U.S. patent application number 15/491572 was filed with the patent office on 2017-08-03 for topical formulations.
The applicant listed for this patent is Crescita Therapeutics Inc.. Invention is credited to Wade A. Hull, Pankaj Karande, Dominic King-Smith, Edward T. Kisak, Samir Mitragotri, John M. Newsam, Ngoc Truc-Chi Vo.
Application Number | 20170216314 15/491572 |
Document ID | / |
Family ID | 54321066 |
Filed Date | 2017-08-03 |
United States Patent
Application |
20170216314 |
Kind Code |
A1 |
Kisak; Edward T. ; et
al. |
August 3, 2017 |
TOPICAL FORMULATIONS
Abstract
The present disclosure is drawn to topical formulations and
related methods. In one embodiment, a topical formulation is
provided that includes an active agent, a first compound, and a
second compound. The first compound and second compound are
different and each is selected from the group consisting of
N-lauroyl sarcosine, sodium octyl sulfate, methyl laurate,
isopropyl myristate, oleic acid, glyceryl oleate, and sodium lauryl
sulfoacetate.
Inventors: |
Kisak; Edward T.; (San
Diego, CA) ; Newsam; John M.; (La Jolla, CA) ;
King-Smith; Dominic; (San Diego, CA) ; Karande;
Pankaj; (Troy, NY) ; Mitragotri; Samir; (Santa
Barbara, CA) ; Hull; Wade A.; (Kaysville, UT)
; Vo; Ngoc Truc-Chi; (Longueuil, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Crescita Therapeutics Inc. |
Mississauga |
|
CA |
|
|
Family ID: |
54321066 |
Appl. No.: |
15/491572 |
Filed: |
April 19, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14578812 |
Dec 22, 2014 |
9642912 |
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15491572 |
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13791460 |
Mar 8, 2013 |
9308181 |
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14578812 |
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|
13680623 |
Nov 19, 2012 |
8513304 |
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13791460 |
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12848792 |
Aug 2, 2010 |
8343962 |
|
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13680623 |
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12281561 |
Jan 12, 2009 |
7795309 |
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PCT/IB2007/001983 |
Mar 6, 2007 |
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12848792 |
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60778847 |
Mar 6, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 8/37 20130101; A61K
9/06 20130101; A61F 2007/0261 20130101; A61K 47/18 20130101; A61K
9/0014 20130101; A61K 2300/00 20130101; A61K 8/42 20130101; A61K
47/14 20130101; A61K 2300/00 20130101; A61K 31/568 20130101; A61K
31/167 20130101; A61K 31/573 20130101; A61K 47/20 20130101; A61K
8/463 20130101; A61K 31/245 20130101; A61K 8/361 20130101; A61K
31/135 20130101; A61K 8/375 20130101; A61K 47/183 20130101; A61Q
19/00 20130101; A61K 47/12 20130101; A61F 7/03 20130101; A61K
31/192 20130101; A61K 31/196 20130101 |
International
Class: |
A61K 31/573 20060101
A61K031/573; A61K 8/46 20060101 A61K008/46; A61K 8/37 20060101
A61K008/37; A61K 8/42 20060101 A61K008/42; A61K 8/36 20060101
A61K008/36; A61K 47/18 20060101 A61K047/18; A61K 31/196 20060101
A61K031/196; A61K 31/192 20060101 A61K031/192; A61K 31/135 20060101
A61K031/135; A61K 31/568 20060101 A61K031/568; A61K 47/20 20060101
A61K047/20; A61Q 19/00 20060101 A61Q019/00; A61K 9/00 20060101
A61K009/00 |
Claims
1. A topical formulation comprising: (i) at least one active agent,
(ii) a first compound, and (iii) a second compound, wherein the
first compound and second compound are different, and each is
selected from the group consisting of N-lauroyl sarcosine, sodium
octyl sulfate, methyl laurate, isopropyl myristate, oleic acid,
glyceryl oleate and sodium lauryl sulfoacetate.
2. The topical formulation of claim 1, wherein the first compound
comprises sodium lauryl sulfoacetate and the second compound
comprises isopropyl myristate.
3. The topical formulation of claim 1, wherein the first compound
comprises sodium lauryl sulfoacetate and the second compound
comprises methyl laurate.
4. The topical formulation of claim 1, wherein the first compound
comprises isopropyl myristate and the second compound comprises
N-lauryl sarcosine.
5. The topical formulation of claim 1, wherein the first compound
comprises glyceryl monooleate and the second compound comprises
methyl laurate.
6. The topical formulation of claim 1, wherein the first compound
comprises N-lauroyl sarcosine and the second compound comprises
oleic acid.
7. The topical formulation of claim 1, wherein the first compound
comprises sodium octyl sulfate and the second compound comprises
oleic acid.
8. The topical formulation of claim 1, wherein the first compound
comprises glyceryl oleate and the second compound comprises sodium
octyl sulfate.
9. The topical formulation of claim 1, further comprising a
biologically acceptable excipient.
10. The topical formulation of claim 1, wherein the total
concentration of the first compound and the second compound is up
to about 50 wt. %, 40 wt. %, 35 wt. %, 30 wt. %, 25 wt. %, 20 wt.
%, 15 wt. %, 10 wt. %, 7.5 wt. % or 5 wt. %, per unit volume of the
formulation.
11. The topical formulation of claim 1, wherein the total
concentration of the first compound and the second compound is in
the range of from about 2 wt. % to about 5 wt. %, per unit volume
of the formulation.
12. The topical formulation of claim 1, wherein the total
concentration of the first compound and the second compound is in
the range of from about 2 wt. % to about 4 wt. %, per unit volume
of the formulation.
13. The topical formulation of claim 1, wherein the weight ratio of
the first compound to the second compound is in the range of from
about 1:9 to about 9:1.
14. The topical formulation of claim 1, wherein the weight ratio of
the first compound to the second compound is in the range of from
about 1:4 to about 4:1.
15. The topical formulation of claim 1, wherein the weight ratio of
the first compound to the second compound is in the range of from
about 1:3 to about 3:1.
16. The topical formulation of claim 1, wherein the weight ratio of
the first compound to the second compound is in the range of from
about 1:2 to about 2:1.
17. The topical formulation of claim 1, wherein the weight ratio of
the first compound to the second compound is about 1:1.
Description
[0001] This application is a continuation application of U.S.
patent application Ser. No. 14/578,812, filed on Dec. 22, 2014,
which was a continuation-in-part of U.S. patent application Ser.
No. 13/791,460 filed on Mar. 8, 2013 and issued as U.S. Pat. No.
9,308,181, which was a continuation-in-part of U.S. patent
application Ser. No. 13/680,623, filed Nov. 19, 2012 and issued as
U.S. Pat. No. 8,513,304, which was a continuation of U.S. patent
application Ser. No. 12/848,792, filed Aug. 2, 2010 and issued as
U.S. Pat. No. 8,343,962, which was a continuation-in-part of U.S.
patent application Ser. No. 12/281,561, filed on Jan. 12, 2009 and
issued as U.S. Pat. No. 7,795,309, which was a national stage of
PCT/IB2007/001983 filed on Mar. 6, 2007, which claimed priority to
and the benefit of U.S. Provisional Application Ser. No.
60/788,847, filed on Mar. 6, 2006, each of which are incorporated
herein by reference.
BACKGROUND
[0002] Topical formulations for application to the skin can be
useful in cosmetic applications, for treating conditions of the
upper skin layers, and for transdermal administration of active
agents to the local tissue underlying the skin or into the blood
for systemic distribution. For example, using a topical formulation
of a pharmaceutical agent is advantageous because it can avoid
first-pass metabolism, circumvent gastrointestinal ("GI")
absorption, allow delivery of an active ingredient with a
relatively short biological half-life and/or a narrow therapeutic
window, and facilitate uniform plasma dosing of the active
ingredient, and/or can improve user compliance.
[0003] In spite of the advantages, transdermal administration is
usually limited to about a dozen small lipophilic drugs, available
in transdermal patch format (including scopolamine, fentanyl,
estradiol, nitroglycerine, nicotine, and testosterone). Skin has
evolved to impede the flux of exogenous molecules so as to provide
a strong barrier to molecular delivery, particularly agents such as
pharmaceutical agents. Transdermal drug administration is difficult
because skin is an excellent diffusion barrier.
[0004] Structurally, the skin consists of two principal parts: (i)
a relatively thin outermost layer (the "epidermis"), and (ii) a
thicker inner region (the "dermis"). The outermost layer of the
epidermis (the "stratum corneum") consists of flattened dead cells
which are filled with keratin. The region between the flattened
dead cells of the stratum corneum is filled with lipids which form
lamellar phases. The highly impermeable nature of skin is due
primarily to the stratum corneum. The viable epidermis underlying
the stratum corneum is akin to other living tissue. The dermis
provides the skin's structural strength as well as the nerve and
vascular networks that support the epidermis.
[0005] Delivering an active agent into or through the skin in
sufficient concentrations often utilizes some means for reducing
the stratum corneum's hindrance of penetration. A number of methods
for lowering the stratum corneum's barrier properties have been
developed, including electrically assisted techniques such as
iontophoresis or ultrasound, and bypassing the stratum corneum
through microneedle arrays or ablation.
[0006] Molecular or chemical penetration enhancers provide an
effective and inexpensive means of temporarily reducing skin
resistance to the administration and passage of actives and other
molecules. Molecular penetration enhancers or MPE.TM.s can enhance
the application to and/or diffusion of molecules across the skin
by, for example, disrupting the lipid bilayers of the stratum
corneum.
[0007] Over 300 substances have been identified as MPE.TM.s but
surprisingly few have been successfully developed into commercial
formulations. Many potent MPE.TM.s are irritating to the cells of
the epidermis which can limit both the choice and concentration of
MPE.TM.s suitable for topical formulations. Discovery of new
MPE.TM.s to increase skin permeability is a highly desirable area
and has had high activity over the last 30 years. However, the
number of substances identified to be penetration enhancers is
still relatively small when considering the more than 25,000,000
substances identified in the CAS registry (Chemical Abstracts
Service, Columbus, Ohio, www.cas.org). The number of candidate
drugs suitable for topical and transdermal administration could be
significantly increased with improved penetration enhancers.
SUMMARY
[0008] With this background in mind, the present disclosure is
drawn to topical formulations transdermal systems, and methods for
treating skin conditions. In one embodiment, a topical formulation
is provided that comprises (i) at least one active agent, (ii) a
first compound, and (iii) a second compound. The first compound and
second compound can be different, and each can be selected from the
group consisting of N-lauroyl sarcosine, sodium octyl sulfate,
methyl laurate, isopropyl myristate, oleic acid, glyceryl oleate,
and sodium lauryl sulfoacetate.
[0009] In another embodiment, a method of treating a skin condition
can comprise topical or transdermal administration the formulation.
In one embodiment, the first and second compound can improve the
flux and/or stability of the topical formulation when compared to a
comparative formulation devoid of the first compound and the second
compound and replaced with an equivalent wt % of water. In another
embodiment, the first and second compound can improve the flux of
the at least one active agent into the skin surface when compared
to a comparative formulation devoid of the first compound and the
second compound and replaced with an equivalent wt % of water. In a
further embodiment, the first and second compound can improve the
stability of the topical formulation when compared to a comparative
formulation devoid of the first compound and the second compound
and replaced with an equivalent wt % of water. For example, the
first and second compound can improve the amount of active
degradation, change in viscosity and/or change in pH over a period
of time.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Reference will now be made to the exemplary embodiments
illustrated, and specific language will be used herein to describe
the same. It will nevertheless be understood that no limitation of
the scope of the invention is thereby intended.
[0011] FIG. 1 is a plot of the pH of several exemplary embodiments
of formulations disclosed herein.
[0012] FIG. 2 is a plot of the viscosity of several exemplary
embodiments of formulations disclosed herein.
[0013] FIG. 3 is a plot of the active pharmaceutical ingredient
amount of several exemplary formulations over a three month time
span.
[0014] FIG. 4 is a plot of the permeation of the active ingredient
of several of the exemplary formulations through a Durapore.RTM.
membrane.
DETAILED DESCRIPTION
[0015] Before particular embodiments of the present invention are
disclosed and described, it is to be understood that this invention
is not limited to the particular process and materials disclosed
herein as such may vary to some degree. It is also to be understood
that the terminology used herein is used for the purpose of
describing particular embodiments only and is not intended to be
limiting, as the scope of the present invention will be defined
only by the appended claims and equivalents thereof.
[0016] In describing and claiming the present invention, the
following terminology will be used.
[0017] The singular forms "a," "an," and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a corticosteroid" includes reference to one
or more of such corticosteroids.
[0018] As used herein, the term "active agent" indicates a compound
or mixture of compounds, that when added to a composition, tend to
produce a particular therapeutic effect.
[0019] As used herein, the term "comparative formulation" is a
formulation that is compositionally identical with the exception
that amounts (wt %) of the first compound and second compound are
each replaced with the same amount (wt %) of water.
[0020] "Multiplexed molecular penetration enhancers" ("MMPE.TM.")
as described herein include N-lauroyl sarcosine, sodium octyl
sulfate, methyl laurate, isopropyl myristate, oleic acid, glyceryl
oleate, and sodium lauryl sulfoacetate, and in accordance with
examples described herein, typically they are used in combination,
e.g., two or more. The use of a permeation enchancer(s) can be
incorporated in a topical formulation to facilitate administration
of one or more active ingredients. The increased penetration
enhancement can also lead to a reduction in the amount of skin
irritants in a formulation.
[0021] The term "penetration enhancer" is used herein to refer to
an agent that improves the transport of molecules such as an active
agent (e.g., a medicine) into or through the skin Various
conditions may occur at different sites in the body either in the
skin or below creating a need to target delivery of compounds. For
example, a psoriasis treatment may benefit from delivery of
therapeutic drug levels in the deeper tissue. A "penetration
enhancer" may be used to assist in the delivery of an active agent
directly to the skin or underlying tissue or indirectly to the site
of the disease through systemic distribution. A penetration
enhancer may be a pure substance or may comprise a mixture of
different chemical entities. In this specification the terms
"penetration enhancer," "chemical penetration enhancer,"
"multiplexed molecular penetration enhancer," and "MMPE.TM." can be
used interchangeably.
[0022] "Skin" is defined to include human skin (intact, diseased,
ulcerous, or broken) as well as mucosal surfaces that are usually
at least partially exposed to air such as lips, genital and anal
mucosa, and nasal and oral mucosa.
[0023] As used herein, the term "skin contact region" refers to an
area wherein the topical formulation contacts the skin.
[0024] The term "subject" as used herein includes all members of
the animal kingdom, including mammals, and most typically, refers
to humans.
[0025] The term "topical administration" is used in its
conventional sense to mean delivery of a substance, such as a
therapeutically active agent, into the skin or a localized region
of the body. Topical administration of a drug may often be
advantageously applied in, for example, the treatment of various
skin disorders or conditions.
[0026] As used herein the term "topical formulation" refers to a
formulation that may be applied to skin or a mucosa. Topical
formulations may, for example, be used to confer therapeutic
benefit to a patient or cosmetic benefits to a consumer. Topical
formulations can be used for both topical and transdermal
administration of substances.
[0027] As used herein, the term "transdermal" means in the broadest
sense into or through the skin. Further the terms "transdermal" and
"percutaneous" are used interchangeably throughout this
specification.
[0028] The term "transdermal administration" is used to mean
administration through the skin. Transdermal administration is
often applied where systemic delivery of an active is desired,
although it may also be useful for delivering an active to tissues
underlying the skin with minimal systemic absorption (i.e.
localized delivery).
[0029] The term "treating" or "treatment" as used herein and as is
well understood in the art, means an approach for obtaining
beneficial or desired results, including clinical results.
Beneficial or desired clinical results can include, but are not
limited to, alleviation or amelioration of one or more symptoms or
conditions, diminishment of extent of disease, stabilizing (i.e.
not worsening) the state of disease, delaying or slowing of disease
progression, amelioration or palliation of the disease state,
diminishment of the reoccurrence of disease, and remission (whether
partial or total), whether detectable or undetectable. "Treating"
and "treatment" can also mean prolonging survival as compared to
expected survival if not receiving treatment. In addition to being
useful as methods of treatment, the methods described herein may be
useful for the prevention or prophylaxis of disease.
[0030] The term "water" as an ingredient in the compositions of the
compositions of the present disclosure refers to
pharmaceutically-acceptable water.
[0031] As used herein, the term "about" is used to provide
flexibility to a numerical range endpoint by providing that a given
value may be "a little above" or "a little below" the endpoint. The
degree of flexibility of this term can be dictated by the
particular variable and would be within the knowledge of those
skilled in the art to determine based on experience and the
associated description herein. For example, in one embodiment, the
degree of flexibility can be within about .+-.10% of the numerical
value. In another embodiment, the degree of flexibility can be
within about .+-.5% of the numerical value. In a further
embodiment, the degree of flexibility can be within about .+-.2%,
.+-.1%, or .+-.0.05%, of the numerical value.
[0032] As used herein, a plurality of active agents and/or
compounds may be presented in a common list for convenience.
However, these lists should be construed as though each member of
the list is individually identified as a separate and unique
member. Thus, no individual member of such list should be construed
as a de facto equivalent of any other member of the same list
solely based on their presentation in a common group without
indications to the contrary.
[0033] Concentrations, amounts, and other numerical data may be
expressed or presented herein in a range format. It is to be
understood that such a range format is used merely for convenience
and brevity and thus should be interpreted flexibly to include not
only the numerical values explicitly recited as the limits of the
range, but also to include all the individual numerical values or
sub-ranges encompassed within that range as if each numerical value
and sub-range is explicitly recited. As an illustration, a
numerical range of "about 0.01 mm to 2.0 mm" should be interpreted
to include not only the explicitly recited values of about 0.01 mm
to about 2.0 mm, but also include individual values and sub-ranges
within the indicated range. Thus, included in this numerical range
are individual values such as 0.5 mm, 0.7 mm, and 1.5 mm, and
sub-ranges such as from 0.5 mm to 1.7 mm, 0.7 mm to 1.5 mm, and
from 1.0 mm to 1.5 mm, etc. Furthermore, such an interpretation
should apply regardless of the breadth of the range or the
characteristics being described. Additionally, it is noted that all
percentages are in weight, unless specified otherwise.
[0034] The present disclosure is drawn to various formulations and
methods in the area of topical and transdermal delivery. MMPE.TM.s
can be used to improve the administration and increase penetration
of active agents, such as corticosteroids into and through the
skin. These compounds can thus act as excellent penetration
enhances, particularly when used in combination--i.e. two (or more)
compounds are selected from N-lauroyl sarcosine, sodium octyl
sulfate, methyl laurate, isopropyl myristate, oleic acid, glyceryl
oleate, or sodium lauryl sulfoacetate.
[0035] Examples of combinations of compounds that can act to
improve penetration include the following:
[0036] the first compound comprises methyl laurate and the second
comprises isopropyl myristate;
[0037] the first compound comprises methyl laurate and the second
comprises oleic acid;
[0038] the first compound comprises methyl laurate and the second
comprises glyceryl oleate;
[0039] the first compound comprises methyl laurate and the second
comprises sodium lauryl sulfoacetate;
[0040] the first compound comprises isopropyl myristate and the
second compound comprises oleic acid;
[0041] the first compound comprises isopropyl myristate and the
second compound comprises glycerol oleate;
[0042] the first compound comprises isopropyl myristate and the
second compound comprises sodium lauryl sulfoacetate;
[0043] the first compound comprises oleic acid and the second
compound comprises glycerol oleate;
[0044] the first compound comprises oleic acid and the second
compound comprises sodium lauryl sulfoacetate; and
[0045] the first compound comprises glycerol oleate and the second
compound comprises sodium lauryl sulfoacetate.
