IE83582B1 - Subsaturated transdermal drug delivery device exhibiting enhanced drug flux - Google Patents
Subsaturated transdermal drug delivery device exhibiting enhanced drug fluxInfo
- Publication number
- IE83582B1 IE83582B1 IE1991/4300A IE430091A IE83582B1 IE 83582 B1 IE83582 B1 IE 83582B1 IE 1991/4300 A IE1991/4300 A IE 1991/4300A IE 430091 A IE430091 A IE 430091A IE 83582 B1 IE83582 B1 IE 83582B1
- Authority
- IE
- Ireland
- Prior art keywords
- drug
- carrier
- reservoir
- skin
- testosterone
- Prior art date
Links
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- 229940079593 drugs Drugs 0.000 title claims description 113
- 230000004907 flux Effects 0.000 title claims description 50
- 229940089114 Drug Delivery Device Drugs 0.000 title description 3
- 230000001747 exhibiting Effects 0.000 title description 2
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- 229960003604 Testosterone Drugs 0.000 claims description 66
- 239000000969 carrier Substances 0.000 claims description 65
- 210000003491 Skin Anatomy 0.000 claims description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
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- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 12
- RJKFOVLPORLFTN-STHVQZNPSA-N Progesterone Natural products O=C(C)[C@@H]1[C@@]2(C)[C@H]([C@H]3[C@@H]([C@]4(C)C(=CC(=O)CC4)CC3)CC2)CC1 RJKFOVLPORLFTN-STHVQZNPSA-N 0.000 claims description 12
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Description
PATENTS ACT, 1992
4300/91
SUBSATURATED TRANSDERMAL DRUG DELIVERY DEVICE
EXHIBITING ENHANCED DRUG FLUX
THERATECH, INC.
83582
S A T D TRAN DE DR DELIVERY
DEVIQE EXHIBITINQ ENHANQED DRQQ FLUX
D i i n
Tgghnigal Field
This invention is in the field of transdermal
drug administration. More particularly it relates to a
device and method that provides the drug at unexpectedly
high flux.
Background
Transdermal drug delivery devices typically
comprise a drug reservoir composed of the drug and a
carrier from which the drug is released by diffusion.
Examples of such devices are described in "Transdermal
Drug Delivery Systems," U.S. Pharmacist, pp. 49-78.
Fick's Law has classically been used to
characterize the drug release kinetics of such
diffusional devices. According to this law the maximum
flux of drug from such a device occurs when the
concentration of drug in the carrier is at saturation.
Correlatively, the art teaches that the maximum flux of
the drug across skin (when the skin is not a rate
controlling barrier to the drug) from a given drug-
carrier combination also occurs when the concentration of
drug in the carrier is at saturation. Since maximum skin
flux is desired with most drugs, diffusional devices have
traditionally been designed to maintain saturation
conditions in the carrier over the dispensing lifetime of
the device.
Applicants have now unexpectedly discovered
that the maximum skin flux from diffusional devices in
which the drug is hydrophobic occurs when the drug is
maintained below saturation in the carrier. This finding
is totally contrary to the conventional wisdom followed
in the transdermal drug device art. Further, applicants
have employed this discovery to permit testosterone to be
delivered across nonscrotal skin at therapeutically
effective levels. As discussed in detail below, the art
teaches that effective transdermal delivery of
testosterone can only be achieved through scrotal skin.
Some prior patents have suggested in passing
that while it is desirable to maintain the concentration
of drug at saturation because maximum flux occurs there
at, that the drug concentration could be below
saturation. See for instance U.S. Pats. Nos. 4,568,343;
4,645,502; 4,816,258; 4,863,738; 4,865,848; and
4,908,027.
maintenance of subsaturation levels of drug throughout
These patents, however, fail to suggest
the dispensing lifetime or that any increase in skin flux
could be achieved with hydrophobic drugs under such
conditions.
Testosterone therapy is currently indicated for
treatment of male hypogonadism, anemia, breast cancer,
and hereditary angioedema. It is also being considered
for treating a variety of other conditions such as male
osteoporosis that appear to be mediated by androgen
deficiency. Traditional modalities for administering
testosterone have included: intramuscular injection of
long-acting testosterone esters such as the enanthate
because testosterone itself is rapidly degraded by the
liver if administered orally; oral administration of
testosterone undecanoate, which provides systemically
available testosterone; and subcutaneous implantation of
fused testosterone pellets.
None of these traditional
modalities provides totally physiological levels or
circadian patterns of testosterone and its active metab-
olites, dihydrotestosterone (DHT) and estradiol (E2).
