U.S. patent application number 10/287789 was filed with the patent office on 2003-09-11 for compositions and methods for drug delivery.
This patent application is currently assigned to Noven Pharmaceuticals, Inc.. Invention is credited to Houze, David, Kanios, David, Mantelle, Juan.
Application Number | 20030170195 10/287789 |
Document ID | / |
Family ID | 27791784 |
Filed Date | 2003-09-11 |
United States Patent
Application |
20030170195 |
Kind Code |
A1 |
Houze, David ; et
al. |
September 11, 2003 |
Compositions and methods for drug delivery
Abstract
A dermal composition for administration of an amphetamine drug
comprising a blend of two or more acrylic-based polymers having
differing functionalities so as to modulate the drug solubility in
the polymer matrix and the delivery rate of the drug, and methods
therefor.
Inventors: |
Houze, David; (Coconut
Grove, FL) ; Mantelle, Juan; (Miami, FL) ;
Kanios, David; (Miami, FL) |
Correspondence
Address: |
FOLEY AND LARDNER
SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Noven Pharmaceuticals, Inc.
|
Family ID: |
27791784 |
Appl. No.: |
10/287789 |
Filed: |
November 5, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10287789 |
Nov 5, 2002 |
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09768831 |
Jan 24, 2001 |
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10287789 |
Nov 5, 2002 |
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09479966 |
Jan 10, 2000 |
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Current U.S.
Class: |
424/70.16 ;
424/487 |
Current CPC
Class: |
A61K 8/0208 20130101;
A61K 31/137 20130101; A61K 8/8147 20130101; A61K 9/7061 20130101;
A61K 2800/54 20130101; A61Q 19/00 20130101; A61K 47/32 20130101;
A61K 2800/594 20130101; A61L 15/585 20130101; A61K 8/8152
20130101 |
Class at
Publication: |
424/70.16 ;
424/487 |
International
Class: |
A61K 007/06; A61K
007/11; A61K 009/14 |
Claims
What is claimed is:
1. A dermal composition comprising a blend of: (a) a polymer
composition of two or more polymers which includes: (i) a first
acrylic-based polymer having a first functionality and solubility
parameter; and (ii) a second acrylic-based polymer having a second
functionality and solubility parameter, wherein the first and
second functionalities differ in the amount and type of functional
groups to provide an acrylic-based polymer combination having a net
functionality proportional to the ratio of the first and second
acrylic-based polymers used, and are present in proportions to
provide a net solubility parameter; and (b) a therapeutically
effective amount of one or more drugs incorporated into the polymer
composition wherein the one or more drugs are selected from the
group consisting of methamphetamine, amphetamine, d-amphetamine,
and phentermine.
2. The dermal composition as claimed in claim 1, wherein the first
acrylic-based polymer has a functionality which provides a lower
drug solubility than the second acrylic-based polymer.
3. The dermal composition as claimed in claim 2, wherein the first
acrylic-based polymer is present in an amount to provide a flux of
the drug in the dermal drug delivery composition which is greater
than a composition based solely on the second acrylic-based
polymer.
4. The dermal composition as claimed in claim 2, wherein the amount
of the second acrylic-based polymer is in the range of 5-95 weight
% and the amount of the first acrylic-based polymer is in the range
of 95 to 5% by weight, all based on the total dry weight of the
polymer.
5. The dermal composition as claimed in claim 2, wherein the amount
of the second acrylic-based polymer is in the range of 20-75 weight
% and the amount of the first acrylic-based polymer is in the range
of 75 to 20% by weight, all based on the total dry weight of the
polymer.
6. The dermal composition as claimed in claim 2, wherein the first
acrylic-based polymer has substantially no functional groups and
the second acrylic-based polymer has functional groups.
7. The dermal composition as claimed in claim 6, wherein the second
acrylic-based polymer has carboxyl and/or hydroxy functional
groups.
8. The dermal composition as claimed in claim 6, wherein the second
acrylic-based polymer is present in an amount to provide a
increased saturation concentration in the dermal drug delivery
composition which is greater than a composition based solely on the
first acrylic-based polymer.
9. The dermal composition as claimed in claim 6, wherein the
functional groups are provided by monomer units containing
functional groups which are incorporated into the second
acrylic-based polymer in an amount of from 0.1 to 20% by weight,
based on the dry weight of the second acrylic-based polymer.
10. The dermal composition as claimed in claim 9, wherein the
functional monomers are incorporated into the second acrylic-based
polymer in an amount of from 0.1 to 8% by weight, based on the dry
weight of the second acrylic-based polymer.
11. The dermal composition as claimed in claim 1, wherein the at
least two polymer polymers contain substantially only the first and
second acrylic-based polymers.
12. The dermal composition as claimed in claim 7, wherein the
second acrylic-based polymer includes carboxyl functional
groups.
13. The dermal composition as claimed in claim 1, wherein the one
or more drugs are present in base form.
14. The dermal composition as claimed in claim 13, wherein the
first acrylic-based polymer has substantially no functional groups
and wherein the second acrylic-based polymer includes carboxyl
functional groups which are present from about 0.1 to 10% by weight
of the polymer.
15. The dermal composition as claimed in claim 1, wherein the drug
includes d-amphetamine.
16. The dermal composition as claimed in claim 15, wherein the
first acrylic-based polymer has substantially no functional groups
and wherein the second acrylic-based polymer includes carboxyl
functional groups present from about 0.1 to 12% by weight of the
polymer.
17. The dermal composition as claimed in claim 16, wherein the
carboxyl functional monomer units are acrylic acid.
18. The dermal composition as claimed in claim 1, wherein the drug
includes methamphetamine.
19. The dermal composition as claimed in claim 18, wherein the
first acrylic-based polymer has substantially no functional groups
and wherein the second acrylic-based polymer includes carboxyl
functional groups present from about 0.1 to 12% by weight of the
polymer.
20. The dermal composition as claimed in claim 19, wherein the
carboxyl containing functional monomer units are acrylic acid.
21. The dermal composition as claimed in claim 1, wherein the drug
includes phentermine.
22. The dermal composition as claimed in claim 21, wherein the
first acrylic-based polymer has substantially no functional groups
and wherein the second acrylic-based polymer includes carboxyl
functional groups present from about 0.1 to 12% by weight of the
polymer.
23. The dermal composition as claimed in claim 22, wherein the
carboxyl containing functional monomer units are acrylic acid.
24. The dermal composition as claimed in claim 1, wherein the drug
includes amphetamine.
25. The dermal composition as claimed in claim 24, wherein the
first acrylic-based polymer has substantially no functional groups
and wherein the second acrylic-based polymer includes carboxyl
functional groups present from about 0.1 to 12% by weight of the
polymer.
26. The dermal composition as claimed in claim 25, wherein the
carboxyl containing functional monomer units are acrylic acid.
27. A method of producing a dermal composition, comprising the
steps of: (1) producing a blend of: (a) a polymer composition of
two or more polymers which includes: (i) a first acrylic-based
polymer having a first functionality and solubility parameter; and
(ii) a second acrylic-based polymer having a second functionality
and solubility parameter, wherein the first and second
functionalities differ in the amount and type of functional groups
to provide an acrylic-based polymer combination having a net
functionality proportional to the ratio of the first and second
acrylic-based polymers used, and are blended in proportions to
provide a net solubility parameter; and (b) a therapeutically
effective amount of one or more drugs selected from the group
consisting of amphetamine, methamphetamine, d-amphetamine, and
phentermine; (2) forming the blend into a polymer matrix; and (3)
drying the polymer matrix to remove the solvent system to form the
dermal composition.
28. The method as claimed in claim 27, wherein the first
acrylic-based polymer has a functionality which provides a lower
solubility parameter than the second acrylic-based polymer.
29. The method as claimed in claim 27, further comprising the step
of applying a backing material to one side of the composition, the
backing material being substantially impermeable to the drug
contained therein.
30. The method as claimed in claim 29, further comprising the step
of applying a release liner to a surface of the composition
opposite said backing material.
