Note: Descriptions are shown in the official language in which they were submitted.
WO 92/19241PCI/VS92/0386~
2102~07
A CONTROLLED, SUSTAINED RELEASE DELIVERY
SYSTEM FOR SMOKING OESSATION
Related Application
This applica~ion is a continuation-in-part of
related application serial No. 07/6g6,637, filed May
7, 1991 for A CONT~OLLED, SUSTAINED RELEASE DELIVERY
SYSTEM FOR SMOKING CESSATION.
Field of the Invention
Embodiments of the present invention feature
drug delivery systems which deliver a controlled,
sustained releaæe of lobeline for the treat~ent of
nicotine~dependency.
Backqround
Recent studies have linked smoking to both heart
disease and~cancer. Smoking also may adversely
affect a fetus during pregnancy. A trend thus has
develo~ed~towards.peopleiwanting to quit;smoking. It
is diff~icult fo~r a person t~ guit smoking since
~nicotine,~a~component of tobacco, is an addictive
dr.ug:("Nicotine Addict:ion", a report of the Surgeon
General, 1988).~ Presently available over-the-counter
products for aiding in smoking c~sation are not
always successful.
:.
WO92/19241 PCT/US92/03860
2~0~j Q - 2 -
Lobeline is an alkaloid obtained from the dried
leaves and tops of the Indian tobacco herb~ Lobelia
inflata. Lobeline is a substituted piperidine
compound that produces several physiological affects,
some of which are similar to those produced by
nicotine. Lobeline's potency in causing these
physiological effects is significantly less than that
of nicotine. Because of lobeline~s pharmacological
similarities with nicotine, it has been considered as
a substitute for nicotine which assists individuals
in lessening addiction to nicotine and in ceasing to
smoke ~igarettes. Although use of lobeline as a
smoking cessation aid has been studied since at least
the 1930's, its efficacy has been a matter of
dispute. Moreover, severe, undesirable side-effects
have been reported.
Presently available over-the-counter products
(Nikoban~, Bantron~, CigArrestT~, and Nic-Fit)
offer lobeline hemi-sulfate as an aid to smoking
cesæation. These products are taken orally and the
recommended daily doses are up to 6 milligrams.
An~acids are incorporated in some of the products to
overcome gastrointestinal discomfort, a side effect
similar to that caused by nicotine. ~igher oral
doses may not be feasible because of the concomitant
, gastriq upset. The effic~acy of oral doses of
lobeline at 6 mg/per day in aiding smoking cessation
has ~ot been proven.
The presently available over-the-counter
lobeline formulations for treating smoking addiction
WO92tl9241 PCT/US92/03860
2102~07
either do not appe~r to provide or do not appear to
maintain therapeutic blood or tissue levels of
lobeline. This may be because of the low dose of
lobeline in the lobeline formulations, poor
a~sorption of oral formulations or metabolism which
does not allow lobeline to reach critical therapeutic
levels.
Although there have been reports of using
lobeline in oral formulations at doses in excess of
10 mg/day, nausea and even vomiting have been
associat~d with su~h doses. ~ further problem with
such oral dose regimens is that self-administration
of as many as 18 tablets per day has been required.
This not only may be considered by patients as
intrusive, but also does not permit the physician to
carefully control dosage.
Kalyuzhnyy (J. of Neural Psychiat 68: 1864-1870
(1968)) describes the use of intramuscular doses of
lobeline hemi-sulfate up to 10 mg/per injection, ._~
administered twice daily. Although the amount of
lobeline administered by Kalyuzhnyy was reported to
be effective, the procedure for administration does
not lend itself to practical application because it
requires twice daily injections of lobeline.
Takagi et al. (JP 1-197,435) describe a
smokin~-substitute adhesive agent containing 0.5 to
10 percent lobeline by weight. Takagi e~ al. report
~hat blood concentrations ~of lobeline remained higher
for several hours compared to blood concentrations of
nicotine delivered using the same adhesive agent
WO92/19241 PCT/US92/03860
- 4 -
delivery system. Takagi et al. did not report the
amounts of lobeline relPased from the adhesive agent.
SummarY of the Invention
The present invention provides a drug delivery
system useful in aiding individuals in the cessation
of smoking or ~hewing nicotine containing products by
providing a delivery system for releasing a
controlled amount of lobeline. The delivery system
eliminates the need for ~wice daily injections o~
multiple daily doses of lobeline, and is capable of
providing lobeline at therapeutically effective
levels for long periods of time.
The drug delivery system has a physical
constraint modulation system (hereinafter PCMS)
containing lobeline. It is constructed and arranged
80 that lobeline is delivered to the individual at
therapeutic levels in a controlled, sustained relea
manner. The delivery of lobeline in such a manner
reduces or eliminates the individual's desire to
smoke or chew nicotine containing products.
The PCMS may involve a hiodegradable polymer
suitable for subcutaneous or intramuscular injection
into the individual~or may be part of a transdermal
patch applied to the skin of an individual. In the
PCMS utilizing the biodegradable polymer, the form of
the delivery sys~em preferab1y is microparticles
which are suspended in a pharmaceutically acceptable
vehicle just prior to subcutaneous or intramuscular
injection.
WO92/19241 PCT/US92/03860
21~07
The PCMS utilizing the transdermal patch may
employ, for example, a diffusion layer matrix
containing lobeline, or may be a multicompartmental
patch containing t~le lobeline in a first compartment
and a delivery substance in a second compartment.
The lobeline, is released from the first compartment
when contacted with the delivery substance. The
transdermal pa'tch having the diffusion layer
typically is replaced every seven days and, the
multicompartmental transdermal patch typically is
replaced on a daily basis.
The present invention also pertains to a method
for treating an individual for nicotine dependence,
i.e., cessation of smoking or chewing nicotine
containing products. The method includes
a~ministering lobeline, to the individual in a
controlled, sustained release manner such that
long-term therapeutic levels of lobeline are provided
to the individual. This method preferably is carri~
out using the delivery systems described above. The
lobeline may be administered to the individual at
time p~riods easily integrated with behavioral
modification support programs.
