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Patent 2395289 Summary

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(12) Patent Application: (11) CA 2395289
(54) English Title: TRANSDERMAL ADMINISTRATION OF PHENYLPROPANOLAMINE
(54) French Title: ADMINISTRATION TRANSDERMIQUE DE PHENYLPROPANOLAMINE
Status: Deemed Abandoned and Beyond the Period of Reinstatement - Pending Response to Notice of Disregarded Communication
Bibliographic Data
(51) International Patent Classification (IPC):
  • A61K 9/70 (2006.01)
  • A61K 31/137 (2006.01)
  • A61K 31/315 (2006.01)
  • A61K 47/02 (2006.01)
(72) Inventors :
  • HSU, TSUNG-MIN (United States of America)
  • MACY, RUSSELL (United States of America)
  • LUO, ERIC C. (United States of America)
(73) Owners :
  • DERMATRENDS, INC.
(71) Applicants :
  • DERMATRENDS, INC. (United States of America)
(74) Agent: ADE & COMPANY
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 2000-12-15
(87) Open to Public Inspection: 2001-06-21
Availability of licence: N/A
Dedicated to the Public: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/US2000/034091
(87) International Publication Number: WO 2001043734
(85) National Entry: 2002-06-17

(30) Application Priority Data:
Application No. Country/Territory Date
09/465,098 (United States of America) 1999-12-16
09/607,892 (United States of America) 2000-06-30
09/738,393 (United States of America) 2000-12-14
09/738,410 (United States of America) 2000-12-14

Abstracts

English Abstract


Methods and systems are provided for the transdermal administration of racemic
phenylpropanolamine, i.e., a mixture of two or more of the four isomers of
phenylpropanolamine, (+)-norephedrine, (-)-norephedrine, (+)-
norpseudoephedrine, and (-)-norpseudoephedrine. Generally, the racemate will
be a mixture of (+)-norephedrine and (-)-norephedrine. The racemic drug is
administered along with a permeation enhancer. The permeation enhancer is
preferably a basic compound, and optimally is a hydroxide-releasing agent such
as sodium hydroxide.


French Abstract

L'invention concerne des procédés et des systèmes d'administration transdermique de phénylpropanolamine racémique, c'est-à-dire un mélange d'au moins deux des quatre isomères de phénylpropanolamine, (+)-noréphédrine, (-)-noréphédrine, (+)-norpseudoéphédrine et (-)-norpseudoéphédrine. D'une manière générale, le racémate sera un mélange de (+)-noréphédrine et (-)-noréphédrine. Le médicament racémique est administré avec un agent favorisant la perméation, lequel agent est, de préférence, un composé basique, et, d'une manière optimale, un agent libérant de l'hydroxyde, par exemple l'hydroxyde de sodium.

Claims

Note: Claims are shown in the official language in which they were submitted.


-41-
CLAIMS
1. A method for treating an individual suffering from or susceptible to
condition,
disorder or disease that is responsive to administration of
phenylpropanolamine,
comprising administering a therapeutically effective amount of racemic
phenylpropanolamine to a localized region of a human patient's body surface,
in
combination with an effective permeation-enhancing amount of a hydroxide-
releasing
agent selected from the group consisting of inorganic hydroxides, inorganic
oxides, and
mixtures thereof.
2. The method of claim 1, wherein the racemic phenylpropanolamine is a mixture
of two or more of (+)-norephedrine, (-)-norephedrine, (+)-norpseudoephedrine,
and (-)-
norpseudoephedrine.
3. The method of claim 2, wherein the racemic phenylpropanolamine is a mixture
of (-)-norephedrine and (+)-norephedrine.
4. The method of claim 3, wherein at least about 50% of the
phenylpropanolamine
is present in uncharged, free base form.
5. The method of claim 1, wherein the racemic phenylpropanolamine is
administered along with a permeation enhancer.
6. Cancelled.
7. The method of claim 1, wherein the hydroxide-releasing agent is applied in
an
amount effective to provide a pH in the range of approximately 8.0 to 13 at
the localized
region of the body surface, during drug administration.
8. The method of claim 7, wherein the pH is in the range of approximately 8.0
to
11.5.

-42-
9. The method of claim 1, wherein the phenylpropanolamine and the hydroxide-
releasing agent are applied to the body surface simultaneously in a single
pharmaceutical
formulation.
10. The method of claim 9, wherein the formulation is aqueous.
11. The method of claim 10, wherein the formulation has a pH in the range of
approximately 8.0 to 13.
12. The method of claim 11, wherein the aqueous formulation is selected from
the
group consisting of a cream, a gel, a lotion, and a paste.
13. The method of claim 1, wherein the hydroxide-releasing agent is
administered
to the localized region of body surface prior to administration of the active
agent, wherein
the hydroxide-releasing agent is in a solution comprised of a protic solvent
having a pH in
the range of approximately 8.0 to 13.
14. The method of claim 1, wherein the hydroxide-releasing agent is selected
from
the group consisting of inorganic hydroxides, inorganic oxides, metal salts of
weak acids,
and mixtures thereof.
15. The method of claim 14, wherein the hydroxide-releasing agent is an
inorganic
hydroxide.
16. The method of claim 14, wherein the hydroxide-releasing agent is an
inorganic
oxide.
17. Cancelled.
18. The method of claim 15, wherein the amount of inorganic hydroxide in the
formulation is the total of (a) the amount required to neutralize any salts
and acidic species

- 43
-
in the formulation plus (b) an amount equal to approximately 0.5 wt.% to 4.0
wt.% of the
formulation.
19. The method of claim 18, wherein the phenylpropanolamine is in the form of
an
acid addition salt, and the amount in (a) is the amount required to neutralize
the acid
addition salt and any other acidic species in the formulation.
20. The method of claim 1, wherein the active agent and hydroxide-releasing
agent
are administered by applying a drug delivery device to the localized region of
the patient's
body surface thereby forming a body surface-delivery device interface, the
device
comprising the drug and the hydroxide-releasing agent, and having an outer
backing layer
that serves as the outer surface of the device during use.
21. The method of claim 1, wherein the active agent and the hydroxide-
releasing
agent are administered without any additional permeation enhancer.
22. A composition of matter useful for the delivery of racemic
phenylpropanolamine through a body surface, comprising an aqueous formulation
of:
(a) a therapeutically effective amount of racemic phenylpropanolamine;
(b) a hydroxide-releasing agent in an amount effective to enhance the flux of
the
drug through the body surface without causing damage thereto, wherein the
hydroxide-
releasing agent is selected from the group consisting of inorganic hydroxides,
inorganic
oxides, and mixtures thereof; and
(c) a pharmaceutically acceptable carrier suitable for transdermal drug
administration.
23. A system for the transdermal administration of racemic
phenylpropanolamine,
comprising:
(a) at least one drug reservoir containing the racemic phenylpropanolamine and
a
hydroxide-releasing agent in an amount effective to enhance the flux of the
drug through
the body surface without causing damage thereto, wherein the hydroxide-
releasing agent is

-44-
selected from the group consisting of inorganic hydroxides, inorganic oxides,
and mixtures
thereof;
(b) a means for maintaining the system in drug- and enhancer-transmitting
relationship to the body surface; and
(c) a backing layer that serves as the outer surface of the device during use.
24. The system of claim 23, wherein the racemic phenylpropanolamine is a
mixture of two or more of (+)-norephedrine, (-)-norephedrine, (+)-
norpseudoephedrine,
and (-)-norpseudoephedrine.
25. The system of claim 24, wherein the racemic phenylpropanolamine is a
mixture of (-)-norephedrine and (+)-norephedrine.
26. The system of claim 23, wherein the drug reservoir is comprised of a
polymeric adhesive.
27. The system of claim 23, wherein the drug reservoir is comprised of a
hydrogel.
28. The system of claim 23, wherein the drug reservoir is comprised of a
sealed
pouch containing the drug and hydroxide-releasing agent in a liquid or semi-
solid
formulation.

Description

Note: Descriptions are shown in the official language in which they were submitted.


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TRANSDERMAL ADMINISTRATION OF PHENYLPROPANOLAMINE
TECHNICAL FIELD
This invention relates generally to the topical and transdermal administration
of
pharmacologically active agents, and more particularly relates to methods,
drug delivery
systems and pharmaceutical compositions for transdermal administration of
phenylpropanolamine.
BACKGROUND ART
The delivery of drugs through the skin provides many advantages; primarily,
such a means of delivery is a comfortable, convenient and noninvasive way of
administering drugs. The variable rates of absorption and metabolism
encountered in oral
treatment are avoided, and other inherent inconveniences--e.g.,
gastrointestinal irritation
and the like--are eliminated as well. Transdermal drug delivery also makes
possible a high
degree of control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving
from the environment into and through intact skin must first penetrate the
stratum corneum
and any material on its surface. They must then penetrate the viable
epidermis, the
papillary dermis, and the capillary walls into the blood stream or lymph
channels. To be so
absorbed, molecules must overcome a different resistance to penetration in
each type of
tissue. Transport across the skin membrane is thus a complex phenomenon.
However, it
is the cells of the stratum corneum which present the primary barrier to
absorption of topical compositions or transdermally administered drugs. The
stratum
corneum is a thin layer of dense, highly keratinized cells approximately 10-15
microns
thick over most of the body. It is believed to be the high degree of
keratinization within
these cells as well as their dense packing which creates in most cases a
substantially
impermeable barrier to drug penetration. With many drugs, the rate of
permeation through
the skin is extremely low without the use of some means to enhance the
permeability of
the skin.

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In order to increase the rate at which a drug penetrates through the skin,
then,
various approaches have been followed, each of which involves the use of
either a
chemical penetration enhancer or a physical penetration enhancer. Physical
enhancement
of skin permeation includes, for example, electrophoretic techniques such as
iontophoresis.
The use of ultrasound (or "phonophoresis") as a physical penetration enhancer
has also
been researched. Chemical enhancers are compounds that are administered along
with the
drug (or in some cases the skin may be pretreated with a chemical enhancer) in
order to
increase the permeability of the stratum corneum, and thereby provide for
enhanced
penetration of the drug through the skin. Ideally, such chemical penetration
enhancers (or
"permeation enhancers," as the compounds are referred to herein) are compounds
that are
innocuous and serve merely to facilitate diffusion of the drug through the
stratum
corneum.
Nevertheless, the number of drugs that can be safely and effectively
administered
through the skin, without concomitant problems such as irritation and
sensitization,
remains limited.
The present invention is directed to the transdermal administration of 2-amino-
1-
phenyl-1-propanol, or "phenylpropanolamine." The drug is described, for
example, by
Kanfer et al., in Analytical Profiles of Drug Substances, vol. 12, K. Florey,
Ed. (New
York: Academic Press, 1983). Phenylpropanolamine is a sympathomimetic agent
that has
been used as an anorectic agent, a decongestant, an anxiolytic agent, and as a
drug for
decreasing fatigue and confusion. See, for example, U.S. Patent Nos. 5,019,594
to
Wurtman et al., 5,260,073 to Phipps, and 5,096,712 to Wurtman.
Phenylpropanolamine has the molecular structure (I)
OH
NHZ
(I) ~ Hs

