U.S. patent application number 15/223876 was filed with the patent office on 2017-04-27 for polyamine enhanced formulations for triptan compound iontophoresis.
The applicant listed for this patent is Teva Pharmaceuticals International GmbH. Invention is credited to Michael Horstmann, Mohammad Sameti, Terri B. Sebree.
Application Number | 20170112779 15/223876 |
Document ID | / |
Family ID | 41431954 |
Filed Date | 2017-04-27 |
United States Patent
Application |
20170112779 |
Kind Code |
A1 |
Sebree; Terri B. ; et
al. |
April 27, 2017 |
POLYAMINE ENHANCED FORMULATIONS FOR TRIPTAN COMPOUND
IONTOPHORESIS
Abstract
A patch and compositions for iontophoresis of triptan compounds
are described.
Inventors: |
Sebree; Terri B.; (Gladwyne,
PA) ; Horstmann; Michael; (Neuwied, DE) ;
Sameti; Mohammad; (Bonn, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Teva Pharmaceuticals International GmbH |
Rapperswil-Jona |
|
CH |
|
|
Family ID: |
41431954 |
Appl. No.: |
15/223876 |
Filed: |
July 29, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13744371 |
Jan 17, 2013 |
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15223876 |
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12214555 |
Jun 19, 2008 |
8366600 |
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13744371 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/4045 20130101;
A61K 9/0009 20130101; A61N 1/30 20130101; A61P 25/06 20180101; A61K
9/7023 20130101; A61N 1/303 20130101; A61K 47/34 20130101; A61K
47/32 20130101; A61K 47/12 20130101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 31/4045 20060101 A61K031/4045; A61K 9/00 20060101
A61K009/00; A61K 47/34 20060101 A61K047/34; A61K 47/12 20060101
A61K047/12; A61N 1/30 20060101 A61N001/30; A61K 47/32 20060101
A61K047/32 |
Claims
1-28. (canceled)
29. An iontophoretic transdermal patch for the delivery of a
triptan compound to a subject in need thereof, wherein the patch
comprises an anode reservoir and a cathode reservoir, wherein the
anode reservoir comprises a polyamine hydrogel formed from a
polyamine salt of a polyacrylate copolymer and an organic acid, and
a gel forming amount of water; and wherein the polyamine hydrogel
further comprises: between about 3% and about 20% of the triptan
compound in intimate mixture with the hydrogel, and optionally one
or more additives.
30. The iontophoretic transdermal patch of claim 29, wherein the
hydrogel comprises at least about 80% water and between about 3.0%
and about 5.0% triptan compound.
31. The iontophoretic transdermal patch of claim 29, wherein the
hydrogel comprises between about 3% and about 10% polyamine
salt.
32. The iontophoretic transdermal patch of claim 29, wherein the
hydrogel comprises between about 10% and about 18% polyamine
salt.
33. The iontophoretic transdermal patch of claim 29, wherein the
polyamine salt is a salt of a methacrylate copolymer.
34. The iontophoretic transdermal patch of claim 29, wherein the
methacrylate co-polymer is an alkylated methacrylate copolymer.
35. The iontophoretic transdermal patch of claim 29, wherein the
hydrogel comprises between about 0.01% and about 1.0% antimicrobial
agent.
36. The iontophoretic transdermal patch of claim 29, wherein the
organic acid comprises lauric acid, which is present in an amount
between about 0.5% and about 7.0%.
37. The iontophoretic transdermal patch of claim 29, wherein the
organic acid comprises adipic acid, which is present in an amount
between about 0.1% and about 2.0%.
38. The iontophoretic transdermal patch of claim 29, wherein the
triptan compound is almotriptan, frovatriptan, eletriptan,
zolmitriptan, rizatriptan, sumatriptan, naratriptan, or a
pharmaceutically acceptable salt thereof.
39. The iontophoretic transdermal patch of claim 29, wherein the
triptan compound is sumatriptan or a salt thereof.
40. The iontophoretic transdermal patch of claim 29, wherein the
triptan compound is sumatriptan succinate or sumatriptan
hydrochloride.
41. The iontophoretic transdermal patch of claim 29, wherein the
patch is capable of administering an effective amount of the
triptan compound without substantially affecting skin pH.
42. The iontophoretic transdermal patch of claim 29, wherein the
patch is capable of administering an effective amount of the
triptan compound without substantially affecting skin
temperature.
43. The iontophoretic transdermal patch of claim 29, wherein the
hydrogel has a pH of between about 3 and about 8.
44. The iontophoretic transdermal patch of claim 43, wherein the
hydrogel has a pH of between about 5.5 and about 7.
45. The iontophoretic transdermal patch of claim 44, wherein the
hydrogel has a pH of about 6.
46. The iontophoretic transdermal patch of claim 29, wherein the
anode reservoir further comprises a solubility enhancer, a
permeation enhancer, an antimicrobial agent or any combination
thereof.
47. The iontophoretic transdermal patch of claim 29, wherein the
patch comprises a battery which operates throughout use of the
patch.
48. The iontophoretic transdermal patch of claim 29, wherein the
patch delivers a desired concentration of the triptan compound in
less than one hour.
49. The iontophoretic transdermal patch of claim 29, wherein the
anode reservoir consists essentially of a polyamine hydrogel formed
from: a polyamine salt of a polyacrylate copolymer and adipic acid,
and a gel forming amount of water; wherein the polyamine hydrogel
further comprises: between about 3% and about 10% of a triptan
compound in intimate mixture with the hydrogel, and between about
0.05% and about 1.0% methyl para-hydroxy benzoate.
50. The iontophoretic transdermal patch of claim 29, wherein the
organic acid is a fatty acid, a dicarboxylic acid or a mixture
thereof.
