U.S. patent application number 11/245180 was filed with the patent office on 2006-04-13 for transdermal drug delivery device including an occlusive backing.
This patent application is currently assigned to Noven Pharmaceuticals, Inc.. Invention is credited to David Kanios, Juan A. Mantelle, Viet Nguyen.
Application Number | 20060078604 11/245180 |
Document ID | / |
Family ID | 36203400 |
Filed Date | 2006-04-13 |
United States Patent
Application |
20060078604 |
Kind Code |
A1 |
Kanios; David ; et
al. |
April 13, 2006 |
Transdermal drug delivery device including an occlusive backing
Abstract
A transdermal drug delivery system for the topical application
of one or more active agents contained in one or more polymeric
and/or adhesive carrier layers, proximate to a non-drug containing
polymeric backing layer which can control the delivery rate and
profile of the transdermal drug delivery system by adjusting the
moisture vapor transmission rate of the polymeric backing
layer.
Inventors: |
Kanios; David; (Miami,
FL) ; Mantelle; Juan A.; (Miami, FL) ; Nguyen;
Viet; (Miami, FL) |
Correspondence
Address: |
DICKSTEIN SHAPIRO MORIN & OSHINSKY LLP
2101 L Street, NW
Washington
DC
20037
US
|
Assignee: |
Noven Pharmaceuticals, Inc.
|
Family ID: |
36203400 |
Appl. No.: |
11/245180 |
Filed: |
October 7, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60616861 |
Oct 8, 2004 |
|
|
|
Current U.S.
Class: |
424/449 |
Current CPC
Class: |
A61K 47/32 20130101;
A61P 29/00 20180101; A61P 23/00 20180101; A61K 9/7061 20130101;
A61P 9/12 20180101; A61K 9/7053 20130101; A61K 31/4168 20130101;
A61K 47/34 20130101; A61P 25/00 20180101; A61K 9/7069 20130101 |
Class at
Publication: |
424/449 |
International
Class: |
A61K 9/70 20060101
A61K009/70 |
Claims
1. A transdermal drug delivery system comprising: (a) a pressure
sensitive adhesive (b) a therapeutically effective amount at least
one drug for transdermal drug delivery, and (c) an occlusive
backing layer, wherein said backing being formed from at least one
layer and having a high moisture vapor transmission rate.
2. The transdermal drug delivery system according to claim 1,
wherein the drug is selected from the group consisting of
amphetamine, d-amphetamine, l-amphetamine, d,l-amphetamine,
methaphetamine, prilocalne, benzocaine, butacaine, butamben,
butanilicaine, corticaine, lidocaine, memantine, pilocarpine,
cyclobenzaprine, paroxetine, fluoxetine, duloxetine, imipramine,
decipramine, doxeprin, nortriptylene, protriptylene, bupropion,
azelastine, chlorphenamine, bisoprolol, pheniramine, alprazolam,
captopril, clonidine, clonazepam, enalapril, ramipril, haloperidol,
ketoprofen, loratadine, methimazole, methylphenidate, methyl
testosterone, nicotine, nitroglycerin, pramipexole, ropinirole,
hydromorphone, scopolamine, testosterone, estradiol,
methamphetamine, frovatriptan and phentermine.
3. The transdermal drug delivery system according to claim 1,
wherein the drug includes clonidine.
4. The transdermal drug delivery system according to claim 1,
wherein the drug is present in said transdermal drug delivery
system from about 0.1% to about 50% by weight.
5. The transdermal drug delivery system according to claim 1,
wherein the drug is present in said transdermal drug delivery
system from about 0.3% to 30% by weight.
6. The transdermal drug delivery system according to claim 1,
wherein the drug is present in said transdermal drug delivery
system from about 0.5% to about 15% by weight.
7. The transdermal drug delivery system according to claim 1,
wherein the drug is present in said transdermal drug delivery
system from about 1% to about 10% by weight.
8. The transdermal drug delivery system according to claim 1,
wherein the backing layer has a thickness of from about 0.2 mm to
about 3 mm.
9. The transdermal drug delivery system according to claim 1,
wherein said backing layer has a moisture vapor transmission rate
of from about 0.5 to about 1500 g/m.sup.2/24 hrs.
10. The transdermal drug delivery system according to claim 1,
wherein said backing layer has a moisture vapor transmission rate
of from about 0.5 to about 1000 g/m.sup.2/24 hrs.
11. The transdermal drug delivery system according to claim 1,
wherein said backing layer has a moisture vapor transmission rate
of from about 1.5 to about 500 g/m.sup.2/24 hrs.
12. The transdermal drug delivery system according to claim 1,
wherein said backing layer has a moisture vapor transmission rate
of from 10 to about 100 g/m.sup.2/24 hrs.
13. The transdermal drug delivery system according to claim 1,
wherein said backing layer is formed of a plurality of layers.
14. The transdermal drug delivery system according to claim 13,
wherein a first layer of said backing layer is formed from a
material selected from the group consisting of acrylonitrile,
cellulose acetate, polycarbonate, ethylene vinyl acetate, ethylene
methyl acrylate, polyester, polyethylene, polypropylene,
polystyrene, polyurethane, polyvinyl alcohol, ethylene vinyl
alcohol, polyamides, polyvinylidene chloride and polyvinyl
chloride.
15. The transdermal drug delivery system according to claim 13,
wherein said backing layer further comprises a second layer having
a greater water vapor transmission rate than said first layer.
16. The transdermal drug delivery system according to claim 15,
wherein said second layer is formed from cellulose acetate, nylon,
polycarbonate, acrylonitrile, polystyrene, polyurethane and
polyvinyl alcohol, or copolymers or multipolymers of these plastics
with additional monomers.
17. The transdermal drug delivery system according to claim 15,
wherein said second layer is formed from polyurethane.
18. The transdermal drug delivery system according to claim 1,
wherein the pressure sensitive adhesive is a rubber based adhesive
which is present in an amount from 5% to 97% by weight of said
transdermal drug delivery system.
19. The transdermal drug delivery system according to claim 18,
wherein said pressure sensitive adhesive includes a rubber adhesive
selected from the group consisting of natural and synthetic
polyisoprene, polybutylene, polyisobutylene, styrene based
polymers, styrene block copolymers, butadiene based polymers,
styrene/butadiene polymers, styrene-isoprene-styrene block
copolymers, hydrocarbon polymers, halogen-containing polymers and
polysiloxanes.
20. The transdermal drug delivery system according to claim 18,
wherein said rubber adhesive includes polyisobutylene.
21. The transdermal drug delivery system according to claim 1,
wherein said pressure sensitive adhesive includes a polysiloxane
polymer.
22. The transdermal drug delivery system according to claim 1,
wherein said pressure sensitive adhesive includes at least one
acrylic-based polymer.
23. The transdermal drug delivery system according to claim 22,
wherein said acrylic-based polymer includes at least 50% by weight
of an acrylate or alkyl acrylate monomer, from 0 to 20% of a
functional monomer copolymerizable with the acrylate or alkyl
acrylate monomer, and from 0 to 40% of other monomers.
24. The transdermal drug delivery composition according to claim
22, wherein said pressure sensitive adhesive is a blend of at least
one acrylic-based polymer and at least one second polymer selected
from the group consisting of silicone-based polymers, rubbers,
gums, polyisobutylenes, polyvinylethers, polyurethanes, styrene
block copolymers, styrene/butadiene polymers, polyether block amide
copolymers, ethylene/vinyl acetate copolymers, vinyl acetate based
adhesives, and bioadhesives.
25. The transdermal drug delivery composition according to claim
24, wherein said at least one second polymer includes a
silicone-based polymer.
26. The transdermal drug delivery composition according to claim
22, wherein the acrylic-based polymer which is present from about
2% to about 95% of the total dry weight of the of the
composition.
27. The transdermal drug delivery composition according to claim 1,
wherein said pressure sensitive adhesive includes: (i) a first
acrylic-based polymer having a first functionality and a first
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.
28. A transdermal drug delivery system comprising: (a) a pressure
sensitive adhesive comprising (i) a pressure sensitive adhesive
present in an amount from 5% to 97% by weight of said transdermal
drug delivery system, (b) 0.1% to about 50% by weight of at least
one drug for transdermal drug delivery, and (c) an occlusive
backing layer, wherein said backing being formed from at least one
layer and having a moisture vapor transmission rate of from about
0.5 to about 1500 g/m.sup.2/24 hrs.
29. The transdermal drug delivery system according to claim 28,
wherein the drug is selected from the group consisting of
amphetamine, d-amphetamine, l-amphetamine, d,l-amphetamine,
methaphetamine, prilocalne, benzocaine, butacaine, butamben,
butanilicaine, corticaine, lidocaine, memantine, pilocarpine,
cyclobenzaprine, paroxetine, fluoxetine, duloxetine, imipramine,
decipramine, doxeprin, nortriptylene, protriptylene, bupropion,
azelastine, chlorphenamine, bisoprolol, pheniramine, alprazolam,
captopril, clonidine, clonazepam, enalapril, ramipril, haloperidol,
ketoprofen, loratadine, methimazole, methylphenidate, methyl
testosterone, nicotine, nitroglycerin, pramipexole, ropinirole,
hydromorphone, scopolamine, testosterone, estradiol,
methamphetamine, frovatriptan, and phentermine.
30. The transdermal drug delivery system according to claim 28,
wherein the drug includes clonidine.
31. The transdermal drug delivery system according to claim 28,
wherein the drug is present in said transdermal drug delivery
system from about 1% to about 10% by weight.
32. The transdermal drug delivery system according to claim 28,
wherein the backing layer has a thickness of from about 0.2 mm to
about 3 mm.
33. The transdermal drug delivery system according to claim 28,
wherein said backing layer has a moisture vapor transmission rate
of from about 0.5 to about 1000 g/m.sup.2/24 hrs.
34. The transdermal drug delivery system according to claim 28,
wherein said backing layer has a moisture vapor transmission rate
of from about 1.5 to about 500 g/m.sup.2/24 hrs.
35. The transdermal drug delivery system according to claim 28,
wherein said backing layer has a moisture vapor transmission rate
of from 10 to about 100 g/m.sup.2/24 hrs.
36. The transdermal drug delivery system according to claim 28,
wherein said backing layer is formed of a plurality of layers.
37. The transdermal drug delivery system according to claim 36,
wherein a first layer of said backing layer is formed from a
material selected from the group consisting of acrylonitrile,
cellulose acetate, polycarbonate, ethylene vinyl acetate, ethylene
methyl acrylate, polyester, polyethylene, polypropylene,
polystyrene, polyurethane, polyvinyl alcohol, ethylene vinyl
alcohol, polyamides, polyvinylidene chloride and polyvinyl
chloride.
38. The transdermal drug delivery system according to claim 36,
wherein said backing layer further comprises a second layer having
a greater water vapor transmission rate than said first layer.
39. The transdermal drug delivery system according to claim 38,
wherein said second layer is formed from cellulose acetate, nylon,
polycarbonate, acrylonitrile, polystyrene, polyurethane and
polyvinyl alcohol, or copolymers or multipolymers of these plastics
with additional monomers.
40. The transdermal drug delivery system according to claim 39,
wherein said second layer is formed from polyurethane.
41. The transdermal drug delivery system according to claim 28,
wherein the pressure sensitive adhesive is a rubber based adhesive
which is present in an amount from 5% to 97% by weight of said
transdermal drug delivery system.
42. The transdermal drug delivery system according to claim 41,
wherein said pressure sensitive adhesive includes a rubber adhesive
selected from the group consisting of natural and synthetic
polyisoprene, polybutylene, polyisobutylene, styrene based
polymers, styrene block copolymers, butadiene based polymers,
styrene/butadiene polymers, styrene-isoprene-styrene block
copolymers, hydrocarbon polymers, halogen-containing polymers and
polysiloxanes.
43. The transdermal drug delivery system according to claim 41,
wherein said rubber adhesive includes polyisobutylene.
44. The transdermal drug delivery system according to claim 28,
wherein said pressure sensitive adhesive includes a polysiloxane
polymer.
45. The transdermal drug delivery system according to claim 28,
wherein said pressure sensitive adhesive includes at least one
acrylic-based polymer.
46. The transdermal drug delivery system according to claim 45,
wherein said acrylic-based polymer includes at least 50% by weight
of an acrylate or alkyl acrylate monomer, from 0 to 20% of a
functional monomer copolymerizable with the acrylate or alkyl
acrylate monomer, and from 0 to 40% of other monomers.
47. The transdermal drug delivery composition according to claim
45, wherein said pressure sensitive adhesive is a blend of at least
one acrylic-based polymer and at least one second polymer selected
from the group consisting of silicone-based polymers, rubbers,
gums, polyisobutylenes, polyvinylethers, polyurethanes, styrene
block copolymers, styrene/butadiene polymers, polyether block amide
copolymers, ethylene/vinyl acetate copolymers, vinyl acetate based
adhesives, and bioadhesives.
48. The transdermal drug delivery composition according to claim
47, wherein said at least one second polymer includes a
silicone-based polymer.
49. The transdermal drug delivery composition according to claim
45, wherein the acrylic-based polymer which is present from about
2% to about 95% of the total dry weight of the of the
composition.
50. The transdermal drug delivery composition according to claim
28, wherein said pressure sensitive adhesive includes: (i) a first
acrylic-based polymer having a first functionality and a first
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.
51. A method for transdermally delivering a drug to a user in need
thereof comprising administering the transdermal drug delivery
device according to claim 1 to said user.
52. A method for transdermally delivering a drug to a user in need
thereof comprising administering the transdermal drug delivery
device according to claim 28 to said user.
53. A method of producing the transdermal drug delivery composition
according to claim 1, comprising the steps of: thoroughly and
uniformly mixing together in a vessel appropriate amounts of the
drug(s), polymer(s), adhesive(s), solvent(s), co-solvent(s),
enhancer(s), additive(s) and/or excipient(s) to form said adhesive
coating layer; casting said adhesive coating layer onto a backing
film having a high moisture vapor transmission rate and exposing
said cast adhesive layer to elevated temperatures to remove the
volatile processing solvents; and applying a release liner to the
surface opposite the backing film to form the transdermal drug
delivery composition.
Description
[0001] This application claims the benefit of provisional
application 60/616,861 filed Oct. 8, 2004, which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates generally to transdermal drug
delivery systems, and more particularly to pharmaceutically
acceptable adhesive matrix compositions. The invention additionally
relates to transdermal drug delivery systems providing acceptable
drug release profiles for an extended period of time of up to seven
days or longer.
[0003] In particular, the present invention is directed to a
transdermal drug delivery system for the topical application of one
or more active agents contained in one or more polymeric and/or
adhesive carrier layers, proximate to a non-drug containing
polymeric backing layer. The backing layer can be processed or
manufactured separately from the polymeric and/or adhesive drug
carrier layer(s) to prevent or minimize loss of drug or other
system components, and combined prior to topical application. In
the alternative, the backing device can be processed together with
the polymeric and/or adhesive drug carrier layer(s). The drug
delivery rate and profile can be controlled by adjusting certain
characteristics of the polymeric backing layer.
BACKGROUND OF THE INVENTION
[0004] The use of transdermal drug delivery systems to topically
administer an active agent is well known. These systems incorporate
the active agent into a carrier composition, such as a polymeric
and/or pressure-sensitive adhesive composition, from which the
active agent is delivered through the skin or mucosa of the
user.
[0005] Many factors influence the design and performance of such
drug delivery devices, such as the individual drugs themselves, the
physical/chemical characteristics of the system's components and
the performance/behavior relative to other system components once
combined, external/environmental conditions during manufacturing
and storage thereafter, the properties of the topical site of
application, the desired rate of drug delivery and onset, the drug
delivery profile, and the intended duration of delivery. Cost,
appearance, size and ease of manufacturing are also important
considerations.
[0006] Active-ingredient-containing transdermal drug delivery
systems ("patches") are essentially divided into two major
technical systems: reservoir systems and matrix systems. The
present invention relates to matrix systems where the active
ingredient(s) are embedded in a semi-solid matrix made up of a
single polymer or a blend of polymers.
[0007] Both types of devices employ a backing layer that forms the
protective outer surface of the finished transdermal system and
which is exposed to the environment during use. A release liner or
protective layer that forms the inner surface covers the polymeric
adhesive which is employed for affixing the system to the skin or
mucosa of a user. The release liner or protective layer is removed
prior to application, exposing the adhesive, typically a
pressure-sensitive adhesive.
[0008] In the "classic" reservoir-type device, the active agent is
typically dissolved or dispersed in a carrier to yield a non-finite
carrier form, such as, for example, a fluid or gel. In the
reservoir-type device, the active agent is generally kept separate
from the adhesive. The device has a pocket or "reservoir" which
physically serves to hold the active agent and carrier, and which
is formed in or by a backing layer. A peripheral adhesive layer is
then used to affix the device to the user.
[0009] The reservoir-type devices have a number of disadvantages
including a non-uniform drug release profile where a high dose of
drug is initially released upon application to the user, often
described as a "burst effect." This burst or high initial release
of drug then drops off after a period of time to a rate that
necessary to achieve a therapeutically effective amount. Drug
delivery according to this profile is generally described as first
order release.
[0010] While classic reservoir-type devices are still in use today,
the term reservoir is being used interchangeably herein with
matrix-type devices which still rely upon a separate adhesive means
used to affix the device to the user.
[0011] In a matrix-type device, the active agent is dissolved or
dispersed in a carrier that typically is in a finite carrier form.
The carrier form can be self-adhesive or non-adhesive. Non-adhesive
matrix-type devices, that is, those which still rely on a separate
adhesive means to affix the device to the user, employ a drug
permeable adhesive layer (often referred to as an "in-line
adhesive" since the drug must pass through this layer) applied over
the drug matrix carrier layer. To better control the release rate
of the drug, the non-adhesive matrix-type devices often employ one
or more additional drug permeable layers such as, for example, rate
controlling membranes. The non-adhesive matrix-type devices often
contain excipients, such as drug delivery enhancers, to help
control the release rate. These devices are often referred to as
multilayer or multilaminate.
[0012] In a "monolithic" or "monolayer" matrix-type device, the
active agent is typically solubilized or homogenously blended in an
adhesive carrier composition, typically a pressure-sensitive
adhesive or bioadhesive, which functions as both the drug carrier
and the means of affixing the system to the skin or mucosa. Such
devices, commonly referred to as drug-in-adhesive devices, are
described, for example, in U.S. Pat. Nos. 4,994,267; 5,446,070;
5,474,783 and 5,656,286, all of which are assigned to Noven
Pharmaceuticals, Inc., Miami, Fla. and herein incorporated by
reference.
[0013] While matrix-type devices, especially drug-in-adhesive
devices, achieve more uniform and controlled drug deliver rates
over longer periods of time, most transdermal systems remain
subject to a higher initial drug release than is required to
achieve therapeutic efficacy. For many drugs and/or therapeutic
situations, it would be advantageous to eliminate or suppress this
higher initial release and achieve a "steady state" (zero order)
release profile which uniformly delivers a therapeutically
effective amount of drug over the extended duration of device's
desired use, preferably up to 7 days or more.
[0014] The high initial blood level concentration of certain drugs
may cause adverse or undesired effects, or create toxicity
concerns, thereby limiting the use of transdermal administration.
In other instances, the higher initial blood level concentration
may reduce the amount of drug required for treatment to the point
of risking under dosing, or the higher initial blood level
concentration may make it impractical to increase the duration of
the device's application while retaining therapeutic effectiveness.