The present invention also pertains to kits~
useful in treating nicotine dependence. For example,
the kits are useful in aiding individuals in the!
cessation of smoking or chewing nicotine containing
products. The kits contain a sustained release
system of the type herein described capable of
delivering long-term therapeutic levels of lobeline,
WO92/19241 PCT/US92/03860
2 102S ~ - 6 -
along with instructions providing information to the
user and/or health care provider regarding the use of
the system for aiding in the cessa~ion of smoking or
chewing a nicotine ccntaining product. The preferred
kits include a delivery system capable of providing
sustained release of therapeutic levels of lobeline
for at least three weeks.
It is an object of the invention to provide a
controlled, sus~ained release delivery system for
passively providing long-term therapeutic levels of
lobeline to individuals.
It is another object of the invention to provide
a delivery system capable of delivering lobeline to
an individual in a manner which reduces or eliminates
the individual's tobacco smoking or chewing habit.
It is yet another object of the invention to
provide a drug delivery system for delivering
lobeline to an individual without passage of the drug
through the gastrointestinal (GI) tract thereby
minimizing GI side effects.
It is yet a further object of the invention to
provide a drug delivery system for delivering
lobeline, in doses which are not overly intrusive to
the individual and are easily integrated with a
behavioral modification program designed to help the
individual quit smoking.
It is yet another object of the invention to
provide sel~-administratable, drug delivery systems
for delivering lobeline, in therapeutically effective
amounts .
WO92/19241 PCT/US92~03~0
~102~ 07
-- 7
Still another object of the invention is to
provide therapeutic levels of lobeline, without the
need for multiple, daily dose~.
Brief Description of the Drawinqs
Figures ~A, lB and lC depict a lobeline
containing microparticle, microcapsule and elongated
rod, respectively.
Figure 2 depicts a transdermal patch having a
diffusion layer matrix.
Figure 3 depicts a multicompartmental
transdermal patch.
Figure 4 depicts a kit containing f our packaged
transdermal patches having a diffusion layer matrix
along with instructions.
Figure 5 depicts a kit containing twenty-eight
packaged multicompartmental transdexmal patches along
with instructions.
Figure 6 depicts a kit including a syringe ;~
¢ontaining microparticles of a biodegradable polymer
containing lobeline, a container of a
pharmaceutically acceptable ~ehicle, and instructions.
Figure 7 depicts the in vitro release of
lobeline free base ~rom PLGA microparticles
(150-180~) at 30%, 40~, and 50% lobeline loading.
Figure 8 depicts the in vitro release of
lobeline free ~ase from PLGA micropartiales
(38-106~) at 30~ lobeline loading.
Figure 9 depicts the in vivo release of lobeline
free base,:expressed as the percentage of lobeline
WO 92/19241 PCr/US92/03860
~o~5o~
remaining at the injec~ion- site, from a formulation
containing 30% lobeline free base and a formulation
containing 40% lobeline free hase.
Figure lo depicts the in vivo effect of lobeline
dose on the number of cigarettes smoked.
Figure 11 depicts the in vivo effect of lobeline
dose on the number of smoking puffs.
Fi~ure 12 depicts the in vivo release of
lo~eline free base, from PLGA microparticles at 35 %
lobeline loading.
Figure 13 depicts the in vivo effect of a
lobeline-containing microparticle formulation on the
number of cigarettes smoked by human volunteers
following subcutaneous injection of the
microparticles.
Detailed Description
The present invention pertains to a method for r~
treating an individual for nicotine dependence. The
method comprises admi~istering a therapeutic level of
lobeline to the ~ndividual in a controlled, sustained
release manner over a period of time having a
duration of at least one day. The method is
particularly useful in combination with a smoking
cessation program. Such programs combine therapies
for treating an i~dividual's physical dependence on
nicotine with behavior modification counseling
directed to reducing the individual's psychological
addiction to smoking or chewing nicotine-containing
WO92/19241 PCT~US92/03860
2102~7
products.
The preferred methods of the invention involve
administration regimens that are easily integrated
with smoking cessation behavioral modification
programs. These programs are designed to tec h
individuals how to quit or reduce their use of
nicotine-containing products, by modifying their
behavior. Typically, these programs involve
regularly scheduled, e.g. weekly or biweekly,
meetings with counselors.
The language "time periods easily integrated
with smoking cessation behavioral modification
support programs" is intended to include time periods
which coincide with regularly scheduled meetings with
counselors, e.g. weekly or biweekly. For example,
the delivery system may be designed such that weekly
subcutaneous or intramuscular injections are required
to maintain a therapeutic level of lobeline in the
individual's circulatory system. The weekly _.
injections are easily coordinated with a weekly
appointment with a counselor from a behavioral
modifica~ion support program. Preferably, the
injection is administered by medical personnel or the
cou~selor. The individual may schedule a weekly
appointment for obtaining both the injection and any
n~cessary behavioral support counseling.
The present invention also pertains to a drug
delivery system useful in aiding an individual in the
cessation o smoking or chewing nicotine containing
products. The delivery system includes a physical
WO92/19241 PCT/U~92/0386~
o~s~1 -10 -
constraint modulation system (PCMS) containinglobeline. The system is constructed and arranged to
deliver a therapeutic level of lobeline to the
individual in a controlled, sustained release manner
for a period of time having a duration of at least
one day. Typically, the delivery system is
constructed and arranged such that the physical
constraint mod~lation system subcutaneously,
intramuscularly or transdermally delivers lobeline
into the circulatory system.
The drug del ivery system is used to provide
long-term therapeutic levels of lobeline, to the
individual. Delivering the lobeline in such a manner
reduces or eliminates the individual's smoking or
chewing habit.
The term individual refers broadly to
indi~iduals who suffer from nicotine dependency.
Thus, individuals refers to individuals who smoke or
chew nicotine containing products. The nicotine
containing products may be any product containing
nicotine, e.g. cigarettes, pipe tobac~o, and chewing
tobacco.
