U.S. patent application number 15/660935 was filed with the patent office on 2018-02-01 for transdermal formulation and delivery method of low solubility or unstable unionized neutral drugs by in situ salt-to-neutral drug conversion of salt drug.
The applicant listed for this patent is Corium International Inc.. Invention is credited to Amit K. Jain, Eun Soo Lee, Appala Sagi, Parminder Singh.
Application Number | 20180028463 15/660935 |
Document ID | / |
Family ID | 59523314 |
Filed Date | 2018-02-01 |
United States Patent
Application |
20180028463 |
Kind Code |
A1 |
Lee; Eun Soo ; et
al. |
February 1, 2018 |
TRANSDERMAL FORMULATION AND DELIVERY METHOD OF LOW SOLUBILITY OR
UNSTABLE UNIONIZED NEUTRAL DRUGS BY IN SITU SALT-TO-NEUTRAL DRUG
CONVERSION OF SALT DRUG
Abstract
Compositions, devices, and methods for transdermal
administration of active agents provided in their salt form instead
of neutral form are provided.
Inventors: |
Lee; Eun Soo; (Redwood City,
CA) ; Jain; Amit K.; (Milpitas, CA) ; Singh;
Parminder; (Union City, CA) ; Sagi; Appala;
(Mountain View, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Corium International Inc. |
Menlo Park |
CA |
US |
|
|
Family ID: |
59523314 |
Appl. No.: |
15/660935 |
Filed: |
July 26, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62504408 |
May 10, 2017 |
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62504391 |
May 10, 2017 |
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62457794 |
Feb 10, 2017 |
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62444763 |
Jan 10, 2017 |
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62444745 |
Jan 10, 2017 |
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62423133 |
Nov 16, 2016 |
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62367542 |
Jul 27, 2016 |
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62367502 |
Jul 27, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/22 20180101;
A61K 31/13 20130101; A61P 25/26 20180101; A61K 31/045 20130101;
A61P 13/02 20180101; A61P 25/02 20180101; A61K 9/7061 20130101;
A61P 25/28 20180101; A61K 9/7023 20130101; A61K 9/7038 20130101;
A61P 13/08 20180101; A61K 31/445 20130101; A61P 25/04 20180101;
A61P 25/36 20180101; A61K 31/00 20130101; A61K 31/18 20130101; A61P
25/24 20180101; C08K 5/0016 20130101; A61K 47/10 20130101; A61P
25/14 20180101; A61K 9/7084 20130101; A61K 9/7092 20130101; A61K
47/32 20130101; A61P 13/00 20180101; A61K 47/12 20130101; A61P
25/00 20180101; A61K 9/7053 20130101; A61K 47/02 20130101; A61K
31/137 20130101; A61P 25/16 20180101; A61K 31/27 20130101; A61P
35/00 20180101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; A61K 31/445 20060101 A61K031/445 |
Claims
1. A composition for transdermal delivery, comprising: a drug
reservoir comprising a salt form of an active agent and a proton
accepting and/or proton donating entity.
2. The composition of claim 1, wherein the drug reservoir comprises
an amine salt form of an active agent and a proton accepting
entity.
3. The composition of claim 1, wherein the active agent is
donepezil, rivastigmine, memantine, or tamsulosin.
4. The composition of claim 1, wherein the drug reservoir comprises
about 1% to about 70% w/w of the active agent.
5. The composition of claim 2, wherein the proton accepting entity
is a proton accepting polymer.
6. The composition of claim 2, wherein the proton accepting entity
is an amine functionalized polystyrene miscrosphere or a dimethyl
aminoethyl methacrylate-based acrylate.
7. The composition of claim 2, wherein the drug reservoir comprises
about 0.5% to about 35% w/w of the proton accepting entity.
8. The composition of claim 1, wherein the drug reservoir comprises
an acid salt form of an active agent and a proton donating
polymer.
9. The composition of claim 8, wherein the active agent is an acid
salt drug selected from the group consisting of sodium alendronate,
tresprostinil sodium, sodium diclofenac, naproxen sodium, and
ketoprofen sodium.
10. The composition of claim 8, wherein the drug reservoir
comprises about 5% to about 35% w/w of the active agent.
11. The composition of claim 8, wherein the proton donating polymer
is an anionic copolymer based on methacrylic acid or a carboxylated
polystyrene microsphere.
12. The composition of claim 8, wherein the drug reservoir
comprises about 0.5% to about 35% w/w of the proton donating
polymer.
13. The composition of claim 1, further comprising a salt form
solubilizer selected from the group consisting of water, alcohols,
glycerol, propylene glycol, ethylene glycol, dimethyl sulfoxide,
and N-methylpyrrolidone.
14. The composition of claim 13, wherein the drug reservoir
comprises up to 15% w/w of the salt form solubilizer.
15. The composition of claim 1, further comprising a neutral form
solubilizer selected from the group consisting of a fatty acid
ester, a dicarboxylic acid ester, a glycerol ester, a lactate, a
fatty alcohol, sorbitan monolaurate, sorbitan monooleate, lauryl
lactate, propylene glycol monolaurate, dimethyl succinate, lauryl
alcohol, and oleyl alcohol.
16. The composition of claim 15, wherein the drug reservoir
comprises up to 15% w/w of the neutral form solubilizer.
17. The composition of claim 1, further comprising a plasticizer
selected from the group consisting of a dicarboxylic acid ester, an
adipate, a sebacate, a maleate, a tricarboxylic ester, triethyl
citrate, tributyl citrate, a glycerol esters, and triacetin.
18. The composition of claim 17, wherein the drug reservoir
comprises up to 20% w/w of the plasticizer.
19. The composition of claim 1, further comprising an additive
selected from the group consisting of crospovidone and colloidal
silicone dioxide.
20. The composition of claim 19, wherein the drug reservoir
comprises up to 25% w/w of the additive.
21. The composition of claim 1, wherein the drug reservoir
comprises an adhesive agent selected from the group consisting of
an acrylate, polyisobutylene, silicone adhesive, and styrene block
copolymer based adhesive.
22. The composition of claim 21, wherein the drug reservoir
comprises up to 65% w/w of the adhesive agent.
23. A transdermal patch comprising a drug reservoir layer
comprising a composition of claim 1; a backing layer; and a contact
adhesive layer.
24. The transdermal patch of claim 23, wherein the backing layer is
an occlusive polymer film.
25. The transdermal patch of claim 23, wherein the contact adhesive
layer comprises an adhesive selected from the group consisting of
an acrylate, polyisobutylene, silicone adhesive, and styrene block
copolymer based adhesive.
26. The transdermal patch of claim 23, further comprising a
nonwoven tie layer between the drug reservoir and the contact
adhesive layer.
27. The transdermal patch of claim 23, further comprising a
rate-controlling membrane between the drug reservoir layer and the
contact adhesive layer.
28. The transdermal patch of claim 23, wherein the patch comprises
at least two drug reservoir layers.
29. The transdermal patch of claim 28, wherein each of the at least
two drug reservoir layers is separated by a nonwoven tie layer.
30. The transdermal patch of claim 28, wherein each of the at least
two drug reservoir layers is separated by a rate-controlling
membrane.
31. A method of transdermally administering an active agent to a
patient in need thereof, comprising providing a composition
according to claim 1 to a patient in need thereof.
32. A method for treating Alzheimer's disease, Parkinson's disease,
attention deficit hyperactivity disorder, narcolepsy, depression,
anxiety disorder, obsessive compulsive disorder, opioid dependence,
benign prostatic hyperplasia, or acute urinary retention comprising
providing a composition according to claim 1 to a patient in need
thereof.
33. The method of claim 31, further comprising administering or
instructing to administer to the skin of the patient the
composition.
34. The method of claim 33, wherein said administering achieves a
therapeutically effective blood concentration of the active
agent.
35. A method of transdermally administering an active agent to a
patient in need thereof, comprising providing a transdermal patch
according to claim 23 to a patient in need thereof.
36. A method for treating Alzheimer's disease, Parkinson's disease,
attention deficit hyperactivity disorder, narcolepsy, depression,
anxiety disorder, obsessive compulsive disorder, opioid dependence,
benign prostatic hyperplasia, or acute urinary retention comprising
providing a transdermal patch according to claim 23 to a patient in
need thereof.
37. The method of claim 35, further comprising administering or
instructing to administer to the skin of the patient the
transdermal patch.
