 22 48 156 19.2 Median
31.0 63.0 168.0 22.20 Maximum 51 92 185 27.0 male, N = 26 white, N
= 26 N 26 26 26 26 Mean 38.2 82.2 182.5 24.67 SD 7.2 7.5 5.7 1.82
CV 18.9 9.1 3.1 7.36 Minimum 27 66 176 20.6 Median 37.0 83.0 181.5
25.20 Maximum 52 100 199 26.9
TABLE-US-00026 TABLE 13 Pilot pharmacokinetic study of an
oxybutynin gel formulation of the present invention in healthy
volunteers: summary kinetic variables for oxybutynin Variable
Statistics Results AUC.sub.T N 54 [ng/ml * h] Mean 156.0676 SD
62.7989 GeoM 143.6709 G_CV 44.4 C.sub.av N 54 [ng/ml] Mean 6.5028
SD 2.6166 GeoM 5.9863 G_CV 44.4 C.sub.max N 54 [ng/ml] Mean 9.7444
SD 5.1062 GeoM 8.6067 G_CV 54.7 C.sub.min N 54 [ng/ml] Mean 4.3767
SD 1.8940 GeoM 4.0096 G_CV 44.5 PTF N 54 Mean 0.77 SD 0.31 GeoM
0.71 G_CV 41.7 R N 54 (coefficient Min -1.000 of correlation) Med
-0.994 Max -0.863 t.sub.1/2 N 54 [h] Mean 29.18 SD 8.35 GeoM 28.16
G_CV 26.7 t.sub.max N 54 [h] Mean 6.67 SD 6.20 CV 93.0 Min 0.00 Med
4.00 Max 24.00 T.sub.cav N 54 [h] Mean 10.42 SD 1.69 CV 16.2 Min
7.24 Med 10.27 Max 15.05 AUC: area under the concentration time
curve; C.sub.AV: average steady state concentration; C.sub.max:
highest concentration determined in the measuring interval;
C.sub.min: lowest concentration determined in the measuring
interval; PTF: peak trough fluctuation; t.sub.1/2: half-life;
t.sub.max: time at which Cmax occurs; T.sub.Cav: time period of
concentration being above Cav; N: number of subjects; SD: standard
deviation; GeoM: geometric mean; G_CV: geometric coefficient of
variance (%) of geometric mean.
TABLE-US-00027 TABLE 14 Pilot pharmacokinetic study of an
oxybutynin gel formulation of the present invention in healthy
volunteers: summary kinetic variables for N-Desethyloxybutynin
Variable Statistics Results AUC.sub.T N 54 [ng/ml * h] Mean
157.7218 SD 88.6001 GeoM 137.7699 G_CV 55.3 C.sub.av N 54 [ng/ml]
Mean 6.5717 SD 3.6917 GeoM 5.7404 G_CV 55.3 C.sub.max N 54 [ng/ml]
Mean 8.9495 SD 5.3402 GeoM 7.6858 G_CV 59.2 C.sub.min N 54 [ng/ml]
Mean 4.6255 SD 2.6520 GeoM 4.0281 G_CV 56.0 PTF N 54 Mean 0.64 SD
0.23 GeoM 0.59 G_CV 40.3 R N 54 (coefficient Min -1.000 of
correlation) Med -0.996 Max -0.872 t.sub.1/2 N 54 [h] Mean 31.17 SD
8.42 GeoM 30.11 G_CV 27.0 t.sub.max N 54 [h] Mean 7.97 SD 4.44 Min
0.00 Med 8.00 Max 24.00 T.sub.Cav N 54 [h] Mean 10.79 SD 1.55 Min
6.96 Med 10.63 Max 13.61 AUC: area under the concentration time
curve; C.sub.AV: average steady state concentration; C.sub.max:
highest concentration determined in the measuring interval;
C.sub.min: lowest concentration determined in the measuring
interval; PTF: peak trough fluctuation; t.sub.1/2: half-life;
t.sub.max: time at which Cmax occurs; T.sub.Cav: time period of
concentration being above Cav; N: number of subjects; SD: standard
deviation; GeoM: geometric mean; G_CV: geometric coefficient of
variance (%) of geometric mean.