The term PCMS is intended to include substances
or components, e.g. solids, liquids, gels or layers,
capable of releasing lobeline, in a sustained release
, manner. Examples of PCMS which are useful within the
present invention include biodegradable polymers and
parts of transdermal patches.
The term lobeline is intended to include
2-~6-(8-hydroxyphene~hyl)-1-methyl-2-piperidyl]
WO92/19241 PCT/US92/03860
2102~.~7
acetophenone as shown below. The lobeline may ~e in
its free base form or may be in the form of a water
soluble salt, e.g. hydrochloride or ~ulfate salts, or
a less soluble salt, e.g. palmoate.
~ X~
where X is the anion.
The term lobeline also is inte~ded to encompass
structural equivalents of the above compound which
share the same or similar functional
characteristi~s. Structural equivalents are
structurally similar to the above compound but may
ha~e one or more substituents on the core structure.
For example, substituents may be placed on either o~
the benzene rings as long as the substituents do not
adversely affect the compound's ability to act as a
substitute for nicotine. Examples of substituents
may include lower alkyl groups, e.g. methyl, ethyl
and propyl groups. For a further example, the methyl
group of the piperidyl nitrogen may be substituted
with a different lower alkyl group, e.g. ethyl or
propyl group.
The term "controlled, sustained release manner"
is intended to include the delivery of lobeline, in a
WO92/19241 PCT/US92/03860
~ i
- 12 -
manner in which only a portion of the lobeline is
released from the PCMS at a given moment while the
remaining lobeline is retained in the PCMS and
released gradually over an extended period of time.
The extended period of time is a period of ~ime
having a duration of at least a day (twenty-four
hours), but may be longer such as up to about thirty
days or even ninety days.
The long-term therapeuti levels of lobeline are
intended to include those levels of lobeline
sufficient to significantly reduce or eliminate the
individual's habit for smoking or chewing a nicotine
containing product over an extended period of time,
as defined above. Examples of such therapeutic
levels include from about five to about thirty
milligrams of lobeline per day, preferably averaging
between about ten to about twenty milligrams per day
over time periods of about one to at least about
thirty days. These doses are based on the free base~
form of lobeline. This dose of about five to about
thirty mg of lobeline is the amount of lobeline
released from the PCMS and does not refer to the
level of lobeline detected in the individual's
circulatory system.
The PCMS of the drug delivery system may be in a
form suitable for subcutaneous or intramuscular
injection, such as combined with a biodegradable
polymer. The term biodegradable polymer includes
polymers capable:of degrading in vivo and delivering
the lobeIine, in a controlled, sustained release
wos2/ls241 PCT/US92/03860
2102~7
- 13 -
manner such that long-term therapeutic levels of
lobeline are attainable. The polymer is selected
such that it does not cause significant adverse
effects to the individual when administered in vivo.
Examples of biodegradable polymers which may he used
in this invention include pol~ lactic/glycolic)acid
copolymers ~PLGA), polylactic acid ~PLA),
polyglycolic acid (PGA), polyesters, e.g.
polyorthoesters, polylactones, polyanhydrides, and
polyaminoacids. The preferred biodegradable polymer
is PLGA.
Polymers prepared from glycolide and lactide
dimers e.g., PLGA, PL~ and PGAi are known to undergo
slow hydrolysis when implanted in tissue and the
by-products of their hydrolysis (lactic and glycolic
acids) both are normal metabolites. PLGA, PL~, and
PGA are believed to be non-toxic, are relatively
non-inflammatory, and non-tissue reactive. The
polymers also exhibit moderate strength and tension~
compression`and pliability. Hereinafter, the term
PLGAs will be u~ed to encompass PLA, PGA, and PLGA.
The specific lactide/glycolide ratio of the
PLGAs polymer and the molecular weight of the polymer
are factors considered when designin~ the drug
dPlivery system. There are di~ferences in the
hydrophobicity and crystallinity of lactic acid, and
glycolic acid, and the use of a fast-hydrolyzing
polymer (low molecular weight, low lactide content)
for rapid ultimate clearance of lobeline, lS balanced
with the need for the sustained release of relatively
wos2/ls241 PCT/US92/03860
- 14 -
:
solu~le lobeline provided by a slow-hydrolyzing
polymer ~high molecular weight, high lactide
content). Based on these needs, the preferred
polymers for delivery of lobeline are in the range of
about 50:50 lactide/glycolide to about 85:15
lactide/glycolide. The preferred polymers also have
molecular weights in the range of about 50,000 to
about 150,000 aaltons, preferably about loo,000
daltons.
Lobeline is loaded into the polymer in an amount
which allows sllstained release of the lobeline from
the polymer at the desired therapeutic levels. The
preferred loading of lobeline into a PLGA polymer
having a lactide/glycolide content of about 85:15 and
a molecular weight of about 100,000 daltons, is about
20 to about 65%, more preferably about 30 to about
50%, most preferably about 30 to about 40% by weight
of lobeline based on the weight of the polymer.
The formulation of the biodegradable polymer a~
lobeline, should be such that it permits subcutaneous
or intramuscular deposition. These include
injec~able form~lations such as microparticles,
microcapsules or elongated rods of the
polymer/lobeline composition.
Figures lA-lC depict a lobeline containing
microparticle, microcapsule and elongated rod
respectively. The lobeline may be distributed
throughout the biodegradable polymer 2 as shown in
Figures lA and lC. Alternatively, the lobeline 1 may
be encapsulated within the biodegradable polymer 2 as
WO92/19241 PCT/US9~/03860
2102~07
- 15 -
shown in Figure lB.
The microparticles, microcapsules, and elongated
rods of the biodegradable polymer are of a size
capable of being subcutaneously or in~ramuscular
injected or implanted while releasing the lobeline,
in a controlled, sustained release manner. Examples
of sizes for microparticles include in the range from
about 38 to abo~t 250 microns, most preferably 38 to
about 106 microns. Examples of sizes for
microcapsules include in the range from a~out 10 to
about 250 microns. Examples of sizes for elongated
rods include a diameter in the range of about 1 to 4
mm and a length in the range of about 0.5 to about 3
cm.