38. The method of claim 37, wherein said administering achieves a
therapeutically effective blood concentration of the active agent.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/504,408, filed May 10, 2017; U.S. Provisional
Application No. 62/504,391, filed May 10, 2017; U.S. Provisional
Application No. 62/457,794, filed Feb. 10, 2017; U.S. Provisional
Application No. 62/444,763, filed Jan. 10, 2017; U.S. Provisional
Application No. 62/444,745, filed Jan. 10, 2017; U.S. Provisional
Application No. 62/423,133, filed Nov. 16, 2016; U.S. Provisional
Application No. 62/367,542, filed Jul. 27, 2016 and U.S.
Provisional Application No. 62/367,502, filed Jul. 27, 2016 each
herein incorporated by reference in its entirety.
TECHNICAL FIELD
[0002] The subject matter described herein relates to compositions,
devices, and methods for transdermal administration of active
agents provided in their salt form instead of neutral form.
BACKGROUND
[0003] Active agents for transdermal delivery are typically
provided in their neutral form because the neutral form is
typically much more skin permeable than a corresponding salt form.
In traditional transdermal formulations, a neutral form of an
active agent is solubilized in a drug reservoir (also referred to
sometimes as an adhesive matrix), and the active agent diffuses
from the drug reservoir and into the skin. Transdermal patches,
therefore, typically contain as much active agent dissolved in the
drug reservoir as the agent's solubility in the components of the
23-30 allows, often with solubilizers to enhance its solubility.
Alternatively, neutral, solid particles of active agent are
sometimes dispersed in the drug reservoir, so long as the
particles' dissolution rate is such that a constant supply of
dissolved active agent is provided.
[0004] For many active agents, however, a neutral form is difficult
to solubilize, formulate, and/or administer to a patient or
subject. When a drug has a low solubility as a unionized neutral
form in a drug reservoir, it is difficult to incorporate sufficient
amount as a solubilized form to deliver at a therapeutic level for
multiple days. Moreover, a dissolved active agent may recrystallize
as large crystals during the process of solvation, coating, and
drying. Further, many active agents are less stable in neutral form
than in salt form.
[0005] There is a need in the art for improved compositions,
devices, patches, systems, and methods for transdermal delivery of
active agents that address these shortcomings.
BRIEF SUMMARY
[0006] The following aspects and embodiments thereof described and
illustrated below are meant to be exemplary and illustrative, not
limiting in scope.
[0007] In one aspect, a composition for transdermal delivery is
provided. The composition comprises a drug reservoir comprising a
salt form of an active agent and a proton accepting and/or proton
donating entity.
[0008] In one aspect, a composition for transdermal delivery is
provided. The composition comprises a drug reservoir comprising an
amine salt form of an active agent and a proton accepting
entity.
[0009] In one embodiment, the active agent is donepezil,
rivastigmine, memantine, fingolimod, or tamsulosin.
[0010] In one embodiment, the drug reservoir comprises between
about 1-70 w/w of the active agent.
[0011] In another embodiment, the proton accepting entity is a
proton accepting polymer.
[0012] In yet another embodiment, the proton accepting entity is an
amine functionalized polystyrene miscrosphere or a dimethyl
aminoethyl methacrylate-based acrylate.
[0013] In still another embodiment, the proton accepting entity is
sodium bicarbonate. In other embodiments, the proton accepting
entity excludes sodium bicarbonate.
[0014] In another embodiment, the drug reservoir comprises between
about 0.5-35% w/w of the proton accepting entity.
[0015] In another aspect, a composition for transdermal delivery
comprises a drug reservoir comprising an acid salt form of an
active agent and a proton donating polymer.
[0016] In one embodiment, the active agent is an acid salt drug
selected from the group consisting of sodium alendronate,
tresprostinil sodium, sodium diclofenac, naproxen sodium, and
ketoprofen sodium.
[0017] In one embodiment, the drug reservoir comprises between
about 5-35% w/w of the active agent.
[0018] In another embodiment, the proton donating polymer is an
anionic copolymer based on methacrylic acid or a carboxylated
polystyrene microsphere.
[0019] In still another embodiment, the drug reservoir comprises
between about 0.5-35% w/w of the proton donating polymer.
[0020] In yet another embodiment, the composition can further
comprise a salt form solubilizer selected from the group consisting
of water, alcohols, glycerol, propylene glycol, ethylene glycol,
dimethyl sulfoxide, and N-methylpyrrolidone.
[0021] In one embodiment, the drug reservoir comprises up to 15%
w/w of the salt form solubilizer.
[0022] In one embodiment, the composition can further comprise a
neutral form solubilizer selected from the group consisting of a
fatty acid ester, a dicarboxylic acid ester, a glycerol ester, a
lactate, a fatty alcohol, sorbitan monolaurate, sorbitan
monooleate, lauryl lactate, propylene glycol monolaurate, dimethyl
succinate, lauryl alcohol, and oleyl alcohol.
[0023] In another embodiment, the drug reservoir comprises up to
15% w/w of the neutral form solubilizer.
[0024] In still another embodiment, the composition can comprises a
plasticizer selected from the group consisting of a dicarboxylic
acid ester, an adipate, a sebacate, a maleate, a tricarboxylic
ester, triethyl citrate, tributyl citrate, a glycerol esters, and
triacetin.
[0025] In yet another embodiment, the drug reservoir comprises up
to 20% w/w of the plasticizer.
[0026] In another embodiment, the composition comprises an additive
selected from the group consisting of crospovidone and colloidal
silicone dioxide.
[0027] In another embodiment, the drug reservoir comprises up to
25% w/w of additive.
[0028] In another embodiment, the drug reservoir comprises an
adhesive agent selected from the group consisting of an acrylate,
polyisobutylene, silicone adhesive, and styrene block copolymer
based adhesive.
[0029] In one embodiment, the drug reservoir comprises up to 65%
w/w of the adhesive agent.
[0030] In another aspect, a transdermal patch comprising a drug
reservoir layer as described herein, a backing layer, and a contact
adhesive layer is provided.
[0031] In one embodiment, the backing layer is an occlusive polymer
film.
[0032] In one embodiment, the contact adhesive layer comprises an
adhesive selected from the group consisting of an acrylate,
polyisobutylene, silicone adhesive, and styrene block copolymer
based adhesive.
[0033] In one embodiment, the transdermal patch further comprises a
nonwoven tie layer between the drug reservoir and the contact
adhesive layer.
[0034] In one embodiment, the transdermal patch further comprises a
rate-controlling membrane between the drug reservoir and the
contact adhesive layer.
[0035] In one embodiment, the transdermal patch comprises at least
two drug reservoir layers.
[0036] In another embodiment, the at least two drug reservoir
layers are separated by a nonwoven tie layer.
BRIEF DESCRIPTION OF THE FIGURES
[0037] FIGS. 1-3 are illustrations of exemplary embodiments of
transdermal patch configurations.
[0038] FIG. 4 is a graph of average skin flux for donepezil
transdermal delivery devices, in .mu.g/cm.sup.2hr, in vitro as a
function of time, in hours, in an in vitro skin permeation test for
devices having formulations according to Example 1 (squares),
Example 2 (triangles), and Example 7 (circles).
[0039] FIG. 5 is a graph of average skin flux for memantine
transdermal delivery devices, in .mu.g/cm.sup.2hr, in vitro as a
function of time, in hours, in an in vitro skin permeation test for
devices having a formulation according to Example 4.
DETAILED DESCRIPTION
I. Definitions
[0040] Various aspects now will be described more fully
hereinafter. Such aspects may, however, be embodied in many
different forms and should not be construed as limited to the
embodiments set forth herein; rather, these embodiments are
provided so that this disclosure will be thorough and complete, and
will fully convey its scope to those skilled in the art.
[0041] Compositions, devices, and methods described herein are not
limited to the specific polymers, excipients, cross-linking agents,
additives, manufacturing processes, or adhesive products described
herein. It will be understood that the particular terminology used
herein is for the purpose of describing particular embodiments and
is not intended to be limiting.
[0042] Where a range of values is provided, it is intended that
each intervening value between the upper and lower limit of that
range and any other stated or intervening value in that stated
range is encompassed within the disclosure. For example, if a range
of 1 .mu.m to 8 .mu.m is stated, it is intended that 2 .mu.m, 3
.mu.m, 4 .mu.m, 5 .mu.m, 6 .mu.m, and 7 .mu.m are also explicitly
disclosed, as well as the range of values greater than or equal to
1 .mu.m and the range of values less than or equal to 8 .mu.m.
[0043] The singular forms "a," "an," and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to a "polymer" includes a single polymer as well
as two or more of the same or different polymers, reference to a
"solvent" includes a single solvent as well as two or more of the
same or different solvents, and the like.
