Note: Descriptions are shown in the official language in which they were submitted.
20~ r~
WPCEN~2529CIP.RLH CASE NO. 2529/1
(CIP o~ 2529)
NOVEL SINGLE LAYER TRANsDERMAL DRUG ADMINISTRATION_SY5TEM
BACKGR ~ _OF THE INVENTION
The present invention comprises a transdermal patch
for the a~ministration of drugs percutaneously. In
p~rticular, khe invention is useful for the administration
of the drug albuterol, a B2 adrenergic agonist, which is
useful, among other things, in the tr~atment of asthma by
virtue of its action of inducing bronchodilation.
The practiGality of administering a given drug
percutaneously on a continuous basis depends upon the
concen~ration of drug in the blood that is required ko
provide the de~ired ph~rmacologic e~ect, the degree to
which the skin is permeable to the drug, and the amount of
skin sur~ace ar~a that is available for drug
administration.
The skin surface area which is available for drug
administration, while theoretically being unlimited, is,
for practical rea~ons, typically confined to a range of
from about five square centimeters to about 100 square
centimet~rs. With the available skin surface area ~ixed
within this range, the mattar then narrows as to whether
2~8~
2~29CIP.RLH -2-
sufficient drug will pass through that much skin surface
area to provide the desired therapy. If it will, then it
may not be difficult to effectively administer the drug
percutaneously. I~, however, the inherent permeability of
the skin to the drug is so high or so low that too much or
too little drug will pass through that area of skin, then
the rate of administration of the drug to the skin must be
controll d, or the permeability of the skin to the drug
must be increased, as the case may be, to make
percutaneous administration practical.
The present invention involves a drug delivery
system in which the percutaneous administration of the
astive drug component is enhanced by the presence of a
diffusion enhancer.
Systemically active drugs are conventionally
administered either orally or by injection, with the
primary objective of either mode being to achieve a given
desired blood level o~ drug in circulation over a period
of time.
These prior conventional methods of administering
drugs to patients, however, possess certain shortcomings
resulting in the failure to this goal.
The oral route of drug adminis~ration, for example,
is inadequate for several reasons, even if the drug is
administered to the patient at periodic intervals
according to a well-defined schedule.
2 ~ .3
2529CIP.RLH ~3-
The rate of absorption of drug through thegastrointestinal tract is affected by both the cantents in
the tract and the passage of time as the drug travels
through the small intestine. Therefore, such variables as
whether the drug is administered before or after eating,
and the type and quantity of food eaten, for example, high
or low fat content, or whether the drug is administered
before or after a bowel movement, affect the rate of
absorption of the drug which takes place in the small
intestine.
Additionally, the time of passage of drug through
the small intestine is affected by the rate of peristaltic
contraction, adding further uncerkainty.
Also important is the rate of circulation of blood
to the small intestine, and the fact that many drugs
administered by this route are rendered inactive by
gastric acid and digestive enzymes of the gastrointestinal
tract or liver, where the drug can he metabolixed to an
inactive product.
These factors make it dif~icult to achieve a desired
time course of concentration of drug in the blood.
The most widely-used dosage form of albuterol, an
orally-administered, instant-release (IR~ tahlet, is
administered to a patient every 6 hours. The controlled-
release (CR) albuterol tablet is administered to a patient
every 12 hours.
2 ~8 ~! ~9
2529CIP.RLH -4-
A significant disadvantaye assuciated with the oral
administration o~ albuterol is that orally-administered
albuterol undergoes ex~ensive first pass metabolism,
probably in the gastrointestinal tract, with the result
that the bioavailability o~ th~ drug formulation is
reduced from a potential bioavailability of 100 percent to
as low as 10 percent.
~The most inevitable result of the oral
administration of drugs through the gastrointestinal tract
is that the level of drug in circulation surges to a peak
level at the time the drug is administered, followed by a
decline in drug concentration in the blood and body
compartments. Thus, a plot of a drug in circulation
versus time a~ter the administration of several tablets of
the drug per day will have the appearance of a series of
peaks which may surpass the toxic threshold of the drug,
and valleys which may fall below the critical point needed
to achieve the desired pharmacologic or therapeutic effect
of the drug, rather than a horizontal straight line
indicating a steady-state concentration ~C~) of the drug
in circulation.
The administration of drugs by injection likewise
entails certain disadvantages. For example, very strict
a~epsis must be maintainPd in order to avoid infection of
the blood, the vascular system and the heart. Drug
administration by poor intravenous injection technique may
result in perivascular .injection, when that was not
~,~3S~
252scIP.RLH -5-
intended. The typical result of injection of a drug into
the blood i5 a sudden rise in the blood concentration of
the drug followed by an uncontrollable decline in drug
concentration. Additionally, adminis~ration of drugs by
injection is inconvenient and painful.
Other dosage forms for systemic administration o~
drugs, such as rec~al suppositories and sublingual
lozenges, also produce non-uniform levels of the
therapeutic agent in circulation. These dosage forms
require great patient cooperation and have low patient
acceptability, resulting in decreased patient compliance
with a prescribed drug regimen, which is the most common
failure of drug therapy.
To avoid the problems discussed above, a new branch
of drug delivery has developed in which systemically-
active drugs are administered through the skin or mucosa
o~ a patient. Uncertainties of administration through the
gastrointestinal tract, and the inconvenience of
administration by injection, are decreased or eliminated
by this system of drug administra~ion. The ease of
application, and simplicity of r2moval, of such a drug
delivery system produces a desirable psychological effect
on the patient. This means better patient cooperation,
resulting in more effective therapy. Because a high
concentration of drug never enters the body, problems with
pulse entry (varying ]evels of drug in the patiPnt's
2 ~ 9
2529CIP.RLH -6-
circulation, depending upon the time of drug
administration) are overcome.
Despite thPse advantages of administering
systemically-active drugs through the skin, many problems
exist with prior art devices dPsigned for this purpose.
Many such devices do not provide a continuous
administration of drug to the patient, or a continuous
delivery rate. Also, many such devices are irritating to
the patient's skin or mucosa and/or have limited
application to a relatively narrow group of therapeutic
drugs. Frequently, new application systems must be
designed for drugs which are incompatible with prior art
application systems.
The release of a drug from a topical preparation can
be materially af~ected by the vehicle in which it is
applied. Correct formulation of a topical agent will
ensure that it exerts its maximal activity, while an
incorrect formulation of th.e agent may reduce its
activity-, or even render a potent drug essentially
ineffective.
The primary requirement for topical drug therapy is
that a drug incorporated in a vehicle reach the skin
surface at an adequate rate and in sufficient amounts.
The drugs must then penetrate the outer horny layer of the
skin.
Drug penetration through the skin depends upon
release of the drug ~rom the topical delivery device and
2 (~ 5 ~ 3
2529CIP.RLH -7-
transport of the drug across the skin barrier. In most
cases, the rate-limiting step is skin transport. However,
formulation changes can aff~ct both of these steps.
Transport of drug substances through the skin is
affected by a variety of factors. For diffusion to occur,
the drug must be in solution. Thus, solubility of the
drug in the fluids in and around the epidermal cells is of
great significance.
The polarity of the drug molecules must also be
considered. When hydrated, the stratum corneum contains
approximately 75% water, 20% protein and 5% lipid. During
hydration, water accumulates near the outer surface of the
protein filaments. Polar molecules are believed to pass
through this aqueous layer, while nonpolar molecules
probably dissolve in, and between, the protein filaments.
The oil-water partition coefficient is also
important. If a substance is more soluble in the stratum
corneum than in the vehicle in which it is dissolved, then
transfer to the former will be ~avored~ In vitro and ln
vlvo studies support the postulate that the release of a
drug will be ~acilitated by using vehicles having a low
affinity for the penetrant. Thus, in formulation, care is
necessary to ensure that the benefits of drug solubility
in relation to skin penetration are not reduced by the use
of excipients which have too high an affinity for the
drug.
2529CIP.Rl~ -8-
A ~urther factor which has been shown to influence
drug effectiveness, and which can be manipulated by the
formulator, is the level of hydration of the stratum
corneum. Hydration results from water diffusing from
underlying epidermal layers or from perspiration that
accumulates under an occlusive vehicle. In general,
increasing the moisture content of the stra-tum corneum
increases the rate of passage of all substances which
penetrate the skin.
Researchers working in the art have conducted
studies of the effects of vehicles containing substances
which materially affect skin penetration. A range of
agents has been recorded as having accelerant action, in
particular propylene glycol, suxface active agents,
dimethylsulfoxide, and dimethylacetamide. These
substances, however, have certain drawbacks, including
skin irritation potential. Their use to date has been
limited.
B. Idson, Cosmetics and To~iletries 95, 59 (1980),
has concluded that the factors affecting drug penetration
into the skin and, consequently, in most cases
effectiveness, are complex. The vehicle that provides
ideal conditions for one drug may prove unsatisfactory for
another.
The present invention seeks to overcome prior
problems with the continuous administration of a drug to a
patient, and with the delivery rate of the drug in
~a~j$o~
2s2scIp.RLH ~9-
general, and has been found to wor~ particularly well with
adrenergic agonists, and especially well with albuterol, a
selective ~2 adrenergic agonist.
Another object of this inventi~n is to provide a
device ror the administration of albuterol to a patient in
a reliable and easily-applied device for continuously
administering the drug to the patient in controlled
quantities through the patient's intact skin or mucosa.
Another object of this invention is to provide for
such a drug delivery device which will cause little, if
any, dermal or mucosal irritation to the patient.
Another object of this invention is to provide a
drug delivery device which will be especially useful and
acceptable in pediatric patients and geriatric patients.
A further object of this invention is to provide for
a unitary, non-lamellar, single-layered drug delivery
device.
Yet another ohject of this inverltion is to provide a
druq administration device which will provide a continuous
dosing of the drug to the patient over a 24 hour period.
The transdermal drug administration patches of the
present invention generally provide a cbntinuous
administration of drug to the patient. In addition, these
patches generally cause liLtle or no dermal or mucosal
irritation to the patient. Both of these qualities are
significant advantages of the patches of the present
invention in comparison with many of the transdermal drug
2529CIP.RLH -10-
administration systems known in the art. Many o~ the
prior art devices ~esigned to deliver systemically active
drugs through the skin or mucosa of a patient fail to
provide a continuous administration o~ the drug to the
patient, and/or do not provide a continuous deli~ery rate
of the drug to the patient. Even if a transdermal patch
does administer a particular drug appropriately through
the s~in or mucosa of a patient, the patch will not be a
desirable form of administration for the drug if the patch
is irritating to the patient's skin or mucosa.
Prior to the invention of the transdermal albuterol
patches described herein, researchers working in the field
were unable to successfully deliver albuterol to a patient
by means of a transdermal patch.
The transdermal albuterol patches of the present
invention feature, in addition to the benefits already
described above, a 100% skin bioavailability o~ drug to a
patient, a good margin o~ sa~ety in pediatric and
geriatric patients and ease of administration.
Albuterol administered transdermally thro-lgh a patch
of the invention is useful for actual asthma therapy,
rather than merely for prophylaxis. It is also useful in
both pediatric age groups and geriatric populations, both
of which require simple-to-administer regimens that do not
rely on the responsibility or memory of the patient to
comply with several daily dosage administrations of the
drug, as is often needed with conventional tablets or
2 ~
2529CIP.RLH
capsules of albuterol. Transdermal albutersl therapy
would also be useful after the treatment of an acute
asthma attack to prevent the exacerbation of such an
attack. Clinically, it would also be useful either as a
substitute for intravenous therapy or as an improvement
over oral therapy.
In addition to being convenient, transdermal
albuterol therapy has a significant margin of sa~ety.
Significantly, an on-going therapy, such as with
sustained-release oral formulations, could be interrupted
if the average plasma level of the drug were too high.
Once the patient was stabilized at a lower plasma level of
drug, the transdermal albuterol patch would be beneficial
to maintain consistent plasma levels of albuterol at a
more desirable lower level.
Additionally, albuterol can be used transdermally as
a tocolytic (obstetric) agent. Preterm labor occurs in
approximately 10~ of preqnancies. Commonly, beta-mlmetic
agents are employed for preterm labor. Albuterol is
currently u~ed for preterm labor, with the plasma
albuterol levels needed for uterine relaxation being 8 to
33 nanograms of drug per milliliter. Such levels are
within the range o~ albuterol delivered by the transdermal
albuterol patches of the present invention.
The albuterol patches of the present invention also
have the potential advantage o~ safety cver the
intravenous route of drug administration, and the further
~Q5~
252scIP.RI~I -12-
advantage o~ a more unif~rm dosing of the druy to the
patient in comparison with the oral route of drug
administration, during the sensitive and critical period
during which labor occurs. Such a use of an albuterol
patch o~ the inven~ion may be adjunctive with bed rest and
intravenous and oral agents, or may be primary therapy as
a substitutiQn for intravenous beta-mimetic agents.
~Additionally, a transdermal albuterol patch of the
invention may find usage as an emergency therapy for the
treatment of urticaria (hives).
The usefulness of albuterol as a bronchodilator is
not limited to the txeatment of asthma. Albuterol can
also be used as a bronchodilator in the treatment of
bronchitis, chronic obstructive pulmonary disease and
other obstructive pulmonary diseases.