31. A method of controlling the flux of a drug from a dermal drug
delivery composition, comprising the steps of: (a) selecting at
least two polymer polymers which includes: (i) a first
acrylic-based polymer having a first functionality and solubility
parameter; and (ii) a second acrylic-based polymer having a second
functionality and solubility parameter, wherein said first and
second functionalities differ in the amount and type of functional
groups to provide a polymer combination having a net solubility of
one or more drugs within the composition proportional to the ratio
of the first and second acrylic-based polymers used; (b) combining
the at least two acrylic-based polymers with a therapeutically
effective amount of one or more drugs selected from the group
consisting of amphetamine, methamphetamine, d-amphetamine, and
phentermine to form the dermal drug delivery composition, wherein
the net solubility is different than the flux of a composition
produced solely from said first or second acrylic-based polymers
alone.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This application is a continuation-in-part of application
Ser. No. 09/768,831 filed May 14, 2001, which is a continuation of
application Ser. No. 09/479,966 filed Jan. 10, 2000. In accordance
with 35 U.S.C. .sctn. 119 (e), the benefit of provisional
application 60/115,927, filed Jan. 14, 1999, is hereby claimed. The
entire contents of this provisional application are incorporated
herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to compositions and methods
for dermal administration of drugs, their method of making and
method of use. In particular, the present invention is directed to
a dermal drug delivery matrix system for the dermal application of
one or more drugs, which includes a blend of two acrylic-based
polymers having differing functionalities and a therapeutically
effective amount of one or more drugs.
[0004] 2. Description of Related Art
[0005] The use of a dermal drug delivery composition, for example a
pressure-sensitive adhesive containing a medicament, namely, a
drug, as a means for administering therapeutically effective
amounts of the medicament is well known. Such known delivery
compositions involve incorporation of a medicament into a carrier
such as a polymeric and/or a pressure-sensitive adhesive
formulation to form a composition of the medicament and a polymer
or pressure-sensitive adhesive which also functions as a reservoir
for the medicament. If the polymer is a pressure-sensitive
adhesive, the pressures-sensitive adhesive also functions to adhere
the composition directly to the skin without the requirement for
any additional adhesives. The pressure-sensitive adhesive must
adhere effectively to the skin and permit migration of the
medicament from the carrier to the site of application and/or
through the skin and into the bloodstream of the living
organism.
[0006] Many factors influence the design and performance of dermal
drug delivery devices, such as desired delivery rate, length of
delivery, and the individual drugs themselves. These factors are
described in detail in U.S. Pat. No. 5,474,783 (assigned to Noven
Pharmaceuticals, Inc., the assignee of the present invention) which
is hereby incorporated by reference in its entirety.
[0007] Dermal drug delivery compositions based on acrylic
pressure-sensitive adhesive polymers are known in the dermal drug
delivery art. These acrylic-based polymers are typically used as
the pressure-sensitive adhesive by themselves as described in U.S.
Pat. No. 4,390,520. They may also be used in combination with other
polymers which may or may not be pressure-sensitive adhesive as
described in U.S. Pat. No. 4,994,267 (assigned to the assignee of
the present application Noven Pharmaceuticals, Inc.). In order to
provide for adequate wear properties and drug delivery,
acrylic-based pressure-sensitive adhesives are typically
polymerized with functional monomers to provide functional groups
on the acrylic-based adhesive.
[0008] By varying the amount of each type of monomer added, the
adhesive and cohesive properties and drug solubility of the
resulting polyacrylate can be changed as is known in the art.
Typically, the polyacrylate is composed of at least 50% by weight
of an acrylate or alkyl acrylate monomer, from 0% to 20% of a
functional monomer copolymerizable with the acrylate, and from 0%
to 40% of other monomers.
[0009] One drawback with the use of acrylic-based polymers with
functional groups is that due to the generally high solubility of
the drug in the polymer matrix, a large amount of drug generally
must be incorporated into the dermal drug delivery composition to
saturate it and provide an adequate flux to the skin of the user.
Another drawback is that the functional groups provide reaction
sites for undesirable degradation reactions of the drug with the
polymer matrix.
[0010] One way of overcoming the problems of high drug loading and
degradation is to physically blend the acrylic-based polymer with
another polymer which has a different solubility parameter in order
to adjust the solubility and flux of a drug in the blend. In other
words, by selectively blending the polymers, a drug delivery system
results which can incorporate low concentrations of drug and
deliver the same at an adequate and controlled rate, or,
alternatively, incorporate high concentrations of drugs while
retaining good physical adhesive properties.
[0011] A blend of polymers which are particularly suitable are
acrylic-based adhesives and polysiloxanes as described in U.S. Pat.
No. 5,474,783. While these blends generally provide good results in
terms of controlling the flux and the solubility of the drug within
the matrix, polysiloxane adhesives are generally more expensive
than acrylic-based adhesives resulting in higher production costs.
Additionally, the usable range of solubility for
silicone-containing blends is significantly lower than is sometimes
desired.
SUMMARY OF THE INVENTION
[0012] An object of the present invention is to provide a
matrix-type polymer dermal drug delivery composition which is
simple and inexpensive. Another object of the present invention is
to provide an acrylic-based polymer dermal drug delivery
composition where the rate of drug delivery from the dermal drug
delivery composition may be selectively modulated. Another object
of the present invention is to provide a dermal drug delivery
composition where the drug loading or drug concentration in the
polymer matrix can be selectively controlled. Another object is to
provide an acrylic-based dermal drug delivery composition which has
a combination of desirable adhesion to mammalian skin in addition
to satisfactory drug concentration and flux requirements.
[0013] Another object of the present invention is to provide a
method for producing a dermal drug delivery composition according
to the present invention. Another object of the present invention
is to provide a method of modulating drug solubility in a dermal
drug delivery composition and drug flux from a polymer matrix.
[0014] According to one aspect of the invention, there has been
provided a dermal drug delivery composition which includes a blend
of: (a) a polymer composition of two or more polymers which
includes: (i) a first acrylic-based polymer having a first
functionality and solubility parameter; and (ii) a second
acrylic-based polymer having a second functionality and solubility
parameter, wherein the first and second functionalities differ in
the amount and type of functional groups to provide an
acrylic-based polymer combination having a net functionality
proportional to the ratio of the first and second acrylic-based
polymers used, and are present in proportions to provide a net
solubility parameter; and (b) a therapeutically effective amount of
one or more drugs incorporated into the polymer composition.
[0015] According to another aspect of the invention, there has been
provided a method of producing a dermal composition, comprising the
steps of: (1) producing a blend of: (a) a polymer composition of
two or more polymers which includes: (i) a first acrylic-based
polymer having a first functionality and solubility parameter; and
(ii) a second acrylic-based polymer having a second functionality
and solubility parameter, wherein the first and second
functionalities differ in the amount and type of functional groups
to provide an acrylic-based polymer combination having a net
functionality proportional to the ratio of the first and second
acrylic-based polymers used, and are blended in proportions to
provide a net solubility parameter; and (b) a therapeutically
effective amount of one or more drugs incorporated into the polymer
composition; (2) forming the blend into a polymer matrix; and (3)
drying the polymer matrix to remove the solvent system to form the
dermal composition.
[0016] According to still another aspect of the invention, there
has been provided a method of controlling the flux of a drug from a
dermal drug delivery composition, comprising the steps of: (a)
selecting at least two polymers which includes: (i) a first
acrylic-based polymer having a first functionality and solubility
parameter; and (ii) a second acrylic-based polymer having a second
functionality and solubility parameter, wherein the first and
second functionalities differ in the amount and type of functional
groups to provide a polymer combination having a net solubility of
one or more drugs within the composition proportional to the ratio
of the first and second acrylic-based polymers used; (b) combining
the at least two acrylic-based polymers with a therapeutically
effective amount of one or more drugs to form the dermal drug
delivery composition, wherein the one or more drugs have a flux
which is determined by the net solubility in the composition and is
different than the flux of a composition produced solely from the
first or second acrylic-based polymers alone.
[0017] These and other objects will be readily apparent to those
skilled in the art from the detailed description of preferred
embodiments which follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is a graphic representation of the average flux of
haloperidol versus time with different proportions of acid
functional and non-functional acrylic-based polymers.
[0019] FIG. 2 is a graphic representation of the average flux of
nicotine versus time with different proportions of acid functional
and non-functional acrylic-based polymers.
[0020] FIG. 3 is a graphic representation of the average flux of
clonidine versus time with different proportions of acid functional
and hydroxy functional acrylic-based polymers.
[0021] FIG. 4 is a graphic representation of the average flux of
scopolamine versus time with different proportions of acid
functional and non-functional acrylic-based polymers.
