U.S. patent application number 15/660924 was filed with the patent office on 2018-02-01 for sodium bicarbonate in situ conversion driven transdermal delivery of amine 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 | 20180028663 15/660924 |
Document ID | / |
Family ID | 59523314 |
Filed Date | 2018-02-01 |
United States Patent
Application |
20180028663 |
Kind Code |
A1 |
Lee; Eun Soo ; et
al. |
February 1, 2018 |
SODIUM BICARBONATE IN SITU CONVERSION DRIVEN TRANSDERMAL DELIVERY
OF AMINE 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) ; Singh; Parminder; (Union City, CA) ;
Sagi; Appala; (Mountain View, CA) ; Jain; Amit
K.; (Milpitas, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Corium International, Inc. |
Menlo Park |
CA |
US |
|
|
Family ID: |
59523314 |
Appl. No.: |
15/660924 |
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 25/04 20180101;
A61K 47/02 20130101; A61P 25/36 20180101; A61K 9/7023 20130101;
A61K 31/445 20130101; A61K 31/137 20130101; A61P 13/02 20180101;
A61K 31/18 20130101; A61P 13/08 20180101; A61P 25/22 20180101; A61P
25/16 20180101; A61K 9/7053 20130101; A61K 47/10 20130101; A61K
47/32 20130101; A61K 9/7092 20130101; A61K 31/27 20130101; A61P
25/02 20180101; A61P 25/28 20180101; A61K 31/00 20130101; A61K
31/13 20130101; A61P 25/14 20180101; A61K 9/7061 20130101; A61P
13/00 20180101; A61P 25/00 20180101; A61P 35/00 20180101; A61P
25/24 20180101; A61K 31/045 20130101; C08K 5/0016 20130101; A61K
47/12 20130101; A61P 25/26 20180101; A61K 9/7038 20130101; A61K
9/7084 20130101 |
International
Class: |
A61K 47/02 20060101
A61K047/02; A61K 31/00 20060101 A61K031/00; C08K 5/00 20060101
C08K005/00; A61K 9/70 20060101 A61K009/70 |
Claims
1. A composition for transdermal delivery, comprising: a drug
reservoir comprising an amine salt form of an active agent and an
amphoteric inorganic base compound, wherein the pKa of the
amphoteric inorganic base compound is lower than that of the amine
salt form of the active agent.
2. The composition of claim 1, wherein the amphoteric inorganic
base compound is sodium bicarbonate.
3. The composition of claim 1, wherein the active agent is selected
from the group consisting of donepezil, memantine, fentanyl,
oxybutynin, rotigotine, ropinirole, rivastigmine, tamsulosin,
methylphenidate, fingolimod, and buprenorphine.
4. The composition of claim 1, wherein the drug reservoir comprises
between about 5-35% w/w of the active agent.
5. The composition of claim 1, wherein the drug reservoir comprises
between about 0.5-35% w/w of the sodium bicarbonate.
6. 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.
7. The composition of claim 6, wherein the drug reservoir comprises
up to 15% w/w of the salt form solubilizer.
8. 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.
9. The composition of claim 8, wherein the drug reservoir comprises
up to 20% w/w of the neutral form solubilizer.
10. 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 ester, and triacetin.
11. The composition of claim 10, wherein the drug reservoir
comprises up to 20% w/w of the plasticizer.
12. The composition of claim 1, further comprising an additive
selected from the group consisting of crospovidone and colloidal
silicone dioxide.
13. The composition of claim 12, wherein the composition comprises
up to 25% w/w of the additive.
14. The composition of claim 1, wherein the drug reservoir further
comprises an adhesive agent selected from the group consisting of
an acrylate, polyisobutylene, silicone adhesive, and styrene block
copolymer based adhesive.
15. The composition of claim 14, wherein the adhesive agent
comprises up to 65% w/w of the composition.
16. A transdermal patch comprising the composition of claim 1 as a
first drug reservoir and a backing layer.
17. The transdermal patch of claim 16, wherein the backing layer is
an occlusive polymer film.
18. The transdermal patch of claim 16, further comprising a contact
adhesive layer comprised of an adhesive selected from the group
consisting of an acrylate, polyisobutylene, silicone adhesive, and
styrene block copolymer based adhesive.
19. The transdermal patch of claim 16, further comprising a
nonwoven tie layer between the drug reservoir and the contact
adhesive layer.
20. The transdermal patch of claim 16, further comprising a
rate-controlling membrane between the drug reservoir and the
contact adhesive layer.
21. The transdermal patch of claim 16, wherein the patch comprises
a second drug reservoir comprising an adhesive matrix comprising an
amine salt form of an active agent and an amphoteric inorganic base
compound, wherein the pKa of the amphoteric inorganic base compound
is lower than that of the amine salt form of the active agent.
22. The transdermal patch of claim 21, wherein the first drug
reservoir and second drug reservoir are separated by a nonwoven tie
layer.
23. The transdermal patch of claim 22, wherein the first drug
reservoir and second drug reservoir are separated by a
rate-controlling membrane.
24. 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.
25. A method for treating Alzheimer's disease, Parkinson's disease,
restless leg syndrome, attention deficit hyperactivity disorder,
narcolepsy, depression, anxiety disorder, obsessive compulsive
disorder, benign prostatic hyperplasia, acute urinary retention,
opioid dependence, moderate acute pain in non-opioid-tolerant
individuals, or moderate chronic pain, comprising: providing a
composition according to claim 1 to a patient in need thereof.
26. The method of claim 25, further comprising administering or
instructing to administer to the skin of the patient the
composition.
27. The method of claim 26, wherein said administering achieves a
therapeutically effective blood concentration of the active
agent.
28. A method of transdermally administering an active agent to a
patient in need thereof, comprising: providing a transdermal patch
according to claim 16 to a patient in need thereof.