Reducing the frequency of replacing the transdermal drug delivery
system would increase user compliance, reduce any lag or drop off
in efficacious blood levels, and reduce the amount of drug required
for treatment (also provided by reducing the higher initial blood
level associated with the higher release rate).
[0015] Drug concentration in transdermal delivery systems can vary
widely depending on the drug and polymers used. Low drug
concentrations in the adhesive can result in difficulties in
achieving an acceptable delivery rate of the medicament, preferably
one approximating zero order kinetics. High drug concentrations, on
the other hand, frequently affect the adhesion properties of the
adhesives, and tend to promote unwanted crystallization.
[0016] Simple diffusion models for permeation of drugs through the
skin suggest that permeation rates are concentration dependent,
that is, dependent on both the amount and the degree of drug within
the pressure-sensitive adhesive composition. Some adhesives, such
as, for example, polyacrylate adhesives have a high affinity for
many drugs and thus tend to solubilize higher concentrations of
drug than do, for example, rubber adhesives. However, the use of
polyacylates alone as the adhesive is not without its drawbacks as
polyacrylate adhesives, for example, may tend to cause skin
irritation, especially when the transdermal device is used for
extended periods of time.
[0017] Various transdermal drug delivery systems have been
described in the literature. For example, U.S. Pat. No. 4,559,222
describes a multi-layer non-adhesive matrix-type device having a
reservoir layer which comprises mineral oil, colloidal silicon
dioxide, a polyisobutylene adhesive and a drug, which may be
clonidine, at a concentration greater than saturation. The system
includes a drug release rate controlling layer through which the
drug may diffuse at a known rate, an adhesive layer, which may also
contain a loading of drug, and a protective strippable coating.
[0018] U.S. Pat. No. 5,762,952 describes a system comprising a
self-crosslinking acrylate adhesive into which a drug, such as
clonidine, is incorporated together with auxiliaries, such as
solvents or absorption promoters, that are volatile at relatively
high temperatures. The patent discusses that the crosslinked
acrylate adhesive is important to increase the consistency of the
adhesive substance and to incorporate either a large amount of the
active drug or a large amount of an inactive solubilizin
[0019] Thus, it would therefore be desirable to provide a system
for use with many types of drugs, in which the permeation rate and
profile can be easily adjusted by employing a backing layer to
modulate flux of drug through the skin or mucosa and while
providing an active agent-containing carrier composition formulated
in a simple and cost effective manner. It would be further
advantageous to avoid drug loss encountered in manufacturing
methods requiring high temperature heating or drying after addition
of a drug to the carrier composition.
SUMMARY OF THE INVENTION
[0020] Based upon the foregoing, it is an object of the present
invention to overcome the limitations of the prior transdermal
systems, and to provide a transdermal drug delivery system which
allows selective modulation of drug permeation and delivery rates
and profiles.
[0021] Another object is to provide a transdermal system, which is
simple and inexpensive to manufacture. The present invention
provides a transdermal drug delivery system for the topical
application of one or more active agents contained in one or more
polymeric and/or adhesive carrier layers, proximate to a non-drug
containing polymeric backing layer which is manufactured to
optimize drug loading while providing desirable adhesion to skin or
mucosa as well as providing modulation of the drug delivery and
profile. The polymeric backing layer is designed to provide control
of permeation rate, onset and profile of the active agent from the
system.
[0022] The transdermal delivery device may comprise at least one
layer formed of a single polymer or a blend of polymers to serve as
a pressure-sensitive adhesive composition for applying the system
to the dermis.
[0023] The invention is also directed to compositions and methods
of controlling drug delivery rates, onset and profiles of at least
one active agent in a transdermal delivery system, comprising
selecting a specific a non-drug containing polymeric backing layer
having specific physical and/or chemical characteristics. The drug
carrier composition may be comprised of (a) one or more
acrylic-based polymers having one or more functionality or (b) one
or more silicone-based polymers having one or more silanol contents
(capping) and/or resin to polymer ratios, alone or in combination,
and are present in proportions to provide a desired solubility for
the drug. By selectively tailoring the moisture vapor transmission
rate of the backing layer, drug delivery, onset and profiles can be
achieved.
[0024] For a better understanding of the present invention,
together with other and further objects thereof, reference is made
to the following description, taken in conjunction with the
accompanying drawings, and its scope will be pointed out in the
appending claims. Further embodiments of the invention include
those described in the detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 shows a schematic cross-sectional view of a
transdermal delivery device according to an embodiment of the
invention prior to use.
[0026] FIG. 2 is a graphic representation of the effects on drug
delivery of clonidine in a transdermal delivery device with varying
backing layers.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] The foregoing and other objects are achieved by this
invention which provides a transdermal drug delivery system to
provide an adhesive matrix composition which effectively delivers
drugs to a user over an extended period of time.
[0028] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the invention pertains.
[0029] As used herein, the term "pressure-sensitive adhesive"
refers to a viscoelastic material which adheres almost
instantaneously to most substrates with the application of very
slight pressure and remains permanently tacky. A polymer is a
pressure-sensitive adhesive within the meaning of the term as used
herein if it has the properties of a pressure-sensitive adhesive
per se or functions as a pressure-sensitive adhesive by admixture
with tackifiers, plasticizers or other additives. The term
pressure-sensitive adhesive also includes mixtures of different
polymers and mixtures of polymers, such as polyisobutylenes (PIB)
of different molecular weights, the resultant mixtures being a
pressure-sensitive adhesive. In the last case, the polymers of
lower molecular weight in the mixture are not considered to be
"tackifiers," the term "tackifier" being reserved for additives
which differ other than in molecular weight from the polymers to
which they are added.
[0030] The term "topical" or "topically" is used herein in its
conventional meaning as referring to direct contact with an
anatomical site or surface area on a mammal including skin, teeth,
nails and mucosa.
[0031] The term "mucosa" as used herein means any moist anatomical
membrane or surface on a mammal such as oral, buccal, vaginal,
rectal, nasal or ophthalmic surfaces.
[0032] The term "transdermal" as used herein means passage into
and/or through skin or mucosa for localized or systemic delivery of
an active agent.
[0033] 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.
[0034] The term "adhesive" means a substance, inorganic or organic,
natural or synthetic that is capable of surface attachment at the
intended topical application site by itself or functions as an
adhesive by admixture with tackifiers, plasticizers, cross-linking
agents or other additives.
[0035] In the most preferred embodiment, the carrier of the present
invention is a "pressure-sensitive adhesive" which 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, plasticizers, cross-linking agents or
other additives.
[0036] 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 may
include the acrylic-based polymers described herein and can
optionally include other polymers discussed more fully below.
[0037] The term "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.
[0038] 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.
[0039] As used herein, "functional monomers or groups," are monomer
units in 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.
[0040] As used herein "non-functional acrylic-based polymer" is
defined as an acrylic-based polymer that 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.
[0041] The term "carrier" as used herein refers to any non-aqueous
material known in the art as suitable for transdermal drug delivery
administration, and includes any polymeric material into which an
active agent may be solubilized in combination or admixture with
the other ingredients of the composition. The polymeric materials
preferably comprise adhesives and, in particular,
pressure-sensitive adhesives. The carrier material is typically
used in an amount of about 40% to about 90%, and preferably from
about 50% to about 80%, by weight based on the dry weight of the
total carrier composition.
[0042] The term "carrier composition" may also refer to enhancers,
solvents, co-solvents and other types of addictives useful for
facilitating transdermal drug delivery.
[0043] The carrier compositions of the present invention can also
contain one or more non-aqueous solvents and/or co-solvents. Such
solvents and/or co-solvents are those known in the art, and are
non-toxic, pharmaceutically acceptable substances, preferably
non-aqueous liquids, which do not substantially negatively affect
the adhesive properties or the solubility of the active agents at
the concentrations used. The solvent and/or co-solvent can be for
the active agent or for the carrier materials, or both.
[0044] Suitable solvents include volatile processing liquids such
as alcohols (e.g., methyl, ethyl, isopropyl alcohols and methylene
chloride); ketones (e.g., acetone); aromatic hydrocarbons such as
benzene derivatives (e.g., xylenes and toluenes); lower molecular
weight alkanes and cycloalkanes (e.g., hexanes, heptanes and
cyclohexanes); and alkanoic acid esters (e.g., ethyl acetate,
n-propyl acetate, isobutyl acetate, n-butyl acetate isobutyl
isobutyrate, hexyl acetate, 2-ethylhexyl acetate or butyl acetate);
and combinations and mixtures thereof. Other suitable co-solvents
include polyhydric alcohols, which include glycols, triols and
polyols such as ethylene glycol, diethylene glycol, propylene
glycol, dipropylene glycol, trimethylene glycol, butylene glycol,
polyethylene glycol, hexylene glycol, polyoxethylene, glycerin,
trimethylpropane, sorbitol, polyvinylpyrrolidone, and the like.
Alternatively, co-solvents may include glycol ethers such as
ethylene glycol monoethyl ether, glycol esters, glycol ether esters
such as ethylene glycol monoethyl ether acetate and ethylene glycol
diacetate; saturated and unsaturated fatty acids, mineral oil,
silicone fluid, lecithin, retinol derivatives and the like, and
ethers, esters and alcohols of fatty acids. As will be described in
more detail hereafter, the solvents or co-solvents used in
accordance with the invention are desirably a low volatile solvent
that does not require excessive temperatures for evaporation
thereof.
[0045] The term "solubilized" is intended to mean that in the
carrier composition there is an intimate dispersion or dissolution
of the active agent at the crystalline, molecular or ionic level,
such that crystals of the active agent cannot be detected using a
microscope having a magnification of 25.times.. As such, the active
agent is considered herein to be in "non-crystallized" form when in
the compositions of the present invention.
[0046] 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), 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 or mucosa.
[0047] As used herein, "therapeutically effective" means an amount
of an active agent that is sufficient to achieve the desired local
or systemic effect or result, such as to prevent, cure, diagnose,
mitigate or treat a disease or condition, when applied topically
over the duration of intended use. The amounts necessary are known
in the literature or may be determined by methods known in the art,
but typically range from about 0.1 mg to about 20,000 mg, and
preferably from about 0.1 mg to about 1,000 mg, and most preferably
from about 0.1 to about 500 mg per human adult or mammal of about
75 kg body weight per 24 hours.
[0048] The term "about", and the use of ranges in general whether
or not qualified by the term about, means that the number
comprehended is not limited to the exact number set forth herein,
and is intended to refer to ranges substantially within the quoted
range not departing from the scope of the invention.
[0049] The term "user" or "subject" is intended to include all
warm-blooded mammals, preferably humans.
[0050] The phrase "substantially zero-order" as used herein means
transdermal delivery of an active agent at a release rate which is
approximately constant once steady state is attained, typically
within 12 to 24 hours after topical application. While variability
in blood levels of active agent are contemplated within the scope
of this meaning once steady state release is attained, the
depletion rate of active agent over the duration of use should
typically not exceed about 20% to about 25%.
[0051] As used herein, the term "rubber" refers to a viscoelastic
material which has the properties of a pressure-sensitive adhesive
and which contains at least one natural or synthetic elastomeric
polymer. Suitable rubbers include polysiloxane, polyisobutylene and
natural rubber.
[0052] Solubility parameter, also referred to herein as "SP," has
been defined as the sum of all the intermolecular attractive
forces, which are empirically related to the extent of mutual
solubility of many chemical species. A general discussion of
solubility parameters is found in an article by Vaughan, "Using
Solubility Parameters in Cosmetics Formulation," J. Soc. Cosmet.
Chem., Vol. 36, pages 319-333 (1985).
[0053] The multiple polymer adhesive system is preferably
formulated so that it is a pressure-sensitive adhesive at room
temperature and has other desirable characteristics for adhesives
used in the transdermal drug delivery art. Such characteristics
include good adherence to skin, ability to be peeled or otherwise
removed without substantial trauma to the skin, retention of tack
with aging, etc. In general, the multiple polymer adhesive system
should have a glass transition temperature (Tg), measured using a
differential scanning calorimeter, of between about -70.degree. C.
and 0.degree. C.
[0054] Further details and examples of silicone pressure-sensitive
adhesives which are useful in the practice of this invention are
described in the following U.S. Pat. Nos. 4,591,622; 4,584,355;
4,585,836; and 4,655,767. These patents are incorporated herein by
reference.
[0055] The term "active agent" (and its equivalents "agent,"
"drug," "medicament" and "pharmaceutical") is intended to have the
broadest meaning and includes at least one of any therapeutic,
prophylactic, pharmacological or physiological active substance,
cosmetic and personal care preparations, and mixtures thereof,
which is delivered to a mammal to produce a desired, usually
beneficial, effect. More specifically, any active agent that is
capable of producing a pharmacological response, localized or
systemic, irrespective of whether therapeutic, diagnostic, cosmetic
or prophylactic in nature, is within the contemplation of the
invention. Also within the invention are such bioactive agents as
pesticides, insect repellents, sun screens, cosmetic agents, etc.
It should be noted that the drugs and/or bioactive agents may be
used singularly or as a mixture of two or more such agents, and in
amounts sufficient to prevent, cure, diagnose or treat a disease or
other condition, as the case may be. The drugs and mixtures thereof
can be present in the composition in different forms, depending on
which form yields the optimum delivery characteristics. Thus, in
the case of drugs, the drug can be in its free base or acid form,
or in the form of salts, esters, amides, prodrugs, enantiomers or
mixtures thereof, or any other pharmacologically acceptable
derivatives, or as components of molecular complexes.
[0056] The drug is used in a "pharmacologically effective amount."
This term means that the concentration of the drug is such that in
the composition it results in a therapeutic level of drug delivered
over the term that the transdermal dosage form 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 and without enhancers. Having determined the flux rate
needed, the transdermal 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
transdermal delivery system also affects the delivery of the drug
from the system.
[0057] Drugs in general can be used in this invention. These drugs
include those categories and species of drugs set forth on page
ther-5 to ther-29 of the Merck Index, 11th Edition Merck & Co.
Rahway, N.J. (1989).
[0058] 1. .alpha.-Adrenergic agonists such as Adrafinil,
Adrenolone, Amidephrine, Apraclonidine, Budralazine, Clonidine,
Cyclopentamine, Detomidine, Dimetofrine, Dipivefrin, Ephedrine,
Epinephrine, Fenoxazoline, Guanabenz, Guanfacine,
Hydroxyamphetamine, Ibopamine, Indanazoline, Isometheptene,
Mephentermine, Metaraminol, Methoxamine Hydrochloride,
Methylhexaneamine, Metizolene, Midodrine, Naphazoline,
Norepinephrine, Norfenefrine, Octodrine, Octopamine, Oxymetazoline,
Phenylephrine Hydrochloride, Phenylpropanolamine Hydrochloride,
Phenylpropylmethylamine, Pholedrine, Propylhexedrine,
Pseudoephedrine, Rilmenidine, Synephrine, Tetrahydrozoline,
Tiamenidine, Tramazoline, Tuaminoheptane, Tymazoline, Tyramine and
Xylometazoline.
[0059] 2. .beta.-Adrenergic agonists such as Albuterol, Bambuterol,
Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, Denopamine,
Dioxethedrine, Dopexamine, Ephedrine, Epinephrine, Etafedrine,
Ethylnorepinephrine, Fenoterol, Formoterol, Hexoprenaline,
Ibopamine, Isoetharine, Isoproterenal, Mabuterol, Metaproterenol,
Methoxyphenamine, Oxyfedrine, Pirbuterol, Prenalterol, Procaterol,
Protokylol, Reproterol, Rimiterol, Ritodrine, Soterenol, Terbuterol
and Xamoterol.
[0060] 3. .alpha.-Adrenergic blockers such as Amosulalol,
Arotinolol, Dapiprazole, Doxazosin, Ergoloid Mesylates, Fenspiride,
Indoramin, Labetalol, Nicergoline, Prazosin, Terazosin, Tolazoline,
Trimazosin and Yohimbine.
[0061] 4. .beta.-Adrenergic blockers such as Acebutolol,
Alprenolol, Amosulalol, Arotinolol, Atenolol, Befunolol, Betaxolol,
Bevantolol, Bisoprolol, Bopindolol, Bucumolol, Befetolol,
Bufuralol, Bunitrolol, Bupranolol, Butidrine Hydrochloride,
Butofilolol, Carazolol, Carteolol, Carvedilol, Celiprolol,
Cetamolol, Cloranolol, Dilevalol, Epanolol, Esmolol, Indenolol,
Labetalol, Levobunolol, Mepindolol, Metipranalol, Metoprolol,
Moprolol, Nadoxolol, Nifenalol, Nipradilol, Oxprenolol, Penbutolol,
Pindolol, Practolol, Pronethalol, Propranolol, Sotalol, Sulfinalol,
Talinolol, Tertatolol, Timolol, Toliprolol and Xibenolol.
[0062] 5. Alcohol deterrents such as Calcium Cyanamide Citrated,
Disulfiram, Nadide and Nitrefazole.
[0063] 6. Aldose reductase inhibitors such as Epalrestat,
Ponalrestat, Sorbinil and Tolrestat.
[0064] 7. Anabolics such as Androisoxazole, Androstenediol,
Bolandiol, Bolasterone, Clostebol, Ethylestrenol, Formyldienolone,
4-Hydroxy-19-nortestosterone, Methandriol, Methenolone,
Methyltrienolone, Nandrolone, Nandrolone Decanoate, Nandrolone
p-Hexyloxyphenylpropionate, Nandrolone Phenpropionate,
Norbolethone, Oxymesterone, Pizotyline, Quinbolone, Stenbolone and
Trenbolone.
[0065] 8. Analgesics (dental) such as Chlorobutanol, Clove and
Eugenol.
[0066] 9. Analgesics (narcotic) such as Alfentanil, Allylprodine,
Alphaprodine, Anileridine, Benzylmorphine, Bezitramide,
Buprenorphine, Butorphanol, Clonitazene, Codeine, Codeine Methyl
Bromide, Codeine Phosphate, Codeine Sulfate, Desomorphine,
Dextromoramide, Dezocine, Diampromide, Dihydrocodeine,
Dihydrocodeinone Enol Acetate, Dihydromorphine, Dimenoxadol,
Dimepheptanol, Dimethylthiambutene, Dioxaphetyl Butyrate,
Dipipanone, Eptazocine, Ethoheptazine, Ethylmethlythiambutene,
Ethylmorphine, Etonitazene, Fentanyl, Hydrocodone, Hydrocodone
Bitartrate, Hydromorphone, Hydroxypethidine, Isomethadone,
Ketobemidone, Levorphanol, Lofentanil, Meperidine, Meptazinol,
Metazocine, Methadone Hydrochloride, Metopon, Morphine, Morphine
Derivatives, Myrophine, Nalbuphine, Narceine, Nicomorphine,
Norlevorphanol, Normethadone, Normorphine, Norpipanone, Opium,
Oxycodone, Oxymorphone, Papaveretum, Pentazocine, Phenadoxone,
Phenazocine, Pheoperidine, Piminodine, Piritramide, Proheptazine,
Promedol, Properidine, Propiram, Propoxyphene, Sufentanil and
Tilidine.