[0044] The use of terms of order or importance, including "first"
and "second," is to distinguish and identify individual elements
and does not denote or imply a particular order or importance
unless clearly indicated by context.
[0045] The term "active agent" as used herein refers to a chemical
material or compound suitable for topical or transdermal
administration and that induces a desired effect. The terms include
agents that are therapeutically effective, prophylactically
effective, and cosmetically effective agents. The terms "active
agent," "drug," and "therapeutic agent" are used interchangeably
herein.
[0046] An "adhesive matrix" as described herein includes matrices
made in one piece, for example, matrices made via solvent casting
or extrusion as well as matrices formed in two or more portions
that are then pressed or joined together.
[0047] The term "skin" as used herein refers to skin or mucosal
tissue, including the interior surface of body cavities that have a
mucosal lining. The term "skin" should be interpreted as including
"mucosal tissue" and vice versa.
[0048] The term "therapeutically effective amount" as used herein
refers to the amount of an active agent that is nontoxic but
sufficient to provide the desired therapeutic effect. The amount
that is "effective" will vary from subject to subject, depending on
the age and general condition of the individual, the particular
active agent or agents, and the like as known to those skilled in
the art.
[0049] The terms "transdermal" or "transdermal delivery" as used
herein refer to administration of an active agent to a body surface
of an individual so that the agent passes through the body surface
(e.g., through the skin) and into the individual's blood stream.
The term "transdermal" is intended to include transmucosal
administration, i.e., administration of a drug to the mucosal
(e.g., sublingual, buccal, vaginal, rectal, etc.) surface of an
individual so that the agent passes through the mucosal tissue and
into the individual's blood stream.
II. Compositions/Devices
[0050] Compositions and/or devices are provided for transdermal
administration of active agents. Compositions may be used in
devices, patches, and/or systems for transdermal delivery of one or
more active agents. Compositions described herein are contemplated
for use in transdermal delivery systems, devices, patches, and/or
methods as described herein.
[0051] Active agents for transdermal delivery are typically
provided in their neutral form because the neutral form is
typically much more skin permeable than a corresponding salt form.
Many active agents, however, are difficult to solubilize in a
sufficient amount in a neutral form, difficult to administer in a
neutral form at a steady rate for multiple days, and/or less stable
in a neutral form than a salt form. As such, the present invention
encompasses the recognition that certain active agents are better
suited for administration in their salt forms.
[0052] In general, compositions described herein provide an active
agent in its salt form and at least one proton donating or proton
accepting entity. The proton donating or proton accepting entity
promotes conversion of the active agent from a salt to its neutral
form to improve skin permeability of the active agent. In some
embodiments, compositions contain one or more additional
ingredients (for example, solubilizers, plasticizers, matrix
modifying additives, and/or adhesives). In some embodiments, active
agent compositions described herein can be provided in the form of
a transdermal drug delivery device, such as a patch.
A. Compositions for Transdermal Delivery of Active Agents
[0053] In a first aspect, compositions comprising a layer or matrix
comprised of an adhesive, a salt form of at least one active agent
and at least one proton accepting or proton donating entity are
provided. In general, the salt form of a provided active agent will
react with a provided proton accepting or proton donating entity in
order to generate a neutral form of the active agent that is more
skin permeable than the salt form. In some embodiments, the
adhesive composition may include one or more additional ingredients
that cause the neutral form of the active agent to be generated at
a specified and/or desired rate. Such compositions can provide, in
some embodiments, a relatively constant activity of an active
agent.
[0054] The compositions may further include one or more of the
following: one salt form solubilizer (total 0-50% w/w), one neutral
form solubilizer (total 0-50% w/w), one plasticizer for a proton
accepting entity and/or proton donating entity (total 0-50% w/w),
matrix modifying additives (total 0-50% w/w), and adhesive polymers
(total 0-95% w/w).
[0055] It will be appreciated that all w/w % or wt % described
herein may refer to wet or dry weight of the composition.
[0056] In some embodiments, compositions comprise micronized
particles of a salt form of one or more active agents dispersed in
an adhesive matrix or a drug reservoir. In some embodiments, the
salt form of at least one active agent is present in the drug
reservoir in an amount between about 1-70 wt %, about 1-50 wt %,
about 1-35 wt %, about 1-25 wt %, about 2-70 wt %, about 2-50 wt %,
about 2-35 wt %, about 5-70 wt %, about 5-50 wt %, about 5-35 wt %,
about 5-30 wt %, about 5-25 wt %, about 5-20 wt %, about 5-15 wt %,
about 5-10 wt %, about 10-35 wt %, about 10-30 wt %, about 10-25 wt
%, about 10-20 wt %, about 10-15 wt %, about 20-35 wt %, about
20-30 wt %, about 20-25 wt %, about 25-35 wt %, about 25-30 wt %,
or about 30-35 wt %.
[0057] In some embodiments, the drug reservoir further comprises a
solubilizer that has a limited solubility for the salt form of an
active agent (the "salt form solubilizer"). In some embodiments,
the micronized particles of a salt form of an active agent will
ionize in the salt form solubilizer. In some embodiments, the
micronized salt form particles will be maintained in equilibrium
with the dissolved, ionized salt form. In some embodiments, the
salt form solubilizer has only a limited degree of solubility for
the micronized salt particles, such that the equilibrium favors the
micronized salt particles over the dissolved, ionized salt
form.
[0058] In some embodiments, a salt form solubilizer has a
solubility for the salt of at least about 0.1% w/w, at least about
0.2% w/w, at least about 0.3% w/w, at least about 0.4% w/w, at
least about 0.5% w/w, or at least about 1.0% w/w. In some
embodiments, the salt form solubilizer has a solubility for the
salt of less than about 30% w/w or less than about 25% w/w or 20%
w/w.
[0059] In some embodiments, a salt form solubilizer is a protic
solvent (e.g., a solvent that has a hydrogen atom bound to an
oxygen (e.g., as in a hydroxyl group) or a nitrogen (e.g., as in an
amine group), and/or any solvent that contains labile protons).
Exemplary salt form solubilizers include, but are not limited to,
water, alcohols (e.g., ethanol, methanol, etc.), glycerol,
propylene glycol, ethylene glycol, dimethyl sulfoxide,
N-methylpyrrolidone, and/or combinations thereof.
[0060] In some embodiments, the drug reservoir comprises about 0-50
wt %, about 0-20 wt %, about 0-10 wt %, about 0-5 wt %, about 1-50
wt %, about 1-20 wt %, about 2-50 wt %, about 2-20 wt %, about 5-50
wt %, about 5-20 wt %, about 5-15 wt %, about 5-10 wt %, or about
10-15 wt % of at least one salt form solubilizer.
[0061] In some embodiments, the dissolved, ionized salt form will
react with a proton accepting entity (for amine drug salt) or a
proton donating entity (for carboxylic drug salt), also provided in
the matrix. In general, proton accepting entities have primary,
secondary, or tertiary amine groups. In general, proton donating
entities have carboxylic groups. In some embodiments, proton
accepting entities and/or proton donating entities are dissolved
and intermixed with the drug reservoir. In some embodiments, proton
accepting entities and/or proton donating entities are dispersed as
fine particles. In some embodiments, proton accepting entities
and/or proton donating entities are plasticized.
[0062] In some embodiments, a drug reservoir comprises about 0.5-30
wt %, about 1-30 wt %, about 5-30 wt %, about 10-30 wt %, about
15-30 wt %, about 20-30 wt %, about 25-30 wt %, about 0.5-25 wt %,
about 1-25 wt %, about 5-25 wt %, about 10-25 wt %, about 15-25 wt
%, about 20-25 wt %, about 0.5-20 wt %, about 1-20 wt %, about 5-20
wt %, about 10-20 wt %, about 15-20 wt %, about 0.5-15 wt %, about
1-15 wt %, about 5-15 wt %, about 10-15 wt %, about 0.5-10 wt %,
about 1-10 wt %, about 5-10 wt %, about 0.5-5 wt %, or about 1-5 wt
% of at least one proton accepting entity or at least one proton
donating entity.
[0063] In some embodiments, a proton accepting entity or proton
donating entity is a polymer. In some embodiments, proton accepting
entities are amine-functional polymers. Exemplary proton accepting
polymers include, but are not limited to, amine-functionalized
polystyrene miscrosphere, dimethyl aminoethyl methacrylate based
acrylates (e.g., EUIDRAGIT.RTM. EPO or EUDRAGIT.RTM. E100), and/or
combinations thereof. In some embodiments, proton donating entities
are carboxylic-functional polymers. Exemplary proton donating
polymers include, but are not limited to, anionic copolymers based
on methacrylic acid and polyacrylic acid (e.g., EUDRAGIT.RTM. L100,
EUDRAGIT.RTM. L100-55, EUDRAGIT.RTM. S100), carboxylated
polystyrene microsphere, and/or combinations thereof.