29. A method for treating Alzheimer's disease, Parkinson's disease,
restless leg syndrome, attention deficit hyperactivity disorder,
narcolepsy, depression, anxiety disorder, obsessive compulsive
disorder, benign prostatic hyperplasia, acute urinary retention,
opioid dependence, moderate acute pain in non-opioid-tolerant
individuals, or moderate chronic pain, comprising: providing a
transdermal patch according to claim 16 to a patient in need
thereof.
30. The method of claim 28, further comprising administering or
instructing to administer to the skin of the patient the
transdermal patch.
31. The method of claim 28, 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 amine active
agents provided in their salt form instead of neutral form.
BACKGROUND
[0003] Amine drugs exist in two forms, a free base and a salt. The
salt form is the conjugated acid salt (i.e., protonated form) of an
amine drug, and the free base is the conjugated base (i.e.,
deprotonated form) of the amine drug. In general, the salt form is
more stable, water soluble, and bioavailable than the free base
form. As such, most oral formulations of amine drugs include the
salt form of the amine drug. In contrast, transdermal formulations
typically use a free base form because the free base is much more
skin permeable than the salt form.
[0004] There are a several significant drawbacks, however, in using
the free base form in a transdermal formulation for many drugs. For
example, it is often difficult to solubilize a sufficient amount of
free base in a drug-in-polymer matrix because the free base often
has low solubility in the polymer matrix and tends to recrystallize
into solid crystals during processing or during storage prior to
use. Further, certain liquid free base drugs are volatile, and a
significant amount of the drug can be lost during processing due to
evaporation. Additionally, drug flux is often difficult to control
and deliver for multiple days at a constant rate when a drug is
very permeable through the skin. Finally, drugs are often more
unstable in the free base form than in the salt form.
[0005] Researchers have attempted to formulate a salt form of a
drug with a basic inorganic salt, so that it converts into a free
base in situ in a drug-in-adhesive matrix in a transdermal
formulation. In those prior attempts, the basic inorganic salts had
a higher pKa value than the conjugated acid salt form of the amine
drug, and as such, the converted free base was not soluble in the
matrix and recrystallized into solid crystals, leading to decreased
skin permeation.
[0006] There is a need in the art for improved compositions,
devices, patches, systems, and methods for transdermal delivery of
amine drugs that address these shortcomings.
BRIEF SUMMARY
[0007] The following aspects and embodiments thereof described and
illustrated below are meant to be exemplary and illustrative, not
limiting in scope.
[0008] In one aspect, a composition for transdermal delivery is
provided. The composition comprises a drug reservoir (also referred
to as an adhesive matrix) comprising an amine salt form of an
active agent and an amphoteric inorganic base compound, wherein the
pKa of the amphoteric inorganic base compound is lower than that of
the amine salt form of the active agent.
[0009] In another aspect, a composition for transdermal delivery is
provided. The composition comprises an adhesive, an amine salt form
of an active agent and an amphoteric inorganic base compound,
wherein the pKa of the amphoteric inorganic base compound is lower
than that of the amine salt form of the active agent.
[0010] In one embodiment, the amphoteric inorganic base compound is
sodium bicarbonate.
[0011] In one embodiment, the active agent is donepezil, memantine,
fentanyl, oxybutynin, rotigotine, ropinirole, rivastigmine,
tamsulosin, methylphenidate, or buprenorphine.
[0012] In another embodiment, the drug reservoir comprises between
about 5-35% w/w of the active agent.
[0013] In yet another embodiment, the composition comprises between
about 0.5-35% w/w of sodium bicarbonate.
[0014] In still another embodiment, the composition further
comprises a salt form solubilizer selected from the group
consisting of water, alcohols, glycerol, propylene glycol, ethylene
glycol, dimethyl sulfoxide, and N-methylpyrrolidone.
[0015] In one embodiment, the drug reservoir or composition
comprises up to 15% w/w of the salt form solubilizer.
[0016] In still another embodiment, the composition comprises 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.
[0017] In one embodiment, the composition comprises up to 20% w/w
of the neutral form solubilizer.
[0018] In one embodiment, the composition further 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 ester, and
triacetin.
[0019] In another embodiment, the composition comprises up to 20%
w/w of the plasticizer.
[0020] In another embodiment, the composition further comprises a
matrix modifying additive selected from the group consisting of
crospovidone and colloidal silicone dioxide.
[0021] In one embodiment, the composition comprises up to 25% w/w
of the matrix modifying additive.
[0022] In another embodiment, the composition comprises an adhesive
agent selected from the group consisting of an acrylate,
polyisobutylene, silicone adhesive, and styrene block copolymer
based adhesive.
[0023] In one embodiment, the adhesive comprises up to 65% w/w of
the composition.
[0024] In another aspect, a transdermal patch is provided, where
the patch comprises a composition as described herein as a first
drug reservoir and a backing layer.
[0025] In one embodiment, the backing layer is an occlusive polymer
film.
[0026] In other embodiments, the transdermal patch comprises a
contact adhesive layer comprised of an adhesive selected from the
group consisting of an acrylate, polyisobutylene, silicone
adhesive, and styrene block copolymer based adhesive.
[0027] In still other embodiments, the transdermal patch comprises
a nonwoven tie layer between the drug reservoir and the contact
adhesive layer.
[0028] In still other embodiments, the transdermal patch comprises
a rate-controlling membrane between the drug reservoir and the
contact adhesive layer.
[0029] In still other embodiments, the transdermal patch comprises
a second drug reservoir comprised of a composition or adhesive
matrix as described herein.
[0030] In still other embodiments, the first drug reservoir and
second drug reservoir are separated by a nonwoven tie layer.
[0031] In other embodiments, the first drug reservoir and second
drug reservoir are separated by a rate-controlling membrane.
[0032] A method of transdermally administering an active agent to a
patient in need thereof, comprising: providing a composition or a
transdermal patch as described herein to a patient in need
thereof.