The preferred form of the biodegradable polymer
is microparticles. The microparticles preferably are
su~pended in a pharmaceutically acceptable vehicle
just prior to the time of injection. The
pharmaceutically acceptable vehicle is selected such
that it can form a suspension with and permit
delivery of the microparticles and such that it does
not have a significant adverse effect on lobeline's
ability to substitute for nicotine when adminis~ered
in vivo.
Examples of pharmaceutically acceptable vehicles
useful for lobeline delivery, include, for example,~
solutions prepared as follows: Formulation No. 1 -
0.38 g carboxymethylcellulose, 3.75 g mannitol, and
O.08 g Tween ~Q in 2Q ml~ of distilled water;
Formulation No. 2 (preferred) - 0.0127 g
WO 92/19241 PCI`/US92/03860
O~ '
- 16 -
carboxymethylcellulose, o.os6 g mannitol, 0.027 g
Tween 80 in 20 ml. of distilled water. ~ syringe
containing the microparticles can be used to draw up
the pharmaceutically acceptable vehicle creating the
suspension. Other methods of preparing the
suspension of course may be used. The suspension may
be created outside of the syringe and then drawn in~o
the syringe. ~The suspension is injected into the
individual preferably at time periods easily
integrated with behavioral modification support
programs, such as smoking cessation programs.
With respect to lobeline-containing
microparticles, it should be understood that the
microparticles cannot be suspended in the vehicle for
a prolonged period of time because significant
amounts of the lobeline would be released from the
microparticles into the vehicle. Prefera~ly the
suspension is injected within about an hour after
being prepared. _.
When using microparticles (or other forms
wherein the amount of drug released will gradually
diminish over time), specific dosing procedures may
be desirable. For example, if at least 15 mg of
lobeline per day were the ~esired level of sustained
release, a dose of microparticles might be prepared
to deliver 20 mg per day on day one, with release
diminishing to 14 mg per day on day eight. As will
~e readily understood, ~he second dose would need to
be smaller than the first dose to attain a level of
15 mg per day for the nexk seven days due to the
WO92/19241 PCTiUS92/03860
2102~07
- 17 -
continued release of lobeline from the residual
microparticles of the first dose. Thus, certain PCMS
delivery system.- will require different dosing
schemes.
However, such tapering off of subsequent dose
concentrations is unnecessary for lobeline, which is
believed to be non-addictive and rapidly cleared from
the circulatory system. It is believed that such
rapid clearance is due to the binding of lobeline to
nicotine receptors located in the brain. Thus,
although lobeline may be rapidly cleared from the
circulatory system, it may persist in the brain for a
substantially longer period of time.
The PCMS also may be part of a transdermal
patch. Transdermal patches have a variety of
advantages including avoidance of the
gastro-intestinal tract, sustained action which
r~adily can be adjusted, self-administration and the
ability to immediately discontinue dosage. The te.r~
transdermal patch is intended to include patches
capable of being affixed to the skin of an individual
and having a part or component capable of delivering
lobeline, in a controlled sustained release manner.
Examples of types of patches useful in this invention
include those having a diffusion layer matrix and/or
multicompartmental type patches. These wil~ be~
described in detail below.
There are many transdermal patches known to
those of ordinary skill in the art and well described
in the prior art. One such patch useful according to
WO92/19241 PCT/US92/03860
- 18 -
the invention is shown generally in Fig. 2. The
patch of Fig. 2 involves a diffusion matrix layer
that uses a retîculated macroporous polymeric foam as
a framework for holding a viscoelastic
lobeline-polymer mixture. The patch 10 is a 4-layer,
laminated composite that is adapted to be adhered to
the skin. The outermost layer, backing layer 12,
functions as the primary structural element of the
device as well as serving as a protective covering to
prevent the lobeline from being transmitted from the
device via the outermost surface. Backing layer 12
preferably is made of a ~heet or film of a resilient
elastomer of about 10-75 microns thick. Examples of
such elastomers include polyether block amide
copolymers, polyethylene methacrylate block
copolymers, polyurethanes, silicon elastomers and the
like.
The lobeline-containing matrix layer 14
functions as a reservoir for lobeline, an enhancer,
and optionalrly a pressure sensitive adhesive. The
framework of the matrix is a reticulated macroporous
polymeric foam 16. Preferably the network is
essentially completely open pores (90~ or greater).
The pore rating of the reticulated foam will normally
be in the range of about 10-40 pores per linear
centimeter and the density (un~illed) ~ill typically
be in the range of about 0.01 to 0.5g/cm3. Suitable
polymers from which s~ch foam frameworks may be
manufactured include polyurethanes and polyethylenes.
A pressure ~ens1tive adhesive layer 18 covers
WO92/19241 PCT/US92/03860
2102507
- 19 -
the exposed face of the matrix layer 14 and a release
liner 20 covers the pressure sensitive adhesive. The
pressure sensitive adhesive layer 14 is a medical
grade adhesive composition having a thickness
normally between about 25 and lOo microns. An
example of such an adhesive is polydimethylsiloxane
(Dow ~ rning 355 medical grade adhesive).
The pores~of the foam are wholly or partly
filled with a viscoelastic hydrophobic
lobeline-permeable polymer and an enhancer. The
polymer acts as a carrier for the lobeline and the
enhancer acts to control the solubility of the
lobeline in the polymer a~d/or absorption of the drug
into the skin. The hydrophobic polymer renders the
device water-resistant and prevents liquid water from
being ~bsorbed by the device, thereby increasing its
functionality and wearability. Examples of such
polymers are polysiloxanes (silicone polymers),
hydrophobic polyacrylates, polyurethanes, plasticiz~
ethylene ~inyl acetate copolymers and the like. An
example of a useful enhancer includes Azone~. Ths
mix~ure including the lobeline optionally includes an
anti-pruritic agent.
Devices of the foregoing nature are generally
described in U.S. patent 4,911,916, entitled
"Diffusion Matrix for Transdermal ~rug Admini~tration
and Transdermal Drug Delivery Devices Including
Same", issued March 27, 1990, the entire disclosure
of which is incorporated herein by reference. Such
patches may be configured to contlin sufficient
WO 92i19241 PC~/US92J03860
- 20 -
lobeline to release from about five to about thirty
milligrams of lobeline per day. Preferahly such
patches are configured to hold sufficient lobeline to
release from about f ive to about thirty milligrams
per day for seven days, such that a single patch may
be worn for one week.