[0064] In some embodiments, the reaction of a salt form of an
active agent with a proton accepting polymer or proton donating
polymer will generate a skin permeable, neutral form of the active
agent and a solid polymer. As the neutral active agent is depleted
(by diffusion into the skin) and the polymer becomes separated as a
solid phase in the matrix, the reaction continues to move forward,
maintaining a relatively steady concentration and/or activity of
the neutral form.
[0065] In some embodiments, the proton accepting entity for an
amine drug salt is an inorganic salt with mild basicity whose pKa
is lower than that of the amine drug salt. For example, sodium
bicarbonate has pKa=6.4 which is lower than most amine salt drugs.
In some embodiments, the proton accepting entity for an amine drug
salt is a sodium bicarbonate. In such embodiments, the reaction
products include a skin permeable, neutral form of the active
agent, water, and carbon dioxide. As the neutral active agent and
CO.sub.2 are depleted (by diffusion into the skin and escaped gas,
respectively), the reaction continues to move forward, maintaining
a relatively steady concentration and/or activity of the neutral
form.
[0066] In some embodiments, compositions further comprise one or
more solubilizers for the neutral form of the active agent (a
"neutral form solubilizer"). In some embodiments, the neutral form
solubilizer helps ensure that a neutral active agent, once formed,
can persist long enough to diffuse into the skin.
[0067] In some embodiments, a neutral form solubilizer has a
solubility for the neutral form of the active agent of at least
about 0.1% w/w. In some embodiments, the neutral form solubilizer
has a solubility for the neutral form of the active agent of less
than about 30% w/w.
[0068] In some embodiments, exemplary neutral form solubilizers
generally include, but are not limited to, fatty acid esters,
lactate esters, dicarboxylic esters, citrate esters, glycerol
esters, fatty alcohols, and/or combinations thereof. In some
embodiments, exemplary neutral form solubilizers include, but are
not limited to, sorbitan monooleate, sorbitan monolaurate
(Span.RTM. 20), propylene glycol monolaurate, lauryl lactate,
dimethyl succinate, triethyl citrate, triacetin, lauryl alcohols,
oleyl alcohols, and/or combinations thereof.
[0069] In some embodiments, the drug reservoir comprises about 0-40
wt %, about 0-30 wt %, about 0-20 wt %, about 0-15 wt %, about 0-10
wt %, about 0-5 wt %, about 1-40 wt %, about 1-30 wt %, about 1-20
wt %, about 2-40 wt %, about 2-30 wt %, about 2-20 wt %, about 5-20
wt %, about 1-15 wt %, about 2-15 wt %, about 5-15 wt %, about 5-10
wt %, or about 10-15 wt % of at least one neutral form
solubilizer.
[0070] In some embodiments, active agents include amine salt drugs
or acid salt drugs.
[0071] In some embodiments, the active agent is an amine salt drug.
In some embodiments, amine salt drugs have a solubility of at least
about 0.1 mg/g, at least about 0.2 mg/g, at least about 0.3 mg/g,
at least about 0.4 mg/g, at least about 0.5 mg/g, or at least about
1.0 mg/g in the drug reservoir. In some embodiments, amine salt
drugs have a solubility of less than about 100 mg/g in the drug
reservoir. Exemplary amine salt drugs include, but are not limited
to, donepezil, rivastigmine, memantine, tamsulosin, rotigotine,
fentanyl, escitalopram, ropinirole, pramipexole, buprenorphine,
fingolimod and lidocaine.
[0072] In some embodiments, a micronized amine salt form of an
active agent is dispersed in a matrix that further comprises at
least one salt form solubilizer. The salt form of the active agent
("DHCl") is partially dissolved and ionized, as shown in Equation
1:
DH Cl Ionized DH + + Cl - ( 1 ) ##EQU00001##
[0073] In some embodiments, the dissolved, ionized active agent
("DH.sup.+") interacts with a proton acceptor amine polymer
("PolymerN") as shown in Equation 2. As the neutral form of the
active agent ("D") is depleted by diffusion, the reaction moves
toward continuous formation of D.
DH + Dissolved & skin impermeable amine salt form + Polymer N
Solid polymer + Cl - Equilibrium Constant = K Polymer NHCl Solid
polymer + D Dissolved & skin permeable neutral form ( 2 )
##EQU00002##
[0074] In some embodiments, the reaction byproduct ("Polymer NHCl")
is sequestered as solid phase in the matrix. In some embodiments,
the neutral form of the active agent ("D") is depleted by diffusion
through into the skin.
[0075] Because a proton is sequestered from DH.sup.+, the
dissolved, ionized active agent in the equilibrium reaction (2),
the equilibrium constant is expressed as in Equation 3:
K = [ D ] [ DH + ] ( 3 ) ##EQU00003##
[0076] In some embodiments, a basic inorganic salt whose pKa is
lower than an amine salt drug can also be used to generate a
neutral form of the drug. For example carbonic acid/sodium
bicarbonate has pKa=6.4. In some embodiments, sodium bicarbonate
can be used as a proton accepting entity for an amine salt drug. In
one embodiment, sodium bisulfate is the protein accepting entity
for an amine salt drug.
[0077] Ionization of sodium bicarbonate is shown in Equation 5,
which generates a sodium ion and a bicarbonate ion:
NaHCO 3 Ionization Na + + HCO 3 - ( 5 ) ##EQU00004##
[0078] The salt form of an active agent ("DHCl") is partially
dissolved and ionized, as shown in Equation 6:
DHCl Ionization DH + + Cl - ( 6 ) ##EQU00005##
[0079] In some embodiments, a bicarbonate ion accepts a proton from
the amine salt drug to form carbonic acid. Carbonic acid decomposes
into water and carbon dioxide, which escapes from the patch. As
carbon dioxide escapes and the neutral active agent "D" is depleted
by diffusion into the skin, the equilibrium of Equation (8) moves
toward the right (continuous formation of neutral drug "D").
DH + + HCO 3 - + NaCl Equilibrium Constant = K D + H 2 CO 3 + NaCl
- Further reaction D + H 2 O + NaCl .dwnarw. + CO 2 .uparw. ( CO 2
escapes as gas ) ( 8 ) K = [ D ] { DH + ] [ HCO 3 - ] ( 8 )
##EQU00006##
[0080] In some embodiments, the active agent is an acid salt drug.
In some embodiments, acid salt drugs have a solubility of at least
about 0.1 mg/g, at least about 0.2 mg/g, at least about 0.3 mg/g,
at least about 0.4 mg/g, at least about 0.5 mg/g, or at least about
1.0 mg/g in the drug reservoir. In some embodiments, acid salt
drugs have a solubility of less than about 100 mg/g in the drug
reservoir. Exemplary acid salt drugs include, but are not limited
to sodium alendronate, tresprostinyl sodium, sodium diclofenac,
ketoprofen sodium, etc.
[0081] In some embodiments, a micronized acid salt form of an
active agent is dispersed in a matrix that further comprises at
least one salt form solubilizer. The salt form of the active agent
("ANa") is partially dissolved and ionized, as shown in Equation
9:
ANa Ionized A - + Na + ( 9 ) ##EQU00007##
[0082] In some embodiments, the dissolved, ionized active agent
("A'") interacts with a proton donor polymer ("PolymerCOOH") as
shown in Equation 10. As the neutral form of the active agent
("AH") is depleted by diffusion, the reaction moves toward
continuous formation of AH.
A - Dissolved & skin impermeable acid salt form + Polymer COOH
Solid polymer + Na + Equilibrium Constant = K Polymer COONa Solid
Polymer + AH Dissolved & skin permeable neutral form ( 10 )
##EQU00008##
[0083] In some embodiments, the reaction byproduct ("Polymer
COONa") is sequestered as solid phase in the matrix. In some
embodiments, the neutral form of the active agent ("AH") is
depleted by diffusion through into the skin.
[0084] Because the reaction byproduct is sequestered as a solid
phase in Equation 10, the equilibrium constant is expressed as in
Equation 11:
K = [ AH ] [ A - ] ( 11 ) ##EQU00009##
[0085] In some embodiments, a composition for transdermal delivery
of an active agent further comprises one or more plasticizers for
the proton accepting or proton donating entity. In some
embodiments, salt form solubilizers and/or neutral form
solubilizers already present in the composition may also serve as
plasticizers for the proton accepting or proton donating entities.