[0022] FIG. 5 is a graphic representation of the average flux of
d-Amphetamine versus time with different proportions of acid
functional and non-functional acrylic-based polymers.
[0023] FIG. 6 is a graphic representation of the average flux of
d-Amphetamine versus time with different proportions of acid
functional and non-functional acrylic-based polymers.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0024] As used herein, the term "dermal" refers to delivery,
administration or application of a drug by means of direct contact
with tissue, such as skin or mucosa. Such delivery, administration
or application is also known as percutaneous, transdermal,
transmucosal and buccal. Similarly, "skin" is meant to include
mucosa which further includes oral, buccal, nasal, rectal and
vaginal mucosa.
[0025] As used herein, a "dermal composition" is defined as a
composition which contains one or more drugs therein. The dermal
composition is applied to a dermal area, described above for dermal
administration or application of the one more drugs. The dermal
composition includes a polymer matrix with the one or more drugs
contained therein. As described below, in a preferred embodiment,
the polymer matrix may be a pressure-sensitive adhesive for direct
attachment to a user's skin. Alternatively, the polymer matrix may
be non-adhesive with separate adhesion means for adhering the
composition to the user's skin.
[0026] As used herein, the terms "blend" and "mixture" are used
herein to mean that there is no, or substantially no, chemical
reaction or crosslinking (other than simple H-bonding) between the
different polymers in the polymer matrix. However, crosslinking
between a single polymer component is fully contemplated to be
within the scope of the present invention.
[0027] As used herein, the term "pressure-sensitive adhesive"
refers to a viscoelastic material which adheres instantaneously to
most substrates with the application of very slight pressure and
remains permanently tacky. A polymer or dermal composition is a
pressure-sensitive adhesive within the meaning of the term as used
herein if it has the adhesive properties of a pressure-sensitive
adhesive per se or functions as a pressure-sensitive adhesive by
admixture with tackifiers, plasticizer or other additives.
[0028] As used herein, a "polymer composition of two or more
polymers" is defined as a physical blend of at least two polymers
and can include 3 or more polymers. The two or more polymers
includes the acrylic-based polymers described herein and can
optionally include other polymers discussed more fully below.
[0029] As used herein, "acrylic-based" polymer is defined as any
polyacrylate, polyacrylic, acrylate and acrylic polymer. The
acrylic-based polymers can be any of the homopolymers, copolymers,
terpolymers, and the like of various acrylic acids or esters. The
acrylic-based polymers useful in practicing the invention are
polymers of one or more monomers of acrylic acids and other
copolymerizable monomers. The acrylic-based polymers also include
copolymers of alkyl acrylates and/or methacrylates and/or
copolymerizable secondary monomers. Acrylic-based polymers with
functional groups as described more fully below, are copolymerized
with functional monomers.
[0030] As used herein, "functional monomers or groups," are monomer
units in an acrylic-based polymers which have reactive chemical
groups which modify the acrylic-based polymers directly or provide
sites for further reactions. Examples of functional groups include
carboxyl, epoxy and hydroxy groups.
[0031] As used herein, "functionality" is broadly defined as a
measure of the type and quantity of functional groups that a
particular acrylic-based polymer has. This definition also
encompasses acrylic-based polymers having no or substantially no
functional groups.
[0032] As used herein "non-functional acrylic" is defined as an
acrylic-based polymer which has no or substantially no functional
reactive moieties present in the acrylic. These are generally
acrylic esters which can be copolymerized with other monomers which
do not have functional groups, such as vinyl acetate.
[0033] As used herein "flux" is defined as the percutaneous
absorption of drugs through the skin, and is described by Fick's
first law of diffusion:
J=-D(dC.sub.m/dx),
[0034] where J is the flux in g/cm.sup.2/sec, D is the diffusion
coefficient of the drug through the skin in cm.sup.2/sec and
dC.sub.m/dx is the concentration gradient of the active agent
across the skin.
[0035] As used herein, "matrix" is defined as a polymer composition
which incorporates a therapeutically effective amount of the drug
therein. The matrix may be monolithic as described below, or it may
use separate attachment means for holding it to the user's skin. A
dermal drug delivery system with a matrix may optionally include
additional drug supply means for continuously replenishing the drug
supply in the matrix.
[0036] As used herein "monolithic" is defined as a matrix device
which is adhesive, pressure-sensitive or otherwise.
[0037] As used herein, the term "drug" (and its equivalents,
"active agent," "bioactive agent," "medicament" and
"pharmaceutical" or any other similar term) is intended to have the
broadest meaning and includes any chemical or biological material
or compound which induces at least one of any therapeutic,
prophylactic, pharmacological, physiological, aesthetic, cosmetic,
or any other desired, usually beneficial, effect, localized or
systemic, to a living organism. It should be noted that the drugs
may be used singularly or in mixtures of two or more drugs, and in
amounts sufficient to prevent, cure, diagnose, mitigate or treat a
disease or condition, as the case may be.
[0038] As used herein, when drug is used in a "therapeutically
effective amount" means that the concentration of the drug in the
dermal drug delivery composition results in a therapeutic level of
the drug being delivered to the site of application or through the
skin and into the bloodstream over the period of time that the
dermal composition is to be used, preferably with zero order
kinetics. Such delivery is dependent on a great number of variables
including the drug, the time period for which the individual dosage
unit is to be used, the flux rate of the drug from the system and a
number of other variables. The amount of drug needed can be
experimentally determined based on the flux rate of the drug
through the system and through the skin when used with or without
enhancers. Having determined the flux rate needed, the dermal
delivery system is designed so that the release rate over the
period of time of therapeutic use will be at least equal to the
flux rate. Of course, the surface area of the dermal delivery
system also affects the delivery of the drug from the system
through the skin.
[0039] The present invention is based on the discovery that a
polymer matrix dermal drug delivery composition having good
adhesion properties, controllable drug solubility and flux can be
achieved by physically blending two acrylic-based polymers which
have different functionalities. The functionality of one of the
acrylic-based polymers is such that it has a high drug solubility
or loading requirements. The functionality of the other
acrylic-based polymer is such that a drug has a lower solubility
which accordingly requires a relatively low drug loading to produce
a flux which is substantially equivalent to the more highly loaded
polymer.
[0040] The combination of these two acrylic-based polymers results
in a dermal drug delivery composition having a characteristic "net
solubility parameter." The net solubility parameter can be adjusted
by the kinds and proportions of the acrylic-based polymers. This
provides a selectable modulation of the delivery rate of the drug
by adjusting the solubility of the drug in the acrylic-based
polymer composition.
[0041] Solubility parameter has been defined as the sum of all
intermolecular attractive forces, which are empirically related to
the extent of mutual solubility of many chemical species. An
in-depth discussion of solubility parameter can be found in U.S.
Pat. No. 5,474,783. In other words, the solubility parameter
determines how much of a drug can be incorporated into a polymer
matrix before the polymer matrix becomes saturated with the
drug.
[0042] Another factor to be considered in formulating the dermal
composition is that if the dermal composition is adhesive at room
temperature according to a preferred embodiment, then the
composition should have good adherence to skin, the ability to be
peeled or otherwise removed without substantial trauma to the skin,
retention of tack, etc. In other words, the dermal drug delivery
must have sufficient wear properties. In general, the dermal
polymer drug delivery composition should have a glass transition
temperature (T.sub.g), measured using a differential scanning
calorimeter, of between about -70.degree. C. to 0.degree. C. Since
dermal drug delivery compositions made with high proportions of
non-functional acrylic-based polymers generally do not have
sufficient wear properties, there is an upper limit on the amount
of non-functional acrylic-based adhesive incorporated into the
composition. This upper limit generally depends on the drug being
loaded into the composition, the drug loading amounts, other
additives such as enhancers, and the type of the other
acrylic-based adhesive used. The upper limit can be determined by
routine experimentation using the present specification as a
guide.
[0043] Non-functional acrylic-based polymers can include any
acrylic based polymer having no or substantially no free functional
groups. The acrylic based polymer can include homopolymers,
copolymers and terpolymers. The monomers used to produce the
polymers can include alkyl acrylic or methacrylic esters such as
methyl acrylate, ethyl acrylate, propyl acrylate, amyl acrylate,
butyl acrylate, 2-ethylbutyl acrylate, hexyl acrylate, heptyl
acrylate, octyl acrylate, nonyl acrylate, 2-ethylhexyl acrylate,
decyl acrylate, dodecyl acrylate, tridecyl acrylate, glycidyl
acrylate and the corresponding methacrylic esters.