The optimum dose range, i.e., the range of doses
within which lobeline exhibits maximum therapeutic
effect and minimum adverse side effects is determined
em~irically. The patch or other delivery system is
configured and formulated to contain sufficient
lobeline to release a dose within the optimum dose
range for the desired period of time.
Another patch useful according to the invention
is shown generally in Fig. 3. The patch of Fig. 3
also is a 4-layer composite defining at least two
separate compartments. One compartment contains
lobeline, and the other compartment contains a
delivery substance that when mixed with lobeline
permits the delivery of the lobeline transdermally.
The patch 22 has a backing layer 24 sealed to a rate
controlling membrane 26 in a manner to create two
chambers, lobeline containing chamber 28 and a
delivery substance containing chamber 30. An
adhesive layer 32 covers ~he rate controlling
membrane and a release sheet 3~ covers the adhesive
layer.
To form the device, a silanized polyester (or
other suitable material treated with a releasing
agent) approximately 75 microns ~hick, is used as a
WO92/19241 PCT/US92/03860
21~2507
- 21 -
release sheet 34. The adhesive layer 3~ is cast onto
the release sheet, and may be for example
polyisobutylene. The adhesive layer then is
laminated to the rate controlling membrane 26, which
may be about lO0 microns thick. Ethylene-vinyl
acetate may be employed for the control membrane.
Next, the materials which will become the
conten~s of th~ lobeline containing chamber 28 and
delivery substance chamber 30 are placed in separate
areas on the rate controlling membrane 26. The
material for the lobeline containing chamber 28 may
be lobeline freebase and the material or the
deli~ery substance containing chamber may be an
alcoholic or aqueous/alcoholic solution.
Finally, a suitable backing 24 having a heat
sealable coating on one surface is placed over the
two areas which are to become chambers 28 and 30, and
the de~ice is heat sealed 36 around the perimeter ànd
between the two are~s to form the two chambers, 28
an~ 30. The heat seal 38 between the two chambers
should be less secure than the heat seal 36 about the
perimeter, so that the seal between the chambers will
selectively burst under pressure applied by~the user.
In this manner, pressure may be applîed to either one
of the chambers to burst the seal between the
chamber!s, thereby mixing the solution and the
lobeline and dissolving the lob~1ine. The lobeline
th~n is in a form which is capable of passing through
the rate controlling membrane 26 for delivery to the
skin of the user. As with the patch of Fig. 2, the
WO92/19241 PCT/US92/03860
- 22 -
chambers may include enhancers for affecting uptake
of the lobeline across the skin.
Preferred forms of the foregoing patch are shown
in greater detail in U.S. patent 4,917,676, issued
April 17, lsso and entitled "User-Activated
Transdermal Therapeutic System", the entire
disclosure of which is incorporated herein by
reference. Su~h patches should contain sufficient
lobeline to release from about five to about thirty
milligrams of lobeline per day, and such patches are
suitable to provide individual, daily patches.
T~is invention also pertains to kits useful in
aiding an individual in the cessation of smoking.
The kits contain a PCMS delivery system according to
the invention, as well as instructions for use. For
example, a kit for treating nicotine dependence may
contain at least one packaged transdermal patch 30
containing the lobeline along with instructions 32
providing information to the user and/or health care,
proYider regarding the use of the patch. The number
of transdermal patches provided in the kit may depend
on the type of transdermal patch and the length of
the smoking cessation program for which the kit is
being designed, e . g . a three week or a four week
smoking cessation program. In general, the course of
treatment is between four and eight weeks, with a six
to eight week program being fairly typical.
A transdermal patch containing the lobeline in a
diffusion layer matrix typically is designed for long
term dru~ delivery, e.g. about seven days. A kit for
W~92JI924~ PCT/VS92tO3860
210~5il~7
- 23 -
a four week smoking cessation program thus-may
contain four such packaged transdermal patches 30 as
shown in Figure 4. The instructions 32 would inform
the individual and/or health care provider to replace
the patches on a weekly basis, e.g. Day 1 - patch no.
1, Day 8 ~ patch no. 2, etc.
A multicompartmental transdermal patch typically
is designed fo~ daily use. A kit for accompanying a
three or four week smoking cessation program may
contain twenty-one or twenty-eight, respectively,
multicompartmental transdermal patches 30 as shown in
Figure 5. The instructions 32 would inform an
individual and/or health care provider to replace the
transdermal pat~h on a daily basis and also would
instruct the individual how to contact the lobeline
in the first compartment with the delivery substance
in the second compartment. For example, the
individual may have to break a pressure sensitive
seal between the two compartments. ;~
The kit also may include at least one container
34 of an injectable or implantable PCMS delivery
system and instructions 32 for use as shown in Figure
6. For exam~le, the kit may include four to eight
containers of polymer~lobeline microparticles useful
for a four to si~ week smoking cessation program. As
! I ~ discussed above, each container may need to contain a:
different amount of:microparticles/lobeline to
account for continued release of the lobeline from
microparticles remaining from each earlier dose.
Alternatively, each container may contain the same
wos2/ls241 PCT/US92/03860
?,~
- 24 -
quantity of microparticles/lobeline with instructions
to inject a reduced volume of resuspended
microparticles/lobeline on subsequent days of the
treatment period. However, as noted above, it may
not be necessary to decrease the dose level during
the treatment program for lobeline because lobeline
is believed to be non-addictive and rapidly cleared
from the circ~latory system.
The kit may further include at least one
container 36 of a pharmaceutically acceptable
vehicle. A syringe 38 also may be provided in the
kit. The syringe may be pre-loaded with
microparticles. -
The following non-limiting examples further
illustrate the present invention.