In some embodiments, a plasticizer that does not also serve as a
salt form and/or neutral form solubilizer is included in a
composition. Exemplary plasticizers include, but are not limited
to, dicarboxylic acid esters (e.g., adipates, sebacates, maleates,
etc.), tricarboxylic esters (e.g., triethyl citrate, tributyl
citrate, etc.), esters of glycerol (e.g., triacetin, etc.), and/or
combinations thereof.
[0086] In some embodiments, an adhesive matrix or drug reservoir
comprises about 0-20 wt %, about 0-15 wt %, about 0-10 wt %, about
0-5 wt %, about 5-20 wt %, about 5-15 wt %, about 5-10 wt %, about
10-20 wt %, about 10-15 wt %, or about 15-20 wt % of at least one
plasticizer.
[0087] In some embodiments, a composition for transdermal delivery
of an active agent further comprises at least one additive, also
referred to as a matrix modifying additive. In some embodiments,
matrix modifying additives modify cohesion and/or diffusivity of
described active agent compositions. In some embodiments, matrix
modifying additives can absorb moisture and/or water emanating from
the skin under occlusion, which improves adhesion to the skin. In
some embodiments, matrix modifying additives facilitate
homogenization of the drug reservoir. Exemplary matrix modifying
additives include, but are not limited to, crospovidone
(KOLLIDON.RTM. CL-M, etc.), cross-linked polyvinylpyrrolidone
(PVP), a soluble polyvinylpyrrolidone (PVP), fumed silica,
colloidal silicone dioxide, a cellulose derivative (e.g.
hydroxypropyl cellulose (HPC), hydroxyethylcellulose (HEC)), a
polyacrylamide, a polyacrylic acid, a polyacrylic acid salt, a clay
(e.g., kaolin, bentonite, etc.), fumed silica, and/or combinations
thereof. An exemplary commercial fumed silica product is
AEROSIL.RTM. 200P, an amorphous, anhydrous colloidal silicon
dioxide (Evonik Industries). Another exemplary fumed silica product
is Cab-O-Sil.RTM. (Cabot Corporation, Boston, Mass.).
[0088] In some embodiments, the drug reservoir comprises about 0-25
wt %, about 0-20 wt %, about 0-15 wt %, about 0-10 wt %, about 0-5
wt %, about 5-25 wt %, about 5-20 wt %, about 5-15 wt %, about 5-10
wt %, about 10-25 wt %, about 10-20 wt %, about 10-15 wt %, about
15-25 wt %, about 15-20 wt %, or about 20-25 wt % of at least one
matrix modifying additive.
[0089] In some embodiments, a composition for transdermal delivery
of an active agent further comprises an adhesive or adhesive
polymer. Exemplary adhesives and adhesive polymers include, but are
not limited to, acrylates, polyisobutylene, silicone adhesive,
styrene block copolymer based adhesives, and/or combinations
thereof. In some embodiments, proton accepting and/or proton
donating polymers are film-formable in the presence of salt form
and/or neutral form solubilizers. In such embodiments, compositions
may not require a separate adhesive polymer.
[0090] In some embodiments, the drug reservoir comprises about 0-65
wt %, about 0-60 wt %, about 0-55 wt %, about 0-50 wt %, about 0-45
wt %, about 0-40 wt %, about 0-35 wt %, about 0-30 wt %, about 0-25
wt %, about 0-20 wt %, about 0-15 wt %, about 0-10 wt %, about 0-5
wt %, 5-65 wt %, about 5-60 wt %, about 5-55 wt %, about 5-50 wt %,
about 5-45 wt %, about 5-40 wt %, about 5-35 wt %, about 5-30 wt %,
about 5-25 wt %, about 5-20 wt %, about 5-15 wt %, about 5-10 wt %,
10-65 wt %, about 10-60 wt %, about 10-55 wt %, about 10-50 wt %,
about 10-45 wt %, about 10-40 wt %, about 10-35 wt %, about 10-30
wt %, about 10-25 wt %, about 10-20 wt %, about 10-15 wt %, 15-65
wt %, about 15-60 wt %, about 15-55 wt %, about 15-50 wt %, about
15-45 wt %, about 15-40 wt %, about 15-35 wt %, about 15-30 wt %,
about 15-25 wt %, about 15-20 wt %, 20-65 wt %, about 20-60 wt %,
about 20-55 wt %, about 20-50 wt %, about 20-45 wt %, about 20-40
wt %, about 20-35 wt %, about 20-30 wt %, about 20-25 wt %, 25-65
wt %, about 25-60 wt %, about 25-55 wt %, about 25-50 wt %, about
25-45 wt %, about 25-40 wt %, about 25-35 wt %, about 25-30 wt %,
30-65 wt %, about 30-60 wt %, about 30-55 wt %, about 30-50 wt %,
about 30-45 wt %, about 30-40 wt %, about 30-35 wt %, 35-65 wt %,
about 35-60 wt %, about 35-55 wt %, about 35-50 wt %, about 35-45
wt %, about 35-40 wt %, 40-65 wt %, about 40-60 wt %, about 40-55
wt %, about 40-50 wt %, about 40-45 wt %, 45-65 wt %, about 45-60
wt %, about 45-55 wt %, about 45-50 wt %, 50-65 wt %, about 50-60
wt %, about 50-55 wt %, 55-65 wt %, about 55-60 wt %, or about
60-65 wt % of at least one adhesive polymer.
[0091] The composition may also include other conventional
additives such as adhesive agents, antioxidants, crosslinking
agents, curing agents, pH regulators, pigments, dyes, refractive
particles, conductive species, antimicrobial agents, opacifiers,
gelling agents, viscosity modifiers, thickening agents, stabilizing
agents, and the like as known in the art. In those embodiments
wherein adhesion needs to be reduced or eliminated, conventional
detackifying agents may also be used. In some embodiments, agents
such as antimicrobial agents are included to prevent spoilage upon
storage, e.g., to inhibit growth of microbes such as yeasts and
molds. Suitable antimicrobial agents are typically selected from
the group consisting of the methyl and propyl esters of
p-hydroxybenzoic acid (e.g., methyl and propyl paraben), sodium
benzoate, sorbic acid, imidurea, and/or combinations thereof. These
additives, and amounts thereof, are selected in such a way that
they do not significantly interfere with the desired chemical and
physical properties of the adhesive and/or active agent.
[0092] Compositions may also contain irritation-mitigating
additives to minimize or eliminate the possibility of skin
irritation and/or skin damage resulting from the active agent, the
proton donating or proton accepting entity, salt form solubilizer,
neutral form solubilizer, plasticizer, matrix modifying additive,
adhesive and/or other components of the composition. Suitable
irritation-mitigating additives include, for example:
corticosteroids; .alpha.-tocopherol; monoamine oxidase inhibitors,
particularly phenyl alcohols such as 2-phenyl-1-ethanol; glycerin;
salicylic acids and salicylates; ascorbic acids and ascorbates;
ionophores such as monensin; amphiphilic amines; ammonium chloride;
N-acetylcysteine; cis-urocanic acid; capsaicin; and chloroquine;
and/or combinations thereof.
[0093] Methods for preparing or manufacturing active agent
compositions are also provided. Exemplary methods are set forth in
the Examples section. Methods for preparing active agent
compositions generally involve mixing an active agent at 5-35% w/w
with a proton accepting or proton donating entity at 0.5-30% w/w,
optionally along with a salt form solubilizer at 0-15% w/w, a
neutral form solubilizer at 0-15% w/w, a matrix modifying additive
at 0-25% w/w, a plasticizer at 0-20% w/w, an adhesive polymer at
0-65% w/w, and/or combinations thereof.
B. Transdermal Devices
[0094] In certain aspects, the compositions described herein are
provided in transdermal devices (e.g., patches). In general,
transdermal patches comprise a backing layer, at least one drug
reservoir, and a contact adhesive layer. It will be appreciated
that the drug reservoir and contact adhesive layer can be in the
form of a single layer or matrix comprised of an adhesive and a
drug. In some embodiments, transdermal patches further comprise one
or more release liners, tie layers, rate-controlling membranes,
and/or various combinations of the foregoing.
[0095] In some embodiments, transdermal patches comprise one or
more of the following components: backing layer, drug reservoir,
contact adhesive layer, release liner, tie layer, rate-controlling
membrane, and/or various combinations of the foregoing.