[0046] The first and second compounds can be present in the topical
formulation at a weight ratio of first compound to second compound
of about 1:9 to about 9:1. In another embodiment, the first and
second compounds can be present in the topical formulation at a
weight ratio of first compound to second compound of about 1:5 to
about 5:1, about 1:4 to about 4:1, about 1:3 to about 3:1, about
1:2 and about 2:1, and about 1:1.
[0047] The first and second compound can collectively be present in
the composition in amounts up to about 50 wt %, e.g., 0.1 wt % to
50 wt %. More typically, the total concentration of the first
compound and the second compound is up to about 40 wt %, e.g., 0.1
wt % to 40 wt %. In another example, the total concentration of the
first compound and the second compound is in the range of from
about 1 wt % to about 35 wt %. Even more typically, the total
concentration of the first compound and the second compound is in
the range of from about 1 wt % to about 30 wt %. Even more
typically, the total concentration of the first compound and the
second compound is in the range of from about 1 wt % to about 25 wt
%. Even more typically, the total concentration of the first
compound and the second compound is in the range of from about 1 wt
% to about 20 wt %. Even more typically, the total concentration of
the first compound and the second compound is in the range of from
about 1 wt % to about 15 wt %. Even more typically, the total
concentration of the first compound and the second compound is in
the range of from about 1 wt % to about 10 wt % per unit volume of
the formulation. Even more typically, the total concentration of
the first compound and the second compound is in the range of from
about 1 wt % to about 7.5 wt %. In still another example, the total
concentration of the first compound and the second compound are in
the range of from about 1 wt % to about 5 wt % per unit volume of
the formulation. Within these ranges, it can in some cases, be
desirable to have the total concentration of the first compound and
the second compound in the range of from about 1.5 wt % to about 3
wt % per unit volume of the formulation.
[0048] In one aspect of the present disclosure, as mentioned, the
at least one active agent is a corticosteroid. Generally, any
corticosteroid known in the art can be incorporated into topical
formulations and systems disclosed herein. Non-limiting examples of
such corticosteroids include alclometasone dipropionate,
amcinonide, beclomethasone dipropionate, betamethasone,
betamethasone benzoate, betamethasone dipropionate, betamethasone
valerate, budesonide, clobetasol propionate, desonide,
desoximetasone, dexamethasone, diflorasone diacetate,
fludrocortisone acetate, flunisolide, flurandrenolide, fluocinolone
acetonide, fluocinonide, fluticasone propionate, halcinonide,
halobetasol, halobetasol propionate, hydrocortisone, hydrocortisone
valerate, methylprednisolone, mometasone furoate, prednisolone,
prednisone, triamcinolone, triamcinolone acetonide, or combinations
thereof. In another embodiment, the topical formulations comprises
a corticosteroid and one or more additional agents selected from
retinoids (e.g. tretinoin, adapalene, tazarotene, among others),
Vitamin D and Vitamin analogs, JAK inhibitors, kinase inhibitors,
phosphodiesterase inhibitors, coal tar and coal tar extracts,
keratolytics and combinations thereof.
[0049] The corticosteroid can be present in the formulation up to
about 20 wt %, e.g., 0.01 wt % to about 20 wt %, typically from
about 0.05 wt % to about 10 wt %, and more typically from about
0.05 wt % to about 5 wt %. In one embodiment, the corticosteroid
can be a pharmaceutically acceptable salt of a corticosteroid. In a
further embodiment, the corticosteroid can be a pharmaceutically
acceptable base of a corticosteroid. In one embodiment, the
corticosteroid can include clobetasol, halobetasol, betamethasone,
triamcinolone acetonide and derivatives and combinations thereof.
Most preferably the corticosteroid is halobetasol propionate, see
Formula I below.
##STR00001##
[0050] In one embodiment, halobetasol propionate is used to treat a
variety of skin conditions including but not limited to psoriasis,
eczema, dermatitis, allergies, and skin rashes. In a preferred
embodiment, the halobetasol propionate formulation is used to treat
psoriasis. In yet another embodiment, the halobetasol propionate
formulation is used to treat moderate to severe plaque psoriasis
and is delivered into the superficial layers of the skin.
[0051] In one embodiment, the formulation comprises 0.05% w/w
halobetasol propionate, 0.5% w/w methyl laurate, and 1% w/w
isopropyl myristate, along with various solvents,
emollients/surfactants, and preservatives. In another embodiment,
the formulation comprises 0.05% w/w halobetasol propionate, 0.5%
w/w methyl laurate, and 1% w/w oleic acid along with various
solvents, emollients/surfactants, and preservatives. In yet another
embodiment, the formulation comprises 0.05% w/w halobetasol
propionate, 0.5% w/w methyl laurate, and 1% w/w glyceryl oleate,
along with various solvents, emollients/surfactants, and
preservatives. In a further embodiment, the formulation comprises
0.05% w/w halobetasol propionate, 0.5% w/w methyl laurate, and 1%
w/w sodium lauryl sulfoacetate, along with various solvents,
emollients/surfactants, and preservatives. In another embodiment,
the formulation comprises 0.05% w/w halobetasol propionate, 1% w/w
isopropyl myristate, and 1% w/w oleic acid, along with various
solvents, emollients/surfactants, and preservatives. In yet another
embodiment, the formulation comprises 0.05% w/w halobetasol
propionate, 1% w/w isopropyl myristate, and 1% w/w glyceryl oleate,
along with various solvents, emollients/surfactants, and
preservatives. In a further embodiment, the formulation comprises
0.05% w/w halobetasol propionate, 1% w/w isopropyl myristate, and
1% w/w sodium lauryl sulfoacetate, along with various solvents,
emollients/surfactants, and preservatives. In another embodiment,
the formulation comprises 0.05% w/w halobetasol propionate, 1% w/w
oleic acid, and 1% w/w glyceryl oleate, along with various
solvents, emollients/surfactants, and preservatives. In yet another
embodiment, the formulation comprises 0.05% w/w halobetasol
propionate, 1% w/w oleic acid, and 1% w/w sodium lauryl
sulfoacetate, along with various solvents, emollients/surfactants,
and preservatives. In a further embodiment, the formulation
comprises 0.05% w/w halobetasol propionate, 1% w/w glyceryl oleate,
and 1% w/w sodium lauryl sulfoacetate, along with various solvents,
emollients/surfactants, and preservatives.
[0052] The combination of at least two MMPE.TM.s in a
corticosteroid containing formulation is shown herein to enhance
stability and/or penetration of the corticosteroid through the
skin. More specifically, the compounds act as excellent penetration
enhancers and are shown to have an amplified effect when used in a
combination, i.e. two (or more) MMPE compounds wherein the first
compound and second compound are each selected from the group of
N-lauroyl sarcosine, sodium octyl sulfate, methyl laurate,
isopropyl myristate, oleic acid, glyceryl oleate, and sodium lauryl
sulfoacetate. Again and in further detail, examples of combinations
of first and second compounds that act as improved penetration
enhancers can include: isopropyl myristate and sodium lauryl
sulfoacetate; oleic acid and sodium lauryl sulfoacetate; glyceryl
oleate and sodium lauryl sulfoacetate; and methyl laurate and
sodium lauryl sulfoacetate; to name a few.
[0053] The formulation can have increased penetration of the
corticosteroid through the skin when compared to a comparative
formulation devoid of the MMPE.TM.s (with an equivalent wt % of
water replacing the MMPE.TM.s). The increase in penetration of the
corticosteroid can be at least 5%, at least 10%, at least 20%, at
least 30%, at least 40%, at least 50%, at least 60%, at least 70%,
at least 80%, at least 90%, at least 100%, at least 250%, at least
500%, at least 750%, at least 1,000%, at least 2,000%, at least
3,000%, at least 4000% or even at least 8,000% greater than the
penetration of the comparative formulation at a given period of
time during the application. Over the course of a thirty hour
application period, the increase in penetration of the
corticosteroid can be at least 800% greater, at least 900% greater,
at least 1,000% greater, at least 1,250% greater, or even at least
1,500% greater when compared to the comparative formulation. This
increased penetration enhancement can also lead to a reduction in
the total concentration of potential skin irritants in a
formulation. It has been found that the presence of the MMPE.TM.s
do not negatively affect the stability of the active ingredient in
the formulation or the physical stability of the formulation.
[0054] Alternatively, or in addition to the ability to improve the
penetration of the corticosteroid through the skin when compared to
a comparative formulation devoid of the MMPE.TM.s (with an
equivalent wt % of water replacing the MMPE.TM.s), the first and
second compounds present in the topical formulations may function
to improve the stability of the formulation.
[0055] Long storage periods can result in increased active
degradation, changes in pH and changes in viscosity. One of the
benefits of the topical formulations disclosed herein is the
improved physical and/or chemical stability of the formulations
when stored. In one embodiment, the formulation comprising a first
compound and a second compound may have an enhanced physical
stability. For example, in one aspect, the topical formulation can
have improved consistency of viscosity after being stored for 12
weeks, 6 months, 12 months or 24 months at 25.degree. C. compared
to a comparative formulation devoid of the first compound and the
second compound (where the first and second compounds are replaced
with a commensurate amount of water, i.e. equal weight percentage
of water to replace the removed first and second compounds). In
still another embodiment, the topical formulation can have a
viscosity that is at least 50% more, at least 25% more, or at least
10% more consistent with the formulation's initial viscosity after
12 weeks, 6 months, 12 months or 24 months when stored at about
25.degree. C. compared to a comparative formulation devoid of the
first compound and the second compound (again as in each of these
examples, replacing the removed first and second compounds with an
equivalent amount of water).
[0056] In addition to the improvements in physical stability, the
topical formulations of the present invention may have improvements
in chemical stability, for example, decreased active degradation
and/or improved pH stability. In one embodiment, the topical
formulations disclosed herein can provide improved chemical
stability after being stored for a period of 12 weeks, 6 months, 12
months or 24 months at 25.degree. C. such that the formulation has
less degradation of the active ingredient as compared to a
comparative formulation devoid of the first and second compound
(again with an equivalent amount of water added thereto to replace
the first and second compounds). In another embodiment, the topical
formulations disclosed herein can provide improved pH stability
after being stored for 12 weeks, 6 months, 12 months or 24 months
at 25.degree. C. compared to a comparative formulation devoid of
the first compound and the second compound (again with an
equivalent amount of water added thereto to replace the first and
second compounds). For example, the topical formulation can have a
pH that is at least 50% more, at least 25% more, or at least 10%
more consistent with the formulation's initial pH after 12 weeks, 6
months, 12 months or 24 months when stored at about 25.degree. C.
compared to a comparative formulation devoid of the first compound
and the second compound stored under the same conditions for the
same amount of time.
[0057] Improved physical and/or chemical stability of topical
formulations may lead to increased commercial shelf life of the
system. In one embodiment, the topical formulation of the invention
can have an increased shelf life of about 3 months, about 6 months,
about 9 months or about 12 months compared to a comparative
formulation devoid of the first compound and the second compound
stored under the same conditions. In another embodiment the shelf
life of the topical formulation can be at least about 27-months, at
least about 30 months, at least about 33 months, or at least about
36 months.
[0058] The topical formulations of the present disclosure may also
be formulated to include other chemical penetration enhancers which
have significant ability to enhance transport of the corticosteroid
and/or other active agents present in the topical formulations.
Such substances may have the character of surfactants, azone-like
compounds, solvents, alcohols, fatty acids, fatty esters, aliphatic
thiols, and the like. Examples of chemical penetration enhancers
are reported in the paper of Santus et al. (Santus, C. G. and
Baker, R. W., Transdermal enhancer patent literature. Journal of
Controlled Release 1993.25:1-20.) The penetration enhancing effect
may be measured using techniques known in the art. An example of
one measurement method is described in the Examples below.
[0059] The topical formulations can also include other components
as well. Examples of additional compounds that can be included in
the topical formulations include water, thickening, gelling and/or
solidifying polymers, emollients/surfactants excipients, fatty acid
esters, parabens, solvents, and/or the like. In one embodiment, the
topical formulation can include water, and in some case, the water
can be the ingredient that is present at the single greatest
concentration.
[0060] Other suitable carriers or excipients that may be used in
the topical formulations discussed herein are known in the art and
include, but are not limited to, solubilizers such as C.sub.2 to
C.sub.8 straight and branched chain alcohols, diols and triols,
moisturizers and humectants such as glycerine, amino acids and
amino acid derivatives, polyaminoacids and derivatives, pyrrolidone
carboxylic acids and their salts and derivatives, surfactants such
as sodium laureth sulfate, sorbitan monolaurate, emulsifiers such
as di-isopropyl adipate, hexylene glycol, cetyl alcohol, stearyl
alcohol, thickeners such as methyl cellulose, ethyl cellulose,
hydroxymethylcellulose, hydroxypropylcellulose,
polyvinylpyrrolidone, polyvinyl alcohol, and acrylic polymers. The
topical formulation may include isopropyl alcohol. The isopropyl
alcohol may be present in the formulation between about 1 wt % to
about 40 wt %. Additionally the topical formulation may also
include di-isopropyl adipate and hexylene glycol. The di-isopropyl
adipate may be present in the formulation between about 1 wt % to
about 10 wt %. The hexylene glycol may be present in the
formulation between about 1 wt % to about 15 wt %. In addition the
topical formulation may include polyoxyl 35 castor oil. The
polyoxyl 35 castor oil may be present in the formulation from about
0 wt % to about 10 wt %. The formulation may also include at least
one moisturizer/humectant. Other examples of suitable excipients,
such as binders and fillers are listed in Remington's
Pharmaceutical Sciences, 18th Edition, Ed. Alfonso Gennaro, Mack
Publishing Co. Easton, Pa., 1995 and Handbook of Pharmaceutical
Excipients, 3rd Edition, Ed. Arthur H. Kibbe, American
Pharmaceutical Association, Washington D.C. 2000.
[0061] The topical formulations of the present disclosure may also
include one or more skin care actives. "Skin care actives" means
all compounds or substances now known or later demonstrated to
provide benefit when applied to skin and all compounds now claimed
or in the future claimed to provide benefit when applied to skin.
Skin care actives may provide benefits, or claimed benefits, in
areas such as one or more of wrinkle removal or wrinkle reduction,
firming of skin, exfoliation of skin, skin lightening, treatment of
dandruff, treatment of acne, skin conditioning, development of tans
and artificial tans, improvement of skin moisture content,
improvement of skin barrier properties, control of sweat,
anti-aging, reduction or avoidance of irritation, and reduction or
avoidance of inflammation. Examples of skin care actives include
molecules such as peptides, proteins, oligonucleotides, fullerenes
as well as small molecules. Skin care actives may be protease
and/or enzyme inhibitors, anti-coenzymes, chelating agents,
antibodies, antimicrobials, humectants, vitamins, skin protectants,
antioxidants and/or skin soothing agents, plant extracts and the
like. Examples of skin care actives include but are not limited to
vitamin C, vitamin E (alpha tocopherol), retinoids, soy derivatives
(e.g. isoflavones), green tea polyphenols, alpha hydroxy acids
(e.g. glycolic and lactic acids), beta hydroxy acids (e.g.
salicylic acid), poly hydroxy acids, alpha lipoic acid, hemp oil
(glycerides), niacinamide, dimethyl amino ethanol, coenzyme Q10,
kinetin (plant growth hormone), dimethyl sulfone, and botulinum
toxin. Other examples of skin care actives may be found in The
Perricone Prescription by Nicholas Perricone, Harper Collins
Publishers Inc., New York, 2002.
[0062] The topical formulation of the present invention may be
formulated to be included in transdermal systems such as those
described above, the topical formulations of the present invention
may be formulated by those skilled in the art as liquids,
solutions, emulsions, creams, lotions, suspensions, triturates,
gels, jellies, foams, pastes, sprays, ointments, shampoos,
adhesives, traditional patches, or the like.
[0063] The present formulation provides an improved topical
formulation for facilitating topical or transdermal administration
of at least one therapeutically active agent, which in accordance
with examples herein, can be a corticosteroid. This enhanced effect
is discussed further below and illustrated in embodiments of the
formulations described in the Examples. In another example, the
topical formulations provide a means for targeting a
therapeutically active agent to a local tissue either in the skin
or the underlying tissue. This latter embodiment may be
particularly beneficially applied for treatment of conditions such
as psoriasis and other dermatological conditions. The topical
formulations may be applied either occlusively or nonocclusively to
the skin. In a one embodiment, when the objective is transdermal
administration, the topical formulation is applied to the skin
under occlusion in a transdermal patch.
[0064] The present topical formulation may be applied to the skin
by any means known in the art including, but not limited to, by an
aerosol, spray, pump-pack, brush, swab, or other applicator. The
applicator may provide either a fixed or variable metered dose
application such as a metered dose aerosol, a stored-energy metered
dose pump, or a manual metered dose pump. In this example, the
topical formulation can be applied to the skin of the human or
animal covering a delivery surface area from about 5 cm.sup.2 to
about 800 cm.sup.2, more typically from about 10 cm.sup.2 to about
400 cm.sup.2, and in another example, from about 10 cm.sup.2 to
about 200 cm.sup.2. The application can be performed by means of a
topical metered dose spray combined with an actuator nozzle shroud
which together accurately control the amount and/or uniformity of
the dose applied. One function of the shroud is to keep the nozzle
at a pre-determined height above, and perpendicular to, the skin to
which the drug delivery system is being applied. This function may
also be achieved by means of a spacer-bar or the like. Another
function of the shroud is to enclose the area above the skin in
order to prevent or limit bounce-back and/or loss of the drug
delivery system to the surrounding environment. The drug delivery
system may be a unit volume dispenser with or without a roll-on or
other type of applicator. It may also be desirable to apply a
number of dosages on untreated skin to obtain the desired
result.
[0065] While the present disclosure is directed primarily to the
formulations and related methods utilizing corticosteroids as the
pharmaceutically active agent (drug), in some aspects, it can be
useful or desirable to include alternative or additional
pharmaceutically active compositions. Discussion of the various
active agents that can be incorporated into the topical
formulations, in addition to or instead of the corticosteroids of
the present disclosure, is provided below.
[0066] In one aspect of the present invention, the at least one
active agent is an aryl alkanoic acid, such as an .alpha.-aryl
alkanoic acid. As is known to a person skilled in the art,
.alpha.-aryl alkanoic acids are chemical compounds having the
general structure of Formula II:
##STR00002##
wherein Ar is an aryl group and R.sup.1 is H or an alkyl group,
wherein aryl includes aromatic and heteroaromatic groups and alkyl
includes acyclic and cyclic alkyl groups. The .alpha.-aryl alkanoic
acid may be an anti-inflammatory drug such as a non-steroidal
anti-inflammatory drug (NSAID) or an analagesic, specific examples
of which are listed below. Preferably, the .alpha.-aryl alkanoic
acids is selected from the group consisting of bromfenac,
diclofenac, fenoprofen, flurbiprofen, ibuprofen, indomethacin,
ketoprofen, ketorolac, naproxen, sulindac and tolmetin, and
pharmaceutically acceptable salts and solvates thereof, and
mixtures thereof. Structures for these .alpha.-aryl alkanoic acids,
along with some common trade names, known to a person skilled in
the art, are shown in Table A.