[0033] In other aspects, a method for treating Alzheimer's disease,
Parkinson's disease, restless leg syndrome, attention deficit
hyperactivity disorder, narcolepsy, depression, anxiety disorder,
obsessive compulsive disorder, benign prostatic hyperplasia, acute
urinary retention, opioid dependence, moderate acute pain in
non-opioid-tolerant individuals, or moderate chronic pain are
provided. The method comprises providing a composition or a
transdermal patch as described herein to a patient in need
thereof.
[0034] The method may further include administering or instructing
to administer to the skin of the patient the composition or
transdermal patch.
[0035] In some embodiments, administering achieves a
therapeutically effective blood concentration of the active agent.
In some embodiments, the therapeutically effective blood
concentration of the active agent is achieved for a period of at
least about 3 days, 5 days or 7 days.
BRIEF DESCRIPTION OF THE FIGURES
[0036] FIG. 1 is a chemical reaction schematic depicting how sodium
bicarbonate drives in situ conversion and transdermal delivery of
an amine drug.
[0037] FIGS. 2-5 are illustrations of exemplary embodiments of
transdermal patch configurations.
[0038] FIG. 6 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 a formulation according to Example 1.
[0039] FIG. 7 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 formulations according to Example 2 (squares),
Comparative Example 3 (diamonds), Comparative Example 4 (circles),
and Comparative Example 5 (triangles).
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] In general, compositions described herein provide an active
agent as an amine salt, and an amphoteric inorganic base compound
whose dissociation constant (pKa) is lower than the pKa of the
conjugated acid salt of the amine drug, such as sodium bicarbonate.
Carbonic acid has two pKa values, 6.4 and 10.3. In the presence of
stronger base, it reacts as an acid by donating a proton and
forming a carbonate ion and water (see Equation 1), with a pKa of
10.3.
HCO 3 - + bicarbonate OH - .fwdarw. acid - base reaction CO 3 2 -
carbonate + H 2 O , pK a = 10.3 ( 1 ) ##EQU00001##
But in the presence of a weak acid, sodium bicarbonate acts as a
base and forms carbonic acid, which is unstable and likely to
dissociate into carbon dioxide and water (see Equation 2). The
dissociation constant of carbonic acid is 6.4.
HCO 3 - + bicarbonate H 2 O .fwdarw. hydrolysis H 2 CO 3 carbonic
acid + OH - .fwdarw. H + 2 H 2 O + CO 2 , pK a = 6.4 ( 2 )
##EQU00002##
[0052] Most conjugated acid amine drugs (depicted herein as
"AMNH.sup.+") are weak acids, and thus sodium bicarbonate acts as a
base in their presence, generating reaction products of carbonic
acid (which rapidly dissociates into water and CO.sub.2) and the
free base of the amine drug (depicted herein as "AMN"). Most
conjugated acid amine drugs, however, have greater pKa values than
does sodium bicarbonate (i.e., they are more basic than sodium
bicarbonate), which means that the reaction equilibrium favors the
conjugated acid amine drug and bicarbonate ion reactants, and only
a small amount of carbonic acid and amine drug free base are
formed. Equation 3 depicts these reactions:
HCO 3 - + AMNH + conjugated acid amine drug H 2 CO 3 + AMN amine
drug free base .fwdarw. H 2 O + CO 2 + AMN ( 3 ) ##EQU00003##
[0053] The equilibrium constant between carbonic acid and
bicarbonate, K.sub.a(carbonic acid), is:
K a ( carbonic acid ) = [ HCO 3 - ] [ H + ] [ H 2 CO 3 ] ( 4 )
##EQU00004##
The equilibrium constant between the conjugated acid amine
AMNH.sup.+ and the conjugated free amine AMN is:
K a ( acid amine ) = [ AMN ] [ H + ] [ AMNH + ] ( 5 )
##EQU00005##
The greater the ratio of
K a ( acid amine ) K a ( carbonic acid ) ##EQU00006##
is, the more AMN is produced per Equation 3. This ratio is
calculated from Equations 4 and 5, and is shown in FIG. 5:
K a ( acid amine ) K a ( carbonic acid ) = [ H 2 CO 3 ] [ AMN ] [
HCO 3 - ] [ AMNH + ] = [ H 2 O ] [ CO 2 ] [ AMN ] [ HCO 3 - ] [
AMNH + ] ( 6 ) ##EQU00007##
[0054] Table 1 presents K.sub.a(acid amine)/K.sub.a(carbonic acid)
ratios for several exemplary amine drugs, assuming an aqueous
medium and that pK.sub.a(carbonic acid)=6.4.
TABLE-US-00001 TABLE 1 Equilibrium Ratios of Exemplary Conjugated
Acid Salt Amines and Conjugated Free Amine in the Presence of
Sodium Bicarbonate. Conjugated Acid Amine Equilibrium Constant of
Acid Amine (pK.sub.a(acid amine)) Ratio of K a ( acid amine ) K a (
carbonic acid ) ##EQU00008## Donepezil HCl 8.6 0.006310 Memantine
HCl 10.27 0.000135 Rotigotine HCl 7.90 0.031623 Ropinirole HCl 9.68
0.000525 Rivastigmine HCl 8.85 0.003548 Tamsulosin HCl 8.37
0.010715 Methyl phenidate HCl 8.77 0.004266 Buprenorphine HCl 8.31
0.012303
[0055] The ratios presented in Table 1 are very small for all
exemplary amine drugs shown. As such, a reaction according to
Equation 3 involving the exemplary amine drugs listed in Table 1
will favor the reactants, and only a very small amount of amine
drug free base product will be formed. Because of this, conjugated
free base amine is not precipitated out as crystals, but instead,
remains solubilized in the equilibrium system and ultimately is
removed by diffusion and permeation through the skin. As the
conjugated free base amine is removed by permeation through the
skin, the reaction is continuously driven forward to generate more
amine drug free base to maintain equilibrium.