2529CIP .RLH ~13--
DESCRIPTION C)F THE DRAWINGS
Figure 1 i5 a plot of the ln vitro transfer of
albuterol transdermally through the skin o~ a hairless
mo~se contained in a Franz Diffusion Cell Assembly
(Example l(a)) versus time, showing how various adjuvant
agents affect the flux of albuterol through the mouse
skin. It can be seen that ethanol was the most e~fective
agent when compared with prior art agents, such as Azone
and isopropyl alcohol (IPA).
Figure 2 is the same type o~ plot as Figure 1,
except that the agents tested are normal hydrocarbon
alcohols. It can ~e seen that, in general, agent effect
on albuterol flux increases as the chain length of the
alcohol increases.
Figure 3 is a plot of alhuterol concentrations
versus time followiny albut0rol transdermal patch
dissolution in a Hanson I 5 Dissolution Test Apparatus
(Example l~b)~ showing the ln vitro release of albuterol
from the patches. The error bars repres~nt the standard
deviation of the mean.
o - Represents a single-layer albuterol transdermal
patch (Example 2) (n=3).
- Represents a double-layer albuterol transdermal
patch (Example 3) (n=6)~
~ ~ 5; 8 ~ r~ ~
2529CIP.RLH
Figure 4 is a plot of serum albutexol concentrations
versus time following the intravenous (n=4) (0) (Example
l(d)), and single-layer (n=4) (~) and double-layer (n=3)
(O) transdermal patch (Example l(e)) administration of
albuterol in Rhesus monkeys. The error bars represent the
standard deviation of the mean.
~ ~3 ~
25Z9CIP.RLH 15
__ Y 0~
The present invention comprises a transdermal patch
for the administration of drugs percuta~eously.
The most preferred embodiment of this invention is a
non-laminated monolayer patch for the transdermal
administration of a drug to a patient comprising an
elastomeric matrix material of predetermined thickness and
area;~an active drug ingredient dispersed throughcut the
matrix; and a diffusion enhancer dispersed throughout the
matrix.
Additionally, a suitable plasticizer and/or a
solubilizing agent for the ac~ive ingredient can
conveniently be incorporated into the patch.
Elastomeric Matrix Materials
Suitable elastomeric matrix materials for use in the
patches of the invention comprise the following polymers:
Pol.yethylene,
Polypropylene,
Polyethylene terephthalate,
Polyvinylidene flunride,
Polymethyl methacrylate,
Polyurethane-polyamide copolymer~,
Poly(2-hydroxyethyl methacrylate)
(HE~A-hydrogel),
Polyalkyl acrylate esters ~bioadhesive polymers),
- ~5~
2529CIP.~LH -16-
Polyisobutylene (bioadhesive polymer),
Polydimethylsilicone with resin (bioadhesive polymer), and
Silico~e elastomers.
The patches of the present invention preferably
utilize a silicone elastomer as the matrix. Silicone
elastomers have alternating silicon and oxygen atoms for a
backbone. Double bonds are generally absent in such a
backbone and, therefore, the numerous forms of
stereoisomers ordinarily found in unsaturated hydrocarbon
rubbers do not have counterparts in the silicone rubbers.
An especially useful silicone elastomer for use in the
patches of the invention i5 Silastomer~ X7-3058, available
from Dow Corning, Inc., Midland, Michigan.
Generally, when an amine or an alcohol, such as
albuterol or n-dodecanol, respecti~ely, is incorporated
into certain elastomeric matrix materials, such as
silicone matrix materials, the alcohol will have an
undesirable ef~ect on the cure of such materials, that is,
the ef~ect of preventing the elastomeric matrix materials
~rom becoming or remaining hardened. Thus, the
elastomeric matrix materials would be expected to have a
sticky consistency, or a consistency like that of a
petroleum jelly, and, thus, would not he suitable for use
in a transdermal drug adminiskration patch. Consequently,
it was surprising and unexpected when elastomeric matrix
materials were discovered which would become hardened, and
,f~,~
2529CIP.RLH ~17-
remain in a suitably-hardened sta-te, when albuterol and/or
various alcohol diffusion enhancers, sush as n~dodecanol,
were dispersed therein.
In the most preferred embodiment of the pres~nt
inventi.on, the active drug ingredient is albuterol, most
preferably as the free base.
Diffusion Enhancers
Diffusion enhancers for use in the patches of the
invention are suitably chosen from the group comprising:
Decymethyl Sulphoxide,
Hexylmethyl Sulphoxide,
Trimethyl phosphine oxide,
N,N-Dimethyl-m-toluamide,
Tetrahydrofuryl alcohol,
Dimethyl acetamide,
Propylene glycol,
n-methyl-2-pyrrolidone,
2-pyrolidone,
1-ethyl-2-pyrolidone,
Sodium lauryl phosphate,
Triethanol amine lauryl phosphate,
Poloxamer 231,
Polyo~yethylene 4 lauryl ether,
Poloxamer 182,
Urea,
Isopropyl myristate,
2 ~
2529CIP.RLH -18-
Isopropyl palmitat~,
~u~yrolactone,
Vanillin,
Stearyl alcohol, and
the normal hydrocarbon alcohols.
Preferred diffusion enhancers for use in the patches
o~ the inventi4n are normal hydrocarbon alcohols, with the
most preferable diffusion enhancer being n-dodecanol,
dispersed throughout the elastomeric matrix.
2529CIP.RLII -19-
DETAILED DESCRIPTION OF THE INVENTION
Permeation of Druq throuqh the_Matrix Material
The present invention comprises a transdermal patch
which is suitable, by virtue of the rate-controlling
materials employed therein, for the predetermined
controlled administration of drug to the skin or mucosa of
a mammal over a period of time. The patch of the
invention is applied to the patient's skin or mucosa and
should be in firm contact therewith so as to form a tight
seal. Flow of drug from the patch to the patient's skin
or mucosa is met~red through the matrix material of the
patch in accordance with the laws of diffusion, as
hereinafter discussed, at a predetermined rate. In
operation, drug molecules are continuously removed from
the patch, migrating through the patch to the skin or
mucosa of the patient, where the drug is absorbed and
enters the patient's circulation through the capillary
network.
The rate of passage or permeation o~ druy through
the elastomeric matrix material o~ the pakch is determined
by the diffusive flux of the drug molecules through the
material, as is the case where the material is of a solid
nature in which the dxug molecules can dissolve in, and
flow through, to a dixection of lower chemical potential.
The release rate of the drug can be controlled in
accordanc~ with "Fick's First Law," depending on the
2 ~ tf3
2529CIP.RLH -20-
design of the particular drug transfer mechanism, whichmay vary according to cer~ain variables, such as th~
diffusivity and ~olubility of the drug being employed in
the diffusive medium, and the thickness of the matrix
material of the patch.
The mechanism of action of the diffusion enhancers
described herein may be to increase the diffusivity of
active ingredient through the patch matrix material. This
mechanism of action shall be understood to attach to the
te~m "diffusion enhancer" as used herein.
Elastomeric M~Aat_ix Materials
Pre~erred elastomeric matrix materials for use in
the patches of the invention are the organopolysiloxane
rubbers, commonly known as silicone rubbers. Suitable
silicone rubbers are the conventional heat vulcanizable
(curable) silicone rubbers and the room temperature
vulcanizable silicone rubbers. Room temperature
vulcanizable silicone rubbers will require the use of a
curing agent or catalyst. The most especially preferred
silicone ruhber for use in the patches of the inventlon is
Silastomer~ X7-3058, available ~rom Dow Corning, Inc.
Other room temperature vulcanizable silicone rubbers
suitable for use in the patches of the invention are also
commerclally available.
2529CIP.RLH -21-
A kypical catalyst that will cure silicone rubber at
room temperature i5 stannous 2-ethyl hexoate, which can be
present in a range of from about 0.0625~ to about 0.5%.
Exemplary patents disclosing ~he preparation of
silicone rubbers are U.S. Patent Nos. 2,541,137;
2,723,966; 2,863,846; 2,890,188; 2,927,907; 3,002,951 and
3,035,016.
~Elastomer can be present in the patches of the
invention in an amount ranging from about 25 to about 95
per cent, weight to weight. More preferably, it can be
present in an amount ranging ~rom about 65 to about 90 per
cent, weight to weight.
Catalysts
Catalysts which may be employed to cure the
elastomeric makrix material component of the patches of
the invention include stannous 2-ethyl hexoate and Dow X7-
3075 catalyst ~Dow Corning, Inc.).
Catalyst can be present in the patches in a range of
from about 0.0625~ to about 0.5%, preferably in a range of
~rom about 0.125% to about 0~25%o
Patch 2hickn ss and Area
The thickness of the transdermal patches of the
invention can be manipulated, as described in Examples 2
and 3 below, by any conventional film casting apparatus,
or other suitable apparatus, Although the thickness of
2 ~3 ~
2529CI~.RLH -22-
the patches may vary betw~en about .05 and about 0~5
millimPters; the preferred range o~ thickness is between
about .20 and about .40 millimeters.
The area of the patches of the invention may also
vary, and may be in the range of from about 1 ko about 100
square centimeters, preferably from about 4 to about 16
square centimeters. The patches, which are generally
light~yellow in color, may be square, circular,
rectangular or triangular in shape, or may be of other
shapes. The patches may be cut to an appropriate size and
shape with any sharp instrument, such as a razor blade.
Diff.usion Enhancers
A diffusion enhancer is employed in the patches of
the present invention, with the most preferred diffusion
enhancers being the normal hydrocarbon alcohols of one to
twenty carbon atoms. As the chain length o~ the alcohol
increases, the effectiveness o~ the diffusion enhancer
generally increases up to a point. The most pref~rred
diffusion enhancer for use in the patches of the invention
is n-dodecanol. n-dodecanol can be present in an amount
xanging from about 3 to about 30 per cent, weight to
weight. More preferably, it can be present in an amount
ranging from about 6 to about 15 per cent, weiyht to
weight.
2~0S~
2529CIP.RI~I -23
Plasticizers
Plasticizers are use~ul for increasing the
plasticity of polymers. In a preferred embodiment of the
patch~s of the present invention, a suitable plasticizer
is employed. Preferred plasticizers include diols,
triols, and other polyols. The mos~ preferred plasticizer
is glycerol.
-
Solubilizing Ag_nts
In a preferred embodiment of the patches of thepresent invention, a solubilizing agent for the active
ingredient is employed. Preferred solubilizing agents
include the normal hydrocarbon alcohols, with n-hexanol
being the most preferred solubilizing agent. n~hexanol
can also act as a useXul plasticizer.
Actlve Agents
The most pre~erred patch of the present invention
comprises, out of 100%, Dow Silastomer~ X7-3058:Dow
X7-3059 crosslinking agent (97.86:2.14), 71.81%, w/w;
albuterol, 15.98%, w/w; n-dodecarlol, g.g9~, w/w; glycerol,
1.75%~ w/w; and hexanol, 0.35~, w/w; with a suitable
organotin catalyst, O.lZ5%, w/w ~generally stannous
2-ethyl hexoate).
2529CIP.RLH ~24-
All m~terials used in the patches of the present
invention are dispersed uni~ormly throughout the matrix
material employed therein. This dispersion results ~rom
the use of an elastomeric matrix material.
The amount of active agent incorporated within the
elastomeric matrix material of the patches of the
invention to obtain the desired therapeutic effect will
vary depending upon the desired dosage of the active
agent, the length of time the patch is to remain on the
skin or the body mucosa of the patient and the area and
thickness of the patch. Patient serum concentrations of
the active agent can thus be adjusted hy varying the
concentration of the active agent in the patch, the length
of time the patch is to remain on the skin or body mucosa
of the patient or the patch size.
Because the patches of this invention are designed
to control drug adminiskration for an extended period Oe
time, ideally 24 hours or more, absent toxicity cancerns,
there i5 no crltical upper limit on khe amount of active
agent incorporated into the patches. The lower limit of
the amount of active agent incorporated into the patches
is determined by the fact that ~ufficient amounts of the
agent must remain in the patches to maintain the desired
dosage of the agent for the particular patient being
treated.
In order to achieve a therapeutic effect of
albuterol in a human adult suffering from a condition
2529CIP.RLH -25-
which is treatable with albuterol, the patient serum
concentration of albuterol should be in the range of
between ~bout 2 and about 33 nanograms of albuterol per
milliliter of serum, and most preferably between about 4
and about 8 nanograms per milliliter. From about 4 to
about 8 nanograms of albuterol per milliliter is desirable
for treating bronchoconstriction, and from about 8 to
about~33 nanograms of albuterol per milliliter is
desirable for using albuterol as a tocolytic agent.
The effecti~e rate of release of the active agent
from the patches of the invention to the skin or mucosa of
a patient can be in the range of from about 0.2 to about
~.0 milligrams of active agent per square centimeter of
skin or mucosa per day (mg.cm~2.day~1). A more preferred
range would be from about 0.3 to about 0.85 milligrams of
active agent per square centimeter of skin or mucosa per
day. The exact amount will depend on the desired dosage
o~ the active agent, as well as the condition being
treated.
Those skilled in the art can readily determine the
rate of permeation of active drug ingredient through a
particular matrix material, and through selected
combinations of matrix materials, to be employed in a
patch of the invention. Standard techniques employed for
making such determinations are described in the
Encyclopedia of Polymer Science and Technology, Volumes 5
and 9, Pages 65 to 85 and 795 to 807 (1968), and the
~3~3~
2529CIP.RLH -26-
references cited therein, the disclosures o~ which are
incorporated herein by reference.