Example l - Preparation of PLGA MicroParticles
Containinq 30% Lobeline
Lobeline free base was obtained from Sigma
Chemical company or prepared from lobeline sulfate~
obtained from Boehringer Ingelheim. The compound was
characterized prior to use by UV spectroscopy, HPLC,
and melting point. MEDISORBT~ 8515DL
lactide/glycolide bioresorbable polymer was obtained
from DuPont. By specification the polymer is 85'5%
lactide and l5~'5% glycolide. The solvents (highest
grade ~vailable) were obtained from Fisher
Scientific. The po~lymer (3.5044 g) was dissolved in
methylene chloride (23 ml. ? as a lS% solutian by
weight. Lobeline (l.~006 g) was added to the polymer
solution and the solution was stirred to insure
WO92/19241 PCT/US92/03860
21~2~Q7
- 25 -
complet~ mixing. The s~ -~tion was then ca~ onto a
c.~ vel ~i2ce o plat- g' 2SS ar.~ s~read ~th a
-~s~.~n-3radie-, adjustable blzde. .~Ler eva?o~alion
~- mos o_ the sol-~2n~ under a ni~rogen a _rea~, the
-ilm was peeled rrom ~he glass and vac~um cesicc2ted.
The fllm formed in he casiing s~ep wzs of ~ery
13~ densi~y because .he solver.~ removal s~e~ lQft a
very l ~rge void vol~wme. The void volume was reduced
c dec ease ~ermea~ion of ~luids into the
micro~ar.icles bv a com~ression step, u-ilizins heat
ar.d hvdrâuiic pressure. Tne ,iim wa~ ex_ruded in~o
.ods w,th a Pasadena Hy~raulic Press 2~ about 70C.
The extruded rods were ground into small
particles using a co~mercial grinder with a cooled
~~inding chamber. ~ollowins grinding, the powder or
small particles were passed through USP sieves to
collect microparticles in the siz~ ranges of abou~ 38
IO 106~, 106-150~ and 150-180~. The
mlcroparticles containing 30% lobeline were collected.
~xample 2 - Preparation of PLGA Micro~articles
containinq 40% Lo~eline
Exam~le 1 was re~eated exce~t 1.0000 g of
_
lobeline was placed in the jar with the polvmer
soiut~on (1.501 g in 10 m;.). The microparticles
contairing~j40% lobeline were formed and collected.
~xample 3 - Pr~a~at~o~ of ?LGA ~.ic-opar~lcles
containinq 50~ Lobeline
Example 1 was repeated except 2.0016 g o.
io~elLne was placed in the jar with ~he ~olvm~r
WO92/19241 PCT/US92/03860
- 26 -
solution (2.0016 g in 13 ml.). The microparticles
containing 50% lobeline were formed and collected.
Example 4 - The In vitro Release of Lobeline from
PLGA
The PLGA/lobeline microparticles prepared in
Examples 1~ 2, and 3 were exposed to a phosphate
buffered salin~ (PBS) solution under simulated sink
conditions such that the drug would never reach more
than 20~ concentration in the buffer. The
microparticles were placed in a thimble which was
further placed in a test tube. Each day the thimble
was moved to a new test tu~e and the lobeline content
in the PBS solution was measured by extraction and
concen~ration in an organic solvent, followed by W
analysis. Analysis of the buffer for lobeline
content was made on a daily basis in the first two to
three days, then on a weekly schedule thereafter.
The results are depicted in Figure 7. Figure 7
depicts the release of lobeline free base from PLG~-
microparticles (150-180~) at 30~, 40%, and 50%
lobeline loading.
In none of the systems was the entire lobeline
content released within one week. The 30% loading
exhibited ~he slowest release. In the 30% loading,
for th~e 150-180~ particles, only 60% of the
lobeline was released at the end of the first week.
wos2/1~241 PCT/US92/03860
2102~f~7
- 27 -
Example 5 The In vitro Release of Lobeline from
PLGA
The method of analysis for this example differs
from example 5 above in that the amount of lobeline
left in the microparticles was measured after
leaching the microparticles in the PBS solution. The
total amount left in the microparticles was
subtracted from the amount initially loaded into the
microparticles to obtain the amount released.
The particles themselves differed as well, in
that 38-106~ sized microparticle, prepared as
described in Example l, were used. The
microparticles were placed in an extraction thimble
and covered with a glass wool plug. The tnimbles
were suspended in phosphate buffered saline
containing 0.1% sodium azide. (9 thimbles/l.7 L).
Each day the samples were removed, air dried, then
vacuum dried. Each dry thimble was transferred ~o a
large tes~ tube and enough C~2C12 was added to ~
cover the thimble. The tube was vortexed to aid in
d~ssolving the microparticle~. To each tube, a
measured volume of O.Ol N H2SO4 was added. After
mixing, the acid layer was removed and the step was
repeated two to three times. The acid ~ractions were
analyæed by W for lobeline content. The total
amountl~found w~s subtracted from the initial value to
obtain the amount of lobeline released from the
microparticles. The results are depicted in Figure
7. Figure 8 d ~icts the release of lobeline free
base from PLGA microparticles ~38-106~) at 30%
WO 92/19241 PCI/US92/03860
- 28 -
lobeline loading. The release was substantially
constant over the first 10 days, tapering off over
the last 4 days.
Example 6 - Materials and Methods - Release Study
of Two formulations in Rats
Formulations
Two formulations were tested. One formulation
contained PLGA microparticles at 30% lobeline free
base loading, and the other formulation contained
PLGA micropar~icles at 40% lobeline free base
loading. Within 1/2 hour of injection, a suspension
containing 20 mg/ml of 30% ~ormulation or 15 mg/ml of
40% formulation was prepared in diluent (.94 g
carboxymethylcellulose, 9.38 g of D-Mannitol, .2 g
polysorbate 80 (Tween 80) in 50 ml of water).
Animal Tests
Female Sprague-Dawley Rats (250-300 g) were
used. Two animals were used as negative controls.
An aliquot of 0.1 ml of ~ehicle was injected into the
scapular region of each animal from a syringe fitted
with a 22 gauge needle. On day 7, the two animals
were sacrified with CO2 and the fatty tissue in the
scapular region was.removed.
