U.S. patent application number 11/380268 was filed with the patent office on 2006-11-23 for transdermal method and patch for nausea.
This patent application is currently assigned to Abeille Pharmaceuticals Inc. Invention is credited to Suresh Borsadia, Kalpana J. Patel.
Application Number | 20060263421 11/380268 |
Document ID | / |
Family ID | 37431574 |
Filed Date | 2006-11-23 |
United States Patent
Application |
20060263421 |
Kind Code |
A1 |
Patel; Kalpana J. ; et
al. |
November 23, 2006 |
Transdermal Method and Patch for Nausea
Abstract
Provided, among other things, is a method of treating acute,
delayed or anticipatory emesis for a sustained period in an
individual, which involves applying to a portion of intact skin on
the individual a composition of i. an antiemetically effective
amount of a 5-HT.sub.3 receptor antagonist; ii. a permeation
enhancing amount of permeation enhancer comprising 0.5% to 15% by
weight of the skin-contacting layer; and iii. an adhesive, wherein
a plasma concentration of the 5-HT.sub.3 receptor antagonist in a
therapeutically effective range is provided for period of time from
an onset time to 12 hours or more after the composition is
removed.
Inventors: |
Patel; Kalpana J.; (West
Windsor, NJ) ; Borsadia; Suresh; (Plainsboro,
NJ) |
Correspondence
Address: |
LAW OFFICES OF ARTHUR E. JACKSON
P.O. BOX 88
HOPEWELL
NJ
08525
US
|
Assignee: |
Abeille Pharmaceuticals Inc
Princeton
NJ
08540-5799
|
Family ID: |
37431574 |
Appl. No.: |
11/380268 |
Filed: |
April 26, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60759381 |
Jan 17, 2006 |
|
|
|
60702744 |
Jul 27, 2005 |
|
|
|
60682251 |
May 18, 2005 |
|
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|
Current U.S.
Class: |
424/448 ;
514/171; 514/381 |
Current CPC
Class: |
A61P 1/08 20180101; A61K
9/7053 20130101; A61K 9/7061 20130101; A61P 1/06 20180101; A61P
43/00 20180101 |
Class at
Publication: |
424/448 ;
514/171; 514/381 |
International
Class: |
A61K 31/573 20060101
A61K031/573; A61K 31/41 20060101 A61K031/41; A61L 15/16 20060101
A61L015/16; A61F 13/02 20060101 A61F013/02 |
Claims
1. A method of treating acute, delayed or anticipatory emesis for a
sustained period in an individual, the method comprising: applying
to a portion of intact skin or mucosa on the individual for 24
hours or more a composition comprising: i. an antiemetically
effective amount of a 5-HT.sub.3 receptor antagonist; ii. a
permeation enhancing amount of permeation enhancer comprising 0.5%
to 15% by weight of the skin-contacting layer; and iii. an
adhesive, wherein a plasma concentration of the 5-HT.sub.3 receptor
antagonist in a therapeutically effective range is provided for
period of time from an onset time to 12 hours or more after the
composition is removed.
2. The method of claim 1, wherein, 12 or more hours after removing
the composition, applying to a portion of intact skin or mucosa on
the individual a second said composition, wherein a plasma
concentration of the 5-HT.sub.3 receptor antagonist in a
therapeutically effective range is provided for period of time from
an onset time to 12 hours or more after the second said composition
is removed.
3. The method of claim 1, further comprising administering an
antiemetically effective amount of a corticosteroid.
4. The method of claim 3, wherein the corticosteroid is
administered transdermally.
5. The method of claim 3, wherein the corticosteroid is
administered orally or by injection.
6. The method of claim 1, further comprising administering an
antiemetically effective amount of an antiemetic agent in a second
dosage form.
7. The method of claim 1, wherein the serotonin 5-HT.sub.3 receptor
antagonist is selected from the group consisting of ondansetron,
granisetron, tropisetron, dolasetron, hydrodolasetron, azasetron,
ramosetron, lerisetron, indisetron, itasetron, palonosetron,
lamosetron, allosetron, and mixtures thereof.
8. The method of claim 1, wherein the 5-HT.sub.3 receptor
antagonist is granisetron.
9. The method of claim 8, further comprising administering an
antiemetically effective amount of a corticosteroid.
10. The method of claim 1, wherein the permeation enhancer consists
essentially of 15% or less by weight of the skin-contacting layer
of a fatty acid ester of fatty acyl chain length C.sub.12-C.sub.18,
or mixtures thereof.
11. The method of claim 1, wherein the permeation enhancer consists
essentially of 15% or less by weight of the skin-contacting layer
of isopropyl myristate.
12. The method of claim 1, further comprising the step of, in
coordination with said applying, administering to the individual a
pharmaceutical or procedure that creates a risk of emesis.
13. The method of claim 12, wherein said applying occurs prior to
said enesis risk-creating administration.
14. A composition for transdermal administration of an antiemetic
comprising: a skin-contacting composition comprising: i. an
antiemetically effective amount of a 5-HT.sub.3 receptor
antagonist; ii. a permeation enhancing amount of permeation
enhancer comprising 0.5% to 15% by weight of the skin-contacting
layer; and iii. an adhesive, wherein, when applied to a portion of
intact skin on an individual for 24 hours and then removed, the
composition provides the individual with a plasma concentration of
the 5-HT.sub.3 receptor antagonist in a therapeutically effective
range for period of time from an onset time to 12 hours or more
after the composition is removed.
15. A device for transdermal prevention, amelioration or treatment
of nausea and vomiting in an individual which comprises a patch
comprising: a. a support layer; and b. a skin-contacting layer
comprising: i. an antiemetically effective amount of a 5-HT.sub.3
receptor antagonist; ii. a permeation enhancing amount of
permeation enhancer comprising 0.5% to 15% by weight of the
skin-contacting layer; and iii. an adhesive, wherein, when applied
to a portion of intact skin on an individual for 24 hours and then
removed, the device provides the individual with a plasma
concentration of the 5-HT.sub.3 receptor antagonist in a
therapeutically effective range for period of time from an onset
time to 12 hours or more after the device is removed.