[0067] 10. Analgesics (non-narcotic) such as Acetaminophen,
Acetaminosalol, Acetanilide, Acetylsalicylsalicylic Acid,
Alclofenac, Alminoprofen, Aloxiprin, Aluminum
Bis(acetylsalicylate), Aminochlorthenoxazin, 2-Amino-4-picoline,
Aminopropylon, Aminopyrine, Ammonium Salicylate, Antipyrine,
Antipyrine Salicylate, Antrafenine, Apazone, Aspirin, Benorylate,
Benoxaprofen, Benzpiperylon, Benzydamine, p-Bromoacetanilide,
5-Bromosalicylic Acid Acetate, Bucetin, Bufexamac, Bumadizon,
Butacetin, Calcium Acetylsalicylate, Carbamazepine, Carbetidine,
Carbiphene, Carsalam, Chloralantipyrine, Chlorthenoxazin(e),
Choline Salicylate, Cinchophen, Ciramadol, Clometacin,
Cropropamide, Crotethamide, Dexoxadrol, Difenamizole, Diflunisal,
Dihydroxyaluminum Acetylsalicylate, Dipyrocetyl, Dipyrone,
Emorfazone, Enfenamic Acid, Epirizole, Etersalate, Ethenzamide,
Ethoxazene, Etodolac, Felbinac, Fenoprofen, Floctafenine,
Flufenamic Acid, Fluoresone, Flupirtine, Fluproquazone,
Flurbiprofen, Fosfosal, Gentisic Acid, Glafenine, Ibufenac,
Imidazole Salicylate, Indomethacin, Indoprofen, Isofezolac,
Isoladol, Isonixin, Ketoprofen, Ketorolac, p-Lactophenetide,
Lefetamine, Loxoprofen, Lysine Acetylsalicylate, Magnesium
Acetylsalicylate, Methotrimeprazine, Metofoline, Miroprofen,
Morazone, Morpholine Salicylate, Naproxen, Nefopam, Nifenazone, 5'
Nitro-2' propoxyacetanilide, Parsalmide, Perisoxal, Phenacetin,
Phenazopyridine Hydrochloride, Phenocoll, Phenopyrazone, Phenyl
Acetylsalicylate, Phenyl Salicylate, Phenyramidol, Pipebuzone,
Piperylone, Prodilidine, Propacetamol, Propyphenazone, Proxazole,
Quinine Salicylate, Ramifenazone, Rimazolium Metilsulfate,
Salacetamide, Salicin, Salicylamide, Salicylamide O-Acetic Acid,
Salicylsulfuric Acid, Salsalte, Salverine, Simetride, Sodium
Salicylate, Sulfamipyrine, Suprofen, Talniflumate, Tenoxicam,
Terofenamate, Tetradrine, Tinoridine, Tolfenamic Acid, Tolpronine,
Tramadol, Viminol, Xenbucin and Zomepirac.
[0068] 11. Anesthetics such as Acetamidoeugenol, Alfadolone
Acetate, Alfaxalone, Amucaine, Amolanone, Amylocalne Hydrochloride,
Benoxinate, Benzocaine, Betoxycaine, Biphenamine, Bupivacaine,
Butacaine, Butaben, Butanilicaine, Burethamine, Buthalital Sodium,
Butoxycaine, Carticaine, 2-Chloroprocaine Hydrochloride,
Cocaethylene, Cocaine, Cyclomethycaine, Dibucaine Hydrochloride,
Dimethisoquin, Dimethocaine, Diperadon Hydrochloride, Dyclonine,
Ecgonidine, Ecgonine, Ethyl Aminobenzoate, Ethyl Chloride,
Etidocaine, Etoxadrol, .beta.-Eucaine, Euprocin, Fenalcomine,
Fomocaine, Hexobarbital, Hexylcaine Hydrochloride, Hydroxydione
Sodium, Hydroxyprocaine, Hydroxytetracaine, Isobutyl
p-Aminobenzoate, Kentamine, Leucinocaine Mesylate, Levoxadrol,
Lidocaine, Mepivacaine, Meprylcaine Hydrochloride, Metabutoxycaine
Hydrochloride, Methohexital Sodium, Methyl Chloride, Midazolam,
Myrtecaine, Naepaine, Octacaine, Orthocaine, Oxethazaine,
Parethoxycaine, Phenacaine Hydrochloride, Phencyclidine, Phenol,
Piperocaine, Piridocaine, Polidocanol, Pramoxine, Prilocaine,
Procaine, Propanidid, Propanocaine, Proparacaine, Propipocaine,
Propofol, Propoxycaine Hydrochloride, Pseudococaine, Pyrrocaine,
Quinine Urea Hydochloride, Risocaine, Salicyl Alcohol, Tetracaine
Hydrochloride, Thialbarbital, Thimylal, Thiobutabarbital,
Thiopental Sodium, Tolycaine, Trimecaine and Zolamine.
[0069] 12. Anorexics such as Aminorex, Amphecloral, Amphetamine,
Benzaphetamine, Chlorphentermine, Clobenzorex, Cloforex,
Clortermine, Cyclexedrine, Destroamphetamine Sulfate,
Diethylpropion, Diphemethoxidine, N-Ethylamphetamine, Fenbutrazate,
Fenfluramine, Fenproporex, Furfurylmethylamphetamine,
Levophacetoperate, Mazindol, Mefenorex, Metamfeproamone,
Methamphetamine, Norpseudoephedrine, Phendimetrazine,
Phendimetrazine Tartrate, Phenmetrazine, Phenpentermine,
Phenylpropanolamine Hydrochloride and Picilorex.
[0070] 13. Anthelmintics (Cestodes) such as Arecoline, Aspidin,
Aspidinol, Dichlorophen(e), Embelin, Kosin, Napthalene,
Niclosamide, Pellertierine, Pellertierine Tannate and
Quinacrine.
[0071] 14. Anthelmintics (Nematodes) such as Alantolactone,
Amoscanate, Ascaridole, Bephenium, Bitoscanate, Carbon
Tetrachloride, Carvacrol, Cyclobendazole, Diethylcarbamazine,
Diphenane, Dithiazanine Iodide, Dymanthine, Gentian Violet,
4-Hexylresorcinol, Kainic Acid, Mebendazole, 2-Napthol, Oxantel,
Papain, Piperazine, Piperazine Adipate, Piperazine Citrate,
Piperazine Edetate Calcium, Piperazine Tartrate, Pyrantel,
Pyrvinium Pamoate, a-Santonin, Stilbazium Iodide,
Tetrachloroethylene, Tetramisole, thiabendazole, Thymol, Thymyl
N-Isoamylcarbamate, Triclofenol piperazine and Urea Stibamine.
[0072] 15. Anthelmintics (Onchocerca) such as Ivermectin and
Suramin Sodium.
[0073] 16. Anthelmintics (Schistosoma) such as Amoscanate,
Amphotalide, Antimony Potassium Tartrate, Antimony Sodium
Gluconate, Antimony Sodium Tartrate, Antimony Sodium
Thioglycollate, Antimony Thioglycollamide, Becanthone, Hycanthone,
Lucanthone Hydrochloride, Niridazole, Oxamniquine, Praziquantel,
Stibocaptate, Stibophen and Urea Stibamine.
[0074] 17. Anthelmintic (Trematodes) such as Anthiolimine and
Tetrachloroethylene.
[0075] 18. Antiacne drugs such as Adapelene, Algestone
Acetophenide, Azelaic Acid, Benzoyl Peroxide, Cyoctol, Cyproterone,
Motretinide, Resorcinol, Retinoic Acid, Tetroquinone and
Tretinonine.
[0076] 19. Antiallergics such as Amlexanox, Astemizole, Azelastine,
Cromolyn, Fenpiprane, Histamine, Ibudilast, Nedocromil, Oxatomide,
Pentigetide, Poison Ivy Extract, Poison Oak Extract, Poison Sumac
Extract, Repirinast, Tranilast, Traxanox and Urushiol.
[0077] 20. Antiamebics such as Arsthinol, Bialamicol, Carbarsone,
Cephaeline, Chlorbetamide, Chloroquine, Chlorphenoxamide,
Chlortetracycline, Dehydroemetine, Dibromopropamidine, Diloxanide,
Dephetarsone, Emetine, Fumagillin, Glaucarubin, Glycobiarsol,
8-Hydroxy-7-iodo-5-quinolinesulfonic Acid, Iodochlorhydroxyquin,
Iodoquinol, Paromomycin, Phanquinone, Phearsone Sulfoxylate,
Polybenzarsol, Propamidine, Quinfamide, Secnidazole, Sulfarside,
Teclozan, Tetracycline, Thiocarbamizine, Thiocarbarsone and
Tinidazole.
[0078] 21. Antiandrogens such as Bifluranol, Cyoctol, Cyproterone,
Delmadinone Acetate, Flutimide, Nilutamide and Oxendolone.
[0079] 22. Antianginals such as Acebutolol, Alprenolol, Amiodarone,
Amlodipine, Arotinolol, Atenolol, Bepridil, Bevantolol, Bucumolol,
Bufetolol, Bufuralol, Bunitrolol, Bupranolol, Carozolol, Carteolol,
Carvedilol, Celiprolol, Cinepazet Maleate, Diltiazem, Epanolol,
Felodipine, Gallopamil, Imolamine, Indenolol, Isosorbide Dinitrate,
Isradipine, Limaprost, Mepindolol, Metoprolol, Molsidomine,
Nadolol, Nicardipine, Nifedipine, Nifenalol, Nilvadipine,
Nipradilol, Nisoldipine, Nitroglycerin, Oxprenolol, Oxyfedrine,
Ozagrel, Penbutolol, Pentaerythritol Tetranitrate, Pindolol,
Pronethalol, Propranolol, Sotalol, Terodiline, Timolol, Toliprolol
and Verapamil.
[0080] 23. Antiarrhythmics such as Acebutol, Acecaine, Adenosine,
Ajmaline, Alprenolol, Amiodarone, Amoproxan, Aprindine, Arotinolol,
Atenolol, Bevantolol, Bretylium Tosylate, Bubumolol, Bufetolol,
Bunaftine, Bunitrolol, Bupranolol, Butidrine Hydrochloride,
Butobendine, Capobenic Acid, Carazolol, Carteolol, Cifenline,
Cloranolol, Disopyramide, Encainide, Esmolol, Flecainide,
Gallopamil, Hydroquinidine, Indecainide, Indenolol, Ipratropium
Bromide, Lidocaine, Lorajmine, Lorcainide, Meobentine,
Metipranolol, Mexiletine, Moricizine, Nadoxolol, Nifenalol,
Oxprenolol, Penbutolol, Pindolol, Pirmenol, Practolol, Prajmaline,
Procainamide Hydrochloride, Pronethalol, Propafenone, Propranolol,
Pyrinoline, Quinidine Sulfate, Quinidine, Sotalol, Talinolol,
Timolol, Tocainide, Verapamil, Viquidil and Xibenolol.
[0081] 24. Antiarteriosclerotics such as Pyridinol Carbamate.
[0082] 25. Antiarthritic/Antirheumatics such as Allocupreide
Sodium, Auranofin, Aurothioglucose, Aurothioglycanide,
Azathioprine, Calcium 3-Aurothio-2-propanol-1-sulfonate, Celecoxib,
Chloroquine, Clobuzarit, Cuproxoline, Diacerein, Glucosamine, Gold
Sodium Thiomalate, Gold Sodium Thiosulfate, Hydroxychloroquine,
Kebuzone, Lobenzarit, Melittin, Methotrexate, Myoral and
Penicillamine.
[0083] 26. Antibacterial (antibiotic) drugs including:
[0084] Aminoglycosides such as Amikacin, Apramycin, Arbekacin,
Bambermycins, Butirosin, Dibekacin, Dihdrostreptomycin,
Fortimicin(s), Gentamicin, Ispamicin, Kanamycin, Micronomicin,
Neomycin, Neomycin Undecylenate, Netilmicin, Paromomycin,
Ribostamycin, Sisomicin, Spectinomycin, Streptomycin,
Streptonicozid and Tobramycin;
[0085] Amphenicols such as Azidamfenicol, Chloramphenicol,
Chloramphenicol Palmitate, Chloramphenicol Pantothenate,
Florfenicol and Thiamphenicol;
[0086] Ansamycins such as Rifamide, Rifampin, Rifamycin and
Rifaximin;
[0087] .beta.-Lactams, including:
[0088] Carbapenems such as Imipenem;
[0089] Cephalosporins such as Cefactor, Cefadroxil, Cefamandole,
Cefatrizine, Cefazedone, Cefazolin, Cefixime, Cefinenoxime,
Cefodizime, Cefonicid, Cefoperazone, Ceforanide, Cefotaxime,
Cefotiam, Cefpimizole, Cefpirimide, Cefpodoxime Proxetil,
Cefroxadine, Cefsulodin, Ceftazidime, Cefteram, Ceftezole,
Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefuzonam,
Cephacetrile Sodium, Cephalexin, Cephaloglycin, Cephaloridine,
Cephalosporin, Cephalothin, Cephapirin Sodium, Cephradine and
Pivcefalexin;
[0090] Cephamycins such as Cefbuperazone, Cefinetazole, Cefminox,
Cefetan and Cefoxitin;
[0091] Monobactams such as Aztreonam, Carumonam and Tigemonam;
[0092] Oxacephems such as Flomoxef and Moxolactam;
[0093] Penicillins such as Amidinocillin, Amdinocillin Pivoxil,
Amoxicillin, Ampicillan, Apalcillin, Aspoxicillin, Azidocillan,
Azlocillan, Bacampicillin, Benzylpenicillinic Acid,
Benzylpenicillin Sodium, Carbenicillin, Carfecillin Sodium,
Carindacillin, Clometocillin, Cloxacillin, Cyclacillin,
Dicloxacillin, Diphenicillin Sodium, Epicillin, Fenbenicillin,
Floxicillin, Hetacillin, Lenampicillin, Metampicillin, Methicillin
Sodium, Mezlocillin, Nafcillin Sodium, Oxacillin, Penamecillin,
Penethamate Hydriodide, Penicillin G Benethamine, Penicillin G
Benzathine, Penicillin G Benzhydrylamine, Penicillin G Calcium,
Penicillin G Hydrabamine, Penicillin G Potassium, Penicillin G
Procaine, Penicillen N, Penicillin 0, Penicillin V, Penicillin V
Benzathine, Penicillin V Hydrabamine, Penimepicycline,
Phenethicillin Potassium, Piperacillin, Pivapicillin, Propicillin,
Quinacillin, Sulbenicillin, Talampicillin, Temocillin and
Ticarcillin;
[0094] Lincosamides such as Clindamycin and Lincomycin;
[0095] Macrolides such as Azithromycin, Carbomycin, Clarithromycin,
Erythromycin, Erythromycin Acistrate, Erythromycin Estolate,
Erythromycin Glucoheptonate, Erythromycin Lactobionate,
Erythromycin Propionate, Erythromycin Stearate, Josamycin,
Leucomycins, Midecamycins, Miokamycin, Oleandomycin, Primycin,
Rokitamycin, Rosaramicin, Roxithromycin, Spiramycin and
Troleandomycin;
[0096] Polypeptides such as Amphomycin, Bacitracin, Capreomycin,
Colistin, Enduracidin, Enviomycin, Fusafungine, Gramicidin(s),
Gramicidin S, Mikamycin, Polymyxin, Polymyxin B-Methanesulfonic
Acid, Pristinamycin, Ristocetin, Teicoplanin, Thiostrepton,
Tuberactinomycin, Tyrocidine, Tyrothricin, Vancomycin, Viomycin,
Viomycin Pantothenate, Virginiamycin and Zinc Bacitracin;
[0097] Tetracyclines such as Apicycline, Chlortetracycline,
Clomocycline, Demeclocycline, Doxycycline, Guamecycline,
Lymecycline, Meclocycline, Methacycline, Minocycline,
Oxytetracycline, Penimepicycline, Pipacycline, Rolitetracycline,
Sancycline, Senociclin and Tetracycline; and
[0098] other antibiotics such as Cycloserine, Mupirocin and
Tuberin.
[0099] 27. Antibacterial drugs (synthetic), including:
[0100] 2,4-Diaminopyrimidines such as Brodimoprim, Tetroxoprim and
Trimethoprim;
[0101] Nitrofurans such as Furaltadone, Furazolium Chloride,
Nifuradene, Nifuratel, Nifurfoline, Nifurpirinol, Nifurprazine,
Nifurtoinol and Nitrofurantoin;
[0102] Quinolones and Analogs such as Amifloxacin, Cinoxacin,
Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin, Flumequine,
Lomefloxacin, Miloxacin, Nalidixic Acid, Norfloxacin, Ofloxacin,
Oxolinic Acid, Pefloxacin, Pipemidic Acid, Piromidic Acid,
Rosoxacin, Temafloxacin and Tosufloxacin;
[0103] Sulfonamides such as Acetyl Sulfamethoxypyrazine, Acetyl
Sulfisoxazole, Azosulfamide, Benzylsulfamide, Chloramine-B,
Chloramine-T, Dichloramine T, Formosulfathiazole, N.sup.2
Formylsulfisomidine, N.sup.2-a-D-Glucosylsulfanilamide, Mafenide,
4'-(Methylsulfamoyl)sulfanilanilide, p-Nitrosulfathiazole,
Noprylsulfamide, Phthalylsulfacetamide, Phthalylsulfathiazole,
Salazosulfadimidine, Succinylsulfathiazole, Sulfabenzamide,
Sulfacetamide, Sulfachlorpyridazine, Sulfachrysoidine, Sulfacytine,
Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine,
Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic
Acid, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole,
Sulfamethomidine, Sulfamethoxazole, Sulfamethoxypyridazine,
Sulfametrole, Sulfamidochrysoidine, Sulfamoxole, Sulfanilamide,
Sulfanilamidomethanesulfonic Acid Triethanolamine Salt,
4-Sulfanilamidosalicylic Acid, N.sup.4-Sulfanilylsulfanilamide,
Sulfanilylurea, N-Sulfanilyl-3,4-xylamide, Sulfanitran,
Sulfaperine, Sulfaphenazole, Sulfaproxyline, Sulfapyrazine,
Sulfapyridine, Sulfasomizole, Sulfasymazine, Sulfathiazole,
Sulfathiourea, Sulfatolamide, Sulfisomidine and Sulfisoxazole;
[0104] Sulfones such as Acedapsone, Acediasulfone, Acetosulfone
Sodium, Dapsone, Diathymosulfone, Glucosulfone Sodium, Solasulfone,
Succisulfone, Sulfanilic Acid, p-Sulfanilylbenzylamine,
p,p'-Sulfonyldianiline-N,N' digalactoside, Sulfoxone Sodium and
Thiazolsulfone; and others such as Clofoctol, Hexedine,
Methenamine, Methenamine Anhydromethylene-citrate, Methenamine
Hippurate, Methenamine Mandelate, Methenamine Sulfosalicylate,
Nitroxoline and Xibornol, Anticholinergics such as Adiphenine
Hydrochloride, Alverine, Ambutonomium Bromide, Aminopentamide,
Amixetrine, Amprotropine Phosphate, Anisotropine Methylbromide,
Apoatropine, Atropine, Atropine N-Oxide, Benactyzine, Benapryzine,
Benzetimide, Benzilonium Bromide, Benztropine Mesylate, Bevonium
Methyl Sulfate, Biperiden, Butropium Bromide, N-Butylscopolammonium
Bromide, Buzepide, Camylofine, Caramiphen Hydrochloride,
Chlorbenzoxamine, Chlorphenoxamine, Cimetropium Bromide, Clidinium
Bromide, Cyclodrine, Cyclonium Iodide, Cycrimine Hydrochloride,
Deptropine, Dexetimide, Dibutoline Sulfate, Dicyclomine
Hydrochloride, Diethazine, Difemerine, Dihexyverine, Diphemanil
Methylsulfate, N-(1,2-Diphenylethyl)nicotinamide, Dipiproverine,
Diponium Bromide, Emepronium Bromide, Endobenzyline Bromide,
Ethopropazine, Ethybenztropine, Ethylbenzhydramine, Etomidoline,
Eucatropine, Fenpiverinium Bromide, Fentonium Bromide, Flutropium
Bromide, Glycopyrrolate, Heteronium Bromide, Hexocyclium Methyl
Sulfate, Homatropine, Hyoscyamine, Ipratropium Bromide,
Isopropamide, Levomepate, Mecloxamine, Mepenzolate Bromide,
Metcaraphen, Methantheline Bromide, Methixene, Methscopolamine
Bromide, Octamylamine, Chloride, Oxyphencyclimine, Oxyphenonium
Bromide, Pentapiperide, Penthienate Bromide, Phencarbamide,
Phenglutarimide, Pipenzolate Bromide, Piperidolate, Piperilate,
Poldine Methysulfate, Pridinol, Prifinium Bromide, Procyclidine,
Propantheline Bromide, Propenzolate, Propyromazine, Scopolamine,
Scopolamine N-Oxide, Stilonium Iodide, Stramonium, Sultroponium,
Thihexinol, Thiphenamil, Tiemonium Iodide, Timepidium Bromide,
Tiquizium Bromide, Tridihexethyl Iodide, Trihexyphenidyl
Hydrochloride, Tropacine, Tropenzile, Tropicamide, Trospium
Chloride, Valethamate Bromide and Xenytropium Bromide.