Albuterol (nonmicronized or micronized) can be
present in the patches of the invention in an amount
ranging from about 2 tG about 30 per cent, weight to
weight~ More preferably, it can be present in an amount
ranging from about 8 to about 24 per cent, weight to
weight, and most preferably, in an amount ranging from
about 12 to about 20 per cent, weight to weight.
Both nonmicronized and micronized albuterol may be
employed in making the transdermal patches of the
invention. Both types of albuterol work well, and neither
type is pre*erable over the other. However, it may be
easiex to obtain micronized albuterol.
Backinq Members
Various occlusive and non-occlusive, flexible and
non flexible backing members can be used in the patches of
the present invention, if desired.
Suitable backing members for use in the pa~ches o~
the invention include cellophane/ cellulose acetate,
ethylcellulose, plasticized vinylacetate-vinylchloride
copolymers, polyethylene terephthalate, nylon,
polyethylene, polypropylene, polyvinylidenechloride,
paper, cloth, foam and aluminum foil.
~ .3
2529CIP . RLH --27--
Protective R~
To prevent the passage of drug away from the exposed
surface of a patch of the invention prior to its use, the
surfare of the patch generally can be covered with a
protective release film or foil, such as waxed paper.
To enhance the stability of the active compound( 5 )
employed in a patch of the invention, the patch is usually
packaged between hermetically~sealed polyethylene
terephthalate films or aluminum foils under an inert
atmosphere, such as yaseous nitrogen.
A~Plichtion of Patches
The patches of the invention are applied to the skin
of patients. A patch should be in firm contact with the
patient's ~kin, preferably forming a tight seal therewith.
Drug within the patch will then migrate through the patch
to the patient's skin by diffusion. When drug is in
contact with the patient's skin, dxuy molecules which are
continuously being removed from the outer surface of the
patch migrate through, and are absorbed by, the skin,
entering the patient's circulation through the capillary
network. The patch can be applied to any area of the
patient's skin, including the oral mucosa, for example, by
application of the patch to the patient's palate or buccal
mucosa. fn addition, the patches of the invention can be
used to administer drugs to other mucosa of the body, for
~$~
2~29CIP.RI~ -28-
example, by application to the vaginal muco~a, the rectal
mucosa, etc.
Patch Handlin~_and Storaqe
The transdermal patches of the invention should be
stored at con~rolled room temperature, and should be
protected from light. Patches stored under cold
conditions tend to show crystallization on the surface.
This is not obsexved for patches st~red at room
temperature.
In order for an operator who i5 administering a
transdermal patch o~ the invention to a patient
(physician, nurse, etc.) to avoid unwanted exposure to an
active drug ingredient dispersed throughout the matrix of
the patch, gloves should be worn when handling the patch,
and direct contact between the pakch and the operator's
skin should be avoided.
While the various aspects o~ the transdermal patches
of the present invention are described herein with some
particularity, those o~ skill in the art will recognize
numerous modifications and variations which remain within
the spirit of the invention. These modifications and
variations are within the scope of the invention as
described and claimed herein~
2529CIP.RLH -29-
Examples
The examples present~d below describe and illustrate
the methods for the preparation of the transdermal patches
of the present invention, as well as other aspects of the
present invention, and the results achieved thereby, in
further detail. Both an explanation of, and the actual
procedures for, the various aspects of the present
invention are described where appropriate. These examples
are intended to be merely illustrative o~ the present
invention, and not limiting thereof in either scope or
spirit. Those of skill in the art will readily understand
that known variations o~ the conditions and processes of
the preparative procedures described in these examples can
be used to prepare the transdermal pa~ches o~ the present
nventlon .
All patents and publications referred to in the
examples, and throughout the specification, are hereby
incorporated herein by reference, without admission that
such is prior art.
In the examples presented below, both single-layer
(Examples 2 and 4) and double-layer (Example 3) albuterol
patches of the invention designed for once-a-day
application w~re prepared.
In vitro and in VlVG experiments were then conducted
(Example 1) with both the single-layer and double-layer
albuterol patches of the present invention, prepared as
~ 3
252scIp.RLH -30-
described in Examples 2 and 3, respectively, or preparedas otherwise described.
In the preliminary ln vitro experiments (Examples
l(a), l(b) and l(c)), the 1n vitro drug release of single-
layer (Example 2) and double layer (Example 3) transdermal
patch formulations of the invention were monitored via the
permeation of albu~erol from the pa~ches through hairless
mouse skin (Example l(a~) and monkey skin (Example l(c)),
and via the dissolution of albuterol from the patches in
water (Example l(b)).
The ln vivo albuterol absorption, bioavailability,
pharmacokinetics and skin irritation were then monitored
in Rhesus monkeys (Examples l(e) and l(f)). Intravenous
albuterol pharmacokinetics was also followed using a
"crossover design" (a study in which the same animals are
used for each of the dif~erent ln vivo experiments
performed, such as for the application of single-layer
transdermal albuterol patches, the application of double-
layer transdermal albuterol patches, and the intravenous
administrati.on of an albuterol aqueous solution) in the
same monkeys (Examples l(d) and 1(~)).
In these ln VlVo experiments, at different times,
single~layer and double~layer albuterol patches of the
invention, prepared as described in Examples 2 and 3,
respectively, were separately applied to the chest area of
four female Rhesus monkeys, designated #388, ~391, #423
and #430, and an albuterol aqueous solution was separately
~8~
Z529CIP.RLH -31-
injected into the saphenous vein of the same monkeys at
another time, in a "crossover design." Blood samples ~rom
the monkeys were withdrawn at regular intervals after
albuterol patch application or injection and analyzed by
an HPLC method. Skin irritation of the monkeys was also
measured by a Draize Score Test.
Further ln vivo skin irritation and sensitization
tests were then conducted with rabbits ~Example l(g)) and
guinea pigs (Example l(h)), respectively.
Finally, ln vitrQ stability studies were conducted
to study the degradation o~ the transdermal albuterol
patches of the invention over time (Example l(i)).
Earh of the experiments described in examples l(a)-
(f~ was conducted several times with both single-layer and
double-layer transdermal albuterol patches of the
invention. The number of times a particular experiment
was conducted is indicated in each example. For example,
(n=3) m ans that a particular experiment was conducted
three times.
Materials and An1mals
Chemicals and solvents used in the experiments ware
obtained from the following sources: nonmicronized
albuterol from Co. Pharmaceutica, Milanese, Italy;
micronized albuterol from Labochim, Milano, Italy;
methanol, acetonitrile and chloroform from Burdick
Jackson, Muskegon, MI; water from Fisher Scientific
2 ~
2529C~P,RL~I -32-
Company, Fairlawn, NJ; Di (2-ekhylhexyl) phosphate tDEHP),
sodium phosphate monobasic, sodium phosphate dibasic,
bamethane sulfate, glycerol, n-hexanol and n-dodecanol
from Sigma Chemical Company, St. Louis, M0; l-pentane
sulfonic acid sodium salt from Kodak, Rochester, NY; 0.9%
sodium chloride irrigation solution from Travenol
Laboratories, Deerfield, IL; Silaskomer~ X7-3058
elastomeric matrix material, X7-3059 crosslinking agent
and X7-3075 catalyst from Dow Corning, Inc., Midland, MI;
and triethylamine from Aldrich Chemical Company, Inc.,
Milwaukee, WI.
All solvents and chemicals were ACS analytical grade
or HPLC grade.
While nonmicronized albuterol was employed in
Examples l(a)-(f), 2 and 3, micronized albuterol was used
in all of the other examples.
The four female Rhesus monkeys used in the
experiments described hereinbelow (~3~8, #391, #423 and
#430) were Macaca Mulata monkeys which were obtained from
the University of Texas in Austin, Texas.
Generally, the computer programs referred to in the
examples merely provide a simpler and quicker means for
obtaining the answers to the mathematical equations
specified or referred to therein.
2529CIP.RI~ -33-
Summary of Exampl~s, Tables and Fi~ures
The examples, tables and figures which correspond to
the various experiments described in the examples are as
follows:
.
Corresponding Corrcsponding Corre~pondiny
Subject MatterExam~le~s~ Table(~ _ Flqure(s)
(1) Franz CellExample l(a) Table I Fi~ures 1
Experiments and 2
~2) Dia~olutionExample l(b) Table II Figure 3
Experiments
(3) ResidueExample l(c) Table III None
Analysis
Experiments
(4) Intravenous Example~ 1(d) Table~ IV Figure 4
Administration and (f) and VI
o~ Albuterol
(5) Patch Ex~mples l(e) Tables III, Figure 4
Administration and (f) V, VII, XI
o~ Albuterol and XII
(6) Compari~on o~ Examples l(a), Table~ I, II, None
In Vitro Patch (b) and (c) III and IX
Parameter~
(7) Rhe3u~ Monkey Example~ l(c), Table~ VII None
In Vitro- (d) and (f) and VIII
In Vivo Data
Compari~on
(8) Hypothetlcal Example 1() Table~ X None
Human Serum and X~
Albut~rol
Concentrations
(9) Rabbit Skin Example l(g) Table~ XIII, None
Irxitation XIV and XV
Experiments
(10) Guinea Pig Skin Example l(h) Table~ XVI, None
Sen~itization XVII and
Experiment~ XVIII
(11) Patch Stability Ex~nple l(i) Tables XIX, None
Studie~ XX and XXI
2 ~J ~ 8 ~ ~ é~
2529CIP.RLH ~34-
xam~le 1
Example l(a~ - In Vitro Franz Cell Expeximents
(1) Alb terol Transdermal Patches
In these preliminary in vl ro experiments, the in
vitro~ albuterol release of single-layer (Example 2) and
double-layer (Exa~ple 3) transdermal patch formulations of
the invention were monitored via the permeation of
albuterol from the patches through hairless mouse skin to
determine whether or not albuterol would pass through the
mouse skin and, if so, the amount of albuterol which
passed through the mouse skin. These experiments were
repeated several times using both single~layer (n=3) and
double-layer (n~6) transdermal alhuterol patches of the
invention, prepared as described in Examples 2 and 3,
respectively.
An eight w~ek old male hairless mouse (Nu/Nu CD-l,
Charles River, Bloominyton, MA) was s~crificed by spinal
dislocation, and then a rectangular piece of abdominal
skin tissue was carefully li~ted from the mouse and
separated from the adhering ~atty tissue and visceral
m~terial.
The abdominal skin tissue was the~ mounted on a
Franz Diffu~ion Cell Assembly (Vanguard International,
Neptune, NJ~ and clamped between the donor and receptor
compartments thereof, wikh the epithelium portion of the
skin tissue facing the donor compartment.
~Jrj~o ~9
2529CIP.RLH -35-
The temperature of the receptor compartment of the
Franz Dif~usion Cell Assembly was maintained by an
external constant temperature water bath set at 370C. A
receptor solution (7 mL of normal saline solution) present
in the receptor compartment was stirred with a magnetic
stirrer to bath the dermis of the mouse skin tissue,
thereby removing the adhering cell debris.
After two hours of this bathing, the receptor
solution was withdrawn and replaced with 7 mL of fresh
saline solution, which had been previously equilibrated at
37C.
Following this, an approximately 1.38 square centimeter
transdermal patch of the invention, prepared as described
in Example 2 (single-layer) or 3 (double-layer), was
applied to the epidermal side o~ the mouse skin tissue,
which was facing the donor compartment of the Franz
Diffusion Cell Assembly, and the ~oil was removed ~rom the
patch.
After a period o~ 2~ hours, a 300 microliter sample
of the receptor solution was then removed from the
sampling port o~ the apparatus and filtered. The
albuterol concentration of the receptor solution sample
was then determined by the High Performance Liquid
Chromatsgraphy Method (HPLC) described below.
The HPLC system consisted of a 25 cm x 4.6 mm Zorhax
CN column (Zorbax, Dupont, Wilmington, DE) and a mobile
phase consisting of 5% acetonitrile and 95% water with
2529CIP.RL~I -36-
0.005 ~ pentane sulfonic acid, pH 2.5, low W (v/v). The
column temperature was ambient, and the mobile phase was
pumped at a flow rate of 1.0 mL/minute. The detector was
a Kratos SF 770 detector ~Kratos Analytical Instrument~,
Ramsey, NJ). Other parameters were as ~ollows: chart
speed, 0.5 cm/minute; wavelength, 200 nm; sensitivity, 0.6
AUFS; run time, 10 minutes; and injection volume, 40~L.
The resulting chromatographic peak height was
quantitated using the Ingrad Data Analysis System ~G. D.
Searle ~ Co., Skokie, IL), and compared with the standard
calibration curve, to determine the unknown concentration
of albuterol in the receptor solution sample. However,
chromatographic peak heights may be calculated by other
methods known by those of ordinary skill in the art.
The albuterol concentration obtained from the HPLC
analysis was then converted into an amount (that amount o~
albuterol which was released from the transdermal
albuterol patch in the donor compartment of the assembly
and which passed across the mouse skin into the receptor
solution contained in the receptor compartment o~ thP
assembly), by the ~ollowing formula:
amount of = concentration of .~ volume
albuterol albuterol (mg/mL) (7 m~)
2 ~
2529CIP.RLH -37-
Once these experiments were performed three times
each (n-3~ ~or the single-layer, and six times each (n=6)
for the double-layer, transdermal albuterol patches of the
invention, the amounts were then normalized (adjusted to a
1 square centimeter patch by dividing the amount of
albuterol calculated by the exact size of the patch
actually cut) for the exposed surface area of the
transdermal albuterol patch (approximately 1.38 square
centimeters) to calculate the ln vitro hairless mouse
"skin permeation rate constant" ~ln vitro ~release rate
constant") (my.cm~2.day~l).