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and, as may be seen contains two chiral centers. Thus, phenylpropanolamine
exists as four
different isomers, as follows:
OH OH
S ~ .,.v~NHz ~ NHz
l
CH3 / CH3
(Ia) (Ib)
OH
NHz Hz
~ cH3
(Ic) (Id)
Isomers (Ia) through (Id) are generally referred to as (+)-norephedrine, (-)-
norephedrine,
(+)-norpseudoephedrine, and (-)-norpseudoephedrine, respectively. Generally,
isomers
(Ib) and (Ic), i.e., (-)-norephedrine and (+)-norpseudoephedrine, are
recognized as the more
active isomers for most physiological uses. The typical formulation, however,
is a
racemic mixture of (+)-norephedrine and (-)-norephedrine. This mixture,
generally
referred to as (+)-phenylpropanolamine (or simply "phenylpropanolamine"), is
commercially available for use as an anorectic agent at a dose of about 50-75
mg/day, and
as a nasal decongestant at a dose of about 75-150 mg/day.
Currently, phenylpropanolamine is administered orally, in tablets, capsules or
syrups. The present invention, however, is directed to the transdermal
administration of
phenylpropanolamine. There are a number of other advantages to administering
phenylpropanolamine transdermally: continuous delivery provides for sustained
blood
levels of the otherwise short-lived drug (the half life of phenylpropanolamine
is on the

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order of 3.8 to 4.3 hours--see Scherzinger et al. (1990) J. Clin. Pharmacol.
30(4):372-
377); there is no first-pass effect; side effects typically associated with
oral administration
may be substantially avoided; continuous delivery provides for sustained blood
levels; the
transdermal patch is easily removable if any side effects do occur; and the
likelihood of
both patient acceptance and patient compliance is significantly improved.
Transdermal administration of phenylpropanolamine has been proposed. In U.S.
Patent No. 4,818,541, transdermal systems are disclosed for delivering
phenylpropanolamine to the skin. In the aforementioned patent, however, it is
noted that
the skin flux of (t)-phenylpropanolamine (i.e., a mixture of (-)-norephedrine
and
(+)-norephedrine) is only 16 ~Lg/cm'/hr, although the skin flux of individual
enantiomers
was found to be higher. Furthermore, the method of the '541 patent requires
neutralization of phenylpropanolamine hydrochloride (i.e., conversion to the
free base), the
commercially available form of the drug, before incorporation into a
transdermal drug
delivery system.
Accordingly, there is a need in the art for a way to transdermally administer
racemic phenylpropanolamine without being limited by the racemate's low skin
flux, and
without having to convert phenylpropanolamine hydrochloride to the base form
of the drug
prior to patch manufacture. The terms "racemic" or "racemate" as used herein
refer to a
mixture of any two or more of the four isomers of phenylpropanolamine, but
typically refer
to a mixture of (-)-norephedrine and(+)-norephedrine.
Various compounds for enhancing the permeability of skin are known in the art
and
described in the pertinent texts and literature. Compounds that have been used
to enhance
skin permeability include: the sulfoxides dimethylsulfoxide (DMSO) and
decylmethylsulfoxide (C,oMSO); ethers such as diethylene glycol monoethyl
ether
(available commercially as Transcutol~) and diethylene glycol monomethyl
ether;
surfactants such as sodium laurate, sodium lauryl sulfate,
cetyltrimethylammonium
bromide, benzalkonium chloride, Poloxamer (231, 182, 184). Tween (20, 40, 60,
80) and
lecithin (U.S. Patent No. 4,783,450); the 1-substituted azacycloheptan-2-ones,
particularly
1-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone~ from
Nelson
Research & Development Co., Irvine, Cali~; see U.S. Patent Nos. 3,989,816,
4,316,893,
4,405,616 and 4,557,934); alcohols such as ethanol, propanol, octanol, benzyl
alcohol, and

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the like; fatty acids such as lauric acid, oleic acid and valeric acid; fatty
acid esters such as
isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate;
polyols and
esters thereof such as propylene glycol, ethylene glycol, glycerol,
butanediol, polyethylene
glycol, and polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Patent No.
4,568,343); amides and other nitrogenous compounds such as urea,
dimethylacetamide
(DMA), dimethylformamide (DMF), 2-pyrrolidone, I-methyl-2-pyrrolidone,
ethanolamine,
diethanolamine and triethanolamine; terpenes; alkanones; and organic acids,
particularly
salicylic acid and salicylates, citric acid and succinic acid. Percutaneous
Penetration
Enhancers, eds. Smith et al. (CRC Press, 1995) provides an excellent overview
of the field
and further background information on a number of chemical and physical
enhancers.
Although many chemical permeation enhancers are known, there is an ongoing
need for enhancers that are highly effective in increasing the rate at which a
drug
permeates the skin, do not result in skin damage, irritation, sensitization,
or the like, and
also allows neutralization of phenylpropanolamine hydrochloride during, rather
than prior
to, patch manufacture. It has now been discovered that hydroxide-releasing
agents are
highly effective permeation enhancers, even when used without co-enhancers,
providing
all of the aforementioned advantages relative to known permeation enhancers.
Furthermore, in contrast to conventional enhancers, transdermal administration
of drugs
with hydroxide-releasing agents as permeation enhancers, employed at the
appropriate
levels, does not result in systemic toxicity.
DISCLOSURE OF THE INVENTION
It is thus a primary object of the invention to address the above-described
need in
the art by providing drug delivery systems, pharmaceutical formulations and
methods for
the transdermal administration of racemic phenylpropanolamine in neutral,
uncharged
form. It is another object of the invention to provide a method for treating
conditions,
disorders or diseases that are responsive to administration of
phenylpropanolamine by
transdermally administering racemic phenylpropanolamine to a patient in need
of such
therapy.
It is still another object of the invention to provide a method for
administering
racemic phenylpropanolamine transdermally at a flux that is therapeutically
effective for

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use as anorectic agent, a decongestant, an anxiolytic agent, or to decrease
fatigue or
confusion.
It is yet another object of the invention to provide a transdermal drug
delivery
system for administration of racemic phenylpropanolamine such that a
therapeutically
effective skin flux is achieved.
It is a further object of the invention to provide a chemical composition
containing
racemic phenylpropanolamine, formulated for transdermal drug delivery.
It is still a further object of the invention to provide a method for
manufacturing a
transdermal drug delivery system wherein phenylpropanolamine hydrochloride is
converted to phenylpropanolamine base during system manufacture.
It is yet a further object of the invention to provide a method for
administering
racemic phenylpropanolamine transdermally in combination with a basic
permeation
enhancer.
Additional objects, advantages and novel features of the invention will be set
forth
in part in the description which follows, and in part will become apparent to
those skilled
in the art upon examination of the following, or may be learned by practice of
the
invention.
In one aspect of the invention, then, a method is provided for treating an
individual
suffering from a condition, disease or disorder that is responsive to
administration of
phenylpropanolamine, by transdermally administering a therapeutically
effective amount
of racemic phenylpropanolamine. The method is premised on the discovery that
racemic
phenylpropanolamine may in fact be administered through the skin or mucosal
tissue at a
therapeutically effective rate to achieve desired systemic effects, when a
permeation
enhancer, particularly a basic permeation enhancer, is coadministered with the
drug.
In another aspect of the invention, a pharmaceutical composition and a
transdermal
therapeutic system are provided for transdermal administration of racemic
phenylpropanolamine. The pharmaceutical composition contains racemic
phenylpropanolamine, and is formulated for transdermal drug delivery. The
transdermal
drug delivery system is a laminated composite comprising a backing layer, a
drug
reservoir, and a means for affixing the composite to the skin. The drug
reservoir and the
affixing means may be distinct, such that a separate contact adhesive layer is
provided

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which serves as the basal surface of the device, or the drug reservoir may
itself be
comprised of an adhesive layer which is suitable for contacting and adhering
to the skin.
Such therapeutic systems are in the nature of "solid matrix" type transdermal
patches.
Alternative systems, containing the drug in a liquid, gel or foam reservoir,
may, however,
be used as well.
In another aspect of the invention. a method is provided for increasing the
rate at
which phenylpropanolamine permeates through the body surface of a patient. The
method
involves administering the drug to a predetermined area of the patient's body
surface in
combination with a hydroxide-releasing agent in a predetermined amount
effective to
enhance the flux of the agent through the body surface without causing damage
thereto.
The predetermined amount of the hydroxide-releasing enhancer is preferably an
amount
effective to provide a pH at the body surface in the range of about 8.0 to 13,
preferably
about 8.0 to 11.5, more preferably about 8.5 to 11.5, during drug
administration. If a skin
patch is used, this is the preferred pH at the interface between the basal
surface of the
patch (i.e., the skin-contacting or mucosa-contacting surface of the patch)
and the body
surface. The optimal amount (or concentration) of any one hydroxide-releasing
agent will,
however, depend on the specific hydroxide-releasing agent, i.e., on the
strength or
weakness of the base, its molecular weight, and other factors as will be
appreciated by
those of ordinary skill in the art of transdermal drug delivery. This optimal
amount may
be determined using routine experimentation to ensure that the pH at the body
surface is
within the aforementioned ranges, i.e., in the range of about 8.0 to 13,
preferably about 8.0
to 11.5, more preferably about 8.5 to 11.5. A conventional transdermal drug
delivery
device or "patch" may be used to administer the active agent, in which case
the drug and
hydroxide-releasing agent are generally present in a drug reservoir or
reservoirs.
However, the drug and hydroxide-releasing agent may also be administered to
the body
surface using a liquid or semisolid formulation. Alternatively, or in
addition, the body
surface may be pretreated with the enhancer, e.g., treated with a dilute
solution of the
hydroxide-releasing agent prior to transdermal drug administration. Such a
solution will
generally be comprised of a protic solvent (e.g., water or alcohol) and have a
pH in the
range of about 8.0 to 13, preferably about 8.0 to 11.5. more preferably about
8.5 to 11.5.

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_g_
In a related aspect of the invention, a composition of matter is provided for
delivering phenylpropanolamine through a body surface using a hydroxide-
releasing agent
as a permeation enhancer. Generally, the formulation comprises (a) a
therapeutically
effective amount of a drug, (b) a hydroxide-releasing agent in an amount
effective to
enhance the flux of the drug through the body surface without causing damage
thereto, and
(c) a pharmaceutically acceptable carrier suitable for topical or transdermal
drug
administration. The composition may be in any form suitable for application to
the body
surface, and may comprise, for example, a cream, lotion, solution, gel,
ointment, paste or
the like, and/or may be prepared so as to contain liposomes, micelles, and/or
microspheres.
The composition may be directly applied to the body surface or may involve use
of a drug
delivery device. In either case, it is preferred although not essential that
water be present
in order for the hydroxide-releasing agent to generate hydroxide ions and thus
enhance the
flux of the active agent through the patient's body surface. Thus, a
formulation or drug
reservoir may be aqueous, i.e., contain water, or may be nonaqueous and used
in
combination with an occlusive overlayer so that moisture evaporating from the
body
surface is maintained within the formulation or transdermal system during drug
administration. In some cases, however, e.g., with an occlusive gel, a
nonaqueous
formulation may be used with or without an occlusive layer.
In another aspect of the invention, a drug delivery system is provided for the
topical or transdermal administration of a drug using a hydroxide-releasing
agent as a
permeation enhancer. The system will generally comprise: at least one drug
reservoir
containing the drug and the hydroxide-releasing agent in an amount effective
to enhance
the flux of the drug through the body surface without causing damage thereto;
a means for
maintaining the system in drug and enhancer transmitting relationship to the
body surface;
and a backing layer that serves as the outer surface of the device during use.
The backing
layer may be occlusive or nonocclusive, although it is preferably occlusive.
The drug
reservoir may be comprised of a polymeric adhesive, which may serve as the
basal surface
of the system during use and thus function as the means for maintaining the
system in drug
and enhancer transmitting relationship to the body surface. The drug reservoir
may also be
comprised of a hydrogel, or it may be a sealed pouch within a "patch"-type
structure