16. The device of claim 15, wherein, when applied to a portion of
intact skin on an individual for 48 hours and then removed, the
device provides the individual with a plasma concentration of the
5-HT.sub.3 receptor antagonist in a therapeutically effective range
for period of time from an onset time to 12 hours or more after the
device is removed.
17. The device of claim 15, wherein, when applied to a portion of
intact skin on an individual for 72 hours and then removed, the
device provides the individual with a plasma concentration of the
5-HT.sub.3 receptor antagonist in a therapeutically effective range
for period of time from an onset time to 12 hours or more after the
device is removed.
18. The device of claim 15, wherein, when applied to a portion of
intact skin on an individual for 96 hours and then removed, the
device provides the individual with a plasma concentration of the
5-HT.sub.3 receptor antagonist in a therapeutically effective range
for period of time from an onset time to 12 hours or more after the
device is removed.
19. The device of claim 15, wherein the 5-HT.sub.3 receptor
antagonist is in free base form.
20. A kit comprising the device of claim 15, and a dosage form
comprising an antiemetically effective amount of a
corticosteroid.
21. The kit of claim 20, wherein the dosage form is for oral
administration or injection of the corticosteroid.
22. The kit of claim 20, wherein the dosage form is for transdermal
administration of the corticosteroid.
23. A kit comprising the device of claim 15, and a dosage form
comprising antiemetic agent(s) in forms adapted for oral
administration or injection.
24. The kit of claim 23, wherein the agent of the dosage form is a
5-HT.sub.3 receptor antagonist, cannabinoid, NK1 receptor
antagonist, dopamine antagonist, corticosteroid, or mixture
thereof.
25. The device of claim 15, wherein the 5-HT.sub.3 receptor
antagonist is selected from the group consisting of ondansetron,
granisetron, tropisetron, dolasetron, hydrodolasetron, azasetron,
ramosetron, lerisetron, indisetron, itasetron, palonosetron,
lamosetron, allosetron, and mixtures thereof.
26. The device of claim 15, wherein the 5-HT.sub.3 receptor
antagonist is granisetron.
27. The device of claim 26, wherein the antiemetically effective
amount of granisetron comprises between 0.1% and 15% by weight of
the skin-contacting layer.
28. The device of claim 15, wherein the permeation enhancer
consists essentially of 15% or less by weight of the
skin-contacting layer of a fatty acid ester of fatty acyl chain
length C.sub.12-C.sub.18, or mixtures thereof.
29. The device of claim 15, wherein the permeation enhancer
consists essentially of 15% or less by weight of the
skin-contacting layer of isopropyl myristate.
30. The device of claim 15, further comprising packaging presenting
labeling describing applying the device to an individual in
conjunction with one or both of (a) administration to the
individual of a pharmaceutical that creates a risk of emesis or (b)
implementing on the individual an operative or other medical
procedure that creates a risk of emesis.
31. The device of claim 30, wherein the labeling describes applying
the device 30 minutes or more prior to the administration or
implementing.
32. The device of claim 15, wherein the device, when applied to a
portion of human cadaver skin for 168 hours or more, provides a
flux rate of between 1 and 25 .mu.g/cm.sup.2/hr, the flux rate
remaining between 1 and 25 .mu.g/cm.sup.2/hr for 168 hours or
more.
33. The device of claim 15, wherein the device, when applied to a
portion of intact skin on an individual for 168 hours, delivers
between 10 and 10,000 .mu.g/day of the 5-HT3 receptor antagonist to
the individual for each day after an onset period.
34. The device of claim 15, wherein the device, when applied to a
portion of intact skin on an individual for a period from 24 hours
to 144 hours and then removed, delivers between 10 and 10,000
.mu.g/day of the 5-HT3 receptor antagonist to the individual for
each day after an onset period through 12 hours after removal.
Description
[0001] This application claims the priority of U.S. Application
60/682,251, filed May 18, 2005, U.S. Application 60/702,744, filed
Jul. 27, 2005, and U.S. Application 60/759,381, filed Jan. 17,
2006.
[0002] The present invention relates to a transdermal device and
method for the treatment of nausea and vomiting, and more
particularly to a transdermal method, composition, and device
containing a 5-HT.sub.3 receptor antagonist for the treatment of
nausea and vomiting for a sustained period of time.
[0003] Most patients undergoing anticancer treatment either by
chemotherapy or radiation suffer from side effects of the treatment
such as nausea and vomiting, a common complaint by patients. To
prevent or minimize these side effects of anticancer treatments,
antagonists of 5-hydroxytryptamine subtype 3 (hereinafter referred
to as `serotonin`) such as ondansetron, granisetron, tropisetron,
dolasetron, hydrodolasetron, azasetron, ramosetron, lerisetron,
indisetron, itasetron, palonosetron, lamosetron, allosetron and
mixtures thereof, known as serotonin receptor antagonists or
5-HT.sub.3 receptor antagonists, have been widely administered,
either parenterally or orally, on multiple days.
[0004] Nausea and vomiting may also occur due to other reasons,
such as for example, post-operatively, from motion sickness, or as
a side effect of other drugs taken by a patient. Examples of drugs
which may cause nausea and vomiting as side effects are certain
antibacterial and antiviral agents, glucose-level-controlling
bioactive agents, such as insulin and amylin or their natural and
synthetic analogs, .alpha.-glucodase inhibitors, sulfonylurea,
meglitinide, thiazolidinediones, biguanide, dual
PPAR.alpha./.gamma.agonists, PPAR.gamma. agonists, and insulin
secretagogues.
[0005] In any situation where a patient is suffering from nausea
and vomiting, oral administration of an antiemetic agent is
challenging and creates more discomfort for the patient.
Intravenous (IV) or intramuscular (IM) administration is generally
impractical for home use. Oral, IM, and IV dosages must be given to
the patient in multiple doses over time to achieve continuous
antiemetic benefits, although these administration routes provide
fluctuating plasma levels of the antiemetic agent. Additionally,
since nausea and vomiting are challenging to reverse, antiemetic
agents are most effective if given prophylactically.
