US 20020004065A1

(19) United States

(12) Patent Application Publication (10) Pub. No.: US 2002/0004065 A1
Kanios (43) Pub. Date: Jan. 10, 2002

(54) COMPOSITIONS AND METHODS TO Related US. Application Data

EFFECT THE RELEASE PROFILE IN THE
TRANSDERMAL ADMINISTRATION OF (63) Non-provisional of provisional application No.
ACTIVE AGENTS 60/ 177,103, ?led on Jan. 20, 2000.

(76) Inventor: David Kanios, Miami, FL (US) Pubhcatlon Classl?catlon

(51) Int. Cl.7 ..................................................... .. A61K 9/70
C d Add (52) US. Cl. ............................................................ .. 424/449
orrespon ence ress:
Noven Pharmaceuticals, Inc. (57) ABSTRACT
11960 S_W_ 144th Street Compositions and methods for the transdermal delivery of
Miami, FL 33186 (Us) active agents up to a period of seven days or more at
substantially a Zero-order release rate comprising a pharma
(21) Appl, N()_j 09/765,932 ceutically acceptable adhesive matrix and a polymeric plas
tic material that provides a release rate regulating effect on
(22) Filed: Jan. 19, 2001 the active agents.
Patent Application Publication Jan. 10, 2002 Sheet 1 0f 6 US 2002/0004065 A1

FIG, 7

12 .LO
Patent Application Publication Jan. 10, 2002 Sheet 2 0f 6 US 2002/0004065 A1

E52;.:

M$E9QuF0.Z
Niwna-26m MwJESBQXM mNid-246m NMARS-(KM

(Imam/6n) xnu saws/w

Patent Application Publication Jan. 10, 2002 Sheet 3 0f 6 US 2002/0004065 A1
Patent Application Publication Jan. 10, 2002 Sheet 4 0f 6 US 2002/0004065 A1

168

4FHGURE 9672
(Thoiumres)

5Ex-a@mple 6Exa~m&-pie E7xF-a<m>ple

1.0 0.8 6
Patent Application Publication Jan. 10, 2002 Sheet 6 0f 6 US 2002/0004065 A1

wmEDwE 3m.2;5
2AmSlND?A.j_nElzONm:D.oi; ml5:c!IF1l?523w8 w<NI5TiSN<l.EJn!OmDHa_O: Qv5E{3l2:oNZ105V218