51. An iontophoretic transdermal patch for the delivery of
sumatriptan or a salt thereof, wherein the patch comprises an anode
reservoir and a cathode reservoir, wherein the anode reservoir
comprises a polyamine hydrogel formed from: an alkylated
methacrylate copolymer, at least about 80% water, between about
1.0% and about 5.0% lauric acid, and between about 0.05% and about
0.75% adipic acid; and wherein the polyamine hydrogel further
comprises: between about 3% and about 10% sumatriptan or salt
thereof in intimate mixture with the hydrogel, and between about
0.02% and about 0.5% methyl para-hydroxy benzoate.
52. The iontophoretic transdermal patch of claim 51, wherein
sumatriptan or a salt thereof is sumatriptan succinate.
53. An iontophoretic transdermal patch for the delivery of
sumatriptan succinate, wherein the patch comprises an anode
reservoir and a cathode reservoir, wherein the anode reservoir
comprises a polyamine hydrogel formed from: between about 84% and
about 88% water; between about 4.0% and about 7.0% alkylated
methacrylate co-polymer; between about 1.0% and about 5.0% lauric
acid; and between about 0.05% and about 0.75% adipic acid; wherein
the polyamine hydrogel further comprises: between about 3.0% and
about 5.0% sumatriptan succinate in intimate mixture with the
hydrogel, and between about 0.05% and about 0.75% methyl
para-hydroxy benzoate.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/744,371, filed Jan. 17, 2013, which is a
continuation of U.S. patent application Ser. No. 12/214,555, filed
Jun. 19, 2008, now U.S. Pat. No. 8,366,600, the entire contents of
which are incorporated herein by reference.
BACKGROUND
[0002] The process of iontophoresis was described by LeDuc in 1908
and has since found commercial use in the delivery of ionically
charged therapeutic agent molecules such as pilocarpine, lidocaine
and dexamethasone. In this delivery method, ions bearing a positive
charge are driven across the skin at the site of an electrolytic
electrical system anode while ions bearing a negative charge are
driven across the skin at the site of an electrolytic system
cathode.
[0003] Earlier, and some present, iontophoretic devices have been
typically constructed of two electrodes attached by adhesive
materials to a patient, each connected by a wire to a remote power
supply, generally a microprocessor-controlled electrical
instrument. A recent publication has indicated that sumatriptan can
be transdermally transported effectively using iontophoresis
(Femenia-Font et al, J. Pharm Sci 94, 2183-2186, 2005). In this
study, iontophoretic transport of sumatriptan was found to be at a
rate 385 fold higher than passive transport.
[0004] Another recent study has concluded that iontophoresis can be
useful in the delivery of anti-migraine compounds. In this study, a
two-component system comprised of an electronic controller
connected by wire to a transdermal patch was used to deliver
zolmitriptan. The company presenting the results from this study
has concluded that programmable capability of its iontophoresis
units may allow rapid initial delivery for fast action, while a
sustained, low level maintenance dose can be utilized for a
prevention of headache recurrence. A significant limitation of this
device lies in the two-component structure of the delivery system;
the wire connections between the controller and patches are a
nuisance to the wearer. Additionally, programmable controllers can
be expensive if utilized on a single use basis, or lost,
contaminated, broken, etc. if used on a reusable basis.
SUMMARY
[0005] The invention is based, at least in part, on the surprising
discovery that the use of polyamines in formulations for
iontophoresis allows for the administration of much higher dosages
of therapeutic agents through the use of higher amounts of
electricity, without causing a subject substantial amounts of skin
irritation. For example, the polyamine formulations of the
invention allow for the use of up to 4 mA of current without
causing significant erythema to the subjects using the patches.
[0006] In one embodiment, the invention pertains, at least in part,
to an iontophoretic transdermal patch for the delivery of a triptan
compound or a salt thereof. The patch comprises an anode reservoir,
a cathode reservoir and appropriate electrical circuitry.
Furthermore, at least one of the reservoirs comprises a mixture
which includes, but is not limited to, a polyamine hydrogel, water,
a triptan compound or salt thereof, and optionally one or more
additives.
[0007] In a further embodiment, the invention also pertains to
iontophoretic patches wherein the anode reservoir comprises:
approximately 3.0% to about 5.0% sumatriptan succinate;
approximately 84% to about 88% water; approximately 4.0% to about
7.0% alkylated methacrylate co-polymer; approximately 1.0% to about
6.0% fatty acids (e.g., about 1.0% to about 5.0% lauric acid and
about approximately 0.05% to about 0.75% adipic acid); and
approximately 0.05% to about 0.75% methyl para-hydroxy
benzoate.
[0008] In another further embodiment, the invention also features
iontophoretic transdermal patches wherein the cathode reservoir
comprises: approximately 95% to about 98% water; approximately 1.0%
to about 3.0% hydroxypropylcellulose; approximately 0.5% to about
1.5% salt; and approximately 0.05% to about 0.75% methyl
para-hydroxy benzoate.
[0009] The invention also pertains, at least in part, to methods of
treating a subject (e.g., for a triptan compound responsive state,
e.g., migraine), by administering an effective amount of a triptan
compound or a salt thereof to the subject using an iontophoretic
transdermal patch as described herein.
DETAILED DESCRIPTION
1. Iontophoretic Patches of the Invention
[0010] The invention pertains, at least in part, to an integrated
iontophoretic transdermal patch for the delivery of a triptan
compound or a salt thereof.
[0011] The term "iontophoretic transdermal patch" includes
integrated devices which allow for the administration of triptan
compounds through the skin by using electrical current to promote
the absorption of the drug from the patch through the skin of the
subject. In one embodiment, the patch comprises electrical
components, the triptan compound, and an adhesive backing
layer.
[0012] In one embodiment, the invention pertains, at least in part,
to an iontophoretic transdermal patch for the delivery of a triptan
compound or a salt thereof. The patch comprises an anode reservoir,
a cathode reservoir and appropriate electrical circuitry.
Furthermore, at least one of the reservoirs comprises a polyamine
and a mixture which includes, but is not limited to, water, a
triptan compound or salt thereof, and optionally one or more
additives, such as, but not limited to a solubility enhancer, a
permeation enhancer, a preservative and/or an antimicrobial
agent.