It is known that steroids, including
testosterone, are absorbed through skin. However, the
permeability to testosterone of skin areas that are
normally used for transdermal delivery (e.g., the neck,
back, chest, arms) is too low to permit delivery of the
amounts of testosterone needed for therapy (typically 5-
mg/day) through a limited area of skin. In this
(Am J Med (1987) 83:471-
) in an article on testosterone delivery for treating
regard, Korenman, S.G., et al.,
hypogonadism concluded "a more permeable skin area with a
much higher absorption rate was required to provide
programmed transdermal delivery to a limited area." This
led Korenman et al. to select scrotal skin--which is
highly permeable to testosterone--as a site for
testosterone delivery. The article further describes a
transscrotal delivery system developed by ALZA
U.S. 4,704,282 describes that system in
It consists of a polymer matrix that contains
Corporation.
detail.
testosterone at subsaturation levels and a fabric
reinforcement incorporated into the matrix that also is a
limited solvent for testosterone. The patent indicates
that a subsaturated matrix is used because a declining
testosterone release rate is desired. The reinforcing
fabric, in addition to providing a structural support
function, is said to act as a secondary reservoir for
testosterone which has the effect of flattening the
release rate profile (see Figure 2 of the patent).
the patent states that permeation enhancers may be
While
present in the matrix, no examples of the use of such
enhancers are described. The patent gives no data on the
skin flux of testosterone provided by its systems.
Example 2 of the patent states that its system may be
applied to nonscrotal skin, particularly the thigh, to
produce "similar results" as when applied to scrotal
skin. This statement is, however, contradicted by the
later Korenman et al. article (which also originates from
ALZA Corporation) which reports that systems applied to
the thigh did not give increased blood levels of
testosterone.
Ahmed, S.R., et al. (J Clin Endocrinol Metab
(1988) 66:546-557) and Findlay, J.C. (J Clin Endocrinol
Metab (1989) 68:369-373) report that the so cmz ALZA
transscrotal system delivers about 3.7 mg/day and
produces low-normal testosterone levels in hypogonadal
men. Such dosages are believed to be somewhat less than
the amount needed to mimic endogenous production (S-10
mg/day).
relatively high level of Sa-reductase, continuous
Furthermore, since scrotal skin has a
transscrotal delivery of testosterone produces levels of
DHT and DHT/testosterone ratios 4- to 5-fold greater than
normal. Such abnormal levels and ratios may give rise to
undesirable side effects.
GB—A—2185l87 refers to transdermal drug delivery
devices having subsaturated systems where the release rate
tends to decrease more rapidly with time when compared with
saturated systems.
EP-A-0267617 describes pharmaceutical compositions
for topical administration with a penetrating—enhancing
vehicle containing a lower alkanol.
_4a_
WO—A—89/12470 describes trahsdermal delivery devices
with subsaturated levels of drug which allegedly
reduces irritation and prevents adhesives losing their
tack.
In sum, the art teaches away from transdermally
administering testosterone through nonscrotal skin
because of the low permeability of such skin to
testosterone. Transscrotal delivery of testosterone is
taught, but such delivery is associated with high DHT and
DHT/testosterone ratio levels and does not provide a
level of testosterone delivery that mimics endogenous
production. Further, scrotal skin is sensitive and
limited in area, which may result in discomfort and poor
patient acceptance of this modality of delivery.
Disclosure of the Invention
As described above, the invention is based on the
discovery that in the case of transdermal administration of
hydrophobic drugs frmn a diffusional device, maximum skin
flux is achieved at concentrations of drug in the carrier
that are below saturation. In some instances the increase in
flux at subsaturation is dramatically higher than at
saturation. The invention thus takes the form of devices for
and methods of administering hydrophobic drugs transdermally
that are based on this finding.
Accordingly, in one aspect, the invention provides a
device for administering by diffusion. a hydrophobic drug
transdermally to a patient for a prolonged period of time of
at least one day, the drug having a solubility in water at
room temperature of less than 50ug/ml and the device
comprising:
(a) a reservoir comprising the drug dissolved in a
carrier, the amount and solubility of the drug in the
carrier defining a condition at the start of the period of
subsaturation that is sufficient to provide a drug skin
flux, over at least 60% of the period, that is at least 25%
greater than the drug skin flux that would be provided if
the carrier were saturated with the drug, and
(b) means for maintaining the reservoir in diffusional
communication with the skin of the patient.
In another aspect, the invention provides the use of a
reservoir which comprises:
a hydrophobic drug having a solubility in water at room
temperature of less than 50ug/ml dissolved in a carrier, the
amount and solubility of the drug in the carrier defining a
condition at the start of a prolonged period of time of at
least one day of subsaturation that is sufficient to provide
a drug skin flux, over at least 60% that is
of the period,
% greater than the drug skin flux that would be provided
if the carrier were saturated with the drug;
for the manufacture of a medicament for administering,
by diffusion, the drug transdermally.
The flux may therefore be increased of a hydrophobic
drug from a reservoir of the drug dissolved in a carrier
that is in drug delivery communication with an area of
unbroken skin of a patient. The concentration of drug in the
carrier is thus below saturation at the start of the period
and is Inaintained. at subsaturation. thereafter for a ‘time
sufficient to provide said increase substantially throughout
the time period.