[0056] FIG. 1 provides a schematic representation of the chemical
reactions driven by certain compositions described herein. The box
in the top left represents ingredients in certain compositions,
i.e., an amine salt of an active agent ("AMN.HCl"), sodium
bicarbonate (NaHCO.sub.3), a salt form solubilizer ("hydrophilic
solubilizer"), and a neutral form solubilizer ("hydrophobic
solubilizer"). In the first step of the reaction, AMN.HCl and
sodium bicarbonate are ionized to form a conjugated acid amine ion
("AMNH.sup.+"), its counterion (e.g., a chloride or other ion with
a single negative charge), a bicarbonate ion (HCO.sub.3.sup.-), and
its counterion (Na.sup.+) (see the box at the top right of FIG. 1).
The salt form solubilizer helps to solubilize and stabilize these
ionized reaction products.
[0057] The arrows connecting the boxes at the top right and lower
right of FIG. 1 depict the equilibrium between the ionized
conjugated acid amine ion and bicarbonate ion (top right) and the
conjugated free base amine ("AMN") and carbonic acid
(H.sub.2CO.sub.3) (bottom right). The neutral form solubilizer
helps to stabilize the conjugated free base amine. The equilibrium
of this step favors the reactants, AMNH.sup.+ and bicarbonate (top
right).
[0058] FIG. 1 depicts the last phase in the reaction scheme, in
which AMN and carbonic acid are cleared from the reaction system.
AMN is cleared by diffusion and permeation into the skin. Carbonic
acid is cleared by its dissociation into water and carbon dioxide
gas. The equilibrium in this last step of the reaction scheme
favors AMN, water, and carbon dioxide.
A. Compositions for Transdermal Delivery of Active Agents
[0059] In some aspects, provided are compositions comprising an
adhesive or polymer, an amine salt form of at least one active
agent and at least one amphoteric inorganic base compound whose pKa
is lower than the pKa of the amine salt drug, such as sodium
bicarbonate. In general, the amine salt form of a provided active
agent and the amphoteric inorganic base will ionize, and the
ionized, positively charged active agent will react with the
ionized, negatively charged inorganic base compound to generate a
neutral form of the active agent that is more skin permeable than
the salt form.
[0060] In some aspects, compositions comprising an adhesive, an
amine salt form of at least one active agent and sodium bicarbonate
are provided. In general, the amine salt form of a provided active
agent and the amphoteric inorganic base will ionize, and the
ionized, positively charged active agent will react with the
negatively charged bicarbonate ion to generate a neutral form of
the active agent that is more skin permeable than the salt
form.
[0061] In some embodiments, an 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. In
some embodiments, such compositions can provide a relatively
constant activity of an active agent. In some embodiments,
compositions may further include one or more of the following: at
least one plasticizer, at least one salt form solubilizer, at least
one neutral form solubilizer, adhesive matrix modifying additive,
and adhesive polymer.
[0062] It will be appreciated that all w/w % or wt % described
herein may refer to wet or dry weight of the composition.
[0063] In some embodiments, compositions comprised of micronized
particles of a salt form of one or more amine-containing active
agents dispersed in an adhesive matrix are provided. In some
embodiments, an adhesive matrix comprises 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 % of a salt form of at least one
active agent.
[0064] In some embodiments, the adhesive matrix composition further
comprises a solubilizer that has a limited solubility for the salt
form of the 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.
[0065] 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 30% w/w or less than about 25% w/w or 20%
w/w.
[0066] 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.
[0067] In some embodiments, the adhesive matrix composition
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.
[0068] In some embodiments, the 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.
[0069] 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 30% w/w.
[0070] 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, isopropyl
myristate, isopropyl palmitate, octyl dodecanol, lauryl alcohols,
oleyl alcohols, and/or combinations thereof.
[0071] In some embodiments, an adhesive matrix comprises 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 least one neutral form solubilizer.
[0072] In some embodiments, active agents include amine salt
drugs.
[0073] 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 adhesive matrix. In some embodiments, amine salt
drugs have a solubility of less than about 100 mg/g in the adhesive
matrix. Exemplary amine salt drugs include, but are not limited to,
donepezil, memantine, rotigotine, ropinirole, rivastigmine,
tamsulosin, methylphenidate, buprenorphine, fentanyl, fingolimod,
and oxybutynin.
[0074] In some embodiments, a composition for transdermal delivery
of an active agent further comprises one or more plasticizers. In
some embodiments, salt form solubilizers and/or neutral form
solubilizers already present in the composition may also serve as
plasticizers. In such embodiments, it may not be necessary to
include an additional plasticizer. 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.
[0075] In some embodiments, an adhesive matrix 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.
[0076] In some embodiments, a composition for transdermal delivery
of an active agent further comprises at least one adhesive
modifying 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, the matrix modifying additive modifies the
solubility of the active agent in the adhesive matrix. 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 adhesive matrix.
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.), 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.).
[0077] In some embodiments, an adhesive matrix 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
adhesive matrix modifying additive.
[0078] In some embodiments, a composition for transdermal delivery
of an active agent further comprises at least one adhesive or
adhesive polymer. Exemplary adhesives include, but are not limited
to, acrylates, polyisobutylene, silicone adhesives, styrene block
copolymer based adhesives, and/or combinations thereof.
[0079] In some embodiments, an adhesive matrix 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.
[0080] 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, permeation enhancers, 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.
[0081] 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 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.
[0082] 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 with sodium
bicarbonate, optionally along with a salt form solubilizer, a
neutral form solubilizer, a matrix modifying additive, a
plasticizer, an adhesive polymer, and/or combinations thereof.
B. Transdermal Devices
[0083] In certain aspects, compositions 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. In some embodiments, transdermal patches further comprise
one or more release liners, tie layers, rate-controlling membranes,
and/or various combinations of the foregoing.