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wherein the drug and hydroxide-releasing agent are present in the pouch as a
liquid or
semi-solid formulation.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph illustrating the cumulative amount of racemic
phenylpropanolamine permeated from matrix patches as described in Example 1.
FIG. 2 is a graph illustrating the cumulative amount of racemic
phenylpropanolamine permeated from matrix patches as described in Example 2.
FIG. 3 is a graph illustrating the cumulative amount of racemic
phenylpropanolamine permeated from matrix patches as described in Example 3.
FIG. 4 is a graph illustrating the cumulative amount of racemic
phenylpropanolamine permeated from matrix patches as described in Example 4.
FIG. 5 is a graph illustrating the cumulative amount of racemic
phenylpropanolamine permeated from matrix patches as described in Example 5.
MODES FOR CARRYING OUT THE INVENTION
DEFINITIONS AND OVERVIEW:
Before describing the present invention in detail, it is to be understood that
this
invention is not limited to specific drug delivery systems, device structures,
enhancers or
carriers, as such may vary. It is also to be understood that the terminology
used herein is
for the purpose of describing particular embodiments only, and is not intended
to be
limiting.
It must be noted that, as used in this specification and the appended claims,
the
singular forms "a," "an" and "the" include plural referents unless the context
clearly
dictates otherwise. Thus, for example, reference to "a pharmacologically
active agent"
includes a mixture of two or more active agents, reference to "an enhancer"
includes
mixtures of two or more enhancers, and the like.
In describing and claiming the present invention, the following terminology
will be
used in accordance with the definitions set out below.

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The terms "treating" and "treatment" as used herein refer to reduction in
severity
and/or frequency of symptoms, elimination of symptoms and/or underlying cause,
prevention of the occurrence of symptoms and/or their underlying cause, and
improvement
or remediation of damage. The present method of "treating" a patient, as the
term is used
herein, thus encompasses both prevention of a disorder in a predisposed
individual and
treatment of the disorder in a clinically symptomatic individual.
The term "hydroxide-releasing agent" as used herein is intended to mean an
agent
that releases free hydroxide ions in an aqueous environment. The agent may
contain
hydroxide ions and thus release the ions directly (e.g., an alkali metal
hydroxide), or the
agent may be one that is acted upon chemically in an aqueous environment to
generate
hydroxide ions (e.g., a metal carbonate).
The terms "active agent," "drug" and "pharmacologically active agent" are used
interchangeably herein to refer to a chemical material or compound that
induces a desired
effect, and include agents that are therapeutically effective,
prophylactically effective, or
cosmetically effective. Also included are derivatives and analogs of those
compounds or
classes of compounds specifically mentioned which also induce the desired
effect. The
primary active agent herein is racemic phenylpropanolamine.
"By therapeutically effective" amount is meant a nontoxic but sufficient
amount of
an active agent to provide the desired therapeutic effect.
By "transdermal" drug delivery is meant administration of a drug to the skin
surface of an individual so that the drug passes through the skin tissue and
into the
individual's blood stream, thereby producing a systemic effect. The term
"transdermal" is
intended to include "transmucosal" drug administration, i.e., administration
of a drug to the
mucosal (e.g., sublingual, buccal, vaginal, rectal) surface of an individual
so that the drug
passes through the mucosal tissue and into the individual's blood stream.
The term "topical administration" is used in its conventional sense to mean
delivery
of a topical drug of a pharmacologically active agent to the skin or mucosa,
as in, for
example, the treatment of various skin disorders. Topical drug administration,
in contrast
to transdermal administration, provides a local rather than a systemic effect.
Unless
otherwise stated or implied, the terms "topical drug administration" and
"transdermal drug
administration" are used interchangeably.

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The term "body surface" is used to refer to skin or mucosal tissue.
By "predetermined area" of skin or mucosal tissue, which refers to the area of
skin
or mucosal tissue through which PPA is delivered, is intended a defined area
of intact
unbroken living skin or mucosal tissue. That area will usually be in the range
of about 5
S cm2 to about 200 cm'-, more usually in the range of about 5 cm'- to about
100 cm'-,
preferably in the range of about 20 cm'- to about 60 cm'-. However, it will be
appreciated
by those skilled in the art of drug delivery that the area of skin or mucosal
tissue through
which the drug is administered may vary significantly, depending on patch
configuration,
dose, and the like.
"Penetration enhancement" or "permeation enhancement" as used herein relates
to
an increase in the permeability of the skin or mucosal tissue to the selected
pharmacologically active agent, i.e., so that the rate at which the agent
permeates
therethrough (i.e., the "flux" of the agent through the body surface) is
increased relative to
the rate that would be obtained in the absence of permeation enhancement. The
enhanced
permeation effected through the use of such enhancers can be observed by
measuring the
rate of diffusion of drug through animal or human skin using, for example, a
Franz
diffusion apparatus as known in the art and as employed in the Examples
herein.
An "effective" amount of a permeation enhancer is meant a nontoxic,
nondamaging
but sufficient amount of the enhancer to provide the desired increase in skin
permeability
and, correspondingly, the desired depth of penetration, rate of
administration. and amount
of drug delivered.
"Carriers" or "vehicles" as used herein refer to carrier materials suitable
for
transdermal drug administration. Carriers and vehicles useful herein include
any such
materials known in the art which is nontoxic and does not interact with other
components
of the composition in a deleterious manner.
The term "aqueous" refers to a formulation or drug delivery system that
contains
water or that becomes water-containing following application to the skin or
mucosal
tissue.
The term "racemic phenylpropanolamine" as used herein refers to a mixture of
two
or more of the four isomers of phenylpropanolamine, i.e., (+)-norephedrine,
(-)-norephedrine, (+)-norpseudoephedrine, and (-)-norpseudoephedrine.
Generally,

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however, the term refers to (t)-phenylpropanolamine, i.e., a racemic mixture
of
(-)-norephedrine and (+)-norephedrine. Phenylpropanolamine is generally
although not
necessarily administered in uncharged (electronically neutral) form, wherein
the amine
group of the molecule exists in free base form, i.e., as an -NH, moiety.
Accordingly, the invention pertains to a method, composition and drug delivery
system for increasing the rate at which an active agent, e.g., racemic
phenylpropanolamine,
permeates through the body surface of a patient at a rate that is effective to
result in
therapeutically effective blood levels. The method involves administering the
agent to a
predetermined area of the patient's body surface in combination with a
hydroxide-releasing
agent in an amount effective to enhance the flux of the agent through the body
surface
without causing damage thereto.
Thus, the present method of transdermally delivering phenylpropanolamine may
vary. but necessarily involves application of a composition containing racemic
phenylpropanolamine to a predetermined area of the skin or mucosal tissue for
a period of
time sufficient to provide an effective blood level of drug for a desired
period of time. The
method may involve direct application of the composition as an ointment, gel,
cream, or
the like, or may involve use of a drug delivery device as taught in the art,
e.g., in
commonly assigned U.S. Patent Nos. 4,915,950, 4,906,463, 5,091,186 or
5,246,705, or as
described below.
THE PERMEATION ENHANCER:
It will generally be necessary to administer racemic phenylpropanolamine in
conjunction with a permeation enhancer, in order to achieve a therapeutically
effective flux
through the skin.
Preferred permeation enhancers are basic compounds, with hydroxide-releasing
agents particularly preferred. Hydroxide-releasing agents are described, for
example, in
co-pending, commonly assigned U.S. Serial No. 09/569,889, filed May 1 l, 2000,
for
"Hydroxide-Releasing Agents as Skin Permeation Enhancers." A "hydroxide-
releasing
agent" is a chemical compound that releases free hydroxide ions in the
presence of an
aqueous fluid. Therefore, any patch that is used should have an occlusive
backing, or

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contain water, or both. Similarly, any topical formulation that is used should
be aqueous
or used in conjunction with an overlayer of an occlusive material.
The "hydroxide-releasing agent" is a chemical compound that releases free
hydroxide ions in the presence of an aqueous fluid. The aqueous fluid may be
natural
moisture at the skin surface, or a patch or composition that is used may
contain added
water, and/or be used in connection with an occlusive backing. Similarly, any
liquid or
semisolid formulation that is used is preferably aqueous or used in
conjunction with an
overlayer of an occlusive material.
Any hydroxide-releasing agent may be used provided that the compound releases
free hydroxide ions in the presence of an aqueous fluid. Examples of suitable
hydroxide-
releasing agents include, but are not limited to, inorganic hydroxides,
inorganic oxides,
and alkali metal or alkaline earth metal salts of weak acids. Inorganic
hydroxides include,
for example, ammonium hydroxide, alkali metal hydroxide and alkaline earth
metal
hydroxides, such as sodium hydroxide, calcium hydroxide, potassium hydroxide,
magnesium hydroxide, and the like. Inorganic oxides include, for example,
magnesium
oxide, calcium oxide, and the like. Metal salts of weak acids include, for
example, sodium
acetate, sodium borate, sodium metaborate, sodium carbonate, sodium
bicarbonate,
sodium phosphate (tribasic), sodium phosphate (dibasic), potassium carbonate,
potassium
bicarbonate, potassium citrate, potassium acetate, potassium phosphate
(dibasic),
potassium phosphate (tribasic), ammonium phosphate (dibasic), and the like.
Preferred
hydroxide-releasing agents are metal hydroxides such as sodium hydroxide and
potassium
hydroxide.
It is important that the amount of hydroxide-releasing agent in any patch or
formulation is optimized so as to increase the flux of the drug through the
body surface
while minimizing any possibility of skin damage. In general, this means that
the pH at the
body surface in contact with a formulation or drug delivery system of the
invention (i.e.,
the interface between the body surface and the formulation or delivery system)
should be
in the range of approximately 8.0 to 13, preferably about 8.0 to I 1.5. more
preferably
about 8.5 to 11.5. This will typically although not necessarily mean that the
pH of the
formulation or the drug composition contained within a delivery system will be
in the

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range of approximately 8.0 to 13, preferably about 8.0 to 11.5, more
preferably about 8.5
to 11.5.
For inorganic hydroxides, the amount of hydroxide-releasing agent will
typically
represent about 0.5 wt.% to 4.0 wt.%, preferably about 0.5 wt.% to 3.0 wt.%,
more
preferably about 0.75 wt.% to 2.0 wt.% and optimally about 1.0 wt.%, of a
topically
applied formulation or of a drug reservoir of a drug delivery system, or
"patch." The
aforementioned amount applies to formulations and patches in which the active
agent is
(1) an uncharged molecule, i.e., the phenylpropanolamine is in nonionized,
free base form,
and (2) there are no additional species in the formulation or patch that could
react with or
be neutralized by the inorganic hydroxide. For formulations and patches in
which the
phenylpropanolamine is in the form of an acid addition salt, and/or wherein
there are
additional species in the formulations or systems that can be neutralized by
or react with
the hydroxide-releasing agent (i.e., acidic inactive ingredients), the amount
of inorganic
hydroxide will be the total of ( 1 ) the amount necessary to neutralize the
acid addition salt
and/or other base-neutralizable species, plus (2) about 0.5 wt.% to 4.0 wt.%,
preferably
about 0.5 wt.% to 3.0 wt.%, more preferably about 0.75 wt.% to 2.0 wt.% and
optimally
about 1.0 wt.%, of the formulation or drug reservoir. That is, for an acid
addition salt of
phenylpropanolamine, the inorganic hydroxide should be present in an amount
just
sufficient to neutralize the salt, plus an additional amount (i.e., about 0.5
wt.% to 4.0 wt.%,
preferably about 0.5 wt.% to 3.0 wt.%, more preferably about 0.75 wt.% to 2.0
wt.% and
optimally about 1.0 wt.%) to enhance the flux of the drug through the skin or
mucosal
tissue. For patches, the aforementioned percentages are given relative to the
total dry
weight of the formulation components and the adhesive, gel or liquid
reservoir.
For other hydroxide-releasing agents such as inorganic oxides and metal salts
of
weak acids, the amount of hydroxide-releasing agent in the formulation or drug
delivery
system may be substantially higher, as high as 20 wt.%, in some cases as high
as 25 wt.%
or higher, but will generally be in the range of approximately 2 wt.% to 20
wt.%.
Still greater amounts of hydroxide-releasing agent may be used by controlling
the
rate and/or quantity of release of the hydroxide-releasing agent preferably
during the drug
delivery period itself.