[0006] To cope with these problems, there has been an attempt to
formulate a composition of an antiemetic agent in the form of
patches so that the antiemetic agent can be administered
transdermally.
[0007] Attempts to develop a transdermally administered antiemetic
agent have raised other problems. For example, some penetration
enhancers used in transdermal compositions, (e.g., terpenes),
induce skin irritation. Alcohols, which are often needed to
solubilize the antiemetic agent for transdermal applications, are
also irritating to the skin. Also, because of rapid depletion of
the alcohol, sustained delivery over a period greater than a few
hours is difficult to achieve. When a transdermal composition
consisting of a solution with a low viscosity is used, the blood
level of the drug may easily drop below the effective level thus
lessening the desired pharmacological effect.
[0008] Other efforts to administer antiemetic agents transdermally
have included complicated application devices or techniques such as
supplemental energy to enhance the transdermal penetration of the
drug. Current art describing transdermal antiemetic treatments
often focuses on mimicking oral or IV agents to achieve therapeutic
plasma levels. Typical delivery of such agents has been attempted
with the salt form of the drug to maintain the stability of the
active agent. However, salt forms of antiemetic agents have
relatively low transdermal permeabilities, and it is difficult to
achieve therapeutic plasma levels over a sustained period. Use of
the free base form is typically not considered since it could be
irritating or considered to be unstable in the dosage form.
[0009] Thus, it is desirable to provide a transdermal composition
of an antiemetic agent which is simple to use, nonirritating to the
skin and which may be left in place on the skin for 24 hours, two
days, three days or more for continuously and effectively
preventing, ameliorating or treating nausea and vomiting. Moreover,
with modest but functionally significant concentrations of active
and permeation enhancer, it is nonetheless possible using the
current teachings to formulate a patch that delivers antiemetic
agent over a very substantial time period, and even maintain
delivery as measured at the blood level well after removal of the
composition.
[0010] Extended delivery to the blood has been reported, but using
transdermal delivery devices that lacked permeation enhancer. See,
WO 2004/069141. With the present invention, remarkably sustained
delivery is achieved with the presence of functionally significant
concentrations of permeation enhancer. The lack of permeation
enhancer is taught in the '141 application to limit instability and
irritation. These same benefits are achieved using the teachings of
the current invention, but using modest but functionally
significant concentrations of permeation enhancer.
SUMMARY OF THE INVENTION
[0011] Provided in one embodiment is a method of treating acute,
delayed or anticipatory emesis for a sustained period in an
individual, the method comprising: applying to a portion of intact
skin or mucosa on the individual for 24 hours or more a composition
comprising:
i. an antiemetically effective amount of a 5-HT3 receptor
antagonist;
ii. a permeation enhancing amount of permeation enhancer comprising
0.5% to 15% by weight of the skin-contacting layer; and
iii. an adhesive,
[0012] wherein a plasma concentration of the 5-HT3 receptor
antagonist in a therapeutically effective range is provided for
period of time from an onset time to 12 hours or more after the
composition is removed. In certain embodiments, 12 or more hours
after removing the composition, one applies a second said
composition, wherein a plasma concentration of the 5-HT3 receptor
antagonist in a therapeutically effective range is provided for
period of time from an onset time to 12 hours or more after the
second said composition is removed.
[0013] In certain embodiments, the 5-HT3 receptor antagonist is
administered in conjunction with another antiemetic agent, or the
same agent in a separate form of administration.
[0014] Additionally provided is a composition for transdermal
administration of an antiemetic comprising: a skin-contacting
composition comprising:
i. an antiemetically effective amount of a 5-HT3 receptor
antagonist;
ii. a permeation enhancing amount of permeation enhancer comprising
0.5% to 15% by weight of the skin-contacting layer; and
iii. an adhesive,
[0015] wherein, when applied to a portion of intact skin on an
individual for 24 hours (or more) and then removed, the composition
provides the individual with a plasma concentration of the 5-HT3
receptor antagonist in a therapeutically effective range for period
of time from an onset time to 12 hours or more after the
composition is removed.
[0016] Further provided is a device for transdermal prevention,
amelioration or treatment of nausea and vomiting in an individual
which comprises a patch comprising: (a) a support layer; and (b) a
skin-contacting layer comprising:
i. an antiemetically effective amount of a 5-HT3 receptor
antagonist;
ii. a permeation enhancing amount of permeation enhancer comprising
0.5% to 15% by weight of the skin-contacting layer; and
iii. an adhesive,
[0017] wherein, when applied to a portion of intact skin on an
individual for 24 hours (or more) and then removed, the device
provides the individual with a plasma concentration of the 5-HT3
receptor antagonist in a therapeutically effective range for period
of time from an onset time to 12 hours or more after the device is
removed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a graph of the in vitro flux of granisetron
through human cadaver skin using an embodiment of a device of the
present invention.
[0019] FIG. 2 is a graph of the in vitro cumulative delivery of
granisetron through human cadaver skin using an embodiment of a
device of the present invention.
[0020] FIG. 3 shows a pharmacokinetic profile obtained using a
device of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0021] As used herein, the term "5-HT.sub.3 receptor antagonist"
refers to any of a class of drugs which act as 5-hydroxytryptamine
receptor antagonists to provide an anti-nausea and anti-vomiting
effect in individuals.
[0022] As used herein, the term "antiemetic" refers to the
prevention, amelioration or treatment of nausea and vomiting in
individuals.
[0023] As used herein, the term "antiemetic agent" refers to a drug
or material that is used to prevent, ameliorate or treat nausea and
vomiting in individuals.
[0024] As used herein, the term "antiemetically effective amount"
refers to the dose or blood level (depending on the context) of an
antiemetic agent that provides relief from (including amelioration
of) nausea and vomiting in an individual. In the case of blood
levels, the level that, if appropriately sustained, provides relief
from (including amelioration of) nausea and vomiting in an
individual. The amount is an amount that can be expected to be
effective in segment(s) of a targeted patient/subject population,
and can be such an amount divided by a reasonable number of
delivery devices or vehicles.
[0025] As used herein, the term "individual" refers to a living
mammal and includes, without limitation, humans and other primates,
livestock and sports animals such as cattle, pigs and horses, and
pets such as cats and dogs.