TABLE-US-00001 TABLE A NSAID TRADE NAME STRUCTURE Diclofenac
Voltaren, Pennsaid ##STR00003## Indomethacin Indocin ##STR00004##
Sulindac Clinoril ##STR00005## Tolmetin Tolectin ##STR00006##
Naproxen Naprosyn, Aleve ##STR00007## Ibuprofen Advil, Brufen,
##STR00008## Flurbiprofen Ansaid, Flurwood, Froben ##STR00009##
Ketoprofen Orudis ##STR00010## Ketorolac Acular, Toradol
##STR00011## Fenoprofen Nalfon ##STR00012## Bromfenac Xibrom
##STR00013##
More preferably the .alpha.-aryl alkanoic acid is selected from the
group consisting of diclofenac, ibuprofen, and ketoprofen, and
pharmaceutically acceptable salts and solvates thereof, and
mixtures thereof. Other NSAIDs that are not .alpha.-aryl alkanoic
acids, as well as other compounds having antipyretic and analgesic
actions are also included in the scope of the present invention.
Examples of such compounds include acetaminophen (paracetamol),
aspirin, celecoxib, diflunisal, etodolac, etoricoxib, meclofenamic
acid, mefenamic acid, meloxicam, nabumetone, oxaprozin, piroxicam,
salsalate, and rofecoxib. Structures for these compounds along with
some common trade names, known to a person skilled in the art, are
shown in Table B.
TABLE-US-00002 TABLE B COMPOUND TRADE NAME STRUCTURE Acetaminophen
Tylenol ##STR00014## Aspirin ##STR00015## Celecoxib Celebrex
##STR00016## Diflunisal Dolobid ##STR00017## Etoricoxib Arcoxia
##STR00018## Piroxicam Feldane, Roxam ##STR00019## Rofecoxib Vioxx
##STR00020## Salsalate Disalcid, Monogesic, Salflex, Salcitab
##STR00021## Meloxicam Mobic ##STR00022## Etodolac Lodine
##STR00023## Oxaprozin Daypro ##STR00024## Nabumetone Relafen
##STR00025## Mefenamic acid Ponstel ##STR00026## Meclofenamic Acid
Meclofen, Meclomen ##STR00027##
[0067] In another aspect of the present invention, the at least one
active agent is a phenethylamine, for example, a phenethylamine
that is an antidepressant, anti-anxiety agent, anticholinergic
agent, cholinergic, dopaminergic, stimulant, serotonin antagonist,
serotonin inhibitor, anti-emetic, antihistamine and/or
antipsychotic, specific examples of which are listed below. As is
known to a person skilled in the art, phenethylamines are chemical
compounds having the general core structure of Formula III:
##STR00028##
wherein the phenyl ring, ethylene chain and nitrogen can be
substituted. The phenethylamine may be a psychoactive agent that
exerts its effect through a monoamine neurotransmitter system, for
example dopamine, serotonin and/or norepinephrine receptors.
Examples of phenethylamines, include, for example, bupropion,
amphetamine, hydroxyamphetamine, dextroamphetamine,
methamphetamine, ephedrine, epinephrine, pseudoephedrine, dopamine,
epinephryl borate, etafedrine, norepinephrine and oxidopamine, and
pharmaceutically acceptable salts and solvates thereof, and
mixtures thereof. Preferably the phenethylamine is bupropion, or a
pharmaceutically acceptable salt or solvate thereof, such as
bupropion hydrochloride. The structure of bupropion, known to a
person skilled in the art, is:
##STR00029##
[0068] In another aspect of the present invention, the at least one
active agent is a steroid, other than coriticosteriods, for
example, steroids that are hormones, glucosteroids, androgens,
anabolics, estrogens and/or progestin, specific examples of which
are listed below. Preferably the steroid is testosterone, or a
pharmaceutically acceptable salt or solvate thereof.
[0069] Other suitable active agents include those in the class of
COX-2 inhibitors such as celecoxib, rofecoxib, valdecoxib,
lumiracoxib, etoricoxib; Antifungals such as tolnaftate, econazole,
ciclopirox; Antibiotics such as clindamycin; Musculoskeletal agents
such as dantrolene; Retinoids such as isotretinoin; Antivirals such
as acyclovir; Vasodilating agents such as nitroglycerine,
papaverine; Hormones and synthetic substitutes such as androgens,
estrogens, insulin; Opiate agonists such as fentanyl, oxycodone,
hydromorphone; Local Anaesthetics such as lidocaine, tocainide and
mexiletine and butyl-para-aminobenzoate; NMDA receptor antagonists
such as ketamine, dextromethorphan and amantadine.
[0070] Examples of other therapeutically active agents that may be
used include the following: adrenergic agent; adrenocortical
steroid; adrenocortical suppressant; aldosterone antagonist; amino
acid; anabolic; analeptic; analgesic; anesthetic; anorectic;
anti-acne agent; anti-adrenergic; anti-allergic; anti-amebic;
anti-anemic; anti-anginal; anti-arthritic; anti-asthmatic;
anti-atherosclerotic; antibacterial; anticholinergic;
anticoagulant; anticonvulsant; antidepressant; antidiabetic;
antidiarrheal; antidiuretic; anti-emetic; anti-epileptic;
antifibrinolytic; antifungal; antihemorrhagic; antihistamine;
antihyperlipidemia; antihypertensive; antihypotensive;
anti-infective; anti-inflammatory; antimicrobial; antimigraine;
antimitotic; antimycotic, antinauseant, antineoplastic,
antineutropenic, antiparasitic; antiproliferative; antipsychotic;
antirheumatic; antiseborrheic; antisecretory; antispasmodic;
antithrombotic; antiulcerative; antiviral; appetite suppressant;
blood glucose regulator; bone resorption inhibitor; bronchodilator;
cardiovascular agent; cholinergic; depressant; diagnostic aid;
diuretic; dopaminergic agent; estrogen receptor agonist;
fibrinolytic; fluorescent agent; free oxygen radical scavenger;
gastric acid suppressant; gastrointestinal motility effector;
glucocorticoid; hair growth stimulant; hemostatic; histamine H2
receptor antagonists; hormone; hypocholesterolemic; hypoglycemic,
hypolipidemic; hypotensive; imaging agent; immunizing agent;
immunomodulator; immunoregulator; immunostimulant;
immunosuppressant, keratolytic; LHRH agonist; mood regulator;
mucolytic; mydriatic; nasal decongestant; neuromuscular blocking
agent; neuroprotective; NMDA antagonist; non-hormonal sterol
derivative; plasminogen activator; platelet activating factor
antagonist; platelet aggregation inhibitor; psychotropic;
radioactive agent; scabicide; sclerosing agent; sedative;
sedative-hypnotic; selective adenosine A1 antagonist; serotonin
antagonist; serotonin inhibitor; serotonin receptor antagonist;
steroid; thyroid hormone; thyroid inhibitor; thyromimetic,
tranquilizer; amyotrophic lateral sclerosis agent; cerebral
ischemia agent; Paget's disease agent; unstable angina agent;
vasoconstrictor; vasodilator; wound healing agent; xanthine oxidase
inhibitor; and the like.
[0071] Specific examples of pharmaceutical agents that may be
included within the present topical formulation, both alone or in
combination, include but are not limited to:
[0072] Adrenergic: Adrenalone; Amidephrine Mesylate; Apraclonidine
Hydrochloride; Brimonidine Tartrate; Dapiprazole Hydrochloride;
Deterenol Hydrochloride; Dipivefrin; Dopamine Hydrochloride;
Ephedrine Sulfate; Epinephrine; Epinephrine Bitartrate; Epinephryl
Borate; Esproquin Hydrochloride; Etafedrine Hydrochloride;
Hydroxyamphetamine Hydrobromide; Levonordefrin; Mephentermine
Sulfate; Metaraminol Bitartrate; Metizoline Hydrochloride;
Naphazoline Hydrochloride; Norepinephrine Bitartrate; Oxidopamine;
Oxymetazoline Hydrochloride; Phenylephrine Hydrochloride;
Phenylpropanolamine Hydrochloride; Phenylpropanolamine Polistirex;
Prenalterol Hydrochloride; Propylhexedrine; Pseudoephedrine
Hydrochloride; Tetrahydrozoline Hydrochloride; Tramazoline
Hydrochloride; and Xylometazoline Hydrochloride.
[0073] Adrenocortical steroid: Ciprocinonide; Desoxycorticosterone
Acetate; Desoxycorticosterone Pivalate; Dexamethasone Acetate;
Fludrocortisone Acetate; Flumoxonide; Hydrocortisone Hemisuccinate;
Methylprednisolone Hemisuccinate; Naflocort; Procinonide;
Timobesone Acetate; and Tipredane.
[0074] Adrenocortical suppressant: Aminoglutethimide; and
Trilostane.
[0075] Alcohol deterrent: Disulfiram.
[0076] Aldosterone antagonist: Canrenoate Potassium; Canrenone;
Dicirenone; Mexrenoate Potassium; Prorenoate Potassium; and
Spironolactone.
[0077] Amino acid: Alanine; Arginine; Aspartic Acid; Carnitine;
Cysteine Hydrochloride; Cystine; Glycine; Histidine; Isoleucine;
Leucine; Lysine; Lysine Acetate; Lysine Hydrochloride; Methionine;
Phenylalanine; Proline; Serine; Threonine; Tryptophan; Tyrosine;
and Valine.
[0078] Ammonia detoxicant: Arginine Glutamate; and Arginine
Hydrochloride.
[0079] Amyotrophic lateral sclerosis agents: Riluzole.
[0080] Anabolic: Bolandiol Dipropionate; Bolasterone; Boldenone
Undecylenate; Bolenol; Bolmantalate; Ethylestrenol; Methenolone
Acetate; Methenolone Enanthate; Mibolerone; Nandrolone Cyclotate;
Norbolethone; Pizotyline; Quinbolone; Stenbolone Acetate; Tibolone;
and Zeranol.
[0081] Analeptic: Modafinil.
[0082] Analgesic: Acetaminophen; Alfentanil Hydrochloride;
Aminobenzoate Potassium; Aminobenzoate Sodium; Anidoxime;
Anileridine; Anileridine Hydrochloride; Anilopam Hydrochloride;
Anirolac; Antipyrine; Aspirin; Benoxaprofen; Benzydamine
Hydrochloride; Bicifadine Hydrochloride; Brifentanil Hydrochloride;
Bromadoline Maleate; Bromfenac Sodium; Buprenorphine Hydrochloride;
Butacetin; Butixirate; Butorphanol; Butorphanol Tartrate;
Carbamazepine; Carbaspirin Calcium; Carbiphene Hydrochloride;
Carfentanil Citrate; Ciprefadol Succinate; Ciramadol; Ciramadol
Hydrochloride; Clonixeril; Clonixin; Codeine; Codeine Phosphate;
Codeine Sulfate; Conorphone Hydrochloride; Cyclazocine; Dexoxadrol
Hydrochloride; Dexpemedolac; Dezocine; Diflunisal; Dihydrocodeine
Bitartrate; Dimefadane; Dipyrone; Doxpicomine Hydrochloride;
Drinidene; Enadoline Hydrochloride; Epirizole; Ergotamine Tartrate;
Ethoxazene Hydrochloride; Etofenamate; Eugenol; Fenoprofen;
Fenoprofen Calcium; Fentanyl Citrate; Floctafenine; Flufenisal;
Flunixin; Flunixin Meglumine; Flupirtine Maleate; Fluproquazone;
Fluradoline Hydrochloride; Flurbiprofen; Hydromorphone
Hydrochloride; Ibufenac; Indoprofen; Ketazocine; Ketorfanol;
Ketorolac Tromethamine; Letimide Hydrochloride; Levomethadyl
Acetate; Levomethadyl Acetate Hydrochloride; Levonantradol
Hydrochloride; Levorphanol Tartrate; Lofemizole Hydrochloride;
Lofentanil Oxalate; Lorcinadol; Lornoxicam; Magnesium Salicylate;
Mefenamic Acid; Menabitan Hydrochloride; Meperidine Hydrochloride;
Meptazinol Hydrochloride; Methadone Hydrochloride; Methadyl
Acetate; Methopholine; Methotrimeprazine; Metkephamid Acetate;
Mimbane Hydrochloride; Mirfentanil Hydrochloride; Molinazone;
Morphine Sulfate; Moxazocine; Nabitan Hydrochloride; Nalbuphine
Hydrochloride; Nalmexone Hydrochloride; Namoxyrate; Nantradol
Hydrochloride; Naproxen; Naproxen Sodium; Naproxol; Nefopam
Hydrochloride; Nexeridine Hydrochloride; Noracymethadol
Hydrochloride; Ocfentanil Hydrochloride; Octazamide; Olvanil;
Oxetorone Fumarate; Oxycodone; Oxycodone Hydrochloride; Oxycodone
Terephthalate; Oxymorphone Hydrochloride; Pemedolac; Pentamorphone;
Pentazocine; Pentazocine Hydrochloride; Pentazocine Lactate;
Phenazopyridine Hydrochloride; Phenyramidol Hydrochloride;
Picenadol Hydrochloride; Pinadoline; Pirfenidone; Piroxicam
Olamine; Pravadoline Maleate; Prodilidine Hydrochloride; Profadol
Hydrochloride; Propiram Fumarate; Propoxyphene Hydrochloride;
Propoxyphene Napsylate; Proxazole; Proxazole Citrate; Proxorphan
Tartrate; Pyrroliphene Hydrochloride; Remifentanil Hydrochloride;
Salcolex; Salicylamide; Salicylate Meglumine; Salsalate; Sodium
Salicylate; Spiradoline Mesylate; Sufentanil; Sufentanil Citrate;
Talmetacin; Talniflumate; Talosalate; Tazadolene Succinate;
Tebufelone; Tetrydamine; Tifurac Sodium; Tilidine Hydrochloride;
Tiopinac; Tonazocine Mesylate; Tramadol Hydrochloride; Trefentanil
Hydrochloride; Trolamine; Veradoline Hydrochloride; Verilopam
Hydrochloride; Volazocine; Xorphanol Mesylate; Xylazine
Hydrochloride; Zomepirac Sodium; and Zucapsaicin.
[0083] Androgen: Fluoxymesterone; Mesterolone; Methyltestosterone;
Nandrolone Decanoate; Nandrolone Phenpropionate; Nisterime Acetate;
Oxandrolone; Oxymetholone; Silandrone; Stanozolol; Testosterone;
Testosterone Cypionate; Testosterone Enanthate; Testosterone
Ketolaurate; Testosterone Phenylacetate; Testosterone Propionate;
and Trestolone Acetate.
[0084] Anesthesia (adjunct to): Sodium Oxybate.
[0085] Anesthetic: Aliflurane; Benoxinate Hydrochloride;
Benzocaine; Biphenamine Hydrochloride; Bupivacaine Hydrochloride;
Butamben; Butamben Picrate; Chloroprocaine Hydrochloride; Cocaine;
Cocaine Hydrochloride; Cyclopropane; Desflurane; Dexivacaine;
Diamocaine Cyclamate; Dibucaine; Dibucaine Hydrochloride; Dyclonine
Hydrochloride; Enflurane; Ether; Ethyl Chloride; Etidocaine;
Etoxadrol Hydrochloride; Euprocin Hydrochloride; Fluroxene;
Halothane; Isobutamben; Isoflurane; Ketamine Hydrochloride;
Levoxadrol Hydrochloride; Lidocaine; Lidocaine Hydrochloride;
Mepivacaine Hydrochloride; Methohexital Sodium; Methoxyflurane;
Midazolam Hydrochloride; Midazolam Maleate; Minaxolone; Norflurane;
Octodrine; Oxethazaine; Phencyclidine Hydrochloride; Pramoxine
Hydrochloride; Prilocaine Hydrochloride; Procaine Hydrochloride;
Propanidid; Proparacaine Hydrochloride; Propofol; Propoxycaine
Hydrochloride; Pyrrocaine; Risocaine; Rodocaine; Roflurane; Salicyl
Alcohol; Sevoflurane; Teflurane; Tetracaine; Tetracaine
Hydrochloride; Thiamylal; Thiamylal Sodium; Thiopental Sodium;
Tiletamine Hydrochloride; and Zolamine Hydrochloride.
[0086] Anorectic compound: Dexfenfluramine.
[0087] Anorexic agents: Aminorex; Amphecloral; Chlorphentermine
Hydrochloride; Clominorex; Clortermine Hydrochloride;
Diethylpropion Hydrochloride; Fenfluramine Hydrochloride;
Fenisorex; Fludorex; Fluminorex; Levamfetamine Succinate; Mazindol;
Mefenorex Hydrochloride; Phemnetrazine Hydrochloride; Phentermine;
and Sibutramine Hydrochloride.
[0088] Antagonist: Atipamezole; Atosiban; Bosentan; Cimetidine;
Cimetidine Hydrochloride; Clentiazem Maleate; Detirelix Acetate;
Devazepide; Donetidine; Etintidine Hydrochloride; Famotidine;
Fenmetozole Hydrochloride; Flumazenil; Icatibant Acetate;
Icotidine; Isradipine; Metiamide; Nadide; Nalmefene; Naloxone
Hydrochloride; Naltrexone; Nilvadipine; Oxilorphan; Oxmetidine
Hydrochloride; Oxmetidine Mesylate; Quadazocine Mesylate;
Ranitidine; Ranitidine Bismuth Citrate; Ranitidine Hydrochloride;
Sufotidine; Teludipine Hydrochloride; Tiapamil Hydrochloride;
Tiotidine; Vapiprost Hydrochloride; and Zaltidine
Hydrochloride.
[0089] Anterior pituitary activator: Epimestrol.
[0090] Anterior pituitary suppressant: Danazol.
[0091] Anthelmintic: Albendazole; Anthelmycin; Bromoxanide;
Bunamidine Hydrochloride; Butonate; Cambendazole; Carbantel Lauryl
Sulfate; Clioxanide; Closantel; Cyclobendazole; Dichlorvos;
Diethylcarbamazine Citrate; Dribendazole; Dymanthine Hydrochloride;
Etibendazole; Fenbendazole; Furodazole; Hexylresorcinol;
Mebendazole; Morantel Tartrate; Niclosamide; Nitramisole
Hydrochloride; Nitrodan; Oxantel Pamoate; Oxfendazole;
Oxibendazole; Parbendazole; Piperamide Maleate; Piperazine;
Piperazine Citrate; Piperazine Edetate Calcium; Proclonol; Pyrantel
Pamoate; Pyrantel Tartrate; Pyrvinium Pamoate; Rafoxanide;
Stilbazium Iodide; Tetramisole Hydrochloride; Thiabendazole;
Ticarbodine; Tioxidazole; Triclofenol Piperazine; Vincofos; and
Zilantel.
[0092] Anti-acne: Adapalene; Erythromycin, Salnacedin; and
Inocoterone Acetate.