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However, for all hydroxide-releasing agents herein, the optimum amount of any
particular agent will depend on the strength or weakness of the base, the
molecular weight
of the base. and any other acidic species in the formulation or patch. One
skilled in the art
may readily determine the optimum amount for any particular hydroxide-
releasing agent
by ensuring that a formulation or drug delivery system should in all cases be
effective to
provide a pH at the skin surface in the range of about 8.0 to 13, preferably
in the range of
about 8.0 to 11.5, more preferably in the range of about 8.5 to 11.5, during
application to
reach the desired pH at the body surface. This in turn ensures that the degree
of
enhancement is optimized while the possibility of damage to the body surface
is
eliminated or at least substantially minimized.
Other enhancers may be used as an alternative or in addition to the hydroxide-
releasing agent. These enhancers include, for example, the following:
sulfoxides such as
dimethylsulfoxide (DMSO" and decylmethylsulfoxide (C,oMSO); ethers such as
diethylene glycol monoethyl ether (available commercially as Transcutol~) and
diethylene
glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl
sulfate,
cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182,
184),
Tween (20, 40, 60, 80) and lecithin (U.S. Patent No. 4,783,450); the 1-
substituted
azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one
(available under
the trademark Azone~ from Nelson Research & Development Co., Irvine, Cali~;
see U.S.
Patent Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557.934); alcohols such as
ethanol,
propanol, octanol, benzyl alcohol, and the like; fatty acids such as lauric
acid, oleic acid
and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl
palmitate,
methylpropionate, and ethyl oleate; polyols and esters thereof such as
propylene glycol,
ethylene glycol, glycerol, butanediol, polyethylene glycol, and polyethylene
glycol
monolaurate (PEGML; see, e.g., U.S. Patent No. 4,568,343); amides and other
nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide
(DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and
triethanolamine; terpenes; alkanones; and organic acids, particularly
salicylic acid and
salicylates, citric acid and succinic acid. As noted earlier herein,
Percutaneous
Penetration Enhancers, eds. Smith et al. (CRC Press, 1995) provides an
excellent

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overview of the field and further information concerning possible secondary
enhancers for
use in conjunction with the present invention.
It is preferred, however, that a hydroxide-releasing agent be used as the
permeation
enhancer without any other permeation enhancers.
In addition, it is preferred that the pH of the body surface in contact with a
formulation or drug delivery system of the invention (i.e., the interface
between the body
surface and the formulation or delivery system) be in the range of
approximately 8.0 to 13,
preferably about 8.0 to 11.5, most preferably about 8.5 to 11.5. Similarly, it
is preferred
that the pH of the formulation or the drug composition contained within a
delivery system
be in the range of approximately 8.0 to 13, preferably about 8.0 to 11.5, most
preferably
about 8.5 to 11.5.
THE ACTIVE AGENT:
The active agent administered is racemic phenylpropanolamine, i.e., a mixture
of
any two or more of the four isomers of phenylpropanolamine, which, as noted
above, are
(+)-norephedrine, (-)-norephedrine, (+)-norpseudoephedrine, and (-)-
norpseudoephedrine.
Normally, the active agent is (~)-phenylpropanolamine, i.e., a racemic mixture
of (-)-
norephedrine and (+)-norephedrine.
If desired, the racemic phenylpropanolamine can be co-administered with any of
a
number of other active agents. These additional active agents include the
broad classes of
compounds normally delivered through body surfaces and membranes, including
skin. In
general, this includes: analgesic agents; anesthetic agents; antiarthritic
agents; respiratory
drugs, including antiasthmatic agents; anticancer agents, including
antineoplastic drugs;
anticholinergics; anticonvulsants; antidepressants; antidiabetic agents;
antidiarrheals;
antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive
agents;
anti-infective agents such as antibiotics and antiviral agents;
antiinflammatory agents;
antimigraine preparations; antinauseants; antineoplastic agents;
antiparkinsonism drugs;
antipruritics; antipsychotics; antipyretics; antispasmodics; antitubercular
agents; antiulcer
agents; antiviral agents; anxiolytics; appetite suppressants; attention
deficit disorder
(ADD) and attention deficit hyperactivity disorder (ADHD) drugs;
cardiovascular
preparations including calcium channel Mockers, CNS agents; beta-blockers and

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antiarrhythmic agents; central nervous system stimulants; cough and cold
preparations,
including decongestants; diuretics; genetic materials; herbal remedies;
hormonolytics;
hypnotics; hypoglycemic agents; immunosuppressive agents; leukotriene
inhibitors;
mitotic inhibitors; muscle relaxants; narcotic antagonists; nicotine;
nutritional agents, such
as vitamins, essential amino acids and fatty acids; ophthalmic drugs such as
antiglaucoma
agents; parasympatholytics; peptide drugs; psychostimulants; sedatives;
steroids;
sympathomimetics; tranquilizers; and vasodilators including general coronary,
peripheral
and cerebral.
Preferred classes of active agents for coadministration with
phenylpropanolamine
using the present systems and methods are, like phenylpropanolamine, anorectic
agents
and drugs commonly used in allergy and cold preparations. Specific examples of
preferred
active agents for co-administration with phenylpropanolamine include, but are
not limited
to, brompheniramine maleate, chlorpheniramine maleate, clemastine fumarate,
acetaminophen, aspirin, guaifenesin, phenylephrine hydrochloride, and
dextromethorphan
hydrobromide.
FORMULATIONS:
The method of delivery of the racemic phenylpropanolamine may vary, but
necessarily involves application of a formulation or drug delivery system
containing a
hydroxide-releasing agent to a predetermined area of the skin or other tissue
for a period of
time sufficient to provide the desired local or systemic effect. The method
may involve
direct, topical application of the composition as an ointment, gel, cream, or
the like, or
may involve use of a drug delivery device. In either case, water must be
present in order
for the hydroxide-releasing agent to generate hydroxide ions and thus enhance
the flux of
the active agent through the patient's body surface. Thus, a formulation or
drug reservoir
may be aqueous, i.e., contain water, or may be nonaqueous and used in
combination with
an occlusive overlayer so that moisture evaporating from the body surface is
maintained
within the formulation or transdermal system during drug administration. In
some cases,
however, e.g., with an occlusive gel, a nonaqueous formulation may be used
with or
without an occlusive layer.

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Suitable formulations include ointments, creams, gels, lotions, pastes, and
the like.
Ointments, as is well known in the art of pharmaceutical formulation, are
semisolid
preparations that are typically based on petrolatum or other petroleum
derivatives. The
specific ointment base to be used, as will be appreciated by those skilled in
the art, is one
that will provide for optimum drug delivery, and, preferably, will provide for
other desired
characteristics as well, e.g., emolliency or the like. As with other carriers
or vehicles, an
ointment base should be inert, stable, nonirritating and nonsensitizing. As
explained in
Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, PA: Mack
Publishing Co., 1995), at pages 1399-1404, ointment bases may be grouped in
four
classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-
soluble bases.
Oleaginous ointment bases include, for example, vegetable oils, fats obtained
from
animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable
ointment
bases, also known as absorbent ointment bases, contain little or no water and
include, for
example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
Emulsion
ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (0/W)
emulsions,
and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and
stearic acid.
Preferred water-soluble ointment bases are prepared from polyethylene glycols
of varying
molecular weight; again, see Remington: The Science and Practice of Pharmacy
for
further information.
Creams, as also well known in the art, are viscous liquids or semisolid
emulsions,
either oil-in-water or water-in-oil. Cream bases are water-washable, and
contain an oil
phase, an emulsifier and an aqueous phase. The oil phase, also called the
"internal" phase,
is generally comprised of petrolatum and a fatty alcohol such as cetyl or
stearyl alcohol.
The aqueous phase usually, although not necessarily, exceeds the oil phase in
volume, and
generally contains a humectant. The emulsifier in a cream formulation is
generally a
nonionic, anionic, cationic or amphoteric surfactant.
As will be appreciated by those working in the field of pharmaceutical
formulation,
gels are semisolid, suspension-type systems. Single-phase gels contain organic
macromolecules distributed substantially uniformly throughout the carrier
liquid, which is
typically aqueous, but also, preferably, contain an alcohol and, optionally,
an oil. Preferred
"organic macromolecules," i.e., gelling agents, are crosslinked acrylic acid
polymers such

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as the "carbomer" family of polymers, e.g., carboxypolyalkylenes that may be
obtained
commercially under the Carbopol~ trademark. Also preferred are hydrophilic
polymers
such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and
polyvinylalcohol; cellulosic polymers such as hydroxypropyl cellulose,
hydroxyethyl
cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose
phthalate, and
methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate;
and gelatin.
In order to prepare a uniform gel, dispersing agents such as alcohol or
glycerin can be
added, or the gelling agent can be dispersed by trituration, mechanical mixing
or stirring,
or combinations thereof.
Lotions, as is known in the art, are preparations to be applied to the skin
surface
without friction, and are typically liquid or semiliquid preparations in which
solid
particles, including the active agent, are present in a water or alcohol base.
Lotions are
usually suspensions of solids, and preferably, for the present purpose,
comprise a liquid
oily emulsion of the oil-in-water type. Lotions are preferred formulations
herein for
treating large body areas, because of the ease of applying a more fluid
composition. It is
generally necessary that the insoluble matter in a lotion be finely divided.
Lotions will
typically contain suspending agents to produce better dispersions as well as
compounds
useful for localizing and holding the active agent in contact with the skin,
e.g.,
methylcellulose, sodium carboxymethyl-cellulose, or the like.
Pastes are semisolid dosage forms in which the active agent is suspended in a
suitable base. Depending on the nature of the base, pastes are divided between
fatty pastes
or those made from a single-phase aqueous gels. The base in a fatty paste is
generally
petrolatum or hydrophilic petrolatum or the like. The pastes made from single-
phase
aqueous gels generally incorporate carboxymethylcellulose or the like as a
base.
Formulations may also be prepared with liposomes, micelles, and microspheres.
Liposomes are microscopic vesicles having a lipid wall comprising a lipid
bilayer, and can
be used as drug delivery systems herein as well. Liposome preparations for use
in the
instant invention include cationic (positively charged), anionic (negatively
charged) and
neutral preparations. Cationic liposomes are readily available. For example,
N[1-2,3-
dioleyloxy)propyl~-N,N,N-triethylammonium (DOTMA) liposomes are available
under
the tradename Lipofectin~ (GIBCO BRL, Grand Island, NY). Similarly, anionic
and