[0084] 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.
[0085] Exemplary transdermal patches are shown in FIGS. 2-5. FIG. 2
shows an exemplary transdermal patch 10 comprising a backing layer
12, multiple drug reservoirs 14, 16 separated by a nonwoven tie
layer 18, a rate-controlling membrane 20, a contact adhesive layer
22, and a release liner 24. This particular example presents
multiple drug reservoirs separated by a tie layer, but in some
embodiments, multiple adhesive drug reservoir layers may be in
direct contact with each other without a tie layer. 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. This
particular example presents a rate-controlling membrane between the
drug reservoirs and the release liners, but in some embodiments,
the rate-controlling membrane is not present. FIG. 3 presents such
an embodiment, in which the transdermal system 30 comprises a
backing layer 32, multiple drug reservoirs 34, 35 separated by a
nonwoven tie layer 36, a contact adhesive layer 38, and a release
liner 39, but no rate-controlling membrane between the drug
reservoirs and the contact adhesive.
[0086] FIG. 4 shows an exemplary transdermal patch 40 comprising a
backing layer 42, a drug reservoir 44, a tie layer or
rate-controlling membrane 46, a contact adhesive layer 48, and a
release liner 49. In some embodiments, a transdermal patch includes
a nonwoven tie layer between the drug reservoir and the contact
adhesive layer. In some embodiments, a transdermal patch includes a
rate-controlling membrane between the drug reservoir and the
contact adhesive layer. In some embodiments, a transdermal patch
includes both a nonwoven tie layer and a rate-controlling membrane
between the drug reservoir and the contact adhesive layer. In some
embodiments, a transdermal patch does not include either a nonwoven
tie layer or a rate-controlling membrane between the drug reservoir
and the contact adhesive layer. FIG. 5 presents such an embodiment,
in which the patch 50 comprises a backing layer 52, a drug
reservoir 54, a contact adhesive layer 56, and a release liner 58,
but no tie layer or rate-controlling membrane between the drug
reservoir and the contact adhesive layer.
[0087] 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.
[0088] 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.
[0089] 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 0-15% w/w), at least one neutral
form solubilizer (total 0-15% w/w), at least one proton accepting
entity a (total 0.5-30% 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.
[0090] In general, a tie layer comprises a nonwoven fabric, porous
polyethylene film and/or a rate controlling polymer membrane.
[0091] In some embodiments, devices further include one or more
fabric or tie layers within or between the adhesive layers. It will
be appreciated that a tie layer may be included between one, some,
or all of the adhesive matrix 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.
[0092] 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, nylon, cotton, porous polyethylene, and the
like, and/or combinations thereof.
[0093] 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), polyesters (e.g.,
REEMAY.RTM.), 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.
[0094] 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 18 and a rate controlling polymer membrane 20 may
both be used when the tie layer is embedded within the drug
reservoir (14, 16) to help improve drug reservoir cohesion (see,
e.g., FIG. 2).
[0095] 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.
[0096] In some embodiments, the delivery system provides an in
vitro skin flux of an active agent between about 0.5-100
.mu.g/cm.sup.2-hr for a period of at least about 2 days. In another
embodiment, the delivery system provides an in vitro skin flux of
an active agent between about 0.5-80 .mu.g/cm.sup.2-hr, 1-80
.mu.g/cm.sup.2-hr, 2-80 .mu.g/cm.sup.2-hr, 2-50 .mu.g/cm.sup.2-hr,
4-50 .mu.g/cm.sup.2-hr, 4-30 .mu.g/cm.sup.2-hr, 0.5-15
.mu.g/cm.sup.2-hr, 1-15 .mu.g/cm.sup.2-hr or 4-15 .mu.g/cm.sup.2-hr
for a period of at least about 1 day, about 2 days, about 3 days,
or about 4 days.
[0097] 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.
[0098] 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 adhesive matrix 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 adhesive matrix
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.
[0099] Transdermal delivery devices were prepared to demonstrate
the delivery of an active agent formulated from an amine salt form
of the active agent and an amphoteric inorganic base compound. The
model amine salt form of the active agent was donepezil
hydrochloride (Example 1) or memantine hydrochloride (Example 2)
and the model amphoteric inorganic base compound was sodium
bicarbonate. Other suitable examples of amphoteric inorganic base
compounds include sodium carbonate, potassium carbonate, potassium
bicarbonate, trisodium phosphate, disodium hydrogen phosphate,
sodium oxylate, sodium succinate, sodium citrate, and sodium
salicylate. As described in Example 1, a donepezil transdermal
delivery system, for transdermal delivery of donepezil base, was
prepared using donepezil hydrochloride and sodium bicarbonate in an
adhesive matrix (polyacrylate) to form a drug reservoir. The drug
reservoir was fabricated into a transdermal delivery system as
depicted in FIG. 4, to have a drug-free contact adhesive layer for
contact with the skin and a rate controlling membrane situated
between the drug reservoir and the contact adhesive layer. A
backing layer and a release liner completed the transdermal system.
The donepezil transdermal system was evaluated in vitro by
measuring release of donepezil from the system and across human
skin, as detailed in Example 1. The donepezil skin flux rate is
shown in FIG. 6. About 20 hours after application of the
transdermal system to the skin, a steady-state flux rate of between
about 4.8-6.4 .mu.g/cm.sup.2-hr was achieved. The flux rate
remained steady for about 5.5 days before decreasing. Accordingly,
in one embodiment, a transdermal delivery system for delivery of a
base form of an active agent is prepared from an amine salt form of
the active agent and sodium bicarbonate, to provide a skin flux
rate or permeation rate that is therapeutic for a period of at
least about 3 days or 5 days or 7 days (or from 3-7 days). In one
embodiment, the steady state in vitro skin flux rate remains within
15%, 20%, 25%, or 30% for a period of at least about 3 days or 5
days or 7 days (or from 3-7 days). That is, the in vitro skin flux
measured at time point y varies from the in vitro skin flux
measured at an earlier adjacent time point x, where x and y are
each time points within a 3 day, 5 day, or 7 day measurement
period, by less than about 20%, 25% or 30%.