[0096] Exemplary transdermal patches are shown in FIGS. 1-3. FIG. 1
shows an exemplary transdermal patch 10 comprising a backing layer
12, multiple drug reservoirs 14, 16 separated by a nonwoven tie
layer or a rate controlling membrane 18, a contact adhesive layer
20, and a release liner 22. This particular example presents
multiple drug reservoirs separated by a tie layer or a rate
controlling membrane 18, but in some embodiments, multiple adhesive
layers may be in direct contact with each other without a tie
layer, such as optional tie layer 19. In such embodiments wherein
the transdermal patch comprises multiple drug reservoirs, each drug
reservoir may comprise the same or different active agents. In such
embodiments wherein the transdermal patch comprises multiple drug
reservoirs, each drug reservoir may comprise different
concentrations of the same active agent.
[0097] FIG. 2 shows an exemplary transdermal patch 30 comprising a
backing layer 32, a drug reservoir 34, a tie layer or
rate-controlling membrane 36, a contact adhesive layer 38, and a
release liner 39.
[0098] FIG. 3 shows an exemplary transdermal patch 40 comprising a
backing layer 42, a drug reservoir 44, a contact adhesive layer 46,
and a release liner 48.
[0099] In some embodiments, a backing layer provides a structural
element for holding or supporting the adhesive layer. A backing
layer may be formed of any suitable material as known in the art.
In some embodiments, a backing layer is occlusive. In some
embodiments, a backing layer is preferably impermeable or
substantially impermeable to moisture. In one exemplary embodiment,
the barrier layer has an MVTR (moisture vapor transmission rate) of
less than about 50 g/m.sup.2-day. In some embodiments, a backing
layer is preferably inert and/or does not absorb components of the
adhesive layer, including the active agent. In some embodiments, a
backing layer preferably prevents release of components of the
adhesive layer through the backing layer. A backing layer may be
flexible or nonflexible. A backing layer is preferably at least
partially flexible such that the backing layer is able to conform
at least partially to the shape of the skin where the patch is
applied. In some embodiments, a backing layer is flexible such that
the backing layer conforms to the shape of the skin where the patch
is applied. In some embodiments, a backing layer is sufficiently
flexible to maintain contact at the application site with movement,
e.g., skin movement. Typically, the material used for a backing
layer should permit the device to follow the contours of the skin
or other application site and be worn comfortably on areas of skin
such as at joints or other points of flexure, that are normally
subjected to mechanical strain with little or no likelihood of the
device disengaging from the skin due to differences in the
flexibility or resiliency of the skin and the device.
[0100] In some embodiments, a backing layer is formed of one or
more of a film, non-woven fabric, woven fabric, laminate, and
combinations thereof. In some embodiments, the film is a polymer
film comprised of one or more polymers. Suitable polymers are known
in the art and include, but are not limited to, elastomers,
polyesters, polyethylene, polypropylene, polyurethanes, polyether
amides, and/or combinations thereof. In some embodiments, a backing
layer is formed of one or more of polyethylene terephthalate,
various nylons, polypropylene, metalized polyester films,
polyvinylidene chloride, aluminum foil, and/or combinations
thereof. In some embodiments, a backing layer is a fabric formed of
one or more of polyesters such as polyethylene terephthalate,
polyurethane, polyvinyl acetate, polyvinylidene chloride,
polyethylene, and/or combinations thereof. In one particular, but
non-limiting embodiment, the backing layer is formed of a polyester
film laminate. Exemplary particular polyester film laminates
include, but are not limited to, the polyethylene and/or polyester
laminates such as those sold under the names Scotchpak.TM. #9723,
Scotchpak.TM. #1012, and the like.
[0101] In some embodiments, the drug reservoir generally comprises
a salt form of an active ingredient(s) (total 5-35% w/w), at least
one salt form solubilizer (total 0-20% w/w), at least one neutral
form solubilizer (total 0-20% w/w), at least one proton accepting
entity and/or proton donating entity (total 0.5-30% w/w),
optionally at least one plasticizer for a proton accepting entity
and/or proton donating entity (total 0-20% w/w), matrix modifying
additives (total 0-25% w/w), and optionally adhesive polymers
(total 0-65% w/w). In some embodiments, the drug reservoir
comprises any of the compositions for transdermal delivery
described herein, e.g., in the Examples and in Section II.A.
[0102] In general, a tie layer comprises a nonwoven fabric and/or a
rate controlling polymer membrane.
[0103] In some embodiments, devices further include one or more
fabric or tie layers within or between the drug reservoir layers.
It will be appreciated that a tie layer may be included between
one, some, or all of the layers. In some embodiments, a tie layer
is useful to increase bonding between layers of the device. Tie
layers may increase bonding by providing chemical groups for the
polymers to bind. In some embodiments, a tie layer is useful as a
separation for adhesive matrix layers.
[0104] In some embodiments, a tie layer does not affect the rate of
release of an active agent from the adhesive layers. In some
embodiments, tie layers may comprise nonwoven films that include,
but are not limited to, nonwoven polyesters (e.g., REEMAY.RTM.),
porous polyethylene film (DELNET.RTM.), nylon, cotton, and the
like, and/or combinations thereof.
[0105] In some embodiments, tie layers may comprise rate
controlling polymer membranes. Exemplary rate controlling polymer
membranes include, but are not limited to, microporous polymer
films such as CELGARD.RTM. 2400 (microporous polypropylene),
polyethylenes (e.g., microporous polyethylene), vinyl acetate
polymers and copolymers, and the like, and/or combinations thereof.
In general, a rate controlling polymer membrane allows for a
rate-controlled release of the drug from the drug reservoir
layer.
[0106] In some embodiments, the tie layer comprises a nonwoven
fabric and does not comprise a rate controlling polymer membrane.
In some embodiments, a tie layer comprises a rate controlling
polymer membrane and does not comprise a nonwoven fabric. In some
embodiments, a tie layer comprises both a nonwoven fabric and a
rate controlling polymer membrane. To give but one example, a
nonwoven fabric and a rate controlling polymer membrane may both be
used when the tie layer is embedded within the drug reservoir to
help improve drug reservoir cohesion (see, e.g., FIG. 1).
[0107] The device includes at least one adhesive layer. In
embodiments, at least one of the adhesive layers is an adhesive
matrix comprising one or more active agents as described below. The
adhesive layer adheres to a drug reservoir, an adjacent adhesive
layer, a tie layer, a release liner, and/or skin at the
administration site. In some embodiments, an adhesive layer serves
to release the active agent to the skin. In some embodiments, one
or more of the drug reservoir adhesive and/or the contact layer
adhesive are formed of an adhesive matrix. Exemplary adhesives
include, but are not limited to, acrylates, polyisobutylene, a
silicone adhesive, a styrene block copolymer based adhesive, or the
like, and/or combinations thereof.
[0108] In some embodiments, the drug reservoir of the delivery
system provides an in vitro skin flux of an active agent between
about 0.5-30 .mu.g/cm.sup.2-hr for a period of at least about 2
days.
[0109] In embodiments, a release liner is at least partially in
contact with at least one of the adhesive layers to protect the
adhesive layer(s) prior to application. A release liner is
typically a disposable layer that is removed prior to application
of the device to the treatment site. In some embodiments, a release
liner does not absorb components of the adhesive layer(s),
including the active agent. In some embodiments, a release liner is
impermeable to components of the adhesive layer(s) (including the
active agent) and prevents release of components of the adhesive
layer(s) through the release liner. In some embodiments, a release
liner is formed of one or more of a film, non-woven fabric, woven
fabric, laminate, and/or combinations thereof. In some embodiments,
a release liner is a silicone-coated polymer film or paper. In some
non-limiting embodiments, a release liner is a silicone-coated
polyethylene terephthalate (PET) film, a fluorocarbon film, a
fluorocarbon coated PET film, and/or combinations thereof.