[0026] As used herein, the term "onset time" refers to the time
after application of the transdermal device or composition to an
individual until an antiemetically effective amount is obtained in
the individual's blood.
[0027] As used herein, the term "permeation enhancement" refers to
an increase in the permeability of skin to a therapeutic agent in
the presence of permeation enhancer(s) as compared to permeability
of skin to the same therapeutic agent in the absence of a
permeation enhancer(s).
[0028] As used herein, the term "permeation enhancer" refers to an
agent or a mixture of agents which acts to increase the
permeability of the skin to therapeutic agents.
[0029] As used herein, the term "permeation-enhancing amount"
refers to an amount of a permeation enhancer which provides
permeation enhancement throughout a substantial portion of the
administration period.
[0030] As used herein, the phrase "portion of intact skin" refers
to a defined area of intact unbroken skin or mucosal tissue. That
area will usually be in the range of about 5 cm.sup.2 to about 100
cm.sup.2.
[0031] As used herein the term "salt" refers to, but is not limited
to, pharmaceutically acceptable organic or inorganic salts. Typical
inorganic salts include hydrogen halides such as hydrochlorides,
carbonates, phosphates, sulfates, hydrogen sulfates, hydrobromides,
nitrates, and sulfides. Organic salts include, but are not limited
to, acid addition salts including salts of monocarboxylic and
polycarboxylic acids such as acetic acid, malic acid, maleic acid,
propionic acid, succinic acid, fumaric acid, citric acid, benzoic
acid, cinnamic acid, tartaric acid, and the like.
[0032] As used herein, the phrase "sustained time period" refers to
about 24 hours or more and will typically intend a period in the
range of about 48 or 72 hours to 168 hours.
[0033] As used herein, the term "transdermal" refers to both
percutaneous and transmucosal administration, i.e., passage of a
drug, such as an antiemetic agent through a body surface or
membrane such as intact unbroken skin or intact unbroken mucosal
tissue into the systemic circulation.
[0034] As used herein, the phrase "transdermal device wear time,"
or "patch wear time" refers to the interval of time during which a
transdermal device is maintained in place on a portion of an
individual's skin or mucosa.
[0035] As used herein, the term "percutaneously absorbable" refers
to the ability of a drug to pass through a body surface or membrane
such as intact unbroken skin or mucosal tissue into the circulation
system when formulated in a transdermal device of the
invention.
[0036] As used herein, the term "acute nausea and vomiting" relates
to nausea and vomiting in an individual lasting up to 24 hours
after the individual receives chemotherapy, radiation, or drug
treatment. It may also relate to post-operative nausea and vomiting
and to nausea and vomiting resulting from motion sickness.
[0037] As used herein, the term "delayed nausea and vomiting"
relates to nausea and vomiting in an individual occurring up to
five (5) days after the individual receives chemotherapy,
radiation, postoperatively or post drug treatment.
[0038] As used herein, the term "anticipatory nausea and vomiting"
relates to a conditioned response in an individual after the
individual receives chemotherapy, radiation, or drug treatment if
the individual expects to experience nausea and vomiting as a
result of the treatment or if the individual experienced nausea and
vomiting as a result of previous treatments. Anticipatory nausea
and vomiting may also be experienced post-operatively or as a
result of motion sickness.
[0039] As used herein, the term "skin-contacting layer" is a layer
of a transdermal device for contacting skin or mucosa.
[0040] As used herein, "flux rate" means the rate as modeled from
applications of the device to human cadaver skin.
[0041] The present invention relates to methods of preventing,
ameliorating or treating nausea and vomiting for a sustained time
period by the transdermal administration of transdermal device, the
free base form of 5-HT.sub.3 receptor antagonists, examples of
which antiemetic agents. The antiemetic agents used in the present
invention are, in the include ondansetron, granisetron,
tropisetron, dolasetron, hydrodolasetron, azasetron, ramosetron,
lerisetron, indisetron, itasetron, palonosetron, lamosetron,
allosetron and mixtures thereof. It will be recognized that after
administration the antagonists will form similar salts or
metabolites as are formed given other means of administration or
the administration of salt forms. The present invention also
relates to devices and compositions for use with the method of the
invention.
[0042] The method of the present invention is effective in the
prevention, amelioration or treatment of nausea and vomiting due to
chemotherapy, radiation therapy, other drug therapy, motion
sickness, or post-operative reaction. Because this method involves
the transdermal administration of an antiemetic agent over the
course of days, it is effective in preventing, ameliorating or
treating nausea and vomiting for an extended time. Additional
benefits of the present invention include improved patient
compliance, since the method involves the placement of a
transdermal device, which in some embodiments is left in place for
2, 3, 4, 5, 6, 7 days or more; patient protection from nausea and
vomiting from the time the device is applied until it is removed,
or for extended periods, such as 6, 9, 12, 18 or 24 hours or more,
after it is removed; increased patient confidence to leave the
hospital or doctor's office after chemotherapy, knowing that the
device will prevent or reduce nausea and vomiting. Additionally,
the device can maintain blood levels of the antiemetic agent in a
therapeutically effective range until it is removed. In some
embodiments, after wearing the device for 24 hours or more (or 36
hours or more, or 48 hours or more, or 72 hours or more), blood
levels are maintained in therapeutically effective range for an
extended period after removal, such as 6, 9, 12, 18 or 24 hours or
more. Since the device delivers the antiemetic agent at a
controlled rate, there is no initial spike in plasma concentration
as when the agent is administered, for example, by IV; therefore,
the method reduces side effects, such as headache and constipation,
sometimes experienced with other forms of administration.
[0043] In certain embodiments, therapeutically effective blood
levels of 5-HT.sub.3 receptor antagonist are obtained within 24
hours of application, 18 hours of application, 12 hours of
application, or within 9 hours, or within 8 hours, or within 7
hours, or within 6 hours. Such onset periods will vary with the
5-HT.sub.3 receptor antagonist and the particular skin-contacting
layer formulation.