The resulting "skin permeation rate constant" values
obtained were then averaged separately for the single-
layer (n=3) and double layer (n=6) patches to determine
the mean (average) "skin permeation rate constant." These
values are presented in Table I.
The mean hairless mouse "s~in permeation rate
constant" indicates the average amoun~ o~ albuterol (in
milligrams) which was released ~rom a 1 square centimeter
transdermal albuterol patch across a 1 square centimeter
portion of skin of a hairless mouse during a period of
twenty-four hours (mg.cm~2.day~1). It i5 a transdermal
drug delivery patch parameter which i5 a characterization
of the particular patch, and which can be compared to the
2529CIP~RLH ~38-
same parameter of other transdermal patches to compare the
ability of thQ various patches to deliver a particular
active agent.
Skin permeation of albuterol incorporated into the
patches was a function of the dissolution of albuterol in
the Dow X7-3058 Silastomer~ elastomeric matrix material,
and albuterol solubility and diffusivity in the hairless
mouse skin membranes, especially the stratum corneum.
(2) Alhuterol Solutions
(a) ifferent Adiuvant Aqents
In order to determine the aff~ct of various adjuvant
agents [ethanol (EtOH), Azone, and isopropyl alcohol
(IPA~] on the flux of albuterol through the skin of a
hairless mouse, the same experiments described above in
Example l(a)(1) were conducted, with the exceptions that:
(1~ rather than applying a transdermal albuterol patch to
the epidermal side of the mouse skin tissue, approximately
3 mL o~ an albukerol solution consisting of approximately
10 mg of albuterol per mL o~ normal saline solution
(NEAT I) with or without 50 mg/mL of ad~uvant agent was
added to the donor compartment of the Franz Diffusion Cell
Assembly; (2~ a 300 microliter sample was removed from the
receptor compartment of the assembly (and replac~d with
the equivalent volume of normal saline solution)
periodically over a period of 2, 5, 7 and 24 hours; and
(3) the amounts of albuterol calculated were corrected for
5 ~
2529CIP,RL~ -39
the dilution fac~or (because the original volume of
receptor solution (7 mL) was diluted every time an
additional 300 microliters of normal saline solution was
added) by methods known by those of skill in the art.
The results of these experiments are presented in
Figure 1, and show that ethanol was the most effeckive
adjuvant agent tested.
(b) Different Hvdrocarbon Alcohols
In order to determine th~ affect of various normal
hydrocarbon alcohols [dodecanol, nonyl alcohol, hexanol,
n-propanol, decanol, and ethanol ~EtOH)] on the flux of
albuterol through the skin of a hairless mouse, these
experiments were conducted again, as described in Example
l(a)(2)(a), but using these different normal hydrocarbon
alcohols.
The results of these experiments are presented in
Figure 2, and show that, generally, the effect of the
alcohol on albuterol flux increases as the chai.n length of
the alcohol increases.
~j3~
2529CIP.RLH -40~
Example l(b) = In Vitro Dissolution Experiments
In these preliminary in vitro experiments, the in
vitro drug release of single-layer (Example 2) and double-
layer tExample 3) transdermal patch formulations of the
invention were also monitored, but via the dissolution o~
albuterol from the patches ir, water.
An approximately 8 square centimeter albuterol
transdermal patch, prepared as described in Example 2
(single-layer) or 3 (double-layer), was mounted on the
holder of a Hanso~'s Dissolution Test Apparatus Model
72 RL (Hanson Research, Northridge, California). The
holder of the apparatus was composed of a stainless steel
rod fitted with a circular disc and a metal screw cap.
The screw cap had a 4 square centimeter open circular area
in the center which was exposed to a dissolution medium
consisting of 300 m~ o~ water at 37C being stirred at 50
rpm.
5 mL samples of the dissolution medillm were removed
from the sampling port of the apparatus at periodic time
intervals following the mounting of the patch on the
apparatus (2, 5, 7 and 2~ hours) for a period of twenty-
four hours. Each volume of sample removed was replacPd
with 5 mL o~ water to keep the amount of dissolution
medium constant.
The albuterol concentxation of each of these S mL
samples was then determined by the method similar to that
described in Example l(a).
~ 3
2529CIP.RLH -41~
The albuterol concentrations were then converted
into amounts in the manner similar to that described in
Example l(a) and corrected for the dilution factor, which
was the volume of the dissolution medium (300 mL), also in
the manner described in Example lta).
Once these experiments were performed three times
each (n=3) for the single-layer, and six times each (n=6)
for the double-layer, transdermal albuterol patches, the
amounts calculated for those samples of dissolution medium
removed from the Hanson's apparatus after 24 hours were
normalized in the manner described in Example l(a)(l) for
the exposed surface area of the albuterol patches
(approximately 4 square centimeters) to calculate the in
vitro "dissolution rate constant" (mg.cm~2.day~1).
The resulting "dissolution rate constant" values
obtained were then averaged separately ~or the sin~le-
layer (n=3) and double-layer (n=6) patches to determine
the mean "dissolution rate constant." These values are
presented in Table II.
The "dissolution rate constant" indicates the
average amount of albuterol (ln milligrams) which was
released from a 1 square centimeter transdermal albuterol
patch into the dissolution medium during a period of
twenty-four hours (mg.cm~2.day~l). This is also a
transdermal drug delivery patch parameter which is a
2 ~
2529CIP.RLH ~2-
characterization of the particular patch, and which can be
compared to the same parameter of o~her transderm~l
patches to compare the ability of the various patches to
deliver a particular active agent. It is also used to
predict the amount of active agent which will be released
from a 1 square centimeter patch into the serum of a
pa~ient during a twenty-four hour period, and should
correlate with the data obtained from ln vlVo experiments
employing the same patches.
The time course of albuterol concentrations
following patch dissolution in the Hanson's Dissolution
Test Apparatus is shown in Figure 3. This ~lot of drug
release versus time was nonlinear and biphasic, showing a
buxst effect (rapid drug depletion in the initial phase).
The magnitude of the burst eff~ct was higher in the
single-layer than in the double-layer patch. However, the
amount of albuterol dissolved in the ~issolution medium at
24 hours was similar in both patches (Table II).
Dissolution of albuterol from the patches into the
dissolution medium was a function of the solubility of the
drug, its diffusivity in the Dow X7-3058 Silastomer~
elastomeric matrix material, the solubi].ity and
diffusivity of albuterol .in water, and the resistance of
the aqueous diffusion layer of the patches.
2 ~ O .
2529CIP.RI~ -43-
Exam~le l(c) - In Vitro Patch Residue Analysl Experiments
In these experiments, the albuterol release of
single-layer (Example 2) (n=4) and double-layer
(Example 3) (n=3) transdermal patch formulations oP the
invention were monitored via the permeation of albuterol
from the patches through Rhesus monkey skin to determine
whether or not albuterol would pass from the patch
formulations through tAe monkey skin and, if so, the
amount of albuterol which passed through the monkey skin.
A~ter overnight fasting, each of Rhesus monkeys
#388, #391, #4~3 and #430 was restrained in a chair, and
then its chest area was clipped to remove hair. Chest
skin surfaces were then wiped clean with an isopropyl
alcohol solution.
An approximately 4 square centimeter transdermal
patch of the invention, prepared as described in Example 2
(single-layer) or 3 (double-layer) was then applied to the
chest area of each Rhesus monkey in the manner described
in Example l(a), pressing gently eOr proper adhesion.
(While single--layer patches were applied to each of the
four monkeys, douhle-layer patches were only applied to
Rhesus monkeys #38B, #391 and #4~3. Only one patch was
appliPd to a monkey per experiment.~
The initial albuterol content in each patch had been
estimated from the weight of the patch, the "content
uniformity" (a value obtained by determining the average
~mount of albuterol extracted from similar-sized patches
2 ~ ~ 8 ~
2529CIP.RLH -44-
in the manner described below), and the "percent loading"
~the percent of albuterol initially incorporated into the
patch).
After 24 hours, the transdermal patch was carefully
removed from each monkey, and then separated from its
adhesive backing.
The residual content of albuterol in each patch was
then determined by extracting the patch with 30 mL of
acetone for a period of twenty-four hours, and then
analyzing the extracts by the HPLC method de~cribed above
in Example l(a). From the initial and residual albuterol
content in the patch, the loss of albuterol from the patch
~ab~orbed amount~ and, hence, the Rhesus monkey "skin
permeation rate constant" (~a vitro "release rate
constant" of albuterol from the patch) in milligrams per
square cen~imeter per day (mg.cm~2.day~l) was calculated in
the following manner:
Rhrsus Monkey ~ In Vitro R~l~ase = Amount of ~ Loss of
skin Parmeation R~to of Albuterol Albuterol Albuterol
Con~t~nt ~mg.cm''.day'') Absorbed lrom the Patch
~mg.cm'.day') ~mg.cm'.day') ~mg.cm'.day'')
- Initial Amount Residual Amount
oi Albuterol - o~ Albuterol
in the Patch In the P~tch
~mg.cm'') ~m3.cm'')
The mean values and standard deviations are
presented in Table III.
In conclusion o~ Examples l(a)-(c), the amount of
albuterol relea~ed from the patches of the invention was
s~3
2529CIP.RLH ~45-
dependent on the in vitro technique used, and decreased in
the following manner: pad dissolution > monkey skin
permeation > hairle~s mouse skin permeation. The in vitro
"dissolukion rates" frsm the patches (Example l(b) and
Table II) were faster than th "skin permeation rates" in
hairless mouse (Example l(a) and Table I) and Rhesus
monkey (Example l(c) and Table III). The hairless mouse
"skin permeation rates" were somewhat lower, but
comparable to the Rhesus monkey ~skin permeation rates."
As shown in Tables I and II, the "dissolution rates"
and hairless mouse "skin permeation ra~es" of the single-
layer and double~layer albuterol patches were similar.
However, as shown in Table III, the value of the Rhesus
monkey "skin permeation rate constant" for a double-layer
patch was higher than that ~or a single layer patch.
In the double-layer patch experiment, albuterol
content was monitored only in the layer o~ khe patch which
contained albuterol. It was not monitored in the layer
which contained other formulation componen~s. It is
suspected that albuterol had migrated into the n-dodecanol
layer, as it did into the skin membrane, thPreby depleting
the drug layer at a faster rate.
2 ~
2529CIP.RLH -46-
Example 1 (d) ~ ntravenous Administration~' o~ ~lbuterol
Rhesus monkeys #388, #391, #423, and ~430 were
employed i~ a "crossover design" for the albuterol
intravenous administration and transdermal patch
administration bioavailability experiments described in
Examples l(d)-(f).
From each monkey, a 7 mL blood sample was removed on
the day previous to the day o~ khe albuterol intravenous
administration bioavailability experiment, and then
centrifuged to obtain the serum. The serum was then
stored at -20C until the analysis described in Example
l(f)(1) was performed. Thase serum samples were used to
make blanks and standards (controls).
Following this, the monkeys were fasted overnight,
restrained and settled in chairs be~ore receiving an
intravenous injectiorl o~ albuterol.
An albuterol solution containing 50 mcg of albuterol
per mL of 0.9% sodium chloride was prepared~ This
solution was injected into the saphenous vein o~ each
monkey at a dose of 1 mL/Kg of bodyweight.
A 5 mL blood sample was then taken from each monkey
at 0.00, O.Q8, 0.17, 0.33, 0~75, 1.00, 1.5, 2.00, 3.00,
4.Q0, and 5.00 hours following the albuterol injection.
The serum from each blood sample was separated ~rom other
blood components via centrifugation, and then stored at
2 52 9CIP . RI~ 7 ~
-20OC un~il the analysis described in Example 1~) (1) was
perf ormed .
~t~3
2529CIP.RLH -48-
Example l(e) - "Transdermal Pakch Administra~ion" of
Albuterol to Rhesus Monkevs
Aft~r overnight fasting, on the day of the albuterol
transdermal patch administration for the bioavailability
experiment, the same four Rhesus monkeys described in
Example l(d) above (#388, ~391, #423 and #430) were
restrained in chairs, and then their chest axeas were
clipped to remove hair, avoiding any injury to the skin
tissue. Chest skin surfaces were wiped with an isopropyl
alcohol swab, and then an approximately 4 square
centimeter albuterol transdermal patch of the invention,
prepared as described in Example 2 (single-layer) or 3
(double-layer), was applied tu the chest area of each
monkey in the manner described in Example l(a) for a
period of 24 hours, a~ter which it was removed in the
manner described in Example l(c). (While single-layer
patches were applied to each of the four mo~keys, double-
layer patches were only applied to Rhesus monkeys ~388,
~391 and ~423. Only one patch was applied to a mankey per
experiment.)
A 5 mL blood sample was taken from each monkey at
0.00, 0.5, 1.00, 1.50, 3.00, 5.00, 7.00, 12.00, 24.00,
31.00, and 48.G0 hours post transdermal albuterol patch
application, centrifuged to obtain the serum, and then
stored at ~20C until the analysis described in Example
l(f)(2) was per~`ormed.