[0105] 28. Anticonvulsants such as Acetylpheneturide, Albutoin,
Aloxidone, Aminoglutethimide, 4-Amino-3-hydroxybutyric Acid,
Atrolactamide, Beclamide, Buramate, Calcium Bromide, Carbamazepine,
Cinromide, Clomethiazole, Clonazepam, Decimemide, Diethadione,
Dimethadione, Doxenitoin, Eterobarb, Ethadione, Ethosuximide,
Ethotoin, Fluoresone, Garbapentin, 5-Hydroxytryptophan,
Lamotrigine, Lomactil, Magnesium Bromide, Magnesium Sulfate,
Mephenyloin, Mephobarbital, Metharbital, Methetoin, Methsuximide,
5-Methyl-5-(3-phenanthryl)hydantoin, 3-Methyl-5-phenylhydantoin,
Narcobarbital, Nimetazepam, Nitrazepam, Paramethadione,
Phenacemide, Phenetharbital, Pheneturide, Phenobarbital,
Phenobarbital Sodium, Phensuximide, Phenylmethylbarbituric Acid,
Phenyloin, Phethenylate Sodium, Potassium Bromide, Pregabatin,
Primidone, Progabide, Sodium Bromide, Sodium Valproate, Solanum,
Strontium Bromide, Suclofenide, Sulthiame, Tetrantoin, Tiagabine,
Trimethadione, Valproic Acid, Valpromide, Vigabatrin and
Zonisamide.
[0106] 29. Antidepressants, including:
[0107] Bicyclics such as Binedaline, Caroxazone, Citalopram,
Dimethazan, Indalpine, Fencamine, Indeloxazine Hydrochcloride,
Nefopam, Nomifensine, Oxitriptan, Oxypertine, Paroxetine,
Sertraline, Thiazesim, Trazodone, Venlafaxine and Zometapine;
[0108] Hydrazides/Hydrazines such as Benmoxine, Iproclozide,
Iproniazid, Isocarboxazid, Nialamide, Octamoxin and Phenelzine;
[0109] Pyrrolidones such as Cotinine, Rolicyprine and Rolipram;
[0110] Tetracyclics such as Maprotiline, Metralindole, Mianserin
and Oxaprotiline.
[0111] Tricyclics such as Adinazolam, Amitriptyline,
Amitriptylinoxide, Amoxapine, Butriptyline, Clomipramine,
Demexiptiline, Desipramine, Dibenzepin, Dimetracrine, Dothiepin,
Doxepin, Fluacizine, Imipramine, Imipramine N-Oxide, Iprindole,
Lofepramine, Melitracen, Metapramine, Nortriptyline, Noxiptilin,
Opipramol, Pizotyline, Propizepine, Protriptyline, Quinupramine,
Tianeptine and Trimipramine; and
[0112] others such as Adrafinil, Benactyzine, Bupropion, Butacetin,
Deanol, Deanol Aceglumate, Deanol Acetamidobenzoate, Dioxadrol,
Etoperidone, Febarbamate, Femoxetine, Fenpentadiol, Fluoxetine,
Fluvoxamine, Fluvoxamine Maleate, Hematoporphyrin, Hypercinin,
Levophacetoperane, Medifoxamine, Minaprine, Moclobemide,
Oxaflozane, Piberaline, Prolintane, Pyrisuccideanol, Rubidium
Chloride, Sulpiride, Sultopride, Teniloxazine, Thozalinone,
Tofenacin, Toloxatone, Tranylcypromine, L-Tryptophan, Viloxazine
and Zimeldine.
[0113] 30. Antidiabetics, including:
[0114] Biguanides such as Buformin, Metformin and Phenformin;
[0115] Hormones such as Glucagon and Insulin;
[0116] Sulfonylurea derivatives such as Acetohexamide,
1-Butyl-3-metanilylurea, Carbutamide, Chlorpropamide, Glibornuride,
Gliclazide, Glipizide, Gliquidone, Glisoxepid, Glyburide,
Glybuthiazol(e), Glybuzole, Glyhexamide, Glymidine, Glypinamide,
Phenbutamide, Tolazamide, Tolbutamide and Tolcyclamide; and
[0117] others such as Acarbose, Calcium Mesoxalate and
Miglitol.
[0118] 31. Antidiarrheal drugs such as Acetyltannic Acid, Albumin
Tannate, Alkofanone, Aluminum Salicylates--Basic, Catechin,
Difenoxin, Diphenoxylate, Lidamidine, Lomotil, Loperamide,
Mebiquine, Trillium and Uzarin.
[0119] 32. Antidiuretics such as Desmopressin, Felypressin,
Lypressin, Ornipressin, Oxycinchophen, Pituitary--Posterior,
Terlipressin and Vasopressin.
[0120] 33. Antiestrogens such as Delmadinone Acetate,
Ethamoxytriphetol, Tamoxifen and Toremifene.
[0121] 34. Antifungal drugs (antibiotics), including:
[0122] Polyenes such as Amphotericin-B, Candicidin, Dermostatin,
Filipin, Fungichromin, Hachimycin, Hamycin, Lucensomycin,
Mepartricin, Natamycin, Nystatin, Pecilocin and Perimycin; and
[0123] others such as Azaserine, Griseofulvin, Oligomycins,
Neomycin Undecylenate, Pyrrolnitrin, Siccanin, Tubercidin and
Viridin.
[0124] 35. Antifungal drugs (synthetic), including:
[0125] Allylamines such as Naftifine and Terbinafine;
[0126] Imidazoles such as Bifonazole, Butoconazole, Chlordantoin,
Chlormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole,
Fenticonazole, Isoconazole, Ketoconazole, Miconazole, Omoconazole,
Oxiconazole, Nitrate, Sulconazole and Tioconazole;
[0127] Triazoles such as Fluconazole, Itraconazole and Terconazole;
and
[0128] others such as Acrisorcin, Amorolfine, Biphenamine,
Bromosalicylchloranilide, Buclosamide, Calcium Propionate,
Chlophenesin, Ciclopirox, Cloxyquin, Coparaffinate, Diamthazole,
Dihydrochloride, Exalamide, Flucytosine, Halethazole, Hexetidine,
Loflucarban, Nifuratel, Potassium Iodide, Propionic Acid,
Pyrithione, Salicylanilide, Sodium Propionate, Sulbentine,
Tenonitrozole, Tolciclate, Tolindate, Tolnaftate, Tricetin,
Ujothion, Undecylenic Acid and Zinc Propionate.
[0129] 36. Antiglaucoma drugs such as Acetazolamide, Befunolol,
Betaxolol, Bupranolol, Carteolol, Dapiprazoke, Dichlorphenamide,
Dipivefrin, Epinephrine, Levobunolol, Methazolamide, Metipranolol,
Pilocarpine, Pindolol and Timolol.
[0130] 37. Antigonadotropins such as Danazol, Gestrinone and
Paroxypropione.
[0131] 38. Antigout drugs such as Allopurinol, Carprofen,
Colchicine, Probenecid and Sulfinpyrazone.
[0132] 39. Antihistamines, including:
[0133] Alkylamine derivatives such as Acrivastine, Bamipine,
Brompheniramine, Chlorpheniramine, Dimethindene, Metron S,
Pheniramine, Pyrrobutamine, Thenaldine, Tolpropamine and
Triprolidine;
[0134] Aminoalkyl ethers such as Bietanautine,
Bromodiphenhydramine, Carbinoxamine, Clemastine, Diphenlypyraline,
Doxylamine, Embrammine, Medrylamine, Mephenphydramine,
p-Methyldiphenhydramine, Orphenadrine, Phenyltoloxamine,
Piprinhydrinate and Setasine;
[0135] Ethylenediamine derivatives such as Alloclamide,
p-Bromtripelennamine, Chloropyramine, Chlorothen, Histapyrrodine,
Methafurylene, Methaphenilene, Methapyrilene, Phenbenzamine,
Pyrilamine, Talastine, Thenyldiamine, Thonzylamine Hydrochloride,
Tripelennamine and Zolamine;
[0136] Piperazines such as Cetirizine, Chlorcyclizine, Cinnarizine,
Clocinizine and Hydroxyzine;
[0137] Tricyclics, including:
[0138] Phenothiazines such as Ahistan, Etymemazine, Fenethazine,
N-Hydroxyethylpromethazine Chloride, Isopromethazine, Mequitazine,
Promethazine, Pyrathiazine and Thiazinamium Methyl Sulfate; and
[0139] others such as Azatadine, Clobenzepam, Cyproheptadine,
Deptropine, Isothipendyl, Loratadine and Prothipendyl; and
[0140] other antihistamines such as Antazoline, Astemizole,
Azelastine, Cetoxime, Clemizole, Clobenztropine, Diphenazoline,
Diphenhydramine, Fluticasone Propionate, Mebhydroline,
Phenindamine, Terfenadine and Tritoqualine.
[0141] 40. Antihyperlipoproteinemics, including:
[0142] Aryloxyalkanoic acid derivatives such as Beclorbrate,
Bazafibrate, Binifibrate, Ciprofibrate, Clinofibrate, Clofibrate,
Clofibric Acid, Etonfibrate, Fenofibrate, Gemfibrozil, Nicofibrate,
Pirifibrate, Ronifibrate, Simfibrate and Theofibrate;
[0143] Bile acid sequesterants such as Cholestyramine Resin,
Colestipol and Polidexide;
[0144] HMG CoA reductase inhibitors such as Fluvastatin,
Lovastatin, Pravastatin Sodium and Simvastatin;
[0145] Nicotinic acid derivatives Aluminum Nicotinate, Acipimox,
Niceritrol, Nicoclonate, Nicomol and Oxiniacic Acid;
[0146] Thyroid hormones and analogs such as Etiroxate, Thyropropic
Acid and Thyroxine; and
[0147] others such as Acifran, Azacosterol, Benfluorex,
a-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Clomestone,
Detaxtran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic
Acid, Eritadenine, Furazbol, Meglutol, Melinamide, Mytatrienediol,
Ornithine, a-Oryzanol, Pantethine, Penataerythritol Tetraacetate,
a-Phenylbutyramide, Pirozadil, Probucol, a-Sitosterol, Sultosilic
Acid, piperazine Salt, Tiadenol, Triparanol and Xenbucin.
[0148] 41. Antihypertensive drugs, including:
[0149] Arylethanolamine derivatives such as Amosulalol, Bufuralol,
Dilevalol, Labetalol, Pronethalol, Sotalol and Sulfinalol;
[0150] Aryloxypropanolamine derivatives such as Acebutolol,
Alprenolol, Arotinolol, Atenolol, Betaxolol, Bevantolol,
Bisoprolol, Bopindolol, Bunitrolol, Bupranolol, Butofilolol,
Carazolol, Cartezolol, Carvedilol, Celiprolol, Cetamolol, Epanolol,
Indenolol, Mepindolol, Metipranolol, Metoprolol, Moprolol, Nadolol,
Nipradilol, Oxprenolol, Penbutolol, Pindolol, Propranolol,
Talinolol, Tetraolol, Timolol and Toliprolol;
[0151] Benzothiadiazine derivatives such as Althiazide,
Bendroflumethiazide, Benzthiazide, Benzylhydrochlorothiazide,
Buthiazide, Chlorothiazide, Chlorthalidone, Cyclopenthiazide,
Cyclothiazide, Diazoxide, Epithiazide, Ethiazide, Fenquizone,
Hydrochlorothiazide, Hydroflumethiazide, Methyclothiazide,
Meticrane, Metolazone, Paraflutizide, Polythiazide,
Tetrachlormethiazide and Trichlormethiazide;
[0152] N-Carboxyalkyl (peptide/lactam) derivatives such as
Alacepril, Captopril, Cilazapril, Delapril, Enalapril, Enalaprilat,
Fosinopril, Lisinopril, Moveltipril, Perindopril, Quinapril and
Ramipril;
[0153] Dihydropyridine derivatives such as Amlodipine, Felodipine,
Isradipine, Nicardipine, Nifedipine, Nilvadipine, Nisoldipine and
Nitrendipine;
[0154] Guanidine derivatives such as Bethanidine, Debrisoquin,
Guanabenz, Guanacline, Guanadrel, Guanazodine, Guanethidine,
Guanfacine, Guanochlor, Guanoxabenz and Guanoxan;
[0155] Hydrazines and phthalazines such as Budralazine,
Cadralazine, Dihydralazine, Endralazine, Hydracarbazine,
Hydralazine, Pheniprazine, Pildralazine and Todralazine;
[0156] Imidazole derivatives such as Clonidine, Lofexidine,
Phentolamine, Phentolamine Mesylate, Tiamenidine and
Tolonidine;
[0157] Quaternary ammonium compounds Azamethonium Bromide,
Chlorisondamine Chloride, Hexamethonium, Pentacynium Bis(methyl
sulfate), Pentamethonium Bromide, Pentolinium Tartate,
Phenactopinium Chloride and Trimethidiunum Methosulfate;
[0158] Quinazoline derivatives such as Alfuzosin, Bunazosin,
Doxazosin, Prasosin, Terazosin and Trimazosin;
[0159] Reserpine derivatives such as Bietaserpine, Deserpidine,
Rescinnamine, Reserpine and Syrosingopine;
[0160] Sulfonamide derivatives such as Ambuside, Clopamide,
Furosemide, Indapamide, Quinethazone, Tripamide and Xipamide;
and
[0161] others such as Ajmaline, a-Aminobutyric Acid, Bufeniode,
Candesartan, Chlorthalidone, Cicletaine, Ciclosidomine,
Cryptenamine Tannates, Eprosartan, Fenoldopam, Flosequinan,
Indoramin, Irbesartan, Ketanserin, Losartan, Metbutamate,
Mecamylamine, Methyldopa, Methyl 4-Pyridyl Ketone
Thiosemicarbarzone, Metolazone, Minoxidil, Muzolimine, Pargyline,
Pempidine, Pinacidil, Piperoxan, Primaperone, Protoveratrines,
Raubasine, Rescimetol, Rilmenidene, Saralasin, Sodium
Nitroprusside, Ticrynafen, Trimethaphan Camsylate, Tyrosinase,
Urapidil and Valsartan.
[0162] 42. Antihyperthyroids such as 2-Amino-4-methylthiazole,
2-Aminothiazole, Carbimazole, 3,5-Dibromo-L-tyrosine,
3,5-Diiodotyrosine, Hinderin, Iodine, Iothiouracil, Methimazole,
Methylthiouracil, Propylthiouracil, Sodium Perchlorate,
Thibenzazoline, Thiobarbital and 2-Thiouracil.
[0163] 43. Antihypotensive drugs such as Amezinium Methyl Sulfate,
Angiotensin Amide, Dimetofrine, Dopamine, Etifelmin, Etilefrin,
Gepefrine, Metaraminol, Midodrine, Norepinephrine, Pholedrinead and
Synephrine.
[0164] 44. Antihypothyroid drugs such as Levothyroxine Sodium,
Liothyronine, Thyroid, Thyroidin, Thyroxine, Tiratricol and
TSH.
[0165] 45. Anti-Inflammatory (non-steroidal) drugs, including:
[0166] Aminoarylcarboxylic acid derivatives such as Enfenamic Acid,
Etofenamate, Flufenamic Acid, Isonixin, Meclofenamic Acid,
Mefanamic Acid, Niflumic Acid, Talniflumate, Terofenamate and
Tolfenamic Acid;
[0167] Arylacetic acid derivatives such as Acemetacin, Alclofenac,
Amfenac, Bufexamac, Cinmetacin, Clopirac, Diclofenac Sodium,
Etodolac, Felbinac, Fenclofenac, Fenclorac, Fenclozic Acid,
Fentiazac, Glucametacin, Ibufenac, Indomethacin, Isofezolac,
Isoxepac, Lonazolac, Metiazinic Acid, Oxametacine, Proglumetacin,
Sulindac, Tiaramide, Tolmetin and Zomepirac;
[0168] Arylbutyric acid derivatives such as Bumadizon, Butibufen,
Fenbufen and Xenbucin;
[0169] Arylcarboxylic acids such as Clidanac, Ketorolac and
Tinoridine;
[0170] Arylpropionic acid derivatives such as Alminoprofen,
Benoxaprofen, Bucloxic Acid, Carprofen, Fenoprofen, Flunoxaprofen,
Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen,
Loxoprofen, Miroprofen, Naproxen, Oxaprozin, Piketoprofen,
Pirprofen, Pranoprofen, Protizinic Acid, Suprofen and Tiaprofenic
Acid;
[0171] Pyrazoles such as Difenamizole and Epirizole;
[0172] Pyrazolones such as Apazone, Benzpiperylon, Feprazone,
Mofebutazone, Morazone, Oxyphenbutazone, Phenybutazone, Pipebuzone,
Propyphenazone, Ramifenazone, Suxibuzone and
Thiazolinobutazone;
[0173] Salicylic acid derivatives such as Acetaminosalol, Aspirin,
Benorylate, Bromosaligenin, Calcium Acetylsalicylate, Diflunisal,
Etersalate, Fendosal, Gentisic Acid, Glycol Salicylate, Imidazole
Salicylate, Lysine Acetylsalicylate, Mesalamine, Morpholine
Salicylate, 1-Naphthyl Salicylate, Olsalazine, Parsalmide, Phenyl
Acetylsalicylate, Phenyl Salicylate, Salacetamide, Salicylamine
O-Acetic Acid, Salicylsulfuric Acid, Salsalate and
Sulfasalazine;
[0174] Thiazinecarboxamides such as Droxicam, Isoxicam, Piroxicam
and Tenoxicam; and
[0175] others such as .epsilon.-Acetamidocaproic Acid,
S-Adenosylmethionine, 3-Amino-4-hydroxybutyric Acid, Amixetrine,
Bendazac, Benzydamine, Bucolome, Difenpiramide, Ditazol,
Emorfazone, Guaiazulene, Nabumetone, Nimesulide, Orgotein,
Oxaceprol, Paranyline, Perisoxal, Pifoxime, Proquazone, Proxazole
and Tenidap.