[0044] In certain embodiments, the patch provides a flux rate of 1
.mu.g/cm.sup.2/hr or more (such as between 1 and 25
.mu.g/cm.sup.2/hr) of the 5-HT.sub.3 receptor antagonist for, after
an onset period, 24 hours or more, 48 hours or more, or 72 hours or
more, or 96 hours or more, or 120 hours or more, or 144 hours or
more, or 168 hours or more. In certain embodiments, the patch
provides a flux rate of 2 .mu.g/cm.sup.2/hr or more (such as
between 2 and 10 .mu.g/cm.sup.2/hr) of the 5-HT.sub.3 receptor
antagonist for, after an onset period, 24 hours or more, 48 hours
or more, or 72 hours or more, or 96 hours or more, or 120 hours or
more, or 144 hours or more, or 168 hours or more.
[0045] In certain embodiments, the patch delivers between 10
.mu.g/day (microgram/day) or more (such as 10 to 10,000 .mu.g/day)
of the 5-HT3 receptor antagonist to the individual for, from an
onset time to 24 hours or more, 48 hours or more, or 72 hours or
more, or 96 hours or more, or 120 hours or more, or 144 hours or
more, or 168 hours or more. In certain embodiments, the patch
delivers between 20 .mu.g/day (microgram/day) or more, or 50
.mu.g/day or more, 100 .mu.g/day or more, 200 .mu.g/day or more,
500 .mu.g/day or more, 1,000 .mu.g/day or more, 2,000 .mu.g/day or
more, 4,000 .mu.g/day or more, 6,000 .mu.g/day or more, of the
5-HT3 receptor antagonist to the individual for, from an onset time
to 24 hours or more, 48 hours or more, or 72 hours or more, or 96
hours or more, or 120 hours or more, or 144 hours or more, or 168
hours or more. It will be recognized that the amount sought to be
delivered will vary with the 5-HT3 receptor antagonist. For
example, with ondansentron amounts may need to be higher than for
granisetron.
[0046] The permeation enhancer used in the device of the present
invention can act to increase the permeability of the skin to the
5-HT.sub.3 receptor antagonist in the skin-contacting layer. In
general, the higher the amount of permeation enhancer, the greater
the increase in the skin's permeability; however, at higher amounts
of permeation enhancer, cold flow of the adhesive can also occur,
making it necessary to remove the transdermal patch prematurely.
"Cold flow" is the phenomenon of lateral flow of the reservoir
material from under its backing layer or the like. Also at higher
amounts of permeation enhancer, the 5-HT.sub.3 receptor antagonist
may crystallize out of the matrix, thus limiting its permeability.
Therefore, it is desirable to use an amount of permeation enhancer
which will reliably enhance the drug's permeability while still
limiting or preventing adhesive cold flow and drug crystallization.
In one embodiment of the device of the present invention, the
permeation enhancer in an amount of 15% or less (or about 14% or
less, or about 13% or less, or about 12% or less, or about 11% or
less, or about 10% or less, or about 9% or less) of the weight of
the skin-contacting layer (or composition) to enhance the
permeability of the drug without causing significant adhesive cold
flow or drug crystallization. The permeation enhancer is present in
a permeation-enhancing amount. The permeation enhancer can be
present, for example, in an amount of about 0.5% or more (or about
1% or more, or about 2% or more, or about 3% or more, or about 4%
or more, or about 5% or more, or about 7% or more) of the weight of
the skin-contacting layer (or composition)
[0047] The amount of 5-HT.sub.3 receptor antagonist can be varied,
for example, from about one of the lower limits described below
(with the limit exclusive or inclusive of the endpoint), or from to
one of the upper limits (exclusive or inclusive). The lower limits
are, based on the weight of the skin contacting layer or the
composition, 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, or 4%. The upper limits
are, based on the weight of the skin contacting layer or the
composition, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8% 7% or 6%. Again,
these amounts may additionally vary with the particular 5-HT3
receptor antagonist.
[0048] One embodiment of the device of the present invention is a
transdermal patch for application to the skin or mucosa of an
individual. The patch has a skin or mucosa-contacting layer
("skin-contacting layer" for simplicity) laminated or otherwise
attached to a support layer. Typically, the skin-contacting layer
is covered by a removable release liner before use to protect the
skin-contacting surface and keep it clean until it is applied to
the skin or mucosa.
[0049] The support layer acts as a support for the skin-contacting
layer and provides a barrier layer that prevents loss of the drug
in the skin-contacting layer to the environment. The material
chosen for such support should be compatible with the adhesive,
drug, and permeation enhancer, and should be minimally permeable to
any components of the patch. The support can be opaque to protect
components of the matrix patch from degradation from exposure to
ultraviolet light. Further, the support should be capable of
binding to and supporting the adhesive layer, yet should be pliable
to accommodate the movements of a person using the patch. Suitable
materials for the carrier include metal foils, metalized polyfoils,
composite foils or films containing polyester such as polyester
terephthalate, polyester or aluminized polyester,
polytetrafluoroethylene, polyether block amide copolymers,
polyethylene methyl methacrylate block copolymers, polyurethanes,
polyvinylidene chloride, nylon, silicone elastomers, rubber-based
polyisobutylene, styrene, styrene-butadiene and styrene-isoprene
copolymers, polyethylene, and polypropylene. A thickness of about
0.0005 to 0.01 inch can, for example, be used. The release liner
can be made of the same materials as the carrier, or other suitable
films coated with an appropriate release surface.
[0050] If present, the permeation enhancer is typically a fatty
acid ester of fatty acyl chain length C.sub.12-C.sub.18. The
alcohol component of the ester is typically C1-C6, or C2-C4, such
as for example isopropanol.
[0051] The patch can further comprise various additives in addition
to the adhesive, antiemetic, and permeation enhancer. These
additives are generally those pharmaceutically acceptable
ingredients that are known in the art of drug delivery and, more
particularly, in the art of transdermal drug delivery. Nonlimiting
examples of additive ingredients include diluents, excipients,
emollients, plasticizers, skin irritation reducing agents (which
can also include agents that reduce irritation to mucosa),
carriers, and mixtures of these. For example, suitable diluents can
include mineral oil, low molecular weight polymers, plasticizers,
and the like. Many transdermal drug delivery formulations have a
tendency to cause irritation after prolonged exposure to the skin
or mucosa, thus addition of an irritation reducing agent aids in
achieving a composition that is better tolerated by the skin or
mucosa.