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neutral liposomes are readily available as well, e.g., from Avanti Polar
Lipids
(Birmingham, AL), or can be easily prepared using readily available materials.
Such
materials include phosphatidyl choline, cholesterol, phosphatidyl
ethanolamine,
dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG),
dioleoylphoshatidyl ethanolamine (DOPE), among others. These materials can
also be
mixed with DOTMA in appropriate ratios. Methods for making liposomes using
these
materials are well known in the art.
Micelles are known in the art as comprised of surfactant molecules arranged so
that
their polar headgroups form an outer spherical shell, while the hydrophobic,
hydrocarbon
chains are oriented towards the center of the sphere, forming a core. Micelles
form in an
aqueous solution containing surfactant at a high enough concentration so that
micelles
naturally result. Surfactants useful for forming micelles include. but are not
limited to,
potassium laurate, sodium octane sulfonate, sodium decane sulfonate, sodium
dodecane
sulfonate, sodium lauryl sulfate, docusate sodium, decyltrimethylammonium
bromide,
dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,
tetradecyltrimethylammonium chloride, dodecylammonium chloride, polyoxyl 8
dodecyl
ether, polyoxyl 12 dodecyl ether, nonoxynol 10 and nonoxynol 30. Micelle
formulations
can be used in conjunction with the present invention either by incorporation
into the
reservoir of a topical or transdermal delivery system, or into a formulation
to be applied to
the body surface.
Microspheres, similarly, may be incorporated into the present formulations and
drug delivery systems. Like liposomes and micelles, microspheres essentially
encapsulate
a drug or drug-containing formulation. They are generally although not
necessarily
formed from lipids, preferably charged lipids such as phospholipids.
Preparation of lipidic
microspheres is well known in the art and described in the pertinent texts and
literature.
Various additives, known to those skilled in the art, may be included in the
phenylpropanolamine compositions. For example, solvents, including relatively
small
amounts of alcohol, may be used to facilitate solubilization of the active
agent. Other
optional additives include opacifiers, antioxidants, fragrance, colorant,
gelling agents,
thickening agents, stabilizers, and the like. Other agents may also be added,
such as
antimicrobial agents, to prevent spoilage upon storage, i.e., to inhibit
growth of microbes

CA 02395289 2002-06-17
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such as yeasts and molds. Suitable antimicrobial agents are typically selected
from the
group consisting of the methyl and propyl esters of p-hydroxybenzoic acid
(i.e., methyl and
propyl paraben), sodium benzoate, sorbic acid, imidurea, and combinations
thereof.
The concentration of the active agent in the formulation can vary a great
deal, and
will depend on a variety of factors, including the disease or condition to be
treated, the
desired effect, the ability and speed of the active agent to reach its
intended target, and
other factors within the particular knowledge of the patient and physician.
Preferred
formulations will typically contain on the order of about 10 wt.% to 30 wt.%
racemic
phenylpropanolamine, optimally about 15 wt.% to 25 wt.% racemic
phenylpropanolamine.
TRANSDERMAL DELIVERY SYSTEMS:
An alternative and preferred method for administering racemic
phenylpropanolamine transdermally involves the use of a drug delivery system,
e.g., a
topical or transdermal "patch," wherein the active agent is contained within a
laminated
structure that is to be affixed to the skin. In such a structure, the drug
composition is
contained in a layer, or "reservoir," underlying an upper backing layer. The
laminated
structure may contain a single reservoir, or it may contain multiple
reservoirs.
In one embodiment, the reservoir comprises a polymeric matrix of a
pharmaceutically acceptable adhesive material that serves to affix the system
to the skin
during drug delivery; typically, the adhesive material is a pressure-sensitive
adhesive
(PSA) that is suitable for long-term skin contact, and which should be
physically and
chemically compatible with the active agent, hydroxide-releasing agent, and
any carriers,
vehicles or other additives that are present. Examples of suitable adhesive
materials
include, but are not limited to, the following: polyethylenes; polysiloxanes;
polyisobutylenes; polyacrylates; polyacrylamides; polyurethanes; plasticized
ethylene-
vinyl acetate copolymers; and tacky rubbers such as polyisobutene,
polybutadiene,
polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and
neoprene
(polychloroprene). Preferred adhesives are polyisobutylenes.
The backing layer functions as the primary structural element of the
transdermal
system and provides the device with flexibility an, preferably, occlusivity.
The material
used for the backing layer should be inert and incapable of absorbing drug,
hydroxide-

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releasing agent or components of the formulation contained within the device.
The
backing is preferably comprised of a flexible elastomeric material that serves
as a
protective covering to prevent loss of drug and/or vehicle via transmission
through the
upper surface of the patch, and will preferably impart a degree of occlusivity
to the system,
such that the area of the body surface covered by the patch becomes hydrated
during use.
The material used for the backing layer should permit the device to follow the
contours of
the skin and be worn comfortably on areas of skin such as at joints or other
points of
flexure, that are normally subjected to mechanical strain with little or no
likelihood of the
device disengaging from the skin due to differences in the flexibility or
resiliency of the
skin and the device. The materials used as the backing layer are either
occlusive or
permeable, as noted above, although occlusive backings are preferred, and are
generally
derived from synthetic polymers (e.g., polyester, polyethylene, polypropylene,
polyurethane, polyvinylidine chloride, and polyether amide), natural polymers
(e.g.,
cellulosic materials), or macroporous woven and nonwoven materials.
During storage and prior to use. the laminated structure includes a release
liner.
Immediately prior to use, this layer is removed from the device so that the
system may be
affixed to the skin. The release liner should be made from a drug/vehicle
impermeable
material, and is a disposable element which serves only to protect the device
prior to
application. Typically, the release liner is formed from a material
impermeable to the
pharmacologically active agent and the hydroxide-releasing agent, and which is
easily
stripped from the transdermal patch prior to use.
In an alternative embodiment, the drug-containing reservoir and skin contact
adhesive are present as separate and distinct layers, with the adhesive
underlying the
reservoir. In such a case, the reservoir may be a polymeric matrix as
described above.
Alternatively, the reservoir may be comprised of a liquid or semisolid
formulation
contained in a closed compartment or "pouch," or is may be a hydrogel
reservoir, or may
take some other form. Hydrogel reservoirs are particularly preferred herein.
As will be
appreciated by those skilled in the art, hydrogels are macromolecular networks
that absorb
water and thus swell but do not dissolve in water. That is, hydrogels contain
hydrophilic
functional groups that provide for water absorption, but the hydrogels are
comprised of
crosslinked polymers that give rise to aqueous insolubility. Generally, then,
hydrogels are

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comprised of crosslinked hydrophilic polymers such as a polyurethane, a
polyvinyl
alcohol, a polyacrylic acid, a polyoxyethylene, a polyvinylpyrrolidone, a
poly(hydroxyethyl methacrylate) (poly(HEMA)), or a copolymer or mixture
thereof.
Particularly preferred hydrophilic polymers are copolymers of HEMA and
polyvinylpyrrolidone.
Additional layers, e.g., intermediate fabric layers and/or rate-controlling
membranes, may also be present in any of these drug delivery systems. Fabric
layers may
be used to facilitate fabrication of the device, while a rate-controlling
membrane may be
used to control the rate at which a component permeates out of the device. The
component
may be a drug, a hydroxide-releasing agent, an additional enhancer, or some
other
component contained in the drug delivery system.
A rate-controlling membrane, if present, will be included in the system on the
skin
side of one or more of the drug reservoirs. The materials used to form such a
membrane
are selected to limit the flux of one or more components contained in the drug
formulation.
Representative materials useful for forming rate-controlling membranes include
polyolefins such as polyethylene and polypropylene, polyamides, polyesters,
ethylene-
ethacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl
methylacetate
copolymer, ethylene-vinyl ethylacetate copolymer, ethylene-vinyl propylacetate
copolymer, polyisoprene, polyacrylonitrile, ethylene-propylene copolymer, and
the like.
Generally, the underlying surface of the transdermal device, i.e., the skin
contact
area, has an area in the range of about 5 cm' to 200 cm', preferably 5 cm' to
100 cm'. more
preferably 20 cm' to 60 cm'. That area will vary, of course, with the amount
of the drug to
be delivered and the flux of the drug through the body surface. Larger patches
will be
necessary to accommodate larger quantities of drug, while smaller patches can
be used for
small quantities of drug and/or drugs that exhibit a relatively high
permeation rate.
Such drug delivery systems may be fabricated using conventional coating and
laminating techniques known in the art. For example adhesive matrix systems
can be
prepared by casting a fluid admixture adhesive, drug and vehicle onto the
backing layer
followed by lamination of the release liner. Similarly the adhesive mixture
may be cast
onto the release liner, followed by lamination of the release liner.
Alternatively. the drug
reservoir may be prepared in the absence of drug or excipient, and then loaded
by

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"soaking" in a drug/vehicle mixture. In general, transdermal systems of the
invention are
fabricated by solvent evaporation, film casting, melt extrusion, thin film
lamination. die
cutting, or the like. The hydroxide-releasing agent will generally be
incorporated into the
device during patch manufacture rather than subsequent to preparation of the
device. For
active agents that are obtained in salt form, an enhancer that doubles as a
neutralizing
agent is incorporated into the device during patch manufacture rather than
subsequent to
preparation of the device. Thus, for acid addition salts of PPA, e.g., the
hydrochloride salt
of racemic phenylpropanolamine, a basic enhancer such as a hydroxide-releasing
agent
will neutralize the drug during manufacture of the transdermal system,
resulting in a final
drug delivery device in which the drug is present in nonionized, neutral form,
preferably
along with an excess of the basic compound to serve as a permeation enhancer.
In a preferred delivery system, an adhesive overlayer that also serves as a
backing
for the delivery system is used to better secure the patch to the body
surface. This
overlayer is sized such that it extends beyond the drug reservoir so that
adhesive on the
overlayer comes into contact with the body surface. The overlayer is useful
because the
adhesive/drug reservoir layer may lose its adhesion a few hours after
application due to
hydration. By incorporating such an adhesive overlayer, the delivery system
remains in
place for the required period of time.
Other types and configurations of transdermal drug delivery systems may also
be
used in conjunction with the method of the present invention, i.e., the use of
a hydroxide-
releasing agent as a permeation enhancer, as will be appreciated by those
skilled in the art
of transdermal drug delivery. See, for example, Ghosh, Transdermal and Topical
Drug
Delivery Systems (Interpharm Press, 1997), particularly Chapters 2 and 8.
As with the formulations of the invention discussed in the preceding section.
the
composition containing the racemic phenylpropanolamine within the drug
reservoirs) of
these laminated system may contain a number of components. In some cases. the
drug and
hydroxide-releasing agent may be delivered "neat," i.e., in the absence of
additional
liquid. In most cases, however, the drug will be dissolved, dispersed or
suspended in a
suitable pharmaceutically acceptable vehicle, typically a solvent or gel.
Other components
which may be present include preservatives, stabilizers. surfactants, and the
like.