[0093] Anti-adrenergic: Acebutolol; Alprenolol Hydrochloride;
Atenolol; Bretylium Tosylate; Bunolol Hydrochloride; Carteolol
Hydrochloride; Celiprolol Hydrochloride; Cetamolol Hydrochloride;
Cicloprolol Hydrochloride; Dexpropranolol Hydrochloride; Diacetolol
Hydrochloride; Dihydroergotamine Mesylate; Dilevalol Hydrochloride;
Esmolol Hydrochloride; Exaprolol Hydrochloride; Fenspiride
Hydrochloride; Flestolol Sulfate; Labetalol Hydrochloride;
Levobetaxolol Hydrochloride; Levobunolol Hydrochloride; Metalol
Hydrochloride; Metoprolol; Metoprolol Tartrate; Nadolol; Pamatolol
Sulfate; Penbutolol Sulfate; Phentolamine Mesylate; Practolol;
Propranolol Hydrochloride; Proroxan Hydrochloride; Solypertine
Tartrate; Sotalol Hydrochloride; Timolol; Timolol Maleate;
Tiprenolol Hydrochloride; Tolamolol; and Zolertine
Hydrochloride.
[0094] Anti-allergic: Amlexanox; Astemizole; Azelastine
Hydrochloride; Eclazolast; Minocromil Nedocromil Nedocromil
Calcium; Nedocromil Sodium; Nivimedone Sodium; Pemirolast Potassium
Pentigetide; Pirquinozol; Poisonoak Extract; Probicromil Calcium;
Proxicromil; Repirinast; Tetrazolast Meglumine; Thiazinamium
Chloride; Tiacrilast; Tiacrilast Sodium; Tiprinast Meglumine; and
Tixanox.
[0095] Anti-amebic: Berythromycin; Bialamicol Hydrochloride;
Chloroquine; Chloroquine Hydrochloride; Chloroquine Phosphate;
Clamoxyquin Hydrochloride; Clioquinol; Emetine Hydrochloride;
Iodoquinol; Paromomycin Sulfate; Quinfamide; Symetine
Hydrochloride; Teclozan; Tetracycline; and Tetracycline
Hydrochloride.
[0096] Anti-androgen: Benorterone; Cioteronel; Cyproterone Acetate;
Delmadinone Acetate; Oxendolone; Topterone; and Zanoterone.
[0097] Anti-anemic: Epoetin Alfa; Epoetin Beta; Ferrous Sulfate,
Dried; and Leucovorin Calcium.
[0098] Anti-anginal: Amlodipine Besylate; Amlodipine Maleate;
Betaxolol Hydrochloride; Bevantolol Hydrochloride; Butoprozine
Hydrochloride; Carvedilol; Cinepazet Maleate; Metoprolol Succinate;
Molsidomine; Monatepil Maleate; Primidolol; Ranolazine
Hydrochloride; Tosifen; and Verapamil Hydrochloride.
[0099] Anti-anxiety agent: Adatanserin Hydrochloride; Alpidem;
Binospirone Mesylate; Bretazenil; Glemanserin; Ipsapirone
Hydrochloride; Mirisetron Maleate; Ocinaplon; Ondansetron
Hydrochloride; Panadiplon; Pancopride; Pazinaclone; Serazapine
Hydrochloride; Tandospirone Citrate; and Zalospirone
Hydrochloride.
[0100] Anti-arthritic: Lodelaben.
[0101] Anti-asthmatic: Ablukast; Ablukast Sodium; Bunaprolast;
Cinalukast; Cromitrile Sodium; Cromolyn Sodium; Enofelast;
Isamoxole; Ketotifen Fumarate; Levcromakalim; Lodoxamide Ethyl;
Lodoxamide Tromethamine; Montelukast Sodium; Ontazolast;
Oxarbazole; Oxatomide; Piriprost; Piriprost Potassium; Pirolate;
Pobilukast Edamine; Quazolast; Ritolukast; Sulukast; Tiaramide
Hydrochloride; Tibenelast Sodium; Tomelukast; Tranilast; Verlukast;
and Verofylline Zarirlukast.
[0102] Anti-atherosclerotic: Mifobate; and Timefuronc.
[0103] Antibacterial: Acedapsone; Acetosulfone Sodium; Alamecin;
Alexidine; Amdinocillin; Amdinocillin Pivoxil; Amicycline;
Amifioxacin; Amifloxacin Mesylate; Amikacin; Amikacin Sulfate;
Aminosalicylate sodium; Aminosalicylic acid; Amoxicillin;
Amphomycin; Ampicillin; Ampicillin Sodium; Apalcillin Sodium;
Apramycin; Aspartocin; Astromicin Sulfate; A vilamycin; A voparcin;
Azithromycin; Azlocillin; Azlocillin Sodium; Bacampicillin
Hydrochloride; Bacitracin; Bacitracin Methylene Disalicylate;
Bacitracin Zinc; Bambermycins; Benzoylpas Calcium; Betamicin
Sulfate; Biapenem; Biniramycin; Bispyrithione Magsulfex; Butikacin;
Butirosin Sulfate; Capreomycin Sulfate; Carbadox; Carbenicillin
Disodium; Carbenicillin Indanyl Sodium; Carbenicillin Phenyl
Sodium; Carbenicillin Potassium; Carumonam Sodium; Cefaclor;
Cefadroxil; Cefamandole; Cefamandole Nafate; Cefamandole Sodium;
Cefaparole; Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin
Sodium; Cefbuperazone; Cefdinir; Cefepime; Cefepime Hydrochloride;
Cefetecol; Cefixime; Cefmenoxime Hydrochloride; Cefinetazole;
Cefinetazole Sodium; Cefonicid Monosodium; Cefonicid Sodium;
Cefoperazone Sodium; Ceforanide; Cefotaxime Sodium; Cefotetan;
Cefotetan Disodium; Cefotiam Hydrochloride; Cefoxitin; Cefoxitin
Sodium; Cefpimizole; Cefpimizole Sodium; Cefpiramide; Cefpiramide
Sodium; Cefpirome Sulfate; Cefpodoxime Proxetil; Cefprozil;
Cefroxadine; Cefsulodin Sodium; Ceftazidime; Ceftibuten;
Ceftiroxime Pivoxetil; Ceftizoxime Sodium; Ceftriaxone Sodium;
Cefuroxime; Cefuroxime Axetil; Cefuroxime Sodium; Cephacetrile
Sodium; Cephalexin; Cephalexin Hydrochloride; Cephaloglycin;
Cephaloridine; Cephalothin Sodium; Cephapirin Sodium; Cephradine;
Cetocycline Hydrochloride; Cetophenicol; Chloramphenicol;
Chloramphenicol Palmitate; Chloramphenicol Pantothenate Complex;
Chloramphenicol Sodium Succinate; Chlorhexidine Phosphanilate;
Chloroxylenol; Chlortetracycline Bisulfate; Chlortetracycline
Hydrochloride; Cinoxacin; Ciprofloxacin; Ciprofloxacin
Hydrochloride; Cirolemycin; Clarithromycin; Clinafloxacin
Hydrochloride; Clindamycin; Clindamycin Hydrochloride; Clindamycin
Palmitate Hydrochloride; Clindamycin Phosphate; Clofazimine;
Cloxacillin Benzathine; Cloxacillin Sodium; Cloxyquin;
Colistimethate Sodium; Colistin Sulfate; Coumermycin; Coumermycin
Sodium; Cyclacillin; Cycloserine; Dalfopristin; Dapsone;
Daptomycin; Demeclocycline; Demeclocycline Hydrochloride;
Demecycline; Denofungin; Diaveridine; Dicloxacillin; Dicloxacillin
Sodium; Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin;
Doxycycline; Doxycycline Calcium; Doxycycline Fosfatex; Doxycycline
Hyclate; Droxacin Sodium; Enoxacin; Epicillin; Epitetracycline
Hydrochloride; Erythromycin; Erythromycin Acistrate; Erythromycin
Estolate; Erythromycin Ethylsuccinate; Erythromycin Gluceptate;
Erythromycin Lactobionate; Erythromycin Propionate; Erythromycin
Stearate; Ethambutol Hydrochloride; Ethionamide; Fleroxacin;
Floxacillin; Fludalanine; Flumequine; Fosfomycin; Fosfomycin
Tromethamine; Fumoxicillin; Furazolium Chloride; Furazolium
Tartrate; Fusidate Sodium; Fusidic Acid; Gentamicin Sulfate;
Gloximonam; Gramicidin; Haloprogin; Hetacillin; Hetacillin
Potassium; Hexedine; Ibafloxacin; Imipenem; Isepamicin;
Isoconazole; Isoniazid; Josamycin; Kanamycin Sulfate; Kitasamycin;
Levofuraltadone; Levopropylcillin Potassium; Lexithromycin;
Lincomycin; Lincomycin Hydrochloride; Lomefloxacin; Lomefloxacin
Hydrochloride; Lomefloxacin Mesylate; Loracarbef; Mafenide;
Meclocycline; Meclocycline Sulfosalicylate; Megalomicin Potassium
Phosphate; Mequidox; Meropenem; Methacycline; Methacycline
Hydrochloride; Methenamine; Methenamine Hippurate; Methenamine
Mandelate; Methicillin Sodium; Metioprim; Metronidazole
Hydrochloride; Metronidazole Phosphate; Mezlocillin; Mezlocillin
Sodium; Minocycline; Minocycline Hydrochloride; Mirincamycin
Hydrochloride; Monensin; Monensin Sodium; Nafcillin Sodium;
Nalidixate Sodium; Nalidixic Acid; Natamycin; Nebramycin; Neomycin
Palmitate; Neomycin Sulfate; Neomycin Undecylenate; Netilmicin
Sulfate; Neutramycin; Nifarthiazole; Nifuradene; Nifuraldezone;
Nifuratel; Nifuratrone; Nifurdazil; Nifurimide; Nifurpirinol;
Nifurquinazol; Nitrocycline; Nitrofurantoin; Nitromide;
Norfloxacin; Novobiocin Sodium; Ofloxacin; Onnetoprim; Oxacillin
Sodium; Oximonam; Oximonam Sodium; Oxolinic Acid; Oxytetracycline;
Oxytetracycline Calcium; Oxytetracycline Hydrochloride; Paldimycin;
Parachlorophenol; Paulomycin; Pefloxacin; Pefloxacin Mesylate;
Penamecillin; Penicillin G Benzathine; Penicillin G Potassium;
Penicillin G Procaine; Penicillin G Sodium; Penicillin V;
Penicillin V Benzathine; Penicillin V Hydrabamine; Penicillin V
Potassium; Pentizidone Sodium; Phenyl Aminosalicylate; Piperacillin
Sodium; Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin
Hydrochloride; Pivampicillin Hydrochloride; Pivampicillin Pamoate;
Pivampicillin Probenate; Polymyxin B Sulfate; Porfiromycin;
Propikacin; Pyrazinamide; Pyrithione Zinc; Quindecamine Acetate;
Quinupristin; Racephenicol; Ramoplanin; Ranimycin; Relomycin;
Repromicin; Rifabutin; Rifametane; Rifamexil; Rifamide; Rifampin;
Rifapentine; Rifaximin; Rolitetracycline; Rolitetracycline Nitrate;
Rosaramicin; Rosaramicin Butyrate; Rosaramicin Propionate;
Rosaramicin Sodium Phosphate; Rosaramicin Stearate; Rosoxacin;
Roxarsone; Roxithromycin; Sancycline; Sanfetrinem Sodium;
Sarmoxicillin; Sarpicillin; Scopafungin; Sisomicin; Sisomicin
Sulfate; Sparfloxacin; Spectinomycin Hydrochloride; Spiramycin;
Stallimycin Hydrochloride; Steffimycin; Streptomycin Sulfate;
Streptonicozid; Sulfabenz; Sulfabenzamide; Sulfacetamide;
Sulfacetamide Sodium; Sulfacytine; Sulfadiazine; Sulfadiazine
Sodium; Sulfadoxine; Sulfalene; Sulfamerazine; Sulfameter;
Sulfamethazine; Sulfamethizole; Sulfamethoxazole;
Sulfamonomethoxine; Sulfamoxole; Sulfanilate Zinc; Sulfanitran;
Sulfasalazine; Sulfasomizole; Sulfathiazole; Sulfazamet;
Sulfisoxazole; Sulfisoxazole Acetyl; Sulfisoxazole Diolamine;
Sulfomyxin; Sulopenem; Sultamicillin; Suncillin Sodium;
Talampicillin Hydrochloride; Teicoplanin; Temafloxacin
Hydrochloride; Temocillin; Tetracycline Phosphate Complex;
Tetroxoprim; Thiamphenicol; Thiphencillin Potassium; Ticarcillin
Cresyl Sodium; Ticarcillin Disodium; Ticarcillin Monosodium;
Ticlatone; Tiodonium Chloride; Tobramycin; Tobramycin Sulfate;
Tosufloxacin; Trimethoprim; Trimethoprim Sulfate;
Trisulfapyrimidines; Troleandomycin; Trospectomycin Sulfate;
Tyrothricin; Vancomycin; Vancomycin Hydrochloride; Virginiamycin;
and Zorbamycin.
[0104] Anti-cancer supplementary potentiating agents:
Amitryptyline; Amoxapine; Amphotericin B; Antiarrhythmic drugs
(e.g., Quinidine); Antihypertensive drugs (e.g., Reserpine); Ca++
antagonists (e.g., Verapamil; Calmodulin inhibitors (e.g.,
Prenylamine; Caroverine); Citalopram); Clomipramine; Clomipramine);
Desipramine; Doxepin; Maprotiline); Nifedipine; Nitrendipine;
Non-tricyclic anti-depressant drugs (e.g., Sertraline;
Nortriptyline; Protriptyline; Sulfoximine) and Multiple Drug
Resistance reducing agents such as Cremaphor EL; Thiol depleters
(e.g., Buthionine; Trazodone; Tricyclic anti-depressant drugs
(e.g., Imipramine; Trifluoroperazine; Trimipramine; and Triparanol
analogues (e.g., Tamoxifen).
[0105] Anticholelithic: Monoctanoin.
[0106] Anticholelithogenic: Chenodiol; Ursodiol.
[0107] Anticholinergic: Alverinc Citrate; Anisotropine
Methylbromide; Atropine; Atropine Oxide Hydrochloride; Atropine
Sulfate; Belladonna; Benapryzine Hydrochloride; Benzetimide
Hydrochloride; Benzilonium Bromide; Biperiden; Biperiden
Hydrochloride; Biperiden Lactate; Clidinium Bromide; Cyclopentolate
Hydrochloride; Dexetimide; Dicyclomine Hydrochloride; Dihexyverine
Hydrochloride; Domazoline Fumarate; Elantrine; Elucaine;
Ethybenztropine; Eucatropine Hydrochloride; Glycopyrrolate;
Heteronium Bromide; Homatropine Hydrobromide; Homatropine
Methylbromide; Hyoscyamine; Hyoscyamine Hydrobromide; Hyoscyamine
Sulfate; Isopropamide Iodide; Mepenzolate Bromide; Methylatropine
Nitrate; Metoquizine; Oxybutynin Chloride; Parapenzolate Bromide;
Pentapiperium Methylsulfate; Phencarbamide; Poldine Methylsulfate;
Proglumide; Propantheline Bromide; Propenzolate Hydrochloride;
Scopolamine Hydrobromide; Tematropium Methylsulfate; Tiquinamide
Hydrochloride; Tofenacin Hydrochloride; Toquizine; Triampyzine
Sulfate; Trihexyphenidyl Hydrochloride; and Tropicamide.
[0108] Anticoagulant: Ancrod; Ardeparin Sodium; Bivalirudin;
Bromindione; Dalteparin Sodium Desirudin; Dicumarol; Lyapolate
Sodium; Nafamostat Mesylate; Phenprocoumon; Tinzaparin Sodium; and
Warfarin Sodium.
[0109] Anticoccidal: Maduramicin.
[0110] Anticonvulsant: Albutoin; Ameltolide; Atolide; Buramate;
Cinromide; Citenamide; Clonazepam; Cyheptamide; Dezinamide;
Dimethadione; Divalproex Sodium; Eterobarb; Ethosuximide; Ethotoin;
Flurazepam Hydrochloride; Fluzinamide; Fosphenytoin Sodium;
Gabapentin; Ilepcimide; Lamotrigine; Magnesium Sulfate;
Mephenytoin; Mephobarbital; Methetoin; Methsuximide; Milacemide
Hydrochloride; Nabazenil; Nafimidone Hydrochloride; Nitrazepam;
Phenacemide; Phenobarbital; Phenobarbital Sodium; Phensuximide;
Phenytoin; Phenytoin Sodium; Primidone; Progabide; Ralitoline;
Remacemide Hydrochloride; Ropizine; Sabeluzole; Stiripentol;
Sulthiame; Topiramate; Trimethadione; Valproate Sodium; Valproic
Acid; Vigabatrin; Zoniclezole Hydrochloride; and Zonisamide.
[0111] Antidepressant: Adinazolam; Adinazolam Mesylate;
Alaproclate; Aletamine Hydrochloride; Amedalin Hydrochloride;
Amitriptyline Hydrochloride; Aptazapine Maleate; Azaloxan Fumarate;
Azepindole; Azipramine Hydrochloride; Bipenamol Hydrochloride;
Bupropion Hydrochloride; Butriptyline Hydrochloride; Caroxazone;
Cartazolate; Ciclazindol; Cidoxepin Hydrochloride; Cilobamine
Mesylate; Clodazon Hydrochloride; Clomipramine Hydrochloride;
Cotinine Fumarate; Cyclindole; Cypenamine Hydrochloride; Cyprolidol
Hydrochloride; Cyproximide; Daledalin Tosylate; Dapoxetine
Hydrochloride; Dazadrol Maleate; Dazepinil Hydrochloride;
Desipramine Hydrochloride; Dexamisole; Deximafen; Dibenzepin
Hydrochloride; Dioxadrol Hydrochloride; Dothiepin Hydrochloride;
Doxepin Hydrochloride; Duloxetine Hydrochloride; Eclanamine
Maleate; Encyprate; Etoperidone Hydrochloride; Fantridone
Hydrochloride; Fenmetramide; Fezolamine Fumarate; Fluotracen
Hydrochloride; Fluoxetine; Fluoxetine Hydrochloride; Fluparoxan
Hydrochloride; Gamfexine; Guanoxyfen Sulfate; Imafen Hydrochloride;
Imiloxan Hydrochloride; Imipramine Hydrochloride; Indeloxazine
Hydrochloride; Intriptyline Hydrochloride; Iprindole;
Isocarboxazid; Ketipramine Fumarate; Lofepramine Hydrochloride;
Lortalamine; Maprotiline; Maprotiline Hydrochloride; Melitracen
Hydrochloride; Minaprine Hydrochloride; Mirtazapine; Moclobemide;
Modaline Sulfate; Napactadine Hydrochloride; Napamezole
Hydrochloride; Nefazodone Hydrochloride; Nisoxetine; Nitrafudam
Hydrochloride; Nomifensine Maleate; Nortriptyline Hydrochloride;
Octriptyline Phosphate; Opipramol Hydrochloride; Oxaprotiline
Hydrochloride; Oxypertine; Paroxetine; Phenelzine Sulfate;
Pirandamine Hydrochloride; Pridefine Hydrochloride; Prolintane
Hydrochloride; Protriptyline Hydrochloride; Quipazine Maleate;
Rolicyprine; Seproxetine Hydrochloride; Sertraline Hydrochloride;
Sulpiride; Suritozole; Tametraline Hydrochloride; Tampramine
Fumarate; Tandamine Hydrochloride; Thiazesim Hydrochloride;
Thozalinone; Tomoxetine Hydrochloride; Trazodone Hydrochloride;
Trebenzomine Hydrochloride; Trimipramine Maleate; Venlafaxine
Hydrochloride; Viloxazine Hydrochloride; Zimeldine Hydrochloride;
and Zometapine.