[0044] Acrylic-based polymers having functional groups are
copolymers or terpolymers which contain in addition to the
nonfunctional monomer units described above, further monomer units
having free functional groups. The monomers can be monofunctional
or polyfunctional. These functional groups include carboxyl groups,
hydroxy groups, amino groups, amido groups, epoxy groups, etc.
Preferred functional groups are carboxyl groups and hydroxy groups.
Preferred carboxyl functional monomers include acrylic acid,
methacrylic acid, itaconic acid, maleic acid, and crotonic acid.
Preferred hydroxy functional monomers include 2-hydroxyethyl
methacrylate, 2-hydroxyethyl acrylate, hydroxymethyl acrylate,
hydroxymethyl methacrylate, hydroxyethyl acrylate, hydroxyethyl
methacrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate,
hydroxybutyl acrylate, hydroxybutyl methacrylate, hydroxyamyl
acrylate, hydroxyamyl methacrylate, hydroxyhexyl acrylate,
hydroxyhexyl methacrylate.
[0045] These functional monomers are incorporated into the
copolymer or terpolymer in an amount of 0.1 to 20% by weight,
preferably 0.1 to 12% by weight, more preferably 0.1 to 8% by
weight and still more preferably 4 to 8% by weight based on the dry
weight of the total acrylic-based polymer.
[0046] Both the acrylic-based polymer having substantially no
functional groups and acrylic-based polymers having functional
groups can optionally include further modifying monomers. These
modifying monomers can include any conceivable monomer that is
capable of undergoing vinyl polymerization. For example, the
incorporation of styrene monomers can be used to increase the glass
transition temperature and are sometimes used to improve the
cohesive strength. The copolymerization of vinyl acetate monomers
with acrylic esters are also used to form acrylic-based polymers.
Ethylene can also be copolymerized with acrylic esters and vinyl
acetate to give suitable acrylic-based polymers.
[0047] In a particularly preferred embodiment, the dermal
composition is a pressure-sensitive adhesive. More preferably, the
adhesive properties of the dermal composition are provided by one
or both of the acrylic-based polymers being pressure-sensitive
adhesive.
[0048] Further details and examples of acrylic-based adhesives,
functional monomers, and polymers which have no functional groups
and which are suitable in the practice of the invention are
described in Satas, "Acrylic Adhesives," Handbook of
Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D.
Satas, ed.), Van Nostrand Reinhold, N.Y. (1989); "Acrylic and
Methacrylic Ester Polymers," Polymer Science and Engineering, Vol.
1, 2nd ed., pp 234-268, John Wiley & Sons, (1984); U.S. Pat.
No. 4,390,520; and U.S. Pat. No. 4,994,267 all of which are
expressly incorporated by reference in their entireties.
[0049] Preferred acrylic-based adhesives which are commercially
available include the acrylic-based adhesives sold under the
trademarks Duro-Tak 87-2287 (a non-crosslinked vinyl acetate
acrylic pressure-sensitive adhesive with hydroxy functionality),
Duro-Tak 87-4098 (a non-functional, non-crosslinked acrylic
pressure sensitive adhesive), Duro-Tak 87-2852 (a crosslinked
acrylic-based pressure-sensitive adhesive with carboxyl
functionality), Duro-Tak 87-2196 (carboxy functional, crosslinked),
Duro-Tak 87-2296 (carboxy functional, crosslinked), Duro-Tak
87-2194 (carboxy functional, crosslinked), Duro-Tak 87-2516
(hydroxy functional, crosslinked), Duro-Tak 87-2070 (carboxy and
hydroxy functional, crosslinked), Duro-Tak 87-2353 (carboxy
functional, non-crosslinked), Duro-Tak 87-2154 (carboxy functional,
crosslinked), and Duro-Tak 87-2510 (hydroxy functional
non-crosslinked), and are all sold by National Starch and Chemical
Corporation, Bridgewater, N.J. Other suitable acrylic-based
pressure-sensitive adhesive include HRJ 4483, 10127, and 11588
(non-functional acrylic-based pressure-sensitive adhesives) sold by
Schenectady International, Inc., Schenectady, N.Y. Other suitable
acrylic-based adhesives are those sold under the trademarks
Gelva-Multipolymer Solution GMS 2480, Gelva 788, Gelva 737, Gelva
263, Gelva 1430, Gelva 1753, Gelva 1151, Gelva 2450, and Gelva 2495
all sold by Monsanto; St. Louis, Mo.
[0050] Additionally preferred acrylic-based adhesives also include
the acrylic-based adhesives described in the chart below. Table 1
below indicates the percentage of the monomers present in each
pressure sensitive adhesive (PSA).
1TABLE 1 PSA MA 2-EHA 2-HEA VA GMA BA AA Amide PSA 1 80 20 PSA 3 24
71 5 PSA 4 50 50 PSA 5 67 5 28 0.14 PSA 6 28 64 8 PSA 8 35 45 20
PSA 9 32 65 3 PSA 10 50 50 PSA 11 30 70 MA = methylacrylate 2-EHA =
2-ethylhexylacrylate 2-HEA = 2-hydroxyethylacrylate VA =
vinylacetate GMA = glycidylmethacrylate BA = butylacrylate AA =
acrylic acid
[0051] The types of acrylic-based polymers having different
functionalities and their proportions in the dermal drug delivery
composition can vary broadly and generally depends on the
solubility of the particular drug being incorporated into the
polymer matrix, the required flux and the amount of time the
composition will be required to deliver a therapeutically effective
amount of the drug to the user's skin.
[0052] The proportion of the two acrylic-based polymers can be
adjusted to either increase or decrease the saturation
concentration or drug loading of the drug in the composition, and
can also be used to modulate the shape of the flux curve. For
example, the saturation concentration of a drug in a first
functional acrylic-based polymer can be lowered by blending in a
non-functional acrylic-based polymer or another acrylic-based
polymer which has either a lower proportion or different functional
groups.
[0053] Alternatively, the saturation concentration in a first
functional acrylic-based polymer can be lowered by blending another
functional acrylic-based polymer which has a functional group which
does not have as great of an affinity for the drug as the
functional group in the first functional acrylic-based polymer,
which results in a lower solubility. This combination of acrylics
is typically used when a non-functional acrylic-based
pressure-sensitive polymer has too great a propensity to solubilize
the drug.
[0054] This combination of a non-functional or lower solubility
functional acrylic-based polymer with a functional acrylic-based
polymer, creates a greater thermodynamic driving force and greater
flux of drug from the composition. As noted above, in the case of
the preferred embodiment where the dermal composition is a
pressure-sensitive adhesive, there is an adhesion limit to the
amount of non-functional acrylic-based polymer that can be
incorporated into the composition.
[0055] Conversely, the saturation concentration of a drug can be
increased by increasing the proportion of the functional
acrylic-based polymer incorporated into the composition. This
creates a greater drug loading capacity or a decreased flux which,
depending on the application, is sometimes desirable.
[0056] Exact proportions of acrylic-based polymers used are
generally dependant on the specific drug, its desired delivery rate
and the duration of drug delivery. Those skilled in the art can
readily determine the rate of delivery of the drug from the dermal
drug delivery composition in order to select suitable combination
of the acrylic-based polymers and drug for a particular
application. Various techniques can be used to determine the rate
of delivery of the drug from the polymer. Illustratively, the rate
of delivery can be determined by measuring the transfer of drug
from one chamber to another through cadaver skin over time, and
calculating from the obtained data, the drug delivery or flux
rate.
[0057] The proportions of acrylic-based polymers also depend on the
content of the functional monomer units in the functional acrylic.
For example, a dermal composition will require less of a functional
acrylic that contains 20% by weight of functional groups as opposed
to one that contains 0.5% by weight of functional groups to achieve
the same effect required for solubility and flux. Broadly speaking,
the amount of functional acrylic is generally within the range of
about 1 to 99 weight % and preferably 5 to 95 weight %, more
preferably 20 to 75 weight %, even more preferably 30 to 65 weight
%, based on the total polymer content of the dermal composition.