[0013] The term "polyamine" particularly includes cationic organic
compounds having at least two positively charged groups, preferably
amino groups including, but not limited to, primary amino groups,
secondary amino groups and/or tertiary amino groups. The invention
also includes polyamines including, for instance, pyrrolidino,
piperidino or morpholino groups. Generally, the polyamines used in
accordance with the present invention preferably include
polyelectrolytes which are polymers or macromolecules comprising
two or more positive charges upon being dissolved in water or an
aqueous solvent.
[0014] In a further embodiment, the term "polyamine" includes
organic compounds having two or more primary amino groups. Examples
include putrescine, cadaverine, spermidine and spermine. Other
polyamines include cyclen and other cyclic polyamines Examples of
polymer polyamines include those based on the aziridine monomer,
such as polyethylene amine
[0015] According to one embodiment of the invention, the polyamine
includes acrylate copolymers, methacrylate copolymers, alkylated
acrylate copolymers and/or alkylated methacrylate copolymers. These
copolymers contain two or more amino groups as defined above.
[0016] The alkyl group may be selected from C.sub.1 to C.sub.12
alkyl groups (linear or branched), such as, for instance, methyl,
ethyl, propyl, isopropyl, or butyl. The alkylated copolymers may
also include hydroxylated alkyl groups, preferably C.sub.1 to
C.sub.12 hydroxyalkyl groups, such as, for instance, hydroxymethyl,
hydroxyethyl or hydroxypropyl. Concerning the polyamines, an
example of an amino group is the "diamino ethyl" moiety present
within an organic compound, optionally within a polymeric organic
compound.
[0017] Other examples of polymeric polyamines of the invention
include, but are not limited to, methacrylate copolymers such as
copolymers of butylated and/or methylated methacrylate(s) and
dimethyl aminoethyl methacrylate. Other examples of copolymers
include the "basic butylated methacrylate copolymer" described in
the Pharmacopoea Europaea (Ph. Eur.), the "amino methacrylate
copolymer" described in the USP/NF, and the "aminoalkyl
methacrylate copolymer E" described in "Japanese Pharmaceutical
Excipients". Such copolymers are commercially available under the
trademark Eudragit.RTM. (from Evonik Industries, formerly Degussa),
for instance, Eudragit.RTM. RL 100, Eudragit.RTM. RL PQ,
Eudragit.RTM. RS 100, Eudragit.RTM. RS PQ, and Eudragit.RTM. E 100.
EUDRAGIT.RTM. E 100 is a cationic copolymer based on
dimethylaminoethyl methacrylate, butylmethacrylate, and methyl
methacrylate. The average molecular weight of this polymer is
approximately 150,000.
[0018] Generally, any polyamines containing at least two amino
groups as defined above may be used in the compositions of the
present invention, provided that they are toxicologically safe and
suitable for use in pharmaceutical products. Polyamines useful for
producing the compositions of the present invention may further be
selected from, for example, cyclic and macrocyclic polyamines, such
as cyclen, polyamines based on the aziridine monomer, such as
polyethylene imines, as well as polyethylene amines, putrescine,
cadaverine, spermidine, spermine, as well as polypropyleneimine,
polyvinylamine, polyvinylimine, polyvinylimidazol,
polyvinylpyridine, and polyguanidines. In one embodiment, the
polyamine compounds of the present invention have a molecular mass
of 1500 or above.
[0019] In a further embodiment, the composition of the present
invention comprises a combination of at least two different
polyamine compounds selected from the polyamine compounds defined
above.
[0020] The polyamine compounds to be used in accordance with the
compositions of the invention are present in the form of polyamine
salts, particularly water-soluble polyamine salts. Suitable salts
are obtainable by combining or reacting the above-mentioned
polyamines with suitable acids, preferably organic acids, by
standard procedures.
[0021] In one embodiment, the proportion of said polyamine(s) or
polyamine salt(s) is in the range of about 1% to about 25%-wt.,
about 5% to about 20%-wt. or about 10% to about 18%-wt., relative
to the total weight of the composition. In a further embodiment, an
anode reservoir may comprise between about 3.0% and about 10.0%,
between about 4.0% and about 9.0%, between about 5.0% and about
8.0%, between about 5.0% and about 6.0%, or about 5.86% alkylated
methacrylate co-polymer, e.g., butylated methacrylate copolymer,
e.g., Eudragit E100.
[0022] In further embodiments of the present invention, the
composition further comprises at least one acid selected from fatty
acids and dicarboxylic acids. However, other types of organic acids
may also be used, such as, for instance, acids selected from
hydroxy alkanoic acids and/or tricarboxylic acids.
[0023] By combining the above-discussed polyamine(s), e.g., amino
group-containing polyacrylate copolymers, with one or more acids
selected from fatty acids and dicarboxylic acids, the corresponding
polyamine salts are obtained. These polyamine salts are generally
water-soluble and, upon dissolution in water, form a polymeric
electrolyte. Furthermore, the present compositions comprising said
polyamine salts have been found to be particularly suitable as a
carrier or reservoir for ionic, dissociated active agents in
iontophoretic devices.
[0024] Further, it was found that by combining polyamine(s) with
one or more of said acids in the presence of water, hydrogels can
be obtained which are particularly useful as reservoir compositions
in iontophoretic systems.
[0025] The term "fatty acids" includes aliphatic monocarboxylic
acids having an aliphatic tail comprising up to 30 carbon atoms,
which acids may be linear or branched, saturated or unsaturated.
Preferably, C.sub.6 to C.sub.14 saturated fatty acids are used.
Fatty acids that may be used in accordance with the present
invention include, for instance, hexanoic acid, decanoic acid,
lauric acid, myristic acid, palmitic acid, caprylic acid and
stearic acid.