[0112] Antidiabetic: Acetohexamide; Buformin; Butoxamine
Hydrochloride; Camighbose; Chlorpropamide; Ciglitazone; Englitazone
Sodium; Etoformin Hydrochloride; Gliamilide; Glibornuride;
Glicetanile Sodium; Gliflumide; Glipizide; Glucagon; Glyburide;
Glyhexamide; Glymidine Sodium; Glyoctamide; Glyparamide; Insulin;
Insulin Human; Insulin Human Zinc; Insulin Human Zinc, Extended;
Insulin Human, Isophane; Insulin Lispro; Insulin Zinc; Insulin
Zinc, Extended; Insulin Zinc, Prompt; Insulin, Dalanated; Insulin,
Isophane; Insulin, Neutral; Linogliride; Linogliride Fumarate;
Metformin; Methyl Palmoxirate; Palmoxirate Sodium; Pioglitazone
Hydrochloride; Pirogliride Tartrate; Proinsulin Human; Seglitide
Acetate; Tolazamide; Tolbutamide; Tolpyrramide; Troglitazone; and
Zopolrestat.
[0113] Antidiarrheal: Diphenoxylate Hydrochloride;
Methylprednisolone; Metronidazole; and Rolgamidine.
[0114] Antidiuretic: Argipressin Tannate; Desmopressin Acetate; and
Lypressin.
[0115] Antidote: Dimercaprol; Edrophonium Chloride; Fomepizole;
Levoleucovorin Calcium; Methylene Blue; and Protamine Sulfate.
[0116] Antidyskinetic: Selegiline Hydrochloride.
[0117] Anti-emetic: Alosetron Hydrochloride; Batanopride
Hydrochloride; Bemesetron; Benzquinamide; Chlorpromazine;
Chlorpromazine Hydrochloride; Clebopride; Cyclizine Hydrochloride;
Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Diphenidol
Pamoate; Dolasetron Mesylate; Domperidone; Dronabinol; Flumeridone;
Galdansetron Hydrochloride; Granisetron; Granisetron Hydrochloride;
Lurosetron Mesylate; Meclizine Hydrochloride; Metoclopramide
Hydrochloride; Metopimazine; Prochlorperazine; Prochlorperazine
Edisylate; Prochlorperazine Maleate; Promethazine Hydrochloride;
Thiethylperazine; Thiethylperazine Malate; Thiethylperazine
Maleate; Trimethobenzamide Hydrochloride; and Zacopride
Hydrochloride.
[0118] Anti-epileptic: Felbamate; lamotrigine; Loreclezole; and
Tolgabide.
[0119] Anti-estrogen: Clometherone; Nafoxidine Hydrochloride;
Nitromifene Citrate; Raloxifene Hydrochloride; Tamoxifen Citrate;
Toremifene Citrate; and Trioxifene Mesylate.
[0120] Antifibrinolytic: Nafamostat Mesylate.
[0121] Antifungal: Acrisorcin; Ambruticin; Azaconazole; Azaserine;
Basifungin; Bifonazole; Butoconazole Nitrate; Calcium Undecylenate;
Candicidin; Carbol-Fuchsin; Chlordantoin; Ciclopirox; Ciclopirox
Olamine; Cilofungin; Cisconazole; Clotrimazole; Cuprimyxin;
Doconazole; Econazole; Econazole Nitrate; Enilconazole; Ethonam
Nitrate; Fenticonazole Nitrate; Filipin; Fluconazole; Flucytosine;
Fungimycin; Griseofulvin; Hamycin; Itraconazole; Kalafungin;
Ketoconazole; Lomoftmgin; Lydimycin; Mepartricin; Miconazole;
Miconazole Nitrate; Monensin; Monensin Sodium; Naftifine
Hydrochloride; Nifuratel Nifurmerone; Nitralamine Hydrochloride;
Nystatin; Octanoic Acid; Orconazole Nitrate; Oxiconazole Nitrate;
Oxifungin Hydrochloride; Parconazole Hydrochloride; Partricin;
Potassium Iodide; Pyrrolnitrin; Rutamycin; Sanguinarium Chloride;
Saperconazole; Selenium Sulfide; Sinefungin; Sulconazole Nitrate;
Terbinafine; Terconazole; Thiram; Tioconazole; Tolciclate;
Tolindate; Tolnaftate; Triacetin; Triafungin; Undecylenic Acid;
Viridofulvin; Zinc Undecylenate; and Zinoconazole
Hydrochloride.
[0122] Antiglaucoma agent: Alprenoxime Hydrochloride; Colforsin;
Dipivefrin Hydrochloride; Naboctate Hydrochloride; Pilocarpine; and
Pirnabine.
[0123] Antihemorrhagic: Poliglusam.
[0124] Antihemorrheologic: Phentoxifylline.
[0125] Antihistaminic: Acrivastine; Antazoline Phosphate; Azatadine
Maleate; Barmastine; Bromodiphenhydramine Hydrochloride;
Brompheniramine Maleate; Carbinoxamine Maleate; Cetirizine
Hydrochloride; Chlorpheniramine Maleate; Chlorpheniramine
Polistirex; Cirmarizine; Clemastine; Clemastine Fumarate;
Closiramine Aceturate; Cycliramine Maleate; Cyclizine;
Cyproheptadine Hydrochloride; Dexbrompheniramine Maleate;
Dexchlorpheniramine Maleate; Dimethindene Maleate; Diphenhydramine
Citrate; Diphenhydramine Hydrochloride; Dorastine Hydrochloride;
Doxylamine Succinate; Ebastine; Fexofenadine HCl; Levocabastine
Hydrochloride; Loratadine; Mianserin Hydrochloride; Noberastine;
Orphenadrine Citrate; Pyrabrom; Pyrilamine Maleate; Pyroxamine
Maleate; Rocastine Hydrochloride; Rotoxamine; Tazifylline
Hydrochloride; Temelastine; Terfenadine; Tripelennamine Citrate;
Tripelennamine Hydrochloride; and Triprolidine Hydrochloride.
[0126] Antihyperlipidemic: Cholestyramine Resin; Clofibrate;
Colestipol Hydrochloride; Crilvastatin; Dalvastatin;
Dextrothyroxine Sodium; Fluvastatin Sodium; Gemfibrozil;
Lecimibide; Lovastatin; Niacin; Pravastatin Sodium; Probucol;
Simvastatin; Tiqueside; and Xenbucin.
[0127] Antihyperlipoproteinemic: Acifran; Beloxamide; Bezafibrate;
Boxidine; Cetaben Sodium; Ciprofibrate; Gemcadiol; Halofenate;
Lifibrate; Meglutol; Nafenopin; Pimetine Hydrochloride;
Theofibrate; Tibric Acid; and Treloxinate.
[0128] Antihypertensive: Alfuzosin Hydrochloride; Alipamide;
Althiazide; Amiquinsin Hydrochloride; Anaritide Acetate; Atiprosin
Maleate; Belfosdil; Bemitradine; Bendacalol Mesylate;
Bendroflumethiazide; Benzthiazide; Bethanidine Sulfate; Biclodil
Hydrochloride; Bisoprolol; Bisoprolol Fumarate; Bucindolol
Hydrochloride; Bupicomide; Buthiazide; Candoxat rilat; Candoxatril;
Captopril; Ceronapril; Chlorothiazide Sodium; Cicletanine;
Cilazapril; Clonidine; Clonidine Hydrochloride; Clopamide;
Cyclopenthiazide; Cyclothiazide; Darodipine; Debrisoquin Sulfate;
Delapril Hydrochloride; Diapamide; Diazoxide; Diltiazem
Hydrochloride; Diltiazem Malate; Ditekiren; Doxazosin Mesylate;
Ecadotril; Enalapril Maleate; Enalaprilat; Enalkiren; Endralazine
Mesylate; Epithiazide; Eprosartan; Eprosartan Mesylate; Fenoldopam
Mesylate; Flavodilol Maleate; Flordipine; Flosequinan; Fosinopril
Sodium; Fosinoprilat; Guanabenz; Guanabenz Acetate; Guanacline
Sulfate; Guanadrel Sulfate; Guancvdine; Guanethidine Monosulfate;
Guanethidine Sulfate; Guanfacine Hydrochloride; Guanisoquin
Sulfate; Guanoclor Sulfate; Guanoctine Hydrochloride; Guanoxabenz;
Guanoxan Sulfate; Guanoxvfen Sulfate; Hydralazine Hydrochloride;
Hydralazine Polistirex; Hydroflumethiazide; Indacrinone Indapamide;
Indolapril Hydrochloride; Indoramin; Indoramin Hydrochloride;
Indorenate Hydrochloride; Lacidipine; Leniquinsin; Lisinopril;
Lofexidine Hydrochloride; Losartan Potassium; Losulazine
Hydrochloride; Mebutamate; Mecamylamine Hydrochloride; Medroxalol;
Medroxalol Hydrochloride; Methalthiazide Methyclothiazide
Methyldopa; Methyldopate Hydrochloride; Metipranolol; Metolazone
Metoprolol Fumarate; Metyrosine; Minoxidil; Muzolimine; Nebivolol;
Nifidipine; Ofornine; Pargyline Hydrochloride; Pazoxide; Pelanserin
Hydrochloride; Perindopril Erbumine; Phenoxybenzamine
Hydrochloride; Pinacidil; Pivopril; Polythiazide; Prazosin
Hydrochloride; Prizidilol Hydrochloride; Quinapril Hydrochloride;
Quinaprilat; Quinazosin Hydrochloride; Quinelorane Hydrochloride;
Quinpirole Hydrochloride; Quinuclium Bromide; Ramipril; Rauwolfia
Serpentina; Reserpine; Saprisartan Potassium; Saralasin Acetate;
Sodium Nitroprusside; Sulfinalol Hydrochloride; Tasosartan;
Temocapril Hydrochloride; Terazosin Hydrochloride; Terlakiren;
Tiamenidine; Tiamenidine Hydrochloride; Ticrynafen; Tinabinol;
Tiodazosin; Tipentosin Hydrochloride; Trichlormethiazide;
Trimazosin Hydrochloride; Trimethaphan Camsylate; Trimoxamine
Hydrochloride; Tripamide; Xipamide; Zankiren Hydrochloride; and
Zofenoprilat Arginine.
[0129] Antihypotensive: Ciclafrine Hydrochloride; and Midodrine
Hydrochloride.
[0130] Anti-infective: Acyclovir; Difloxacin Hydrochloride;
Integrase Inhibitors of HIV and other retroviruses; Lauryl
Isoquinolinium Bromide; Moxalactam Disodium; Ornidazole;
Pentisomicin; Protease inhibitors of HIV and other retroviruses;
and Sarafloxacin Hydrochloride.
[0131] Anti-infective (topical): Alcohol; Aminacrine Hydrochloride;
Benzethonium Chloride; Bithionolate Sodium; Bromchlorenone;
Carbamide Peroxide; Cetalkonium Chloride; Cetylpyridinium Chloride;
Chlorhexidine Hydrochloride; Domiphen Bromide; Fenticlor;
Fludazonium Chloride; Fuchsin, Basic; Furazolidone; Gentian Violet;
Halquinols; Hexachlorophene; Hydrogen Peroxide; Ichthammol;
Imidecyl Iodine; Iodine; Isopropyl Alcohol; Mafenide Acetate;
Meralein Sodium; Mercufenol Chloride; Mercury, Ammoniated;
Methylbenzethonium Chloride; Nitrofarazone; Nitromersol; Octenidine
Hydrochloride; Oxychlorosene; Oxychlorosene Sodium;
Parachlorophenol, Camphorated; Potassium Permanganate;
Povidone-Iodine; Sepazonium Chloride; Silver Nitrate; Sulfadiazine,
Silver; Symclosene; Thimerfonate Sodium; Thimerosal; and Troclosene
Potassium.
[0132] Anti-inflammatory: Alclofenac; Alclometasone Dipropionate;
Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac
Sodium; Amiprilose Hydrochloride; Anakinra; Anitrazafen; Apazone;
Balsalazide Disodium; Bendazac; Bromelains; Broperamole;
Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen;
Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone
Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort;
Desonide; Desoximetasone; Dexamethasone Dipropionate; Diclofenac
Potassium; Diclofenac Sodium; Diflorasone Diacetate; Diflumidone
Sodium; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide;
Endrysone; Enlimomab; Enolicam Sodium; Etodolac; Felbinac;
Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone;
Fentiazac; Flazalone; Fluazacort; Flufenamic Acid; Flumizole;
Flunisolide Acetate; Fluocortin Butyl; Fluorometholone Acetate;
Fluquazone; Fluretofen; Fluticasone Propionate; Furaprofen;
Furobufen; Halcinonide; Halobetasol Propionate; Halopredone
Acetate; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol;
Ilonidap; Indomethacin Sodium; Indomethacin; Indoprofen Indoxole;
Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen;
Lomoxicam; Loteprednol Etabonate; Meclofenamate Sodium;
Meclofenamic Acid; Meclorisonc Dibutyrate; Mesalamine; Meseclazone;
Methylprednisolone Suleptanate; Morniflumate; Nabumetone; Nimazone;
Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin; Oxyphenbutazone;
Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone
Sodium Glycerate; Piroxicam; Piroxicam Cinnamate; Pirprofen;
Prednazate; Prednisolone Sodium Phosphate; Prifelone; Prodolic
Acid; Proquazone; Rimexolone; Romazarit; Salnacedin; Seclazone;
Sermetacin; Sudoxicam; Sulindac; Suprofen; Talniflumate; Tenidap;
Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Tixocortol Pivalate;
Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; and
Zidometacin.
[0133] Antikeratinizing agent: Doretinel; Linarotene; and
Pelretin.
[0134] Antimalarial: Amodiaquine Hydrochloride; Amquinate;
Artefiene; Chloroquine; Chloroquine Hydrochloride; Cycloguanil
Pamoate; Enpiroline Phosphate; Halofantrine Hydrochloride;
Hydroxychloroquine Sulfate; Mefloquine Hydrochloride; Menoctone;
Primaquine Phosphate; Pyrimethamine; Quinine Sulfate; and
Tebuquine.
[0135] Antimicrobial: Aztreonam; Chlorhexidine Gluconate; Imidurea;
Lycetamine; Nibroxane; Pirazmonam Sodium; Propionic Acid;
Pyrithione Sodium; and Tigemonam Dicholine.
[0136] Antimigraine: Naratriptan Hydrochloride; Sergolexole
Maleate; Sumatriptan Succinate; and Zatosetron Maleate.
[0137] Antimitotic: Podofilox.
[0138] Antimycotic: Amorolfine.
[0139] Antinauseant: Buclizine Hydrochloride; and Cyclizine
Lactate.
[0140] Antineoplastic: Acivicin; Aclarubicin; Acodazole
Hydrochloride; Acronine; Adozelesin; Aldesleukin; Altretamine;
Ambomycin; Ametantrone Acetate; Amsacrine; Anastrozole;
Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa;
Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene
Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate;
Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone;
Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin
Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cisplatin;
Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine;
Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine;
Dexorinaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone;
Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene;
Droloxifene Citrate; Dromostanolone Propionate; Duazomycin;
Edatrexate; Eflornithine Hydrochloride; Elsamitrucin; Enloplatin;
Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole;
Esorubicin Hydrochloride; Estramustine; Estramustine Phosphate
Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide; Etoposide
Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine;
Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil;
Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine;
Gemcitabine Hydrochloride; Gold Au 198; Hydroxyurea; Idarubicin,
Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a;
Interferon Alfa-2b; Interferon Alfan3; Interferon Alfa-nl;
Interferon Beta-I a; Interferon Gamma-I b; Iproplatin; Irinotecan
Hydrochloride; Isotretinoin; Lanreotide Acetate; Letrozole;
Leuprolide Acetate; Liarozole Hydrochloride; Lometrexol Sodium;
Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine;
Mechlorethamine Hydrochloride; Megestrol Acetate; Melengestrol
Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate;
Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide;
Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin;
Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid;
Nocodazole; Nogalamvcin; Ormaplatin; Oxisuran; Paclitaxel;
Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate;
Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride;
Plicamycin; Plomestane; Porfimer Sodium; Prednimustine;
Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride;
Pyrazofurin; Riboprine; Rogletimide; Safingol Safingol
Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium;
Sparsomycin; Spiro germanium Hydrochloride; Spiromustine;
Spiroplatin; Streptonigrin; Streptozocin; Strontium Chloride Sr 89;
Sulofenur; Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur;
Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teroxirone;
Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofarin;
Tirapazamine; Topotecan Hydrochloride; Triciribine Phosphate;
Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozole
Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin;
Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine
Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine
Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine
Sulfate; Vorozole; Zeniplatin; Zinostatin; and Zorubicin
Hydrochloride.