[0052] For delivery of the antiemetic agent according to an
embodiment of the present invention, a patch device containing an
adhesive, a 5-HT3 receptor antagonist, and a permeation enhancer is
brought in contact with the skin or mucosa at a selected portion of
intact skin or mucosa and is held in place by the adhesive.
[0053] In certain embodiments, the transdermal composition (prior
to application to a patient) is essentially free of water. In
certain embodiments, the transdermal composition is essentially
free of tetraglycol (also known as glycofurol or
tetrahydrofurfurylpolyethilenglycole). In certain embodiments, the
transdermal composition is essentially free of a hydrophilic
organic solvent, including essentially free of ethanol,
isopropanol, butanol, benzyl alcohol, propylene glycol, glycerin,
polyethylene glycol having a molecular weight of 600 or less,
diethylene glycol monoethyl ether, triacetin, N-methylpyrrolidone,
2-pyrrolidone, dimethyl sulfoxide, decylmethyl sulfoxide, dioxane,
lactone or mixtures thereof. For the purposes of the preceding
proviso, "hydrophilic organic solvent" does not include fatty acid
esters of fatty acyl chain length C12-C18. It will be understood
that nominal amounts of such components, when the transdermal
composition is essentially free thereof, may be present in amounts
consistent with process parameters, but are not present in amounts
having a material effect on function, handling, storage, or some
factor material to the effective use or marketing of a transdermal
device.
[0054] In another embodiment the present invention provides a
method for the prevention, amelioration or treatment of nausea and
vomiting due to chemotherapy, radiation therapy, other drug
therapy, motion sickness, or post-operative reaction by the
transdermal administration of a 5-HT.sub.3 receptor antagonist
combined with the administration (e.g., oral, injection (such as
IV, IP, IM, SC), transdermal, buccal, rectal) of another antiemetic
agent (e.g., a corticosteroid), or the same 5-HT.sub.3 receptor
antagonist administered by separate administration route. A second
administration form can be administered by a separate dosing
schedule, as appropriate for the given dosage form.
[0055] Concurrent administration of 5-HT.sub.3 receptor antagonists
and corticosteroids for the treatment of nausea and vomiting is
known. For example, U.S. Pat. No. 5,929,059 (Sanger et al.)
discloses a method of treatment and/or prophylaxis of nausea and
vomiting, which comprises administering to a human or animal
subject, granisetron and steroid such as dexamethasone or a
pharmaceutically acceptable salt or ester thereof. Sanger et al.
further disclose that these two ingredients may be administered
orally, rectally, parenterally, or buccally, with oral
administration being preferred.
[0056] However, as earlier described herein, oral administration of
anti-emetic compounds can be challenging and may lead to greater
discomfort for the patient. Additionally, oral, IV, IM, rectal, and
buccal administration of active ingredients produce fluctuation in
plasma levels of the active ingredients. Therefore, it would be
advantageous to transdermally administer a 5-HT.sub.3 receptor
antagonist, thus preventing, ameliorating, or treating nausea and
vomiting, and then to administer an antiemetically effective amount
of an antiemetic corticosteroid, which can enhance the antiemetic
properties of the 5-HT.sub.3 receptor antagonist. The antiemetic
corticosteroid administration can be started at the same time as
the beginning of the transdermal administration of the 5-HT.sub.3
receptor antagonist or after the 5-HT.sub.3 receptor antagonist has
been transdermally administered for one hour or more, 12 hours or
more, or 24 hours or more. Administrations can be maintained for 12
hours or more, or 24 hours or more, 48 hours or more, 72 hours or
more, 96 hours or more, 120 hours or more, 144 hours or more, or
168 hours or more. The corticosteroid administration may occur as a
single dosage or additional dosages may be administered at selected
intervals. Useful routes of administration include, for example,
oral or parenteral routes.
[0057] Antiemetic corticosteroids suitable for use in this
embodiment of the invention can include, for example,
dexamethasone, methylprednisolone, prednisolone, their
physiologically acceptable salts or esters, or combinations
thereof. Dexamethasone may be administered as dexamethasone alcohol
or in the form of a pharmaceutically acceptable salt or ester.
Suitable salts and esters include the acetate, isonicotinate,
phenylpropionate, pivalate, t-butyl acetate, trioxaundecanoate,
disodium metasulphabenzoate and disodium phosphate.
[0058] A dose of steroid such as dexamethasone for use according to
the method of this embodiment of the invention can, for example, be
in the range of 0.5 to 20 mg per dosage unit. The unit doses may be
administered from 1 to 4 times per day. However, the exact dose
will depend on the route of administration and the condition being
treated, and it will be appreciated that it may be necessary to
make routine variations to the dosage depending on the age and
weight of the patient, as well as the nature and severity of the
condition being treated.
[0059] Compositions for oral administration of dexamethasone, such
as tablets and capsules, may be prepared by conventional means with
pharmaceutically acceptable excipients such as binding agents (e.g.
pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl
methylcellulose); fillers (e.g. lactose, microcrystalline cellulose
or calcium hydrogen phosphate); lubricant (e.g. magnesium stearate,
talc or silica); disintegrants (e.g. potato starch or sodium starch
glycollate); or wetting agent (e.g. sodium lauryl sulphate).
Tablets may be coated by methods well known in the art. Liquid
preparations for oral administration may take the form of, for
example, solutions, syrups or suspensions, or they may be presented
as a dry product for constitution with water or other suitable
vehicle before use. Such liquid preparations may be prepared by
conventional means with pharmaceutically acceptable additives such
as suspending agents (e.g. sorbitol syrup, cellulose derivatives or
hydrogenated edible fats); emulsifying agents (e.g. lecithin or
acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl
alcohol or fractionated vegetable oils); and preservatives (e.g.
methyl or propyl-p-hydroxybenzoates or sorbic acid). The
preparations may also contain buffer salts, flavoring, coloring and
sweetening agents as appropriate.