R: 18; -?d -23 13.0 8d

US 2002/0004065 A1
COMPOSITIONS AND METHODS TO EFFECT
THE RELEASE PROFILE IN THE TRANSDERMAL
ADMINISTRATION OF ACTIVE AGENTS
FIELD OF INVENTION
[0001] This invention relates generally to transdermal
drug delivery systems, and more particularly to pharmaceu
tically acceptable adhesive matrix compositions, that use
polymeric plastic materials, in particular insoluble cellulose
derivatives such as ethyl celluloses, to regulate the drug
release pro?le. The invention additionally relates to trans
dermal drug delivery systems providing substantially Zero
order drug release pro?les for an extended period of time of
up to seven days or longer.
BACKGROUND OF THE INVENTION
[0002] The use of transdermal drug delivery systems as a
means to topically administer an active agent is Well knoWn.
Such 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 deliv
ered through the skin or mucosa of the user.
[0003] In general, transdermal drug delivery systems are
either reservoir-type or matrix-type devices. Both types of
devices employ a backing layer that forms the protective
outer surface of the ?nished transdermal system and Which
is exposed to the environment during use, and a release liner
or protective layer that forms the inner surface and Which
covers Whatever adhesive means is employed for af?xing the
system to the skin or mucosa of a user. The release liner or
protective layer is removed prior to application, exposing
the adhesive means, Which is typically a pressure-sensitive
adhesive.
[0004] In the classic reservoir-type device, the active
agent is usually dissolved or dispersed in a carrier that
typically yields a non-?nite carrier form, like a ?uid or gel,
and Which is kept separate from the adhesive means used to
af?x the device to the user. The device has a pocket or
reservoir Which physically serves to hold the active agent
and carrier, and Which is formed in or by the backing layer
itself. A peripheral adhesive layer is then used to af?x the
device to the user. The early reservoir-type devices incor
porated drugs Which Were readily absorbed through the skin
like nitroglycerin and nicotine.
[0005] Such devices have a number of disadvantages
including a non-uniform drug release pro?le Wherein a high
dose of drug is released initially 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 is less than is able to achieve a therapeutically effective
amount. Drug delivery according to this pro?le is described
as ?rst order release.
[0006] While such classic devices are still in use today, the
term reservoir is being used interchangeably With matrix
type devices Which still rely upon a separate adhesive means
used to affix the device to the user.
[0007] In a matrix-type device, the active agent is dis
solved or dispersed in a carrier that typically yields a ?nite
carrier form, Which can be self-adhesive or non-adhesive.
Non-adhesive matrix-type devices, that is, those Which still
rely upon a separate adhesive means to affix the device to the
Jan. 10, 2002
user, employ a drug permeable adhesive layer (often referred
to as an in-line adhesive since the drug must pass
through), applied over the drug matrix carrier layer. In an
attempt to better control the release rate of the drug, such
devices often employ one or more additional drug permeable
layers such as rate controlling membranes, or containing
excipients, such as drug delivery enhancers. Hence, such
devices are also commonly referred to as multilayer or
multilaminate.
[0008] 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
US. 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.
[0009] While matrix-type devices, especially drug-in-ad
hesive devices, have achieved more uniform and controlled
drug deliver rates, and for longer periods of time, most
transdermal systems remain subject to a higher initial drug
release than is required to achieve therapeutic ef?cacy. For
many drugs and/or therapeutic situations, it Would be advan
tageous to eliminate or suppress this higher initial release
and achieve a steady state (Zero order) release pro?le
Which uniformly delivers a therapeutically effective amount
of drug over the extended duration of devices desired use.
[0010] For example, the high initial release of certain
drugs may cause adverse or undesired effects, or create
toxicity concerns, thereby foreclosing the use of transdermal
administration. In other instances, the higher initial release
may reduce the amount of drug required for treatment to the
point of risking underdosing, or may make it impractical to
try and increase the duration of the devices application
While retaining therapeutic effectiveness. The ability to
reduce the frequency of replacing the transdermal drug
delivery system Would concomitantly increase user compli
ance, reduce any lag or drop off in ef?cacious blood levels,
and reduce the amount of drug required for treatment (also
provided by reducing the higher initial blood level associ
ated With the higher release rate).
[0011] Therefore, despite the existence of many different
types of transdermal delivery systems in the art, there
remains a continuing need for improving the release pro?le
of drugs to achieve substantially Zero order, as Well as
extending the duration of use of each transdermal system.
[0012] US. patent Ser. No. 07/897,269 discloses the use
of glycerin to counteract the burst effect of drugs in trans
dermal formulations.
[0013] It has noW been found that the addition of certain
polymeric plastic polymers, in particular insoluble cellulose
derivatives such as ethyl celluloses, into a pressure-sensitive
adhesive matrix composition, eliminates or suppresses the
initial high release rate of a drug subject to a ?rst order
release rate pro?le such that the system achieves substan
tially Zero order release, and is able to maintain a substan
tially Zero order release pro?le for an extended period of
time up to seven days or longer.
[0014] Although not Wishing to be bound by theory,
particularly in this case Where the structure of the compo
US 2002/0004065 A1
sition has not been analyzed, it is postulated that the
insoluble polymeric plastic material affects the uptake/ab
sorption of Water or moisture from the application site into
the matrix composition Which Would otherWise create some
of the kinetic driving force for release of the drug. This
appears especially signi?cant in the presence of hydrophobic
drugs and/or in conjunction With the use of hydrophilic
crystalliZation inhibitors, such as polyvinylpyrrolidones.
[0015] Ethyl celluloses have been extensively used in
industrial applications since their commercial introduction
in the mid-1930s. They are recognized and Widely used as
Well for many different purposes in pharmaceutical appli
cations, especially in conjunction With Water-sensitive ingre
dients. Ethyl celluloses are most frequently used as binders,
?llers, ?avor ?xatives, controlled release coatings/barriers in
microencapsulation and other solid dosage forms, particu
larly multiparticulate systems, granulation aids, tablet ?lm
formers and taste maskers.
[0016] The prior art generally discloses the use of
insoluble polymers such as ethyl cellulose as optional com
ponents in transdermal systems as thickening agents and as
cohesiveness strengthening agents Which effect the carriers
adhesive properties. For example, US. Pat. No. 5,232,702
discloses the use of a variety of substances that include ethyl
cellulose and polyvinyl alcohol as cohesive strengthening
agents (reducing ?oW properties of silicone adhesives) in a
transdermal delivery system.
[0017] The present invention is able to regulate the release
pro?le of the drug in a transdermal system Without modi
fying the adhesive properties of the pressure-sensitive adhe
sive matrix so that the transdermal system possesses the
required degree of adhesion and tackiness to remain af?xed
to the site of application for extended periods of time, Which
can be seven days or more, but at the same time can be easily
removed as required.
[0018] The prior art further generally discloses the use of
insoluble polymers in transdermal systems as the non
adhesive matrix carrier itself, and even as a suitable adhe
sive for the matrix carrier itself (but Which presumably
includes the addition of a plasticiZer or tacki?er, or plasti
ciZing liquid drug like nicotine, to create stickiness since
such polymers are not adhesives). For example, US. Pat.
No. 6,010,715 discloses the use of thermoplastic polymers
that are melt-blended With active agents and enhancers that
are heat stable at the melt temperature of the polymer. The
melt-blend can then be thermoformed into carrier layers
Without the use of common solvents to produce a controlled
release layer in a transdermal drug delivery system. Cellu
lose derivatives such as ethyl cellulose are generally dis
closed as suitable adhesives for use as the matrix.
[0019] US. Pat. No. 5,904,931 discloses the use of ethyl
cellulose as a crystalliZation inhibitor in a transdermal drug
delivery system. Cellulose ether and polyvinyl compounds
are generally described as additional matrix additives.
SUMMARY OF THE INVENTION
[0020] It is therefore an objective of the present objective
to provide for methods and pharmaceutically acceptable
?exible, ?nite compositions and systems for the transdermal
administration of active agents that achieve a substantially
Zero-order release pro?le When applied to a user.
Jan. 10, 2002
[0021] It is another object of the invention to provide an
adhesive matrix-type transdermal drug delivery system
Which achieves a substantially Zero-order release pro?le of
the active agent by incorporating a polymeric plastic mate
rial into an adhesive drug matrix.
[0022] It is still another object of the invention to achieve
a substantially Zero-order release pro?le of the active agent
for an extended period of time of up to seven days or longer,
and effectively continue to deliver the active agent in a
therapeutically effective amount.
[0023] It is a further object of the invention to provide a
method of eliminating or suppressing the high initial release
or burst of active agent from an adhesive matrix type
transdermal drug delivery system containing a drug subject
to a ?rst order release pro?le.
[0024] It is yet another object of the invention to provide
a transdermal drug delivery system that can deliver an active
agent at substantially Zero-order for an extended period of
time in excess of 72 hours and up to seven days or more
Without substantially increasing the surface area of the
transdermal delivery system.
BRIEF DESCRIPTION OF DRAWINGS
[0025] FIG. 1 is a schematic illustration of a matrix-type
transdermal drug delivery system of the present invention.
[0026] FIG. 2 is a graphical representation comparing the
in vitro ?ux rate of estradiol and norethindrone acetate
through cadaver skin from a pressure-sensitive adhesive
matrix composition of the present invention With the ?ux
rate for a composition of the prior art.
[0027] FIG. 3 is a graphical representation of the in vitro
?rst order ?ux rate of estradiol through cadaver skin from a
transdermal drug delivery system of the prior art as com
pared to the in vitro steady state ?ux rate of estradiol through
cadaver skin from an transdermal drug delivery system of
the present invention.
[0028] FIG. 4 is a graphical representation of the in vitro
?ux rates of estradiol through cadaver skin from tWo pres
sure-sensitive adhesive matrix compositions of the present
invention using various amounts of ethyl cellulose as com
pared to the in vitro ?ux rate of estradiol from a pressure
sensitive adhesive matrix composition Without ethyl cellu
lose.
[0029] FIG. 5 is a graphical representation of the in vitro
?ux rates of estradiol through cadaver skin from pressure
sensitive adhesive matrix compositions of the present inven
tion comparing the effect of varying amounts of ethyl
cellulose With varying amounts of estradiol.
[0030] FIG. 6 is a graphical representation of the in vitro
?ux rates of estradiol and norethindrone acetate through
cadaver skin from pressure-sensitive adhesive matrix com
positions comparing the effect of using a combination of
ethyl cellulose and cellulose acetate butyrate versus either
polymer alone.
DETAILED DESCRIPTION OF THE
INVENTION
[0031] The foregoing and other objects are achieved by
this invention Which provides a transdermal drug delivery
US 2002/0004065 A1
system wherein the use of a polymeric plastic material
provides a release rate regulating effect on the active agents
incorporated into the adhesive matrix composition.
[0032] Unless de?ned otherWise, all technical and scien
ti?c terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art to Which the
invention pertains.
[0033] 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.
[0034] 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.
[0035] The term transdermal as used herein means pas
sage into and/or through skin or mucosa for localiZed or
systemic delivery of an active agent.
[0036] 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. As such, the active agent is considered herein
to be in non-crystallized form When in the compositions of
the present invention.
[0037] As used herein, the term ?ux is de?ned as the
absorption of the drug through the skin or mucosa, and is
described by Ficks ?rst laW of diffusion:
[0038] Where J is the ?ux in g/cm2/sec, D is the diffusion
coef?cient of the drug through the skin or mucosa in cm2/sec
and Dcm/dx is the concentration gradient of the drug across
the skin or mucosa.
[0039] The phrase pharmaceutically acceptable ?exible,
?nite is intended to mean a solid form capable of conform
ing to a surface to Which it is applied, and Which is capable
of maintaining the contact in such solid form so as to
facilitate topical application Without adverse physiological
response, and Without being appreciably decomposed by
aqueous contact during use by a subject.
[0040] The term user or subject is intended to include
all Warm-blooded mammals, preferably humans.
[0041] 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%.
[0042] Any polymeric plastic material may be employed
for the present invention provided it is insoluble or substan
tially insoluble in Water, and includes cellulose derivatives
such as cellulose acetates, (cellulose acetate butyrate, cel
lulose acetate propionate, cellulose acetate phthalate, etc.),
methyl, ethyl and propyl celluloses; polycarbonates; poly
styrenes; alkylacrylates such as polymethyl methacrylate,
polyethyl ethacrylate, polyethylene methacrylate and other
loWer alkyl acrylates; vinyl polymers; polyurethanes; poly
Jan. 10, 2002
acrylonitriles; and mixtures, combinations and multipoly
mers (copolymers, terpolymers, etc.) thereof.
[0043] In preferred embodiments, the polymeric plastic
material is a cellulose derivative. Preferred are cellulose
esters such as cellulose acetates including cellulose acetate,
cellulose acetate butyrate, cellulose acetate phthalate, cellu
lose acetate propionate, and cellulose ethers.
[0044] Copending provisional application, Ser. No.
60/137,827, describes the use of cellulose derivatives, par
ticularly cellulose esters, as drug solubility enhancers in
matrix carrier compositions.
[0045] Particularly preferred cellulose ethers are ethyl
cellulose polymers. Ethyl cellulose polymers can be manu
factured in a variety of molecular Weights, Which translates
into a range of viscosities When in solution. In practicing the
subject invention, it has been found that solution viscosities
ranging from about 3 centipoise to about 49 centipoise are
preferred, and more preferably from about 6 centipoise to
about 40 centipoise, and optimally from about 6 centipoise
to about 22 centipoise (viscosities are for 5% solutions, in
80% toluene and 20% ethanol, measured at 25 C. in an
Ubbelohde viscometer). Ethyl cellulose polymers having
such solution viscosities exhibit melting point temperatures
in the range of about 165 C. to about 200 C. Suitable ethyl
cellulose polymers are commercially available and include
those sold under the trademark ETHOCEL by the DoW
Chemical Company, Midland, Mich. Preferred ETHOCEL
polymers are ETHOCEL Standard 7, 10, 14 and 20,
Premium or Industrial grades.
[0046] A crystalliZation inhibitor or solubility enhancer
may also be employed in the invention, for example poly
vinylpyrrolidone polymers, polyethylene oxide, polyacrylic
acid, polyvinyl alcohol, silicone dioxide, silica, celluloses
and cellulose derivatives such as hydroxymethyl cellulose,
hydroxypropyl cellulose, gelatins, gums, starches, dextrins
and dextrans, sterols, bile acids and other absorptive agents
that possess the capability to absorb and hold Water or
moisture.
[0047] Particularly preferred compounds are PVPs. The
term polyvinylpyrrolidone or PVP refers to a polymer,
ether a homopolymer or copolymer, containing vinylpyr
rolidone (also referred to as N-vinylpyrrolidone, N-vinyl-2
pyrrolidone and N-vinyl-2-pyrrolidinone) as a monomeric
unit. PVP polymers include soluble and insoluble
homopolymeric PVPs, and copolymers such as vinylpyrroli
done/vinyl acetate and vinylpyrrolidone/dimethylamino
ethylmethacryLate. The cross-linked hompolymer (such as
KOLLIDON CL from BASF) is insoluble and is generally
knoWn in the pharmaceutical industry under the designations
polyvinylpolypyrrolidone, crospovidone and PVP. The
copolymer vinylpyrrolidone-vinyl acetate is generally
knoWn in the pharmaceutical industry under the designations
Copolyvidon (e), Copolyvidonum or VP-VAc.
[0048] Particularly preferred PVPs are soluble. The term
soluble When used With reference to PVP means that the
polymer is soluble in Water and generally is not substantially
cross-linked, and has a molecular Weight of less than about
2,000,000. See, generally, Biihler, KOLLIDON: POLYVI
NYLPRYRROLIDONE FOR THE PHARMACEUTICAL
INDUSTRY, BASF Aktiengesellschaft (1992). Soluble PVP
polymers have been identi?ed in the pharmaceutical indus
US 2002/0004065 A1
try under a variety of names, the most commonly used
include Povidone, Polyvidon (e), Polyvidonum, poly (N-vi
nyl-2- pyrrolidinone, poly (N-vinylbutyrolactam), poly
(1-vinyl-2-pyrrolidinone, poly [1-(2-oxo-1pyrrolidinyl)eth
ylene].
[0049] The amount and type of PVP required in the
preferred embodiments Will depend on the quantity and type
of drug present in the adhesive matrix composition, as Well
as the type of adhesives, but can be readily determined
through routine experimentation.
[0050] Typically, the PVP is present in an amount from
about 5% to about 50% by Weight, preferably from about
10% to about 40% by Weight based on the dry Weight of the
total adhesive matrix composition. HoWever, the amount of
PVP can be higher than 20% for example, up to 40%,
depending on the particular drug used and on the desired
properties of the matrix blend.
[0051] Said PVP preferably has a molecular Weight of
about 2,000 to 2,000,000, more preferably 5,000 to 100,000,
and most preferably 7,000 to 54,000. PVP having a molecu
lar Weight of about 1,000,000 to about 1,500,000 is also
preferred.
[0052] PVPs are sold to the pharmaceutical industry under
the trademarks KOLLIDON by BASF (Parsippanny, N.J.);
PLASDONE, POLYPLASDONE and COPOLYMER 958
by ISP Technologies, Wayne, N.J. Preferred PVPs are KOL
LIDON 12PF, 17PF, 25, 30, 90 and VA-64.
[0053] Particularly preferred embodiments of the inven
tion include soluble PVP in a polyacrylate and polysiloxane
pressure-sensitive adhesive matrix blend.
[0054] The amount and type of polymeric plastic material
required in the practice of the invention Will depend on the
one or more additional materials used in the adhesive matrix
composition, and on the amount and type of active agent(s).
Generally, the amount of polymeric plastic material to be
used is an amount suf?cient 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 ?rst order release pro?le. Typically, the amount
of polymeric plastic material to be used ranges from about
0.5% to about 30%, preferably from about 2.5% to 20%, and
more preferably from about 5.0% to 15% by Weight based
on the dry Weight of the total adhesive matrix composition.
Amounts greater than 30% typically result in loss of adhe
sive properties necessary to maintain the system topically
for an extended period of time.
[0055] The adhesive matrix compositions of the present
invention are designed to effectively deliver an active agent
in a therapeutically effective amount for an extended period
of time up to seven days or longer. As used herein, thera
peutically 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 dura
tion of intended use. Seven days is generally the preferred
maximum duration for application of a transdermal drug
delivery system of the present invention because the site of
application is typically adversely affected When occluded for
a period of time greater than seven days. HoWever, if a
Jan. 10, 2002
non-occlusive backing material (i.e., permeable to Water
vapor and/or oxygen) is used, then the transdermal system
may be applied for periods longer than seven days Without
adverse effects occurring, if at all, until a much later time.
While delivery of drug by the present invention is preferred
for at least a seven-day continuous application, the trans
dermal system may be used discontinuously (i.e., replaced at
any time during rather than at the end of the intended
duration of use) since the drug release pro?le is substantially
Zero order.
[0056] 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 bene?cial, effect.
More speci?cally, any active agent that is capable of pro
ducing a pharmacological response, localiZed or systemic,
irrespective of Whether therapeutic, diagnostic, cosmetic or
prophylactic in nature, is Within the contemplation of the
invention. It should be noted that the active agents can be
used singularly or in combinations and mixtures.
[0057] There is no limitation on the type of active agent
that can be used in this invention. HoWever, active agents
that are solid or crystalline at room temperature are preferred
over liquid drugs, especially nicotine. Moreover, drug forms
other than the free base form are also preferred.
[0058] The active agents contained in the adhesive matrix
composition can be in different forms such as pharmaceu
tically acceptable salts, bases, esters, amides or pro-drugs, or
may be modi?ed by appending one or more appropriate
functionalities to enhance selected physical or biological
properties, for example as neutral molecules, components of
molecular complexes or free bases to improve solubility or
release characteristics; or as pharmaceutically acceptable
ethers, esters, amides and the like Which have desirable
retention and release characteristics but Which are easily
metaboliZed at body pH.
[0059] Compounds may be converted into pharmaceuti
cally acceptable salts, and the salts may be converted into
pharmaceutically acceptable free compound using standard
procedures knoWn to those skilled in the art of synthetic
organic chemistry and described, for example, by J. March,
Advanced Organic Chemistry: Reactions, Mechanisms and
Structure, 4th Ed. (NeW York: Wiley-Interscience, 1992).
Acid addition salts are prepared from the free base (e.g.,
compounds having a neutral NH2 or cyclic amine group)
using conventional means, involving reaction With a suitable
acid. An acid addition salt may be converted to the free base
by treatment With a suitable base. Basic salts of acid
moieties Which may be present (e.g., carboxylic acid groups)
can be prepared in a similar manner using pharmaceutically
acceptable inorganic or organic bases. Compounds may also
be converted into pharmaceutically acceptable esters. Suit
able esters include branched or unbranched, saturated or
unsaturated C1 to C6 alky esters, for example, methyl, ethyl
and vinyl esters. Preparation of esters involves functional
iZation of hydroxyl and/or carboxyl groups Which may be
present. Pharmaceutically acceptable esters may be prepared
using methods knoWn to those skilled in the art and/or
described in the pertinent literature. Esters can be recon
US 2002/0004065 A1 Jan. 10, 2002