2529CIP.RLH -4~-
Monkey skin irritation was evaluated 24 hours post
patch application by a Draize Score technique, as
described ~y J. H. Draize, Assoç. Food Druq__ff., 46-47
( 1959 ) . The maximum possible score in this test is 4,
indicating maximum skin irritation.
The scores obl:ained from this modif ied Draize Score
technique were o or 1 for each of the four monkeys tested,
indicating little or no skin irritation from the
transdermal albuterol patches of the invention.
Moreover, no adverse skin reactions or
sensitizations were seen when the monkeys were monitored
for 7 days post patch application.
2 ~
2529CIP.RLH -50-
Exam~le 1 (f~ - Analysis o~ 5erum SamPles from the
Albuterol "Intravenous A~dministration" and
"Transdermal Patch Administration
Experiments
Serum albuterol and bamethane sulphate, which was
employed as an internal standard, were extracted from each
of the serum samples described in Examples l~d) and (e)
into chloroform to remove polar interfering substances,
and were then reextracted into the aqueous phasa of the
initial extraction to eliminate nonpolax materials, in the
manner described directly below~
In separate clean test tubes, 1.5 mh o~ serum
standard (Example l(d))l serum sample (Examples l(d) and
(e)) and blank (Example l(d)) was separately buf~ered with
150 microliters of a 0~42 M phosphate buffer, pH 7~2.
2ach serum sample was then extracted with 4.5 mL o~
chlorsform containing 0.1 M Di (2-ethylhexyl) phosphate
~DEHP). The chloroform lay~r was separated into clean
screw cap tesk tubes and mixed with 375 microliters of a
0.5 M HCl solution.
The aqueous extracts were then separated by
centrifugation and analyzed by the HPLC-~luorescence
procedure described directly below.
The HPLC system consisted of a Waters Model 590
(Millipore Corporation, Bed~ord, MA) solvent delivery
syst~m equipped wi~h a Waters Model 710 B Wisp auto
J ~
2529CIP.RLH -51-
injector, a Zorbax CN column (Dupont, 6 micron particles,
25 cm x 4.6 mm internal diameter), Kratos (Kratos
Analytical Instruments) Model 970 fluorescence detector
(excitation 225 nm and emission 280 nm), and the Ingrad
Data ~nalysis system (G. D. Searle ~ Co.). The mobile
phase consisted of a mixture o~ 6 parts methanol in 94
parts aqueous solution of 0.005 M pentane sulfonic acid
(pH 2.5). The mobile phase was pumped at a flow rate of
1.0 mL/minute. The injection volume was 100 microliters.
The sensitivity of the m~thud was 2.0 ng/mL.
The resulting chromatographic peak heights were
quantitated using the Ingrad Data Analysis system, and
compared with the standard calibration curve, to determine
the unknown concentration of albuterol in each of the
serum samples. However, chromatographic peak heights may
be calculated by other methods known by those of ordinary
skill in the art.
The standard calibration curve was linear over the
concentration range o~ ~.5 to 200 ng/mL, as evidenced by
the correlation coefficient o~ better than 0.99. The
coefficient of variation associated with low (10 ng/mL)
and high (80 ng/mL) quality control standard solutions
were 4.5 and 3.4 percent, respectivelyO
Pharmacokinetic parameters were then estimated as
d~scribed directly below, by conventional pharmacokinetic
methods well known to those of ordinary skill in the art,
2 ~
2529CIP.RI~I -52-
and described by M. Gibaldi et al., Pharmacokinetics (New
York 1975).
(1) Data Analtrsis of Serum concentration Versus Time
Profiles after "Intravenous Administration" of
Albuterol
serum albu~erol concen~ration time data obtained
after albuterol "intravenous administration" are presented
in Table IV, and were fitted to a two-compartment open
model using 'C strip~ and 'Nonlin' statistical computer
programs, as described by J. G. Wagner, J. Pharm. Sci. 65,
1006-1010 (1976) and C. M. Metzler, Research
Biostatistics, The Upjohn Co., Kalamazoo, MI (1974).
Model parameters were calculated using conventional
pharmacokinetic equations, as described by M. Gibaldi
et al., supra.
As can be seen in Table I~ and Figure 4, albuterol
concentrations a~ter "intravenous Administration" declined
biexponentially. (The initial portion of each o~ the
curves in Figure 4 was attributed to the distribution of
albuterol to different tissues, and the terminal portion
of the curves was attributed to the removal of albuterol
via elimination processes.)
The mean pharmacokinetic parameters obtained via
the 'Nonlin' program are shown in Tahle VI. The mean
"initial half lifell (the amount of time it took for 50~ of
the albuterol to get distributed into different body
~ 3
2529CIP.RLH 53~
comparkments) obtained was 60 0 minutes. T~e mean
"terminal half-life" (the amount of time it took for 50%
of the albuter~l to be eliminated ~rom the body),
"clearance" (Cl) [rate of elimination of albuterol from
the body (in milliliters of "apparent volume of
distribution" per minute per kilogram o~ body weight
(mL.minute~l.Kg~l)), as described by M. Gibaldi et al.,
supra.], and 1'apparent volume of distribution" (a measure
which indicates the extent of the distribution of
albut~rol in the body) obtained from the serum
concentration time data (Table IV and Figure 4) following
the 50 mcg/mL intravenous injection of albuterol were
135.6 + 26.93 minutes, lO.2 + 1.8 mL.minute~l.Kg~l, and
1935.9 + 37.2 mL.Kg l, respectively.
- The mean "terminal half~ e" in monkeys is
comparable ~o that in man, which rang0s ~rom 3 ~o 6 hours
(~rom 180 to 360 minutes). The 1'clearance" value in
monkeys agrees reasonably well with the previously-
reported values of 6-8 mL.minute~l.Kg~l in humans.
Moreover, ~he '1apparent volume of distribution'1 in humans
is Z200 mL.Kg~l, which is similar to that in monkeys.
In summaxy, the pharmacokinetic parameters
determined for the Rhesus monkeys are similar to those
reported for humans.
2529CIP.~LH -54~
(2) Serum Analysis after 7'Transdermal Patch
Adm ni5tration~7 of Albuterol
The serum albuterol concentration time data obtained
after the single-layer (~xample 2) and double-layer
(Example 3) albuterol transdermal patch application
described in Example l(e) to the four Rhesus monkeys is
presented in Table V (single-layer) and Tabl~ XII (double-
layer), and in Figure 4.
Pharmacokinetic parameters were then estimated in
the manner described directly balow, and the mean values
are presented in Table VII.
Following patch application, there was lag time (tL)
of approximately 3 hours before albuterol concentrations
could be detected in the serum (Figure 4). The time
course release o~ albuterol adminis-tered transdermally
through a patch of the i.nvention showed a steady incline
in each of the ~our monkPys tested up to 12 hours
following the patch application. Thereafter, the
"steady state" serum albuterol conoentrations (C~) (the
concenkration of albuterol remaining essentially the same
over time, 50 that a plot of time versus albuterol
concentration would show a horizontal plateau, due to the
equili~rium reached between the rate of al~uterol
absorption and the rate o~ alhutero~ elimination ~rom the
body) were maintained until the transdermal patch was
removed at 24 hours. As shown in Figure 4 and Tables V
and XII, serum drug levels were sustained ~or the 24 hour
2 ~
2529CIP.RLH -55-
period, reaching steady state sometime between 12 and 24
hours. In all o~ the monkeys tes~ed, albuterol
concentrations declined rapidly af~er the patch was
removed, with no measurable albuterol concentration
remaining at 48 hours.
The albuterol "steady-st2te concentrations" (C3R) in
nanograms of albuterol per mL of serum (ng.mL~1) after
transdermal patch administra~ion were calculated by
averaging the mean 12- and 24-hour drug concentrations in
serum.
In vivo "absorption rate constants" (Ko) in
mil.igrams of albuterol absorbed from a 1 square
centimetPr patch over a period of twenty-four hours
(mg.cm-2.day~l) were then calculated assuming an
intravenous in~usion-like input and using the formula:
[Ko = Ca~ Cl]
where Cl is the "clearance" (rate of elimination of the
drug from the body), and is calculated in the manner
described by M. Gibaldi et al., supra~ These values are
presented in Table VII.
"Area under the curve" (AUC~ values [values of the
amount o~ albuterol in the serum at a ~iven point in time
(ng.mL~l.hours)] were then calculated using th~ standard
trapezoidal rule and the following mathematical formula,
as described by M. Gibaldi et al. at PagP 447:
2 ~
2529CIP.RLH ~56-
~rea Under the Curve = (Cl ~ C2) x (t2 ~ ~1)
(AUC) 2
where Cl represents the first concentration, C2 reprPs~nts
the second concentration, Tl represents the first time and
t2 represents the second time, as shown below:
Serum
Conc~ntration
of Albuterol
(ng.mL~l) / ~C
/~ F;l
/ . ~ )--~
1 .1 t2
Time
(Hours~
The re~ulting AUC values were then used to calculate
the "bioavailability" (F) of albuterol administered
transdermally through a single-layer or double~layer patch
o~ the invention. The~e values are presented in Table
VII.
The "skin bioa~ailability" (F) of albuterol
administered transdermally through a single-layer or
double-layer transdermaI patch was calculated using thP
following mathematical equation, and using the dose and
area under the curve (AUC) values obtained following the
intravenous or transdermal administration of albuterol
which are presented in Table XI:
iJ ~3
2529C~P.RLH 57
Skin
Bioavailability
AUC~R DOSEI V
(F) = AUCIv DOSETR
where, TR and IV represent transdermal and intraYenOUS
administration, respectively, and Dose represents the dose
of albuterol given to the Rhesus monkey, either
intravenously (50 mcg of albuterol per Kg of body weight)
or transd~rmally. The "transdermal dosel' was determined
from the Rhesus monkey "skin permeation rate constant"
("in vitro release rate constant"~ presented in Table III.
[The "transdermal dose" is equal to the Rhesus monkey
"~kin permeation rate constant" ("in vitro release rate
constant"~].
The "skin bioavailability" (F) of single-layer
patche~ was calculated to be 115.0 ~ 16 percent ~Table
VII). (The "skin bioavailability" (F) of the dvuble-layer
patches was not calculated.) This shows that, unlike the
oral administration of albuterol, albuterol administered
transdermally throuyh a patch o~ the invention did not
undergo a substan~ial ~irst pass metabolism, and was 100%
bioavailabl~. In ~ddition, tha patches maintained
sustained serum drug levels of albuterol for a 24-hour
period, with insignificant skin irritation.
The in v1vo "absorpti.on rate constant" calculated
for the double-layer patch was higher than that calculated
for the single-layer patch (Table VII). However, this
2529CIP.RI~I -58-
difference was statistically insignificant [p < 0.05,
based on the stud~nt's t-test (a statistical test
employed to determine the difference between 2 means,
which is known by those of skill in the art)~.
The single-layer and double-layer transdermal
albuterol patch formulations were bioe~uivalent in that
their "steady-state concentration" (C33), in v.ivo
"absorption rate constant" (Ko) and "area under the curve"
(AUC) values (Table VII) were not statistically different
(p < .05, based on the student's t-test).
(3) Comparison of In Vitro and In Vivo Data
A summary of the ln vitro parameters of the
albuterol patches of the invention is presented in
Table IX. The hairless mouse "skin permeation rate
constants," n vitro "dissolution rate constants" and
Rhesus monkey "skin permeation rate constants" were
obtained from Tables 1, II and III, respectively.
The ln vitro Rhesus monkey "skin permeation rate
constants" (ln vitro "release rate constants") determined
in Example l(c) (Table III~ were thPn compared with the ln
vivo ~hesus monkey "absorption rate constants" (Ko)
calculated in Example l(f3(2) (Table VII) to determine
whether or not the Rhesus monkey ln vitro data correlated
with the Rhe~us monkey ln vivo data. These numbers are
presented in Table VIII.
2 ~ f~J
25~9CIP.RLH -53~
As can b~ seen in Table VIII, the in v Q Rhesus
monkey "skin permeation rate constant" shows approximately
a 1:1 correlation with the corresponding Rhesus monkey ln
viyo "absorption rate constant."
(4) H~E~thetical Human Serum Albuterol Concentrations
The transdermal albuterol dose calculated in
Example l(f)(2) (Table XI) was extrapolated from a 5-Kg
Rhesus monkey to a 70-Kg human to predict the human serum
albuterol concentrations shown in Table X. Assuming that
the "clearance" (Cl) and ln vivo "absorption rate
constants" (Ko) for albuterol administered transdermally
to monkeys are the same as those f~r humans, these values
were used to predict albuterol concentration in a
hypothetical 70-Kg human.
As shown in Table X, hypothetical albuterol serum
concentrations were in the range of 8-10 ng/mL following
applications o~ an 8 square centimeter single- or double-
layer transdermal albuterol patch. These values compare
reasonably well with those ~11.0 and 11.1 ng/mL) o~tained
from the four-times-a-day instant release (IR) (4 mg) and
the two-times-a-day controlled release (CR) (8 my~
albuterol sulphate tablet formulations in humans, as
reported by R. S. Sykes et al., Bio~harm ~ru~ Dis~o., 9,
551-556 (1988) and M. L. Powell et al., J. Clin.
Pharmacol. 26, 643-646 (1986).