[0110] Transdermal devices and systems (e.g., patches) may be
prepared by any suitable methods as known in the art. In some
general embodiments, transdermal devices are prepared by coating an
appropriate amount of an adhesive polymer composition (with or
without an active agent) onto a substrate such as a release liner
or a backing layer. In some embodiments, the adhesive polymer
composition is coated onto the release liner. In some embodiments,
the adhesive polymer composition is coated onto the substrate or
liner to a desired thickness. The thickness and/or size of the
device and/or drug reservoir may be determined by one skilled in
the art based at least on considerations of wearability and/or
required dose. It will be appreciated that the administration site
for the device will affect the wearability considerations due to
the available size of the administration site and the use of the
administration site (e.g., need for flexibility to support
movement). In some embodiments, the device and/or drug reservoir
has a thickness of between about 25-500 .mu.m. The adhesive polymer
composition and substrate are at least partially dried to remove
any solvents. A release liner or backing layer is applied to the
opposite side of the substrate. Where the substrate is not a
release liner or backing layer, the substrate is replaced with the
appropriate release liner or substrate. In embodiments that include
multiple adhesive polymer layers, a first adhesive polymer
composition is applied or coated onto the substrate, a tie layer
material is applied to the formulation, and the second adhesive
polymer composition is applied to the tie layer material. Adhesive
polymer compositions and tie layers are laminated using any
suitable methods known in the art. In some embodiments, adhesive
layers are coated onto separate substrates or liners and then
joined to form the transdermal delivery device. Where the delivery
device includes a reservoir adhesive layer and a contact adhesive
layer, adhesive polymer compositions may be coated onto the
substrate or liner and laminated. It will be appreciated that any
or all of the adhesive polymer composition layers may be dried
before laminating the layers.
III. Methods of Treatment
[0111] In another aspect, methods of treating a disease, condition,
and/or disorder by transdermal administration of at least one
active agent by the transdermal compositions, devices, and/or
systems described herein are provided, and several non-limiting
exemplary embodiments are set forth.
[0112] In some embodiments, compositions comprise methylphenidate
(RITALIN.RTM.) as an active agent and are used for treating
attention deficit hyperactivity disorder (ADHD), narcolepsy, and/or
depression, e.g., through administration of methylphenidate by a
transdermal patch. The FDA has approved doses of methylphenidate of
2.5 mg, 5 mg, 10 mg, 15 mg, 18 mg, 20 mg, 27 mg, 30 mg, 36 mg, 40
mg, 50 mg, 54 mg, and 60 mg.
[0113] In other embodiments, compositions as described herein
comprising donepezil (ARICEPT.RTM.) as an active agent are used for
treating Alzheimer's disease, e.g., through administration of
donepezil by a transdermal patch. The FDA has approved doses of
donepezil of 5 mg, 7 mg, 10 mg, 14 mg, and 23 mg. In some
embodiments, compositions described herein allow for administration
of doses that correspond to FDA approved doses.
[0114] In some embodiments, compositions as described herein
comprising rivastigmine (Exelon.RTM.) as an active agent are used
for treating Alzheimer's disease and/or Parkinson's disease
dementia, e.g., through administration of rivastigmine by a
transdermal patch. The FDA has approved daily doses of rivastigmine
of 1.5 mg, 2.0 mg, 3.0 mg, 4.5 mg, 4.6 mg, 6.0 mg, 9.0 mg, 9.5 mg,
and 13.3 mg. In some embodiments, compositions as described herein
comprising memantine as an active agent are used for treating
Alzheimer's disease, obsessive compulsive disorder, anxiety
disorder, ADHD, and opioid dependence, e.g., through administration
of memantine by a transdermal patch. The FDA has approved doses of
memantine of 2 mg, 5 mg, 7 mg, 10 mg, 14 mg, 21 mg, and 28 mg.
[0115] In some embodiments, compositions as described herein
comprising tamsulosin as an active agent are used for treating
benign prostatic hyperplasia and/or acute urinary retention, e.g.,
through administration of tamsulosin by a transdermal patch. The
FDA has approved doses of tamsulosin of 0.4 mg and 0.5 mg.
[0116] Transdermal compositions, devices, and/or systems described
herein may be designed for long term use and/or continuous
administration of at least one active agent. It will be appreciated
that the total dose of the active agent per transdermal device will
be determined by the nature of the active agent(s), the size of the
device, and/or the loading of the active agent within the drug
reservoir. In some embodiments, the application period for the
transdermal device is between about 1-10 days, 1-7 days, 1-5 days,
1-2 days, 1-3 days, 1-4 days, 3-10 days, 3-7 days, 3-5 days, 5-10
days, and 5-7 days, inclusive. In some embodiments, the active
agent is released from the drug reservoir as a continuous and/or
sustained release over the application period.
IV. Examples
[0117] The following examples are illustrative in nature and are in
no way intended to be limiting.
[0118] Unless otherwise specified, the following materials were
used in the examples described below: the backing layer was
SCOTCHPAK.TM. 9723; the release liner was a silicone-coated
polyester (PET) film; the nonwoven tie layer was REEMAY.RTM. 2250;
the rate controlling membrane was CELGARD.RTM. 2400 microporous
polypropylene; and the contact adhesive layer was acrylate,
polyisobutene (PIB), and/or silicone adhesive.
Example 1
Donepezil Transdermal Formulation
Preparation of Drug Reservoir
[0119] An amount of 9 grams of EUDRAGIT.RTM. EPO (a proton
accepting polymer) was dissolved in 74.71 grams of ethyl acetate.
To the resulting solution, 6 grams of triacetin, 6 grams of
glycerin, and 3 grams of SPAN.RTM. 20 (sorbitan monolaurate) were
added and mixed. To the mixture, 12.6 grams of donepezil
hydrochloride powder was dispersed. After addition of 7.8 grams of
KOLLIDON.RTM. CL-M to the drug dispersed solution, the mixture was
homogenized well. To the homogenized drug dispersion, 30.89 grams
of DURO-TAK.RTM. 387-2287 (solid content 50.5%) was added and mixed
well. The wet adhesive formulation was coated on a release liner
and dried using a lab coater (Werner Mathis coater) to get a dry
coat weight of 10 mg/cm.sup.2.
Preparation of Contact Adhesive
[0120] An amount of 4.00 grams of triacetin was mixed with 2.00
grams of sorbitan monolaurate and 34.52 grams of ethyl acetate.
After addition of 8 grams of KOLLIDON.RTM. CL-M, the resulting
mixture was homogenized. To the homogenized mixture, 51.48 grams of
DURO-TAK.RTM. 387-2287 (solid content 50.5%) was added and mixed
well. The wet adhesive formulation was coated on a release liner
and dried to give a dry coat weight of 5 mg/cm.sup.2.
Lamination and Die-Cut
[0121] CELGARD.RTM. 2400 rate controlling membrane or REEMAY.RTM.
2250 was laminated onto the adhesive side of the drug reservoir.
Contact adhesive was then laminated on top of the CELGARD.RTM. 2400
membrane laminated with drug reservoir. The release liner on the
drug reservoir side was replaced and laminated with backing film.
The final five-layer laminate was die-cut into patches.
In Vitro Skin Flux Testing
[0122] Dermatomed human cadaver skin was obtained from a skin bank
and frozen until ready for use. The skin was placed in water at
60.degree. C. for 1-2 mins minute after thawing and the epidermis
carefully separated from dermis. The epidermis was either used
immediately or wrapped and frozen for later use.
[0123] In vitro skin flux studies were performed using a Franz type
diffusion cell with an active diffusion area of 0.64 cm.sup.2. The
epidermis was mounted between the donor and receptor compartments
of the diffusion cell. The transdermal delivery system was placed
over the skin and the two compartments were clamped tight
together.
[0124] The receptor compartment was filled with 0.01 M phosphate
buffer, pH 6.5, containing 0.01% gentamicin. The solution in the
receptor compartment was continually stirred using a magnetic
stirring bar in the receptor compartment. The temperature was
maintained at 32.+-.0.5.degree. C. Samples were drawn from the
receptor solution at periodic intervals and the receptor solution
was replaced with fresh phosphate buffers solution. Drug content in
the samples was analyzed using HPLC for donepezil.
[0125] The results were calculated in terms of amount of drug
diffused through the epidermis per cm.sup.2 per unit time. Each
data point is an average of four replica of diffusion cells. FIG. 4
shows the in vitro skin flux profile of donepezil formulated
according to Example 1 (squares).
Example 2
Donepezil Transdermal Formulation
Preparation of Drug Reservoir
[0126] An amount of 1.20 grams of SPAN.RTM. 20 was dissolved in a
mixture of 6.00 g of triethyl citrate, and mixed with 1.80 grams of
lauryl lactate and 89.69 grams of ethyl acetate. 6.00 grams of
glycerin was added and mixed with the SPAN.RTM. 20 solution. To the
mixture, 9.00 grams of donepezil hydrochloride and 1.82 grams of
sodium bicarbonate were dispersed. After addition of 12.00 grams of
KOLLIDON.RTM. CL-M to the drug dispersed solution, the mixture was
homogenized well. To the homogenized drug dispersion, 43.93 grams
of DURO-TAK.RTM. 387-2287 (solid content 50.5%) was added and mixed
well. The wet adhesive formulation was coated on a release liner
and dried using a lab coater (Werner Mathis coater) to get a dry
coat weight of 12 mg/cm.sup.2.