[0176] 46. Antimalarial drugs such as Acedapsone, Amodiaquin,
Arteether, Artemether, Artemisinin, Artesunate, Bebeerine,
Berberine, Chirata, Chlorguanide, Chloroquine, Chlorproguanil,
Cinchona, Cinchonidine, Cinchonine, Cycloguanil, Gentiopicrin,
Halofantrine, Hydroxychloroquine, Mefloquine Hydrochloride,
3-Methylarsacetin, Pamaquine, Plasmocid, Primaquine, Pyrimethamine,
Quinacrine, Quinine, Quinine Bisulfate, Quinine Carbonate, Quinine
Dihydrobromide, Quinine Dihydrochloride, Quinine Ethylcarbonate,
Quinine Formate, Quinine Gluconate, Quinine Hydriodide, Quinine
Hydrochloride, Quinine Salicylate, Quinine Sulfate, Quinine
Tannate, Quinine Urea Hydrochloride, Quinocide, Quinoline and
Sodium Arsenate Diabasic.
[0177] 47. Antimigraine drugs such as Alpiropride,
Dihydroergotamine, Eletriptan, Ergocomine, Ergocominine,
Ergocryptine, Ergot, Ergotamine, Flumedroxone acetate, Fonazine,
Lisuride, Methysergid(e), Naratriptan, Oxetorone, Pizotyline,
Rizatriptan and Sumatriptan.
[0178] 48. Antinauseant drugs such as Acetylleucine
Monoethanolamine, Alizapride, Benzquinamide, Bietanautine,
Bromopride, Buclizine, Chlorpromazine, Clebopride, Cyclizine,
Dimenhydrinate, Dipheniodol, Domperidone, Granisetron, Meclizine,
Methalltal, Metoclopramide, Metopimazine, Nabilone, Ondansteron,
Oxypendyl, Pipamazine, Piprinhydrinate, Prochlorperazine,
Scopolamine, Tetrahydrocannabinols, Thiethylperazine,
Thioproperzaine and Trimethobenzamide.
[0179] 49. Antineoplastic drugs, including:
[0180] Alkylating agents, including:
[0181] Alkyl sulfonates such as Busulfan, Improsulfan and
Piposulfan;
[0182] Aziridines such as Benzodepa, Carboquone, Meturedepa and
Uredepa;
[0183] Ethylenimines and methylmelamines such as Altretamine,
Sulfosamide, Triethylenemelamine, Triethylenephosphoramide,
Triethylenethiophosphoramide and Trimethylolomelamine;
[0184] Nitrogen mustards such as Chlorambucil, Chlornaphazine,
Chclophosphamide, Estramustine, Ifosfamide, Mechlorethamine,
Mechlorethamine Oxide Hydrochloride, Melphalan, Novembichin,
Phenesterine, Prednimustine, Trofosfamide and Uracil Mustard;
[0185] Nitrosoureas such as Carmustine, Chlorozotocin, Fotemustine,
Lomustine, Nimustine and Ranimustine; and
[0186] others such as Camptothecin, Dacarbazine, Mannomustine,
Mitobronitol, Mitolactol and Pipobroman;
[0187] Antibiotics such as Aclacinomycins, Actinomycin F.sub.1,
Anthramycin, Azaserine, Bleomycins, Cactinomycin, Carubicin,
Carzinophilin, Chromomycins, Dactinomycin, Daunorubicin,
6-Diazo-5-oxo-L-norleucine, Doxorubicin, Epirubicin, Mitomycins,
Mycophenolic Acid, Nogalamycin, Olivomycins, Peplomycin,
Plicamycin, Porfiromycin, Puromycin, Rufocromomycin, Streptonigrin,
Streptozocin, Tubercidin, Ubenimex, Zinostatin and Zorubicin;
[0188] Antimetabolites, including:
[0189] Folic acid analogs such as Denopterin, Methotrexate,
Pteropterin and Trimetrexate;
[0190] Purine analogs such as Fludarabine, 6-Mercaptopurine,
Thiamiprine and Thioguanaine; and
[0191] Pyrimidine analogs such as Ancitabine, Azacitidine,
6-Azauridine, Carmofur, Cytarabine, Doxifluridine, Enocitabine,
Floxuridine, Fluroouracil and Tegafur;
[0192] Enzymes such as L-Asparaginase; and
[0193] others such as Aceglatone, Amsacrine, Bestrabucil,
Bisantrene, Bryostatin 1, Carboplatin, Cisplatin, Defofamide,
Demecolcine, Diaziquone, Dolastatins, Elfornithine, Elliptinium
Acetate, Etoglucid, Etoposide, Gallium Nitrate, Hydroxyurea,
Interferon-a, Interferon-a, Interferon-a, Interleukine-2, Lentinan,
Letrozole, Lonidamine, Mitoguazone, Mitoxantrone, Mopidamol,
Nitracrine, Pentostatin, Phenamet, Pirarubicin, Podophyllinicc
Acid, 2-Ethythydrazide, Polynitrocubanes, Procarbazine, PSK7,
Razoxane, Sizofiran, Spirogermanium, Symplostatin 1, Taxol,
Teniposide, Tenuazonic Acid, Triaziquone,
2,2',2''-Trichlorotriethylamine, Urethan, Vinblastine, Vincristine,
Vindesine and Vinorelbine.
[0194] 50. Antineoplastic (hormonal) drugs, including:
[0195] Androgens such as Calusterone, Dromostanolone Propionate,
Epitiostanol, Mepitiostane and Testolactone;
[0196] Antiadrenals such as Aminoglutethimide, Mitotane and
Trilostane;
[0197] Antiandrogens such as Flutamide and Nilutamide; and
[0198] Antiestrogens such as Tamoxifen and Toremifene.
[0199] 51. Antineoplastic adjuncts including folic acid
replenishers such as Frolinic Acid.
[0200] 52. Antiparkinsonian drugs such as Amantadine, Apomorphine,
Benserazide, Bietanautine, Biperiden, Bromocriptine, Budipine,
Cabergoline, Carbidopa, Dexetimide, Diethazine, Diphenhydramine,
Droxidopa, Ethopropazine, Ethylbenzhydramine, Levodopa, Naxagolide,
Pergolide, Piroheptine, Pramipexole, Pridinol, Prodipine,
Quinpirole, Remacemide, Ropinirole, Terguride, Tigloidine and
Trihexyphenidyl Hydrochloride.
[0201] 53. Antipheochromocytoma drugs such as Metyrosine,
Phenoxybenzamine and Phentolamine.
[0202] 54. Antipneumocystis drugs such as Effornithine, Pentamidine
and Sulfamethoxazole.
[0203] 55. Antiprostatic hypertrophy drugs such as Gestonorone
Caproate, Mepartricin, Oxendolone and Proscar7.
[0204] 56. Antiprotozoal drugs (Leshmania) such as Antimony Sodium
Gluconate, Ethylstibamine, Hydroxystilbamidine, N-Methylglucamine,
Pentamidine, Stilbamidine and Urea Stibamine.
[0205] 57. Antiprotozoal drugs (Trichomonas) such as Acetarsone,
Aminitrozole, Anisomycin, Azanidazole, Forminitrazole,
Furazolidone, Hachimycin, Lauroguadine, Mepartricin, Metronidazole,
Nifuratel, Nifuroxime, Nimorazole, Secnidazole, Silver Picrate,
Tenonitrozole and Tinidazole.
[0206] 58. Antiprotozoal drugs (Trypanosma) such as Benznidazole,
Eflornithine, Melarsoprol, Nifurtimox, Oxophenarsine,
Hydrochloride, Pentamidine, Propamidine, Puromycin, Quinapyramine,
Stilbamidine, Suramin Sodium, Trypan Red and Tryparasmide.
[0207] 59. Antipuritics such as Camphor, Cyproheptadine,
Dichlorisone, Glycine, Halometasone, 3-Hydroxycamphor, Menthol,
Mesulphen, Methdilazine, Phenol, Polidocanol, Risocaine, Spirit of
Camphor, Thenaldine, Tolpropamine and Trimeprazine.
[0208] 60. Antipsoriatic drugs such as Acitretin, Ammonium
Salicylate, Anthralin, 6-Azauridine, Bergapten(e), Chrysarobin,
Etretinate and Pyrogallol.
[0209] 61. Antipsychotic drugs, including:
[0210] Butyrophenones such as Benperidol, Bromperidol, Droperidol,
Fluanisone, Haloperidol, Melperone, Moperone, Pipamperone,
Sniperone, Timiperone and Trifluperidol;
[0211] Phenothiazines such as Acetophenazine, Butaperazine,
Carphenazine, Chlorproethazine, Chlorpromazine, Clospirazine,
Cyamemazine, Dixyrazine, Fluphenazine, Imiclopazine, Mepazine,
Mesoridazine, Methoxypromazine, Metofenazate, Oxaflumazine,
Perazine, Pericyazine, Perimethazine, Perphenazine, Piperacetazine,
Pipotiazine, Prochlorperazine, Promazine, Sulforidazine,
Thiopropazate, Thioridazine, Trifluoperazine and
Triflupromazine;
[0212] Thioxanthenes such as Chlorprothixene, Clopenthixol,
Flupentixol and Thiothixene;
[0213] other tricyclics such as Benzquinamide, Carpipramine,
Clocapramine, Clomacran, Clothiapine, Clozapine, Opipramol,
Prothipendyl, Tetrabenazine, and Zotepine; and
[0214] others such as Alizapride, Amisulpride, Buramate,
Fluspirilene, Molindone, Penfluridol, Pimozide, Spirilene and
Sulpiride.
[0215] 62. Antipyretics such as Acetaminophen, Acetaminosalol,
Acetanilide, Aconine, Aconite, Aconitine, Alclofenac, Aluminum
Bis(acetylsalicylate), Aminochlorthenoxazin, Aminopyrine, Aspirin,
Benorylate, Benzydamine, Berberine, p-Bromoacetanilide, Bufexamac,
Bumadizon, Calcium Acetysalicylate, Chlorthenoxazin(e), Choline
Salicylate, Clidanac, Dihydroxyaluminum Acetylsalicylate,
Dipyrocetyl, Dipyrone, Epirizole, Etersalate, Imidazole Salicylate,
Indomethacin, Isofezolac, p-Lactophenetide, Lysine
Acetylsalicylate, Magnesium Acetylsalicylate, Meclofenamic Acid,
Morazone, Morpholine Salicylate, Naproxen, Nifenazone,
5'-Nitro-2'-propoxyacetanilide, Phenacetin, Phenicarbazide,
Phenocoll, Phenopyrazone, Phenyl Acetylsalicylate, Phenyl
Salicylate, Pipebuzone, Propacetamol, Propyphenazone, Ramifenazone,
Salacetamide, Salicylamide O-Acetic Acid, Sodium Salicylate,
Sulfamipyrine, Tetrandrine and Tinoridine.
[0216] 63. Antirickettsial drugs such as p-Aminobenzoic Acid,
Chloramphenicol, Chloramphenicol Palmitate, Chloramphenicol
Pantothenate and Tetracycline.
[0217] 64. Antiseborrheic drugs such as Chloroxine,
3-O-Lauroylpyridoxol Diacetate, Piroctone, Pyrithione, Resorcinol,
Selenium Sulfides and Tioxolone.
[0218] 65. Antiseptics, including:
[0219] Guanidines such as Alexidine, Ambazone, Chlorhexidine and
Picloxydine;
[0220] Halogens and halogen compounds such as Bismuth Iodide Oxide,
Bismuth Iodosubgallate, Bismuth Tribromophenate, Bornyl Chloride,
Calcium Iodate, Chlorinated Lime, Cloflucarban, Flurosalan, Iodic
Acid, Iodine, Iodine Monochloride, Iodine Trichloride, Iodoform,
Methenamine Tetraiodine, oxychlorosene, Povidone-Iodine, Sodium
Hypochlorite, Sodium Iodate, Symclosene, Thymol Iodide,
Triclocarban, Triclosan and Troclosene Potassium;
[0221] Mercurial compounds such as Hydragaphen, Meralein Sodium,
Merbromin, Mercuric Chloride, Mercuric Chloride, Ammoniated,
Mercuric Sodium p-Phenolsulfonate, Mercuric Succinimide, Mercuric
Sulfide, Red, Mercurophen, Mercurous Acetate, Mercurous Chloride,
Mercurous Iodide, Nitromersol, Potassium Tetraiodomercurate(II),
Potassium Triiodomercurate(II) Solution, Thimerfonate Sodium and
Thimerosal;
[0222] Nitrofurans such as Furazolidone,
2-(Methoxymethyl)-5-nitrofuran, Nidroxyzone, Nifuroxime, Nifurzide
and Nitrofurazone;
[0223] Phenols such as Acetomeroctol, Bithionol, Cadmium
Salicylate, Carvacrol, Chloroxylenol, Clorophene, Cresote,
Cresol(s), p-Cresol, Fenticlor, Hexachlorophene, 1-Napthyl
Salicylate, 2-Napthyl Salicylate, 2,4,6-Tribromo-m-cresol, and 3',
4',5-Trichlorosalicylanilide;
[0224] Quinolines such as Aminoquinuride, Benzoxiquine,
Broxyquinoline, Chloroxine, Chlorquinaldol, Cloxyquin,
Ethylhydrocupreine, Euprocin, Halquinol, Hydrastine,
8-Hydroxquinoline, 8-Hydroxquinoline Sulfate and
Iodochlorhydroxyquin; and
[0225] others such as Aluminum Acetate Solution, Aluminum
Subacetate Solution, Aluminum Sulfate, 3-Amino-4-hydroxybutyric
Acid, Boric Acid, Chlorhexidine, Chloroazodin, m-Cresyl Acetate,
Cupric Sulfate, Dibromopropamidine, Ichthammol, Negatol7,
Noxytiolin, Ornidazole, a-Propiolactone, a-Terpineol.
[0226] 66. Antispasmodic drugs such as Alibendol, Ambucetamide,
Aminopromazine, Apoatropine, Bevonium Methyl Sulfate,
Bietamiverine, Butaverine, Butropium Bromide, N-Butylscopolammonium
Bromide, Caroverine, Cimetropium Bromide, Cinnamedrine, Clebopride,
Coniine Hydrobromide, Coniine Hydrochloride, Cyclonium Iodide,
Difemerine, Diisopromine, Dioxaphetyl Butyrate, Diponium Bromide,
Drofenine, Emepronium Bromide, Ethaverine, Feclemine, Fenalamide,
Fenoverine, Fenpiprane, Fenpiverinium Bromide, Fentonium Bromide,
Flavoxate, Flopropione, Gluconic Acid, Guaiactamine,
Hydramitrazine, Hymecromone, Leiopyrrole, Mebeverine, Moxaverine,
Nafiverine, Octamylamine, Octaverine, Pentapiperide, Phenamacide
Hydrochloride, Phloroglucinol, Pinaverium Bromide, Piperilate,
Pipoxolan Hydrochloride, Pramiverin, Prifinium Bromide,
Properidine, Propivane, Propyromazine, Prozapine, Racefemine,
Rociverine, Spasmolytol, Stilonium Iodide, Sultroponium, Tiemonium
Iodide, Tiquizium Bromide, Tiropramide, Trepibutone, Tricromyl,
Trifolium, Trimebutine, N,N-1Trimethyl-3,3-diphenyl-propylamine,
Tropenzile, Trospium Chloride and Xenytropium Bromide.
[0227] 67. Antithrombotic drugs such as Anagrelide, Argatroban,
Cilostazol, Chrysoptin, Daltroban, Defibrotide, Enoxaparin,
Fraxiparine7, Indobufen, Lamoparan, Ozagrel, Picotamide,
Plafibride, Reviparin, Tedelparin, Ticlopidine, Triflusal and
Warfarin.
[0228] 68. Antitussive drugs such as Allocamide, Amicibone,
Benproperine, Benzonatate, Bibenzonium Bromide, Bromoform,
Butamirate, Butethamate, Caramiphen Ethanedisulfonate,
Carbetapentane, Chlophedianol, Clobutinol, Cloperastine, Codeine,
Codeine Methyl Bromide, Codeine N-Oxide, Codeine Phosphate, Codeine
Sulfate, Cyclexanone, Dextromethorphan, Dibunate Sodium,
Dihydrocodeine, Dihydrocodeinone Enol Acetate, Dimemorfan,
Dimethoxanate, a,a-Diphenyl-2-piperidinepropanol, Dropropizine,
Drotebanol, Eprazinone, Ethyl Dibunate, Ethylmorphine, Fominoben,
Guiaiapate, Hydrocodone, Isoaminile, Levopropoxyphene, Morclofone,
Narceine, Normethadone, Noscapine, Oxeladin, Oxolamine, Pholcodine,
Picoperine, Pipazethate, Piperidione, Prenoxdiazine Hydrochloride,
Racemethorphan, Taziprinone Hydrochloride, Tipepidine and
Zipeprol.
[0229] 69. Antiulcerative drugs such as Aceglutamide Aluminum
Complex, .epsilon.-Acetamidocaproic Acid Zinc Salt, Acetoxolone,
Arbaprostil, Benexate Hydrochloride, Bismuth Subcitrate Sol
(Dried), Carbenoxolone, Cetraxate, Cimetidine, Enprostil,
Esaprazole, Famotidine, Ftaxilide, Gefamate, Guaiazulene,
Irsogladine, Misoprostol, Nizatidine, Omeprazole, Ornoprostil,
a-Oryzanol, Pifamine, Pirenzepine, Plaunotol, Ranitidine,
Rioprostil, Rosaprostol, Rotraxate, Roxatidine Acetate, Sofalcone,
Spizofurone, Sucralfate, Teprenone, Trimoprostil, Thrithiozine,
Troxipide and Zolimidine.
[0230] 70. Antiurolithic drugs such as Acetohydroxamic Acid,
Allopurinol, Potassium Citrate and Succinimide.
[0231] 71. Antivenin drugs such as Lyovac7 Antivenin.
[0232] 72. Antiviral drugs, including:
[0233] Purines and pyrimidinones such as Acyclovir, Cytarabine,
Dideoxyadenosine, Dideoxycytidine, Dideoxyinosine, Edoxudine,
Floxuridine, Ganciclovir, Idoxuridine, Inosine Pranobex, MADU,
Penciclovir, Trifluridine, Vidrarbine and Zidovudiine; and
[0234] others such as Acetylleucine Monoethanolamine, Amantadine,
Amidinomycin, Cosalane, Cuminaldehyde Thiosemicarbzone, Foscarnet
Sodium, Imiquimod, Interferon-a, Interferon-a, Interferon-a,
Kethoxal, Lysozyme, Methisazone, Moroxydine, Podophyllotoxin,
Ribavirin, Rimantadine, Stallimycin, Statolon, Tromantadine and
Xenazoic Acid.
[0235] 73. Anxiolytic drugs, including:
[0236] Arylpiperazines such as Buspirone, Gepirone, Isapirone and
Tondospirone.