A device may be provided for administering testosterone
transdermally across an area of unbroken nonscrotal skin at
a flux from 5 to 30 pg/cm2/hr comprising:
(a) a reservoir comprising testosterone dissolved in a
and a the amount and
carrier, skin permeation enhancer,
solubility of testosterone in the carrier defining a
condition of subsaturation that causes enhanced permeation
of testosterone through nonscrotal skin and wherein the
combined permeation enhancement resulting from said
condition of subsaturation and said permeation enhancer
provide said flux; and
(b) means for maintaining the reservoir in diffusional
communication with said area of unbroken nonscrotal skin.
Brief Description of the Drawings
Figures 1 and 2 are graphs of the results of the tests
described in Example 9.
Figures 3 and 4 are bar graphs comparing the
results of the tests described in Example 9 with the
prior art.
Figures 5 and 6 are graphs of the test results
of Example 10.
Figures 7, 8 and 9 are graphs of data described
in Example 10.
Modes for Carrving Out the Invention
The term "drug" as used to describe the
principal active ingredient of the invention device
intends a biologically active compound or mixture of
compounds that has a therapeutic, prophylactic and/or
physiological effect on the wearer of the device.
Examples of the types of drugs that may be used in the
device are antiinflammatory drugs, analgesics,
antiarthritic drugs, antispasmodics, antidepressants,
antipsychotic drugs, tranquilizers, antianxiety drugs,
narcotic antagonists, antiparkinsonism agents,
cholinergic agonists, anticancer drugs, imunosuppressive
agents, antiviral agents, antibiotic agents, appetite
suppressants, antiemetics, anticholinergics,
antihistamines, antimigrane agents, vasodilators,
hormonal agents, contraceptive agents, diuretics,
antihypertensive agents, cardiovascular drugs, and the
like.
As used herein the term "hydrophobic" intends
that the solubility of the drug in water at room
temperature is <50 pg/ml. Specific examples of
hydrophobic drugs are steroids such as estrogens,
progestogens, testosterone, norgestrel, norethindrone
acetate and medroxyprogesterone acetate.
The phrase "prolonged time period" means a
period of at least about one day, usually 1-14 days, more
usually 1-7 days. The term "substantially throughout"
intends at least about 60% of the time period, more
usually at least 80%, and preferably 100% of the period.
The term "skin flux" intends the rate of
transfer of drug across skin as measured by the method of
on r 11 R l (1984) lzlsl).
The units of flux are preferably pg/cmz/hr.
Merritt and Cooper (J
The term "significantly greater" that is used
to characterize the increase in skin flux achieved
through use of the invention will typically denote an
increase in skin flux of at least about 25%, usually 25%
to 400%, and more usually 50% to 200% over the skin flux
provided when the carrier is saturated with the drug.
The term "nonscrotal skin" means human skin
It will
normally denote the skin of relatively hair-free portions
of the body such as the limbs, back, chest, buttocks,
hips, and neck.
excepting the skin of the male human genitalia.
As used here, the term "testosterone therapy"
intends treatment of any indication for which
testosterone is indicated, including, without limitation,
primary, secondary and other male hypogonadal states in
adults and adolescents, anemia, hereditary angioedema,
male contraception, male infertility disorders, post-
surgical recovery, male impotence, hormone replacement in
elderly males, and hypogonadal states associated with
AIDS.
include Klinefelder's Syndrome, viral orchitis, and low
Primary (testicular) hypogonadism disorders
testosterone production caused by trauma, radiation or
chemotherapy, or alcohol abuse. Secondary
(hypothalamic/pituitary) disorders include those
associated with hypothalamic hypogonadism, suprasellar
tumors, and pituitary tumors. Other male hypogonadism
disorders include those associated with aging, systemic
illnesses, stress, and diabetes mellitus.
The phrase "corresponds substantially to
endogenous blood levels produced by healthy young adult
male humans" intends a blood level profile that closely
approximates the circadian rhythm of testosterone
production shown in Figure 7 of the drawings.
The devices of the invention release drug
continuously by diffusion. In this mode, the driving
force is the difference in drug concentration between the
device reservoir and the skin and underlying tissue. The
drug, which is entirely dissolved in the carrier or
vehicle in the case of the present invention, permeates
through the carrier to the skin. The carrier is, of
course, in drug delivery (diffusional) comunication with
the skin--which means that it either contacts the skin
directly or contacts material interposed between the
carrier and the skin that provides a permeation pathway
for the drug and, if present, permeation enhancer, to
migrate from the reservoir to the skin. The interposed
material may be homogeneous, heterogeneous, or be
composed of a multiplicity of distinct layers. In any
event the interposed material is permeable to the drug
and preferably is not a rate-controlling barrier to
diffusion (i.e., it is at least as permeable to the drug,
and, if present, permeation enhancer, as the carrier).