The remaining animals were divided into two
groups: those receiving the 30% formulation and
those receiving the 40% formulation. From each
group, four animals were used as positive controls.
These animals were sacrificed and the fatty tissue
and facia in the scapular region was removed. Prior
WO 92/19241 PCI`/US92/03860
2102~07
- 29 -
to the time of analysis, an ali~uot of o.l ml of the
formulation in vehicle was added to the tissue sample.
From each group, five additional subgroups were
selected, representing different periods of time that
the suspensions were left in the animal prior to
obtaining a tissue sample: 4 hrs; 1 day; 2 days; 5
days; and 7 days. There were four animals in each of
these subgroups.
The formulations were prepared for use as
described above, and in every case a o.1 ml aliquot
was given. At the time of sacrifice, the fatty
tissue and facia i~ the scapular region of each
animal was removed. In most, but not all cases,
areas of tissue containing microparticles could be
obser~ed. It seems likely, however, that some of the
microparticles migrated to areas beyond the excisisn
site and that this material was thus not recovered.
Tissue Extraction
. ~
A tissue sample along with 2-3 ml CH2Cl~ was
placed in a short glass test tube. lOOul of a 1
mg/ml solution of triprolidine in CH2C12
(internal standard) was added. Using the Tissue
TearorT~ at 45Q0 - 8000 rpm, the sample was
homogenized. The sample was transferred to a
centrifuge tube with a teflon-lined screw cap and
centrifuged for 7 min. The CH2C12 was carefully
pipetted out and transferred to a test tube. To this
solution 1 ml of O.OlN H2SO4 was added and the
mixture was vortexed for 15-20 seconds. After
wos2/ls241 PCT/US92/03860
?,~e~
- 30 -
separation of phases had occurred, the top (acid)
layer was carefully r~moved with a pipette and the
volume of this acid solution was measured. The acid
solution was then transferred to a new, clean test
tube or vial and filter~d through 0.45u nylon filter
prior to injection. The extraction of the CH2Cl~
with acid was repeated until no more lobeline was
detected or a maximum of f ive repeats .
AnalYsis
The acid samples were analyzed directly by
HPLC. The amount of lobeline recovered was based on
a standard curve of extracted lobeline
concentration/internal standard concentration from
spiked tissue control samples at various lobeline
levels.
The HPLC System used was as follows: Waters 510
pump: Waters U6, injector; Waters Lambda Max 481 LC
Spectrophotometer; spectra Physics SP 4~70 _~
Int~grator; Phenomenex Partisil C8 5u lOQX4.6 mm
column with 30X4.6 mm guard column with same packing.
The mobile Phase was: ~0% Phosphate Buffer, pH
3:40% (50:50 CH3CN/MeOH). The flow rate was 1.2
ml/min; A~FS 1.0; detection at 249 mn; with 4 ul
sample injection volume.
'rhe results for 30% and 40% loaded
microparticles were adjusted for an efficiency of
extraction from excised tissue of 75.4%. ~o
adjustment has been made for efficiency of recovery
of microparticles from the animals.
WOs2/1s241 PCT/US92/03860
2102~07
The restllts (shown in Figure ~ are presented
graphically, with the percent of ~he dose found in
the tissue sample plotted against different kinds of
treatment duration. The 30% loading exhibited a
somewhat more linear release profile than the 40%
loading.
Example 7 - Evaluation of PolYethylene 'IPouches''
for in vi~o Release Studies in Rats
Formulation
The method of analysis for this example differs
from example 6 above in that a single formulation
containing PLGA microparticles at 35% lobeline free
base loading was tested. The formulation was sealed
into polyethylene bags with 20~ pores prior to
implantion in the scapular region of rats. These
bags are porous enough for use in dissolution
studies, yet have pores small enough to retain the
microparticle~ (smallest particle diameter is 38
Method
Polyethylene pouches (Biotek, Woburn, MA) were
used. Twelve pouches were heat sealed without
filling and cut to a size of about l cm x 1 cm. The
remaining pouches were each filled with approximately
4 mg of the above formulation and similarly sealed
and trimmed. Female Sprague Dawley rats of
approximately 250 g each were obtained and
quarantined. At time zero (T = 0), each rat was
anesthetized and an incision just larger than the
WO 92/19~41 PCI/US9~/03860
- 32 -
width of the pouch was m~de in the scapular area.
The pouch was held wi~h forceps and dipped into
normal saline, then the forceps were used to slip the
pouch under the skin. The incision was closed with
one or two staples. On days 1, 2, 3 and 7, the
pouches were removed from six controls (empty
pouches) and six animals (for each time point) which
had received the formulation. The method of removal
was to anesthetize the animal and then to make an "L"
shaped incision around the site of the pouch. The
pouch was exposed by lifting the skin. Each pouch
was rinsed in a normal saline solution and patted dry
on a paper towel. The pouches were stored in sealed
polyethylene bags overnight in the freezer and
analyzed the next day. All animals were sacrificed
immediately following removal of the pouches.
le PreParation for HPLC AnalYsis
Each pouch was cut open and its contents, along
with the emptied, shredded pouch, were added to a 10
ml volumetric flask containing approximately 5 ml of
acetonitrile. The flask was sonicated for 10
minutes, allowed to cool to room temperature
(approximately 30 minutes) and the total volume in
the flask was brought to 10 ml (i.e., "Q.S. to
volume") with acetonitrile to prepare a "stock
solution". Thereafter, 0.1 ml of the stock solution
was accurately transferred to a 10 ml volumetric
flask and Q.S. to volume with working diluent
(described below). A 2.5 ml aliquot of this solution
WO92/19241 PCT~VS9~/03X6~
2102~7
- 33 -
was then transferred to another 10 ml volumetric
flask and Q.S. to volume with working diluent.
HPLC Analysis
The acid samples were analyzed directly by
HPLC. The amount of lobeline released from each
pouch was based on a standard curve of lobeline
concentration~internal standard concentration at
various lobeline levels. HPLC analysis was performed
as described above, with the following modifications.