2529CIP.RL~ ~60~
Moreover, due to the increased bioavailability
associated with the transdermal albuterol patches of the
invention (6 mg of albuterol permeated fxom an 8 square
centimeter patch), equivalent serum concentrations can be
achieved with transdermal albuterol patches containing
albuterol amounts of approximately 40 percent of that of
the oral dose [16 mg total from either an instant-release
(IR) tablet (4 mg of albuterol 4 times per day) or a
controlled-release (CR) tablet (8 mg of albuterol 2 times
per day)].
In patients, the once-a day application of a
transdermal albuterol patch of the invention should
provide a similar therapeutic effect. This would also
reduce the "Cmax value" (the maximum concentration of
albuterol in the serum during a given period of time) in
the serum, thereby minimizing side effects.
2~rj~
2529CIP.RLH -61-
Example l(q) - Rabbit Skin Irr~ La~-E~;3~
Rabbit skin irritation experiments were conducted in
order to assess the potential irritant and/or corrosive
effects of the transdermal albuterol patches of the
invention on the skin of rabbits. The rabbit was the
system of choice because rabbits have been used
historically for this type of study. Thus, the data
generated from this study could be compared to that
generated from rahbits for other topical preparations.
Six young adult New Zealand White Rabbits,
designated #7658/Male, ~7661/~ale, #7708/Female,
#7687/Female, ~7689/~emale and #76s2/Male, were obtained
from a SLS and USDA approved supplier. The animals were
maintained under standard laboratory conditions adhering
to AAALAC standards. Animals were acclimatizad for a
min.imum of five days prior to dosin~.
On the day prior to dosing, the fur was clipped ~rom
the dorsal area of the trunk of each rahbit, using a small
animal clipper.
on the day o~ dosing, a transdermal albuterol patch
of the invention, prepared as described in Example 4
(single-layer), was applied to a small area of the exposed
skin on two of the rabbits, and held in plac~ with
nonirritating tape~ A stockinette sleeve was placed over
the trunk of the two rabbits and secured at both ends with
tape to prevent the removal and ingestion of the patches.
~3~
2529CIP.R~ -62-
The rabbits were ob6erved ~or pharmacological signs
of ~oxicity at one and three hours both post patch
application and prior to patch removal (appr~ximately 24
hours post patch application). Following the 24-hour
exposure period, there were no significant signs of
toxicity ko the two rabbits. Thus, the remaining four
rabbits were dosed with a test patch in a similar manner.
The test patch was also removed from these four
rabbits at 24 hours post patch application. The rabbit
test site on each of the six rabbits was examined for
signs of erythema and edema at scoring intervals of 24 and
72 hours post patch removal according to the dermal
irritation grading system presented in Table XIII. If
there was no evidence of dermal irritation at the 72-hour
scoring interval, the study was terminated. If dexmal
irritation persisted at any test site, the observation
period was extended for the a~fec~ed animals (scored on
day 7). Animals re~uiring an extended observation period
remained on test until the irritation wa5 resolved or
permanent injury was evident.
The 24-hour, 72-hour and 7-day erythema and edema
scores ohtained for the six rabbits according to the
dermal irritation system presented in Table XIII are
presented in Tab}e XV.
The 24- and 72 hour erythema and edema scores for
each of the six rabbits were then added together, and the
resulting total was divided by 12 (2 X 6 rabbits) to yield
2529CIP .RLH -63--
the mean Primary Irritation Index (P.I.I.~. The mean
P.I~I. was calcuIated to be 2.83, and wa8 classi~ied
according to ~he standard evaluation criteria presen~ed in
Table XIV.
~$~
2529CIP.~LH -64-
Example l(h) - Guinea Piq Skin Sensitization Tests
Guinea pig s~in sensitization tests were conducted
in order to assess the potential of the transdermal
albuterol patches of the invention to elicit a delayed
contact hypersensitivity response (adverse skin reaction)
in guinea piys after multiple, separate applications of
the patches to the guinea pigs. The guinea pig was the
system of choice because guinea pigs have been used
historically for this type of a study. Thus, the data
generated f~om this study could be compared to that
generated from guinea pigs for other topical preparations.
All transdermal albuterol patches of the invention
employed in these experiments were prepared in the manner
described in Example 4 ~single-layer), were circular in
shape and were approximately 1 centimeter in diameter.
Twenty-seven male Harley derived guinea pigs were
obtained from an SLS and USDA approved supplier. Th~
guinea pig5 were maintained under the standard laboratory
conditions adhering to the AAAI~C standards, and were
acclimati~ed ~or a minimum o~ five days prior to dosing.
Two guin~a pigs were assigned to "Dermal Dose Range
Finding Studies." Fi~teen guinea pigs were assigned to
"Dermal Sensitization Induction Studies," followed by
"Dermal Sensitization Challenge Studies," followed by
"Dermal Sensitization Rechallenge Studies." Five control
guinea pigs were assigned to the "Dermal Sensitization
Challenge Studies," and five control guinea pigs were
3 j ~ r~
2529CIP.~LH -65-
assigned to the "Dermal Sensitization ~echallenge
Studies."
(1) Dermal Dose Ranqe Findinq Studies
On the day prior to the dosiny, the hair was clipped
from the dorsal trunk area of the two guin~a pigs
designated for this study using a small animal clipper.
On the following day, one transdermal albuterol
patch was applied to the exposed skin o~ each animal.
Following this, a sheet of ru~ber dental dam was pulled
taut over the dorsal trunk of each animal to completely
occlude the test site.
Approximately six hours a~ter dosing, the dental dam
and patches were remo~ed from each animal. The test sites
were wiped with gauze moistened with distilled water, and
the animals were returned to their individual cages.
Approximately twenty hours later, residual hair was
removed from the exposure site on each guinea piy using a
commercial depilatory. The depilatory was applied
dixectly to the test sites and surrounding skin on each
animal. Within 15 minutes, the depilatory was removed
using warm running water and tha animals were blot~ed dry
using paper towels. A minimum of two hours a~ter
depilation, the test sites were graded for irritation
according to the following scale:
2529CIP.RLH -66-
Scorin~ Mekhod
o = No Reaction
+ = Slight, Patchy Erythema
1 = Slight, but Confluent or Mod~rate, Patchy Erythema
2 = Modexate Confluent Erythema
3 = Severe Erythema with or without Edema
Re~ults of the 'YDermal Dose Range Finding Studies"
are presented in Table XVI. De~al reaction in the two
guinea pigs was limited to O and + Scores. Thus, the
patches were acceptable for the subsequent studies.
(2) Dermal_Sensitization Induction Studies
on the day prior to dosing, the hair was clipped
from the left flank area of each of the fifteen guinea
pigs designated for these experiments, using a small
animal clipper.
On the followiny day, one kransdermal albuterol
patch was applied to the exposed skin o~ each animal.
Following this, a sheet o~ rubber dental dam was pulled
taut over the left flank area of each animal to completely
occlude the test sites.
Approximately six hours after dosing, the dental dam
and patches were removed from each animal. ~he test sites
were wiped with gauze moistened with distilled water, and
the animals were returned to their individual cages.
2529CIP.RLH -57-
The induction procedur was repeated for each test
animal three times per week, until a to~al of nine
induction applications had been made.
Following each induction procedure, test sites were
scored 24- and 48-hours postdose for dermal irritation
using the scoring method described above.
Following the final induction procedure, the guinea
pigs were left untreated for a period of 14 days.
Results of the "Dermal Sensitization Induction
Studies" are presented in Table XVII. Dermal reaction in
the guinea pigs was limited to O and + scores.
(3) Dermal_Sensitization Challenqe Studies
0~ the day prior to the Dermal S~nsitization
Challenge Studies, the hair was clipped from the posterior
left flank area of the ~i~teen test guinea pigs, and from
the five control guinea pigs, designaked for these
experiments using a small animal clipper.
On the following day, one transdermal albuterol
patch was applied to the exposed virgin skin of each
animal. Following this, a sheet of rubber dental dam was
pulled taut over the posterior left flank arsa of each
animal to completely occlude the test sites.
~ pproximately six hours after dosing, the dental dam
and patches were removed from each animal. The test sites
were wiped with gauze moistened with distilled water and
the animals were returned to their individual cages.
~$~
2529CIP.RLH -68-
Approximately twenty hours later, residual hair was
removed from the exposure site on each animal using the
commercial depilatory described above. The depilatory was
applied directly to the test sites and surrounding skin on
each animal. Within 15 minutes the depilatory was removed
using warm running water, and the animals were blotted dry
using paper towels. A minimum of two hours after
depilation, the test sites were graded for irritation
a~cording to thP scoring method described above.
Results of the "Dermal Sensitizat~ion Challenge
Studies" are presented in Table XVIII. Dermal reaction in
the guinea pigs was limited to O and ~ Scores. Dermal
reaction in control animals was limited to O scores.
~4) Dermal Sensitization Rechallen~e Studies
Dermal Sensitization Rechallenge Studies were nok
conduct~d, because they were determined not to be
necessary.
From these experiments, it was concluded that the
transdermal albuterol patches of the invention ar~ not
contact sensitizers ~do not cause adverse skin reaction as
a result of multiple s~parate applications of the patches~
in guinea pig5.
2529CIP . RLH - 69-
Example 1 ( i ~ - I'ransdermal Albuterol Patch Stability
Studies
Stability studies were conduct d to study the
degradation of the transdermal albuterol patches of the
invention at dif ~erent temperatures (3 n J C, 45C and 55C)
over a period of time (20 and/or 12 weeks) and, thus, to
estimate the shelf lives of these patches.
The content of albuterol in several transdermal
albuterol patches of ths invention, wh.ich were prepared in
the manner described in Example 4 (single-layer), was
analyzed over a period of several weeks (20 and 12) as a
function of loss of albuterol from the patches over time,
which was calculated in the manner described in Example
1 (c) -
(1) Stabilitv Study at 30C
Transdermal alhuterol patches of the invention were
separately wrapped in aluminum foil, and then placed in a
sachet which was lined with polyethylene. The sachet was
placed in a 30C oven. At perivdic intervals over a
period of 20 weeks, sample patches were removed from the
oven, and then removed from the sachet and the aluminum
f~ils.
The patches were then analyzed by the HPLC procedure
described in ~xample l(a).
The results of these experiments showed a 95 to 100
percent recovery of albuterol from patch samples stored at
~5~
2529CIP~RLH -70-
30~c during the period of 20 wee~s. Thus, the transdermal
albuterol patches of the inv~ntion were stable at 30C ~or
the 20-week periodO
(2) Stabilitv Studies at 45C and 55C
Further stability studies were conducted at 45C and
55C in the manner described directly above, with the
exceptions that: (a) 45C and 55C conkrolled-temperatUre
cabinets were used in place of the oven; (b) patch samples
were analyzed over a 12-week p~riod according to the
schedule presented bslow, where "Patch Analysis" indicates
that 3 patches were removed from the controlled~-
temperature cabinet at the corresponding time and
analyzed; and (c) a different HPLC method was used.
Time 45C Experiments _5~ a:hmE~5
0 WeeksPa~,ch Analysis Patch ~nalysis
2 Weeks ~ Patch Analysis
3 WeeksPatch Analysis ----
4 Weeks -~
6 WeeksPatch Analysis Patch Analy~i.s
9 WeeksP~tch Analysis - --
12 WeeksPatch Analysis Patch Analysis
After the sample patches were removed from the ~5C
and 55C controlled-temperature cabinets, and then
separated from the sachet and the aluminum f~ils, they
were then subjected to HPLC analy6is using the HPLC system
described directly below.
2529CIP.~IH -71-
This HPLC system consis~ed of an ~ltex Ultrasphere
ODS, Cl8 (25 cm x ~.6 mm i~d.) 5 micron column (Altex
Corporation, CA), and a mobile phase consisting ~f 1%
triethylamine (~EA) buffer:methanol:acetonitrile (89:7:4).
The column temperature was ambient, and the mobile phase
was pumped at a flow rate o~ 1.0 mL per minute. Other
parameters were as follows: detection, UV 210 nm at 0.2
AUFS; run time, 45 minutes; injection volume, lO0 mcL; and
sample conce~tration, 40 mcg/mL.
Results of the individual stability studies (per
cent recovery of albuterol from patch samples, determined
in the manner described above, and in the manner described
in Example l(c)) are presented in Tables XX (stability
studies at ~5C) and XXI (stability studies at 55C).
The percent of albuterol remaining in each patch
vexsus time data at 45C and 55C was then simultaneously
fitted to a nonlinear curve-~itting SAS computer program,
which is known by those o~ skill in the art.
Following this, the values o~ k~5C, k45C, k55C
and Ea w~re estimated using the SAS computer program,
where k is the "degradation rate constant" and Ea is the
"activation energy." From the value of k25C, shelf-life
(T85%, time required to reach 85~ of the original potency)
was estimated using a nonlinear regression analysis and
the statistical computer program.
The "degradation rate constant," "activation energy"
and 'Ishelf life estimation" values are shown in Table XIX.
O ~i ~
2529CIP.RLH -72-
It appears that the "degradation rate constant" at 55C is
at least three times faster than that at 45~C, and at
least 50 to 60 times faster than that ak 25C. The
activation energy is approximately 25 KCal/mole.