TABLE-US-00028 TABLE 15 Pilot pharmacokinetic study of an
oxybutynin gel formulation of the present invention in healthy
volunteers: number and percent of subjects (N = 56) reporting
adverse events occurring after 1.sup.st administration Total number
(%) of subjects with AE 28 (50%) Cardiac disorders 0 (0%)
Tachycardia 0 (0%) Eye disorders 3 (5%) Vision blurred 2 (4%) Dry
eye 1 (2%) Eye irritation 0 (0%) Gastrointestinal disorders 10
(18%) Dry mouth 7 (13%) Nausea 3 (5%) Flatulence 2 (4%) Abdominal
distension 1 (2%) Vomiting 1 (2%) Abdominal pain 0 (0%) Abdominal
pain upper 1 (2%) Constipation 1 (2%) General disorders and
administration site conditions 8 (14%) Fatigue 2 (4%) Application
site erythema 1 (2%) Application site pruritus 1 (2%) Application
site anaesthesia 0 (0%) Application site cold feeling 1 (2%)
Application site exfollation 0 (0%) Application site irritation 1
(2%) Asthenia 1 (2%) Non-cardiac chest pain 1 (2%) Pyrexia 1 (2%)
Infections and infestations 4 (7%) Nasopharyngltis 4 (7%) Cystitis
0 (0%) Gastroenteritis 0 (0%) Urinary tract infection 0 (0%)
Injury, poisoning and procedural complications 1 (2%) Skin
laceration 0 (0%) Vessel puncture site paraesthesia 1 (2%)
Metabolism and nutrition disorders 2 (4%) Anorexla 2 (4%)
Musculoskeletal and connective tissue disorders 0 (0%) Myotonia 0
(0%) Nervous system disorders 12 (21%) Headache 11 (20%) Dizziness
1 (2%) Post-traumatic headache 0 (0%) Renal and urinary disorders 1
(2%) Micturition urgency 0 (0%) Pollakluria 1 (2%) Reproductive
system and breast disorders 1 (2%) Breast pain 0 (0%) Menstrual
disorder 0 (0%) Metrorrhagia 1 (2%) Respiratory, thoracic and
mediastinal disorders 2 (4%) Oropharyngeal pain 2 (4%)
[0212] Plasmatic oxybutynin concentration reached a steady state
after 6 repeated doses. The average plasmatic concentration of
oxybutynin was 5.99 ng/ml. C.sub.max was 8.61 ng/ml (geometric
mean). T.sub.max, the time at which the concentration of oxybutynin
(C.sub.max) peaks, occurred about 4 hours (median) after
application. The terminal half-life T.sub.1.2 was 28.16 hours
(geometric mean). See FIG. 6.
[0213] Plasmatic N-desethyloxybutynin concentration reached also
steady state after 6 repeated doses. The average plasmatic
concentration of oxybutynin was 5.74 ng/ml. C.sub.max was 7.69
ng/ml (geometric mean). T.sub.max, the time at which the
concentration of oxybutynin (C.sub.max) peaks, occurred about 8
hours (median) after application. The terminal half-life T.sub.1/2
was 30.11 hours (geometric mean). See FIG. 7.
[0214] The majority of the reported adverse events (AEs) was
classified as related to the study medication itself. The most
often observed AE was dry mouth (13% of subjects), reported as a
common side-effect of oxybutynin. The other common side-effects
were reported infrequently (5% of subjects or less). The observed
skin-tolerability of the treatment was good, with only eight
subjects reporting mild skin reactions. No significant changes in
vital signs, electrocardiogram parameters, physical findings or in
clinical laboratory variables were detected. The results are shown
in Table 15 herein.
[0215] Additional examples of oxybutynin formulations have been
presented in U.S. application Ser. No. 12/614,216 and are expressly
adopted herein by reference thereto.
[0216] Additional examples of formulations of other active agents,
such as selegilline, fentanyl, and buspirone, can be found in U.S.
Pat. No. 7,335,379.
[0217] While the invention has been described and pointed out in
detail with reference to operative embodiments thereof, it will be
understood by those skilled in the art that various changes,
modifications, substitutions, and omissions can be made without
departing from the spirit of the invention. It is intended
therefore, that the invention embrace those equivalents within the
scope of the claims that follow.
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