As indicated above, the carrier or vehicle is
permeable to drug. In this regard the diffusion
coefficient of the drug in the carrier will usually be
between 1 x 10-6 and 1 x lO'l2 cm2/sec, more usually
7 and l x l0'l0 The solubility
of the drug in the carrier should be such that sufficient
between 1 x 10' cm;/sec.
drug is contained in the device to provide the required
cumulative dose of drug, which will vary from drug to
drug. At the same time, the solubility should not be so
low as to require the device to be impractically large in
area or thickness. In most instances, the solubility of
drug in the carrier will be in the range of l to 500
mg/ml, more usually 1 to 200 mg/ml (measured at room
temperature). The amount of drug in the carrier will
normally range between 0.001 and 100 mg, more usually
between 1 and 50 mg. The thickness of the reservoir will
usually be about 0.01 to 5 m, more usually 0.03 to 2 m.
The area of the device in drug delivery (diffusional)
contact with the skin will usually be between about 1 and
150 cm2, more usually between S and 40 cm2.
In the case of testosterone, its solubility in
the carrier should be such that sufficient testosterone
is contained in the device to provide the required
cumulative dose of testosterone, which will normally be
in the range of 5 to 10 mg/day. At the same time, the
solubility should not be so low as to require the device
to be impractically large in area or thickness. The
amount of testosterone in the carrier will normally range
between 5 and 50 mg per unit dosage form, more usually
between 10 and 20 mg. The thickness of the reservoir
will usually be about 0.01 to S m, more usually 0.03 to
2 mm.
The carrier may be a solid or semi-solid
polymer that enables the device to be a "solid-state"
device (i.e., no liquid component at room temperature).
Alternatively, the carrier may be in a fluid form (e.g.,
liquid, gel, emulsion, suspension, and be aqueous or
nonaqueous. Examples of fluid carriers that may be used
are alcohols such as ethanol, alcohol-water mixtures, and
low molecular weight polymers such as polyethylene
glycol. Examples of solid polymeric carriers that may be
used in this invention are polyacrylates,
polymethacrylates, silicone polymers, polyalkyloxides,
natural and synthetic rubbers and the dermatologically
acceptable adhesives described in U.S. 3,934,097.
In the case of testosterone, the carrier is
preferably a fluid. Examples of fluid carriers that may
be used are alcohols such as ethanol, alcohol-water
mixtures, and low molecular weight polymers such as
polyethylene glycol. Ethanol is preferred and also
provides permeation enhancement. In the case of ethanol,
the carrier normally constitutes 20% to 70% by volume of
the reservoir, more usually 40% to 60%, and preferably
approximately 50%. Alternatively, the carrier may be a
solid or semisolid matrix suxh as a pressure-sensitive
adhesive.
The concentration of drug in the carrier
will usually be between lO% and 80%, particularly from
% to 80% or between 15% and 60% of saturation
substantially throughout the administration period.
Depending upon the nature of the carrier and other
components of the reservoir (permeation enhancers), the
concentration of drug relative to saturation may decrease
If the
solubility of the drug in the carrier (whether modified
or increase over the administration period.
or not by other components) remains constant over the
period, the concentration relative to saturation will
decrease. On the other hand, if the solubility decreases
(for instance, through delivery of a permeation enhancer
that also increases solubility), then the concentration
relative to saturation will increase.
A permeation enhancer may be administered
concurrently with the drug in order to further increase
the skin flux of drug across the skin. For testosterone,
an enhancer is necessary. The enhancer may also be
contained within the reservoir or be administered from a
separate reservoir underlying or overlying the drug
reservoir. For design simplicity, when Used, the
enhancer will preferably be contained in the drug
reservoir. Aside from the requirements that the enhancer
be compatible with the drug and carrier, there are no
limitations on the enhancers that may be used in the
Examples of enhancers known in the art are
those described in U.S. 3,989,816; 4,316,893;
4,863,970; 4,764,379; 4,537,776; and EPA (Pub. No.) 272,987. A
preferred enhancer for use with testosterone is a mixture
of ethanol (also carrier), glycerol monooleate (GMO) and
(ML). The amounts of each of GMO and ML
in the reservoir will normally be 0.5% to 5% by volume,
invention.
Pats. Nos.
methyl laurate
preferably approximately 2.5%. The amount of ethanol
will be that previously described. The reservoir may
also contain amounts of other materials such as gelling
agents and antiirritants. Glycerin is a preferred
antiirritant and may be present at 5% to 50%, preferably
% to 30% by volume.
irritant is described in U.S.
The use of glycerin as an anti-
4,855,294.
The skin testosterone flux provided by the
invention is about 5 to 30 pg/cm2/hr, and preferably
about 10 to 20 pg/cmz/hr.
skin flux provided by conventional transdermal
In contrast, the testosterone
administration is typically less than 0.5 pg/cmz/hr. The
high skin fluxes realized through the invention are a
result of enhancement due to the subsaturation
concentration of testosterone in the carrier and the
enhancement due to the permeation enhancer.
For treating male hypogonadism it is desired to
provide daily administration in a 24—hr release rate
profile that mimics the endogenous diurnal testosterone
This in turn leads to a circadian
Figure 7 of the drawings
(open circles) shows a representative circadian rhythm of
production pattern.
rhythm in testosterone levels.
testosterone production over a one-day period. As shown,
testosterone levels peak in the early morning hours and
then decline to trough values in the evening.