verted to the free acids, if desired, by using conventional norethindrone acetate (NETA) in a polyacrylate/polysilox
hydrogenolysis or hydrolysis procedures. Preparation of ane adhesive blend With 10% PVP, Formula 4 comprising
amides and pro-drugs can be performed in an analogous 5.0% ethyl cellulose and 5.0% cellulose acetate butyrate
manner. demonstrated an improved release pro?le as compared to
[0060] Steroids and hormonal active agents (including either Formula 1 (only 10% PVP), Formula 2 (5.0% ethyl
both natural, semi-synthetic and synthetic compounds and cellulose) or Formula 3 (5.0% cellulose acetate butyrate).
their derivatives having steroidal or hormonal activity) are The foregoing formulas Were prepared using the method of
preferred and include, for example, (a) estrogens such as Example 1 to yield the folloWing ingredient concentrations
set forth in tabular form in TABLE I.
Colpormon, Conjugated Estrogens, Estradiol (17B- and ot-)
and its Esters (e.g., Acetate, BenZoate, Cypionate, Dipropi
TABLE I
onate Diacetate, Enanthate, Estradiol-16,17-Hemisuccinate,
Undececenoate, Undecylate and Valerate), Estriol, Estrone, Formula
Ethinyl Estradiol, Equilenin, Equilin, Mestranol, Methyl 1 Formula 2 Formula 3 Formula 4
Estradiol, Moxestrol, Mytatrienediol, Quinestradiol, Polysiloxane 71.3 60.0 60.0 55.0
Quinestrol, Dienestrol, Clomifen, Chlorotrianisen, and Adhesive
Cyclofenil; (b) progestagenically effective hormones such as (BIO-PSA 7-4603)
Allylestrenol, Anagestone, Chlormadinone Acetate, Delma Polyacrylate 0.0 5.0 5.0 5.0
dinone Acetate, Demegestone, Desogestrel, 3-Keto Adhesive
Desogestrel, Dimethisterone, Dydrogesterone, Ethinylestre (DURO-TAK 87-2287)
Polyacrylate 5.0 0.0 0.0 0.0
nol, Ethisterone, Ethynodiol (and Diacetate), Flurogestone Adhesive
Acetate, Gestodene, Gestonorone Caproate, Haloprogester (Gelva 737)
one, (17-Hydroxy- and 17-Acetate-) 16-Methylene-Proges Ethyl Cellulose 0.0 5.0 0.0 5.0
terone, 17ot-Hydroxyprogesterone (Acetate and Caproate), (Ethocel 10)
Cellulose Acetate 0.0 0.0 5.0 5.0
Levonorgestrel, Lynestrenol, Medrogestone, Medrox Butyrate
yprogesterone (and Acetate), Megestrol Acetate, (CAB-381-0.5)
Melengestrol, Norethindrone (Acetate and Enanthate), Polyvinylpyrrolidone 10.0 10.0 10.0 10.0
KOLLIDON 30)
Norethisterone, Norethynodrel, Norgesterone, Norgesti Oleic Acid 6.0 0.0 0.0 0.0
mate, Norgestrel, Norgestrienone, 19-Norprogesterone, Dipropylene Glycol 4.0 9.0 9.0 9.0
Norvinisterone, Pentagestrone, Progesterone, Promege Oleyl Alcohol 0.0 6.0 6.0 6.0
stone, Quingestrone and Trengestone; and (c) androgeni Estradiol 0.7 1.0 1.0 1.0
Norethindrone 3.0 4.0 4.0 4.0
cally effective hormones such as Aldosterone, Androsterone, Acetate
Boldenone, Cloxotestosterone, Dehydroepiandrosterone,
Fluoxymesterone, Mestanolone, Mesterolone, Methandros
tenolone, Methyltestosterone, 17ot-Methyltesteosterone, [0064] Other speci?c drugs for Which the invention can be
17ot-Methyltestosterone 3-Cyclopentyl Enol Ether, Nore particularly usefully employed include:
thandrolone, Normethandrone, Oxandrolone, Oxymester
one, Oxymetholone, Prasterone, Stanlolone, StanoZolol, [0065] 1. ot-Adrenergic agonists such as Adra?nil, Adre
Testosterone (Acetate, Enanthate, Isobutyrate, Propionate nolone, Amidephrine, Apraclonidine, BudralaZine, Cloni
and Undecanoate), Testosterone 17-Chloral Hemiacetal, dine, Cyclopentamine, Detomidine, Dimetofrine, Dipiv
Testosterone 17[3-Cypionate and Tiomesterone. efrin, Ephedrine, Epinephrine, FenoxaZoline, GuanabenZ,
[0061] The adhesive matrix composition of the invention Guanfacine, Hydroxyamphetamine, Ibopamine, IndanaZo
preferably contains 17[3-estradiol or ethinyl estradiol as the line, Isometheptene, Mephentermine, Metaraminol, Meth
estrogen alone, or in combination With, Norethindrone oxamine Hydrochloride, Methylhexaneamine, MetiZolene,
(Acetate and Enanthate) or Norethisterone, as the proge
Midodrine, NaphaZoline, Norepinephrine, Norfenefrine,
stagen, and mixtures thereof. Octodrine, Octopamine, OxymetaZoline, Phenylephrine
Hydrochloride, Phenylpropanolamine Hydrochloride, Phe
[0062] In embodiments containing combinations and mix nylpropylmethylamine, Pholedrine, Propylhexedrine, Pseu
tures of estrogens and progestagens, the use of combinations doephedrine, Rilmenidine, Synephrine, TetrahydroZoline,
and mixtures of cellulose derivatives, particularlly cellulose Tiamenidine, TramaZoline, Tuaminoheptane, TymaZoline,
esters and ethers, provide improved drug release pro?les for Tyramine and XylometaZoline.
an extended period of time as compared to an adhesive
matrix composition containing either one alone or none. [0066] 2. [3-Adrenergic agonists such as Albuterol, Bam
Preferred combinations or mixtures of cellulose esters and buterol, Bitolterol, Carbuterol, Clenbuterol, Clorprenaline,
ethers are ethyl cellulose With cellulose acetate butyrate or Denopamine, Dioxethedrine, Dopexamine, Ephedrine, Epi
With cellulose acetate propionate. When used in combina nephrine, Etafedrine, Ethylnorepinephrine, Fenoterol, For
tions and mixtures, the amount of each such polymer typi moterol, Hexoprenaline, Ibopamine, Isoetharine, Isoproter
cally ranges from about 2.5% to about 10% by Weight based enal, Mabuterol, Metaproterenol, Methoxyphenamine,
on the dry Weight of the total adhesive matrix composition. Oxyfedrine, Pirbuterol, Prenalterol, Procaterol, Protokylol,
Particularly preferred embodiments of such mixtures and Reproterol, Rimiterol, Ritodrine, Soterenol, Terbuterol and
combinations include soluble PVP, and typically in an Xamoterol.
amount of about 5% to about 15% by Weight based on the
[0067] 3. ot-Adrenergic blockers such as Amosulalol, Aro
dry Weight of the total adhesive matrix composition. tinolol, DapipraZole, DoxaZosin, Ergoloid Mesylates, Fen
[0063] As shoWn in FIG. 6, in pressure-sensitive adhesive spiride, Indoramin, Labetalol, Nicergoline, PraZosin, Tera
matrix compositions containing both 17[3-estradiol (E2) and Zosin, TolaZoline, TrimaZosin and Yohimbine.
US 2002/0004065 A1
[0068] 4. [3-Adrenergic blockers such as Acebutolol,
Alprenolol, Amosulalol, Arotinolol, Atenolol, Befunolol,
BetaXolol, Bevantolol, Bisoprolol, Bopindolol, Bucumolol,
Befetolol, Bufuralol, Bunitrolol, Bupranolol, Butidrine
Hydrochloride, Buto?lolol, CaraZolol, Carteolol,
Carvedilol, Celiprolol, Cetamolol, Cloranolol, Dilevalol,
Epanolol, Esmolol, Indenolol, Labetalol, Levobunolol,
Mepindolol, Metipranalol, Metoprolol, Moprolol, NadoX
olol, Nifenalol, Nipradilol, OXprenolol, Penbutolol, Pin
dolol, Practolol, Pronethalol, Propranolol, Sotalol, Sul?
nalol, Talinolol, Tertatolol, Timolol, Toliprolol and
Xibenolol.
[0069] 5. Alcohol deterrents such as Calcium Cyanamide
Citrated, Disul?ram, Nadide and NitrefaZole.
[0070] 6. Aldose reductase inhibitors such as Epalrestat,
Ponalrestat, Sorbinil and Tolrestat.
[0071] 7. Anabolics such as AndroisoXaZole, Androstene
diol, Bolandiol, Bolasterone, Clostebol, Ethylestrenol.
Formyldienolone, 4-HydroXy-19-nortestosterone, Meth
andriol, Methenolone, Methyltrienolone, Nandrolone, Nan
drolone Decanoate, Nandrolone p-HeXyloXyphenylpropi
onate, Nandrolone Phenpropionate, Norbolethone,
OXymesterone, PiZotyline, Quinbolone, Stenbolone and
Trenbolone.
[0072] 8. Analgesics (dental) such as Chlorobutanol,
Clove and Eugenol.
[0073] 9. Analgesics (narcotic) such as Alfentanil, Allyl
prodine, Alphaprodine, Anileridine, BenZylmorphine, BeZ
itramide, Buprenorphine, Butorphanol, ClonitaZene,
Codeine, Codeine Methyl Bromide, Codeine Phosphate,
Codeine Sulfate, Desomorphine, DeXtromoramide, DeZo
cine, Diampromide, Dihydrocodeine, Dihydrocodeinone
Enol Acetate, Dihydromorphine, DimenoXadol, Dimephep
tanol, Dimethylthiambutene, DioXaphetyl Butyrate, Dipi
panone, EptaZocine, EthoheptaZine, Ethylmethlythiam
butene, Ethylmorphine, EtonitaZene, Fentanyl,
Hydrocodone, Hydrocodone Bitartrate, Hydromorphone,
HydroXypethidine, Isomethadone, Ketobemidone, Levor
phanol, Lofentanil, Meperidine, MeptaZinol, MetaZocine,
Methadone Hydrochloride, Metopon, Morphine, Morphine
Derivatives, Myrophine, Nalbuphine, Narceine, Nicomor
phine, Norlevorphanol, Normethadone, Normorphine, Nor
pipanone, Opium, OXycodone, OXymorphone, Papavere