The amount of non-functional acrylic or acrylic with a functional
group which does not have as great of an affinity for the drug, is
within the range of about 99 to 1 weight %, preferably 95 to 5
weight %, more preferably 75 to 20 weight % and even more
preferably 30 to 65 weight %, based on the total polymer content of
the dermal composition.
[0058] Other natural or synthetic polymers, which may or may not be
adhesives, can also be included in the dermal composition according
to the present invention. For example, polyvinylpyrrolidone ("PVP")
can be included to increase the maximum concentration of the drug
in the composition. The use of PVP in a dermal composition is fully
described in U.S. Pat. No. 5,656,286 which is expressly
incorporated in its entirety. Other suitable polymers and
pressure-sensitive adhesives include polysiloxanes and rubbers. The
addition of such other polymers to a dermal composition is fully
described in U.S. Pat. No. 5,474,783 which is incorporated herein
in its entirety.
[0059] The drugs used in the present invention can include a single
drug or mixtures of one or more drugs. Any drug suitable for dermal
administration by methods previously known in the art and by the
methods of the present invention can be used in the present
invention, and further include such active agents that may be later
established as drugs and are suitable for delivery by the present
invention. These drugs include those categories and species of
drugs set forth on page ther-1 to ther-28 of the Merck Index, 12th
Edition Merck and Co. Rahway, N.J. (19969). This reference is
incorporated by reference in its entirety. Exemplary of drugs that
can be administered by the novel dermal drug delivery system
include, but are not limited to:
[0060] 1. .alpha.-Adrenergic agonist agents such as
Phenylpropanolamine.
[0061] 2. Analgesics and/or Anti-Migraine such as Acetaminophen,
Acetylsalicylic Acid, Buprenorphine, Codeine, Fentanyl, Lisuride,
Salicylic Acid derivatives and Sumatriptan.
[0062] 3. Androgen agents such as Fluoxymesterone, Methyl
Testosterone, Oxymesterone, Oxymetholone, Testosterone and
Testosterone derivatives.
[0063] 4. Anesthetic agents such as Benzocaine, Bupivicaine,
Cocaine, Dibucaine, Dyclonine, Etidocaine, Lidocaine, Mepivacaine,
Prilocaine, Procaine and Tetracaine.
[0064] 5. Anoretic agents such as Fenfluramine, Mazindol and
Phentermine.
[0065] 6. Anti-Bacterial (antibiotic) agents including
Aminoglycosides, .beta.-Lactams, Cephamycins, Macrolides,
Penicillins, Polypeptides and Tetracyclines.
[0066] 7. Anti-Cancer agents such as Aminolevulinic Acid and
Tamoxifen.
[0067] 8. Anti-Cholinergic agents such as Atropine, Eucatropine and
Scopolamine.
[0068] 9. Anti-Diabetic agents such as Glipizide, Glyburide,
Glypinamide and Insulins.
[0069] 10. Anti-Fungal agents such as Clortrimazole, Ketoconazole,
Miconazole, Nystatin and Triacetin.
[0070] 11. Anti-Inflammatory and/or Corticoid agents such as
Beclomethasone, Betamethasone, Betamethasone Diproprionate,
Betamethasone Valerate, Corticosterone, Cortisone,
Deoxycortocosterone and Deoxycortocosterone Acetate, Diclofenac,
Fenoprofen, Flucinolone, Fludrocortisone, Fluocinonide,
Fluradrenolide, Flurbiprofen, Halcinonide, Hydrocortisone,
Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Ketorolac, Naproxen,
Oxametacine, Oxyphenbutazone, Piroxicam, Prednisolone, Prednisone,
Suprofen and Triamcinolone Acetonide.
[0071] 12. Anti-Malarial agents such as Pyrimethamine.
[0072] 13. Anti-Parkinson's and/or Anti-Alzhiemer's agents such as
Bromocriptine, 1-Hydroxy-Tacrine, Levodopa, Lisaride Pergolide,
Pramipexole, Ropinirole, Physostigimine, Selegiline (Deprenyl and
L-Deprenyl), Tacrine Hydrochloride and Teruride.
[0073] 14. Anti-Psychotic and/or Anti-Anxiety agents such as
Acetophenazine, Azapirones, Bromperidol, Chlorproethazine,
Chlorpromazine, Fluoxetine, Fluphenazine, Haloperidol, Loxapine,
Mesoridazine, Molindone, Ondansetron, Perphenazine, Piperacetazine,
Thiopropazate, Thioridazine, Thiothixene, Trifluoperazine and
Triflupromazine.
[0074] 15. Anti-Ulcerative agents such as Enprostil and
Misoprostol.
[0075] 16. Anti-Viral agents such as Acyclovir, Rimantadine and
Vidarabine.
[0076] 17. Anxiolytic agents such as Buspirone, Benzodiazepines
such as Alprazolam, Chlordiazepoxide, Clonazepam, Clorazepate,
Diazepam, Flurazepam, Halazepam, Lorazepam, Oxazepam, Oxazolam,
Prazepam and Triazolam.
[0077] 18. .beta.-Adrenergic agonist agents such as Albuterol,
Carbuterol, Fenoterol, Metaproterenol, Rimiterol, Quinterenol,
Salmefamol, Soterenol, Tratoquinol, Terbutaline and Terbuterol.
[0078] 19. Bronchodilators such as Ephedrine derivatives including
Epiniphrine and Isoproterenol, and Theophylline.
[0079] 20. Cardioactive agents such as Atenolol,
Benzydroflumethiazide, Bendroflumethiazide, Calcitonin, Captopril,
Chlorothiazide, Clonidine, Dobutamine, Dopamine, Diltiazem,
Enalapril, Enalaprilat, Gallopamil, Indomethacin, Isosorbide
Dinitrate and Mononitate, Nicardipine, Nifedipine, Nitroglycerin,
Papaverine, Prazosin, Procainamide, Propranolol, Prostaglandin
E.sub.1, Quinidine Sulfate, Timolol, and Verapamil.
[0080] 21. Central nervous system stimulants and agents such as
Dextroamphetamine, Amphetamine, Methamphetamine, D-Amphetamine,
Phentermine, Methylphenidate and Nicotine.
[0081] 22. Cholinergic agents such as Acetylcholine, Arecoline,
Bethanechol, Carbachol, Choline, Methacoline, Muscarine and
Pilocarpine.
[0082] 23. Estrogens such as Conjugated Estrogenic Hormones,
Equilenin, Equilin, Esterified Estrogens, 17.beta.-Estradiol,
Estradiol Benzoate, 17.beta.-Estradiol Valerate, Estradiol
17.beta.-Cypionate, Estriol, Estrone, Estropipate, 17.beta.-Ethinyl
Estradiol and Mestranol.
[0083] 24. Muscle relaxants such as Baclofen.
[0084] 25. Narcotic antagonist agents such Nalmfene and
Naloxone.
[0085] 26. Progestational agents such as Chlormadinone and
Chlormadinone Acetate, Demegestone, Desogestrel, Dimethisterone,
Dydrogesterone, Ethinylestrenol, Ethisterone, Ethynodiol and
Ethynodiol Diacetate, Gestodene, 17.alpha.-Hydroxyprogesterone,
Hydroxygesterone Caproate, Medroxyprogesterone and
Medroxyprogesterone Acetate, Megestrol Acetate, Melengestrol,
Norethindrone and Norethidrone Acetate, Norethynodrel,
Norgesterone, Norgestrel, 19-Norprogesterone, Progesterone,
Promegestone and esters thereof.
[0086] Particularly preferred drugs include alprazolam, captopril,
clonidine, clonaazepam, enalapril, fluoxetine, haloperidol,
ketoprofen, loratadine, methimazole (anti-hyperthyroid),
methylphenidate, methyl testosterone, nicotine, nitroglycerin,
pramipexole, ropinirole, selegiline (deprenyl and L-deprenyl),
scopolamine, testosterone, methamphetamine, d-amphetamine and
phentermine. When the preferred drugs are methamphetamine,
d-amphetamine and phentermine, the drugs are preferably present in
their base form.
[0087] The drugs and mixtures thereof can be present in the
composition in different forms, depending on which yields the
optimum delivery characteristics. Thus, the drug can be in its free
base form or in the form of salts, esters, or any other
pharmacologically acceptable derivatives, or as prodrugs,
components of molecular complexes or as combinations of these. Free
base forms of drugs which have a greater affinity for the acid
(carboxyl) functional group in a carboxyl functional acrylic-based
polymer are preferred in some applications.