[0026] The term "dicarboxylic acid" includes organic compounds that
are substituted with two carboxylic acid functional groups, which
compounds include linear, branched and cyclic compounds, which
compounds may be saturated or unsaturated. For instance, the
dicarboxylic acid may be selected from dicarboxylic fatty acids,
particularly from C.sub.4 to C.sub.10 dicarboxylic acids. Examples
of fatty dicarboxylic acids include glutaric acid, adipic acid and
pimelic acid.
[0027] In further embodiments, the composition may contain a
combination comprising at least two fatty acids, or a combination
comprising at least two dicarboxylic acids, or a combination
comprising at least one fatty acid and at least one dicarboxylic
acid.
[0028] Generally, the amount of fatty acid(s) and/or dicarboxylic
acid(s) is adjusted so as to be at least sufficient to solubilize
the polyamine(s), and/or other components present in the
composition(s). Such solubility may be important, for example, in
order to obtain a hydrogel composition having one or more
properties, such as, for example, semi-solid or solid consistency
as well as skin-adhesive properties.
[0029] Preferably, the total amount of fatty acid(s) and/or
dicarboxylic acid(s) in the composition is in the range of 0.1% to
15%-wt., particularly in the range of 0.5% to 10%-wt. According to
a further embodiment, the concentration of the fatty acid(s) may be
about 0.1% to 10%-wt, preferably 0.5% to 7.0%-wt. According to
another further embodiment, the concentration of the dicarboxylic
acid(s) may be about 0.05% to 5%-wt., or about 0.1% to 2.0%-wt.
[0030] The compositions of the invention may be formulated as
hydrogels which include at least one gel-forming polymer (e.g., a
polyamine or a salt thereof as described above, and/or other
gel-forming polymers as generally known in the field of
pharmaceutical preparations), together with a gel-forming amount of
water or aqueous solvent mixture.
[0031] The relative amounts of water and gel-forming components may
be adjusted so as to obtain a hydrogel having solid or semi-solid
consistency. However, the formulations of the present invention may
also be formulated as liquids.
[0032] In a further embodiment, the hydrogel compositions may
comprise additional gel-forming polymers which may be selected from
the group consisting of polyacrylates or cellulose derivatives such
as hydroxypropylmethyl cellulose, hydroxypropyl cellulose or
hydroxyethyl cellulose.
[0033] The ionic strength can be adjusted by varying the proportion
of water within the hydrogel. Thus, the ionic strength can be
adjusted to optimize the efficacy of the iontophoretic process in
each particular case.
[0034] The term "triptan compound" includes triptan compounds,
derivatives and salts thereof. The term also includes compounds
that contain a 2-(1H-indol-3-yl)-N,N-dimethylethanamine moiety.
Examples of triptan compounds include, but are not limited to,
almotriptan, frovatriptan, eletriptan, zolmitriptan, rizatriptan,
sumatriptan, naratriptan, and pharmaceutically acceptable salts
thereof.
[0035] Examples of triptan compounds that may be used in the
methods of the invention include those listed in Table 1. The
concentrations of the triptan compound in the plasma to maintain an
effective amount will vary with the compound used. In the case of
sumatriptan, an initial plasma concentration of 15-20 ng/mL may
generally be effective. However, an initial concentration between
20 and 25, possibly 22.5 ng/mL, may be desired.
[0036] Table I shows additional triptan pharmacokinetics where
C.sub.max is the expected maximum concentration in the patient's
plasma and AUC is the total plasma concentration.
TABLE-US-00001 TABLE I Triptan Pharmacokinetics Drug C.sub.max
ng/mL AUC ng hr/mL Almotriptan 52 310 Frovatriptan 5 45 Eletriptan
200 1,300 Naratriptan 8 75 Rizatriptan 22 78 Zolmitriptan 4 20
[0037] Examples of pharmaceutically acceptable salts of triptan
compounds which may be used in the methods and patches of the
invention include, but are not limited to, chloride, bromide,
iodide, sulfate, phosphate, lactate, citrate, tartarate,
salicylate, succinate, maleate, gluconate, mesylate, laurate,
dodecylate, myristate, palmitate, stearate, coconoate, behinate,
oleate, linoleate, linolenate, eicosapentaenoate, eicosahexaenoate,
docosapentaenoate, docosahexaenoate, eicosanoids and the like. In a
further embodiment, the triptan compound is sumatriptan succinate.
In certain embodiments, the salt of the triptan compound may be
selected such that it does not react with the other components of
the patch, such as the metal electrode. In certain embodiments, the
salt may be selected such that it does not form a significant
amount of an insoluble residue when in contact with the metal
components of the patch of the invention.
[0038] In one embodiment, the reservoir includes a mixture that
includes between about 0.1% and about 20%, between about 0.2% and
about 10%, between about 2% and about 10%, between about 3% and
about 5% triptan, or between about 0.1% and about 0.5% of a
triptan, e.g., sumatriptan.
[0039] The reservoirs may be comprised of a hydrogel into which the
sumatriptan solution may be absorbed. The hydrogel may or may not
be substantially cross linked. The hydrogel may be comprised of one
or more polymers. Examples of polymers that the hydrogel may be
based upon include polyacrylates, polyisobutylene, cellulose
derivatives, polyisoprene, styrene-polybutylene-styrene block
copolymers, polysiloxanes, polyurethanes, and combinations
thereof.
[0040] In a further embodiment, an ion compensator is added to the
formulation to enhance solubility of the hydrogel by, for example,
compensating for the missing hydrophilic ions.
[0041] In one embodiment, the ion compensator is adipic acid. In
one embodiment, the formulation comprises an effective amount of a
fatty acid, e.g., an amount sufficient to solubilize the hydrogel
or polyamine such that the patch performs its intended function.
The fatty acid may be a dicarboxylic fatty acid, e.g., a
C.sub.4--C.sub.10 dicarboxylic acid. Examples of fatty dicarboxylic
acids include glutaric, adipic and pimelic acids. In another
embodiment, the patch comprises between about 0.1% and about 1.0%,
between about 0.15% and about 0.5% or between about 0.20% and about
0.40% adipic acid.