tum, PentaZocine, PhenadoXone, PhenaZocine,
Pheoperidine, Piminodine, Piritramide, ProheptaZine,
Promedol, Properidine, Propiram, PropoXyphene, Sufentanil
and TilidLine.
[0074] 10. Analgesics (non-narcotic) such as Acetami
nophen, Acetaminosalol, Acetanilide, Acetylsalicylsalicylic
Acid, Alclofenac, Alminoprofen, AloXiprin, Aluminum
Bis(acetylsalicylate), AminochlorthenoXaZin, 2-Amino-4
picoline, Aminopropylon, Aminopyrine, Ammonium Sali
cylate, Antipyrine, Antipyrine Salicylate, Antrafenine, Apa
Zone, Aspirin, Benorylate, BenoXaprofen, BenZpiperylon,
BenZydamine, p-Bromoacetanilide, S-Bromosalicylic Acid
Acetate, Bucetin, BufeXamac, BumadiZon, Butacetin, Cal
cium Acetylsalicylate, CarbamaZepine, Carbetidine, Carbi
phene, Carsalam, Chloralantipyrine, ChlorthenoXaZin(e),
Choline Salicylate, Cinchophen, Ciramadol, Clometacin,
Cropropamide, Crotethamide, DeXoXadrol, DifenamiZole,
Di?unisal, DihydroXyaluminum Acetylsalicylate, Dipyro
Jan. 10, 2002
cetyl, 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, Indometha
cin, Indoprofen, IsofeZolac, Isoladol, IsoniXin, Ketoprofen,
Ketorolac, p-Lactophenetide, Lefetamine, LoXoprofen,
Lysine Acetylsalicylate, Magnesium Acetylsalicylate, Meth
otrimepraZine, Metofoline, Miroprofen, MoraZone, Mor
pholine Salicylate, NaproXen, Nefopam, NifenaZone, 5
Nitro-2 propoXyacetanilide, Parsalmide, PerisoXal, Phen
acetin, PhenaZopyridine Hydrochloride, Phenocoll, Phe
nopyraZone, Phenyl Acetylsalicylate, Phenyl Salicylate,
Phenyramidol, PipebuZone, Piperylone, Prodilidine, Propac
etamol, PropyphenaZone, ProXaZole, Quinine Salicylate,
RamifenaZone, RimaZolium Metilsulfate, Salacetamide,
Salicin, Salicylamide, Salicylamide O-Acetic Acid, Salicyl
sulfuric Acid, Salsalte, Salverine, Simetride, Sodium Sali
cylate, Sulfamipyrine, Suprofen, Talni?umate, TenoXicam,
Terofenamate, Tetradrine, Tinoridine, Tolfenamic Acid, Tol
pronine, Tramadol, Viminol, Xenbucin and Zomepirac.
[0075] 11. Anesthetics such as Acetamidoeugenol, Alfa
dolone Acetate, AlfaXalone, Amucaine, Amolanone, Amy
locaine Hydrochloride, BenoXinate, BenZocaine, BetoX
ycaine, Biphenamine, Bupivacaine, Butacaine, Butaben,
Butanilicaine, Burethamine, Buthalital Sodium, ButoX
ycaine, Carticaine, 2-Chloroprocaine Hydrochloride, Coca
ethylene, Cocaine, Cyclomethycaine, Dibucaine Hydrochlo
ride, Dimethisoquin, Dimethocaine, Diperadon
Hydrochloride, Dyclonine, Ecgonidine, Ecgonine, Ethyl
AminobenZoate, Ethyl Chloride, Etidocaine, EtoXadrol,
[3-Eucaine, Euprocin, Fenalcomine, Fomocaine, HeXobar
bital, HeXylcaine Hydrochloride, HydroXydione Sodium,
HydroXyprocaine, HydroXytetracaine, Isobutyl p-Ami
nobenZoate, Kentamine, Leucinocaine Mesylate, LevoXa
drol, Lidocaine, Mepivacaine, Meprylcaine Hydrochloride,
MetabutoXycaine Hydrochloride, MethoheXital Sodium,
Methyl Chloride, MidaZolam, Myrtecaine, Naepaine,
Octacaine, Orthocaine, OXethaZaine, ParethoXycaine, Phen
acaine Hydrochloride, Phencyclidine, Phenol, Piperocaine,
Piridocaine, Polidocanol, PramoXine, Prilocaine, Procaine,
Propanidid, Propanocaine, Proparacaine, Propipocaine, Pro
pofol, PropoXycaine Hydrochloride, Pseudococaine, Pyr
rocaine, Quinine Urea Hydochloride, Risocaine, Salicyl
Alcohol, Tetracaine Hydrochloride, Thialbarbital, Thimylal,
Thiobutabarbital, Thiopental Sodium, Tolycaine, Tri
mecaine and Zolamine.
[0076] 12. AnoreXics such as AminoreX, Amphecloral,
Amphetamine, BenZaphetamine, Chlorphentermine,
ClobenZoreX, CloforeX, Clortermine, CycleXedrine, Destro
amphetamine Sulfate, Diethylpropion, DiphemethoXidine,
N-Ethylamphetamine, FenbutraZate, Fen?uramine, Fenpro
poreX, Furfurylmethylamphetamine, Levophacetoperate,
MaZindol, MefenoreX, Metamfeproamone, Methamphet
amine, Norpseudoephedrine, PhendimetraZine, Phendime
traZine Tartrate, PhenmetraZine, Phenpentermine, Phenyl
propanolamine Hydrochloride and PiciloreX.
[0077] 13. Anthelmintics (Cestodes) such as Arecoline,
Aspidin, Aspidinol, Dichlorophen(e), Embelin, Kosin,
Napthalene, Niclosamide, Pellertierine, Pellertierine Tan
nate and Quinacrine.
[0078] 14. Anthelmintics (Nematodes) such as Alantolac
tone, Amoscanate, Ascaridole, Bephenium, Bitoscanate,
US 2002/0004065 A1
Carbon Tetrachloride, Carvacrol, CyclobendaZole, Diethyl
carbamaZine, Diphenane, DithiaZanine Iodide, Dymanthine,
Gentian Violet, 4-Hexylresorcinol, Kainic Acid, Mebenda
Zole, 2-Napthol, Oxantel, Papain, PiperaZine, PiperaZine
Adipate, PiperaZine Citrate, PiperaZine Edetate Calcium,
PiperaZine Tartrate, Pyrantel, Pyrvinium Pamoate, a-Santo
nin, StilbaZium Iodide, Tetrachloroethylene, Tetramisole,
thiabendaZole, Thymol, Thymyl N-Isoamylcarbamate, Tri
clofenol PiperaZine and Urea Stibamine.
[0079] 15. Anthelmintics (Onchocerca) such as Ivermectin
and Suramin Sodium.
[0080] 16. Anthelmintics (Schistosoma) such as Amoscan
ate, Amphotalide, Antimony Potassium Tartrate, Antimony
Sodium Gluconate, Antimony Sodium Tartrate, Antimony
Sodium Thioglycollate, Antimony Thioglycollamide,
Becanthone, Hycanthone, Lucanthone Hydrochloride, Niri
daZole, Oxamniquine, PraZiquantel, Stibocaptate, Stibophen
and Urea Stibamine.
[0081] 17. Anthelmintic (Trematodes) such as Anthi
olimine and Tetrachloroethylene.
[0082] 18. Antiacne drugs such as Adapelene, Algestone
Acetophenide, AZelaic Acid, BenZoyl Peroxide, Cyoctol,
Cyproterone, Motretinide, Resorcinol, Retinoic Acid, Tetro
quinone and Tretinonine.
[0083] 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.
[0084] 20. Antiamebics such as Arsthinol, Bialamicol,
Carbarsone, Cephaeline, Chlorbetamide, Chloroquine,
Chlorphenoxamide, Chlortetracycline, Dehydroemetine,
Dibromopropamidine, Diloxanide, Dephetarsone, Emetine,
Fumagillin, Glaucarubin, Glycobiarsol, 8-Hydroxy-7-iodo
S-quinolinesulfonic Acid, Iodochlorhydroxyquin,
Iodoquinol, Paromomycin, Phanquinone, Phearsone Sul
foxylate, PolybenZarsol, Propamidine, Quinfamide, Sec
nidaZole, Sulfarside, TecloZan, Tetracycline, Thiocarbam
iZine, Thiocarbarsone and TinidaZole.
[0085] 21. Antiandrogens such as Bi?uranol, Cyoctol,
Cyproterone, Delmadinone Acetate, Flutimide, Nilutamide
and Oxendolone.
[0086] 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, Gallo
pamil, Imolamine, Indenolol, Isosorbide Dinitrate, Israd
ipine, Limaprost, Mepindolol, Metoprolol, Molsidomine,
Nadolol, Nicardipine, Nifedipine, Nifenalol, Nilvadipine,
Nipradilol, Nisoldipine, Nitroglycerin, Oxprenolol, Oxy
fedrine, OZagrel, Penbutolol, Pentaerythritol Tetranitrate,
Pindolol, Pronethalol, Propranolol, Sotalol, Terodiline,
Timolol, Toliprolol and Verapamil.
[0087] 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, Clo
Jan. 10, 2002
ranolol, Disopyramide, Encainide, Esmolol, Flecainide,
Gallopamil, Hydroquinidine, Indecainide, Indenolol, Iprat
ropium Bromide, Lidocaine, Lorajmine, Lorcainide,
Meobentine, Metipranolol, Mexiletine, MoriciZine, Nadox
olol, Nifenalol, Oxprenolol, Penbutolol, Pindolol, Pirmenol,
Practolol, Prajmaline, Procainamide Hydrochloride, Prone
thalol, Propafenone, Propranolol, Pyrinoline, Quinidine Sul
fate, Quinidine, Sotalol, Talinolol, Timolol, Tocainide, Vera
pamil, Viquidil and Xibenolol.
[0088] 24. Antiarteriosclerotics such as Pyridinol Carbam
ate.
[0089] 25. Antiarthritic/Antirheumatics such as Allocupre
ide Sodium, Aurano?n, Aurothioglucose, Aurothiogly
canide, 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 Penicil
lamine.
[0090] 26. Antibacterial (antibiotic) drugs including:
[0091] Aminoglycosides such as Amikacin, Apramy
cin, Arbekacin, Bambermycins, Butirosin, Dibeka
cin, Dihdrostreptomycin, Fortimicin s), Gentamicin,
Ispamicin, Kanamycin, Micronomicin, Neomycin,
Neomycin Undecylenate, Netilmicin, Paromomycin,
Ribostamycin, Sisomicin, Spectinomycin, Strepto
mycin, StreptonicoZid and Tobramycin;
[0092] Amphenicols such as AZidamfenicol,
Chloramphenicol, Chloramphenicol Palmitate,
Chloramphenicol Pantothenate, Florfenicol and
Thiamphenicol;
[0093] Ansamycins such as Rifamide, Rifampin,
Rifamycin and Rifaximin;
[0094] [3-Lactams, including:
[0095] Carbapenems such as Imipenem,
[0096] Cephalosporins such as Cefactor,
Cefadroxil, Cefamandole, CefatriZine, CefaZe
done, CefaZolin, Ce?xime, Ce?nenoxime, Cefo
diZime, Cefonicid, CefoperaZone, Ceforanide,