[0088] As noted above, with the present invention a greater flux of
the drug(s) can be achieved with the same loading of the drug(s)
into the dermal drug delivery composition. Put in a slightly
different way, using a lower loading or concentration of the drug
in the dermal drug delivery composition according to the present
invention will result in a comparable flux to conventional
acrylic-based dermal drug delivery compositions. The concentration
of the drug incorporated in the dermal drug delivery composition
varies depending on the drug, the composition of the acrylic-based
polymers, the required flux or desired therapeutic effect and the
duration for which the dermal drug delivery composition is to
provide therapy.
[0089] For most drugs, the passage of the drugs through the skin or
mucosa will be the rate-limiting step in delivery. Thus, the amount
of drug and the rate of release is typically selected so as to
provide delivery characterized by a pseudo-zero order time
dependency for a prolonged period of time. The minimum amount of
drug in the system is selected based on the amount of drug which
passes through the skin or mucosa in the time span for which the
device is to provide therapy. Normally, the amount of drug in the
system can vary from about 0.1 to 40% by weight, preferably 0.5 to
20% by weight, and optimally 1-10% by weight, based on the total
dry weight of the dermal composition.
[0090] The dermal drug delivery composition can also contain one or
more agents known to accelerate the delivery of the drug through
the skin or mucosa. These agents have been referred to as
penetration enhancers, accelerants, adjuvants, and absorption
promoters, and are collectively referred to as "enhancers." Some
examples of enhancers are monohydric alcohols such as ethanol and
isopropyl, butyl and benzyl alcohols, or dihydric alcohols such as
ethylene glycol, diethylene glycol, or propylene glycol,
dipropylene glycol and trimethylene glycol, or polyhydric alcohols
such as glycerin, sorbitol and polyethylene glycol, which enhance
drug solubility; polyethylene glycol ethers of aliphatic alcohols
(such as cetyl, lauryl, oleyl and stearyl) including
polyoxyethylene (4) lauryl ether, polyoxyethylene (2) oleyl ether
and polyoxyethylene (10) oleyl ether commercially available under
the trademark BRIJ.RTM. 30, 93 and 97, respectively, from ICI
Americas, Inc., and others such as BRIJ.RTM. 35, 52, 56, 58, 72,
76, 78, 92, 96, 700 and 721; vegetable, animal and fish fats and
oils such as olive and castor oils, squalene, and lanolin; fatty
acids such as oleic, linoleic, and capric acid; fatty acid esters
such as propyl oleate, decyl oleate, isopropyl palmitate, glycol
palmitate, glycol laurate, dodecyl myristate, isopropyl myristate
and glycol stearate which enhance drug diffusibility; fatty acid
alcohols such as oleyl alcohol and its derivatives; fatty acid
amides such as oleamide and its derivatives; urea and urea
derivatives such as allantoin which affect the ability of keratin
to retain moisture; polar solvents such as
dimethyldecylphosphoxide, methyloctylsulfoxide,
dimethyllaurylamide, dodecylpyrrolidone, isosorbitol,
dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide and
dimethylformamide which affect keratin permeability; salicylic acid
which softens the keratin; amino acids which are penetration
assistants; benzyl nicotinate which is a hair follicle opener; and
higher molecular weight aliphatic surfactants such as lauryl
sulfate salts which change the surface state of the skin; and
esters of sorbitol and sorbitol anhydride such as polysorbate 20
commercially available under the trademark Tween.RTM. 20 from ICI
Americas, Inc., as well as other polysorbates such as 21, 40, 60,
61, 65, 80, 81, and 85. Other enhancers include enzymes, ascorbic
acid, panthenol, butylated hydroxytoluene, tocopherol, tocopherol
acetate, tocopheryl linoleate.
[0091] The dermal compositions of the present invention may also
contain one or more solvents or co-solvents. Such solvents and
co-solvents are those known in the art, and are non-toxic,
pharmaceutically acceptable substances, preferably liquids, which
do not substantially negatively affect the properties of the
polymer composition or solubility of the active agents at the
concentrations used. The solvent and co-solvent can be for the
active agent or for the polymers composition, or both. The solvent
is preferably a polyhydric alcohol or combination of polyhydric
alcohols.
[0092] The term "polyhydric alcohol" means any organic polyalcohol
and includes dipropylene glycol, propylene glycol, polyethylene
glycol, glycerin, butylene glycol, hexylene glycol,
polyoxyethylenes, polypropylene glycol, sorbitol, ethylene glycol,
and the like. Other suitable solvents include fatty acids such as
oleic acid, linoleic acid, capric acid and the like; polyethylene,
polypropylene and ethers of fatty acids, as well as fatty esters,
for example isopropyl myristate, or fatty alcohols. Further
suitable solvents include vegetable, animal and fish oils such as
castor oil, canola oil, safflower oil, cod liver oil, and lanolin,
mineral oil, lecithin, tocopherol and tocopheryl acetate, and other
non-toxic, non-volatile solvents commonly used in transdermal or
transmucosal compositions.
[0093] The above-mentioned polyhydric alcohols may include those
having 2 to 6 alcoholic hydroxyl groups. Such polyhydric alcohols
include glycols, triols and polyols having 4 to 6 alcoholic
hydroxyl groups. Typical of said glycols are glycols containing 2
to 6 carbon atoms, e.g. ethylene glycol, propylene glycol, butylene
glycol, polyethylene glycol (average molecular weight about
200-8,000, preferably about 200 to 6,000), etc. Examples of said
triols include glycerin, trimethylolpropane, etc. Said polyols are
exemplified by sorbitol (sorbit), polyvinylpyrrolidone, etc. These
polyhydric alcohols may be used either singularly or in combination
(preferably, of two or three). Thus, for example, glycerin or
dipropylene glycol alone, or a mixture of either glycerin or
dipropylene glycol with butylene glycol, can be employed.
[0094] Among those polyhydric alcohols, those which are low in
volatility such as dipropylene glycol, glycerin propylene glycol,
butylene glycol, and sorbitol are generally preferred.
[0095] Although the exact amount of the polyhdric alcohols, or
fatty acids, esters, ethers or alcohols, that may be used in the
dermal composition depends on the nature and amount of other
components, and therefore cannot be stated in general terms, the
proportion may range up to about 30% by weight, and preferably from
about 3% to about 15% by weight, and more preferably from about 5%
to about 10% by weight based on the dry weight of the dermal
composition.
[0096] Some drugs, for example nitroglycerin, nicotine and
selegiline, function as plasticizers in the polymer matrix because
they are readily soluble to a certain degree in the polymers
comprising the matrix. For drugs which are not readily soluble, or
for which a saturation or super-saturation of the drug is desired,
a co-solvent can be added. As used herein, "co-solvents" are
defined to include solvents and other agents which increase the
solubility of a drug in the polymer matrix. Co-solvents include
lecithin, retinol derivatives, tocopherol, dipropylene glycol,
triacetin, propylene glycol, saturated and unsaturated fatty acids,
mineral oil, silicone fluid, alcohols, butyl benzyl phthalate,
butylene glycol, glycerin and the like. The co-solvents are present
in an amount up to about 30% by weight, more preferably from about
2% to about 15% and more preferably from about 3% to about 10% by
weight, based on the dry weight of the dermal composition.
[0097] In addition to the above ingredients, there may also be
incorporated various pharmaceutically acceptable additives and
excipients available to those skilled in the art. These additives
include tackifying agents, such as aliphatic hydrocarbons, mixed
aliphatic and aromatic hydrocarbons, aromatic hydrocarbons,
substituted aromatic hydrocarbons, hydrogenated esters,
polyterpenes and hydrogenated wood rosins. Additional additives
include binders such as lecithin which "binds" the other
ingredients, or Theological agents (thickeners) containing silicone
such as fumed silica, reagent grade sand, precipitated silica,
amorphous silica, colloidal silicon dioxide, fused silica, silica
gel, quartz and particulate siliceous materials commercially
available as Syloid.RTM., Cabosil.RTM., Aerosil.RTM., and
Whitelite.RTM. for purposes of enhancing the uniform consistency or
continuous phase of the final composition. Other additives and
excipients include diluents, stabilizers, fillers, clays, buffering
agents, crosslinking agents, biocides, humectants, anti-irritants,
antioxidants, preservatives, flavoring agents, colorants, pigments
and the like. Such additives or excipients are typically used in
amounts up to 25% by weight, and preferably from about 0.1% to
about 10% by weight based on the drug weight of the dermal
composition.