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UTILITY AND ADMINISTRATION:
The formulations and delivery systems of the invention are useful for
transdermal
administration of racemic phenylpropanolamine to treat any condition, disease
or disorder
that is responsive to administration of phenylpropanolamine. Typically, the
formulations
and delivery systems of the invention are used to administer
phenylpropanolamine as an
anorectic agent (i.e., for appetite suppression), as a decongestant, as an
anxiolytic agent, or
to decrease fatigue and confusion. Most commonly, the drug is used as either
an anorectic
agent or a decongestant.
The daily dosage administered will, of course, vary from subject to subject
and
depend on the particular disorder or condition, the severity of the symptoms,
the subject's
age, weight and general condition, and the judgment of the prescribing
physician. Other
factors specific to transdermal drug delivery include the solubility and
permeability of the
carrier and adhesive layer in a drug delivery system, if one is used, and the
period of time
for which such a device will be affixed to the skin or other body surface.
Generally,
however, a daily dosage of racemic phenylpropanolamine using the present
formulations
and delivery systems will be in the range of about 10 mg/day to about 250
mg/day,
preferably about 25 mg/day to about 200 mg/day.
The invention accordingly provides a novel and highly effective means for
administering racemic phenylpropanolamine through the body surface (skin or
mucosal
tissue) of a human or animal. Surprisingly, the increase in permeation
achieved by co-
administration of a basic enhancer is not accompanied by any noticeable tissue
damage,
irritation, or sensitization. The invention thus represents an important
advance in the field
of transdermal drug delivery.
The practice of the present invention will employ, unless otherwise indicated,
conventional techniques of drug formulation, particularly topical drug
formulation. which
are within the skill of the art. Such techniques are fully explained in the
literature. See
Remington: The Science and Practice of Pharmacy, cited supra, as well as
Goodman &
Gilman's The Pharmacological Basis of Therapeutics, 9th Ed. (New York: McGraw-
Hill,
1996).

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It is to be understood that while the invention has been described in
conjunction
with the preferred specific embodiments thereof, the foregoing description, as
well as the
examples which follow, are intended to illustrate and not limit the scope of
the invention.
Other aspects, advantages and modifications will be apparent to those skilled
in the art to
which the invention pertains.
The following examples are put forth so as to provide those of ordinary skill
in the
art with a complete disclosure and description of how to make and use the
compounds of
the invention, and are not intended to limit the scope of what the inventors
regard as their
invention. Efforts have been made to ensure accuracy with respect to numbers
(e.g.,
amounts, temperature, etc.) but some errors and deviations should be accounted
for.
Unless indicated otherwise, parts are parts by weight, temperature is in
°C and pressure is
at or near atmospheric.
EXAMPLE 1
An in vitro skin permeation study was conducted using four phenylpropanolamine
hydrochloride (PPA-HC1) transdermal systems. The formulations used to prepare
these
systems are listed in Table 1, which includes weight and weight percent of
each
component in the formulations. The weight of sodium hydroxide was 0 g, 0.16 g,
0.195
g, and 0.23 g for formulation #PPA-N7, -Nl, -N2, -and -N5, respectively. Each
formulation was coated onto a release liner and dried in an oven at
55°C for two hours to
remove water and other solvents. The dried drug-in-adhesive/release liner film
was
laminated to a backing film. The backing/drug-in-adhesive/release liner
laminate was then
cut into round discs with a diameter of 11/16 inch. The theoretical percent
weight for each
component after drying (calculated assuming all the volatile ingredients were
completely
removed during drying) is listed in Table 2.
The in vitro permeation of PPA-HCl through human cadaver skin from these discs
was performed using Franz-type diffusion cells with a diffusion area of 1 cm'-
. The
volume of receiver solution was 8 ml. Human cadaver skin was cut to the
desired size and
placed on a flat surface with the stratum corneum side facing up. The release
liner was
peeled away from the disc laminate. The backing/drug-in-adhesive film was
placed and
pressed on the skin with the adhesive side facing the stratum corneum. The

3~-~1-2002 . , CA 02395289 2002-06-17
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skin/adhesive/backing laminate was clamped between the donor and receiver
chambers of
the diffusion cell with the skin side facing the receiver solution. Three
diffusion cells were
used for each formulation.
The cells were filled with DI water. The receiver solution was completely
withdrawn and replaced with fresh DI water at each time point. The samples
taken were
analyzed by an HPLC for the concentration of PPA-HCl in the receiver solution.
The
cumulative amount of PPA-HCl that permeated across the human cadaver skin was
calculated using the measured PPA-HCl concentrations in the receiver
solutions, which
were plotted versus time and shown in FIG. 1.
Since PPA-HCl is an acid addition salt of a free base, it reacts with NaOH.
The
concentration of NaOH in the system after the reaction is completed depends on
the
amount of PPA-HCl added. The remaining NaOH concentration after the reaction
is
completed is defined as "excess NaOH concentration," calculated as explained
in the
foregoing example. The excess NaOH concentration for four PPA-HCl systems,
#PPA-N7,
-N1, -N2, -and -N5, were calculated and listed in Table 3.
The pH of the patch was measured using the following procedures. A 2.5 cm2
circular patch was punched out. Ten ml purified water was pipetted into a
glass vial, and a
stir bar was added; the liner was removed from the patch and placed in the
vial along with
the patch. The vial was then placed on a stir plate and the water/patch/liner
mixture was
stirred fox 5 minutes, at which point the liner was removed from the vial and
discarded.
The vial was again placed on a stir plate and stirring continued for an
additional 18 hours.
After 18 hours, the stir bar was removed from the vial and the pH of the
solution
determined using a calibrated pH meter. The measured pHs for the PPA-HCl
transdermal
systems are listed in Table 3.
AMENDED SHEET

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Table 1
Weight and Weight Percent of Each Component (Based on Total Solution Weight)
for Four PPA-HCl Transdermal Systems
PPA-N7 PPA-N1 PPA-N2 PPA-NS
PPA-HC1 0.75 g 0.75 g (8.2%)0,75 g ($.1%)0.75 g (8.1%)
(8.S%)
NaOH 0 0.165 g 0.195 g 0.23 g (2.S%)
( 1.8%) (2.1 %)
DI water 1.1 g (12.4%)1265 g (13.8%)1.295 g 1.33 g (14.3%)
(14.0'/0)
Propylene glycol 0.5 g (S.6%)0.5 g (S.4%)0.S g (S.4%)O.S g (S.4%)
Methylal I g (11.3%)1 g (10.9%)1 g (10.8%)I g (10.7%)
Heptane 1.5 g (16.9%)1.5 g (16.3%)1.5 g (16.2%)I.S g (16.1%)
PIB adhesive (30%4 g (45.2%)4 g (43.6%)4 g (43.3%)4 g (43.0'/0)
solid)
Table 2
Weight and Theoretical Weight Percent of Each Component in the Dried Film
for Four PPA-HCl Transdermal Systems
PPA-N7 PPA-N1 PPA-N2 PPA-NS
PPA-HCI 0.75 g 0.75 g (28.7%)0.75 g 0.75 g (28.0%)
(30.6%) (28.4%)
NaOH 0 0.165 g (6.3%)0.195 g 0.23 g (8.6%)
(7.4%)
PIB adhesive 1.2 g (49.0%)1.2 g (45.90I .2 g I .2 g (44.8%)
(45.4%)
Propylene glycol 0.5 g (20.4%)O.S g ( 19.10.5 g ( O.S g (
%) I $.9%) 18.7%)
Table 3
Excess NaOH Concentration and pH of Four PPA-HCl Transdennal Systems
PPA-N7 PPA-N1 PPA-N2 PPA-NS
Excess NaOH Concentration 0.20 % I .33 % 2.62 %
(wt. %)
pH 7.33 10.08 10.16 10.88
Even though patch #PPA-Nl contained 6.3% NaOH (Table 2), the cumulative amount
of
PPA-HCl that permeated across the human cadaver skin at 24 hours from this
formulation
(1.35 mg/cm2, FIG. 1) was only slightly higher than that from the formulation
without
NaOH (PPA-N7, 0.56 mg/cm2). This may be due to the consumption of NaOH by the
CA 02395289 2002-06-17
AMENDED SHEET

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reaction between NaOH and PPA-HCI, which reduced the NaOH concentration to
only
0.20% as the excess NaOH concentration shown in Table 3. This result indicated
that the
permeation of PPA-HCI could be enhanced with an excess NaOH concentration as
low as
0.20%.
The cumulative amount of PPA-HCl across human cadaver skin at 24 hours
increased from 1.35 mg/cm2 to 5.99 mg/cm2 when the calculated excess NaOH
concentration in the dried patch was increased from 0.20% to 2.62%. The
cumulative
amount of PPA-HCl across human cadaver skin at 24 hours from the formulation
with an
excess NaOH concentration of 1.33% (PPA-N2, 5.2 mg/cm2) is about 5 times
higher than
that from the formulation with an excess NaOH concentration of 0.20% (PPA-N1,
1.35
mg/cm2).
The pH of the PPA-HCl patch increased from I 0.08 to 10.88 when the calculated
excess NaOH concentration in the dried patch was increased from 0.20% to
2.62%. Skin
irritation could be related to the pH of the patch, which depends on the
excess NaOH
concentration.
EXAMPLE 2
An in vitro skin permeation study was conducted using four phenylpropanolamine
hydrochloride (PPA-HCl) transdermal systems. The formulations used to prepare
these
systems are listed in Table 4, which includes weight and weight percent of
each component
in the formulations. The weight of sodium carbonate (Na2C0;) was 0 g, 0.29 g,
0.44 g,
and 0.74 g for formulations #PPA-PCI, -PC2, -PC3, and -PC4 respectively. The
matrix
patches were prepared and evaluated using the same procedures as set forth in
Example 1.
The theoretical percent weight for each ingredient after drying (calculated
assuming all the
volatile ingredients were completely removed during drying) is listed in Table
5. The
cumulative amount of PPA-HCI across human cadaver skin was calculated using
the
measured PPA-HCl concentrations in the receiver solutions, which are shown in
Table 6
and FIG. 2.
AMENDED SHEET

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added. The remaining sodium carbonate concentration after the reaction is
completed is
defined as "excess Na,C03 concentration," which is calculated by the following
equation.
~Na~CO~ excess ~a?C~3 total ~a?CO3 needed for neutralization
The excess Na~C03 concentration for four PPA-HC1 systems, #PPA-PC1, -PC2,
-PC3 and -PC4 were calculated and listed in Table 7.
The pH of the patch was determined using the procedure of example 1 and the
results are listed in Table 7.
Table 4
Weight and Weight Percent of Each Component (Based on Total Solution Weight)
for Four PPA-HC1 Transdermal Systems
PPA-PCl PPA-PC2 PPA-PC3 PPA-PC4
PPA-HCl 0.5 g (6.7%)0.5 g (5.7%)0.5 g (5.6%)0.5 g (5.5%)
Na,C03 0 0.29 g (3.3%)0.44 g (5.0%)0.74 g (8.1
%) ~I
DI water 1.0 g (13.5%)2.0 g (23.0%)2.0 g (22.6%)2.0 g (21.9%)
Methyl alcohol0.5 g (6.7%)0.5 g (5.7%)0.5 g (5.6%)0.5 g (5.5%)
Propylene 0.2 g (2.7%)0.2 g (2.3%)0.2 g (2.3%)0.2 g (2.2%)
glycol
HPMC 0.01 g (0.1 0.01 g (0.1 0.01 g (0.1 0.01 g (0.1
%) %) %) %)
Heptane 1.2 g (16.2%)1.2 g (13.8%)1.2 g (13.6%)1.2 g (13.1%)
PIB adhesive 4 g (54.0%) 4 g (46.0%) 4 g (45.2%) 4 g (45.2%)
(30% solid)