[0042] In a further embodiment, the reservoir may comprise a
hydrogel or a liquid aqueous composition which includes an
alkylated methacrylate polyamine copolymer, between about 0.5% and
about 10%-wt. of at least one triptan or salt thereof, between
about 0.02% and about 0.5%-wt. methyl para-hydroxybenzoate, between
about 1.0% and about 5.0%-wt. lauric acid, and between about 0.05%
and about 0.75%-wt. adipic acid, and said hydrogel composition has
a water content of at least about 80%-wt.
[0043] In a further embodiment, the reservoir may comprise a
hydrogel or a liquid aqueous composition which comprises about 4%
to about 7%-wt. alkylated methacrylate polyamine copolymer, about
3% to about 5%-wt. of at least one triptan compound or salt
thereof, about 1% to about 5%-wt. lauric acid, about 0.05% to about
0.75%-wt. adipic acid, about 0.05% to about 0.75%-wt. methyl
para-hydroxybenzoate, and about 84% to about 88%-wt. water.
[0044] In a further embodiment, the reservoir may comprise about
4.00%-wt. of triptan compound, about 86.37%-wt. of water, about
5.86%-wt. of alkylated methacrylate copolymer i.e., polyamine),
about 3.40%-wt. of lauric acid, about 0.27%-wt. of adipic acid, and
about 0.10%-wt. of methyl para-hydroxybenzoate, wherein each
specified value may vary by .+-.10% relative to the indicated mean
value.
[0045] In one embodiment, the reservoirs each have a surface area
of about 1 cm.sup.2, about 2 cm.sup.2, about 3 cm.sup.2, about 4
cm.sup.2, about 5 cm.sup.2, about 6 cm.sup.2, about 7 cm.sup.2,
about 8 cm.sup.2, about 9 cm.sup.2, about 10 cm.sup.2, about 11
cm.sup.2, about 12 cm.sup.2, about 13 cm.sup.2, about 14 cm.sup.2,
about 15 cm.sup.2, about 16 cm.sup.2, about 17 cm.sup.2, about 18
cm.sup.2, about 19 cm.sup.2, about 20 cm.sup.2, about 21 cm.sup.2,
about 22 cm.sup.2, about 23 cm.sup.2, about 24 cm.sup.2, about 25
cm.sup.2, about 26 cm.sup.2, about 27 cm.sup.2, about 28 cm.sup.2,
about 29 cm.sup.2, about 30 cm.sup.2, about 31 cm.sup.2, about 32
cm.sup.2, about 33 cm.sup.2, about 34 cm.sup.2, about 35 cm.sup.2,
about 36 cm.sup.2, about 37 cm.sup.2, about 38 cm.sup.2, about 39
cm.sup.2, about 40 cm.sup.2, about 41 cm.sup.2, about 42 cm.sup.2,
about 43 cm.sup.2, about 44 cm.sup.2, about 45 cm.sup.2, about 46
cm.sup.2, about 47 cm.sup.2, about 48 cm.sup.2, about 49 cm.sup.2,
or about 50 cm.sup.2 or greater.
[0046] In a further embodiment, the reservoir is self-adhesive. The
reservoir may also contain an additional tackifier, such as, but
not limited, to hydrocarbon resins, rosin derivatives, glycols
(e.g., glycerol, 1,3 butanediol, propylene glycol, polyethylene
glycol), and succinic acid.
[0047] The term "solubility enhancer" includes compounds which
increase the solubility of the triptan compound in its vehicle.
This can be achieved, for example, either through changing triptan
compound-vehicle interaction by introducing different excipients,
or through changing the crystallinity of the triptan compound.
Examples of solubility enhancers include water diols, such as
propylene glycol and glycerol; mono-alcohols, such as ethanol,
propanol, and higher alcohols; DMSO; dimethylformamide;
N,N-dimethylacetamide; 2-pyrrolidone; N-(2-hydroxyethyl)
pyrrolidone; N-methylpyrrolidone; 1-dodecylazacycloheptan-2-one and
other n-substituted-alkyl-azacycloalkyl-2-ones.
[0048] The term "permeation enhancer" includes compounds which
increase the permeability of skin to the triptan compound, i.e., so
as to increase the rate at which the triptan compound permeates
through the skin and enters the bloodstream. The enhanced
permeation effect (e.g., through the use of such enhancers) can be
observed, for example, by measuring the rate of diffusion of the
triptan compound through animal or human skin using a diffusion
cell apparatus.
[0049] Examples of permeation enhancers include, but are not
limited to, dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA),
decylmethylsulfoxide (C.sub.10 MSO), polyethylene glycol
monolaurate (PEGML), propylene glycol (PG), PGML, glycerol
monolaurate (GML), lecithin, 1-substituted azacycloheptan-2-ones
(e.g., 1-n-dodecylcyclazacycloheptan-2-one), alcohols, and the
like. The permeation enhancer may also be a vegetable oil such as,
for example, safflower oil, cotton seed oil and corn oil.
[0050] In addition, other agents may be used to enhance the
solubility of the polyamines Examples of such solubilizing agents
include, but are not limited to, fatty acids, e.g.,
C.sub.6-C.sub.14 saturated fatty acids. Examples of saturated fatty
acids include hexanoic, decanoic, myristic, palmitic, lauric and
caprylic acids. In a further embodiment, the fatty acid is lauric
acid and is present in amounts between about 0.1% and about 10%,
between about 0.2% and about 9.5%, between about 0.3% and about
9.0%, between about 0.4% and about 8.5%, between about 0.5% and
about 8.0%, between about 1.0% and about 7.0%, between about 1.5%
and about 6.0%, between about 2.0% and about 5.0%, between about
3.0% and about 4.0%, or about 3.40%.