[0098] The dermal compositions according to the present invention
can be prepared by mixing the two or more polymers, in powder or
liquid form, with the active agent, with or without the other
ingredients. When a pressure-sensitive adhesive is used, a
volatile, lower molecular weight solvent, for example an organic
solvent, is typically supplied with the pressure-sensitive
adhesive, for example, an acrylic adhesive. Typical liquids for use
as such volatile solvents, as distinct from emulsion (typically
aqueous) polymerization, either singularly or in combination with
other volatile and non-volatile solvents, are volatile polar and
non-polar organic liquids such as lower molecular weight alkanols
(e.g., isopropanol and ethanol), aromatics such as benzene
derivatives (e.g., xylene and toluene), lower molecular weight
alkanes and cycloalkanes (e.g., hexane, heptane and cyclohexane)
and alkanoic acid ester such as ethyl or butyl acetate.
[0099] Preferably, the mixture is cast at ambient temperature and
pressure followed by evaporation of any volatile solvents, for
example, by evaporation at slightly elevated temperatures, to form
the matrix. The non-volatile or higher boiling point solvents such
as the polyols used in the dermal composition remain therein.
[0100] An individual unit or device (often referred to as a
"delivery system") comprising the present invention can be prepared
in any manner known to those of skill in the art. An exemplary
general method of preparation is as follows:
[0101] 1. Appropriate amounts of the polymers, drugs and/or
pressure-sensitive adhesive(s), solvent(s), co-solvent(s),
enhancer(s), additive(s) and excipient(s) are combined and
thoroughly and uniformly mixed together in a vessel.
[0102] 2. The matrix is then transferred to a coating operation
where it is coated onto a release liner at a controlled specified
thickness. The coated composition is then passed through an oven in
order to drive off all volatile processing solvents.
[0103] 3. The composition coated on the release liner is then
brought into contact with a backing (layer) and wound into
rolls.
[0104] 4. Appropriate size and shape delivery systems are prepared
from the roll material and then pouched.
[0105] The order of steps, the amount of the ingredients, and the
amount and time of agitation or mixing may be important process
variables which will depend on the specific polymers, active
agents, solvents or co-solvents, enhancers and additives and
excipients used in the composition. These factors can be adjusted
by those skilled in the art, while keeping in mind the objects of
achieving a solubilized active agent and providing a uniform
product. It is believed that a number of other methods, for
example, other methods of coating backings that are well-known in
the art such as Mayer rod, gravure, knife-over roll, extrusion,
casting, calendaring and molding, or changing the order of certain
steps, can be carried out and will also give desirable results.
[0106] The backing layer, typically occlusive to water permeation,
serves to retain and maintain the bioadhesive composition disposed
thereon in a defined size and shape, prevent loss of the active
agent and/or enhancers to the environment, render the individual
unit or delivery system (in conjunction with the release liner)
transportable, and generally provide protection both prior to and
after application of the unit or system to a subject.
[0107] Suitable materials that can be used, singularly, in
combination, as laminates or as coextrusions, to form the backing
layer are well known in the art and include films or sheets of
polyethylene, polyester, polypropylene, polyurethane, polyolefin,
polyvinyl alcohol, polyvinyl chloride, polyvinylidene, polyamide,
vinyl acetate resins, BAREX.RTM., ethylene/vinyl acetate
copolymers, ethylene/ethylacrylate copolymers, metal-vapor
deposited films or sheets thereof, rubber sheets or films, expanded
synthetic resin sheets or films, non-woven fabrics, fabrics,
knitted fabrics, clothes, foils and papers.
[0108] The backing layer generally has a thickness in the range of
2 to 1000 micrometers and the matrix is generally disposed on the
backing layer in a thickness ranging from about 12 to 250
micrometers. The backing layer may be pigmented, for example
colored to either match with or conversely easily distinguish from
the site of application, and/or contain printing, labeling and
other means of identification and/or traceability of the unit or
system itself. The backing layer may further be made opaque or
substantially opaque (i.e., preventing light or certain energy
wavelengths from penetrating or passing through), such as by
metallization, fillers, inks, dyes and the like, for purposes of
protecting photosensitive active agents, such as ketoprofen, from
degradation and/or preventing photoallergic reactions or
irritations on the subject.
[0109] The release liner or peel strip is also intended to prevent
loss of the active agent and/or enhancers to the environment, and
render the individual unit or delivery system (in conjunction with
the backing layer) transportable, as well as generally protect the
dermal composition from contamination and the like until its
application to a subject. The release liner is typically also
impermeable and occlusive, and must be compatible with the
particular polymers or active agents so as not to interfere with
the composition's ultimate application and therapeutic effect.
[0110] Suitable materials that can be used, singularly, in
combination, as laminates or as coextrusions, to form the release
liner are also well known in the art and include any material
suitable for the backing layer. When the release liner is composed
of a material which typically does not readily release (i.e., is
not easily removed or separated from the bioadhesive composition),
for example paper, a coating material such as a silicone may be
applied to the release liner by any conventional means. Preferred
release liners are films commercially available from DuPont,
Wilmington, Del., under the trademark Mylar.RTM., and fluropolymer
(silicone) coated films commercially available from Rexam Release,
Oak Brook, Ill. under the trademark FL2000.RTM. and MRL2000.RTM.,
and from 3M Corporation, St. Paul, Minn. under the trademark
ScotchPak.RTM. 1022.
[0111] The configuration of an individual unit or delivery system
of the present invention can be in any shape, preferably a defined
geometric shape, and size (i.e., surface area of application) as is
necessary or desirable. The shape is achieved by conventional
techniques, for example, cutting or punching, and such techniques
are described, for example, in U.S. Pat. Nos. 5,032,207, 5,405,486
and 5,656,285. The intended site of application is an important
factor in determining the size and shape of an individual unit or
delivery system of the present invention, and can be adjusted by
those skilled in the art as is necessary to effect therapy.
Typically the size should not exceed 100 cm.sup.2. Preferred sizes
range from about 0.1 cm.sup.2 to about 60 cm.sup.2, and more
preferred range from about 1.5 cm.sup.2 to about 30 cm.sup.2, and
optimally from about 2.0 cm.sup.2 to about 10 cm.sup.2.
[0112] The dermal compositions of the present invention preferably
comprise the active agents solubilized therein, and attach directly
to the skin after removal of the release liner.
[0113] Alternatively, the dermal composition may be a multi-layer
delivery system that includes an adhesive layer which attaches
directly to the skin after removal of the release liner, and
wherein the active agent is initially solubilized or contained in
one or more other layers, and which other layers may or may not
comprise embodiments of the polymer compositions of the present
invention.
[0114] In yet another aspect, the dermal composition of the present
invention may be a reservoir-type delivery system which is attached
to the skin by means of peripheral or intermittent adhesive layers
or strips, and wherein the active agent is solubilized or contained
in one or more separate matrix reservoir or depot areas. The
peripheral or intermittent adhesive layers or strips may or may not
comprise embodiments of the polymer compositions of the present
invention.
EXAMPLES
[0115] In Examples 1-4 and Comparative Example 1, the effect of
acrylic functionality on haloperidol flux is determined.
Haloperidol and other non-polymer components of a dermal delivery
system are formulated in the indicated order to provide a
masterbatch.
[0116] Masterbatch (All Amounts Are in Grams)
2 1. toluene 17.55 2. ethanol 17.80 3. oleic acid 1.50 4.
dipropylene glycol 2.51 5. Brij 52 2.04 6. haloperidol 5.00 Total
46.40 grams.
[0117] To the masterbatch the following acrylic-based polymers are
added in the amounts indicated (all amounts are in grams of
solution, i.e., solids and solvents):
[0118] DT 87-2196 (carboxy functional acrylic PSA, 50% solids)
produced by National Starch, Inc.
[0119] HRJ 4483 (non-functional acrylic PSA, 50% solids)--produced
by Schenectady, International, Inc.