Cefotaxime, Cefotiam, CefpimiZole, Cefpirimide,
Cefpodoxime Proxetil, Cefroxadine, Cefsulodin,
CeftaZidime, Cefteram, CefteZole, Ceftibuten,
CeftiZoxime, Ceftriaxone, Cefuroxime, Cefu
Zonam, Cephacetrile Sodium, Cephalexin, Cepha
loglycin, Cephaloridine, Cephalosporin, Cephal
othin, Cephapirin Sodium, Cephradine and
Pivcefalexin;
[0097] Cephamycins such as CefbuperaZone,
Ce?netaZole, Cefminox, Cefetan and Cefoxitin;
[0098] Monobactams such as AZtreonam, Caru
monam and Tigemonam;
[0099] Oxacephems such as Flomoxef and Mox
olactam;
[0100] Penicillins such as Amidinocillin, Amdi
nocillin Pivoxil, Amoxicillin, Ampicillan, Apalcil
lin, Aspoxicillin, AZidocillan, AZlocillan,
Bacampicillin, BenZylpenicillinic Acid, BenZyl
penicillin Sodium, Carbenicillin, Carfecillin
US 2002/0004065 A1
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, Penicil
lin G BenZhydrylamine, Penicillin G Calcium,
Penicillin G Hydrabamine, Penicillin G Potas
sium, Penicillin G Procaine, Penicillen N, Peni
cillin O, Penicillin V, Penicillin V BenZathine,
Penicillin V Hydrabamine, Penimepicycline,
Phenethicillin Potassium, Piperacillin, Pivapicil
lin, Propicillin, Quinacillin, Sulbenicillin,
Talampicillin, Temocillin and Ticarcillin;
[0101] Lincosamides such as Clindamycin and
Lincomycin;
[0102] Macrolides such as AZithromycin, Carbomy
cin, Clarithromycin, Erythromycin, Erythromycin
Acistrate, Erythromycin Estolate, Erythromycin
Glucoheptonate, Erythromycin Lactobionate, Eryth
romycin Propionate, Erythromycin Stearate, Josa
mycin, Leucomycins, Midecamycins, Miokamycin,
Oleandomycin, Primycin, Rokitamycin, Rosarami
cin, RoXithromycin, Spiramycin and Troleandomy
cm;
[0103] Polypeptides such as Amphomycin, Bacitra
cin, Capreomycin, Colistin, Enduracidin, Enviomy
cin, Fusafungine, Gramicidin(s), Gramicidin S,
Mikamycin, PolymyXin, PolymyXin [3-Methane
sulfonic Acid, Pristinamycin, Ristocetin, Teicopla
nin, Thiostrepton, Tuberactinomycin, Tyrocidine,
Tyrothricin, Vancomycin, Viomycin, Viomycin Pan
tothenate, Virginiamycin and Zinc Bacitracin;
[0104] Tetracyclines such as Apicycline, Chlortetra
cycline, Clomocycline, Demeclocycline, DoXycy
cline, Guamecycline, Lymecycline, Meclocycline,
Methacycline, Minocycline, OXytetracycline, Pen
imepicycline, Pipacycline, Rolitetracycline, Sancyc
line, Senociclin and Tetracycline; and
[0105] other antibiotics such as Cycloserine, Mupi
rocin and Tuberin.
[0106] 27. Antibacterial drugs (synthetic), including:
[0107] 2,4-Diaminopyrimidines such as Brodi
moprim, TetroXoprim and Trimethoprim;
[0108] Nitrofurans such as Furaltadone, FuraZolium
Chloride, Nifuradene, Nifuratel, Nifurfoline,
Nifurpirinol, NifurpraZine, Nifurtoinol and Nitro
furantoin;
[0109] Quinolones and Analogs such as Ami?oXacin,
CinoXacin, Cipro?oXacin, Di?oXacin, EnoXacin,
FleroXacin, Flumequine, Lome?oXacin, MiloXacin,
NalidiXic Acid, Nor?oXacin, O?oXacin, OXolinic
Acid, Pe?oXacin, Pipemidic Acid, Piromidic Acid,
RosoXacin, Tema?oXacin and Tosu?oXacin;
[0110] Sulfonamides such as Acetyl SulfamethoXy
pyraZine, Acetyl Sul?soXaZole, AZosulfamide, Ben
Zylsulfamide, Chloramine-B, Chloramine-T,
Dichloramine T, FormosulfathiaZole,
NzFormylsul?somidine,NZ-a-D-Glucosylsulfanil
amide, Mafenide, 4-(Methylsulfamoyl)sulfanilanil
Jan. 10, 2002
ide, p-NitrosulfathiaZole, Noprylsulfamide,
Phthalylsulfacetamide, PhthalylsulfathiaZole, Sala
Zosulfadimidine, SuccinylsulfathiaZole, SulfabenZa
mide, Sulfacetamide, SulfachlorpyridaZine, Sulfach
rysoidine, Sulfacytine, SulfadiaZine, Sulfadicramide,
SulfadimethoXine, SulfadoXine, Sulfaethidole, Sulf
aguanidine, Sulfaguanol, Sulfalene, SulfaloXic Acid,
SulfameraZine, Sulfameter, SulfamethaZine, Sul
famethiZole, Sulfamethomidine, SulfamethoXaZole,
SulfamethoXypyridaZine, Sulfametrole, Sulfamido
chrysoidine. SulfamoXole, Sulfanilamide, Suifanil
amidomethanesulfonic Acid Triethanolamine Salt,
4-Sulfanilamidosalicylic Acid, N4-Sulfanilylsulfa
nilamide, Sulfanilylurea, N-Sulfanilyl-3,4-Xylamide,
Sulfanitran, Sulfaperine, SulfaphenaZole. Sul
faproXyline, SulfapyraZine, Sulfapyridine, Sulfa
somiZole, SulfasymaZine, SulfathiaZole, Sulfathio
urea, Sulfatolamide, Sul?somidine and
Sul?soXaZole;
[0111] Sulfones such as Acedapsone, Acediasulfone,
Acetosulfone Sodium, Dapsone, Diathymosulfone, Gluco
sulfone Sodium, Solasulfone, Succisulfone, Sulfanilic Acid,
p-SulfanilylbenZylamine, p,p-Sulfonyldianiline-N.N diga
lactoside, SulfoXone Sodium and ThiaZolsulfone; and others
such as Clofoctol, HeXedine, Methenamine, Methenamine
Anhydromethylene-citrate, Methenamine Hippurate, Meth
enamine Mandelate, Methenamine Sulfosalicylate, NitroXo
line and Xibornol. Anticholinergics such as Adiphenine
Hydrochloride, Alverine, Ambutonomium Bromide, Amino
pentamide, AmiXetrine, Amprotropine Phosphate, Anisotro
pine Methylbromide, Apoatropine, Atropine, Atropine
N-Oxide, BenactyZine, BenapryZine, BenZetimide, BenZilo
nium Bromide, BenZtropine Mesylate, Bevonium Methyl
Sulfate, Biperiden, Butropium Bromide, N-Butylscopolam
monium Bromide, BuZepide, Camylo?ne, Caramiphen
Hydrochloride, ChlorbenZoXamine, ChlorphenoXamine,
Cimetropium Bromide, Clidinium Bromide, Cyclodrine,
Cyclonium Iodide, Cycrimine Hydrochloride, Deptropine,
DeXetimide Dibutoline Sulfate, Dicyclomine Hydrochlo
ride, DiethaZine, Difemerine, DiheXyverine, Diphemanil
Methylsulfate, N-(l,2-Diphenylethyl)nicotinamide, Dip
iproverine, Diponium Bromide, Emepronium Bromide,
EndobenZyline Bromide, EthopropaZine, EthybenZtropine,
EthylbenZhydramine, Etomidoline, Eucatropine, Fenpiver
inium Bromide, Fentonium Bromide, Flutropium Bromide,
Glycopyrrolate, Heteronium Bromide, HeXocyclium Methyl
Sulfate, Homatropine, Hyoscyamine, Ipratropium Bromide,
Isopropamide, Levomepate, MecloXamine, MepenZolate
Bromide, Metcaraphen, Methantheline Bromide, MethiX
ene, Methscopolamine Bromide, Octamylamine, Chloride,
OXyphencyclimine, OXyphenonium Bromide, Pentapip
eride, Penthienate Bromide, Phencarbamide, Phenglutarim
ide, PipenZolate Bromide, Piperidolate, Piperilate, Poldine
Methysulfate, Pridinol, Pri?nium Bromide, Procyclidine,
Propantheline Bromide, PropenZolate, PropyromaZine, Sco
polamine, Scopolamine N-OXide, Stilonium Iodide, Stramo
nium, Sultroponium, ThiheXinol, Thiphenamil, Tiemonium
Iodide, Timepidium Bromide, TiquiZium Bromide, Tridi
heXethyl Iodide, TriheXyphenidyl Hydrochloride, Tropacine,
TropenZile, Tropicamide, Trospium Chloride, Valethamate
Bromide and Xenytropium Bromide.
[0112] 28. Anticonvulsants such as Acetylpheneturide,
Albutoin, AloXidone, Aminoglutethimide, 4-Amino-3-hy
droXybutyric Acid, Atrolactamide, Beclamide, Buramate,
Calcium Bromide, CarbamaZepine, Cinromide, Clomethia
Zole, ClonaZepam, Decimemide, Diethadione, Dimethadi
one, DoXenitoin, Eterobarb, Ethadione, EthosuXimide, Etho
US 2002/0004065 A1
toin, Fluoresone, Garbapentin, S-Hydroxytryptophan,
Lamotrigine, Lomactil, Magnesium Bromide, Magnesium
Sulfate, Mephenytoin, Mephobarbital, Metharbital, Meth
etoin, MethsuXimide, S-Methyl-S-(3-phenanthryl)hydan
toin, 3-Methyl-5-phenylhydantoin, Narcobarbital,
NimetaZepam, NitraZepam, Paramethadione, Phenacemide,
Phenetharbital, Pheneturide, Phenobarbital, Phenobarbital
Sodium, PhensuXimide, Phenylmethylbarbituric Acid,
Phenytoin, Phethenylate Sodium, Potassium Bromide, Pre
gabatin, Primidone, Progabide, Sodium Bromide, Sodium
Valproate, Solanum, Strontium Bromide, Suclofenide,
Sulthiame, Tetrantoin, Tiagabine, Trimethadione, Valproic
Acid, Valpromide, Vigabatrin and Zonisamide.
[0113] 29. Antidepressants, including:
[0114] Bicyclics such as Binedaline, CaroXaZone,
Citalopram, DimethaZan, Indalpine, Fencamine,
IndeloXaZine Hydrochcloride, Nefopam,
Nomifensine, OXitriptan, OXypertine, ParoXetine,
Sertraline, ThiaZesim, TraZodone, VenlafaXine and
Zometapine;
[0115] HydraZides/HydraZines such as BenmoXine,
IprocloZide, IproniaZid, IsocarboXaZid, Nialamide,
OctamoXin and PhenelZine;
[0116] Pyrrolidones such as Cotinine, Rolicyprine
and Rolipram;
[0117] Tetracyclics such as Maprotiline, Metralin
dole, Mianserin and OXaprotiline.
[0118] Tricyclics such as AdinaZolam, Amitriptyline,
Amitriptylinoxide, Amoxapine, Butriptyline, Clomi
pramine, DemeXiptiline, Desipramine, DibenZepin,
Dimetracrine, Dothiepin, DoXepin, FluaciZine, Imi