[0100] A memantine transdermal system was prepared as described in
Example 2. The memantine transdermal system was evaluated in vitro
by measuring release of memantine from the system and across human
skin and the results are shown in FIG. 7 (squares). About 18 hours
after application of the transdermal system to the skin, a
steady-state flux rate of between about 12-15 .mu.g/cm.sup.2-hr was
achieved. The flux rate remained steady for about 6.5 days before
decreasing. Accordingly, in one embodiment, a transdermal delivery
system for delivery of a base form of an active agent is prepared
from an amine salt form of the active agent and sodium bicarbonate,
to provide a skin flux rate or permeation rate that is therapeutic
for a period of at least about 3 days or 5 days or 7 days (or from
3-7 days). In one embodiment, the steady state in vitro skin flux
rate remains within 15%, 20%, 25%, or 30% for a period of at least
about 3 days or 5 days or 7 days (or from 3-7 days). That is, the
in vitro skin flux measured at time point y varies from an in vitro
skin flux measured at an earlier adjacent time point x, where x and
y are each time points within a 3 day, 5 day, or 7 day measurement
period, by less than 15%, 20%, 25% or 30%.
[0101] Comparative examples were also conducted to illustrate the
inventive composition, system and methods described herein Data for
comparative Examples 3-5 is included in FIG. 7 to illustrate that
adhesive compositions (transdermal systems) prepared with the free
base form of the drug (Comparative Example 3), with the amine salt
form of drug but without sodium bicarbonate (Comparative Example 4)
or a salt form of an amine drug and an amphoteric inorganic base
compound, but where the pKa of the amphoteric inorganic base
compound is not lower than that of the amine salt form of the
active agent but is higher (Comparative Example 5). In these
comparative examples, the in vitro skin flux of the drug is
insufficient for therapy (FIG. 7, diamonds, circles, triangles,
corresponding to Comparative Examples 3, 4, and 5,
respectively).
III. Methods of Treatment
[0102] In other aspects, 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.
[0103] In some 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. Contemplated daily doses of
donepezil are 5 mg, 10 mg, and 23 mg, with a range of daily dose
from about 1-30 mg and about 2.5-25 mg and about 5-23 mg.
[0104] In some embodiments, compositions as described herein
comprising memantine (NAMENDA.RTM.) 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. Contemplated
daily doses of memantine are 2 mg, 5 mg, 7 mg, 10 mg, 14 mg, 21 mg,
and 28 mg, with a range of daily dose from about 1-30 mg and about
1-28 mg.
[0105] In some embodiments, compositions as described herein
comprising rotigotine (NEUPRO.RTM.) as an active agent are used for
treating Parkinson's disease and restless leg syndrome, e.g.,
through administration of rotigotine by a transdermal patch.
Contemplated daily doses of rotigotine are 1 mg, 2 mg, 3 mg, 4 mg,
6 mg, and 8 mg, with a range of daily dose from about 0.5-10 mg and
about 1-8 mg.
[0106] In some embodiments, compositions as described herein
comprising ropinirole (REQUIP.RTM., REPREVE.RTM., RONIROL.RTM.,
ADARTREL.RTM.) as an active agent are used for treating Parkinson's
disease and restless leg syndrome, e.g., through administration of
ropinirole by a transdermal patch. Contemplated daily doses of
ropinirole are of 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6
mg, 8 mg, and 12 mg, with a range of daily dose from about 0.1-15
mg and about 0.25-15 mg.
[0107] 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. Contemplated daily doses of rivastigmine are 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, with a range of daily dose from about 0.5-18 mg, about
1-15 mg and about 1.5-13.3 mg.
[0108] In some embodiments, compositions as described herein
comprising tamsulosin (FLOMAX.RTM.) as an active agent are used for
treating benign prostatic hyperplasia, acute urinary retention,
passage of kidney stones, e.g., through administration of
tamsulosin by a transdermal patch. Contemplated daily doses of
tamsulosin are 0.4 mg and 0.5 mg, with a range of daily dose from
about 0.1-1.0 mg, about 0.2-0.8 mg and about 0.4-0.5 mg.
[0109] In some embodiments, compositions as described herein
comprising methylphenidate (RITALIN.RTM.) as an active agent are
used for treating attention deficit hyperactivity disorder (ADHD),
narcolepsy, and/or depression, e.g., through administration of
methylphenidate by a transdermal patch. Contemplated daily doses of
methylphenidate are 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, with a range of
daily dose from about 1-75 mg, about 2-65 mg, and about 2.5-60
mg.
[0110] In some embodiments, compositions as described herein
comprise buprenorphine (CIZDOL.RTM., SUBUTEX.RTM., TEMGESIC.RTM.,
BUPRENEX.RTM., NORSPAN.RTM., BUTRANS.RTM.) as an active agent are
used for treating opioid addiction, moderate acute pain in
non-opioid-tolerant individuals, and moderate chronic pain, e.g.,
through administration of buprenorphine by a transdermal patch.
Contemplated doses of buprenorphine are 5 .mu.g/hr, 7.5 .mu.g/hr,
10 .mu.g/hr, 15 .mu.g/hr, 20 .mu.g/hr, 0.075 mg, 0.15 mg, 0.3 mg,
0.36 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.71 mg, 0.75 mg, 0.9 mg,
1 mg, 1.4 mg, 2 mg, 2.1 mg, 2.9 mg, 3 mg, 4 mg, 4.2 mg, 5.7 mg, 6.3
mg, 8 mg, 8.6 mg, 11.4 mg, 12 mg, 80 mg, with a range of daily dose
from about 0.01-100 mg, about 0.1-100 mg, about 0.075-80 mg, and
about 0.075-15 mg.