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Table 5
Weight and Theoretical Weight Percent of Each Component in the Dried Film for
Four PPA-HCl Transdermal Systems
PPA-PC1 PPA-PC2 PPA- PPA-PC4
PC3
PPA-HCl 0.5 g (26.2%)0.5 g (22.7%)0.5 g (21.3%)0.5 g (18.9%)
NazC03 0 0.29 g ( 0.44 g ( 0.74 g (27.9%)
13.2%) 18.7%)
Propylene 0.2 g (I0.5%)0.2 g (9.1%)0.2 g (8.5%)0.2 g (7.5%)
glycol
HPMC 0.01 g (0.5%)0.01 g (0.5%)0.01 g (0.4%)0.01 g (0.4/a}
PIB adhesive 1.2 62.8% 1.2 (54.5%) 1.2 51.1 1.2 45.3%
%
Table 6
Cumulative Amount of PPA-HCl across human cadaver skin for
PPA-HCI Transdermal Systems (pg/cm2)
PPA-PC 1 PPA-PC2 PPA-PC3 PPA-PC4
S hours 152.8 68.0 81.1 144.8
1 S hours 359.5 222.7 400.8 631.2
19 hours 442.7 295.7 551.5 8
64,3
24 hours 545.1 410.4 705.6 _
1147.5
ble 7
Excess NazC03 Concentration and pH of Four PPA-HC1 Transdermal Systems
PPA-PC PPA-PC2 PPA-PC3 PPA-PC4
1
Excess NazC03 Concentration - 0.4 % 6.? % 16.7%
(wt. %)
H 6.54 9.81 9.86 10.17
Even though patch #PPA-PC2 contained 13.2% NazC03 (Table 5), the cumulative
amount of PPA-HCI that permeated across the human cadaver skin at 24 hours
(410.4
~tg/cm2, Table 6) was lower than that from the formulation without NazC03 (PPA-
PC l,
545.1 ~g/cm2). This may be due to the consumption of NazC03 by the reaction
between
NazC03 and PPA-HCI, which reduced the NazC03 concentration to only 0.4 % as
the
excess NazC03 concentration (Table 7).
AMENDED SHEET

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When the calculated excess Na,C03 concentration in the dried patch was further
increased from 0.4% to 16.7%, the cumulative amount of PPA-HCl that permeated
across
the human cadaver skin at 24 hours was increased from 410.4 to 1147.5 ~g/cm'.
This
result indicated that the permeation of PPA-HCl could be enhanced by Na~CO,,
even
though the required excess Na~CO; concentration is higher than that of NaOH.
Greater
amounts of Na,C03 may be necessary because it is a weaker base compared to
NaOH and
the molecular weight of Na~C03 is higher than that of NaOH.
The pH of the PPA-HCl patch measured using the procedures listed above
increased from 9.81 to 10.17 when the calculated excess Na,CO; concentration
in the dried
patch was increased from 0.4% to 16.7%.
EXAMPLE 3
An in vitro skin permeation study was conducted using four phenylpropanolamine
hydrochloride (PPA-HCl) transdermal systems. The formulations used to prepare
these
systems are listed in Table 8, which includes weight and weight percent of
each
component in the formulations. The weight of potassium phosphate, tribasic
(K;PO~) was
0 g, 0.57 g, 0.6 g, and 0.66 g for formulation #PPA-PK1, -PK2, -PK3, and -PK4
respectively. The matrix patches were prepared and evaluated using the same
procedures
as set forth in Example 1. The theoretical percent weight for each ingredient
after drying
(calculated assuming all the volatile ingredients were completely removed
during drying)
is listed in Table 9. The cumulative amount of PPA-HCl across human cadaver
skin was
calculated using the measured PPA-HCl concentrations in the receiver
solutions, which
were shown in Table 10 and FIG. 3.
Since PPA-HCl is a salt of a free base, it reacts with K;PO~. The
concentration of
K3P04 in the system after the reaction is completed depends on the amount of
PPA-HCl
added. The remaining K3P0~ concentration after the reaction is completed is
defined as
"excess K;P04 concentration," which is calculated by the following equation.
[K;PO~ excess) _- [K~POa totan - [K;POa needed for neutralization
The excess K;PO:~ concentration for four PPA-HCI systems, #PPA-PK1, -PK2,

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- 33 -
-PK3 and -PK4 were calculated and listed in Table 11.
The pH of the patch was determined using the procedure of Example 1 and the
results are listed in Table 11.
Table 8
Weight and Weight Percent of Each Component (Based on Total Solution Weight)
for Four PPA-HCl Transdermal Systems
PPA-PK 1 PPA-PKZ PPA-PK3 PPA-PK4
PPA-HCl 0.5 g (6.6%)0.5 g (6.1 0.5 g (6.1 0.5 g (6.1
%) %) %)
K3P0, 0 0.57 g (7.0%)0.6 g (7.3%)0.66 g (8.0%)
DI water 1.0 g (13.2%)1.0 g (12.2%)1.0 g (12.2%)1.0 g (12.1
%)
Propylene glycol0.5 g (6.6 0.5 g (6.1 0.5 g (6.1 0.5 g (6.1
%) %) %) %)
Methyl alcohol0.5 g (6.6%)0.5 g (6.1 0.5 g (6.1 0.5 g (6.1
%) %) %)
PIB adhesive 4 g (52.6 4 g (49.0 4 g (48.8 4 g (48.4
(30 % % ) %) % ) %)
solid)
HPMC 0.1 g (1.3%)0.1 g (1.2%)0.1 g (1.2%)0.1 g (1.2%)
He Lane 1 13.2 % 1 12.2 % 1 12.2 % 1 12.1 %
Table 9
Weight and Theoretical Weight Percent of Each Component in the Dried Film for
Four
PPA-HCl Transdermal Systems
PPA-PK 1 PPA-PK2 PPA-PK3 PPA-PK4
PPA-HCl 0.5 g (21.7%)0.5 g (17.4%)0.5 g (17.2%)0.5 g (16.9%)
K3P04 0 0.57 g (19.9%)0.6 g (20.7%)0.66 g (22.3%)
Propylene glycol0.5 g (21.7%)0.5 g (I7.4%)0.5 g (17.2%)0.5 g (I6.996)
PIB adhesive 1. 2 g (52.1.2 g (41. 1.2 g (41.4 1. 2 g (40.
2 % ) 8 % ) % ) 5 % )
HPMC 0.1 4.3% 0.1 3.5% 0.1 3.4% 0.1 3.46
AMENDED SHEET

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-34-
able
Cumulative Amount of PPA-HC1 across human cadaver skin for
PPA-HCl Transdermal Systems (~g/cm=)
S PPA-PK 1 PPA-PK2- ppA-PK3 PpA-PK4
hours 94.7 660.0 421.6 362.9
16 hours 445.9 1701.3 1420.3 1607.5
20 hours 576.8 1919.2 1633.1 1872.5
24 hours 680.5 2055.2 1762.9 2021.1
a 1e 11
Excess K3P04 Concentration and pH of Four PPA-HCI Transdermal Systems
PPA-PKI PPA-PK2 PPA-PK3 PPA-PK4
Excess K3P04 Concentration- 0.2 % 1.2 % 3.2%
(Wrt. %)
H 6.75 9.68 9.62 10.08
The cumulative amount of PPA-HCl that permeated across the human cadaver skin
at 24 hours for PPA-PK2 (2055.2 ~g/cm2, Table 10) with a calculated excess
K3P04
concentration of 0.2% was three times higher than that from the formulation
without
K3P04 (PPA-PK1, 680.5 ~tg/cm2). This result indicated that the permeation of
PPA-HCI
could be enhanced with an excess K3P04 concentration as low as 0.2%.
The cumulative amount of PPA-HCl across human cadaver skin at 24 hours
remained about the same when the excess K3P04 concentration in the dried patch
was
increased from 0.2% to 3.2% (Tables 10 and 11 ).
The pH of the PPA-HCI patch measured using the procedures listed above
increased from 6.75 to 9.68 when the K,P04 concentration in the dried patch
was increased
from 0% to 19.9'/0 (or 0.2% excess K3P04 concentration, Tables 9 and 11).
However, the
pH of the PPA-HCl patch remained about the same when the excess K3P04
concentration
in the dried patch was further increased from 0.2% to 3.2% (Table 11 ).
CA 02395289 2002-06-17
AMENDED SHEET

30-01-2002 . CA 02395289 2002-06-17
Atty. Dkt.: 3200_10003.40
-35-
EXAMPLE 4
An in vitro skin permeation study was conducted using four phenylpropanolamine
hydrochloride (PPA-HCl) transdermal systems. The formulations used to prepare
these
systems are listed in Table 12, which includes weight and weight percent of
each
component in the formulations. The weight of potassium phosphate, tribasic
(K3P04) was
0 g, 0.57 g, 0.73 g, and 1.05 g for formulation #PPA-PK 1 R, -PK2R, -PKS, and -
PK6
respectively. The matrix patches were prepared and evaluated using the same
procedures
as set forth in Example 1. The theoretical percent weight for each ingredient
after drying
(calculated assuming all the volatile ingredients were completely removed
during drying)
is listed in Table 13. The cumulative amount of PPA-HCl across human cadaver
skin was
calculated using the measured PPA-HCl concentrations in the receiver
solutions, which
were shown in Table 14 and FIG. 4.
The excess K3P04 concentration for four PPA-HCl systems, #PPA-PK1R, -PK2R, -
PKS and -PK6 were calculated using the procedure of Example 3 and the results
are listed
in Table 15. The pH of each patch was determined using the procedure of
Example l and
the results are listed in Table 15.
Table 12
Weight and Weight Percent of Each Component (Based on Total Solution Weight)
for Four PPA-HCl Transdermal Systems
PPA-PK 1 ~ PPA-PK2R PPA-PKS PPA-PK6
R ~
PPA-HCl 0.5 g (6.9%)0.5 g (6.4%)0.5 g (6.3%)0.5 g (6.1%)
K3P04 0 0.57 g (7.3%)0.73 g (9.2%)1.05 g (12.7%)
DI water 1.0 g ( 1.0 g ( 12.9%)1.0 g ( 12.6%)1.0 g ( 12.1
13.9%) %}
Methyl alcohol0.5 g (6.9%)0.5 g (6.4%)0.5 g (6.3%)0.5 g (6.1%)
Propylene glycol0.2 g (2.8%)0.2 g (2.6%)0.2 g (2.5%)0.2 g (2.4%)
HPMC 0.0 I g 0.01 g (O. 0.01 g (0.1 0.01 g (0.1
(0.1 %) I %) %) %)
Heptane 1 g ( 13.9%)1 g ( 12.9%)1 g ( 12.6%}I g ( 12.1
%)
PIB adhesive 4 g (55.5%)4 g (51.4%) 4 g (50.4%) 4 g (48.4%)
[ (30% solid) [
I
AMENDED SHEET