pramine, Imipramine N-OXide, Iprindole,
Lofepramine, Melitracen, Metapramine, Nortrip
tyline, NoXiptilin, Opipramol, PiZotyline,
PropiZepine, Protriptyline, Quinupramine, Tianept
ine and Trimipramine; and
[0119] others such as Adra?nil, BenactyZine, Bupro
pion, Butacetin, Deanol, Deanol Aceglumate,
Deanol AcetamidobenZoate, DioXadrol, Etoperi
done, Febarbamate, FemoXetine, Fenpentadiol, Flu
oXetine, FluvoXamine, FluvoXamine Maleate,
Hematoporphyrin, Hypercinin, Levophacetoperane,
MedifoXamine, Minaprine, Moclobemide, OXa?oZ
ane, Piberaline, Prolintane, Pyrisuccideanol,
Rubidium Chloride, Sulpiride, Sultopride, TeniloX
aZine, ThoZalinone, Tofenacin, ToloXatone, Tranyl
cypromine, L-Tryptophan, ViloXaZine and Zimel
dine.
[0120] 30. Antidiabetics, including:
[0121] Biguanides such as Buformin, Metformin and
Phenformin;
[0122] Hormones such as Glucagon and Insulin;
[0123] Sulfonylurea derivatives such as AcetoheXa
mide, 1-Butyl-3-metanilylurea, Carbutamide, Chlo
rpropamide, Glibornuride, GliclaZide, GlipiZide,
Gliquidone, GlisoXepid, Glyburide, GlybuthiaZol(e),
GlybuZole, GlyheXamide, Glymidine, Glypinamide,
Phenbutamide, TolaZamide, Tolbutamide and Tolcy
clamide; and
[0124] others such as Acarbose, Calcium MesoXalate
and Miglitol.
Jan. 10, 2002
[0125] 31. Antidiarrheal drugs such as Acetyltannic Acid,
Albumin Tannate, Alkofanone, Aluminum Salicylates-Ba
sic, Catechin, DifenoXin, DiphenoXylate, Lidamidine,
Lomotil, Loperamide, Mebiquine, Trillium and UZarin.
[0126] 32. Antidiuretics such as Desmopressin, Fely
pressin, Lypressin, Ornipressin, OXycinchophen, Pituitary
Posterior, Terlipressin and Vasopressin.
[0127] 33. Antiestrogens such as Delmadinone Acetate,
EthamoXytriphetol, Tamoxifen and Toremifene.
[0128] 34. Antifungal drugs (antibiotics), including:
[0129] Polyenes such as Amphotericin-B, Candici
din, Dermostatin, Filipin, Fungichromin, Hachimy
cin, Hamycin, Lucensomycin, Mepartricin, Natamy
cin, Nystatin, Pecilocin and Perinycin; and
[0130] others such as AZaserine, Griseofulvin, Oli
gomycins, Neomycin Undecylenate, Pyrrolnitrin,
Siccanin, Tubercidin and Viridin.
[0131] 35. Antifungal drugs (synthetic), including:
[0132] Allylamines such as Nafti?ne and Terbin
a?ne;
[0133] ImidaZoles such as BifonaZole, ButoconaZole,
Chlordantoin, ChlormidaZole, CloconaZole, Clotri
maZole, EconaZole, EnilconaZole, FenticonaZole,
IsoconaZole, KetoconaZole, MiconaZole, Omocona
Zole, OXiconaZole, Nitrate, SulconaZole and Tio
conaZole;
[0134] TriaZoles such as FluconaZole, ItraconaZole
and TerconaZole; and
[0135] others such as Acrisorcin, Amorol?ne, Biphe
namine, Bromosalicylchloranilide, Buclosamide,
Calcium Propionate, Chlophenesin, CiclopiroX,
CloXyquin, Coparaf?nate, DiamthaZole, Dihydro
chloride, EXalamide, Flucytosine, HalethaZole, Hex
etidine, Lo?ucarban, Nifuratel, Potassium Iodide,
Propionic Acid, Pyrithione, Salicylanilide, Sodium
Propionate, Sulbentine,
[0136] TenonitroZole, Tolciclate, Tolindate, Tolnaf
tate,
[0137] Tricetin, Ujothion, Undecylenic Acid and
Zinc Propionate.
[0138] 36. Antiglaucoma drugs such as AcetaZolamide,
Befunolol, BetaXolol, Bupranolol, Carteolol, DapipraZoke,
Dichlorphenamide, Dipivefrin, Epinephrine, Levobunolol,
MethaZolamide, Metipranolol, Pilocarpine, Pindolol and
Timolol.
[0139] 37. Antigonadotropins such as DanaZol, Gestrinone
and ParoXypropione.
[0140] 38. Antigout drugs such as Allopurinol, Carprofen,
Colchicine, Probenecid and Sul?npyraZone.
[0141] 39. Antihistamines, including:
[0142] Alkylamine derivatives such as Acrivastine,
Bamipine, Brompheniramine, Chlorpheniramine,
Dimethindene, Metron S, Pheniramine, Pyrrob
utamine, Thenaldine, Tolpropamine and Triproli
dine;
[0143] Aminoalkyl ethers such as Bietanautine, Bro
modiphenhydramine, CarbinoXamine, Clemastine,
US 2002/0004065 A1
10
Diphenlypyraline, DoXylamine, Embrammine,
Medrylamine, Mephenphydramine, p-Methyl
diphenhydramine, Orphenadrine, PhenyltoloXamine,
Piprinhydrinate and Setasine;
[0144] Ethylenediamine derivatives such as Allocla
mide, p-Bromtripelennamine, Chloropyramine,
Chlorothen, Histapyrrodine, Methafurylene, Meth
aphenilene, Methapyrilene, PhenbenZamine, Pyril
amine, Talastine, Thenyldiamine, ThonZylamine
Hydrochloride, Tripelennamine and Zolamine;
[0145] PiperaZines such as CetiriZine, ChlorcycliZ
ine, CinnariZine, ClociniZine and HydroXyZine;
[0146] Tricyclics, including:
[0147] PhenothiaZines such as Ahistan, Etyme
maZine, FenethaZine, N-HydroXyethylpromethaZ
ine Chloride, IsopromethaZine, MequitaZine,
PromethaZine, PyrathiaZine and ThiaZinamium
Methyl Sulfate; and
[0148] others such as AZatadine, ClobenZepam,
Cyproheptadine, Deptropine, Isothipendyl, Lora
tadine and Prothipendyl; and
[0149] other antihistamines such as AntaZoline,
AstemiZole, AZelastine, CetoXime, ClemiZole,
ClobenZtropine, DiphenaZoline, Diphenhydramine,
Fluticasone Propionate, Mebhydroline, Phenin
damine, Terfenadine and Tritoqualine.
[0150] 40. Antihyperlipoproteinemics, including:
[0151] AryloXyalkanoic acid derivatives such as
Beclorbrate, BaZa?brate, Bini?brate, Cipro?brate,
Clino?brate, Clo?brate, Clo?bric Acid, Eton?brate,
Feno?brate, Gem?broZil, Nico?brate, Piri?brate,
Roni?brate, Sim?brate and Theo?brate;
[0152] Bile acid sequesterants such as
Cholestyramine Resin, Colestipol and PolideXide;
[0153] HMG CoA reductase inhibitors such as Flu
vastatin, Lovastatin, Pravastatin Sodium and Simv
astatin;
[0154] Nicotinic acid derivatives Aluminum Nicoti
nate, AcipimoX, Niceritrol, Nicoclonate, Niconol and
OXiniacic Acid;
[0155] Thyroid hormones and analogs such as
EtiroXate, Thyropropic Acid and ThyroXine; and
[0156] others such as Acifran, AZacosterol, Ben?uo
reX, a-BenZalbutyramide, Carnitine, Chondroitin
Sulfate, Clomestone, DetaXtran, DeXtran Sulfate
Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Erita
denine, FuraZbol, Meglutol, Melinamide,
Mytatrienediol, Ornithine, a-oryZanol, Pantethine,
Penataerythritol Tetraacetate, a-Phenylbutyramide,
PiroZadil, Probucol, a-Sitosterol, Sultosilic Acid,
PiperaZine Salt, Tiadenol, Triparanol and Xenbucin.
[0157] 41. Antihypertensive drugs, including:
[0158] Arylethanolamine derivatives such as Amosu
lalol, Bufuralol, Dilevalol, Labetalol, Pronethalol,
Sotalol and Sul?nalol;
Jan. 10, 2002
[0159] AryloXypropanolamine derivatives such as
Acebutolol, Alprenolol, Arotinolol, Atenolol, BetaX
olol, Bevantolol, Bisoprolol, Bopindolol, Bunitrolol,
Bupranolol, Buto?lolol, CaraZolol, CarteZolol,
Carvedilol, Celiprolol, Cetamolol, Epanolol, Inde
nolol, Mepindolol, Metipranolol, Metoprolol,
Moprolol, Nadolol, Nipradilol, OXprenolol, Penb
utolol, Pindolol, Propranolol, Talinolol, Tetraolol,
Timolol and Toliprolol;
[0160] BenZothiadiaZine derivatives such as AlthiaZ
ide, Bendro?umethiaZide, BenZthiaZide, BenZylhy
drochlorothiaZide, ButhiaZide, ChlorothiaZide, Chlo
rthalidone, CyclopenthiaZide, CyclothiaZide,
DiaZoXide, EpithiaZide, EthiaZide, FenquiZone,
HydrochlorothiaZide, Hydro?umethiaZide, Methy
clothiaZide, Meticrane, MetolaZone, Para?utiZide,
PolythiaZide, TetrachlormethiaZide and Trichlorme
thiaZide;
[0161] N-Carboxyalkyl (peptide/lactam) derivatives
such as Alacepril, Captopril, CilaZapril, Delapril,
Enalapril, Enalaprilat, Fosinopril, Lisinopril, Movel
tipril, Perindopril, Quinapril and Ramipril;
[0162] Dihydropyridine derivatives such as Amlo
dipine, Felodipine, Isradipine, Nicardipine, Nife
dipine, Nilvadipine, Nisoldipine and Nitrendipine;
[0163] Guanidine derivatives such as Bethanidine,
Debrisoquin, GuanabenZ, Guanacline, Guanadrel,
GuanaZodine, Guanethidine, Guanfacine, Gua
nochlor, GuanoXabenZ and GuanoXan;
[0164] HydraZines and phthalaZines such as Budrala
Zine, CadralaZine, DihydralaZine, EndralaZine, Hyd
racarbaZine, HydralaZine, PhenipraZine, PildralaZine
and TodralaZine;
[0165] ImidaZole derivatives such as Clonidine,
LofeXidine, Phentolamine, Phentolamine Mesylate,
Tiamenidine and Tolonidine;
[0166] Quaternary ammonium compounds AZame
thonium Bromide, Chlorisondamine Chloride, Hex
amethonium, Pentacynium Bis(methyl sulfate), Pen
tamethonium Bromide, Pentolinium Tartate,
Phenactopinium Chloride and Trimethidiunum
Methosulfate;
[0167] QuinaZoline derivatives such as AlfuZosin,