Preparation of Contact Adhesive
[0127] An amount of 0.60 grams of SPAN.RTM. 20 (sorbitan
monolaurate) was dissolved in 3.00 grams of triethyl citrate, and
mixed with 0.9 grams of lauryl lactate, 25.45 grams of ethyl
acetate, and 1.34 grams of isopropyl alcohol. After addition of
6.00 grams of KOLLIDON.RTM. CL-M, the mixture was homogenized. To
the homogenized mixture, an amount of 38.61 grams of DURO-TAK.RTM.
387-2287 (solid content 50.5%) was added and mixed well. The wet
adhesive formulation was coated on a release liner and dried to
give a dry coat weight of 5 mg/cm.sup.2.
Lamination and Die-Cut
[0128] CELGARD.RTM. 2400 rate controlling membrane or REEMAY.RTM.
2250 was laminated on adhesive side of the drug reservoir. Then
contact adhesive was laminated on top of the CELGARD.RTM. 2400
membrane laminated with drug reservoir. The release liner on the
drug reservoir side was replaced and laminated with backing film.
The final five-layer laminate was die-cut into patches.
In Vitro Skin Flux Testing
[0129] The in vitro skin flux of donepezil from the transdermal
system was measured as described in Example 1. FIG. 4 shows the in
vitro skin flux profile of donepezil (triangles).
Example 3
Tamsulosin Transdermal Formulation
Preparation of Drug Reservoir
[0130] An amount of 3.00 grams of EUDRAGIT.RTM. EPO was dissolved
in 24.51 g of ethyl acetate. To the resulting solution, 2.00 grams
of triethyl citrate, 2.00 grams of glycerin, and 1.00 grams of
SPAN.RTM. 20 (sorbitan monolaurate) were added/mixed. To the
mixture, 4.00 grams of tamsulosin hydrochloride powder was
dispersed. After addition of 2.4 grams of KOLLIDON.RTM. CL-M to the
drug dispersed solution, the mixture was homogenized well. To the
homogenized drug dispersion, 11.09 grams of DURO-TAK.RTM. 387-2287
(solid content 50.5%) was added and well mixed. The wet adhesive
formulation was coated on a release liner and dried using a lab
coater (Werner Mathis coater) to get a dry coat weight of 10
mg/cm.sup.2.
Preparation of Contact Adhesive
[0131] An amount of 3.00 grams of triethyl citrate was mixed with
1.50 grams of sorbitan monolaurate (SPAN.RTM. 20) and 25.89 grams
of ethyl acetate. After addition of 6.00 grams of KOLLIDON.RTM.
CL-M, the mixture was homogenized. To the homogenized mixture, an
amount of 38.61 grams of DURO-TAK 387-2287 (solid content 50.5%)
was added and mixed well. The wet adhesive formulation was coated
on a release liner and dried to give a dry coat weight of 5
mg/cm.sup.2.
Lamination and Die-Cut
[0132] CELGARD.RTM. 2400 rate controlling membrane or REEMAY.RTM.
2250 was laminated on adhesive side of the drug reservoir. Then
contact adhesive was laminated on top of CELGARD.RTM. 2400 membrane
laminated with drug reservoir. The release liner on the drug
reservoir side was replaced and laminated with backing film. The
final five-layer laminate was die-cut into patches.
Example 4
Memantine Transdermal Formulation
Preparation of Drug Reservoir
[0133] An amount of 18.00 grams of EUDRAGIT.RTM. EPO was dissolved
in 14.53 g of ethyl acetate. To the resulting solution, 5.00 grams
of triethyl citrate was added and mixed. To the resulting solution,
5.25 grams of memantine hydrochloride powder was added and well
dispersed by homogenizing, and then 2.50 grams of glycerin were
added and mixed. After addition of 1.75 grams of AEROSIL.RTM. 200P
to the drug dispersed solution, the dispersion mixture was
homogenized well. To the homogenized dispersion, 2.97 grams of
DURO-TAK.RTM. 387-2287 (solid content 50.5%) was added and well
mixed. The wet adhesive formulation was coated on a release liner
and dried using a lab coater (Werner Mathis coater) to get a dry
coat weight of 15 mg/cm.sup.2.
Preparation of Contact Adhesive
[0134] An amount of 3.00 grams of triethyl citrate was mixed with
17.26 grams of ethyl acetate. After addition of 4.00 grams of
KOLLIDON.RTM. CL-M the mixture was homogenized. To the homogenized
mixture, an amount of 25.74 grams of DURO-TAK.RTM. 387-2287 (solid
content 50.5%) was added and mixed well. The wet adhesive
formulation was coated on a release liner and dried to give a dry
coat weight of 5 mg/cm.sup.2.
Lamination and Die-Cut
[0135] CELGARD.RTM. 2400 rate controlling membrane was laminated to
the drug reservoir. Then contact adhesive was laminated to the
other side of CELGARD.RTM. 2400 membrane laminated with the drug
reservoir. The release liner on the drug reservoir was replaced and
laminated with backing film. The final five-layer laminate was
die-cut into patches.
In Vitro Skin Flux Testing
[0136] The in vitro skin flux of memantine from the transdermal
system was measured as described in Example 1, where memantine
content in the samples drawn from receptor solution were analyzed
for memantine using LCMS. FIG. 5 shows the in vitro skin flux
profile of memantine.
Examples 5-8
Additional Transderm al Formulations
[0137] Additional formulations were prepared according to the
ingredients and quantities set forth in Table 1 and the general
methods set forth in Example 1. FIG. 4 shows a flux profile of
donepezil formulated according to the formulation identified as
Example No. 7 in Table 1 below (circles).
TABLE-US-00001 TABLE 1 Example No. .fwdarw. 1 2 3 4 5 6 7 8
Composition (w/w %) Drug Donepezil HCl 21 15 -- -- 15 25 24 25.2
reservoir Tamsulosin HCl -- -- 20 -- -- -- -- -- Memantine HCl 21
Triethyl citrate -- 10 10 20 10 10 -- -- Triacetin 10 -- -- -- --
-- 10 -- Sorbitan monolaurate 5 2 -- -- 5 -- 5 -- Lauryl lactate --
3 -- -- -- 6 -- 5 Dimethyl succinate -- -- -- -- -- -- -- 5
Glycerin 10 10 10 10 10 10 10 -- Dimethylsulfoxide -- -- -- -- --
-- -- 1 Eudragit EPO 15 -- 15 36 -- 17.7 17 17.8 Sodium bicarbonate
-- 3.03 -- -- 0.75 -- -- -- Kollidon CL-M 13 15 12 -- 20 -- --
Aerosil 200P -- -- 7 -- 7 7 7 Duro-Tak 387-2287 26 36.97 28 6 37.7
27 -- Duro-Tak 387-2516 -- -- -- -- -- 31.3 -- 29 RCM or tie
Celgard 2400 yes yes yes yes -- yes yes yes layer Reemay 2250 -- --
-- -- yes -- -- -- Contact Triethyl citrate -- 10 10 15 10 10 -- --
adhesive Triacetin 10 -- -- -- -- -- 10 -- Sorbitan monolaurate 5 2
5 -- 5 -- 5 -- Lauryl lactate -- 3 -- -- -- 6 -- 5 Dimethyl
succinate -- -- -- -- -- -- -- 5 Dimethyl sulfoxide -- -- -- -- --
-- -- 1 Kollidon CL-M 20 20 20 20 20 20 -- -- Aerosil 200P -- -- --
-- -- 7 7 Duro-Tak 387-2287 65 65 65 65 65 64 78 -- Duro-Tak
387-2516 -- -- -- -- -- -- -- 82 168 hour average flux 4.88 5.09
N/A 8.16 8.16 4.61 4.58 3.25 (.mu.g/cm.sup.2-hr)
[0138] While a number of exemplary aspects and embodiments have
been discussed above, those of skill in the art will recognize
certain modifications, permutations, additions and sub-combinations
thereof. It is therefore intended that the following appended
claims and claims hereafter introduced are interpreted to include
all such modifications, permutations, additions and
sub-combinations as are within their true spirit and scope.
[0139] All patents, patent applications, patent publications, and
other publications mentioned herein are hereby incorporated by
reference in their entirety. Where a patent, application, or
publication contains express definitions, those definitions should
be understood to apply to the incorporated patent, application or
publication in which they are found and not to the present
application unless otherwise indicated.
* * * * *