[0237] Benzodiazepine derivatives such as Alprazolam, Bromazepam,
Camazepam, Chlordiazepoxide, Clobazam, Clorazepate, Chotiazepam,
Cloxazolam, Diazepam, Ethyl Loflazepate, Etizolam, Fluidazepam,
Flutazolam, Flutoprazepam, Halazepam, Ketazolam, Lorazepam,
Loxapine, Medazepam, Metaclazepam, Mexazolam, Nordazepam, Oxazepam,
Oxazolam, Pinazepam, Prazepam and Tofisopam;
[0238] Carbamates such as Cyclarbamate, Emylcamate,
Hydroxyphenamate, Meprobamate, Phenprobamate and Tybamate; and
[0239] others such as Alpidem, Benzoctamine, Captodiamine,
Chlormezanone, Etifoxine, Flesinoxan, Fluoresone, Glutamic Acid,
Hydroxyzine, Lesopitron, Mecloralurea, Mephenoxalone, Mirtazepine,
Oxanamide, Phenaglycodol, Suriclone and Zatosetron.
[0240] 74. Benzodiazepine antagonists such as Flumazenil.
[0241] 75. Bronchodilators, including:
[0242] Ephedrine derivatives such as Albuterol, Bambuterol,
Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, Dioxethedrine,
Ephedrine, Epiniphrine, Eprozinol, Etafedrine, Ethylnorepinephrine,
Fenoterol, Hexoprenaline, Isoetharine, Isoproterenol, Mabuterol,
Metaproterenol, N-Methylephedrine, Pirbuterol, Procaterol,
Protokylol, Reproterol, Rimiterol, Salmeterol, Soterenol,
Terbutaline and Tulobuterol;
[0243] Quaternary ammonium compounds such as Bevonium Methyl
Sulfate, Clutropium Bromide, Ipratropium Bromide and Oxitropium
Bromide;
[0244] Xanthine derivatives such as Acefylline, Acefylline
piperazine, Ambuphylline, Aminophylline, Bamifylline, choline
Theophyllinate, Doxofylline, Dyphylline, Enprofylline,
Etamiphyllin, Etofylline, Guaithylline, Proxyphylline, Theobromine,
1-Theobromineacetic Acid and Theophylline; and
[0245] others such as Fenspiride, Medibazine, Montekulast,
Methoxyphenanime, Tretoquinol and Zafirkulast.
[0246] 76. Calcium channel blockers, including:
[0247] Arylalkylamines such as Bepridil, Ditiazem, Fendiline,
Gallopanil, Prenylamine, Terodiline and Verapamil;
[0248] Dihydropyridine derivatives such as Felodipine, Isradipine,
Nicardipine, Nifedipine, Nilvadipine, Nimodipine, Nisoldipine and
Nitrendipine;
[0249] Piperazine derivatives such as Cinnarizine, Flunarisine and
Lidoflazine; and
[0250] others such as Bencyclane, Etafenone and Perhexiline.
[0251] 77. Calcium regulators such as Calcifediol, Calcitonin,
Calcitriol, Clodronic Acid, Dihydrotachysterol, Elcatonin,
Etidronic Acid, Ipriflavone, Pamidronic Acid, Parathyroid Hormone
and Teriparatide Acetate.
[0252] 78. Cardiotonics such as Acefylline, Acetyldigititoxins,
2-Amino-4-picoline, Amrinone, Benfurodil Hemisuccinate,
Buclasdesine, Cerberoside, Camphotamide, Convallatoxin, Cymarin,
Denopamine, Deslanoside, Ditalin, Digitalis, Digitoxin, Digoxin,
Dobutamine, Dopamine, Dopexamine, Enoximone, Erythrophleine,
Fenalcomine, Gitalin, Gitoxin, Glycocyamine, Heptaminol,
Hydrastinine, Ibopamine, Lanotodises, Metamivam, Milrinone,
Neriifolin, Oleandrin, Ouabain, Oxyfedrine, Prenalterol,
Proscillaridin, Resibufogenin, Scillaren, Scillarenin,
Strophanthin, Sulmazole, Theobromine and Xamoterol.
[0253] 79. Chelating agents such as Deferozmine, Ditiocarb Sodium,
Edetate Calcium Disodium, Edetate Disodium, Edeate Sodium, Edetate
Trisodium, Penicillamine, Pentetate Calcium Trisodium, Pentectic
Acid, Succimer and Trientine;
[0254] 80. Cholecystokinin antagonists such as Proglumide.
[0255] 81. Cholelitholytic agents such as Chenodiol, Methyl
tert-Butyl Ether, Monooctanoin and Ursodiol.
[0256] 82. Choleretics such as Alibendol, Anethole Trithion,
Azintamide, Cholic Acid, Cicrotoic Acid, Clanobutin, Cyclobutyrol,
Cyclovalone, Cynarin(e), Dehydrocholic Acid, Deoxycholic Acid,
Dimecrotic Acid, a-Ethylbenzyl Alcohol, Exiproben, Feguprol,
Fencibutirol, Fenipentol, Florantyrone, Hymecromone, Menbutone,
3-(o-Methoxyphenyl)-2-phenylacrylic Acid, Metochalcone, Moquizone,
Osalmid, Ox Bile Extract, 4,4'-Oxydi-2-butanol, Piprozolin,
Prozapine, 4-Salicyloylmorpholine, Sincalide, Taurocholic Acid,
Timonacic, Tocamphyl, Trepibutone and Vanitiolide.
[0257] 83. Cholinergic agents such as Aceclidine, Acetylcholine
Bromide, Acetylcholide Chloride, Aclatonium Napadisilate,
Benzpyrinium Bromide, Bethanechol chloride, Carbachol, Carpronium
chloride, Demecarium Bromide, Dexpanthenol, Diisopropyl Paraoxon,
Echothiophate Iodide, Edrophomium chloride, Eseridine,
Furtrethonium, Isoflurophate, Methacholine chloride, Muscarine,
Neostigmine, Oxapropanium Iodide, Physostigmine and Pyridostigmine
Bromide.
[0258] 84. Cholinesterase inhibitors such as Ambenonium Chloride,
Distigmine Bromide and Galanthamine.
[0259] 85. Cholinesterase reactivators such as Obidoximine Chloride
and Pralidoxime Chloride.
[0260] 86. Central nervous system stimulants and agents such as
Amineptine, Amphetimine, Amphetaminil, Bemegride, Benzphetamine,
Brucine, Caffeine, Chlorphentermine, Clofenciclan, Clortermine,
Coca, Demanyl Phosphate, Dexoxadrol, Dextroamphetamine Sulfate,
Diethlpropion, N-Ethylamphetamine, Ethamivan, Etifelmin,
Etryptamine, Fencamfamine, Fenethylline, Fenosolone, Flurothyl,
Galanthamine, Hexacyclonate Sodium, Homocamfin, Mazindol,
Megexamide, Methamphetamine, Methylphenidate, Nikethamide,
Pemoline, Pentylenetetrazole, Phenidimetrazine, Phenmetrazine,
Phentermine, Picrotoxin, Pipradrol, Prolintane and
Pyrovalerone.
[0261] 87. Decongestants such as Amidephrine, Cafaminol,
Cyclopentamine, Ephedrine, Epinephrine, Fenoxazoline, Indanazoline,
Metizoline, Naphazoline, Nordefrin Hydrochloride, Octodrine,
Oxymetazoline, Phenylephrine Hydrochloride, Phenylpropanolamine
Hydrochloride, Phenylpropylmethylamine, Propylhexedrine,
Pseudoephedrine, Tetrahydrozoline, Tymazoline and
Xylometazoline.
[0262] 88. Dental agents, including:
[0263] Bisphosphonates (anti-periodontal disease and bone
resorption) such as Alendronate, Clodronate, Etidronate,
Pamidronate and Tiludronate;
[0264] Carries Prophylactics such as Arginine and Sodium Fluoride;
Desensitizing Agents such as Potassium Nitrate and Citrate
Oxalate.
[0265] 89. Depigmentors such as Hydroquinine, Hydroquinone and
Monobenzone.
[0266] 90. Diuretics, including:
[0267] organomercurials such as Chlormerodrin, Meralluride,
Mercamphamide, Mercaptomerin Sodium, Mercumallylic Acid,
Mercumatilin Sodium, Mercurous Chloride and Mersalyl;
[0268] Pteridines such as Furterene and Triamterene;
[0269] Purines such as Acefylline, 7-Morpholinomethyltheophylline,
Pamabrom, Protheobromine and Theobromine;
[0270] Steroids such as Canrenone, Oleandrin and
Spironolactone;
[0271] Sulfonamide derivatives such as Acetazolmide, Ambuside,
Azosemide, Bumetanide, Butazolamide, Chloraminophenamide,
Clofenamide, Clopamide, Clorexolene,
Diphenylmethane-4,4'-disulfonamide, Disulfamide, Ethoxzolamide,
Furosemide, Indapamide, Mefruside, Methazolamide, Piretanide,
Quinethazone, Torsemide, Tripamide and Xipamide;
[0272] Uracils such as Aminometradine and Amisometradine;
[0273] others such as Amanozine, Amiloride, Arbutin, Chlorazanil,
Ethacrynic Acid, Etozolin, Hydracarbazine, Isosorbide, Mannitol,
Metochalcone, Muzolimine, Perhexiline, Ticrynafen and Urea.
[0274] 91. Dopamine receptor agonists such as Bromocriptine,
Dopexamine, Fenoldopam, Ibopamine, Lisuride, Naxagolide and
Pergolide.
[0275] 92. Ectoparasiticides such as Amitraz, Benzyl Benzoate,
Carbaryl, Crotamiton, DDT, Dixanthogen, Isobornyl
Thiocyanoacetate--Technical, Lime Sulfurated Solution, LIndane,
Malathion, Mercuric Oleate, Mesulphen and
Sulphur--Pharmaceutical.
[0276] 93. Enzymes, including:
[0277] Digestive enzymes such as a-Amylase (Swine Pancreas),
Lipase, Pancrelipase, Pepsin and Rennin;
[0278] Mucolytic enzymes such as Lysozyme;
[0279] Penicillin inactivating enzymes such as Penicillinase;
and
[0280] Proteolytic enzymes such as Collagenase, Chymopapain,
Chymotrypsins, Papain and Trypsin.
[0281] 94. Enzyme inducers (hepatic) such as Flumecinol.
[0282] 95. Estrogens (non-steroidal) such as Benzestrol,
Broparoestrol, Chlorotrianisene, Dienestrol, Diethylstilbestrol,
Diethylstilbestrol Diproprionate, Dimestrol, Fosfestrol, Hexestrol,
Methallenestril and Methestrol.
[0283] 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
[0284] 96. Gastric secretion inhibitors such as Enterogastrone and
Octreotide.
[0285] 97. Glucocorticoids such as 21-Acetoxyprefnenolone,
Aalclometasone, Algestone, Amicinonide, Beclomethasone,
Betamethasone, Budesonide, Chloroprednisone, Clobetasol,
Blovetasone, Clocortolone, Cloprednol, Corticosterone, Cortisone,
Cortivazol, Deflazacort, Desonide, Desoximetasone, Dexamethasone,
Diflorasone, Diflucortolone, Difluprednate, Enoxolone, Fluazacort,
Flucloronide, Flumehtasone, Flunisolide, Fluocinolone Acetonide,
Fluocinonide, Fluocortin Butyl, Fluocortolone, Fluorometholone,
Fluperolone Acetate, Fluprednidene Acetate, Fluprednisolone,
Flurandrenolide, Formocortal, Halcinonide, Halometasone,
Halopredone Acetate, Hydrocortamate, Hydrocortisone, Hydrocortisone
Acetate, ydrocortisone Phosphate, Hydrocortisone 21-Sodium
Succinate, Hydrocortisone Tebutate, Mazipredone, Medrysone,
Meprednisone, Methyolprednisolone, Mometasone Furoate,
Paramethasone, Prednicarbate, Prednisolone, Prednisolone
21-Diethylaminoacetate, Prednisone Sodium Phosphate, Prednisolone
Sodium Succinate, Prednisolone Sodium 21-m-Sulfobenzoate,
Prednisolone 21-Stearoylglycolate, Prednisolone Tebutate,
Prednisolone 21-Trimethylacetate, Prednisone, Prednival,
Prednylidene, Prednylidene 21-Diethylaminoacetate, Tixocortal,
Triamcinolone, Triamcinolone Acetonide, Triamcinolone Benetonide
and Triamcinolone Hexacetonide.
[0286] 98. Gonad-Stimulating principles such as Buserelin,
Clomiphene, Cyclofenil, Epimestrol, FSH, HCG and LH-RH.
[0287] 99. Gonadotropic hormones such as LH and PMSG.
[0288] 100. Growth hormone inhibitors such as Octreotide and
Somatostatin.
[0289] 101. Growth hormone releasing factors such as Semorelin.
[0290] 102. Growth stimulants such as Somatotropin.
[0291] 103. Hemolytic agents such as Phenylhydrazine and
Phenylhydrazine Hydrochloride.
[0292] 104. Heparin antagonists such as Hexadimethrine Bromide and
Protamines.
[0293] 105. Hepatoprotectants such as S-Adenosylmethionine,
Betaine, Catechin, Citolone, Malotilate, Orazamide,
Phosphorylcholine, Protoporphyrin IX, Silymarin-Group, Thiotic Acid
and Tiopronin.
[0294] 106. Immunomodulators such as Amiprilose, Bucillamine,
Ditiocarb Sodium, Inosine Pranobex, Interferon-y, Interleukin-2,
Lentinan, Muroctasin, Platonin, Procodazole, Tetramisole,
Thymomodulin, Thymopentin and Ubenimex.
[0295] 107. Immunosuppressants such as Azathioprine, Cyclosporins
and Mizoribine.
[0296] 108. Ion exchange resins such as Carbacrylic Resins,
Cholestyramine Resin, Colestipol, Polidexide, Resodec and Sodium
Polystyrene Sulfonate.
[0297] 109. Lactation stimulating hormone such as Prolactin.
[0298] 110. LH-RH agonists such as Buserelin, Goserelin, Goserelin
Acetate, Leuprolide, Nafarelin, and Triptorelin.
[0299] 111. Lipotropic agents such as N-Acetylmethionine, Choline
Chloride, Choline Dehydrocholate, Choline Dihydrogen Citrate,
Inositol, Lecithin and Methionine.
[0300] 112. Lupus erythematosus suppressants such as Bismuth Sodium
Triglycollamate, Bismuth Subsalicylate, Chloroquine and
Hydroxychloroquine.
[0301] 113. Mineralcorticoids such as Aldosterone,
Deoxycorticosterone, Deoxycorticosterone Acetate and
Fludrocortisone.
[0302] 114. Miotic drugs such as Carbachol, Physostigmine,
Pilocarpine and Pilocarpus.
[0303] 115. Monoamine oxidase inhibitors such as Deprenyl,
Iproclozide, Iproniazid, Isocarboxazid, Moclobemide, Octomoxin,
Pargyline, Phenelzine, Phenoxypropazine, Pivalylbenzhydrazine,
Prodipine, Toloxatone and Tranylcypromine.
[0304] 116. Mucolytic agents such as Acetylcysteine, Bromhexine,
Carbocysteine, Domiodol, Letosteine, Lysozyme, Mecysteine
Hydrochloride, Mesna, Sobrerol, Stepronin, Tiopronin and
Tyloxapol.
[0305] 117. Muscle relaxants (skeletal) such as Afloqualone,
Alcuronium, Atracurium Besylate, Baclofen, Benzoctamine,
Benzoquinonium Chloride, C-Calebassine, Carisoprodol,
Chlormezanone, Chlorphenesin Carbamate, Chlorproethazine,
Chlozoxazone, Curare, Cyclarbamate, Cyclobenzaprine, Dantrolene,
Decamethonium Bromide, Diazepam, Eperisone, Fazadinium Bromide,
Flumetramide, Gallamine Triethiodide, Hexacarbacholine Bromide,
Hexafluorenium Bromide, Idrocilamide, Lauexium Methyl Sulfate,
Leptodactyline, Memantine, Mephenesin, Mephenoxalone, Metaxalone,
Methocarbamol, Metocurine Iodide, Nimetazepam, Orphenadrine,
Pancuronium Bromide, Phenprobamate, Phenyramidol, Pipecurium
Bromide, Promoxolane, Quinine Sulfate, Styramate, Succinylcholine
Bromide, Succinylcholine Chloride, Succinylcholine Iodine,
Suxethonium Bromide, Tetrazepam, Thiocolchicoside, Tizanidine,
Tolperisone, Tubocurarine Chloride, Vecuronium Bromide and
Zoxolamine.
[0306] 118. Narcotic antagonists such as Amiphenazole, Cyclazocine,
Levallorphan, Nadide, Nalmfene, Nalorphine, Nalorphine
Dinicotinate, Naloxone and Naltrexone.
[0307] 119. Neuroprotective agents such as Dizocilpine.
[0308] 120. Nootropic agents such as Aceglutamide, Acetylcarnitine,
Aniracetam, Bifematlane, Exifone, Fipexide, Idebenone, Indeloxazune
Hydrochloride, Nizofenone, Oxiracetam, Piracetam, Propentofylline,
Pyritinol and Tacrine.
[0309] 121. Ophthalmic agents such as 15-ketoprostaglandins.
[0310] 122. Ovarian hormone such as Relaxin.
[0311] 123. Oxytocic drugs such as Carboprost, Cargutocin,
Deaminooxytocin, Ergonovine, Gemeprost, Methylergonovine, Oxytocin,
Pituitary (Posterior), Prostaglandin E.sub.2, Prostaglandin
F.sub.2a and Sparteine.
[0312] 124. Pepsin inhibitors such as Sodium Amylosulfate.
[0313] 125. Peristaltic stimulants such as Cisapride.
[0314] 126. Prolactin inhibitors such as Metergoline.
[0315] 127. Prostaglandins and prostaglandin analogs such as
Arbaprostil, Carboprost, Enprostil, Bemeprost, Limaprost,
Misoprostol, Ornoprostil, Prostacyclin, Prostaglandin E.sub.1,
Prostaglandin E.sub.2, Prostagland in F.sub.2a Rioprostil,
Rosaprostol, Sulprostone and Trimoprostil.
[0316] 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. 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.
[0317] 128. Protease inhibitors such as Aprotinin, Camostat,
Gabexate and Nafamostat.
[0318] 129. Respiratory stimulants such as Almitrine, Bemegride,
Carbon Dioxide, Cropropamide, Crotethamide, Dimefline,
Dimorpholamine, Doxapram, Ethamivan, Fominoben, Lobeline,
Mepixanox, Metamivam, Nikethamide, Picrotoxin, Pimeclone,
Pyridofylline, Sodium Succinate and Tacrine.
[0319] 130. Sclerosing agents such as Ethanolamine, Ethylamine,
2-Hexyldecanoic Acid, Polidocanol, Quinine Bisulfate, Quinine Urea
Hydrochloride, Sodium Ricinoleate, Sodium Tetradecyl Sulfate and
Tribenoside.