[0060] Preparations for oral administration of the corticosteroid
may be suitably formulated to give controlled release of the active
ingredient.
[0061] For parenteral administration the compositions may be
presented in a form suitable for bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form e.g. in syringes, ampoules or in multi-dose containers,
with an added preservative. The compositions may take such forms as
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents. Alternatively, the active ingredients may
be in powder form for constitution with a suitable vehicle, e.g.
sterile pyrogen-free water, before use.
[0062] In certain embodiments of this invention a transdermal patch
with a skin-contacting layer comprising: [0063] i. an
antiemetically effective amount of a free base of a 5-HT.sub.3
receptor antagonist; [0064] ii. a permeation-enhancing amount of a
permeation enhancer selected from the group consisting of isopropyl
myristate, isopropyl palmitate or fatty acid esters of fatty acyl
chain length C12-C18; and [0065] iii. an adhesive selected from the
group consisting of acrylics (including alkyl acrylics), vinyl
acetates, natural and synthetic rubbers, ethylenevinylacetate
copolymers, polysiloxanes, polyacrylates, polyurethanes,
plasticized polyether block amide copolymers, plasticized
styrene-butadiene rubber block copolymers, and mixtures thereof, is
applied to the skin or mucosa of an individual in need of
anti-emetic treatment or prevention. Subsequently, an
antiemetically effective amount of a systemic corticosteroid is
orally administered to the individual to enhance the antiemetic
effectiveness of the 5-HT3 receptor antagonist.
[0066] In a further embodiment, the transdermal device is provided
together with a systemic corticosteroid, such as dexamethasone, in
the form of a kit.
[0067] In another embodiment the present invention provides a
method for the prevention, amelioration or (including amelioration
of succeeding symptoms following prophylactic administration) or
treatment of nausea and vomiting due to chemotherapy, radiation
therapy, other drug therapy, motion sickness, or post-operative
reaction by the transdermal administration of a 5-HT.sub.3 receptor
antagonist combined with the oral or administration by injection of
antiemetic agent(s). The antiemetic agent can be selected from the
group consisting of 5-HT.sub.3 receptor antagonists, cannabinoids,
NK1 receptor antagonists, dopamine antagonists, corticosteroids, or
any other known antiemetic agent. In certain embodiments, the
antiemetic agent is administered to the individual at the same time
that the transdermal device is applied to the individual's skin. In
other embodiments, other antiemetic agent(s) are administered with
a timing selected to provide an initial delivery to plasma during
the lag phase of the transdermal administration.
[0068] In one embodiment the transdermal device is provided with an
antiemetic agent in the form of a kit. In a further embodiment, the
kit comprises labeling describing administering the antiemetic
agent to the individual at about the same time that the transdermal
device is applied to the individual's skin. Examples of the second
component include a dosage form comprising the same or a separate
antiemetic agent as in the first transdermal device. The second
dosage form can be, for example, for administration orally, by
injection (such as IV, IP, IM, SC), transdermally, buccally,
rectally, or the like.
[0069] In another embodiment, the transdermal device is applied to
the individual's skin up to, for example, 24 hours before the
individual is to be subjected to an event that creates a risk of
emesis. Such events include administration of a pharmaceutical
compound that creates a risk of emesis, such as, for example,
chemotherapeutic agents for anticancer therapy, and surgical or
other medical procedures that create a risk of emesis. In a further
embodiment, the transdermal device is applied to the individual's
skin 0.5 or more hours (1 or more hours, or 2 or more hours, or 4
or more hours, or 8 or more hours, or 10 or more hours, or 12 or
more hours) before the individual is to be subjected to an event
that creates a risk of emesis.
[0070] In other transdermal devices adapted to give long-term
delivery of granisetron, such long term delivery is achieved by
avoiding permeation enhancers. The current invention provides a
device that includes such enhancer, but nonetheless provides long
term delivery, while at the same time avoiding irritation and
instability that can be associated with enhancers. Moreover, in
certain embodiments the current device provides, on a device
area-normalized basis, greater transdermal delivery to the plasma
as measured by peak plasma levels or AUC (area under the curve)
than a device that corresponds in all but the absence of permeation
enhancer. In certain embodiments, such delivery is 1.5 times or
more, or 1.7 times or more, or 2 times or more, as measured at 24,
48, 72, 96 or 120 hours after application of the device.
EXAMPLE 1
Preparation of Adhesive Mixture and Transdermal Delivery Device
[0071] TABLE-US-00001 TABLE 1 Composition Formulation A Formulation
B Patch Size 15.0 cm.sup.2 15.0 cm.sup.2 Estimated Target Daily 1.2
mg 1.2 mg Dose Dry % Dry % Styrene-butadiene rubber 44.04 --
pressure sensitive adhesive Acrylate-vinylacetate -- 43.8 pressure
sensitive adhesive Isopropyl Myristate 3.01 4.07 Granisetron Base
3.05 3.05 Polyester Release liner 35.8 35.8 Polyester Backing 13.3
13.3
Components
[0072] Formulation A and Formulation B were prepared using the
amounts of each component as shown in Table 1 above.
[0073] The styrene-butadiene rubber pressure sensitive adhesive
used in the examples herein was DURO-TAK.RTM.87-6173 adhesive,
available from National Starch and Chemical in Bridgewater, N.J.
The acrylate-vinylacetate pressure sensitive adhesive used in the
examples herein was DURO-TAK.RTM.87-2516 adhesive, available from
National Starch and Chemical in Bridgewater, N.J. The isopropyl
myristate used in the examples herein was of NF grade. The
polyester release liner used in the examples herein is available
from Loparex, Inc., and the polyester backing used in the examples
herein is available from 3M as 2610F.
Procedure
[0074] The granisetron base is dissolved in an appropriate solvent
such as toluene and mixed with the selected adhesive. The isopropyl
myristate is then added to the mixture and the contents are mixed
until a homogeneous solution is achieved.
[0075] The homogeneous solution is coated onto the siliconized
surface of the polyester release liner to the desired thickness.