[0141] Anti-neoplastic compounds (additional): 20-epi-1,25
Dihydroxyvitamin D3; 5-Ethynyluracil; Abiraterone; Acylfulvene;
Adecypenol; ALL-TK Antagonists; Ambamustine; Amidox; Amifostine;
Aminolevulinic Acid; Amrubicin; Anagrelide; Andrographolide;
Angiogenesis Inhibitors; Antagonist D; Antagonist G; Antarelix;
Antiandrogen, Prostatic Carcinoma; Anti-Dorsalizing Morphogenetic
Protein-I; Antiestrogen; Antineoplaston; Antisense
Oligonucleotides; Aphidicolin Glycinate; Apoptosis Gene Modulators;
Apoptosis Regulators; Apurinic Acid; Ara-CDP-DL-PTBA; Arginine
Deaminase; Asulacrine; Atamestane; Atrimustine; Axinastatin 1;
Axinastatin 2; Axinastatin 3; Azasetron; Azatoxin; Azatyrosine;
Baccatin III Derivatives; Balanol; BCR/ABL Antagonists;
Benzochlorins; Benzoylstaurosporine; Beta Lactam Derivatives;
Beta-Alethine; Betaclamycin B; Betulinic Acid; bFGF Inhibitor;
Bisantrene; Bisaziridinylspermine; Bisnafide; Bistratene A;
Breflate; Budotitane; Buthionine Sulfoximine; Calcipotriol;
Calphostin C; Camptothecin Derivatives; Canarypox IL-2;
Capecitabine; Carboxamide-Amino-Triazole; Carboxyamidotriazole;
CaRest MI; CARN 700, Cartilage Derived Inhibitor; Casein Kinase
Inhibitors (ICOS); Castanospermine; Cecropin B; Cetrorelix;
Chlorins; Chloroquinoxaline Sulfonamide; Cicaprost; Cis-Porphyrin;
Clomifene analogues; Collismycin A; Collismycin B; Combretastatin
A4; Combretastatin Analogue; Conagenin; Crambescidin 816;
Crisnatol; Cryptophycin 8; Cryptophycin A Derivatives; Curacin A;
Cyclopentanthraquinones; Cycloplatam; Cypemycin; Cytarabine
Ocfosfate; Cytolytic Factor; Cytostatin; Dacliximab;
Dehydrodidenmin B; Dexifosfamide; Dexverapamil; Didemnin B; Didox;
Diethylnorspennine; Dihydro Azacytidine; 9-Dihydrotaxol;
Dioxamycin; Diphenyl Spiromustine; Docosanol; Dolasetron;
Doxifluridine; Duocarmycin SA; Ebselen; Ecomustine; Edelfosine;
Edrecolomab; Eflomithine; Elemene; Emitefur; Epirubicin;
Estramustine Analogue; Estrogen Agonists; Estrogen Antagonists;
Exemestane; Fadrozole; Fiezelastine; Flavopiridol; Fluasterone;
Fludarabine; Fluorodaunorunicin Hydrochloride; Forfenimex;
Formestane; Fostriecin; Fotemustine; Gadolinium Texaphyrin; Gallium
Nitrate; Galocitabine; Ganirelix; Gelatinase Inhibitors;
Glutathione Inhibitors; Hepsulfam; Heregulin; Hexamethylene
Bisacetamide; Hypericin; Ibandronic acid; Idarubicin; Idoxifene;
Idramantone; Ilomastat; Imidazoacridones; Immunostimulant Peptides;
Insulin-Like Growth Factor-1 Receptor Inhibitor; Interferon
Agonists; Interferons; Interleukins; Iobenguane; Iododoxorubicin;
4-Ipomeanol; Irinotecan; Iroplact; Irsogladine; Isobengazole;
Isohomohalicondrin B; Itasetron; Jasplakinolide; Kahalalide F;
Lamellarin-N Triacetate; Lanreotide; Leinamycin; Lentinan Sulfate;
Leptolstatin; Leukemia Inhibiting Factor; Leukocyte Alpha
Interferon; Leuprolide+Estrogen+Progesterone; Leuprorelin;
Levamisole; Liarozole; Linear Polyamine Analogue; Lipophilic
Disaccharide Peptide; Lipophilic Platinum Compounds; Lissoclinamide
7; Lobaplatin; Lombricine; Lometrexol; Lonidamine; Losoxantrone;
Lurtotecan; Lutetium Texaphyrin; Lysofylline; Lytic Peptides;
Maitansine; Mannostatin A; Marimastat; Maspin; Matrilysin
Inhibitors; Matrix Metalloproteinase Inhibitors; Merbarone;
Meterelin; Methioninase; Metoclopramide; MIF Inhibitor;
Mifepristone; Miltefosine; Mirimostim; Mismatched Double Stranded
RNA; Mitoguazone; Mitolactol; Mitomycin analogues; Mitonafide;
Mitotoxin Fibroblast Growth Factor-Saporin; Mitoxantrone;
Mofarotene; Monoclonal Antibody, Human Chorionic Gonadotrophin;
Monophosphoryl Lipid A+Myobacterium Cell Wall Sk; Mopidamol;
Multiple Drug Resistance Gene Inhibitor; Multiple Tumor Suppressor
I-Based Therapy; Mustard Anticancer Agent; Mycaperoxide B;
Mycobacterial Cell Wall Extract; Myriaporone; NAcetyldinaline;
Nafarelin; Nagrestip; Naloxone+Pentazocine; Napavin; Naphterpin;
Nartograstim; Nedaplatin; Nemorubicin; Neridronic Acid; Neutral
Endopeptidase; Nilutamide; Nisamycin; Nitric Oxide Modulators;
Nitroxide Antioxidant; Nitrullyn; N-Substituted Benzamides;
06-Benzylguanine; Okicenone; Oligonucleotides; Onapristone;
Ondansetron; Oracin; Oral Cytokine Inducer; Osaterone; Oxaliplatin;
Oxaunomycin; Paclitaxel Analogues; Paclitaxel Derivatives;
Palauamine; Palmitoylrhizoxin; Pamidronic Acid; Panaxytriol;
Panomifene; Parabactin; Pazelliptine; Peldesine; Pentostatin;
Pentrozole; Perflubron; Perilly Alcohol; Phenazinomycin;
Phenylacetate; Phosphatase Inhibitors; Picibanil; Pilocarpine
Hydrochloride; Pirarubicin; Piritrexim; Placetin A; Placetin B;
Plasminogen Activator Inhibitor; Platinum Complex; Platinum
Compounds; Platinum-Triamine Complex; Propyl Bis-Acridone;
Prostaglandin J2; Proteasome Inhibitors; Protein A-Based Immune
Modulator; Protein Kinase C Inhibitor; Protein Kinase C Inhibitors,
Microalgal; Protein Tyrosine Phosphatase Inhibitors; Purine
Nucleoside Phosphorylase Inhibitors; Purpurins; Pyrazoloacridine;
Pyridoxylated Hemoglobin Polyoxyethylene Conjugate; Raf
Antagonists; Raltitrexed; Ramosetron; Ras Famesyl Protein
Transferase Inhibitors; Ras Inhibitors; Ras-GAP Inhibitor;
Retelliptine Demethylated; Rhenium, Re 186 Etidronate; Rhizoxin;
Ribozymes; RH Retinamide; Rohitukine; Romurtide; Roquinimex;
Rubiginone B 1; Ruboxyl; Safingol; Saintopin; SarCNU; Sarcophytol
A; Sdi 1 Mimetics; Senescence Derived Inhibitor 1; Sense
Oligonucleotides; Signal Transduction Inhibitors; Signal
Transduction Modulators; Single Chain Antigen Binding Protein;
Sizofiran; Sobuzoxane; Sodium Borocaptate; Sodium Phenylacetate;
Solverol; Somatomedin Binding Protein; Sonermin; Sparfosic Acid;
Spicamycin D; Splenopentin; Spongistatin 1; Squalamine; Stem Cell
Inhibitor; Stem-Cell Division Inhibitors; Stipiamide; Stromelysin
Inhibitors; Sulfinosine; Superactive Vasoactive Intestinal Peptide
Antagonist; Suradista; Suramin; Swainsonine; Synthetic
Glycosaminoglycans; Tallimustine; Tamoxifen Methiodide;
Tauromustine; Tellurapyrylium; Telomerase Inhibitors; Temozolomide;
Tetrachlorodecaoxide; Tetrazomine; Thaliblastine; Thalidomide;
Thiocoraline; Thrombopoietin; Thrombopoietin Mimetic; Thymalfasin;
Thymopoietin Receptor Agonist; Thymotrinan; Thyroid Stimulating
Hormone; Tin Ethyl Etiopurpurin; Titanocene Dichloride; Topotecan;
Topsentin; Toremifene; Totipotent Stem Cell Factor; Translation
Inhibitors; Triacetyluridine; Triciribine; Tropisetron;
Turosteride; Tyrosine Kinase Inhibitors; Tyrphostins; UBC
Inhibitors; Ubenimex; Urogenital Sinus-Derived Growth Inhibitory
Factor; Urokinase Receptor Antagonists; Variolin B; Vector system,
Erythrocyte Gene Therapy; Velaresol; Veramine; Verdins;
Vinorelbine; Vinxaltine; Vitaxin; Zilascorb; and Zinostatin
Stimalamer.
[0142] Antineutropenic: Filgrastim; Lenograstim; Molgramostim;
Regramostim; and Sargramostim.
[0143] Antiobsessional agent: Fluvoxamine Maleate.
[0144] Antiparasitic: Abamectin; Clorsulon; and Ivermectin.
[0145] Antiparkinsonian: Benztropine Mesylate; Biperiden; Biperiden
Hydrochloride; Biperiden Lactate; Carbidopa-Levodopa; Carmantadine;
Ciladopa Hydrochloride; Dopamantine; Ethopropazine Hydrochloride;
Lazabemide; Levodopa; Lometraline Hydrochloride; Mofegiline
Hydrochloride; N axagolide Hydrochloride; Pareptide Sulfate;
Procyclidine Hydrochloride; Ropinirole Hydrochloride; and
Tolcapone.
[0146] Antiperistaltic: Difenoximide Hydrochloride; Difenoxin;
Fluperamide; Lidamidine Hydrochloride; Loperamide Hydrochloride;
Malethamer; Nufenoxole; Paregoric.
[0147] Antipneumocystic: Atovaquone.
[0148] Antiproliferative agent: Piritrexim Isethionate.
[0149] Antiprostatic hypertrophy: Sitogluside.
[0150] Antiprotozoal: Amodiaquine; Azanidazole; Banmidazole;
Camidazole; Chlortetracycline Bisulfate Chlortetracycline
Hydrochloride; Flubendazole; Flunidazole; Halofuginone
Hydrobromide; Imidocarb Hydrochloride; Ipronidazole; Misonidazole;
Moxnidazole; Nitarsone; Ronidazole; Sulnidazole; and
Tinidazole.
[0151] Antipruritic: Methdilazine; Methdilazine Hydrochloride; and
Trimeprazine Tartrate.
[0152] Antipsoriatic: Acitretin; Anthralin; Azaribine;
Calcipotriene; Cycloheximide; Enazadrem Phosphate; Etretinate;
Liarozole Fumarate; Lonapalene; and Tepoxalin.
[0153] Antipsychotic: Acetophenazine Maleate; Alentemol
Hydrobromide; Alpertine; Azaperone; Batelapine Maleate; Benperidol;
Benzindopyrine Hydrochloride; Brofoxine; Bromperidol; Bromperidol
Decanoate; Butaclamol Hydrochloride; Butaperazine; Butaperazine
Maleate; Carphenazine Maleate; Carvotroline Hydrochloride;
Chlorprothixene; Cinperene; Cintriamide; Clomacran Phosphate;
Clopenthixol; Clopimozide; Clopipazan Mesylate; Cloroperone
Hydrochloride; Clothiapine; Clothixamide Maleate; Clozapine;
Cyclophenazine Hydrochloride; Droperidol; Etazolate Hydrochloride;
Fenimide; Flucindole; Flumezapine; Fluphenazine Decanoate;
Fluphenazine Enanthate; Fluphenazine Hydrochloride; Fluspiperone;
Fluspirilene; Flutroline; Gevotroline Hydrochloride; Halopemide;
Haloperidol; Haloperidol Decanoate; Iloperidone; Imidoline
Hydrochloride; Lenperone; Mazapertine Succinate; Mesoridazine;
Mesoridazine Besylate; Metiapine; Milenperone; Milipertine;
Molindone Hydrochloride; Naranol Hydrochloride; Neflumozide
Hydrochloride; Ocaperidone; Olanzapine; Oxiperomide; Penfluridol;
Pentiapine Maleate; Perphenazine; Pimozide; Pinoxepin
Hydrochloride; Pipamperone; Piperacetazine; Pipotiazine Palmitate;
Piquindone Hydrochloride; Promazine Hydrochloride; Remoxipride;
Remoxipride Hydrochloride; Rimcazole Hydrochloride; Seperidol
Hydrochloride; Sertindole; Setoperone; Spiperone; Thioridazine;
Thioridazine Hydrochloride; Thiothixene; Thiothixene Hydrochloride;
Tioperidone Hydrochloride; Tiospirone Hydrochloride;
Trifluoperazine Hydrochloride; Trifluperidol; Triflupromazine;
Triflupromazine Hydrochloride; and Ziprasidone Hydrochloride.
[0154] Antirheumatic: Auranofin; Aurothioglucose; Bindarit;
Lobenzarit Sodium; Phenylbutazone; Pirazolac; Prinomide
Tromethamine; and Seprilose.
[0155] Antischistosomal: Becanthone Hydrochloride; Hycanthone;
Lucanthone Hydrochloride; Niridazole; Oxamniquine; Pararosaniline
Pamoate; and Teroxalene Hydrochloride.
[0156] Antiseborrheic: Chloroxine; Piroctone; Piroctone Olamine;
and Resorcinol Monoacetate.
[0157] Antisecretory: Arbaprostil; Deprostil; Fenoctimine Sulfate;
Octreotide; Octreotide Acetate; Omeprazole Sodium; Rioprostil;
Trimoprostil.
[0158] Antispasmodic: Stilonium Iodide; Tizanidine
Hydrochloride.
[0159] Antithrombotic: Anagrelide Hydrochloride; Dalteparin Sodium;
Danaparoid Sodium; Dazoxiben Hydrochloride; Efegatran Sulfate;
Enoxaparin Sodium; Ifetroban; Ifetroban Sodium; and
Trifenagrel.
[0160] Antitussive: Benzonatate; Butamirate Citrate; Chlophedianol
Hydrochloride; Codeine Polistirex; Codoxime; Dextromethorphan;
Dextromethorphan Hydrobromide; Dextromethorphan Polistirex; Ethyl
Dibunate; Guaiapate; Hydrocodone Bitartrate; Hydrocodone
Polistirex; Levopropoxyphene Napsylate; Noscapine; Pemerid Nitrate;
Pipazethate; and Suxemerid Sulfate.
[0161] Anti-ulcerative: Aceglutamide Aluminum; Cadexomer Iodine;
Cetraxate Hydrochloride; Enisoprost; Isotiquimide; Lansoprazole;
Lavoltidine Succinate; Misoprostol; Nizatidine; Nolinium Bromide;
Pantoprazole; Pifarnine; Pirenzepine Hydrochloride; Rabeprazole
Sodium; Remiprostol; Roxatidine Acetate Hydrochloride; Sucralfate;
Sucrosofate Potassium; and Tolimidone.
[0162] Anti-urolithic: Cysteamine; Cysteamine Hydrochloride; and
Tricitrates.
[0163] Antiviral: Acemannan; Acvclovir; Acyclovir Sodium; Adefovir;
Alovudine; Alvircept Sudotox; Amantadine Hydrochloride; Aranotin;
Arildone; Atevirdine Mesylate; Avridine; Cidofovir; Cipamfylline;
Cytarabine Hydrochloride; Delavirdine Mesylate; Desciclovir;
Didanosine; Disoxaril; Edoxudine; Enviradene; Enviroxime;
Famciclovir; Famotine Hydrochloride; Fiacitabine; Fialuridine;
Fosarilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir;
Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; Lobucavir;
Memotine Hydrochloride; Methisazone; Nevirapine; Penciclovir;
Pirodavir; Ribavirin; Rimantadine Hydrochloride; Saquinavir
Mesylate; Somantadine Hydrochloride; Sorivudine; Statolon;
Stavudine; Tilorone Hydrochloride; Trifluridine; Valacyclovir
Hydrochloride; Vidarabine; Vidarabine Phosphate; Vidarabine Sodium
Phosphate; Viroxime; Zalcitabine; Zidovudine; and Zinviroxime.
[0164] Appetite suppressant: Dexfenfluramine Hydrochloride;
Phendimetrazine Tartrate; and Phentermine Hydrochloride.
[0165] Benign prostatic hyperplasia therapy agent: Tamsulosin
Hydrochloride.
[0166] Blood glucose regulators: Acetohexamide and Glipizide;
Chloropropamide; and Human insulin.
[0167] Bone resorption inhibitor: Alendronate Sodium; Etidronate
Disodium; and Pamidronate Disodium.
[0168] Bronchodilator: Albuterol; Albuterol Sulfate; Azanator
Maleate; Bamifylline Hydrochloride; Bitolterol Mesylate; Butaprost;
Carbuterol Hydrochloride; Clorprenaline Hydrochloride; Colterol
Mesylate; Doxaprost; Doxofylline; Dyphylline; Enprofylline;
Ephedrine; Ephedrine Hydrochloride; Fenoterol; Fenprinast
Hydrochloride; Guaithylline; Hexoprenaline Sulfate; Hoquizil
Hydrochloride; Ipratropium Bromide; Isoetharine; Isoetharine
Hydrochloride; Isoetharine Mesylate; Isoproterenol Hydrochloride;
Isoproterenol Sulfate; Metaproterenol Polistirex; Metaproterenol
Sulfate; Nisbuterol Mesylate; Oxtriphylline; Picumeterol Fumarate;
Piquizil Hydrochloride; Pirbuterol Acetate; Pirbuterol
Hydrochloride; Procaterol Hydrochloride; Pseudoephedrine Sulfate;
Quazodine; Quinterenol Sulfate; Racepinephrine; Racepinephrine
Hydrochloride; Reproterol Hydrochloride; Rimiterol Hydrobromide;
Salmeterol; Salmeterol Xinafoate; Soterenol Hydrochloride;
Sulfonterol Hydrochloride; Suloxifen Oxalate; Terbutaline Sulfate;
Theophylline; Xanoxate Sodium; Zindotrine; and Zinterol
Hydrochloride.
[0169] Carbonic anhydrase inhibitor: Acetazolamide; Acetazolamide
Sodium; Dichlorophenamide; Dorzolamide Hydrochloride;
Methazolamide; and Sezolamide Hydrochloride.
[0170] Cardiac depressant: Acecainide Hydrochloride; Acetylcholine
Chloride; Actisomide; Adenosine; Amiodarone; Aprindine; Aprindine
Hydrochloride; Artilide Fumarate; Azimilide Dihydrochloride;
Bidisomide; Bucainide Maleate; Bucromarone; Capobenate Sodium;
Capobenic Acid; Cifenline; Cifenline Succinate; Clofilium
Phosphate; Disobutamide; Disopyramide; Disopyramide Phosphate;
Dofetilide; Drobuline; Edifolone Acetate; Emilium Tosylate;
Encainide Hydrochloride; Flecainide Acetate; Ibutilide Fumarate;
Indecainide Hydrochloride; Ipazilide Fumarate; Lorajmine
Hydrochloride; Lorcainide Hydrochloride; Meobentine Sulfate;
Mexiletine Hydrochloride; Modecainide; Moricizine; Oxiramide;
Pirmenol Hydrochloride; Pirolazamide; Pranolium Chloride;
Procainamide Hydrochloride; Propafenone Hydrochloride; Pyrinoline;
Quindonium Bromide; Quinidine Gluconate; Quinidine Sulfate;
Recainam Hydrochloride; Recainam Tosylate; Risotilide
Hydrochloride; Ropitoin Hydrochloride; Sematilide Hydrochloride;
Suricainide Maleate; Tocainide; Tocainide Hydrochloride; and
Transcainide.
[0171] Cardioprotectant: Dexrazoxane; and Draflazine.
[0172] Cardiotonic agent: Actodigin; Amrinone; Bemoradan;
Butopamine; Carbazeran; Carsatrin Succinate; Deslanoside;
Digitalis; Digitoxin; Digoxin; Dobutamine; Dobutamine
Hydrochloride; Dobutamine Lactobionate; Dobutamine Tartrate;
Enoximone; Imazodan Hydrochloride; Indolidan; Isomazole
Hydrochloride; Levdobutamine Lactobionate; Lixazinone Sulfate;
Medorinone; Milrinone; Pelrinone Hydrochloride; Pimobendan;
Piroximone; Prinoxodan; Proscillaridin; Quazinone; Tazolol
Hydrochloride; and Vesnarinone.
[0173] Cardiovascular agent: Dopexamine; and Dopexamine
Hydrochloride.
[0174] Cerebral ischemia agent: Dextrorphan Hydrochloride.
[0175] Choleretic: Dehydrocholic Acid; Fencibutirol; Hymecromone;
Piprozolin; Sincalide; Tocamphyl.
[0176] Cholinergic: Aceclidine; Bethanechol Chloride; Carbachol;
Demecarium Bromide; Dexpanthenol; Echothiophate Iodide;
Isoflurophate; Methacholine Chloride; Neostiamine Methylsulfate;
Neostigmine Bromide; Physostigmine; Physostigmine Salicylate;
Physostigmine Sulfate; Pilocarpine Nitrate; and Pyridostigmine
Bromide.
[0177] Cholinergic agonist: Xanomeline; and Xanomeline
Tartrate.