[0320] 131. Sedatives and hypnotics, including:
[0321] Acyclic ureides such as Acecarbromal, Apronalide,
Bomisovalum, Capuride, Carbromal and Ectylurea;
[0322] Alcohols such as Chlorhexadol, Ethchlorvynol, Meparfynol,
4-Methyl-5-thiazoleethanol, tert-Pentyl Alcohol and
2,2,2-Trichloroethanol;
[0323] Amides such as Butoctamide, Diethylbromoacetamide,
Ibrotamide, Isovaleryl Diethylamide, Niaprazine, Tricetamide,
Trimetozine, Zolpidem and Zopiclone;
[0324] Barbituric acid derivatives such as Allobarbital,
Amobarbital, Aprobarbital, Barbital, Brallabarbital, Butabarbital
Sodium, Butalbital, Butallylonal, Butethal, Carbubarb,
Cyclobarbital, Cyclopentobarbital, Enallylpropymal,
5-Ethyl-5-(1-piperidyl) barbituric Acid,
5-Furfuryl-5-isopropylbarbituric Acid, Heptabarbital, Hexethal
Sodium, Hexobarbital, Mephobarbital, Methitural, Narcobarbital,
Nealbarbital, Pentobarbital Sodium, Phenallymal, Phenobarbital,
Phenobarbital Sodium, Phenylmethylbarbituric Acid, Probarbital,
Propallylonal, Proxibarbal, Reposal, Secobarbital Sodium, Talbutal,
Tetrabarbital, Vinbarbital Sodium and Vinylbital;
[0325] Benzodiazepine derivatives such as Brotizolam, Doxefazepam,
Estazolam, Flunitrazepam, Flurazepam, Haloxazolam, Loprazolam,
Lormetazepam, Nitrazepam, Quazepam, Temazepam and Triazolam;
[0326] Bromides such as Ammonium Bromide, Calcium Bromide, Calcium
Bromolactobionate, Lithium Bromide, Magnesium Bromide, Potassium
Bromide and Sodium Bromide;
[0327] Carbamates such as Amyl Carbamate--Tertiary, Ethinamate,
Hexaprpymate, Meparfynol Carbamate, Novonal and
Tricholorourethan;
[0328] Chloral derivatives such as Carbocloral, Chloral Betaine,
Chloral Formamide, Chloral Hydrate, Chloralantipyrine,
Dichloralphenazone, Pentaerythritol Chloral and Triclofos;
[0329] Piperidinediones such as Glutehimide, Methyprylon,
Piperidione, Pyrithyldione, Taglutimide and Thalidomide;
[0330] Quinazolone derivatives such as Etaqualone, Mecloqualone and
Methaqualone; and
[0331] others such as Acetal, Acetophenone, Aldol, Ammonium
Valerate, Amphenidone, d-Bornyl a-Bromoisovalerate, d-Bornyl
Isovalerate, Bromoform, Calcium 2-Ethylbutanoate, Carfinate,
a-Chlorolose, Clomethiazole, Cypripedium, Doxylamine, Etodroxizine,
Etomidate, Fenadiazole, Homofenazine, Hydrobromic Acid,
Mecloxamine, Menthyl Valerate, Opium, Paraldehyde, Perlapine,
Propiomazine, Rilmazafone, Sodium Oxybate, Sulfonethylmethane and
Sulfonmethane.
[0332] 132. Thrombolytic agents such as APSAC, Plasmin,
Pro-Urokinase, Streptokinase, Tissue Plasminogen Activator and
Urokinase.
[0333] 133. Thyrotropic hormones such as TRH and TSH.
[0334] 134. Uricosurics such as Benzbromarone, Ethebenecid, Orotic
Acid, Oxycinchophen, Probenecid, Sulfinpyrazone, Ticrynafen and
Zoxazolamine.
[0335] 135. Vasodilators (cerebral) such as Bencyclane,
Cinnarizine, Citicoline, Cyclandelate, Ciclonicate,
Diisopropylamine Dichloractetate, Ebumamonine, Fenoxedil,
Flunarizine, Ibudilast, Ifenprodil, Nafronyl, Nicametate,
Nicergoline, Nimodipine, Papaverine, Pentifylline, Tinofedrine,
Vincamine, Vinpocetine and Viquidil.
[0336] 136. Vasodilators (coronary) such as Amotriphene, Bendazol,
Benfurodil Hemisuccinate, Benziodarone, Chloacizine, Chromonar,
Clobenfurol, Clonitrate, Dilazep, Dipyridamole, Droprenilamine,
Efloxate, Erythritol, Erythrityl Tetranitrate, Etafenone,
Fendiline, Floredil, Ganglefene, Hexestrol Bis(p-diethylaminoethyl
ether), Hexobendine, Itramin Tosylate, Khellin, Lidoflazine,
Mannitol Hexanitrate, Medibazine, Nicorandil, Nitroglycerin,
Pentaerythritol Tetranitrate, Pentrinitrol, Perhexiline,
Pimethylline, Prenylamine, Propatyl Nitrate, Pyridofylline,
Trapidil, Tricromyl, Trimetazidine, TroInitrate Phosphate and
Visnadine.
[0337] 137. Vasodilators (peripheral) such as Aluminum Nicotinate,
Bamethan, Bencyclane, Betahistine, Bradykinin, Brovincamine,
Bufoniode, Buflomedil, Butalamine, Cetiedil, Ciclonicate,
Cinepazide, Cinnarizine, Cyclandelate, Diisopropylamine
Dichloracetate, Eledoisin, Fenoxidil, Flunarisine, Heronicate,
Ifenprodil, Inositol Niacinate, Isoxsuprine, Kallidin, Kallikrein,
Moxisylyte, Nafronyl, Nicametate, Nicergoline, Nicofuranose,
Nicotinyl Alcohol, Nylidrin, Pentifylline, Pentoxifylline,
Piribedil, Protaglandin E.sub.1, Suloctidil and Xanthinal
Niacinate.
[0338] 138. Vasoprotectants such as Benzarone, Bioflavonoids,
Chromocarb, Clobeoside, Diosmin, Dobesilate Calcium, Escin,
Rolescutol, Leucocyanidin, Metescufylline, Quercetin, Rutin and
Troxerutin.
[0339] 139. Vitamins, vitamin sources, and vitamin extracts such as
Vitamins A, B, C, D, E, and K and derivatives thereof, Calciferols,
Glycyrrhiza and Mecobalamin.
[0340] 140. Vulnerary agents such as Acetylcysteine, Allantoin,
Asiaticoside, Cadexomer Iodine, Chitin, Dextranomer and
Oxaceprol.
[0341] 141. Anticoagulants such as heparin.
[0342] 142. Miscellaneous such as Erythropoietin (Hematinic),
Filgrastim, Finasteride (Benign Prostate Hypertrophy), Interferon
Beta 1--Alpha (Multiple Sclerosis) and Tretinonin (Urinary
Incontinence).
[0343] Particular drugs that are usable in the present invention
include low molecular weight drugs. Any drug which is liquid at or
about room temperature can be used according to the present
invention. As used herein, the term "low molecular weight" is
defined to include any drug and its equivalent forms that has a
melting point such that it exists as a liquid at or about room
temperatures. This term encompasses low molecular weight drugs
having a molecular weight of less than about 300 daltons. A drug
which is of low molecular weight and liquid at or about room
temperatures is generally in its free-base or free-acid form, and,
as such, is encompassed by this term. Drugs usable in practicing
the invention include amphetamine, d-amphetamine, l-amphetamine,
d,l-amphetamine, methaphetamine, prilocalne, benzocaine, butacaine,
butamben, butanilicaine, corticaine, lidocaine, memantine,
pilocarpine, cyclobenzaprine, paroxetine, fluoxetine, duloxetine,
imipramine, decipramine, doxeprin, nortriptylene, protriptylene,
bupropion, azelastine, chlorphenamine, bisoprolol, pheniramine,
alprazolam, captopril, clonidine, clonazepam, enalapril, ramipril,
haloperidol, ketoprofen, loratadine, methimazole
(anti-hyperthyroid), methylphenidate, methyl testosterone,
nicotine, nitroglycerin, pramipexole, ropinirole, hydromorphone,
scopolamine, testosterone, methamphetamine, frovatriptan and
phentermine. For desired therapeutic effect, it may be desirable
certain drugs, such as methylphenidate, d-amphetamine,
methamphetamine and phentermine, be used in their base form.
[0344] The amount of drug to be incorporated in the composition
varies depending on the particular drug, the desired therapeutic
effect, and the time span for which the device is to provide
therapy. For most drugs, the passage of the drugs through the skin
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
transdermal delivery characterized by a 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 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 about 50%. However, the composition of this invention
is particularly useful for drugs which are used in relatively low
concentrations, especially 0.3% to 30% of the total composition,
more preferably from about 0.5% to about 15% of the total
composition, most preferably from about 1% to about 10% of the
total composition.
[0345] One preferred drug in clonidine. Clonidine is an
anti-sympathicotonic agent having an imidazoline structure. It has
affinity for .alpha..sub.1-adrenoceptors and--more strongly--for
pre- and post-synaptic .alpha..sub.2-adrenoceptors and lowers
peripheral sympathetic tone. It is believed that clonidine lowers
blood pressure by decreasing cardiac output and--in the case of
prolonged medication--by reducing peripheral vascular resistance.
At the same time, it is believed that clonidine reduces the release
of renin with a decrease in angiotensin II in the blood plasma,
with aldosterone being released from the adrenal cortex.
[0346] Clonidine may be used, for example, in treating the
following indications: hypertension, migraine, anxiety states,
hyperkinetic behavioural disorders, withdrawal symptoms in alcohol
or drug withdrawal, and menopausal symptoms.
[0347] Clonidine hydrochloride exists in the form of a mesomeric
component. The chemical name is
2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride. Clonidine
has the following molecular formula:
C.sub.9H.sub.9Cl.sub.2N.sub.3HCl, and a molecular weight of
266.56.
[0348] As used herein, the term "supersaturated" used in reference
to the drug means that the amount of drug present is in excess of
its solubility or dispersability in a multiple polymer adhesive
system.
[0349] Referring to FIG. 1, the most preferred embodiment of the
invention, transdermal drug delivery system 10 comprises a carrier
composition layer 12 incorporating the active agent. Surface 14 of
the adhesive carrier composition layer 12 is affixed to release
liner 15 to protect the carrier composition layer prior to use but
which is removed upon topical application of the carrier
composition layer to the skin or mucosa of the user. A non-drug
containing backing layer 18 is affixed to the other surface 20 of
the carrier composition layer 12. As discussed in more detail
below, backing layer 18 may be made of any suitable material to
tailor delivery of the active agent from the carrier composition
layer 12 to the skin or mucosa of the user. The backing layer 18
may be processed separately from carrier layer 12 or may be
processed together with the carrier composition layer 12.
[0350] Carrier composition layer 12 can comprise any polymer or
adhesive generally known in the art for formulating a drug carrier
composition, and include all of the non-toxic natural and synthetic
polymers known or suitable for use in transdermal systems including
solvent-based, hot melt and grafted adhesives, and may be used
alone or in combinations, mixtures or blends. Examples include
acrylic-based polymer(s), silicone-based polymer(s), rubbers, gums,
polyisobutylenes, polyvinylethers, polyurethanes, styrene block
copolymers, styrene/butadiene polymers, polyether block amide
copolymers, ethylene/vinyl acetate copolymers, and vinyl acetate
based adhesives, and bioadhesives as set forth in U.S. Pat. No.
6,562,363 which is expressly incorporated by reference in its
entirety.
[0351] The term "silicone-based" polymer is intended to be used
interchangeably with the terms siloxane, polysiloxane, and
silicones as used herein and as known in the art. The
silicone-based polymer may also be a pressure-sensitive adhesive,
with a polysiloxane adhesive prepared by cross-linking an
elastomer, typically a high molecular weight polydiorganosiloxane,
with a resin, to produce a three-dimensional siloxane structure,
via a condensation reaction in an appropriate organic solvent. The
ratio of resin to elastomer is a critical factor that can be
adjusted in order to modify the physical properties of polysiloxane
adhesives. Sobieski, et al., "Silicone Pressure Sensitive
Adhesives," Handbook of Pressure-Sensitive Adhesive Technology. 2nd
ed., pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York
(1989). Further details and examples of silicone pressure-sensitive
adhesives which are useful in the practice of this invention are
described in the following U.S. Pat. Nos. 4,591,622; 4,584,355;
4,585,836; and 4,655,767, all expressly incorporated by reference
in their entireties. Suitable silicone pressure-sensitive adhesives
are commercially available and include the silicone adhesives sold
under the trademarks BIO-PSA.RTM. by Dow Corning Corporation,
Medical Products, Midland, Mich. (such as -2685, -3027, -3122,
-4101, -4102, -4203, -4301, -4302, -4303, -4401 -4403, -4501,
-4503, -4602, -4603 and -4919). Capped silicones with high resin
content are preferred.
[0352] In the practice of the preferred embodiments of the
invention, the carrier composition layer 12 includes an
acrylic-based polymer. The acrylic-based polymer can be any of the
homopolymers, copolymers, terpolymers, and the like of various
acrylic acids. In such preferred embodiments, the acrylic-based
polymer constitutes from about 2% to about 95% of the total dry
weight of the of the carrier composition, and preferably from about
2% to about 90%, and more preferably from about 2% to about 85% of
the carrier composition, wherein the amount of the acrylic-based
polymer is dependent on the amount and type of drug used.
[0353] The acrylic-based polymers usable in the invention are
polymers of one or more monomers of acrylic acids and other
copolymerizable monomers. The acrylate polymers also include
copolymers of alkyl acrylates and/or methacrylates and/or
copolymerizable secondary monomers or monomers with functional
groups. By varying the amount of each type of monomer added, the
cohesive properties of the resulting acrylate polymer can be
changed as is known in the art. In general, the acrylate polymer 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.
[0354] Acrylate monomers which can be used include acrylic acid,
methacrylic acid, butyl acrylate, butyl methacrylate, hexyl
acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl
methacrylate, isooctyl acrylate, isooctyl methacrylate,
2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate,
decyl methacrylate, dodecyl acrylate, dodecyl methacrylate,
tridecyl acrylate, and tridecyl methacrylate.
[0355] Functional monomers, copolymerizable with the above alkyl
acrylates or methacrylates, which can be used include acrylic acid,
methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl
acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide,
acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl
methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl
methacrylate, methoxyethyl acrylate and methoxyethyl
methacrylate.
[0356] Suitable acrylic-based polymers may also be a
pressure-sensitive adhesive which are commercially available and
include the acrylic-based adhesives sold under the trademarks
Duro-Tak.RTM. by National Starch and Chemical Corporation,
Bridgewater, N.J. (such as 87-2287, -4098, -2852, -2196, -2296,
-2194, -2516, -2070, -2353, -2154, -2510, -9085 -9088 and 73-9301).
Other suitable acrylic-based adhesives include those sold by
Monsanto; St. Louis, Mo., under the trademarks Gelva.RTM.
Multipolymer Solution (such as 2480, 788, 737, 263, 1430, 1753,
1151, 2450, and 2495 and Eudragit.RTM. sold by Roehm Pharma GmbH,
Darmstadt, Federal Republic of Germany.
[0357] The carrier composition may comprise blends of acrylic-based
polymers, silicone-based polymers and rubbers based upon their
differing solubility parameters, alone or in combination with other
polymers, for example polyvinylpyrrolidone, as more fully described
in U.S. Pat. Nos. 5,474,783; 5,656,286; 5,958,446; 6,024,976;
6,221,383; and 6,235,306; which are incorporated herein in their
entirety. The amount of each polymer is selected to adjust the
saturation concentration of the drug in the multiple polymer
system, and to result in the desired rate of delivery of the drug
from the system and through the skin or mucosa.
[0358] Combinations of acrylic-based polymers based on their
functional groups is also contemplated. Acrylic-based polymers
having functional groups are copolymers or terpolymers which
contain in addition to nonfunctional monomer units, 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. 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 methacrylate, 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.
[0359] 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.
[0360] For example, a 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 transdermal
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 composition.
[0361] 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.
[0362] The required proportions of acrylic-based or other polymers
used are generally dependant on the specific drug, its desired
delivery rate and the desired duration of drug delivery. In
general, proportions of acrylic-based polymers also depend on the
content of the functional monomer units in the functional
acrylic.
[0363] When the drug carrier composition is intended to function as
the face layer, that is the layer 14 that comes in contact with the
topical site of application as depicted in FIG. 1, it is preferable
that the carrier composition comprise a pressure-sensitive adhesive
or bioadhesive.
[0364] The backing layer 18 comprises at least one layer, the
primary layer having a high water vapor transmission rate and a
moderate to low gas transmission rate. Thus, the backing has a
water vapor transmission rate about equal to or in excess of that
of ethylene vinyl alcohol copolymer (EVOH) and a gas transmission
rate about equal to or less than EVOH, in which the EVOH is of
about 0.2 to 3 mil thickness. The backing can comprise additional
polymeric layers, for example, a second layer having a high water
vapor transmission rate, as well as additional layers. The
additional layers can be placed on one or both sides of the first
layer. Suitable backings are disclosed in U.S. Pat. No. 4,994,278
which is herein incorporated by reference in its entirety.
[0365] Basically, the backing material is constructed of a barrier
polymer or resin or other permeable material. The term "barrier" is
used here in reference to a material's resistance to absorption,
diffusion, and desorption of gases, moisture and other chemicals.
By the use of certain barrier materials, a film can be made
selectively permeable to water or other liquid vapor rather than
gas or vice versa. The backing layer 18 has a thickness from about
0.2 mm to about 3 mm.
[0366] The permeability to gas and moisture vapor is known or can
be computed using standardized tests. A comparison of different
plastics is found in "Barrier Resins Key New Package Development",
Plastics Packaging, July/August 1988, pp. 17-21. TABLE-US-00001
TABLE 1 Comparison of Barrier Properties for Commercial polymers
Moisture Vapor Oxygen Transmission Transmission Rate 25.degree. C.,
65/RH Rate, 40.degree. C., 90/RH (cc-mil/100 in.sup.2 - (cc-mil/100
in.sup.2 Material 24 hours) 2 hours) Ethylene vinyl 0.05 to 0.18
1.4 to 5.4 alcohol Polyvinylidene 0.15 to 0.90 0.1 to 0.2 chloride
Acrylonitrile 0.80 5.0 Amorphous nylon 0.74 to 2.0 Oriented
polyester 2.60 1.2 terephthalate Oriented nylon 2.10 9.0 Rigid
polyvinyl 14.0 3.0 chloride Low density 420 1.0 to 1.5 polyethylene
High density 150 0.4 polyethylene Polypropylene 150 0.69
Polystyrene 350 7 to 10
[0367] In the above table, oxygen transmission rate is expressed in
cubic centimeters of oxygen of 1 mil film per 100 square inches
surface area per 24 hours at 65% relative humidity (RH) and
25.degree. Celsius (.degree. C.) and moisture vapor transmission
rate is expressed in cubic centimeters per 100 square inches of
surface area of 1 mil film per 24 hours at 40 degrees Celsius
(.degree. C.) and 90% relative humidity
[0368] Additional moisture vapor transmission rates are:
TABLE-US-00002 TABLE 2 Moisture Vapor Transmission Rate (40.degree.