The coated release liner is then passed through a drying oven until
the solvents are evaporated. The dry adhesive-coated release liner
is removed from the oven and is then laminated with the polyester
backing layer. The multi-layer laminate is cut by punching out
units of the desired size and geometry for delivery of the desired
target daily dose, or it may be wound into rolls for storage or
transport to another location. The rolled laminate may then be
unwound and cut by punching out units of the desired size and
geometry. These punched units are then placed in individual pouches
and sealed for later use as patches.
Irritation Data
[0076] Formulation A was tested in a rabbit irritation test, a
guinea pig sensitization test, a dog toxicokinetic and a human
irritation test, and found non-irritating and non-toxic.
EXAMPLE 2
Test for Flux of Granisetron from the Transdermal Delivery
Device
Procedure
[0077] Heat-separated human cadaver skin was cut to the desired
size and mounted on a Franz diffusion cell. The release liner was
peeled away from a patch made according to Formulation B as
described in EXAMPLE 1 above. The patch was placed on the skin and
the patch and skin were clamped together. Receptor solution was
added to the diffusion cell, and the assembly was maintained at
32.degree. C. Aliquots of the receptor solution were taken at
periodic time points (24 hours, 48 hours, 72 hours, 96 hours, and
120 hours). The concentration of the granisetron in the receptor
solution was measured at each time point, and the flux rate from
examples A and B was calculated. The resulting data is illustrated
in FIG. 1. Cumulative delivery of granisetron over the indicated
time was likewise calculated from the concentration of granisetron
in the receptor solution at each time point and is illustrated in
FIG. 2.
EXAMPLE 3
Stability of Granisetron in Illustrative Examples
[0078] TABLE-US-00002 TABLE 2 Formulation C Formulation D
Composition Dry % Dry % Styrene-butadiene rubber 49.88% -- pressure
sensitive adhesive Acrylate-vinylacetate 43.77% pressure sensitive
adhesive Isopropyl Myristate -- 5.09% Granisetron Base* 1.02% 2.04%
Polyester Release liner 35.8% 35.8% Polyester Backing 13.3%
13.3%
[0079] Patches were made according to the procedure described in
Example 1 above using the formulations shown in Table 2. The
patches were then tested for granisetron stability using the method
described below.
[0080] Samples of the patches are stored at 50.degree. C. for up to
2 months. Stability of the product is assessed by testing
periodically for granisetron content and the total amount of
impurities using high performance liquid chromatography. The
results are shown below in Table 3. TABLE-US-00003 TABLE 3 Total
impurities Granisetron Potency (% of granisetron) (% w/w) Formu-
Time Formulation C Formulation D lation C Formulation D T.sub.o
99.9 99.5 0.05 0.25 1 month at 99.8 99.2 0.12 0.41 50.degree. C. 2
month at 99.6 98.4 0.19 0.81 50.degree. C.
[0081] The data in Table 3 show that the granisetron remains stable
for at least 2 months at 50.degree. C. in the composition of the
example of the invention with little loss of granisetron potency
and low amounts of impurities relative to the formulations at
starting time T.sub.o.
EXAMPLE 4
Samples for in vivo Test
[0082] Patches were made according to the method described above
using the ingredients and respective amounts shown in Table 4.
TABLE-US-00004 Weight % Wt in finished product Ingredient/Component
(mg/cm.sup.2) Composition (mg/25 cm.sup.2 patch) Granisetron base
0.75 2.54 18.75 Isopropyl myristate 1.20 4.06 30.00 Acrylic
adhesive 13.05 44.13 326.25 Total 15.00 50.73 375.00 Polyester
backing 3.91 13.22 97.75 Release liner 10.66 36.05 266.50 Total
weight 29.57 100.00 739.25
[0083] The acrylic adhesive used in Example 4 was
DURO-TAK.RTM.87-2516, available from National Starch and Chemical
in Bridgewater, N.J.
[0084] A randomized crossover clinical study was conducted in 11
individuals who received either a transdermal patch or an IV
solution of granisetron. Each 25 cm.sup.2 patch was formulated to
deliver 2 mg/day of granisetron. The 25 cm.sup.2 patches of Example
4 were applied to the skin of individuals and left in place for 96
hours, at which time they were removed. This was followed by a 10
day wash-out period, after which the same individuals received
granisetron IV in once-daily dosages of 2 mg/day Individuals who
received the IV treatment in the first period received a
transdermal patch in the cross over treatment. Blood plasma levels
of granisetron for all of the individuals in the test were measured
periodically during the 96 hour time that the patches were being
worn and the IV dosages were being administered, and for an
additional 2 days after the patches were removed and the IV
administration discontinued.
[0085] The results (FIG. 3A) indicated that the individuals
receiving IV granisetron experienced sharp spikes in blood plasma
levels of the granisetron after each daily dose was administered
and the blood plasma levels decreased very quickly. On the other
hand, the blood plasma levels of granisetron in the individuals
wearing the patches increased steadily and reached a plateau that
was maintained until the patches were removed after 96 hours, at
which time the blood plasma levels decreased slowly and steadily,
while still remaining in the therapeutically effective range for
more than 24 hours after the patches were removed. With
granisetron, typical plasma levels were observed to be in the range
of 0.1-25 ng/ml over the whole wear time and for two additional
days following patch removal. Thus, the patch of this example
provided a blood plasma level in a therapeutically effective range
both for the entire patch wear time and for more than 24 hours
after it was removed.
[0086] Publications and references, including but not limited to
patents and patent applications, cited in this specification are
herein incorporated by reference in their entirety in the entire
portion cited as if each individual publication or reference were
specifically and individually indicated to be incorporated by
reference herein as being fully set forth. Any patent application
to which this application claims priority is also incorporated by
reference herein in the manner described above for publications and
references.
[0087] While this invention has been described with an emphasis
upon certain embodiments, it will be obvious to those of ordinary
skill in the art that variations in the preferred devices and
methods may be used and that it is intended that the invention may
be practiced otherwise than as specifically described herein.
Accordingly, this invention includes all modifications encompassed
within the spirit and scope of the invention as defined by the
claims that follow.
* * * * *