[0111] In other embodiments, compositions as described herein
comprise fentanyl (DURAGESIC.RTM.) as an active agent and are used
for the relief of chronic pain and for managing severe chronic pain
and for relief of moderate or severe chronic pain. Contemplated
doses of fentanyl are 12.5 .mu.g/hr, 25 .mu.g/hr, 37.5 .mu.g/hr, 50
.mu.g/hr, 62.5 .mu.g/hr, 75 .mu.g/hr, 87.5 .mu.g/hr, and daily
doses of 0.3 mg, 0.6 mg, 0.9 mg, 1.2 mg, 1.5 mg, 1.8 mg, and 2.1
mg, with a range of daily dose from about 0.1-5 mg, about 0.1-2.5
mg, about 0.2-2.5, and about 0.3-2.1 mg.
[0112] In other embodiments, compositions as described herein
comprise oxybutynin and are for use in reducing muscle spasms of
the bladder and urinary tract, for treating symptoms of overactive
bladder, including frequent or urgent urination, incontinence and
increased night-time urination. Contemplated daily doses of
oxybutynin are 3.9 mg, 5 mg, 10 mg, 15 mg, and 20 mg and 30 mg,
with a dosage range of about 1-35 mg, about 2-35 mg, about 3-30 mg,
and about 3.9-30 mg.
[0113] In other embodiments, compositions as described herein
comprise fingolimod and are for use in treating multiple sclerosis
or relapsing-remitting multiple sclerosis.
[0114] 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 adhesive
matrix. 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 adhesive matrix as a continuous and/or
sustained release over the application period.
IV. Examples
[0115] The following examples are illustrative in nature and are in
no way intended to be limiting.
[0116] 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,
polyisobutylene (PIB), and/or silicone adhesive.
Example 1
Donepezil Salt Transdermal Formulation with Sodium Bicarbonate
Preparation of Drug-in-Adhesive
[0117] An amount of 1.20 g of SPAN.RTM. 20 was dissolved in 6.00 g
of triethyl citrate, and the solution was mixed with 1.80 g of
lauryl lactate and 89.69 g of ethyl acetate. To the solution was
added 6.00 g of glycerine and was mixed well. To the mixture, 9.00
g of donepezil hydrochloride and 1.82 g of sodium bicarbonate were
dispersed. After addition of 12.00 g of KOLLIDON.RTM. CL-M to the
drug dispersed solution, the mixture was homogenized by a Silverson
mixer homogenizer. To the homogenized drug dispersion, 43.93 g 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 Werner Mathis lab coater to get a dry coat weight
of 12 mg/cm.sup.2.
Preparation of Contact Adhesive
[0118] An amount of 0.60 g of sorbitan monolaurate (SPAN.RTM. 20)
was dissolved in 3.00 g of triethyl citrate, and mixed with 0.9 g
of lauryl lactate, 25.45 g of ethyl acetate, and 1.34 grams of
isopropyl alcohol. After addition of 6.00 g of crosslinked
polyvinylpyrrolidone (KOLLIDON.RTM. CL-M), the mixture was
homogenized by a Silverson homogenizer. To the homogenized mixture,
an amount of 38.61 g 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 using a Werner Mathis lab coater.
Lamination and Die-Cut
[0119] A microporous polypropylene membrane (CELGARD.RTM. 2400) was
laminated between the drug-in-adhesive and the contact adhesive
layers. The release liner on the drug reservoir side was replaced
and laminated with a backing film, 3M SCOTCHPAK.RTM. 1012. The
final five layer laminate was die-cut into patches. FIG. 4 depicts
the design of the patch described in Example 1.
Evaluation of In Vitro Skin Flux
[0120] 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 minutes after thawing and the epidermis
carefully separated from dermis. The epidermis was either used
immediately or wrapped and frozen for later use.
[0121] 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.
[0122] 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. The flux profile
results are shown in FIG. 6. The flux in this example is relatively
high and remains relatively constant over 7 days.
Example 2
Memantine Salt Transdermal Formulation with Sodium Bicarbonate
Preparation of Drug-in-Adhesive
[0123] An amount of 2.0 g of glycerine and 2.0 g of octyl dodecanol
were mixed with a mixture of 29.35 g of ethyl acetate and 1.86 g of
isopropyl alcohol. In the solution, 5.0 g of memantine
hydrochloride and 1.95 g of sodium bicarbonate were dispersed by
stirring. To the dispersion, 3.0 g of crosslinked
polyvinylpyrrolidone (KOLLIDON.RTM. CL-M) was added and homogenized
using a Silverson mixer homogenizer. To the homogenized drug
dispersion, 11.99 g of acrylate copolymer (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 Werner
Mathis coater to get a dry coat weight of 15 mg/cm.sup.2.
Preparation of Contact Adhesive
[0124] An amount of 2.0 g of octyl dodecanol was mixed with 20.67 g
of n-heptane. After addition of 4.00 g of crosslinked
polyvinylpyrrolidone (KOLLIDON.RTM. CL-M) to the solution, the
mixture was homogenized using a Silverson mixer homogenizer. To the
homogenized mixture, an amount of 23.33 g of polyisobutylene
adhesive solution (solid content 60%) 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
[0125] A microporous polypropylene membrane (CELGARD.RTM. 2400) was
laminated between the drug-in-adhesive layer and the contact
adhesive layer. The release liner on the drug-in-adhesive side was
replaced and laminated with a backing, 3M SCOTCHPAK.RTM. 1012. The
final five layer laminate was die-cut into patches. FIG. 4 depicts
the design of the patch.
Evaluation of In Vitro Skin Flux
[0126] 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 liquid chromatography mass spectrometry (LCMS).