[0178] Cholinesterase Deactivator: Obidoxime Chloride; Pralidoxime
Chloride; Pralidoxime Iodide; and Pralidoxime Mesylate.
[0179] Coccidiostat: Arprinocid; Narasin; Semduramicin; and
Semduramicin Sodium.
[0180] Cognition adjuvant: Ergoloid Mesylates; Piracetam;
Pramiracetam Hydrochloride; Pramiracetam Sulfate; and Tacrine
Hydrochloride.
[0181] Cognition enhancer: Besipirdine Hydrochloride; Linopirdine;
and Sibopirdine.
[0182] Contrast Media: Barium Sulfate; Diatrizoate Sodium;
Erythrosine Sodium; Iopanoic Acid; Ipodate Calcium; Metyrapone; and
Tyropanoate Sodium.
[0183] Diagnostic aid: Aminohippurate Sodium; Anazolene Sodium;
Arclofenin; Bentiromide; Benzylpenicilloyl Polylysine; Butedronate
Tetrasodium; Butilfenin; Coccidioidin; Corticorelin Ovine
Triflutate; Corticotropin Zinc Hydroxide; Corticotropin,
Repository; Diatrizoate Meglumine; Diatrizoic Acid; Diphtheria
Toxin for Schick Test; Disofenin; Ethiodized Oil; Etifenin;
Exametazime; Ferristenc; Ferumoxides; Ferumoxsil; Fluorescein;
Fluorescein Sodium; Gadobenate Dimeglumine; Gadodiamide;
Gadopentetate Dimegiumine; Gadoteridol; Gadoversetamide;
Histoplasmin; Impromidine Hydrochloride; Indigotindisulfonate
Sodium; Indocyanine Green; Iobenguane Sulfate I 123; Iobenzamic
Acid; Iocarmate Meglumine; Iocarmic Acid; Iocetamic Acid; Iodamide;
Iodamide Megiumine; Iodipamide Meglumine; Iodixanol; Iodoxamate
Meglumine; Iodoxamic Acid; Ioglicic Acid; Ioglucol; Ioglucomide;
Ioglycamic Acid; Iogulamide; Iohexol; Iomeprol; Iopamidol;
Iopentol; Iophendylate; Ioprocemic Acid; Iopronic Acid; Iopydol;
Iopydone; Iosefamic Acid; Ioseric Acid; Iosulamide Meglumine;
Iosumetic Acid; Iotasul; Iotetric Acid; Iothalamate Meglumine;
Iothalamate Sodium; Iothalamic Acid; Iotrolan; Iotroxic Acid;
Ioversol; Ioxagiate Sodium; Ioxaglate Meglumine; Ioxaglic Acid;
Ioxilan; Ioxotrizoic Acid; Ipodate Sodium; Iprofenin; Isosulfan
Blue; Leukocyte Typing Serum; Lidofenin; Mebrofenin; Meglumine;
Metrizamide; Metrizoate Sodium; Metyrapone Tartrate; Mumps Skin
Test Antigen; Pentetic Acid; Propyliodone; Quinaldine Blue; Schick
Test Control; Sermorelin Acetate; Sodium Iodide I 123; Sprodiamide;
Stannous Pyrophosphate; Stannous Sulfur Colloid; Succimer;
Teriparatide Acetate; Tetrofosmin; Tolbutamide Sodium; Tuberculin;
and Xylose.
[0184] Diuretic: Ambuphylline; Ambuside; Amiloride Hydrochloride;
Azolimine; Azosemide; Brocrinat; Bumetanide; Chlorothiazide;
Chlorthalidone; Clazolimine; Clorexolone; Ethacrynate Sodium;
Ethacrynic Acid; Etozolin; Fenquizone; Furosemide;
Hydrochlorothiazide; Isosorbide; Mannitol Mefruside; Ozolinone;
Piretanide; Spiroxasone; Torsemide; Triamterene; Triflocin; and
Urea.
[0185] Dopaminergic agent: Ibopamine.
[0186] Ectoparasiticide: Nifluridide; Permethrin.
[0187] Emetic: Apomorphine Hydrochloride.
[0188] Enzyme inhibitor: 30 Polignate Sodium; Acetohydroxamic Acid;
Alrestatin Sodium; Aprotinin; Benazepril Hydrochloride;
Benazeprilat; Benurestat; Bromocriptine; Bromocriptine Mesylate;
Cilastatin Sodium; Flurofamide; Lergotrile; Lergotrile Mesylate;
Levcycloserine; Libenzapril; Pentopril; Pepstatin; Perindopril;
Sodium Amylosulfate; Sorbinil; Spirapril Hydrochloride;
Spiraprilat; Taleranol; Teprotide; Tolfamide; and Zofenopril
Calcium.
[0189] Estrogen: Chlorotrianisene; Dienestrol; Diethylstilbestrol;
Diethylstilbestrol Diphosphate; Equilin; Estradiol; Estradiol
Cypionate; Estradiol Enanthate; Estradiol Undecylate; Estradiol
Valerate; Estrazinol Hydrobromide; Estriol; Estrofurate; Estrogens,
Conjugated; Estrogens, Esterified; Estrone; Estropipate; Ethinyl
Estradiol; Fenestrel; Mestranol; Nylestriol; and Quinestrol.
[0190] Fibrinolytic: Anistreplase; Bisobrin Lactate; and
Brinolase.
[0191] Free oxygen radical scavenger: Pegorgotein.
[0192] Gastric Acid Suppressant: Lansoprazole, Pantoprazole and
Omeprazole.
[0193] Gastrointestinal Motility agents: Cisapride.
[0194] Glucocorticoid: Amcinonide; Beclomethasone Dipropionate;
Betamethasone; Betamethasone Acetate; Betamethasone Benzoate;
Betamethasone Dipropionate; Betamethasone Sodium Phosphate;
Betamethasone Valerate; Carbenoxolone Sodium; Clocortolone Acetate;
Clocortolone Pivalate; Cloprednol; Corticotropin; Cortisone
Acetate; Cortivazol; Descinolone Acetonide; Dexamethasone;
Dexamethasone Sodium Phosphate; Diflucortolone; Diflucortolone
Pivalate; Flucloronide; Flumethasone; Flumethasone Pivalate;
Flunisolide; Fluocinolone Acetonide; Fluocinonide; Fluocortolone;
Fluocortolone Caproate; Fluorometholone; Fluperolone Acetate;
Fluprednisolone; Fluprednisolone Valerate; Flurandrenolide;
Formocortal; Hydrocortisone; Hydrocortisone Acetate; Hydrocortisone
Buteprate; Hydrocortisone Butyrate; Hydrocortisone Sodium
Phosphate; Hydrocortisone Sodium Succinate; Hydrocortisone
Valerate; Medrysone; Methylprednisolone Acetate; Methylprednisolone
Sodium Phosphate; Methylprednisolone Sodium Succinate; Nivazol;
Paramethasone Acetate; Prednicarbate; Prednisolone; Prednisolone
Acetate; Prednisolone Hemisuccinate; Prednisolone Sodium Succinate;
Prednisolone Tebutate; Prednisone; Prednival; Ticabesone
Propionate; Tralonide; Triamcinolone; Triamcinolone Acetonide;
Triamcinolone Acetonide Sodium; Triamcinolone Diacetate; and
Triamcinolone Hexacetonide.
[0195] Gonad-stimulating principle: Buserelin Acetate; Clomiphene
Citrate; Ganirelix Acetate; Gonadorelin Acetate; Gonadorelin
Hydrochloride; Gonadotropin, Chorionic; and Menotropins.
[0196] Hormone: 17 Alpha Dihydroequilenin; 17 Alpha Dihydroequilin;
17 Alpha Estradiol; 17 Beta Estradiol; 17 Hydroxy Progesterone;
Androstenedione; Clomiphene; Cosyntropin; Dehydroepiandrosterone;
Dihydroestosterone; Equilenin; Ethyndiol; Follicle Regulatory
Protein; Follicle Stimulating Hormone; Folliculostatin;
Gonadoctrinins; Gonadorelin; Gonadotropins; Han Memopausal
Gonadotropins; Human Chorionic Gonadotropin; Insulin Growth Factor;
Leuprolide; Levonorgestrel; Luteinizing hormone; Luteinizing
Hormone Releasing Hormone and Analogs; Medroxyprogesterone;
Megestrol; Metogest; Norethindrone; Norethynodrel; Norgestrel;
Oocyte Maturation Inhibitor; Oxytocin; Pituitary, Posterior;
Progesterone; Relaxin; Seractide Acetate; Somalapor; Somatrem;
Somatropin; Somenopor; Somidobove; Tamoxifen; Urofollitropin; and
Vasopressin.
[0197] Hypocholesterolemic: Lifibrol.
[0198] Hypoglycemic: Darglitazone Sodium; and Glimepiride.
[0199] Hypolipidemic: Azalanstat Dihydrochloride; Colestolone;
Surfomer; and Xenalipin.
[0200] Hypotensive: Viprostol.
[0201] Immunizing agent: Antirabies Serum; Antivenin; Antivenin
(Crotalidae) Polyvalent; BCG Vaccine; Botulism Antitoxin; Cholera
Vaccine; Diphtheria Antitoxin; Diphtheria Toxoid; Diphtheria Toxoid
Adsorbed; Globulin, Immune; Hepatitis B Immune Globulin; Hepatitis
B Virus Vaccine Inactivated; Influenza Virus Vaccine; Measles Virus
Vaccine Live; Meningococcal Polysaccharide Vaccine Group A;
Meningococcal Polysaccharide Vaccine Group C; Mumps Virus Vaccine
Live; Pertussis Immune Globulin; Pertussis Vaccine; Pertussis
Vaccine Adsorbed; Plague Vaccine; Poliovirus Vaccine Inactivated;
Poliovirus Vaccine Live Oral; Rabies Immune Globulin; Rabies
Vaccine; Rho(D) Immune Globulin; Rubella Virus Vaccine Live;
Smallpox Vaccine; Tetanus Antitoxin; Tetanus Immune Globulin;
Tetanus Toxoid; Tetanus Toxoid Adsorbed; Typhoid Vaccine; Vaccinia
Immune Globulin; Varicella Zoster Immune Globulin; and Yellow Fever
vaccine.
[0202] Immunomodulator: Dimepranol Acedoben; Imiquimod; Interferon
Beta-1b; Lisofylline; Mycophenolate Mofetil; and Prczatide Copper
Acetate.
[0203] Immunoregulator: Azarole; Fanetizole Mesylate; Frentizole;
Oxamisole Hydrochloride; Ristianol Phosphate; Thymopentin; and
Tilomisole.
[0204] Immunostimulant: Loxoribine; and Teceleukin.
[0205] Immunosuppressant: Azathioprine; Azathioprine Sodium;
Cyclosporine; Daltroban; Gusperimus Trihydrochloride; Sirolimus;
and Tacrolimus.
[0206] Impotence therapy adjunct: Delequamine Hydrochloride.
[0207] Inhibitor: Acarbose; Atorvastatin Calcium; Benserazide;
Brocresine; Carbidopa; Clavulanate Potassium; Dazmegrel;
Docebenone; Epoprostenol; Epoprostenol Sodium; Epristeride;
Finasteride; Flurbiprofen Sodium; Furegrelate Sodium; Lufironil;
Miglitol; Orlistat; Pimagedine Hydrochloride; Pirmagrel;
Ponalrestat; Ridogrel; Sulbactam Benzathine; Sulbactam Pivoxil;
Sulbactam Sodium; Suronacrine Maleate; Tazobactam; Tazobactam
Sodium; Ticlopidine Hydrochloride; Tirilazad Mesylate; Tolrestat;
Velnacrine Maleate; Zifrosilone; and Zileuton.
[0208] Keratolytic: Alcloxa; Aldioxa; Dibenzothiophene; Etarotene;
Motretinide-I Picotrin Diolamine; Salicylic Acid; Sumarotene;
Tazarotene; Tetroquinone; and Tretinoin.
[0209] LHRH agonist: Deslorelin; Goserelin; Histrelin; Lutrelin
Acetate; and Nafarelin Acetate.
[0210] Liver disorder treatment: Malotilate.
[0211] Luteolysin: Fenprostalene.
[0212] Memory adjuvant: Dimoxamine Hydrochloride; and
Ribaminol.
[0213] Mental performance enhancer: Aniracetam.
[0214] Mood regulator: Fengabine.
[0215] Mucolytic: Acetylcysteine; Carbocysteine; and Domiodol.
[0216] Mucosal Protective agents: Misoprostol (Cytotec).
[0217] Mydriatic: Berefrine.
[0218] Nasal decongestant: Nemazoline Hydrochloride;
Pseudoephedrine Polistirex.
[0219] Neuroleptic: Duoperone Fumarate; and Risperidone.
[0220] Neuromuscular blocking agent: Atracurium Besylate;
Cisatracurium Besylate; Doxacurium Chloride; Gallamine
Triethiodide; Metocurine Iodide; Mivacurium Chloride; Pancuronium
Bromide; Pipecuronium Bromide; Rocuronium Bromide; Succinylcholine
Chloride; Tubocurarine Chloride; and Vecuronium Bromide.
[0221] Neuroprotective: Dizocilpine Maleate.
[0222] NMDA antagonist: Selfotel.
[0223] Non-hormonal sterol derivative: Pregnenolone Succinate.
[0224] Oxytocic: Carboprost; Carboprost Methyl; Carboprost
Tromethamine; Dinoprost; Dinoprost Tromethamine; Dinoprostone;
Ergonovine Maleate; Meteneprost; Methylergonovine Maleate; and
Sparteine Sulfate.
[0225] Paget's disease agents: Tiludronate Disodium.
[0226] Progestin: Algestone Acetophenide; Amadinone Acetate;
Anagestone Acetate; Chlormadinone Acetate; Cingestol; Clogestone
Acetate; Clomegestone Acetate; Desogestrel; Dimethisterone;
Dydrogesterone; Ethynerone; Ethynodiol Diacetate; Etonogestrel;
Flurogestone Acetate; Gestaclone; Gestodene; Gestonorone Caproate;
Gestrinone; Haloprogesterone; Hydroxyprogesterone Caproate;
Lynestrenol; Medrogestone; Medroxyprogesterone Acetate; Methynodiol
Diacetate; Norethindrone Acetate; Norgestimate; Norgestomet;
Oxogestone Phenpropionate; Quingestanol Acetate; Quingestrone; and
Tigestol.
[0227] Prostaglandin: Cloprostenol Sodium; Fluprostenol Sodium;
Gemeprost; Prostalene; and Sulprostone.
[0228] Prostate growth inhibitor: Pentomone.
[0229] Prothyrotropin: Protirelin.
[0230] Psychotropic: Minaprine.
[0231] Radioactive agent: Fibrinogen I 125; Fludeoxyglucose F 18;
Fluorodopa F 18; Insulin I 125; Insulin I 131; Iobenguane I 123;
Iodipamide Sodium I 131; Iodoantipyrine I 131; Iodocholesterol I
131; Iodohippurate Sodium I 123; Iodohippurate Sodium I 125;
Iodohippurate Sodium I 131; Iodopyracet I 125; Iodopyracet I 131;
Iofetamine Hydrochloride I 123; Iomethin I 125; Iomethin I 131;
Iothalamate Sodium I 125; Iothalamate Sodium I 131; Iotyrosine I
131; Liothyronine I 125; Liothyronine I 131; Merisoprol Acetate Hg
197; Merisoprol Acetate Hg 203; Merisoprol Hg 197; Selenomethionine
Se 75; Technetium Tc 99m Antimony Trisulfide Colloid; Technetium Tc
99m Bicisate; Technetium Tc 99m Disofenin; Technetium Tc 99m
Etidronate; Technetium Tc 99m Exametazime; Technetium Tc 99m
Furifosmin; Technetium Tc 99m Gluceptate; Technetium Tc 99m
Lidofenin; Technetium Tc 99m Mebrofenin; Technetium Tc 99m
Medronate; Technetium Tc 99m Medronate Disodium; Technetium Tc 99m
Mertiatide; Technetium Tc 99m Oxidronate; Technetium Tc 99m
Pentetate; Technetium Tc 99m Pentetate Calcium Trisodium;
Technetium Tc 99m Sestamibi; Technetium Tc 99m Siboroxime;
Technetium Tc 99m Succimer; Technetium Tc 99m Sulfur Colloid;
Technetium Tc 99m Teboroxime; Technetium Tc 99m Tetrofosmin;
Technetium Tc 99m Tiatide; Thyroxine I 125; Thyroxine 1131;
Tolpovidone 1131; Triolein 1125; and Triolein 1131.
[0232] Regulator: Calcifediol; Calcitonin; Calcitriol; Clodronic
Acid; Dihydrotachysterol; Etidronic Acid; Oxidronic Acid;
Piridronate Sodium; Risedronate Sodium; and Secalciferol.
[0233] Relaxant: Adiphenine Hydrochloride; Alcuronium Chloride;
Aminophylline; Azumolene Sodium; Baclofen; Benzoctamine
Hydrochloride; Carisoprodol; Chlorphenesin Carbamate;
Chlorzoxazone; Cinflumide; Cinnamedrine; Clodanolene;
Cyclobenzaprine Hydrochloride; Dantrolene; Dantrolene Sodium;
Fenalamide; Fenyripol Hydrochloride; Fetoxylate Hydrochloride;
Flavoxate Hydrochloride; Fletazepam; Flumetramide; Hexafluorenium
Bromide; Isomylamine Hydrochloride; Lorbamate; Mebeverine
Hydrochloride; Mesuprine Hydrochloride; Metaxalone; Methixene
Hydrochloride; Methocarbamol; Nafomine Malate; Nelezaprine Maleate;
Papaverine Hydrochloride; Pipoxolan Hydrochloride; Quinctolate;
Ritodrine; Ritodrine Hydrochloride; Rolodine; Theophylline Sodium
Glycinate; Thiphenamil Hydrochloride; and Xilobam.
[0234] Repartitioning agent: Cimaterol.
[0235] Scabicide: Amitraz; Crotamiton.
[0236] Sclerosing agent: Ethanolamine Oleate; Morrhuate Sodium;
Tribenoside.
[0237] Sedative: Propiomazine.
[0238] Sedative-hypnotic: Allobarbital; Alonimid; Alprazolam;
Amobarbital Sodium; Bentazepam; Brotizolam; Butabarbital;
Butabarbital Sodium; Butalbital; Capuride; Carbocloral; Chloral
Betaine; Chloral Hydrate; Chlordiazepoxide Hydrochloride;
Cloperidone Hydrochloride; Clorethate; Cyprazepam; Dexclamol
Hydrochloride; Diazepam; Dichloralphenazone; Estazolam
Ethchlorvynol; Etomidate; Fenobam; Flunitrazepam; Fosazepam;
Glutethimide; Halazepam; Lon-netazepam; Mecloqualone; Meprobamate;
Methaqualone; Midaflur; Paraldehyde; Pentobarbital; Pentobarbital
Sodium; Perlapine; Prazepam; Quazepam; Reclazepam; Roletamide;
Secobarbital; Secobarbital Sodium; Suproclone; Tracazolate;
Trepipam Maleate; Triazolam; Tricetamide; Triclofos Sodium;
Trimetozine; Uldazepam; Zaleplon; Zolazepam Hydrochloride; and
Zolpidem Tartrate.
[0239] Selective adenosine A1 antagonist: Apaxifylline.