BunaZosin, DoXaZosin, Prasosin, TeraZosin and Tri
maZosin;
[0168] Reserpine derivatives such as Bietaserpine,
Deserpidine, Rescinnamine, Reserpine and Syrosin
gopine;
[0169] Sulfonamide derivatives such as Ambuside,
Clopamide, Furosemide, Indapamide, QuinethaZone,
Tripamide and Xipamide; and
[0170] 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, MinoXi
dil, MuZolimine, Pargyline, Pempidine, Pinacidil,
US 2002/0004065 A1
11
PiperoXan, Prirnaperone, Protoveratrines,
Raubasine, Rescirnetol, Rilrnenidene, Saralasin,
Sodium Nitroprusside, Ticrynafen, Trirnethaphan
Carnsylate, Tyrosinase, Urapidil and Valsartan.
[0171] 42. Antihyperthyroids such as 2-Arnino-4-rneth
ylthiaZole, 2-ArninothiaZole, CarbirnaZole, 3,5-Dibrorno-L
tyrosine, 3,5-Diiodotyrosine, Hinderin, Iodine, Iothiouracil,
MethirnaZole, Methylthiouracil, Propylthiouracil, Sodium
Perchlorate, ThibenZaZoline, Thiobarbital and 2-Thiouracil.
[0172] 43. Antihypotensive drugs such as ArneZiniurn
Methyl Sulfate, Angiotensin Amide, Dirnetofrine, Dopam
ine, Etifelrnin, Etilefrin, Gepefrine, Metararninol, Mido
drine, Norepinephrine, Pholedrinead and Synephrine.
[0173] 44. Antihypothyroid drugs such as LevothyroXine
Sodium, Liothyronine, Thyroid, Thyroidin, ThyroXine,
Tiratricol and TSH.
[0174] 45. Anti-In?ammatory (non-steroidal) drugs,
including:
[0175] ArninoarylcarboXylic acid derivatives such as
Enfenarnic Acid, Etofenarnate, Flufenarnic Acid,
IsoniXin, Meclofenarnic Acid, Mefanarnic Acid,
Ni?urnic Acid, Talni?urnate, Terofenarnate and
Tolfenarnic Acid;
[0176] Arylacetic acid derivatives such as Acerneta
cin, Alclofenac, Arnfenac, BufeXarnac, Cinrnetacin,
Clopirac, Diclofenac Sodiurn, Etodolac, Felbinac,
Fenclofenac, Fenclorac, FencloZic Acid, FentiaZac,
Glucarnetacin, Ibufenac, Indornethacin, IsofeZolac,
IsoXepac, LonaZolac, MetiaZinic Acid, OXarnetacine,
Proglurnetacin, Sulindac, Tiararnide, Tolrnetin and
Zornepirac;
[0177] Arylbutyric acid derivatives such as Burnadi
Zon, Butibufen, Fenbufen and Xenbucin;
[0178] ArylcarboXylic acids such as Clidanac,
Ketorolac and Tinoridine;
[0179] Arylpropionic acid derivatives such as Alrni
noprofen, BenoXaprofen, BucloXic Acid, Carprofen,
Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibupro
fen, Ibuproxarn, Indoprofen, Ketoprofen, LoXopro
fen, Miroprofen, NaproXen, OXaproZin, Piketopro
fen, Pirprofen, Pranoprofen, ProtiZinic Acid,
Suprofen and Tiaprofenic Acid;
[0180] PyraZoles such as DifenarniZole and Epiri
Zole;
[0181] PyraZolones such as ApaZone, BenZpiperylon,
FepraZone, MofebutaZone, MoraZone, OXyphenb
utaZone, PhenybutaZone, PipebuZone, Propy
phenaZone, RarnifenaZone, SuXibuZone and ThiaZ
olinobutaZone;
[0182] Salicylic acid derivatives such as Acetarninos
alol, Aspirin, Benorylate, Brornosaligenin, Calciurn
Acetylsalicylate, Di?unisal, Etersalate, Fendosal,
Gentisic Acid, Glycol Salicylate, IrnidaZole Salicy
late, Lysine Acetylsalicylate, Mesalarnine, Morpho
line Salicylate, l-Naphthyl Salicylate, OlsalaZine,
Parsalrnide, Phenyl Acetylsalicylate, Phenyl Salicy
late, Salacetarnide, Salicylarnine O-Acetic Acid,
Salicylsulfuric Acid, Salsalate and SulfasalaZine;
Jan. 10, 2002
[0183] ThiaZinecarboXarnides such as DroXicarn,
IsoXicarn, PiroXicarn and TenoXicarn; and
[0184] others such as a-Acetarnidocaproic Acid,
S-Adenosylrnethionine, 3-Arnino-4-hydroXybutyric
Acid, ArniXetrine, BendaZac, BenZydarnine, Buco
lorne, Difenpirarnide, DitaZol, ErnorfaZone, Guaia
Zulene, Naburnetone, Nirnesulide, Orgotein,
OXaceprol, Paranyline, PerisoXal, PifoXirne, Proqua
Zone, ProXaZole and Tenidap.
[0185] 46. Antirnalarial drugs such as Acedapsone, Arno
diaquin, Arteether, Arternether, Arternisinin, Artesunate,
Bebeerine, Berberine, Chirata, Chlorguanide, Chloroquine,
Chlorproguanil, Cinchona, Cinchonidine, Cinchonine,
Cycloguanil, Gentiopicrin, Halofantrine, HydroXychloro
quine, Me?oquine Hydrochloride, 3-Methylarsacetin, Pam
aquine, Plasrnocid, Prirnaquine, Pyrirnetharnine, Quina
crine, Quinine, Quinine Bisulfate, Quinine Carbonate,
Quinine Dihydrobrornide, Quinine Dihydrochloride, Qui
nine Ethylcarbonate, Quinine Forrnate, Quinine Gluconate,
Quinine Hydriodide, Quinine Hydrochloride, Quinine Sali
cylate, Quinine Sulfate, Quinine Tannate, Quinine Urea
Hydrochloride, Quinocide, Quinoline and Sodiurn Arsenate
Diabasic.
[0186] 47. Antirnigraine drugs such as Alpiropride, Dihy
droergotarnine, Eletriptan, Ergocornine, Ergocorninine,
Ergocryptine, Ergot, Ergotarnine, FlurnedroXone acetate,
FonaZine, Lisuride, Methysergid(e), Naratriptan, OXetorone,
PiZotyline, RiZatriptan and Surnatriptan.
[0187] 48. Antinauseant drugs such as Acetylleucine
Monoethanolarnine, AliZapride, BenZquinarnide, Bietanau
tine, Brornopride, BucliZine, ChlorprornaZine, Clebopride,
CycliZine, Dirnenhydrinate, Dipheniodol, Dornperidone,
Granisetron, MecliZine, Methalltal, Metocloprarnide,
MetopirnaZine, Nabilone, Ondansteron, OXypendyl, Piparn
aZine, Piprinhydrinate, ProchlorperaZine, Scopolarnine, Tet
rahydrocannabinols, ThiethylperaZine, ThioproperZaine and
TrirnethobenZarnide.
[0188] 49. Antineoplastic drugs, including:
[0189] Alkylating agents, including:
[0190] Alkyl sulfonates such as Busulfan, Impro
sulfan and Piposulfan;
[0191] AZiridines such as BenZodepa, Carbo
quone, Meturedepa and Uredepa;
[0192] Ethylenirnines and rnethylrnelarnines such
as Altretarnine, Sulfosarnide, Triethylen
ernelarnine, Triethylenephosphorarnide, Triethyl
enethiophosphorarnide and Trirnethylolorn
elarnine;
[0193] Nitrogen rnustards such as Chlorarnbucil,
ChlornaphaZine, Chclophospharnide, Estrarnus
tine, Ifosfarnide, Mechloretharnine, Mechlore
tharnine Oxide Hydrochloride, Melphalan,
Novernbichin, Phenesterine, Prednirnustine, Tro
fosfarnide and Uracil Mustard;
[0194] Nitrosoureas such as Carrnustine, Chloro
Zotocin, Foternustine, Lornustine, Nirnustine and
Ranirnustine; and
US 2002/0004065 A1
[0195] others such as Camptothecin, DacarbaZine,
Mannomustine, Mitobronitol, Mitolactol and
Pipobroman;
[0196] Antibiotics such as Aclacinomycins, Acti
nomycin F1, Anthramycin, AZaserine, Bleomy
cins, Cactinomycin, Carubicin, CarZinophilin,
Chromomycins, Dactinomycin, Daunorubicin,
6-DiaZo-5-oXo-L-norleucine, DoXorubicin, Epiru
bicin, Mitomycins, Mycophenolic Acid, Nogala
mycin, Olivomycins, Peplomycin, Plicamycin,
Por?romycin, Puromycin, Rufocromomycin,
Streptonigrin, StreptoZocin, Tubercidin, Uben
imeX, Zinostatin and Zorubicin;
[0197] Antimetabolites, including:
[0198] Folic acid analogs such as Denopterin,
MethotreXate, Pteropterin and TrimetreXate;
[0199] Purine analogs such as Fludarabine, 6-Mer
captopurine, Thiamiprine and Thioguanaine; and
[0200] Pyrimidine analogs such as Ancitabine,
AZacitidine, 6-AZauridine, Carmofur, Cytarabine,
DoXi?uridine, Enocitabine, FloXuridine, Fluroou
racil and Tegafur;
[0201] Enzymes such as L-Asparaginase; and
[0202] others such as Aceglatone, Amsacrine,
Bestrabucil, Bisantrene, Bryostatin 1, Carbopl
atin, Cisplatin, Defofamide, Demecolcine, DiaZi
quone, Dolastatins, Elformithine, Elliptinium
Acetate, Etoglucid, Etoposide, Gallium Nitrate,
HydroXyurea, Interferon-a, Interferon-a, Inter
feron-a, Interleukine-2, Lentinan, LetroZole,
Lonidamine, MitoguaZone, MitoXantrone, Mopi
damol, Nitracrine, Pentostatin, Phenamet, Piraru
bicin, Podophyllinicc Acid, 2-EthythydraZide,
Polynitrocubanes, ProcarbaZine, PSK7, RaZoX
ane, SiZo?ran, Spirogermanium, Symplostatin 1,
TaXol, Teniposide, TenuaZonic Acid, TriaZiquone,
22.2-Trichlorotriethylamine, Urethan, Vinblas
tine, Vincristine, Vindesine and Vinorelbine.
[0203] 50. Antineoplastic (hormonal) drugs, including:
[0204] Androgens such as Calusterone, Dromo
stanolone Propionate, Epitiostanol, Mepitiostane and
Testolactone;
[0205] Antiadrenals such as Aminoglutethimide,
Mitotane and Trilostane;
[0206] Antiandrogens such as Flutamide and Niluta
mide; and
[0207] Antiestrogens such as Tamoxifen and
Toremifene.
[0208] 51. Antineoplastic adjuncts including folic acid
replenishers such as Frolinic Acid.
[0209] 52. Antiparkinsonian drugs such as Amantadine,
Apomorphine, BenseraZide, Bietanautine, Biperiden, Bro
mocriptine, Budipine, Cabergoline, Carbidopa, Deprenyl
(a/k/ a L-deprenyl, L-deprenil, L-deprenaline and selegiline),