The device of the invention may be embodied in
various types of structures known in the transdermal drug
delivery art. For instance, the drug reservoir, which is
the most important component of the device, may comprise
a simple matrix of a subsaturated solution of the drug in
the carrier or be in the form of a fibrous body
impregnated with the subsaturated solution of drug in the
carrier. In addition to the reservoir, the device
includes means for maintaining the reservoir in drug-
delivery comunication with the skin. Such means include
a carrier which is also an adhesive, a separate basal
adhesive layer underlying the reservoir, a peripheral
ring of adhesive that is interconnected to the reservoir,
an adhesive overlay for the reservoir, and straps.
Preferably the means is either an adhesive carrier or a
Preferably the
device is in the form of a laminated composite.
separate underlying adhesive layer.
In addition to the reservoir and affixation
means, the device may further include a backing that
overlies the reservoir and protects the reservoir and/or
prevents back—diffusion of drug from the reservoir, one
or more structural layers to provide the device with
appropriate mechanical properties, and/or a release liner
layer that underlies the reservoir and which is removed
prior to use.
These devices may be manufactured by
conventional techniques used in the transdermal drug
delivery device art. For instance the drug and carrier
may be mixed in the desired proportions to form a
homogeneous mix and cast or otherwise applied to a
backing layer, followed by lamination to a release liner
layer. If a separate basal adhesive layer is desired, it
may be cast onto the release liner layer prior to such
lamination. As indicated above, the solubility of drug
in the carrier and the size (thickness of reservoir and
area in drug delivery communication with the skin) are
chosen to maintain subsaturation in the reservoir over
the desired dispensing lifetime of the device and provide
the necessary cumulative dose of drug.
The following examples further illustrate the
invention and its unique characteristics.
In the following examples ig gitrg steady state
transdermal flux across human cadaver skin was determined
using the method of Merritt and Cooper, supra. Unless
otherwise indicated percentages and proportions are by
volume.
Example 1
Formulations of progesterone at varying
concentrations were made by mixing progesterone with the
indicated ingredients and applied to cadaver skin. The
transdermal fluxes for these formulations are reported in
Table 1 below. The meanings of the abbreviations that
appear in the table are: Gly = glycerine; GDO = glycerol
dioleate; ML = methyl laurate; OA = oleic acid; GMO =
glycerol monooleate.
Iahle_l
Progesterone Flux
EtOH/H20/Gly/GDO/ML/OA 75.0 8 2.12 i 0.47
2. so/22.5/1o/2.5/2.5/2.5
EtOH/H20/Gly/GDO/ML/OA so 18 4.51 i 1.37
3. 60/22.5/10/2.5/2.5/2.5
EtOH/H20/Gly/GDO/ML/OA 25 3 5.52 i 1.38
4. so/22.5/1o/2.5/2.5/2.5
EtOH/H20/Gly/GMO/ML/OA 75 8 3.35 i 2.18
. so/22.5/1o/2.5/2.5/2.5
EtOH/H20/Gly/GMO/ML/OA so 18 7.63 i 3.00
. so/22.5/1o/2.5/2.5/2.5
EtOH/H20/Gly/GMO/ML/OA 37.5 5 8.18 i 0.90
7. 60/22.5/10/2.5/2.5/2.5
EtOH/H20/Gly/GM0/ML/OA 25 18 6.37 i 1.88
8. so/22.5/10/2.5/2.5/2.5
EtOH/H20/Gly/GMO/ML/OA 10 3 1.84 1 0.33
* Systems #1 - #8 were gelled by adding 2.5% (w/v)
CarbOpol®1342, pHs were unadjusted (3.2 - 3.5) and
loading doses were 0.075 Nd.
In Table 1, systems 1 and 4 contain progester-
one at saturation.
Systems 1-3 are alike except for
progesterone concentration, and systems 4-8 are alike
.16-
The two sets of
systems are alike except that one (1-3) contains GDO and
the other (4-8) contains GMO. As shown by the flux data
in Table 1, the flux is significantly greater in those
systems (except 8) in which the progesterone is at
subsaturated concentrations (systems 1, 3, 5-7) than when
except for progesterone concentration.
the progesterone is at saturation.
Example 2
Additional progesterone systems were formulated
and tested as in Example 1. The results of these tests
are shown in Table 2 below. Abbreviations are as in
Example 1. Progesterone was present at saturation in
system 1 and below saturation in systems 2-6.
.01 i 1.73
13.03 i 3.35
12.98 3 2.06
.89 1 6.81
13.13 3 1.87
11.13 i 1.98
* Systems were gelled by adding 2.5% (w/V) Carbopol®1342
and the loading doses were 0.075 ml.
As in Example 1, the fluxes of progesterone at
concentrations below saturation were significantly
greater than at saturation.