[0051] The term "antimicrobial agent" includes agents which prevent
the growth of microbials in the patch. Examples of antimicrobials
include, but are not limited to, salts of chlorhexidine, such as
iodopropynyl butylcarbamate, diazolidinyl urea, chlorhexidene
digluconate, chlorhexidene acetate, chlorhexidene isethionate, and
chlorhexidene hydrochloride. Other cationic antimicrobial agents
may also be used, such as benzalkonium chloride, benzethonium
chloride, triclocarban, polyhexamethylene biguanide, cetylpyridium
chloride, methyl and benzothonium chloride. Other antimicrobial
agents include, but are not limited to: halogenated phenolic
compounds, such as 2,4,4'-trichloro-2-hydroxy diphenyl ether
(Triclosan); parachlorometa xylenol (PCMX); and short chain
alcohols, such as ethanol, propanol, and the like. Other examples
of antimicrobial agents include methyl para-hydroxybenzoate or
methyl 4-hydroxy benzoate.
[0052] In a further embodiment, the compositions of the invention
comprise between about 0.01% and about 1.0%, between about 0.05%
and about 0.5%, between about 0.07% and about 0.4%, between about
0.08% and about 0.3%, between about 0.09% and about 0.2%, or about
0.10% methyl para-hydroxybenzoate.
[0053] In a further embodiment, the solution has a pH of about 3 to
about 8, about 5.5 to about 7, or about 6. In another further
embodiment, the pH of solution is selected such that usage of the
patch does not substantially affect the pH of the skin. In a
further embodiment, the pH of the skin changes about .+-.4.0 or
less, about .+-.3.5 or less, about .+-.3.0 or less, about .+-.2.5
or less, about .+-.2.0 or less, about .+-.1.5 or less, about
.+-.1.0 or less, or about .+-.0.5 or less.
[0054] The backing layer can be any material known in the art for
being suitable for such purposes. The backing layer is preferably
flexible and suitable materials include without limitation,
cellophane, cellulose acetate, ethylcellulose, plasticized
vinylacetate-vinylchloride coploymers, polyethylene terephthalate,
nylon, polyethylene, polypropylene, polyvinylidene chloride, coated
flexible fibrous backings such as paper and cloth and aluminum
foil. The adhesive material may be any material known in the art
which is suitable for use in the iontophoretic patches of the
invention.
[0055] In a further embodiment, the patch comprises an electrode
which does not significantly react with the triptan compound or
anti-migraine compound to form an insoluble salt. In a further
embodiment, the electrode is comprised of a metal with a reactivity
similar to zinc. In another further embodiment, the electrode
includes silver, iron, aluminum, tin, copper, zinc, nickel, brass,
metal alloys, conductive polymers, or coatings or mixtures
thereof.
[0056] In a further embodiment, the electrical circuitry of the
patch comprises a battery which operates throughout the use of the
patch. In a further embodiment, the battery is integrated into the
patch and may be the main, if not sole, source of power of the
patch. The invention also includes embodiments in which said
composition is soaked or impregnated into an adsorbent material and
embodiments in which the device of the invention further comprises
an adsorbent material that is soaked or impregnated with said
composition, which is generally a liquid aqueous composition or
hydrogel composition.
[0057] The adsorbent material which is soaked or impregnated with
the aqueous or hydrogel composition(s) serves to keep said
composition in place and, at the same time, to maintain the
low-viscosity structure. Suitable adsorbent materials may be
selected from fibrous pads, fabrics, sponges, tissues, non-woven or
woven materials, felts or felt-like materials, etc.
[0058] According to a further embodiment, the composition and/or
patch of the present invention has adhesive properties, to ensure
that the composition is maintained in direct and complete contact
with the skin at the site of application during the whole time
period of transdermal drug administration. Adhesiveness can be
obtained by incorporating one or more adhesive polymers into said
compositions. Adhesive polymers suitable for this purpose are
generally known to the skilled person. In one embodiment, a
polyamine or polyamine salt having adhesive properties is used as
said adhesive polymer(s).
[0059] In a further embodiment, the compositions and/or patches of
the invention are self-adhesive. To render the compositions and/or
patches self-adhesive, they may further contain one or more
additives selected from tackifiers which includes, but are not
limited to, hydrocarbon resins, rosin derivatives, glycols (such as
glycerol, 1,3-butanediol, propylene glycol, polyethylene glycol),
and succinic acid.
[0060] In yet another embodiment, the invention pertains to an
iontophoretic transdermal patch for the delivery of sumatriptan or
a salt thereof, which comprises an anode reservoir, a cathode
reservoir, appropriate electrical circuitry and a polyamine. In a
further embodiment, the anode reservoir comprises: approximately
3.0% to about 5.0% sumatriptan succinate (advantageously about
4.00%.+-.10%); approximately 84% to about 88% water (advantageously
about 86.37%.+-.10%); approximately 4.0% to about 7.0% alkylated
methacrylate co-polymer (advantageously about 5.86%.+-.10%);
approximately 1.0% to about 5.0% lauric acid (advantageously about
3.40% .+-.10%); approximately 0.05% to about 0.75% adipic acid
(advantageously about 0.27%.+-.10%); and approximately 0.05% to
about 0.75% methyl para-hydroxy benzoate (advantageously about
0.10%.+-.10%).
[0061] Generally, the compositions of the present invention can be
manufactured by conventional methods. The compositions of the
present invention are obtainable by dissolving or dispersing the
various ingredients (e.g., triptan compound, polyamine, additives)
in water or an aqueous solvent mixture. The resulting mixture may
then be spread on a flat surface or poured into moulds or extruded,
and then allowed to solidify to obtain hydrogel compositions having
the desired shape. During these process steps, or after
solidification, the composition may be combined with additional
components as required to produce the final product, generally a
pharmaceutical administration form.
[0062] However, various alternative methods for manufacturing the
compositions of the present invention may be used, as will be
readily realized by the skilled person.
[0063] The present invention further encompasses the use of the
above-described composition(s) as an integral component of a
transdermal patch. Preferably, such composition is incorporated
into said patch during manufacture, to form the active substance
reservoir of the patch. Further, the present invention encompasses
the use of the above-described composition(s) as an integral
component of an iontophoretic patch, for example, as an anodic
reservoir of the patch. Such composition may be incorporated into
the iontophoretic patch during manufacture, to form the anodic
reservoir of the patch. The above-mentioned administration forms
are obtainable by manufacturing methods generally known in the
art.