C./90% R.H.) g 30 microns/ g. mil/100 m.sup.2/24 Hrs in.sup.2/24
Hrs Biaxially Oriented 5 0.38 Polypropylene High Density 5 0.38
Polyethylene Polypropylene 9 0.69 Low Density 15 1.14 Polyethylene
Biaxially Oriented 15 1.2 Polyester Terephthalate Rigid Polyvinyl
Chloride 40 3.1 Polystyrene 112 8.5 Biaxially Oriented Nylon 6 134
10.0 Polycarbonate 14.5 1.1 EVAL EP-F 50 3.8 EVAL EP-H 28 2.1 EVAL
EP-K 28 2.1 EVAL EP-E 19 1.4 EVAL EP-G 19 1.4 Saran 5253 PVC 3 0.22
Barex 210 Nitrile 80 6.1
[0369] A suitable backing layer 18 according to the present
invention should:
[0370] 1. Maintain its physical and chemical integrity in the
environment of use;
[0371] 2. Provide mechanical support for the other laminae forming
a laminate carrier;
[0372] 3. Be substantially impermeable to the pharmacological
agent;
[0373] 4. Be selectively permeable to the passage of internal water
vapor; and
[0374] 5. Be substantially impermeable to gases to water or
moisture but permeable to water vapor.
[0375] The molecular weight of the polymers selected for the
backing are such that the backing has the foregoing characteristics
and the layers, the indicated water vapor and oxygen transmission
rates.
[0376] Suitable polymeric materials for the transdermal backing
include acrylonitrile, cellulose acetate, polycarbonate, ethylene
vinyl acetate, ethylene methyl acrylate, polyester, polyethylene,
polypropylene, polystyrene, polyurethane, polyvinyl alcohol,
ethylene vinyl alcohol, polyamides, polyvinylidene chloride and
polyvinyl chloride. Some polymers increase barrier properties by
orienting the polymer chains in one or two directions.
[0377] The backing material of this invention comprises at least
one, and can contain two or more natural or synthetic polymeric
layers. At least one layer of the backing is composed of a polymer
which is compatible with the drug chosen and with which the drug is
compatible, is flexible, and has a water vapor transmission rate
equal to or greater than EVOH of 0.2 to 3 mil thickness, namely a
rate equal to or in excess of about 2 to 4 grams/100 in.sup.2 per
24 hours, at 40.degree. C. and 90% RH and more preferably 6 grams
and an oxygen transmission rate equal to or less than EVOH of 0.2
to 3 mil thickness, namely of less than 0.01 to 0.1 cubic
centimeters per 100 square inch when measured over 24 hours at one
atmosphere pressure, 20.degree. C. and 65% relative humidity.
[0378] The backing can also have a second or additional layers
composed of a polymer which is compatible with the drug chosen and
with which the drug is compatible, is flexible, and has a water
vapor transmission rate in excess of that of EVOH of 0.2 to 3 mil
thickness, namely in excess of about 2 to 4 grams per 100 square
inches per 24 hours, at 40.degree. C. and 90% relative humidity and
preferably in excess of 6 grams.
[0379] The water vapor transmission rate of a given polymer is a
function of the polymer and thus varies with the average molecular
weight, configuration and orientation, chain length, nature of
repeating units, the degree of cross linking, the degree of
crystallinity, the nature and extent of the monomer and the like,
as well as time, temperature, relative humidity and thickness of
the film. The rate thus varies, not only from polymer to polymer,
but to different types of a specific polymer.
[0380] The preferred polymers for the additional layers are those
having the greater water vapor transmission rate, thus the
preferred polymers are cellulose acetate, nylon, polycarbonate,
acrylonitrile, polystyrene, polyurethane and polyvinyl alcohol, or
copolymers or multipolymers of these plastics with additional
monomers. Polyurethane is an especially preferred material for the
secondary layer.
[0381] Thus, the breathable backing of this invention comprises at
least one layer of a substance having a high water vapor
transmission rate and a low gas transmission rate. These physical
properties can be found in the highly polar polymers, such as those
containing hydroxyl groups such as polyvinyl alcohol, and ethylene
vinyl alcohol, see e.g., Barrier Polymers article, 1977, p. 156.
More particularly, ethylene vinyl alcohol copolymer (EVOH) has a
particularly low gas transmission rate.
[0382] The backing material can consist of a single layer having
the indicated high water vapor transmission rate and low gas
transmission rate. In addition, a single or multi-layered material
can be used on one or both sides of the primary layer. These
secondary layers need only have the high water vapor transmission
rate and can be used to minimize potential degradation of the
primary layer by the presence of air and moisture. The substances
selected for additional polymeric layers can be the same or of
different polymers.
[0383] In general, the additional layers have a moisture vapor
transmission rate (MVTR) in excess of that of EVOH of 0.2 to 3 mil
thickness, namely in excess of about 2 to 4 grams per 100 square
inches at 40.degree. C., 90% relative humidity over 24 hours, and
more preferably in excess of about 6 grams per 100 square inch and
more preferably in excess of 9 grams per 100 square inch.
[0384] The backing can be prepared by any of the methods used to
join plastics in a film, including lamination or coextrusion. In
the case of lamination, various means known in the art can be
utilized to cause the layers to adhere.
[0385] Typically, each layer of the laminate is approximately 5 to
100 microns, and preferably 12 to 75 microns in thickness.
[0386] The preferred backing material for use in this invention is
a layer of ethylene vinyl alcohol copolymer laminated or coextruded
with polyurethane. An especially preferred backing material for use
in this invention is one in which the polyurethane film is that
available from JP Stevens, East Hampton, Mass. The preferred
ethylene vinyl alcohol copolymer is the polymer sold under the
trademark "EVAL" item EF-F, available from EVAL Company of America,
Lisle, Ill.
[0387] The layers are juxtaposed face to face, and are bonded to
each other. They are sufficiently flexible to be able to adapt to
the contour of the skin and movements therein.
[0388] It is known that the mole percent ethylene in an ethylene
vinyl alcohol copolymer affects not only the oxygen transmission
rate of the copolymer, but the sensitivity of that oxygen
transmission rate to relative humidity. Thus, the lower the
percentage of ethylene in ethylene vinyl alcohol copolymer, the
lower the oxygen transmission rate. Thus, it has been reported that
a 1.0 mil ethylene vinyl alcohol copolymer containing 29 mole
percent ethylene has an oxygen transmission rate of less than 0.02
at 0% relative humidity and 68.degree. F., and approximately 0.05
at 80% relative humidity. On the other hand, under the same
conditions of relative humidity and temperature, ethylene vinyl
alcohol copolymer containing 38 mole percent and 44 mole percent of
ethylene has an oxygen transmission rate of about 0.06 to 0.07 at
0% relative humidity, rising to approximately 0.2% at 80% relative
humidity. In contrast, a 1.0 mil nylon film has an oxygen
transmission rate of just above 2 at relative humidities ranging
from 0% to in excess of 80% at 73.degree. F. Similarly, the
coextrusion of an ethylene vinyl alcohol copolymer and nylon tends
to lower the oxygen transmission rate through a wide range of
relative humidities, as compared with the non-coextruded ethylene
vinyl alcohol copolymer.
[0389] The backing layer 18 according to the present invention has
a moisture vapor transmission rate of from 0 to about 1500
g/m.sup.2/24 hrs, preferably about 0.5 to about 1000 g/m.sup.2/24
hrs, still more preferably from about 1.5 to about 500 g/m.sup.2/24
hrs, still more preferably from about 3 to about 250 g/m.sup.2/24
hrs, most preferably from about 10 to about 100 g/m.sup.2/24
hrs.
[0390] In general, therapeutic amounts of drug can be delivered
from the transdermal drug delivery system containing about 0.1% to
about 50% by weight of drug. However, the transdermal drug delivery
system of this invention is particularly useful for drugs which are
used in relatively low concentrations, especially 0.3% to 30% of
the total transdermal drug delivery system, more preferably from
about 0.5% to about 15% of the total transdermal drug delivery
system, most preferably from about 1% to about 10% of the total
transdermal drug delivery system.
[0391] The polymeric backing layer can be prepared to selectively
control the desired delivery rate, onset and profile for the drug
by varying the moisture vapor transmission rate of the backing
layer. As demonstrated in the examples, employing a backing layer
with a lower moisture vapor transmission rate, the flux of the drug
increased. When the moisture vapor transmission rate was increased,
the flux of the drug decreased. Thus, it is believed that by
varying the moisture vapor transmission rate, the delivery rate of
the drug from the transdermal device can be tailored.
[0392] While one or more acrylic-based adhesives are preferred for
use as the non-drug loaded coating, other polymers, alone or in
combination, may be used provided such polymers have the ability to
(a) incorporate and hold drug from the drug-loaded carrier
composition after manufacture, (b) maintain contact/adhesion to
both the carrier composition and either the backing film/layer or
the release liner, preferably without the use of additional
adhesives, (c) not degrade or interfere with stability of the drug,
and (d) release or deliver the drug to the skin or mucosa after
topical application of the transdermal system.
[0393] In certain embodiments of the invention, an enhancer can be
incorporated into either the carrier composition or the polymeric
coating, or both. The term "enhancers" as used herein refers to
substances used to increase permeability and/or accelerate the
delivery of an active agent through the skin or mucosa, and include
monhydric alcohols such as ethyl, 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 stearly) 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 from ICI Americas, Inc., and BRIJ.RTM. 35, 52, 56, 58, 72,
76, 78, 92, 96, 700 and 721; vegetable, animal and fish fats and
oils such as cotton seed, corn, safflower, olive and castor oils,
squalene, and lanolin; 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 drugs
administered 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
suitable enhancers include oleic and linoleic acids, triacetin,
ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol,
tocopherol acetate, tocopheryl linoleate. If enhancers are
incorporated into the transdermal system, the amount typically
ranges up to about 30%, and preferably from about 0.1% to about
15%, by weight based on the dry weight of the total carrier
composition.
[0394] In addition to enhancers, 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, silicone
fluid, mineral oil and hydrogenated wood rosins. Additional
additives include binders such as lecithin which "bind" the other
ingredients, or rheological 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 composition or coating. Other additives
and excipients include diluents, stabilizers, fillers, clays,
buffering agents, biocides, humectants, anti-irritants,
antioxidants, preservatives, plasticizing agents, cross-linking
agents, flavoring agents, colorants, pigments and the like. Such
substances can be present in any amount sufficient to impart the
desired properties to the composition or coating. Such additives or
excipients are typically used in amounts up to 25%, and preferably
from about 0.1% to about 10%, by weight based on the dry weight of
the total carrier composition.
[0395] Transdermal system 10 further employs release liners 15 or
removable/peelable covers and backings to protect and/or anchor the
system or its components during manufacturing as described herein,
or thereafter, and to enable handling and transportation.
[0396] The release liner is typically 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. Some suitable materials that
can be used, singularly, in combination, as laminates, films, or as
coextrusions, to form the release liner are well known in the art.
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 coating or composition to which it is affixed), for
example paper, a releasable material such as a silicone,
Teflon.RTM., or the like may be applied to the surface by any
conventional means. Preferred release liners are films commercially
available from DuPont, Wilmington, Del., under the trademarks
Mylar.RTM., and fluropolymer (silicone) coated films commercially
available from Rexam Release, Oak Brook, Ill. under the trademarks
FL2000.RTM. and MRL2000.RTM., and from 3M Corporation, St. Paul,
Minn. Sold under the trademarks ScotchPak.RTM. such as 1022.
[0397] The backing layer 18 may generally have a thickness in the
range of 0.2 to 3 mm. The backing layer 18 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 transdermal unit or system itself. The backing layer 18 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 from
degradation and/or preventing photoallergic reactions or
irritations on the subject.
[0398] An exemplary general method of preparing transdermal system
10 is as follows:
[0399] An exemplary general method for the preparation of a
preferred embodiment is as follows:
[0400] 1. Appropriate amounts of pressure sensitive adhesive
polymer, solvent(s), enhancer(s), and organic solvent(s) (for
example toluene) are combined and thoroughly mixed together in a
vessel.
[0401] 2. The drug is then added to the mixture and agitation is
carried out until the drug is uniformly mixed in.
[0402] 3. The formulation is then transferred to a coating
operation where it is coated onto a protective release liner at a
controlled specified thickness. The coated product is then passed
through an oven in order to drive off all volatile processing
solvents.
[0403] 4. The dried product on the release liner is then joined to
the backing material and wound into rolls for storage.
[0404] 5. Thereafter, desired size and shape delivery systems 10
are prepared by die-cutting or the like, from the rolled laminate
and then packaged.
[0405] In certain other preferred embodiments, a non-woven drug
permeable film/layer, such as a polyester film, may be
interdisposed, such as pressure lamination, for structural support
or ease of manufacturing (i.e., has no effect on controlling drug
permeation or delivery) between the non-drug loaded coating and the
drug-loaded carrier composition.
[0406] The order of the processing 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 transdermal system. These
factors can be adjusted by those skilled in the art, while keeping
in mind the objects of achieving the interaction between the drug
carrier composition and the non-drug loaded coating. It is believed
that a number of other methods, for example, other methods of
coating 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.
[0407] The weight per unit area of the dried contact adhesive layer
(matrix) is usually in the range of from about 1 mg/cm.sup.2 to
about 20 mg/cm.sup.2, and more preferably in the range of from
about 2.5 mg/cm.sup.2 to about 15 mg/cm.sup.2. The delivery rate is
in the range of from about 0.01 mg to about 100 mg of active agent
per day, and more preferably in the range of from about 0.1 mg to
about 50 mg per day.
[0408] Generally, the amount of drug sufficient to deliver a
therapeutically effective amount of the active agent at a
substantially zero-order kinetic rate of delivery for an extended
period of time of at least three days and up to seven days or
longer, and to eliminate or suppress the high initial release rate
of a drug subject to a first order release profile.
[0409] Those skilled in the art can readily determine the rate of
delivery of drugs from the multiple polymer adhesive system in
order to select suitable combinations of 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.
[0410] The compositions of this invention may further be provided
with various thickeners, fillers and other additives known for use
with transdermal drug delivery systems. Where the composition tends
to absorb water, for example, when lecithin is used as a
co-solvent, hydrophilic substances are especially useful. One type
of hydrophilic substance which has been successfully employed is
clay. The addition of clay has been found to improve adhesiveness
in transdermal formulations without reducing the rate of drug
delivery. Suitable clays include kaolinites such as baolinite,
anauxite, dickite and nacrite, montmorillonites such as
montinorillonite, bentonite, berdellite and montronite,
illites/muscovites such as illite and glauconite, chlorites,
polygorshites such as attapulgite, halloysite, metabolloysite,
allophane and aluminum silicate clays.
[0411] In a device aspect of the invention, the pressure-sensitive
adhesive composition can be used as an adhesive portion of any
transdermal drug delivery system (e.g., a reservoir device) or it
can comprise an adhesive monolithic. Of course, the principles of
the invention would still apply to embodiments where the
transdermal drug delivery composition is not a pressure-sensitive
adhesive and comprises a drug reservoir.
[0412] The configuration of the transdermal delivery system of the
present invention can be in any shape or size as is necessary or
desirable. Illustratively, a single dosage unit may have a surface
area in the range of 1 to 200 cm.sup.2. Preferred sizes are from 5
to 60 cm.sup.2.
[0413] In a method aspect of the invention, a plurality of polymers
are blended (but not chemically reacted or cross-linked) to result
in a pressure-sensitive adhesive composition which controls
delivery of an incorporated drug through the skin or mucosa. The
term "blending," of course, incorporates choosing the appropriate
polymeric components, and the proportions thereof, to achieve the
desired effect.
[0414] The present invention is illustrated by the following
examples, without limiting the scope of the invention.
EXAMPLES
[0415] In the Examples, the effect of variations in the
occlusiveness of the backing layer are determined, indicating the
flux rate as a function of backing moisture vapor transmission
rate. While the Examples are directed to formulations using
clonidine, it should be understood that similar drug modulation can
be achieved with other active agents, and through the use of other
polymers and system configurations as discussed.
[0416] All drug-loaded carrier compositions contained 7% clonidine
by weight and were prepared using a blend of 83% by weight of a
non-functional, acrylic-based pressure sensitive adhesive (DuroTak
73-9301) and 10% by weight of a carboxy functional acrylic-based
pressure sensitive adhesive (DuroTak 87-2852). The clonidine and
the two acrylic pressure sensitive adhesives were blended together.
The composition was coated onto a fluropolymer release liner and
dried for in a 76.degree. C. oven to produce a pressure-sensitive
adhesive carrier composition.
[0417] Determination of drug flux of the described formulations was
conducted on a modified Franz Diffusion cell through a disc of
stratum corneum obtained from human cadaver skin. The transdermal
system formulations were die-cut to punched, mounted on the disc,
and placed on the cell, which contained an isotonic saline
solution. The cells were stored at 32.degree. C. for the duration
of each flux study while having the solution stirred at a constant
rate of approximately 300 rpm.
Example 1
[0418] In Example 1, a backing layer comprising polyester and
ethylene vinyl acetate was used. The backing layer is commercially
available from 3M as ScotchPak 9732. The backing layer had a
moisture vapor transmission rate of 15.5 g/m.sup.2/24 hours. The
maxtix blend which included 7% by weight clonidine, 83% by weight
of a non-functional, acrylic-based pressure sensitive adhesive
(DuroTak 73-9301) and 10% by weight of a carboxy functional
acrylic-based pressure sensitive adhesive (DuroTak 87-2852) was
formed over the backing layer. The matrix was identical to that
used in Examples 1 and 3. As can be seen in Table 3, the flux of
the transdermal delivery device was 1.69 .mu.g/cm.sup.2/hr.
Example 2
[0419] In Example 2, a backing layer comprising polyurethane and
ethylene vinyl alcohol commercially available from J.P. Stevens Co.
of East Hampton, Mass. was used. The backing layer had a moisture
vapor transmission rate of 100 g/m.sup.2/24 hours. The maxtix blend
which included 7% by weight clonidine, 83% by weight of a
non-functional, acrylic-based pressure sensitive adhesive (DuroTak
73-9301) and 10% by weight of a carboxy functional acrylic-based
pressure sensitive adhesive (DuroTak 87-2852) was formed over the
backing layer. The matrix was identical to that used in Examples 1
and 3. As can be seen in Table 3, the flux of the transdermal
delivery device was 0.93 .mu.g/cm.sup.2/hr.
Example 3
[0420] In Example 3, a polyurethane backing layer commercially
available from J.P. Stevens Co. of East Hampton, Mass. was used.
The backing layer had a moisture vapor transmission rate of 1500
g/m.sup.2/24 hours. The maxtix blend included 7% by weight
clonidine, 83% by weight of a non-functional, acrylic-based
pressure sensitive adhesive (DuroTak 73-9301) and 10% by weight of
a carboxy functional acrylic-based pressure sensitive adhesive
(DuroTak 87-2852) was formed over the backing layer and was
identical to that used in Examples 1 and 2. As can be seen in Table
3, the flux of the transdermal delivery device was 0.32
.mu.g/cm.sup.2/hr. TABLE-US-00003 TABLE 3 Backing Material MVTR
(g/m.sup.2/24 hrs) Flux (.mu.g/cm2/hr) Example 1 PET/EVA 15.5 1.69
Example 2 PU/EVOH 100 0.93 Example 3 PU 1500 0.32
[0421] The results from Examples 1 to 3 are set forth graphically
in FIG. 2. As illustrated in the forgoing Examples and in FIG. 2,
backing layers having a low water vapor transmission rates increase
the flux of clonidine. As such, varying the moisture vapor
transmission rate of the backing layer can be utilized to control
permeation rates of transdermal systems.
[0422] The above description and example are only illustrative of
preferred embodiments which achieve the objects, features, and
advantages of the present invention, and it is not intended that
the present invention be limited thereto.
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