This Example shows that the phenomenon of
higher drug flux at subsaturation unexpectedly occurs
only with hydrophobic drugs.
Formulations of the hydrophilic drugs
oxybutynin Hcl and mecamylamine Hcl were prepared and
tested as in Examples 1 and 2. Tables 3 and 4 below
report the results of those tests. The formulations of
Table 3 containing oxybutynin HCl at 40 mg/ml were
saturated and the formulations of Table 4 containing 80
mg/ml of mecamylamine Hcl were saturated. All other
systems were at drug concentrations below saturation.
T 1 3
Oxybutyrin Flux
Egggncer Syggggg ggng , gmgzmlz
/53/5/2
EtOH/H20/Gly/GMO 40 4 29.1
12 16.9
6 13.3
5.6
/54/S/1
EtOH/H20/Gly/GMO 40 S 38.8
12 17.5
10.1
8.0
/63/5/2
ECOH/H20/Gly/GMO 40 6 23.9
12 14.8
9 .3
S .2
/64/S/1
EtOH/H20/Gly/GMO 40 6 27.5
15 13.6
6 .4
1.7
:+|+
iolnmm
|+ |+
p (A »- m
H |+
K) m +4 o
H |+
Q ln B) H
The flux data of Tables 3 and 4 indicate that
in each instance the drug release profile was Fickian
with flux decreasing with decreasing concentration below
saturation.
Similar tests were carried out on ointment and
solid matrix systems containing pindolol free base as the
hydrophilic drug. Again, systems exhibited classic
Fickian dependence of flux on drug concentration.
Example 4
Formulations of testosterone at saturation and
below saturation were prepared and tested as in Example
1. The carrier used was EtOH/H20/Gly/GMO/M in a ratio
of so/30/5/2.5/2.5.
in Table 5 below.
The results of these tests are shown
The formulations containing 50 mg/ml
testosterone were saturated, whereas the systems
containing 40 mg/ml and below were subsaturated. The
results are expressed in terms of cumulative permeations
at 24 hr (i.e., yg/cmz) rather than as flux.
>m.mmm
nm.mnn
wm.noa
vm.>om
no.~om
mn.~mm
nn.wmm
mm.vwm
mm.ovm
eH.mnH
mH.mmm
mH.NHN
mm.omn
m«.omm
mm.mn
nH.nmm
Hh.NmN
~m.mmv
mm.>am
>m.no¢
mm.wm~
nn.«
>m.v
vm ¢v.mmH
¢N ve.mmH
ow
mm.vm
eo.m«H
mm.oma
m~.m~a
mw.H~H
vm.mmH
eo.mmH
.mEU\U:. u: «N um EOHUGWEHND m>wumH:fi:o
._EVmc.~_ .05
m manna
am
cam:
cflxm
As shown, the permeation was significantly
greater when the testosterone was present at
subsaturation concentrations. Similar tests were carried
out using the following carrier compositions:
EtOH/H20/Gly/GM0/ML/OA 60/27.5/5/2.5/2.5/2.5
EtOH/H20/Gly/GMO/M - 60/33/S/1/1
EtOH/H20/Gly/GMO/ML - 60/25/S/5/S
ECOH/H20/Gly/GMO/ML - S0/35/5/5/5
EtOH/H20/Gly/GMO/ML/OA 50/37.5/S/2.5/2.5/2.5
In each instance the formulations below
saturation exhibited higher permeations than the
corresponding formulation at saturation.
Ex 1
Estradiol-containing matrices were prepared by
mixing acrylic adhesive (National Starch DurOtaC®1l94),
sorbitan monooleate (Arlacel®80) and estradiol at a ratio
of 80—X/20/X where X is the proportion (wt%) of
estradiol. The cumulative permeation at 24 hr of
estradiol from these matrices were tested as above and
are reported in Table 7 below. The matrix containing 8%
estradiol was saturated; the others were subsaturated.
ov.a ¢~.o vo.m m¢.v mo.m m~.m
om.Ha Hn.m~ mm.o¢ em.vq mm.- nm.mH
Ma wm mm wv we wm
HOAUMHUWW w
MIMANHH
m m m
.D.m
A ao\m:.
cowwmmfiuwm
0>HUmH5E5U
As reported in the table, the maximum
permeation values observed at subsaturation were
approximately three-fold that observed at saturation.
Similar tests were carried out on estradiol-
containing matrices in which sorbitan monolaurate was
substituted for sorbitan monooleate and in ointments
using the carrier EtOH/H20/Gly/GMO/ML - 20/60/5/7.5/7.5.
In these other estradiol formulations, maximum permeation
was observed at estradiol concentrations below
saturation.
Example 7
Estradiol-containing matrices were prepared and
tested as in Example 6 except that these matrices did not
The
cumulative permeations at 24 hr from these matrices are
contain permeation enhancer (sorbitan monooleate).
reported in Table 8 below. The matrix containing 8%
estradiol was saturated; the others were subsaturated.