2. Methods of Treating Subjects using the Patches of the
Invention
[0064] In some embodiments, the invention pertains to a method for
treating a subject for a triptan compound responsive state by
administering to a subject a steady state concentration of a
triptan compound for at least one hour, wherein the compound is not
administered intravenously. In a further embodiment, the compound
is administered via an iontophoretic patch.
[0065] In one embodiment, the patch of the invention allows for the
delivery of an effective amount of a triptan compound to a subject
in less than about two hours, less than about 90 minutes, less than
about one hour, less than about 45 minutes, less than about 30
minutes or less than about 20 minutes.
[0066] The term "subject" includes living organisms capable of
having triptan compound responsive states (e.g., mammals). Examples
of subjects include humans, dogs, cats, horses, cows, goats, rats
and mice. In one embodiment, the subject is a human. In a further
embodiment, the term includes subjects suffering from a triptan
compound responsive state.
[0067] The term "effective amount" includes the amount of the
triptan compound which is effective to treat a particular triptan
compound responsive state.
[0068] In one embodiment, the particular triptan compound is
sumatriptan and the effective amount is effective to treat a
migraine. In this case, the effective amount of sumatriptan may be
a concentration of about 10 ng/mL or greater, about 11 ng/mL or
greater, about 12 ng/mL or greater, about 13 ng/mL or greater,
about 14 ng/mL or greater, about 15 ng/mL or greater, about 16
ng/mL or greater, about 17 ng/mL or greater, about 18 ng/mL or
greater, about 19 ng/mL or greater, about 20 ng/mL or greater,
about 21 ng/mL or greater, about 22 ng/mL or greater, or about 22.5
ng/mL or greater in said subject's plasma. In another embodiment,
the effective amount of sumatriptan delivered systemically is
greater than about 5 mg, greater than about 10 mg, or greater than
about 15 mg.
[0069] The term "treat" includes the reduction or amelioration of
one or more symptoms of a triptan compound responsive state. It
also may include the prevention of the occurrence or reoccurrence
of a triptan compound responsive state.
[0070] The term "triptan compound responsive state" includes
almotriptan responsive states, zolmitriptan responsive states,
rizatriptan responsive states, sumatriptan responsive states, and
naratriptan responsive states. The term also includes migraines,
familiar hemiplegic migraines (with and without aura), chronic
paroxysmal headaches, cluster headaches, migraine headaches,
basilar migraines, and atypical headaches accompanied by autonomic
symptoms. In certain embodiments, the triptan compound responsive
state is a migraine.
[0071] The term "delivery" includes the transport of the triptan
compound from the patch to the plasma of a subject. In certain
embodiments, approximately 1%-30% (or higher) of the triptan
compound in the patch is delivered to the plasma of the subject
over the course of treatment. The term "systemic delivery" includes
delivery to a subject through non-oral administration. Preferred
systemic administration methods include transdermal
administration.
[0072] In an embodiment, the invention pertains to an iontophoretic
transdermal patch for the delivery of a triptan compound, e.g.,
sumatriptan or a salt thereof, wherein the patch allows for the
systemic delivery of an effective amount of sumatriptan or a salt
thereof to a subject.
[0073] The term "delivery time" includes the period of time which
the patch is functioning by actively delivering the triptan
compound to the subject iontophoretically.
[0074] In another embodiment, the patch is able to maintain a
steady state concentration of the triptan compound in the subject's
plasma for at least one hour, for at least two hours, for at least
three hours, for at least four hours, or for at least five hours or
more.
[0075] In yet a further embodiment, the patch allows for the
delivery of an effective amount of sumatriptan in less than about
one hour. In another further embodiment, the patch maintains a
steady state concentration for at least two hours.
[0076] The language "maintain a steady state concentration" refers
to the maintenance of a particular concentration (e.g., a desired
concentration, e.g., an effective amount) for a particular length
of time. In one embodiment, the concentration of the triptan
compound in the subject's plasma fluctuates from the average
concentration by about 10 ng/ml or less, about 9 ng/ml or less,
about 8 ng/ml or less, about 7 ng/ml or less, about 6 ng/ml or
less, about 5 ng/ml or less, about 4 ng./ml or less, about 3 ng/ml
or less, about 2 ng/ml or less, about 1 ng/ml or less, or by about
0.5 ng/ml or less.
[0077] The invention also pertains to a method for treating a
subject, by transdermally administering to the subject an effective
amount of a triptan compound in less than one hour using an
integrated iontophoretic patch. In this embodiment, the patch uses
a current density selected such that the current does not
substantially irritate the subject's skin. The patch may use an
average current density of 0.25 mA/cm.sup.2 or less for a
significant portion of the delivery time of the triptan
compound.
[0078] The patch may employ a current which is effective to deliver
the amount of the triptan compound needed to treat the triptan
compound state of the invention. In one embodiment, the patch is
uses a current greater than about 0.5 mA, greater than about 1 mA,
greater than about 2 mA, greater than about 3 mA, greater than
about 4 mA, or greater than about 5 mA, without substantially
irritating a subject's skin. In one embodiment, the patch employs a
current of about 4 mA for about an hour.
[0079] In another embodiment, the patch delivers about 100 mA min
or greater, about 200 mA min or greater, about 300 mA min or
greater, about 400 mA min or greater, about 500 mA min or greater,
about 600 mA min or greater or about 700 mA min or greater of
current with out substantially irritating a subject's skin.
[0080] The term "significant portion" includes at least about 30%
of the delivery time or more, at least about 40% of the delivery
time or more, at least about 50% of the delivery time or more, at
least about 60% of the delivery time or more, at least about 70% of
the delivery time or more, at least about 75% of the delivery time
or more, at least about 80% of the delivery time or more, at least
about 85% of the delivery time or more, at least about 90% of the
delivery time or more, or at least about 95% of the delivery time
or more.