DeXetimide, DiethaZine, Diphenhydramine, DroXidopa,
EthopropaZine, EthylbenZhydramine, Levodopa, NaX
agolide, Pergolide, Piroheptine, PramipeXole, Pridinol,
Jan. 10, 2002
Prodipine, Quinpirole, Remacemide, Ropinirole, Terguride,
Tigloidine and TriheXyphenidyl Hydrochloride.
[0210] 53. Antipheochromocytoma drugs such as Mety
rosine, PhenoXybenZamine and Phentolamine.
[0211] 54. Antipneumocystis drugs such as Efformithine,
Pentamidine and SulfamethoXaZole.
[0212] 55. Antiprostatic hypertrophy drugs such as Gesto
norone Caproate, Mepartricin, OXendolone and Proscar7.
[0213] 56. AntiprotoZoal drugs (Leshmania) such as Anti
mony Sodium Gluconate, Ethylstibamine, HydroXystilbami
dine, N-Methylglucamine, Pentamidine, Stilbamidine and
Urea Stibamine.
[0214] 57. AntiprotoZoal drugs (Trichomonas) such as
Acetarsone, AminitroZole, Anisomycin, AZanidaZole, Form
initraZole, FuraZolidone, Hachimycin, Lauroguadine,
Mepartricin, MetronidaZole, Nifuratel, NifuroXime,
NimoraZole, SecnidaZole, Silver Picrate, TenonitroZole and
TinidaZole.
[0215] 58. AntiprotoZoal drugs (Trypanosma) such as
BenZnidaZole, E?ornithine, Melarsoprol, NifurtimoX,
OXophenarsine, Hydrochloride, Pentamidine, Propamidine,
Puromycin, Quinapyramine, Stilbamidine, Suramin
Sodium, Trypan Red and Tryparasmide.
[0216] 59. Antipuritics such as Camphor, Cyproheptadine,
Dichlorisone, Glycine, Halometasone, 3-HydroXycamphor,
Menthol, Mesulphen, MethdilaZine, Phenol, Polidocanol,
Risocaine, Spirit of Camphor, Thenaldine, Tolpropamine
and TrimepraZine.
[0217] 60. Antipsoriatic drugs such as Acitretin, Ammo
nium Salicylate, Anthralin, 6-AZauridine, Bergapten(e),
Chrysarobin, Etretinate and Pyrogallol.
[0218] 61. Antipsychotic drugs, including:
[0219] Butyrophenones such as Benperidol, Bromp
eridol, Droperidol, Fluanisone, Haloperidol, Melp
erone, Moperone, Pipamperone, Sniperone, Timiper
one and Tri?uperidol;
[0220] PhenothiaZines such as AcetophenaZine,
ButaperaZine, CarphenaZine, ChlorproethaZine,
ChlorpromaZine, ClospiraZine, CyamemaZine, Dix
yraZine, FluphenaZine, ImiclopaZine, MepaZine,
MesoridaZine, MethoXypromaZine, MetofenaZate,
OXa?umaZine, PeraZine, PericyaZine, PerimethaZ
ine, PerphenaZine, PiperacetaZine, PipotiaZine,
ProchlorperaZine, PromaZine, SulforidaZine, Thio
propaZate, ThioridaZine, Tri?uoperaZine and Tri?u
promaZine;
[0221] ThioXanthenes such as ChlorprothiXene, Clo
penthiXol, FlupentiXol and ThiothiXene;
[0222] other tricyclics such as BenZquinamide,
Carpipramine, Clocapramine, Clomacran,
Clothiapine, CloZapine, Opipramol, Prothipendyl,
TetrabenaZine, and Zotepine; and
[0223] others such as AliZapride, Amisulpride, Bura
mate, Fluspirilene, Molindone, Pen?uridol,
PimoZide, Spirilene and Sulpiride.
[0224] 62. Antipyretics such as Acetaminophen, Acetami
nosalol, Acetanilide, Aconine, Aconite, Aconitine,
US 2002/0004065 A1
Alclofenac, Aluminum Bis(acetylsalicylate), Aminochlorth
enoXaZin, Aminopyrine, Aspirin, Benorylate, BenZydamine,
Berberine, p-Bromoacetanilide, BufeXamac, BumadiZon,
Calcium Acetysalicylate, ChlorthenoXaZin(e), Choline Sali
cylate, 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, Salaceta
mide, Salicylamide O-Acetic Acid, Sodium Salicylate, Sul
famipyrine, Tetrandrine and Tinoridine.
[0225] 63. Antirickettsial drugs such as pAminobenZoic
Acid, Chloramphenicol, Chloramphenicol Palmitate,
Chloramphenicol Pantothenate and Tetracycline.
[0226] 64. Antiseborrheic drugs such as ChloroXine, 3-O
-LauroylpyridoXol Diacetate, Piroctone, Pyrithione, Resor
cinol, Selenium Sul?des and TioXolone.
[0227] 65. Antiseptics, including:
[0228] Guanidines such as AleXidine, AmbaZone,
ChlorheXidine and PicloXydine;
[0229] Halogens and halogen compounds such as
Bismuth Iodide Oxide, Bismuth Iodosubgallate, Bis
muth Tribromophenate, Bornyl Chloride, Calcium
Iodate, Chlorinated Lime, Clo?ucarban, 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;
[0230] Mercurial compounds such as Hydragaphen,
Meralein Sodium, Merbromin, Mercuric Chloride,
Mercuric Chloride, Ammoniated, Mercuric Sodium
p-Phenolsulfonate, Mercuric Succinimide, Mercuric
Sul?de, Red, Mercurophen, Mercurous Acetate,
Mercurous Chloride, Mercurous Iodide, Nitromer
sol, Potassium Tetraiodomercurate(II), Potassium
Triiodomercurate(II) Solution, Thimerfonate
Sodium and Thimerosal;
[0231] Nitrofurans such as FuraZolidone, 2-(Meth
oXymethyl)-5-nitrofuran, NidroXyZone, NifuroXime,
NifurZide and NitrofuraZone;
[0232] Phenols such as Acetomeroctol, Bithionol,
Cadmium Salicylate, Carvacrol, ChloroXylenol, Clo
rophene, Cresote, Cresol(s), p-Cresol, Fenticlor,
HeXachlorophene, l-Napthyl Salicylate, 2-Napthyl
Salicylate, 2,4,6-Tribromo-m-cresol, and 3,4,5
Trichlorosalicylanilide;
[0233] Quinolines such as Aminoquinuride, BenZoX
iquine, BroXyquinoline, ChloroXine, Chlorquinaldol,
CloXyquin, Ethylhydrocupreine, Euprocin,
Halquinol, Hydrastine, 8-HydroXquinoline, 8-Hy
droXquinoline Sulfate and IodochlorhydroXyquin;
and
[0234] others such as Aluminum Acetate Solution,
Aluminum Subacetate Solution, Aluminum Sulfate,
Jan. 10, 2002
3-Amino-4-hydroXybutyric Acid, Boric Acid, Chlo
rheXidine, ChloroaZodin, m-Cresyl Acetate, Cupric
Sulfate, Dibromopropamidine, Ichthammol, Nega
tol7, NoXytiolin, OrnidaZole, a-Propiolactone, a-Ter
pineol.
[0235] 66. Antispasmodic drugs such as Alibendol, Ambu
cetamide, AminopromaZine, Apoatropine, Bevonium
Methyl Sulfate, Bietamiverine, Butaverine, Butropium Bro
mide, N-Butylscopolammonium Bromide, Caroverine,
Cimetropium Bromide, Cinnamedrine, Clebopride, Coniine
Hydrobromide, Coniine Hydrochloride, Cyclonium Iodide,
Difemerine, Diisopromine, DioXaphetyl Butyrate, Dipo
nium Bromide, Drofenine, Emepronium Bromide, Ethaver
ine, Feclemine, Fenalamide, Fenoverine, Fenpiprane, Fen
piverinium Bromide, Fentonium Bromide, FlavoXate,
Flopropione, Gluconic Acid, Guaiactamine, Hydramitra
Zine, Hymecromone, Leiopyrrole, Mebeverine, MoXaverine,
Na?verine, octamylamine, Octaverine, Pentapiperide, Phe
namacide Hydrochloride, Phloroglucinol, Pinaverium Bro
mide, Piperilate, PipoXolan Hydrochloride, Pramiverin, Pri
?nium Bromide, Properidine, Propivane, PropyromaZine,
ProZapine, Racefemine, Rociverine, Spasmolytol, Stilonium
Iodide, Sultroponium, Tiemonium Iodide, TiquiZium Bro
mide, Tiropramide, Trepibutone, Tricromyl, Trifolium, Tri
mebutine, N,N-1Trimethyl-3,3-diphenyl-propylamine, Tro
penZile, Trospium Chloride and Xenytropium Bromide.
[0236] 67. Antithrombotic drugs such as Anagrelide,
Argatroban, CilostaZol, Chrysoptin, Daltroban, De?bzrotide,
EnoXaparin, FraXiparine7, Indobufen, Lamoparan, OZagrel,
Picotamide, Pla?bride, Reviparin, Tedelparin, Ticlopidine,
Tri?usal and Warfarin.
[0237] 68. Antitussive drugs such as Allocamide, Amici
bone, Benproperine, BenZonatate, BibenZonium Bromide,
Bromoform, Butamirate, Butethamate, Caramiphen
Ethanedisulfonate, Carbetapentane, Chlophedianol, Clobu
tinol, Cloperastine, Codeine, Codeine Methyl Bromide,
Codeine N-OXide, Codeine Phosphate, Codeine Sulfate,
CycleXanone, DeXtromethorphan, Dibunate Sodium, Dihy
drocodeine, Dihydrocodeinone Enol Acetate, Dimemorfan,
DimethoXanate, a,a-Diphenyl-2-piperidinepropanol, Dro
propiZine, Drotebanol, EpraZinone, Ethyl Dibunate, Ethyl
morphine, Fominoben, Guiaiapate, Hydrocodone, Isoami
nile, LevopropoXyphene, Morclofone, Narceine,
Normethadone, Noscapine, OXeladin, OXolamine, Pholcod
ine, Picoperine, PipaZethate, Piperidione, PrenoXdiaZine
Hydrochloride, Racemethorphan, TaZiprinone Hydrochlo
ride, Tipepidine and Zipeprol.
[0238] 69. Antiulcerative drugs such as Aceglutamide
Aluminum Complex, a-Acetamidocaproic Acid Zinc Salt,
AcetoXolone, Arbaprostil, BeneXate Hydrochloride, Bis
muth Subcitrate Sol (Dried), CarbenoXolone, CetraXate,
Cimetidine, Enprostil, EsapraZole, Famotidine, FtaXilide,
Gefarnate, GuaiaZulene, Irsogladine, Misoprostol, NiZati
dine, OmepraZole, Ornoprostil, a-OryZanol, Pifarnine,
PirenZepine, Plaunotol, Ranitidine, Rioprostil, Rosaprostol,
RotraXate, RoXatidine Acetate, Sofalcone, SpiZofurone,
Sucralfate, Teprenone, Trimoprostil, ThrithioZine, TroXipide
and Zolimidine.
[0239] 70. Antiurolithic drugs such as AcetohydroXamic
Acid, Allopurinol, Potassium Citrate and Succinimide.
[0240] 71. Antivenin drugs such as Lyovac7 Antivenin.