It appears that the patches, when stored at 25C
would maintain 85% of their original potency for 169-182
weeks according to the "Mean Prediction Method," a method
known by those of skill in the art, and for 143-156 weeks
according to the "One Sided 95% Lower Confidence Level
Prediction Method" (95% LCLPM), a method also known by
those of skill in the art. Moreover, according to 95%
LCLPM, it is predicted that future lots of the patches,
when stored at 25C, would maintain ~5% of their original
potency for 143-156 weeks.
In conclusion, from the stability experiments
described above, it was predicted that the transdermal
albuterol patches of the invention would retain a potency
of 85% at ambient temperature over a 2-year period.
2529CIP.RLH -73
Table I
In Vitro Hairless Mouse Skin Perm~ation Rate C~E
(In Vitro Release Rate Constants)
(1) Sinqle-Layer Albu~erol Transdermal Patch !Example 2)
Mean = 0.~0 mg.cm~2.day~l (n-3)
Standard Deviation = 0.02 mg.cm~2.day~l
(2) Double-Laver Albuterol Transdermal Patch (ExamPle 3)
Mean = 0.45 my.cm~2.day 1 (n=6)
Standard Deviation = 0.05 mg.cm~2.day~
.... . . ..
2529CIP.~LH -74
Table I~
In Vitro Albuterol Transdermal Patch
Dissolution Rate Constants
(mg.cm-2.day-l)
(1~ Sinqle~Layer Albuterol Transdermal Patch (Example 2)
Mean = 2.34 mgOcm~2.day 1 (n=3)
Standard Deviation = 0.14 mg.cm~2.day~
(2) Double-Layer Albuterol Transder_al Patch (Example 3
Mean = 2.37 mg.cm~2.day~1 ~n=6)
Standard Deviation = 0.25 mg.cm~2.day~
~ _ , .. ..... .
~ ~}~ 3'~
2529CIP.RLH -75-
'rable III
Transdermal Patch Analysis bePore and after
Application to the Skin of Four Rhesus Monkeys
~#388, #391, #423 and #430)
(1) Sinqle-Layer Albuterol Transdermal Patch ~xample 2)
Amounts_of Albuterol in Transdermal Patch
_ g~ _ Standard Deviation
(1) Initial Amount 6.26 2.30
(mg.cm-2) ~n=4)
~2) Residual Amount 5.50 1098
(mg.cm~2) (n=4)
(3) Rhesus Monkey Skin 0.76 0.28
Permeation Rate (n=4)
Constant
(In vitro Release
Rate Constant)
(mg.cm-2.day-l)
._ _ ~ , .
3~
2529CIP.XLH ~76-
~2) Double-Layer Albuterol_Transdermal Patch_~Example 3)
Amounts~of Albuterol in Transdermal Patch
MeanStandard Deviation
~ . _ . _
(1) Initial Amount 5.561.30
(mg.cm~2) (n-3)
(2) Residual Amount 3.600.82
(mg.cm~2) (n=3)
(3) Rhesus Monkey Skin 1.960.46
Permeation Rate (n=3)
Constant
(In vitro Release
Rata Conskant)
~mg cm~2 day~
-77--
O
f~ ~
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~ ~ ol o o o o o o o
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a
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E~~ ~ ~r
~ O ~ o ~ o o o ~o co In ~ o
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~ ~u~
a) Q) r~ O~ O O O O O O O O O ~r
v ~ X al ~o o o o a~ r~ r~
~ ~ ~ .. . . ~ . . ..
O (~-1 O ~~ OO 0~1r~\ ~r~l rJ O )
t,) O X r1 t~ ~r~
I
~ l
~ .
n
cn
c~ ~
. I a)~G O~OO~`OOOOr~o
I X r~ o o o o c~ o a~ o ~r ~ o
s: ~
I o ~ o ~ o o ~ ~ o c~ o
¦ lE r1 ~1 ~1 ~
~;
U U~
a;~0 i~ o Ln o Ln o o o o o o o
Ln~ o o o ~ ~1 ~ m r~ ~ ~ ~1 ~
~~1 ~ ~ ~r
~ .~3 ~
2529CIP.RL~I ~79-
Table yI
Mean and Standard Deviation of Pharmacokinetic
Parameters obtained after Intravenous Iniection
of a 50 mc~tKq Albuterol Solution in Rhesus Monkeys
Parameter _ean Standard Deviation
(n-4)
(1) Area Under the 84.19 16.15
~ Curve (AUC)
(ng.mL~l.hour~l)
(2) Initial Half-Life 6.0 3.4
(minutes)
(3) Terminal Half- 135.6 26.93
Life (minutes)
(4) Terminal0.0053 0.00094
Elimination
Rate Constant
(minute~l )
~5) Apparent Volume 1~35.9 37.2
of Distribution
(mL.Kg 1)
~6) Clearance (Cl) 10.2 1.8
(mL.minute~1.Xy~1)
J
2529CIP.RLH -80-
Table VII
Mean and Standar~d Deviation o~ Pharmacokinetic
Parameters obtained after Tra~ om~L :L~LI~LLl4l
of an Albuterol Transdermal Patch in Four Rhesus Monkeys
(1) Sinale-Laver Albuterol Transdermal Pat~h (Example 2)
Parameter Mean S dard Deviation
(n=4)
_
(1) Weight of the5.39 0.025
monkey (Kg)
(2) Area Under1070.6 394010
the Curve (AUC)
(ng mL-1 hrs)
(3) Steady State42.0 14.45
Serum Albuterol
Concentration
(C88) (12-24 hrs)
(ng.mL~l)
(4) Clearance (Cl) 10.2 1.8
(mL.minute~1.Kg 1)
(5) In vivo 0.81 0.20
Absorption
Rate Constant (Ko)
(mg.cm-2.day-l)
(6) Skin Bioavailability 115 16
(F~ of Albuterol
(per cent (%))
2 0 ~ ,3 ~
2529CIP.RLH -81
Table VII (Contlnued~
(2) Double-Layer Albuterol Transdermal Patch (ExamPle 3)
_
Parameter_ Mean Standard Deviation
(n=3)
_
(1) Weight oP the 5.33 0.2
Monkey (Kg)
(2) Area Under 1500.80 191.47
- the Curve (AUC)
(ng.mL l.hrs)
(3) Steady State 57.9 2.16
Serum Albuterol
Concentration
(C~s) (12-24 hrs)
(ng.mL~l)
(4) Clearance (Cl) 9.78 1.99
(mL.minute~1.Kg~1)
(5) In vivo 1.09 0.23
Absorption
Rate Constant (Ko)
(mg . cm-2 . day~l )
(6) Skin Bioavailability NC* NC*
(F) oP Albuterol
(per cent (%))
*NC Not Calculated
2529CIP.RLH -82-
Table VIII
Com~arlson of t_e In Vitro Rhesus Monkey
Skin Permeation Rate Constant
and the In-Vivo Rhesus Monkey
Absorptlon Rate Constant fKo) after the
Application of a Transdermal Albuterol Patch
to ~h sus Monkeys
Rhesus Monkey In Vivo
Skin Permeation Rhesus Monkey
Rate Constant Absorption Rate
Constant (Ko)
(In Vitro
Release Rate
Constant)
tma.cm 2.day 1~ f q cm~2 day~
. . .
Mean Standard Mean Standard
Deviation Devlation
1. Sin~le 0.76 0.28 .81 0.20
Layer
Patch
(n=4)
2. Double- 1.96 0.46 1.09 0.23
~E
Patçh
(n=3)
2529CIP~RL~ -83-
Comparison o~ In Vitro
Parameters of Transdermal Albu~erol Patches
(l) Sinqle-LaYer Albuterol Transdermal Patch (Example 2)
_
Standard
Parameter Table Mean Deviation
_ _ _ _ _ ~ _
Hairless Mouse Skin Table I 0.50 0.02
Permeation Rate (n=3)
Constant
(mg.cm~2.day~l)
DissolutionTable II 2.34 0.14
Rate Constant(n=3)
(mg.cm~2.day-l)
Rhesus MonkeyTable III 0.76 0.28
Skin Pexmeation (n=4)
Rate Constant
(mg.cm-2.day-l)
(2) Double-Layer Albuterol Transdermal Patch ~Exam~le 3)
Standard
Parameter Table MeanDeviation
Hairless Mouse Skin Table I 0.45 0.05
Permeation Rate (n=6)
Constant
(mg cm-2 day-l)
Dissolution Table II 2.37 0025
Rate Constant (n=3)
(mg.cm-2.day-l)
Rhesus ~onkeyTable III 1.96 0.46
Skin Permeation (n=3)
Rate Constant
~mg.cm~2.day-l)
~3~5 '-;~
2529CIP~RLH -84-
Comparison o~ HvT~othetical Human Serum
Albuterol Conce trations ~rom Transdarmal Albuterol
Patches Versus Literature-Reported Concentration5 of
Albuterol Tablets in a 70 Kq Human Beinq
Serum Concentration of Various Albuterol Formulations
Sin~le-LaYer Double-Laver Controlled-ReLease (CR) Instant-Release ~IR~
Patch Patch Table Formulation Tablet Formulation~
teverv 24 hours~ (everv 24 hours)
Serum Patch Serum Patch (8 mq of albueerol everv (4 m~ of albuterol
Concenerati_n Size Concentration Size12 hours~ everY 6 hours
(ng/mL) tcm2)(ng~mL) tcm~) tng/mL~ (ng/mL~
2-4 4 3-5 4 11.0 11.1
4-3 B* 6-10 8~
8-16 16 12-20 16
Approximntely 6 mg of albuterol permeated from an 8 square centimeter patch.
2 5 2 9CIP . RLH ~8 5 -
Table Xl
Dose versus Are~ Under the CUrVc_C_mp~riSOn
follouinq Intravenous and Transdermal Prtch Ar~Plication
of Albuterol in Rhesus ~onkevs
Paremeter ~ean Standard
Deviation
(1) Intravenous~ 0.05 0.0
Dose
(m~.~s~')
ln~
~2) TransdcrmalA~ 0.76 0.28
Dose: Sin0le-
Layer R~tch
(mg.Kg'')
~n=4)
13) Transdermal Dose:~ NC~* NC~
Double-Layer Patch
~mg.Kg'')
(n-3)
14) Area Ur~er the 8b.19 16.15
Curve lAUC) after Intra-
venous Administratior
ln~.mL''. hour'')
ln=4)
15) Aree Under the 1070.6 394.1
Curve lAUC) afser
Single-Layer
Transdermal Patch
Administration
lng.mL''. hour-'~
ln=4)
16) Area Ur,der the Curve 1500.80 1~1.47
~AUC) after Double~Layer
Tr~nsdcrmal Petch
Administration
ln9~mL~.hour~)
(n~3)
Amount of albuterol injected into e~ch of the Rhesus mcnkeys.
~ Calculated from the Rhesus monkey "skin permeation rate r,onstants" (~In vicro release rate
constants") in Table 111.
IC - ~ot Calculated
O~,J
-86-
~q
.Y
n m co ~ r o
Ql . ~ O ~D ~ ~ ~ U~ O
_ ~ ~ ~ O ~ O
fa u~
E~ .,1
3 P~ t~ ~o ~ o ~ o o
_~ h t~r ~ ~ ~ r` O
, ~ ~ ........
O O ~ O d' ~ r ~ O
~ ~ S~ ~
H
X ~ :~
I ~
C ~ ~ O O O ~ O O O O O O O
la ~3 ~, Q~ t~1 O o O t` ~ O o o o O O
E.1 '~ '1) Y ~ O O O 1` t` ~ ~I d' W t~ O
::~ ~ ~r
~ O ~ O O O O co ~ ~ ~ L~ O
~0 ~ ~ r~
.,~ a)
~1
S~
O
a ~ ~ o o o o o o o o o o
Q) ~ co O O O r~ o o o o o o
~ ~ ~ a- ~ o o o ~ 4. ~ a~ ~ ~ o
O ~ O ~ O O O O ~ ~ ~ ~ CO ~D O
c~ o X
I .~
I
t) ~ ooc~oooooooo
,~ ~ co o o o o 1~ o o o o o o
,~ X co o o o o ~ ~ ~ u) ~ cn o
o ~ o o o o ~ ~ ~ o o
~ :~ ~ ~ u~
P~
H
C~ I
~ tu I o In ~ o o o o o o
f~ ~ I
~1 I 'I ~ ~ ~ ~ ~ er ,~ co
E~ 5 ,~
2529CIP.RLH -87
Table X~E~
Rabbit Dermal Irritation Gradina SYstem
A~ Erythema Value
~1) No erythema; O
(2~ Very slight erythema (barely perceptible);
(3) Well-de~ined erythema; 2
(4) Moderate to severe erythema; and 3
(5) Severe erythema (heet redness) to slight 4
eschar formations ~injuries in depth)
B. Edema
(1) No edema; O
(2) Very slight edema (barely perceptible);
(3) Slight edema (edges of area well defined 2
by definite rai.sing);
(4) Moderate edema (raised approximately 1 mm); 3
and
(5) S~vere edema (r.aised more than 1 mm 4
extending beyond the area o~ exposure).
2529CIP.RLH -88-
~k~
Dermal Evaluatlon Criterla
Primary Irritation Index* Irritation Ratina
(P~I.I.)
0.00 Nonirritant
0.01-0.49 Negligible Irritant
0O50-I.g9 Slight Irritant
2~00-4.99 Moderate Irritant
5~00-8.00 Strong Irritant
-
* Mean Primary Irritat.ion Index - 2.83
(n=6)
2~ 7~
2529CIP . RLH -89-
Toblo XV
Scores Obtsined Frr th2 Rabbit Skin Irritotion Tests
Score
Parameter Interval 7658/M 7661/M ~ L~ 7687~F 76~9/F 7692/F
.