3 TABLE 2 Component (grams) Comp. Ex. 1 Ex. 1 Ex. 2 Ex. 3 Ex. 4
Master-batch 4.63 4.63 4.63 4.65 4.64 DT 87-2196 7.92 6.88 5.87 4.9
3.85 HRJ 4483 -- 1.05 2.05 2.98 4.01
[0120] The blends are drawn down to 20 mil thickness on a silicone
coated release liner using a Gardner fixed gap applicator. The
coated release liner is dried at 5 minutes at room temperature and
5 minutes at 85.degree. C. in a convection oven. The coated release
liner is then laminated to a 3M 1012 backing layer.
[0121] The effect of the acrylic functionality on cumulative
haloperidol flux is shown in FIG. 1. For the purposes of this
graph, only Examples 2 and 4 and Comparative Example 1 are plotted.
As the graph clearly indicates, increasing the amount of
non-functional acrylic in the dermal composition, reduces the
solubility of the haloperidol resulting in a greater thermodynamic
driving force. As a result of the increased thermodynamic driving
force, the flux of the haloperidol across the skin increases.
[0122] In Examples 5-8 and Comparative Example 2, the effect of
acrylic functionality on nicotine flux was determined. Nicotine was
combined with the following acrylic polymers in the order and
amounts shown. All amounts are shown in grams:
[0123] Duro-Tak 87-2852 (carboxy functional acrylic PSA, 34%
solids)--produced by National Starch, Inc.
[0124] Duro-Tak 87-2097 (non-functional acrylic PSA, 42.5%
solids)--produced National Starch, Inc.
[0125] HRJ 4483 (see Examples 1-4).
4TABLE 3 Component (grams) Comp. Ex. 2 Ex. 5 Ex. 6 Ex. 7 Ex. 8 DT
87-2852 13.99 10.25 6.63 2.93 6.64 DT 87-2097 -- -- -- -- 6.31 HRJ
4483 -- 2.51 5.01 7.53 -- Nicotine 0.25 0.25 0.25 0.25 0.26
[0126] The blends were prepared according to Examples 1-4, except
that the coated release liner was dried in a convection oven at
5.degree. C. for 5 minutes. The effect of the acrylic functionality
on nicotine flux is shown in FIG. 2. For purposes of this graph,
only Examples 5-7 and Comparative Example 2 were plotted. As the
graph indicates, increasing the amount of a non-functional acrylic
results in a increasing flux.
[0127] In Examples 9-14 and Comparative Example 3, the effect of
acrylic functionality on clonidine flux was determined. Clonidine
was combined with the following acrylic polymers in the order and
amounts shown. All amounts are shown in grams:
[0128] Duro-Tak 87-2852 (carboxy functional acrylic PSA, 34 wt %
solids)--produced by National Starch, Inc.
[0129] Duro-Tak 87-2287 (hydroxy functional vinyl acetate acrylic
PSA, 32 wt % solids)
5TABLE 4 Component Ex. (grams) Comp. Ex. 3 Ex. 9 10 Ex. 11 Ex. 12
Ex. 13 Ex. 14 DT 87-2852 14.53 11.76 8.82 5.88 2.94 1.47 -- DT
87-2287 -- 2.00 5.13 8.25 11.38 12.94 14.53 Clonidine Base 0.36
0.36 0.36 0.36 0.36 0.36 0.36
[0130] The blends were drawn down to 15 mil thickness on a silicone
coated release liner using a Gardner fixed gap applicator. The
coated release liner was dried at 5 minutes at room temperature and
5 minutes at 85.degree. C. in a convection oven. The coated release
liner was then laminated to a 3M 1012 backing layer. The effect of
different acrylic functionality on clonidine flux is shown in FIG.
3. For clarity purposes, only Examples 9-11 and Comparative Example
3 were plotted. As FIG. 3 clearly indicates, increasing the amount
of hydroxy functional acrylic in which clonidine has a lower
solubility, increases the flux of the clonidine.
[0131] In Examples 15-20, the effect of acrylic functionality on
scopolamine flux was determined. 0.6 grams of scopolamine, 0.3
grams of oleic acid and 0.2 grams of dipropylene glycol were
combined with the following acrylic polymers in the order and
amounts shown. All amounts are shown in grams:
[0132] Duro-Tak 87-2852 (carboxy functional acrylic PSA, 34 wt %
solids)--produced by National Starch, Inc.
[0133] Duro-Tak 87-2097 (non-functional acrylic PSA, 42.5%
solids)--produced National Starch, Inc.
[0134] Duro-Tak 87-2296 (carboxy functional, crosslinked acrylic
PSA, 45 wt % solids)--produced by National Starch, Inc.
6TABLE 5 Component (grams) Ex. 15 Ex. 16 Ex. 17 Ex. 18 Ex. 19 Ex.
20 DT 87-2852 -- -- -- 3.09 6.18 9.26 DT 87-2097 7.88 5.25 2.63
7.88 5.25 2.63 DT 87-2296 2.33 4.67 7.0 -- -- -- Scopolamine 0.6
0.6 0.6 0.6 0.6 0.6 Base Oleic Acid 0.3 0.3 0.3 0.3 0.3 0.3
Dipropylene 0.2 0.2 0.2 0.2 0.2 0.2 glycol
[0135] The blends were drawn down to 15 mil thickness on a silicone
coated release liner using a Gardner fixed gap applicator. The
coated release liner was dried at 5 minutes at room temperature and
5 minutes at 85.degree. C. in a convection oven. The coated release
liner was then laminated to a 3M 1012.RTM. or a Dow Chemical
Saranex.RTM. 2050 backing layer. The effect of different acrylic
functionality on scopolamine flux is shown in FIG. 4, along with a
commercially available product Transderm Scop.RTM. available from
Ciba Geigy, Inc. FIG. 4 clearly indicates that increasing the
amount of carboxy functional acrylic decreases the flux of the
scopolamine. FIG. 4 also shows the effect that a crosslinked versus
non-crosslinked acrylic has on solubility and flux of a drug.
[0136] In Examples 21-25, the effect of acrylic functionality on
d-amphetamine flux was determined. D-amphetamine was combined with
the following acrylic polymers in the order shown. All amounts are
shown as a percentage of the finished composition:
[0137] PSA 1 (non-functional acrylic PSA, including 80% methyl
acrylate and 20% 2-ethylhexyl acrylate)
[0138] PSA 9 (carboxy functional acrylic PSA, including 32%
2-ethylhexylacrylate, 65% butyl acrylate and 3% acrylic acid)
7TABLE 6 Component Ex. 21 Ex. 22 Ex. 23 Ex. 24 Ex. 25 PSA 1 0 30 45
60 90 PSA 9 90 60 45 30 0 d-Amphetamine Base 10 10 10 10 10
[0139] The blends were formed according to the previous examples.
The effect of different acrylic functionality on d-amphetamine flux
is shown in FIG. 5.
[0140] In Examples 26-31, the effect of acrylic functionality on
d-amphetamine flux was determined. D-amphetamine was combined with
the following acrylic polymers in the order shown. All amounts are
shown as a percentage of the finished composition:
[0141] Non-functional PSA
[0142] PSA 1 (non-functional acrylic PSA, including 80% methyl
acrylate and 20% 2-ethylhexyl acrylate)
[0143] PSA 10 (non-functional acrylic PSA, including 50% methyl
acrylate and 50% 2-ethylhexyl acrylate)
[0144] PSA 11 (non-functional acrylic PSA, including 30% methyl
acrylate and 70% 2-ethylhexyl acrylate)
[0145] Functional PSA
[0146] PSA 9 (carboxy functional acrylic PSA, including 32%
2-ethylhexylacrylate, 65% butyl acrylate and 3% acrylic acid)
8TABLE 7 Component Ex. 26 Ex. 27 Ex. 28 Ex. 29 Ex. 30 Ex. 31 PSA 1
30 60 -- -- -- -- PSA 10 -- -- 30 60 -- -- PSA 11 -- -- -- -- 30 60
PSA 9 60 30 60 30 60 30 d-Amphetamine Base 10 10 10 10 10 10
[0147] The blends were formed according to the previous examples.
The effect of different acrylic functionality on d-amphetamine flux
is shown in FIG. 6.
[0148] Other embodiments of the invention will be apparent to those
skilled in the art from consideration of the specification and
practice of the invention disclosed herein. It is intended that the
specification be considered as exemplary only, with the true scope
and spirit of the invention being indicated by the following
claims.
* * * * *