CA 02395289 2002-06-17
30-01-2002 , , US0034091
Atty. Dkt.: 3200-QOOCi.40
-36-
Ta 1e 13
Weight and Theoretical Weight Percent of Each Component in the Dried Film for
Four PPA-HCl Transdermal Systems
PPA-PKIR PPA-PK2R PPA-PK5 PPA-PK6
PPA-HC1 0.5 g (26.2%)0.5 g (20.2%)0.5 g (18.9'/0)0.5 g (16.5%)
K3P04 0 0.57 g (23.6%)0.73 g (27.7%)1.05 g (35.5/a)
Propylene glycol0.2 g ( 0.2 g (8. 0.2 g (7.6%)0.2 g (6.8%)
10.5%) l %)
HPMC 0.01 g (0.5%)0.01 g (0.4%)0.01 g (0.4%)0.01 g (0.3%)
PIB adhesive 1.2 62.8% 1.2 48.4% 1.2 45.5% 1.2 40.5%
Table 14
Cumulative Amount of PPA-HCI across human cadaver skin for
PPA-HCl Transdernial Systems (~eg/cm2)
PPA-PKIR PPA-PK2R PPA-PK5 PPA-PK6
5 hours 336.8 553.1 291.5 186.7
16 hours 879.5 1702.4 1172.5 873.1
hours 1091.2 2031.2 I 711.5 1204.3
20 24 hours 1324.0 2378.4 2222.7 1628.0
Table
Excess K3P04 Concentration and pH of Four PPA-HCI Transdermal Systems
PPA-PK PPA-PKZR PPA-PKS PPA-PK6
I R
Excess K~PO~ Concentration 0.2 % 6.2 % 16.4%
(wt. %)
H 7 9.72 10.17 10.44
The cumulative amount of PPA-HCl that permeated across the human cadaver skin
at 24 hours for PPA-PK2R (2378.4 ~tg/cm2, Table 14) with a calculated excess
K3P0,,
concentration of 0.2% was about two times higher than that from the
formulation without
K3PO4 (PPA-PK I R, I 324.0 ~tg/cm2). This result indicated that the permeation
of PPA-HCI
is enhanced with an excess K3P04 concentration as low as 0.2%.
The cumulative amount of PPA-HCl across human cadaver skin at 24 hours
remained about the same when the excess K3P04 concentration in the dried patch
was
AMENDED SHEET

CA 02395289 2002-06-17
WO 01/43734 PCT/US00/34091
-37
increased from 0.2% to 6.2% (Tables 14 and 15). When the excess K;P04
concentration in
the dried patch was further increased from 6.2% to 16.4% (Table 15), the
cumulative
amount of PPA-HCl across human cadaver skin at 24 hours decreased from 2222.7
to
1628.0 ~g/cm'. This decrease in flux may be because the high concentration of
K3P04
made the adhesive matrix more hydrophobic and the amount of K3P04 that could
be
dissolved by the small amount of water on the top of the skin was reduced.
The pH of the PPA-HCl patch measured using the procedures listed above
increased from 7 to 9.72 when the K;P04 concentration in the dried patch was
increased
from 0% to 23% (or 0.2% excess K~PO~ concentration, Tables 13 and 15). The pH
of the
PPA-HCl patch increased from 9.72 to 10.44 when the excess K;PO~ concentration
in the
dried patch was further increased from 0.2% to 16.4% (Table 15).
EXAMPLE 5
An in vitro skin permeation study was conducted using four phenylpropanolamine
hydrochloride (PPA-HCl) transdermal systems. The formulations used to prepare
these
systems are listed in Table 16, which includes weight and weight percent of
each
component in the formulations. The weight of magnesium oxide (Mg0) was 0 g,
0.11 g,
0.26 g and 0.50 g for formulation #PPA-PM1, -PM2, -PM3, and -PM4 respectively.
The
matrix patches were prepared and evaluated using the same procedures as set
forth in
Example 1. The theoretical percent weight for each ingredient after drying
(calculated
assuming all the volatile ingredients were completely removed during drying)
is listed in
Table 17. The cumulative amount of PPA-HC1 across human cadaver skin was
calculated
using the measured PPA-HCl concentrations in the receiver solutions, which
were shown
in Table 18 and FIG. 5.
Since PPA-HCl is a salt of a free base, it reacts with MgO. The concentration
of
Mg0 in the system after the reaction is completed depends on the amount of PPA-
HCl
added. The remaining Mg0 concentration after the reaction is completed is
defined as
"excess Mg0 concentration," which is calculated by the following equation.
[Mg0 excess - [Mg0 totaa - [Mg0 needed for neutralization

CA 02395289 2002-06-17
WO 01/43734 PCT/US00/34091
-38-
The excess Mg0 concentration for four PPA-HCl systems. #PPA-PMl, -PM2,
-PM3 and -PM4 were calculated and listed in Table 19.
The pH of the patch was determined using the procedure of Example 1 and the
results are listed in Table 19.
S
Table 16
Weight and Weight Percent of Each Component (Based on Total Solution Weight)
for Four PPA-HCl Transdermal Systems
PPA-PM 1 PPA-PM2 PPA-PM3 PPA-PM4
PPA-HCl 0.5 g (6.9%)0.5 g (6.0%)0.5 g (5.9%)0.5 g (5.7%)
Mg0 0 0.11 g (1.3%)0.26 g (3.1%)0.50 g (5.7%)
DI water 1.0 g ( 2.0 g (24.0%)2.0 g (23.6%)2.0 g (22.9%)
13.9%)
Methyl alcohol0.5 g (6.9%)0.5 g (6.0%)0.5 g (5.9%)0.5 g (5.7%)
Propylene 0.2 g (2.8%)0.2 g (2.4%)0.2 g (2.4%)0.2 g (2.3%)
glycol
HPMC 0.02 g (0.3%)0.02 g (0.2%)0.02 g (0.2%)0.02 g (0.2%)
PIB adhesive 4 g (55.4%)4 g (48.0%) 4 g (47.2%)4 g (45.9%)
(30% solid)
He tane 1.0 13.9% 1.0 12.0% 1.0 a 11.8%1.0 (11.5%
Table 17
Weight and Theoretical Weight Percent of Each Component in the Dried Film for
Four PPA-HCl Transdermal Systems
PPA-PM I PPA-PM2 PPA-PM3 PPA-PM4
PPA-HCl 0.5 g (26.0%)0.~ g (24.6%)0.5 g (22.9%)0.5 g (20.7%)
Mg0 0 0.11 g (5.4%)0.26 g (11.9%)0.50 g (20.7%)
Propylene 0.2 g (10.4%)0.2 g (9.9%)0.2 g (9.2%)0.2 g (8.3%)
glycol
HPMC 0.02 g ( 0.02 g ( 0.02 g (0.9%)0.02 g (0.8%)
1.0%) 1.0%)
PIB adhesive 1.2 (62.5%) 1.2 (59.1%) 1.2 ~ (55.0%)1.2 ~ (49.6%)

30-01-2002 , , US0034091
Atty. Dkt~.: 3200003.40
-39-
Table 1
Cumulative Amount of PPA-HCl Across Human Cadaver Skin for
PPA-HCl Transdermal Systems (~eglcm2)
PPA-PM1 PPA-PM2 PPA-PM3 PPA-PM4
hours 18.7 296.8 222.1 489.4
hours 77.8 621.5 1362.9 1255.2
19 hours 102.7 711.4 1920.9 1524.9
24 hours 129.8 801.9 2533.4 1831.3
T 9
Excess Mg0 Concentration and pH of Four PPA-HCI Transdermal Systems
PPA-PM PPA-PM2 PPA-PM3 PPA-PM4
1
Excess Mg0 Concentration 0.1 % 7.0 % 16.2%
(wt. %)
H 7.89 9.60 10.09 10.10
The cumulative amount of PPA-HCI that permeated across the human cadaver skin
at 24 hours for PPA-PM2 (801.9 ~g/cm2, Table 18) with a calculated excess Mg0
concentration of 0.1 % was about six times higher than that from the
formulation without
Mg0 (PPA-PM1, 129.8 ~g/cm~. This result indicated that the permeation of PPA-
HCl is
enhanced with an excess Mg0 concentration as low as 0.1 %.
The cumulative amount of PPA-HCl across human cadaver skin at 24 hours
increased from 801.9 to 2533.4 ~g/cm~ when the excess Mg0 concentration in the
dried
patch was increased from 0.1 % to 7.0% (Tables 18 and 19). When the excess Mg0
concentration in the dried patch was further increased from 7.0% to 16.2%
(Table 19), the
cumulative amount of PPA-HCI across human cadaver skin at 24 hours decreased
from
2533.4 to 1831.3 ~g/cm2. This decrease in flux may be because the high
concentration of
Mg0 made the adhesive matrix more hydrophobic and the amount of Mg0 that could
be
dissolved by the small amount of water on the top of the skin was reduced.
The pH of the PPA-HCl patch measured using the procedures listed above
increased from 7.89 to 9.60 when the Mg0 concentration in the dried patch was
increased
from 0% to 5.4% (or 0.1% excess MgOconcentration, Tables 17 and 19). The pH of
the
CA 02395289 2002-06-17
AMENDED SHEET

CA 02395289 2002-06-17
WO 01/43734 PCT/US00/34091
-40
PPA-HCl remained about the same when the excess Mg0 concentration in the dried
patch
was further increased from 0.1 % to 16.2% (Table 19).

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

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Event History

Description Date
Inactive: IPC from MCD 2006-03-12
Application Not Reinstated by Deadline 2004-12-15
Time Limit for Reversal Expired 2004-12-15
Deemed Abandoned - Failure to Respond to Maintenance Fee Notice 2003-12-15
Letter Sent 2003-04-03
Letter Sent 2003-04-03
Letter Sent 2003-04-03
Letter Sent 2003-04-03
Inactive: Correspondence - Transfer 2003-01-22
Inactive: Cover page published 2002-11-22
Inactive: Notice - National entry - No RFE 2002-11-21
Inactive: Courtesy letter - Evidence 2002-11-19
Inactive: <RFE date> RFE removed 2002-11-19
Application Received - PCT 2002-09-06
National Entry Requirements Determined Compliant 2002-06-17
Application Published (Open to Public Inspection) 2001-06-21

Abandonment History

Abandonment Date Reason Reinstatement Date
2003-12-15

Maintenance Fee

The last payment was received on 2002-12-16

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  • the reinstatement fee;
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Fee History

Fee Type Anniversary Year Due Date Paid Date
Registration of a document 2002-06-17
Basic national fee - standard 2002-06-17
MF (application, 2nd anniv.) - standard 02 2002-12-16 2002-12-16
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
DERMATRENDS, INC.
Past Owners on Record
ERIC C. LUO
RUSSELL MACY
TSUNG-MIN HSU
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Representative drawing 2002-06-17 1 12
Description 2002-06-17 40 2,062
Abstract 2002-06-17 2 66
Drawings 2002-06-17 5 81
Claims 2002-06-17 4 149
Cover Page 2002-11-22 1 42
Reminder of maintenance fee due 2002-11-19 1 109
Notice of National Entry 2002-11-21 1 192
Courtesy - Certificate of registration (related document(s)) 2003-04-03 1 130
Courtesy - Certificate of registration (related document(s)) 2003-04-03 1 130
Courtesy - Certificate of registration (related document(s)) 2003-04-03 1 130
Courtesy - Certificate of registration (related document(s)) 2003-04-03 1 130
Courtesy - Abandonment Letter (Maintenance Fee) 2004-02-09 1 176
PCT 2002-06-17 27 1,100
Correspondence 2002-11-19 1 19