A. Erythema 24 hours Z 2 2 1 2 2
72 hrurs 4~ 2 2 0 1 2
7 daYs 1*~ 0 - 0 0
B. Edems 24 hours, 2 1 1 1 1 2
72 hou_s 1 1 0 0
7~ys O O 0 - O O
b Blanching
Desquamstion
5,s~
2529CIP.RI~I 90~-
Table XVI
Data Obtained ~rom the ( uinea Piq Dermal Dose
~ t:L Studies
Animal Score
2 4 Hour 4 8 Hour
4 64 8 /~ale + +
4 64 9 /Male + 0
2 5 2 9CIP . RI~I -9 1-
C)ata Obtained ~rom the G~i~ea Piq_Dermal Sensitizatlon
f ~ h
(n=15 )
Induction ~ 2 4 -Hour 4 8 -~lour
Mean + Mean +
Standard Standard
Deviation De~liation
0.0 + 0.0 0.0 + 0.0
2 o.o t o.o o.o -t o.o
3 0.3 + 0.1 0.0 + 0.0
4 o.0 + 0.0 0.0 + 0.0
0.3 ~ 0.1 0.0 + 0.0
6 0.3 + 0.1 0.0 + 0.0
7 0.3 + 0.1 0.0 + 0.0
8 0,0 + 0.~ 0.0 + 0.0
9 0.1 + 0.2 0.0 + 0.0
~ ~3 ~
2 52 9CIP . RLH -92 -
Data Obtained from ~ke 5uinea Piq Dermal Sensitization
Challen~ Studies
Dermal score
(Mean + Standarcl l:)eviation)
Animals 24_Hour 48 Hour
Test Guin~a Piys (n=15) O. 3 + 0 . 3 0.1 + 0 . 2
Control Guinea Pigs (n=5) 0. 0 + 0. 0 U. 0 + O . O
2 ~J ~j 8 ~ 3 ~
2529CIP.RLH -93-
Table XlX
Parameters Generated ~rom StabilitY Studies
Parameter _ _ Value
(1) Degradation Rate 0.00096 + 0.00011
Constant (k~ Mean Standard Deviation
at 25C ~k25C) (n=3)
(1/week)
(2) Degradation Rate 0.01603 + 0.00063
Constant (k) Mean Standard Deviation
at 45C (k45C) (n=3)
(1/week)
(3) Degradation Rate 0.05759 + 0.00096
Constant (k) Mean Standard Deviation
at 55C (n=3)
(1/week)
(4) Arrhenius 26.54 + 0.74
Activation Mean Standard Deviation
Energy (Ea) (n=3)
(kCal/mole)
Z529CIP.RI~I ~4
(5) Mean (n=3~ 169-182 Weeks
Prediction o~ (Mean Prediction Method)
Time Required to
Reach B5% of the 143-156 Weeks
Original Potency (One Sided 95% Lower Confidence
(T85%) at 25C Level Prediction Method)
(Weeks~
143-156 Weeks
(One Sided 95% Lower Confidence
Level Prediction Method for
Future Samples)
2~B~
2529CIP.RI~I ~95~
Table XX
Sta ility S~udies of Albukel~ol Transdermal Patches
at 45C
Recoverv of
Albuterol
from Patch
Sample
Time(Percent) Mean and Standard Deviation
(n=3)(Percent)
tl) 0 Weeks99.77 100.39 + 0.864
101. 00
(2) 3 Weeks94.12 96~31 + 2.gl
99.61
95.19
(3) 6 Weeks90.18 90.27 ~ 0.5
89.7~
90.88
(4) 9 Weeks86.47 86.65 + 0.~4
87.6Ç
85.81
2 ~
2 5 2 9CIP . RLH -9 6--
(5) 12 Wee3cs 82.82 83.06 ~ 1.27
81.9~
84 .43
2529CIP.RLH -97~
Table XXI
Stability Studies of Albuterol Transdermal Patches
at_55C
Recovery of
Albuterol
rom Patch
Time (Percent) Mean and Standard Deviation
(n=3)(Percent)
(1) 0 ~eeks 99.77100.39 + 0.864
1~1. 00
tz) 2 Weeks 89.51 88.83 ~ 1.10
87.56
B9.42
~3) 6 Weeks 73.21 71.33 + 3.67
67.11
73.67
(4) 12 Weeks 41.94 50.14 i 7.12
53.67
54.80
2529CIP.RLH -98-
In summary, the results of Experiments 1(a)-(i)
conducted with the transdermal albuterol patches described
in Examples 2 (single-layer), 4 (single-layer) and 3
(double-layer) below showed an in v1vo - ln vitro
correlation, a 100% albuterol skin bioavailability,
sustained serum drug concentrations for 24 hours upon a
once-a-day patch application, ease of administration of
the patches, little or no skin irritation at the patch
application site in either Rhesus monkeys or rabbits and
good stability over a 2-year shelf life. In addition,
Experiment l(h) showed that these patches are not contact
sensitizers in quiena pigs.
~5 ~1rr~
2529CIP.RLH -99-
XAMPLE 2
PIa~a~5ion of Sinqle Layer Trans~ermal Pa~ch
100 g of an albuterol patch formulation was prepar~d
with 71.81 of Dow X7-3058 SilastomerTM elastomeric matrix
material:Dow X7-3059 crosslinking agent (97.86:2.14),
15.98 g of nonmicronized albuterol, 9.99 g of n-dodecanol,
1.75 g of glycerol, 0.35 g of hexanol and 0.125 g of
X7-3075 catalyst.
In a clean mortar, the catalyst was mixed with the
matrix material and crosslinking agent in a geometric
dilution.
In a separate clean mortar, a fine paste of albuterol,
n-dodecanol, hexanol and glycerol was made by combining
and mixing the above-described amounts of these
transdermal patch components. One portion of the matrix
material-crosslinking age~t-catalyst blend was then mixed
thoroughly with the albuterol paste. Following this, the
remaining two portions of the matrix material-crosslinking
agent-catalyst blend were mixed one at a time with the
matrix material-crosslinking agent-catalyst blend-
albuterol paste.
The resulting mass was passed through a triple roller
mill to obtain a homogeneous mixture. (A homogeneous
mixture of the mass may be obtained by any suitable
method, or with the use of any suitable equipment, as
known by those of skill in the art.)
The mixture was then placed between two sheets o-f mylar
plastic film (3M Corporation, St. Paul, MN), and passed
2 ~
252~CIP.RLH -100-
through twin aluminum rollers of a film castiny apparatus
built by Applicants to adjust the thickness o~ khe mixture
to 0.3 mm by manipulating the gap between the two rollers
of the apparatus to ~.3 mm. (The thickness of the mixture
can be adjusted by any conventional film casting apparatus
or other suitable equipment, as known by those of skill in
the art.)
The resulting spread was then cured in an oven at 800c
for 25 minutes.
The cured film was then cut into several pieces (from 1
to 16 square centimeters), and each piece was then
separately glued with 355 Medical Adhesive ~Dow Corning,
Inc.) onto a piece of aluminum foil of corresponding size.
The surface of the foil not in contact with the film
was then adhered to a piece of adhesive-lined foam backin~
(Fasson, Painvile, Ohio) of corresponding size with 355
Medical Adhesive.
2529CIP . RLH -101-
EXAMPLE 3
Preparation of Double Layer Transdermal Patch
A double-layer formulation transdermal albuterol patch
of th~ invention was made, havirlg separate albuterol and
d~decanol layers.
100 g of an albuterol transdermal patch layer was
prepared as described below using 73.875 g of Dow X7-3058
5ilastomerTM matrix material:Dow X7-3059 crosslinking agent
(97.86:2.14), 20 g of nonmicronized albuterol, 5.0 g of
glycer~l, 1.0 g of hexanol and .125 g of Dow X7-3075
catalyst.
100 g of an n-dodecanol transdermal patch layer was
separately prepared as described below using 89.875 g of
Dow X7-3058 SilastomerT~ matrix material:Dow X7-3059
crosslinking agent (97:86:2.14), 10 g of n-dodecanol and
.125 g of catalyst.
For each lay~r, catalyst was first mixed with the
matrix material and crosslinking agent in a geometric
dilution in a clean mortar to ~orm a matrix material-
crosslinking agent-catalyst blend.
In a separate clean mortar, a fine paste of albuterol,
hexanol and glycerol was made using the above-described
amounts of these transdermal patch components~ One
portion of the first matrix material-catalyst blend was
mixed thoroughly with the albuterol paste. Following
this, the remaining two portions of the first matrix
material--catalyst blend were mixed one at a time with the
.3 ~ ~
2529CIP.RLH -102-
matrix material-crosslinking agent-catalyst blend-
albuterol paste.
The n-dodecanol txansdermal patch layer was prepared
separately by mixing the n-dodecanol described above with
the other matrix material-crosslinking agent-catalyst
blend.
The resulting masses of the albuterol and n-dodecanol
layers were separately processed as follows. Each mass
was passed through the triple roller mill describecl in
Example 2 to obtain a homogeneous mixture. Each mixture
was then separately placed between two sheets of mylar
plastic film, as described above in Example 2, and passed
through two aluminum rollers of the film casting apparatus
described in Example 2. Each resulting spread was then
cured in an oven at 80C for 25 minutes.
The cured albuterol and n-dodecanol film layers were
then cut into pieces, each measuriny from 1 to 16 square
centimeters. Each n-dodecanol layer was then placed upon
an albuterol layer o~ corresponding size, and adhered
naturally thereto.
The surface of the n-dodecanol layer not in contact
with the albuterol layer was then gllled to a piece of
aluminum foil of corresponding size with 355 Medical
Adhesive.
The surface of the foil not in contact with ths n-
dodecanol layer was then adhered to a piece of adhesive-
lined foam backing (Fasson, supra.) of corresponding size
with 355 Medical Adhesive.
~ ~o~
2529'._IP.RI~ 103-
E~MPLE J,
~i~9~r Transdermal Patch
(Preferred Method of Preparation)
Using the same materials set forth in Example 2, with
the exception of the subs~itution of micronized albuterol
for nonmicronized albuterol, and the same quantities
thereof, single-layer tran~dsrmal albuterol patches of the
invention were prepared in the ~ollowing manner.
In a clean mortar, the Dow X7-305~ ~ilastomer~
elastomeric matrix material was mixed with X7-3059
crosslinking agent in the proportion of 97.86:2.14. This
mixture was then aged for two days prior to use. (It
should be aged for not less than 2, and not more than 7,
days prior to USQ. )
In a separate clean container, the albuterol,
n-dodecanol, glycerol, hexanol and catalyst were mixed
with a spatula to make a fine pasteO
Then, the matrix material-crosslinking agent blend was
added to the other mixture and mixed thoroughly in a
porcelain mortar with a pestle~
The resulting mixture was then passed twice through the
triple roller mill described in Example 2.
An aliquot of the mixture was then transferred into a
syringe which had had its tip cu~. (The size of the
aliquot is not critical, and may vary according to the
size of the syringe employed.) The aliquot of the mixture
was then placed betwe~n two sheets of mylar plastic film
~3M ~orporation) with the syringe.
t~
2529CIP.RLH -104-
From this point on, ~his experiment was conduc~ed in
the manner describ2d in Example 2.
This method is preferable to the method described in
Example 2 for preparing single~layer transdermal albuterol
patches of the present invention.
8 ~3 ~ ~ ~
2529CIP.RLH -105-
Therapeutically-active agents which produce a systemic
activity, and which are deliverable by the present
invention are, for instance, and without limitation,
anti-infectives, ~or example pentamidine and lomefloxacin,
antibiotics, ~or example metronidaæole, hormones,
antipyretics, antidiabetics, coronary dilation agents,
glycosides, spasmolytics, antihypertensives, for example
verapamil and its enantiomers and betaxolol, psychoactive
agenks, for example zolpidem, cycloserine and milacemide,
corticosteroids, analgesics, contraceptives, nonsteroidal
anti-inflammatory drugs, for example oxaprozen,
anticholinergics, sympatholytics, sympathomimetics,
vasodilatory agents, anticoagulants, antiarrhythmics, for
example disopyramide or disobutamide, and prostaglandins
having various pharmacologic activities, for example
misoprostol and enisoprost.
While the transde~mal patches of the present invention
have been described and illustrated herein some
specifivity, and with reference to certain prepared
embodiments thereof, those slcilled in the art will
appreciate that various changes, modifications and
substitutions can be made therein without departing from
the spirit and scope of the invention. For example,
effective dosages of active agent other than the preferred
ranges set forth hereinabove may be applicable as a
consequence of variations in the responsiveness of the
patient being treated, dosage related adverse effects, if
any, and analogous considerations. Likewise, the speclfic
& ~ ~ q:)
2529CIP.RLH 106-
pharmacological responses obser~gd may vary according to,
and depending upon, the particular active compounds
selected for incorporation into khe patches. Such
expec~ed variations andlor di~ferences in the results are
contemplated in accordance with the objects and practices
of the present invention. It is intended therefore that
all of these modifications and variations be within the
scope of the present invention as described and claimed
herein, and that the invention be limited only by the
scope of the claims which ~ollow, and that such claims be
interpreted as broadly as is reasonable.