Internal Standard Preparation: Triprolidine
(10.O mg) was accurately weighed and quantitatively
transferred to a 10 ml type A volumetric flask and
Q.S. to volume with mobile phase to give an Internal
Standard Stock Solution having a Triprolidine
concentration of 1.0 mg/ml. This stock solution was
uæed to prepare the Working Diluent.
Working Diluent: A type A volumetric pipette was
used to accurately transfer 1 ml of the Internal ,~-
~Standard Stock Solution to a 100 ml volumetric flask
and Q.S. to volume with mobile phase (described
below). Thereafter, 5 ml of the latter solution was
accurately transferred (t~pe~A volum~tric pipette) to
a second 100 ml volumetric flask and Q.S. to volume
with mobile phase to prepare the Working Diluent.
The Working Diluent had a Triprolidine concentration
of 500 ng/-l.
Standard Preparation: Lobeline reference
standard (10.0 mg~ was accurately weighed and
quantitatively transferred to a 10 ml type A
wos2/ls24l PCT/US92~0386~
, .
- 34
volumetric flask and Q.s. to volume with mobile phase
to pro~ide a Lobeline Stock Solution having a
lobeline concentration of 1.O mg/ml. A type A
volumetric pipette was used to accurately transfer 1
ml of the Lobeline Stock Solution to a 10 ml
volumetric flask and Q.S. to volume with Working
Diluent. Thereafter, 1 ml of the latter solution was
accurately transferred (type A volumetric pipette) to
a second 10 ml volumetric flask and Q.S. to volume
with Working Diluent to prepare the Standard Lobeline
Solution. The Standard Lobeline Solution had a
lobeline concentration of 0.01 mg~ml.
Mobile Phase: All solutions were degassed and
filtered through a 0.2 micron membrane filter before
use. The mobile phase was prepared by adding 200
~1 triethylamine to one liter of a mixture
containing 62% 40 mM phosphoric acid (pH 3.00) and
38% acetonitrile.
Operating Conditions: The Column was _~
Phenomenex/Partisil 5C8 (25.0 cm x 4.6 mm i.d.). The
flow rate was 1.0 ml/min; detection was at 249 nm;
with a 35 ~1 injection volume.
The results (shown in Figure 12) are presented
graphically, with the average percent of lobeline
released from the six pouches plotted as a function
of treatment duration. The time points set forth in
the figure r~present the average of six replicates.
At the end of one week, the percent lobeline released
fram the pounch in the test samples was approximately
95%. The results indicate that substantially all of
the lobeline contained in the microparticles is
released by day seven.
WO92/19241 PCT/US92/03860
'2il- a ~
- 35 -
Example 8 - Materials and Methods ~ EfficacY Study
._
of Lobeline S'llfate in Humans
Test Subjects
The test subjects consisted of long-term or
chronic smokers who were smoking regularly for more
than five years. They were smoking habitually 20 or
more cigarettes per day. All volunteers were
healthy, non-obese, male adults without history of
gastrointestinal, hepatic, neurological or
hematological abnormalities. Prior to enrollment for
the study, each volunteer was examined for normalcy.
Method
On days 1, 2, 3, and 4 of the drug
administration test, a quantity of 0.4, 0.6, 0.8 or 1
ml of 20 mg/ml lobeline sulfate solution was injected
subcutaneously on the upper 1/3 of ventral aspect of
the forearm. The vol~nteers were then free to smoke
as per their desire and report on the number of
cigarettes smoked and puffs taken for 2 hours after~
the injection.
Res~lts
Both the number of cigarettes smoked and the
number of puf~s taken in the period of 2 hours after
lobeline injection decreased as the dose si~en
increased. The results are illustrated in Figures 10
and 11. As shown in figure 10, the average nu~ber of
cigarettes smoked in a two hour period immediately
following treatment with lobeline sulfate decreased
WO92/ls241 PCT/US92/~3860
- 36 -
substantially linearly as a function of the lobeline
dose. Similarly, the average number of puffs taken
in a two hour period immediately after treatment with
lobeline sulfate decreased markedly as lobeline
increased, although the initial effects were not
observed until a dose of at least 12 miligrams was
administered.
xample 9 - Mat r _ls and Methods - EfficacY StudY
of Lobeline-Containinq Microparticles
in Humans
Test Subiects
A total of twelve volunteers (9 test subjects
and 3 placebo subjects) were selected according to
the criteria described above in Example 8. With the
exception of two volunteers who smoked 7 and 10
cigarettes per day, the remaining volunteers s~oked,
on average, approximately 20 cigarettes per day.
Formulation ~
A ~ormulation comprising PLGA microparticles
containing lobeline was prepared according to the
method described in Example 1. However, the
concentration of lobeline was adjusted to pro~ide
microparticles containing 35~ lobeline by weight.
Prior to injection, the formulation was resuspended
in a diluent (D-mannitol (50 mg), carboxymethyl
cellulose sodium (5 mg), polysorbate-80 (1 mg) and
water for injection Q.S. to 1 ml) to form a
homogeneous suspension.
WO92/19241 PCT~US92~0386~
210~
- 37 -
Method
On days 1 and/or 2 of the drug administration
test, a guantity of between approximately 0.6 ml to
0.8 ml of the above-described lo~eline suspension was
injected subcutaneously as described in Example 8.
The vol~nteers were then fr~e to smoke as per their
desire and rRport on the number of cigarettes smoked
for eight days. These results are shown in Figure
13, where day 1 represents the first full day
following initial injection.
Results
The number of cigarettes smoked in the period
following the injections decreased in comparison to
the number of cigarettes consumed prior to
injection. The results are illustrated ln Figure
13. As shown in figure 13, the number of cigarettes
smoked in a 24 hour period compared to the number of
cigarettes smoked prior to treatment is reported as
the % cigarettes smoked. This percentage decreased
substantially following injection of the lobeline
æuspension.
E~QUIVALE~TS
Those skilled in the ar~ will be able to
ascertain, using no more than routine
experimentation, many equivalents of the specific
embodiments of the invention described herein.
These and ail other equivalents are intended to
be encompassed by the following claims.