The flux profile results are shown in FIG. 7 (squares). The flux in
this example is relatively high and remains relatively constant
over 7 days.
Comparative Example 3
Memantine Free Base Transdermal Formulation
Preparation of Drug-in-Adhesive
[0127] An amount of 3.20 g of memantine free base was mixed in a
mixture of 5.48 g of ethyl acetate and 8.23 g of n-heptane. To the
mixture, 4.00 grams of crosslinked polyvinylpyrrolidone
(KOLLIDON.RTM. CL-M) was dispersed and homogenized by a Silverson
mixer homogenizer. To the homogenized dispersion, 29.09 g of
polyisobutylene (PIB) adhesive solution (solid content 44%) was
added and well mixed. The wet adhesive formulation was coated on a
release liner and dried using a Werner Mathis lab coater to get a
dry coat weight of 9 mg/cm.sup.2.
Lamination and Die-cut
[0128] A nonwoven polyethylene terephthalate fabric, REEMAY.RTM.
2250, was inserted between two drug-in-adhesive layers. One release
liner was replaced with a backing, SCOTCHPAK.RTM. 1012 film. The
final five layer laminate was die-cut into patches. FIG. 4 depicts
the design of the patch described in the comparative example.
Evaluation of In Vitro Skin Flux
[0129] 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. The flux profile results are shown in
FIG. 7 (diamonds). Memantine free base diffuses through the matrix
and skin very quickly and is depleted in a relatively short time.
The flux is difficult to control and to maintain at a constant rate
for multiple days.
Comparative Example 4
Memantine Salt Transdermal Formulation Without Sodium
Bicarbonate
Preparation of Drug-in-Adhesive
[0130] An amount of 7.5 g of memantine HCl and 7.5 g of crosslinked
polyvinylpyrrolidone (KOLLIDON.RTM. CL-M) were homogenized in 46.46
g of ethyl acetate with a Silverson mixer homogenizer. The
homogenized dispersion was mixed well with 81.4 g of acrylate
copolymer (DURO-TAK.RTM. 87-900A acrylate adhesive solution (43%
solid)). The solution was coated and dried using a Werner Mathis
Lab coater to get a coat weight of 9 mg/cm.sup.2. A porous
polyethylene film, DELNET.RTM. X540NAT was inserted between two
drug-in-adhesive layers. One of adhesive release liners was
replaced with a backing, 3M SCOTCHPAK.RTM. 1012.
Preparation of Contact Adhesive
[0131] An amount of 7.5 g of crosslinked polyvinylpyrrolidone
(KOLLIDON.RTM. CL-M) was homogenized in 36.52 g of ethyl acetate
with a Silverson mixer homogenizer. The homogenized dispersion was
mixed well with 98.84 g of DURO-TAK.RTM. 87-900A (43% solid
content) acrylate adhesive solution.
Lamination and Die-Cut
[0132] The release liner of drug-in-adhesive layer was removed and
the contact adhesive layer was laminated directly to the
drug-in-adhesive layer. The six layer laminate was die-cut into
patches. FIG. 3 depicts the design of the patch described in the
comparative example.
Evaluation of In Vitro Skin Flux
[0133] 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. The flux profile results are shown in
FIG. 7 (circles).
[0134] Skin flux of memantine salt in this example is negligible.
The conjugated acid salt form of memantine is barely permeable
through the in vitro human skin.
Comparative Example 5
Memantine Salt Transdermal Formulation with Sodium Carbonate
Preparation of Drug-in-Adhesive
[0135] An amount of 2.0 g of glycerine and 2.0 g of triethyl
citrate were mixed with a mixture of 26.44 g of ethyl acetate and
1.70 g of isopropyl alcohol. In the solution, 5.0 g of memantine
hydrochloride and 1.96 g of sodium carbonate were dispersed by
stirring. To the dispersion, 3.0 g of crosslinked
polyvinylpyrrolidone (KOLLIDON.RTM. CL-M) was added and homogenized
using a Silverson mixer homogenizer. To the homogenized drug
dispersion, 11.95 g of acrylate copolymer (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 Werner
Mathis coater to get a dry coat weight of 15 mg/cm.sup.2.
Preparation of Contact Adhesive
[0136] An amount of 2.0 g of triethyl citrate was mixed with a
mixture of 14.78 g of ethyl acetate and 1.50 g of isopropyl
alcohol. After addition of 4.00 g of crosslinked
polyvinylpyrrolidone (KOLLIDON.RTM. CL-M) to the solution the
mixture was homogenized by a Silverson mixer homogenizer. To the
homogenized mixture an amount of 27.72 g of acrylate copolymer
(DURO-TAK.RTM. 387-2287 acrylic adhesive solution (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
[0137] A microporous polypropylene membrane (CELGARD.RTM. 2400) was
laminated between the drug-in-adhesive layer and the contact
adhesive layer. The release liner on the drug-in-adhesive side was
replaced and laminated with a backing, 3M SCOTCHPAK.RTM. 1012. The
final five layer laminate was die-cut into patches. FIG. 4 depicts
the design of the patch described in this comparative example.
Evaluation of In Vitro Skin Flux
[0138] 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. The flux profile results are shown in
FIG. 7 (triangles). The flux profile is similar to that of the free
base formulation of Example 3. Sodium carbonate has pKa of 10.3,
which is much higher than that of sodium bicarbonate, and is
similar to that of conjugated acid memantine salt (pKa 10.27).
Therefore, the pKa ratio between sodium carbonate and memantine HCl
is close to one, at which almost an equal fraction of the memantine
free base is produced relative to the memantine salt. As such, this
patch behaves like a free base formulation. If the free base is a
solid form, it will be recrystallized as this reaction proceeds,
and the skin flux will rapidly drop to zero as crystals form in the
drug-in-adhesive.
EQUIVALENTS
[0139] 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.
[0140] 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.
* * * * *