¢m.a ~«.H oa.~ vo.o n~.o mm.n
mn.m mm.oa am.H~ HH.wa me.ma o~.m
«Ma am an »¢ wo wm
Hoficmuumm »
w manna
m H w
.o.w
A so\m:.
coammmfiuwm
@>«#mH5EDU
Norethindrone acetate-containing matrices were
prepared by mixing a cross-linked acrylic adhesive
(Monsanto, Gelva®737), permeation enhancer (a 50:50 (w/w)
mix of GMO and ML), and norethindrone acetate at a ratio
of 80-X/15/X where X is the proportion of norethindrone
acetate. Fluxes from these matrices were tested as above
and are reported in Table 9 below. The matrix containing
% norethindrone acetate was saturated; all others were
subsaturated.
IEDLQJE
% Norethindrone Acetate
% 8% 10% 15% 30%
Flux
(pg/cm2/hr) 0.44 0.65 0.93 0.46 0.35
the fluxes from the subsaturated
matrices were significantly higher than the flux frontthe
As reported,
matrix that contained the drug at saturation.
Example 9
Five-layer laminated composites of the general
structure described in U.S. Patent No. 4,849,224 were
prepared. The layers of the composite (basal to top)
were as follows:
1. 5 mil thick silicon-coated polyethylene
terephthalate(Tekkote% release liner
2. 1.5 mil thick pressure—sensitive adhesive
(AR MA3l acrylic, Adhesives Research)
. 4 mil thick peel seal disc of
ethylene/vinyl acetate copolymer film
(Bertek®2216)
. 2 mil thick microporous polyethylene film
(Cotran®,ZM4)and a 4-5 mil thick cavity
(5 cm2 surface area) filled with an
ointment composed of 6.06 mg micronized
testosterone, 296.88 mg ethanol, 200.10 mg
water, 38.31 mg glycerin, 5.64 mg GMO,
.27 mg M, 0.61 mg Vitamin E, and
.13 mg Klucel®
. 2 mil thick polyester/ethylene-vinyl
acetate laminate (3M Scotchpak®10l2) film
backing
The release liner and peel seal disc are
removed for application to skin.
of the reservoir was 5 cm2.
The basal surface area
Placebo composites (four each) and the above
composites (four each) were placed on the lower back skin
of three hypogonadal men according to the regimen shown
in Figure 1. Periodic blood samples were taken and
analyzed for testosterone and DHT levels using an
established radioimmunoassay.
Figures 1 and 2 show, respectively, the
testosterone and DHT levels resulting from these tests.
Figure 3 shows a comparison of the testosterone
and DHT blood levels provided by the composite of this
examle and by the ALZA transscrotal system as reported
by Findlay, gppgg. As shown, the blood levels of
testosterone provided by the composite of this example
are significantly higher than those provided by the
transscrotal system. correspondingly, the blood levels
of DHT are significantly lower for the composite of this
example as compared to the transscrotal system.
Figure 4 shows a comparison of the DHT to
testosterone ratios provided by the composite of this
example and the transscrotal system (again, as reported
by Findlay). As shown, the ratio for the composite of
this example is significantly less than the ratio for the
transscrotal system.
Example 10
A laminated composite of the same structure as
that of Example 9 was prepared except that the ointment
composition was: 12.4 mg testosterone, 342.40 mg
ethanol, 123.40 mg water, 311.90 mg glycerin, 19.2 mg
GMO, 19.9 mg ML, 27.7 mg Carbomer®1342 and 10.2 mg 2 N
NaOH. The reservoir cavity surface was 7.5 cm2.
These composites (2 each) were placed on the
lower backs of six hypogonadal men for 24 hr. Blood was
sampled periodically over that period and their
testosterone and DHT levels determined as in Example 9.
Figures 5 and 6 report the results of these tests.
Figures 7, 8 and 9 depict average 24 hr plasma
levels for testosterone, DHT, and E2 in five hypogonadal
subjects following 28 days of continuous transdermal
dosing as described above. Open circles in Figures 7 and
8 depict average testosterone and DHT levels determined
in 12 normal male volunteers. These data demonstrate
that physiological levels and circadian rhythms of
testosterone and its active metabolites can be achieved
and maintained using nonscrotal transdermal delivery
systems according to the present invention.
Claims (16)
1. A device for administering by diffusion a hydrophobic drug transdermally to a patient for a prolonged period of time of at least one day, the drug having a solubility in water at room temperature of less than 50ug/ml and the device comprising: (a) a reservoir comprising the drug dissolved in a carrier, the amount and solubility of the drug in the carrier defining a condition at the start of the period of subsaturation that is sufficient to provide a drug skin flux, over at least 60% of the period, that is at least 25% greater than the drug skin flux that would be provided if the carrier were saturated with the drug; and (b) means for maintaining the reservoir in diffusional communication with the skin of the patient.
2. A device according to claim 1 where the hydrophobic drug is estradiol, progesterone, norethindrone acetate or medroxyprogesterone acetate.