[0081] The language "does not substantially irritate a subject's
skin" includes patches which result in a skin erythema score of
about 2.50 or less, about 2.00 or less, or about 1.00 or less about
two hours, about 24 hours, about two days, about three days, about
four days or about one week after patch removal. In another further
embodiment, the language "does not substantially irritate a
subject's skin" includes patches which result in a skin erythema
score of about 2.50 or less, about 2.00 or less, or about 1.00 or
less immediately after patch removal. In another further
embodiment, the patches of the invention do not cause punctuate
lesions when used according to the methods of the invention.
[0082] In another further embodiment, the invention also pertains
to a method for treating a triptan compound responsive state in a
subject. The method includes administering transdermally to the
subject an effective steady state concentration of a triptan
compound using an integrated patch. In a further embodiment, the
effective concentration is at least about 20 ng/mL.
[0083] In another embodiment, the invention also pertains, at least
in part, to a method for treating a subject for a sumatriptan
responsive state. The method includes transdermally administering
to the subject an effective amount (e.g., about 5 mg or greater, or
about 10 mg or greater) of sumatriptan or a salt thereof, such that
the subject is treated. The transdermal administration may include
the use of a iontophoretic patch.
[0084] The term "transdermal" includes delivery methods which occur
through the skin of a subject without puncturing the subject's
skin.
[0085] As used herein, the terms "about" and "approximately" are
used interchangeably.
EXEMPLIFICATION OF THE INVENTION
Example 1
Use of Iontophoretic Patches to Deliver Sumatriptan Succinate
[0086] A single center, open label, single-dose, five period study
was conducted to compare the pharmacokinetics of four prototypes of
sumatriptan iontophoretic transdermal patches of the invention with
100 mg oral sumatriptan succinate in healthy volunteers. Subjects,
at minimum, participated in Treatment A and Treatment B.
[0087] The iontophoretic patches used were self-contained, with an
external power source, designed to be applied to the surface of the
skin and to deliver medication systemically.
[0088] The patch treatments and prototype iontophoretic patches
prepared for this example are detailed in Table 2 below.
TABLE-US-00002 TABLE 2 Iontophoretic Patch Dosing Treatments Wear
Anode Time Theoretical mA Electrode Period Treatment Placement (hr)
Waveform Delivery Dose Minutes Size 1 A Upper 6 3 mA 1.0 hr 3 mg/hr
.times. 1 hr + 630 5 cm.sup.2 arm then 1.5 mA 1.5 mg/hr .times. for
5.0 hrs 5 hrs = 10.5 mg 3 C Upper 6 3 mA 1.0 hr 3 mg/hr .times. 1
hr + 630 5 cm.sup.2 arm then 1.5 mA 1.5 mg/hr .times. for 5.0 hrs 5
hrs = 10.5 mg 4 D Upper 6 4 mA 1.0 hr 4 mg/hr .times. 1 hr + 840 10
cm.sup.2 back then 2.0 mA 2 mg/hr .times. 5 hr = for 5.0 hrs 14.0
mg 5 E Upper 4 4 mA 1.0 hr 4 mg/hr .times. 1 hr + 600 10 cm.sup.2
back then 2.0 mA 2 mg/hr .times. 3 hr = for 3.0 hrs 10.0 mg
[0089] Nine subjects participated in Treatment B a 100 mg
sumatriptan succinate oral tablet. The study consisted of a
screening visit followed by Treatments A, B, C, D and E. Each of
the treatment periods were separated by a 2 day washout period.
[0090] The patches for Treatments A and C were applied to a clean,
dry, relatively hair free area of the upper arm. Treatments were
applied to alternating arms. The patches for Treatments D and E
were applied to a clean, dry, relatively hair free area of the
upper back. Treatments were applied to alternating right and left
positions on the upper back. PK blood samples were scheduled for
collection per subject for each of the five periods.
[0091] Iontophoretic delivery system assessments including adhesion
and dermal irritation and the amount of adhesive residue on the
skin were performed during Treatments A, C, D and E.
[0092] The subjects were healthy adult volunteers (four males and
five females) who were willing to attend the clinic for five
treatment periods. The subjects received no other medication
(prescription or over-the-counter) for two weeks prior to study
entry, unless approved by the designated physician. Study
participants were between 19 and 50 years old. The mean age was 28
years old.
[0093] The five treatments, as described in Table 2, were
administered in five clinical periods. Four of the five dosing
treatments were using the patches comprising the formulations of
the invention. The patch was applied to the upper arm or upper back
depending on the Treatment period.
[0094] In treatment B, the subjects received an Imigran FTab oral
tablet (100 mg sumatriptan succinate) with 240 mL of water after an
overnight fast. Subjects remained fasted for 4 hours after
dosing.
[0095] The drug reservoir pad (anode) formulation for Treatment A,
C, D and E was: 10% polyamine formulation plus 4% sumatriptan
succinate (loaded with up to 120 mg of sumatriptan).
[0096] The salt reservoir pad (cathode) formulation for Treatments
A, C, D and E was: 2% hydroxypropylcellulose (HPC) and NaCl.
[0097] There were no serious adverse events reported during the
study periods. The most frequently reported adverse event was
headache related to treatment B (sumatriptan succinate 100 mg oral
tablet) and tingling and itching at patch site for patch treatments
A, C, D and E.
[0098] Mean skin erythema scores were also calculated for each of
the patch treatments. Immediately after patch removal, mean scores
were 1.40 or below for each of the four patch treatments. After 72
hours, the mean scores were each below 1.00.
Equivalents
[0099] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, numerous
equivalents to the specific procedures described herein. Such
equivalents are considered to be within the scope of the present
invention and are covered by the following claims. The contents of
all references, patents, and patent applications cited throughout
this application are hereby incorporated by reference. The
appropriate components, processes, and methods of those patents,
applications and other documents may be selected for the present
invention and embodiments thereof.
* * * * *