3. A device according to claim 1 wherein the drug is testosterone, the skin is nonscrotal skin, and the drug skin flux substantially throughout the period is from 5 to 30 ug/cmz/hr.
4. A device according to claim 1, 2 or 3 where the reservoir also contains a permeation enhancer.
5. A device according to any preceding claim wherein the prolonged period is from one to fourteen days.
6. A device according to any preceding claim where the solubility of the drug in the carrier is in the range of from 1 to 500 mg/ml.
7. A device according to any preceding claim wherein the concentration of drug in the carrier is from 20% to 80% of the saturation concentration of drug in the carrier substantially throughout the period.
8. A device according to any preceding claim wherein the means is the carrier and the carrier is an adhesive.
9. A device according to any preceding claim wherein the means is a basal adhesive layer underlying the reservoir, an adhesive overlay, or a ring of adhesive that is peripheral to the reservoir and is interconnected to the reservoir.
10. A device according to claim 3 wherein the carrier is a fluid.
11. A device according to claim 10 wherein the carrier is ethanol.
12. A device according to claim 11 wherein the permeation enhancer comprises glycerol monooleate and methyl laurate in combination with the ethanol.
13. A device according to any of claims 3 and 10 and 11 wherein the amount of testosterone in the reservoir is from 5 to 50 mg.
14. A device according to claim 12 or 13 wherein the reservoir contains 5% to 50% by volume glycerin.
15. A device as defined in any preceding claim for use in a method of treatment practised on the human body by therapy.
16. The use of a reservoir which comprises: ya hydrophobic drug having a solubility in water at room temperature of less than 50ug/ml dissolved in a carrier, the amount and solubility of the drug in the carrier defining a condition at the start of a prolonged period of time of at least one day of subsaturation that is sufficient to provide a drug skin flux, over at least 60% of the period, that is 25% greater than the drug skin flux that would be provided if the carrier were saturated with the drug; for the manufacture of a medicament for administering, by diffusion, the drug transdermally. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
USUNITEDSTATESOFAMERICA11/12/19906 | |||
US07/626,685 US5164190A (en) | 1990-12-11 | 1990-12-11 | Subsaturated transdermal drug delivery device exhibiting enhanced drug flux |
US07/652,127 US5152997A (en) | 1990-12-11 | 1991-02-07 | Method and device for transdermally administering testosterone across nonscrotal skin at therapeutically effective levels |
Publications (2)
Publication Number | Publication Date |
---|---|
IE83582B1 true IE83582B1 (en) | |
IE914300A1 IE914300A1 (en) | 1992-06-17 |
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ID=27090229
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE430091A IE914300A1 (en) | 1990-12-11 | 1991-12-10 | Subsaturated transdermal drug delivery device exhibiting¹enhanced drug flux |
Country Status (14)
Country | Link |
---|---|
US (1) | US5152997A (en) |
EP (1) | EP0562041B1 (en) |
JP (3) | JP3068187B2 (en) |
KR (1) | KR100200002B1 (en) |
AT (1) | ATE225166T1 (en) |
AU (1) | AU651165B2 (en) |
CA (1) | CA2098195C (en) |
DE (1) | DE69133123T2 (en) |
DK (1) | DK0562041T3 (en) |
ES (1) | ES2179820T3 (en) |
HK (1) | HK1013803A1 (en) |
IE (1) | IE914300A1 (en) |
PT (1) | PT99751B (en) |
WO (1) | WO1992010231A1 (en) |
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- 1991-12-10 IE IE430091A patent/IE914300A1/en not_active IP Right Cessation
- 1991-12-10 PT PT99751A patent/PT99751B/en not_active IP Right Cessation
- 1991-12-11 DK DK92904175T patent/DK0562041T3/en active
- 1991-12-11 CA CA002098195A patent/CA2098195C/en not_active Expired - Lifetime
- 1991-12-11 AT AT92904175T patent/ATE225166T1/en not_active IP Right Cessation
- 1991-12-11 AU AU91757/91A patent/AU651165B2/en not_active Ceased
- 1991-12-11 WO PCT/US1991/009408 patent/WO1992010231A1/en active IP Right Grant
- 1991-12-11 JP JP4504326A patent/JP3068187B2/en not_active Expired - Lifetime
- 1991-12-11 DE DE69133123T patent/DE69133123T2/en not_active Expired - Lifetime
- 1991-12-11 EP EP92904175A patent/EP0562041B1/en not_active Expired - Lifetime
- 1991-12-11 KR KR1019930701724A patent/KR100200002B1/en not_active IP Right Cessation
- 1991-12-11 ES ES92904175T patent/ES2179820T3/en not_active Expired - Lifetime
-
1998
- 1998-12-24 HK HK98115313A patent/HK1013803A1/en not_active IP Right Cessation
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2000
- 2000-01-13 JP JP2000005099A patent/JP2000153001A/en not_active Withdrawn
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2002
- 2002-02-27 JP JP2002051683A patent/JP2002249425A/en not_active Withdrawn
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