[0240] Serotonin antagonist: Altanserin Tartrate; Amesergide;
Ketanserin; and Ritanserin. Serotonin inhibitor: Cinanserin
Hydrochloride; Fenclonine; Fonazine Mesylate; and Xylamidine
Tosylate.
[0241] Serotonin receptor antagonist: Tropanserin
Hydrochloride.
[0242] Steroid: Dexamethasone Acefurate; and Mometasone
Furoate.
[0243] Stimulant: Amfonelic Acid; Amphetamine Sulfate; Ampyzine
Sulfate; Arbutamine Hydrochloride; Azabon; Caffeine; Ceruletide;
Ceruletide Diethylamine; Dazopride Fumarate; Dextroamphetamine;
Dextroamphetamine Sulfate; Difluanine Hydrochloride; Dimefline
Hydrochloride; Doxapram Hydrochloride; Ethamivan; Etryptamine
Acetate; Fenethylline Hydrochloride; Flubanilate Hydrochloride;
Flurothyl; Histamine Phosphate; Indriline Hydrochloride;
Mefexamide; Methamphetamine Hydrochloride; Methylphenidate
Hydrochloride; Pemoline; Pyrovalerone Hydrochloride; Xamoterol; and
Xamoterol Fumarate.
[0244] Suppressant: Amflutizole; Colchicine; Tazofelone.
[0245] Symptomatic multiple sclerosis: Fampridine.
[0246] Synergist: Proadifen Hydrochloride.
[0247] Thyroid hormone: Levothyroxine Sodium; Liothyronine Sodium;
and Liotrix.
[0248] Thyroid inhibitor: Methimazole; and Propylthiouracil.
[0249] Thyromimetic: Thyromedan Hydrochloride.
[0250] Tranquilizer: Bromazepam; Buspirone Hydrochloride;
Chlordiazepoxide; Clazolam; Clobazam; Clorazepate Dipotassium;
Clorazepate Monopotassium; Demoxepam; Dexmedetomidine; Enciprazine
Hydrochloride; Gepirone Hydrochloride; Hydroxyphenamate;
Hydroxyzine Hydrochloride; Hydroxyzine Pamoate; Ketazolam;
Lorazepam; Lorzafone; Loxapine; Loxapine Succinate; Medazepam
Hydrochloride; Nabilone; Nisobamate; Oxazepam; Pentabamate;
Pirenperone; Ripazepam; Rolipram; Sulazepam; Taciamine
Hydrochloride; Temazepam; Triflubazam; Tybamate; and
Valnoctamide.
[0251] Unstable angina agents: Tirofiban Hydrochloride.
[0252] Uricosuric: Benzbromarone; Irtemazole; Probenecid;
Sulfinpyrazone.
[0253] Vasoconstrictor: Angiotensin Amide; Felypressin;
Methysergide; and Methysergide Maleate.
[0254] Vasodilator: Alprostadil; Azaclorzine Hydrochloride;
Bamethan Sulfate; Bepridil Hydrochloride; Buterizine; Cetiedil
Citrate; Chromonar Hydrochloride; Clonitrate; Dipyridamole;
Droprenilamine; Erythrityl Tetranitrate; Felodipine; Flunarizine
Hydrochloride; Fostedil; Hexobendine; Inositol Niacinate;
Iproxamine Hydrochloride; Isosorbide Dinitrate; Isosorbide
Mononitrate; Isoxsuprine Hydrochloride; Lidoflazine; Mefenidil;
Mefenidil Fumarate; Mibefradil Dihydrochloride; Mioflazine
Hydrochloride; Mixidine; Nafronyl Oxalate; Nicardipine
Hydrochloride; Nicergoline; Nicorandil; Nicotinyl Alcohol;
Nimodipine; Nisoldipine; Oxfenicine; Oxprenolol Hydrochloride;
Pentaerythritol Tetranitrate; Pentoxifylline; Pentrinitrol;
Perhexiline Maleate; Pindolol; Pirsidomine; Prenylamine; Propatyl
Nitrate; Suloctidil; Terodiline Hydrochloride; Tipropidil
Hydrochloride; Tolazoline Hydrochloride; and Xanthinol
Niacinate.
[0255] Wound healing agent: Ersofermin.
[0256] Xanthine oxidase inhibitor: Allopurinol; and Oxypurinol.
[0257] Other active agents include: 16-Alpha Fluoroestradiol;
16Alpha-Gitoxin; 16-Eplestriol; 17 Alpha Estradiol; 17Beta
Estradiol; 1Alpha-Hydroxyvitamin D2; 1-Decpyrrolidinone;
1-Dodecpyrrolidinone; 22-Oxacalcitriol; 2CVV; 2'-Nor-cGMP;
3-Isobutyl GABA; 6-FUDCA; 7-Methoxytacrine; Abacavir Sulfate;
Abanoquil; Abecarnil; Acadesine; Acamprosate; Acebutolol
Hydrochloride; Aceclofenac; Acetomepregenol; Acetrizoate Sodium;
Acetylcysteine, N--; Acetyldigitoxin; Acetyl-L-carnitine;
Acetylmethadol; Acipimox; Acitemate; Aclatonium; Aconiazide;
Acrivastinet; Adafenoxate; Adatanserin; Adefovir Dipivoxil;
Adelmidrol; Ademetionine; Adiposin; Adrafinil; Alacepril;
Aladapcin; Alaptide; Alatrofloxacin Mesylate; Albolabrin; Albumin
Chromated Cr-51 Serum; Albumin Human; Albumin Iodinated I-125
Serum; Albumin Iodinated 1-131 Serum; Aldecalmycin; Alendronic
Acid; Alentemol; Alfacalcidol; Alfuzosin; Alglucerase; Alinastine;
Alitretinoin; Alkavervir; Allopurinol Sodium; Almotriptan Malate;
Alosetron; Alpha Idosone; Alpha-Tocopherol; Alpha-Tocopherol
Acetate; Alseroxylon; Altromycin B; Amantadine-HCl; Ambenonium
Chloride; Amelometasone; Amezinium Metilsulfate; Amfebutamone;
Amifloxacin; Aminolevulinic Acid Hydrochloride; Aminosalicylic Acid
Resin Complex; Amiodarone Hydrochloride; Amisulpride; Amlodipine;
Ammonium Lactate; Amphetamine Adipate; Amphetamine Aspartate;
Amphetamine Resin Complex; Ampiroxicam; Amprenavir; Amylin;
Amythiamicin; Ananain; Anaritide; Anileridine Phosphate;
Anisindione; Anordrin; Apadoline; Apafant; Apraclonidine;
Aprepitant; Aprosulate Sodium; Aprotinin Bovine; Aptiganel;
Aranidipine; Arbekacin; Arbidol; Arbutamine; Arecatannin B 1;
Argatroban; Aripiprazol; Aripiprazole; Arotinolol; Articaine
Hydrochloride; Ascorbic Acid; Asimadoline; Aspalatone; Asperfuran;
Aspoxicillin; Atazanavir Sulfate; Atenolol, S--; Atevirdine;
Atomoxetine Hydrochloride; Atpenin B; Atrinositol; Aureobasidin A;
Avobenzone; Azadirachtine; Azelaic Acid; Azelastine; Azelnidipine;
Azimilide; Azithromycin Dihydrate; Aztreonwn; Baccatin III;
Bacoside A; Bacoside B; Bactobolamine; Balazipone; Balhimycin;
Balofloxacin; Balsalazide; Bambuterol; Baohuoside 1; Barnidipine;
Batebulast; Beauvericin; Becaplermin; Becliconazole; Beclomethasone
Dipropionate Monohydrate; Befloxatone; Bellenamine; Benflumetol;
Benidipine; Bentoquatam; Benzisoxazole; Benzoidazoxan; Benzoyl
Peroxide; Benzphetamine Hydrochloride; Benzquinamide Hydrochloride;
Benztropine; Benzyl Benzoate; Benzyl Penicilloyl-Polylysine;
Bepridil; Beractant; Beraprost; Berlafenone; Bertosamil;
Besipirdine; Beta-Carotene; Betaine, Anhydrous; Betamipron;
Betaxolol; Betazole Hydrochloride; Bevantolol; Bexarotene;
Bifemelane; Bimakalim; Bimatoprost; Bimithil; Binospirone; Biotin;
Bioxalomycin Alpha2; Biriperone; Bisaramil; Bisaziridinylspermine;
Bis-Benzimidazole A; Bis-Benzimidazole B; Bismuth Subsalicylate;
Bistramide D; Bistramide K; Boldine; Bopindolol; Bortezomib;
Brefeldin; Brimonidine; Brinzolamide; Bromfenac; Bucindolol;
Budipine; Bunazosin; Butenafine; Butenafine Hydrochloride;
Butixocort Propionate; Cabergoline; Caffeine Citrate; Calanolide A;
Calcitonin Human; Calcitonin, Salmon; Calcium; Calcium Acetate;
Calcium Gluceptate; Calcium Metrizoate; Calfactant; Camonagrel;
Candesartan; Candesartan Cilexetil; Candoxatrilat; Capromab;
Capsaicin; Carbamazepine; Carbazomycin C; Carbetocin;
Carbidopa/Levodopa; Carbovir; Carboxymethylated Beta-1,3-Glucan;
Carperitide; Carteolol; Carumonam; Carvotroline; Caspofungin
Acetate; Cebaracetam; Cefadroxil; Cefadroxil Hemihydrate; Cefcapene
Pivoxil; Cefdaloxime Pentexil Tosilate; Cefditoren Pivoxil;
Cefepime Hydrochloride (Arginine Formulation); Cefetamet; Cefetamet
Pivoxil; Cefffietazole; Cefluprenam; Cefminox; Cefodizime;
Cefoselis; Cefotiam; Cefotiam Hexetil; Cefozopran; Cefpirome;
Cefsulodin; Ceftazidime (Arginine Formulation); Ceftazidime Sodium;
Cefteram; Ceftibuten Dihydrate; Ceftriaxone; Celastrol; Celecoxib;
Celikalim; Celiprolol; Cellulose Sodium Phosphate; Cepacidine A;
Cericlamine; Cerivastatin; Cerivastatin Sodium; Certoparin Sodium;
Cetiedil; Cetirizine; Cetyl Alcohol; Cevimeline Hydrochloride;
Chlormerodrin, Hg-197; Chlormezanone; Chloroorienticin A;
Chloroorienticin B; Cholecalciferol; Cholestyramine;
Choriogonadotropin Alfa; Chromic Phosphate, P-32; Chymopapain;
Chymotrypsin; Cibenzoline; Ciclesonide; Cicloprolol; Cilansetron;
Cilnidipine; Cilobradine; Cilostazol; Cimetropiurn Bromide;
Cinitapride; Cinolazepam; Ciprostene; Cisapride Monohydrate;
Cisatracurium, Besilate; Cistinexine; Citalopram; Citalopram
Hydrobromide; Citicoline; Citreamicin Alpha; Clausenamide;
Clidinium Bromide; Clinafloxacin; Clomethiazole; Clopidogrel;
Clopidogrel Bisulfate; Cobalt Chloride, Co-57; Cobalt Chloride,
Co-60; Colesevelam Hydrochloride; Colestimide; Colfosceril
Palmitate; Complestatin; Contignasterol; Contortrostatin;
Corticotropin Zinc Hydroxide; Cosalane; Costatolide; Cotinine;
Cournermycin AI; Cryptenamine Acetates; Cryptenamine Tannates;
Cucumariosid; Curdlan Sulfate; Curiosin; Cyanocobalamin;
Cyanocobalamin, Co-57; Cyanocobalamin, Co-58; Cyanocobalamin,
Co-60; Cyclazosin; Cyclic HPMPC; Cyclobenzaprine; Cyclobut A;
Cyclobut G; Cyclocapron; Cyclosin; Cyclothialidine;
Cyclothiazomycin; Cycrimine Hydrochloride; Cyproterone; Cysteamine
Bitartrate; Cytochalasin B; Dactimicin; Daidzein; Daidzin;
Danaparoid; Daphnodorin A; Dapiprazole; Dapitant; Darifenacin;
Darlucin A; Darsidomine; Daunorubicin Citrate; DdUTP; Decamethonium
Bromide; Deferiprone; Deferoxamine Mesylate; Dehydrodidemnin B;
Delapril; Delequarnine; Delfaprazine; Delmopinol; Delphinidin;
Deoxypyridinoline; Deprodone; Depsidomycinderamciclane; Dermatan
Sulfate; Deserpidine; Desirudin; Desloratadine; Desmopressin;
Desoxoamiodarone; Desoxyribonuclease; Detajrniurn Bitartrate;
Dexketoprofen; Dexloxiglumide; Dexmethylphenidate Hydrochloride;
Dexrazoxane Hydrochloride; Dexsotalol; Dextrin 2-Sulphate;
Dextroamphetamine Adipate; Dextroamphetamine Resin Complex;
Dextroamphetamine Saccharate; Dextrose; Diclofenac Digolil;
Dicranin; Dienogest; Diethylhomospennine; Diethylnorspermine;
Difenoxin Hydrochloride; Dihydrexidine; Diltiazeim; Dimethyl
Prostaglandin A1; Dimethylhomospermine; Dimiracetarn; Dimyristoyl
Lecithin; Diphemanil Methylsulfate; Diphencyprone; Diphenylpyraline
Hydrochloride; Diprafenone; Dipropylnorspermine; Discodermolide;
Divalproex; Docarparnine; Docosanol, 1-; Dolasetron Mesylate
Monohydrate; Domitroban; Donepezil Hydrochloride; Dorzolamide;
Dosmalfate; Dotarizine; Doxazosin; Doxercalciferol; Draculin;
Drosperidone; Drospirenone; Drotaverine Acephyllinate; Droxicam;
Dutasteride; Ebiratide; Ebrotidine; Ecabapide; Ecabet; Ecdisteron;
Echicetin; Echistatin; Ecteinascidin 722; Ecteinascidin 729;
Ecteinascidin 743; Edaravone; Edetate Calcium Disodium; Edetate
Disodium; Edobacomab; Edrecolornab; Efavirenz; Efegatran;
Efonidipine; Egualen; Elcatonin; Eletriptan; Eletriptan
Hydrobromide; Elgodipine; Eliprodil; Eltenac; Emakalim; Emedastine;
Emedastine Difumarate; Emiglitate; Emoctakin; Emtricitabine;
Enalapril; Enazadrem; Enfuvirtide; Englitazone; Entacapone; Entero
statin; Eplerenone; Epoxymexrenone; Eptastigmine; Eptifibatide;
Erdosteine; Ergocalciferol; Ersentilide; Ertapenem Sodium;
Erythritol; Escitalopram Oxalate; Esomeprazole Magnesium;
Estazolam; Estradiol Acetate; Esuprone; Etanterol; Ethacizin;
Ethchlorvynol; Ethinamate; Ethinylestradiol; Ethoxzolamide;
Etidocaine Hydrochloride; Etizolam; Etrabamine; Eveminomicin;
Examorelin; Ezetimibe; Faerieftmgin; Fantofarone; Farnciclovir;
Faropenem; Fasidotril; Fasudil; Fedotozine; Felbamate; Fenofibrate;
Fenoldopam; Fenspiride; Fentanyl; Fenticonazole; Fepradinol;
Ferpifosate Sodium; Ferristene; Ferrixan; Ferrous Citrate, Fe-59;
Fexofenadine Hydrochloride; Fibrinogen, 1-125; Fibrinolysin;
Flecainide; Flerobuterol; Flesinoxan; Flezelastine; Flobufen;
Flomoxef; Florfenicol; Florifenine; Flornastat; Flosatidil;
Fludeoxyglucose, F-18; Flumecinol; Flunarizine; Fluocalcitriol;
Fluoxetine, R--; Fluoxetine, S--; Fluparoxan; Flupirtine;
Flurbiprofen Axetil; Flurithromycin; Flutamide; Flutrimazole;
Fluvastatin; Fluvoxamine; Folic Acid; Follitropin Alfa; Follitropin
Alfa/Beta; Fomivirsen Sodium; Fondaparinux Sodium; Forasartan;
Formoterol; Formoterol Fumarate; Formoterol, R,R; Fosinopril;
Fosphenytoin; Frovatriptan Succinate; Fulvestrant; Furosernide;
Gadobenic Acid; Gadobutrol; Gadodiamide-EOB-DTPA; Gadopentetate
Dimeglumine; Gadoteric Acid; Galantamine; Galantamine Hydrobromide;
Galdansetron; Gallopamil; Gamolenic Acid; Gatifloxacin; Gefitinib;
Gemifloxacin Mesylate; Gemtuzumab Ozogamicin; Gepirone; Girisopam;
Glaspimod; Glatiramer Acetate; Glaucocalyxin A; Glucagon
Hydrochloride; Glucagon Hydrochloride Recombinant; Glucagon
Recombinant; Gluconolactone; Glutapyrone; Glutathione Disulfide;
Glycopine; Glycopril; Goserelin Acetate; Grepafloxacin;
Grepafloxacin Hydrochloride; Guaifenesin; Guanidine Hydrochloride;
Halichondrin B; Halofantrine; Halomon; Haloperidol Lactate;
Halopredone; Hatomarubigin C; Hatornambigin D; Hatornamicin;
Hatomarubigin A; Hatomarubigin B; Heparin Calcium; Heparin Sodium;
Hexocyclium Methylsulfate; Hexylcaine Hydrochloride; Histrelin
Acetate; Hyaluronidase; Hydrocortamate Hydrochloride;
Hydrocortisone Cypionate; Hydrocortisone Probutate; Hydroquinone;
Hydroxocobalamin; Hydroxypropyl Cellulose; Hydroxystilbamidine
Isethionate; Ibandronate Sodium; Ibogaine; Ibudilast; Ibuprofen
Potassium; Icodextrin; Illimaquinone; Iloprost; Imatinib Mesylate;
Imidapril; Imidazenil; Imiglucerase; Imipramine Pamoate; Inamrinone
Lactate; Indapamide; Indinavir; Indinavir Sulfate; Indium In-Ill
Oxyquinoline; Indium In-Ill Pentetate Disodium; Indium In-Ill
Pentetreotide Kit; Indometacin; Indometacin Farnesil; Indomethacin
Sodium; Inocoterone; Inogatran; Inolimomab; Insulin Aspart; Insulin
Aspart Protamine; Insulin Glargine; Insulin Lispro Protamine;
Interferon Alfa; Interferon Alfa-NI; Interferon Beta; Interferon
Beta-lal; Interferon Gamma-I A; Interferon Gamma-I B; Interferon
Omega; Interferon, Consensus; Interieukin-3; Interleukin-1;
Interleukin-I Beta; Interleukin-10; Interleukin-11; Interleukin-12;
Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-5;
Interleukin-7; Interleukin-8; InterleukinI Alpha; Intrinsic Factor;
Inulin; Invert Sugar; Iobenguane Sulfate I 131; Iobitridol;
Iodamide Meglumine; Iodipamide Sodium; Iodoamiloride; Iodohippurate
Sodium, 1-123; Iodohippurate Sodium, 1-131; Iofetamine
Hydrochloride 1-123; Iofratol; Iopromide; Iopyrol; Iorneprol;
Iothalamate Sodium, 1-125; Iotriside; Ioxaglate Sodium; Ipazilide;
Ipenoxazone; Ipidacrine; Ipomeanol, 4; Ipriflavone; Ipsapirone;
Irbesartan; Irloxacin; Iron Dextran; Iron Sucrose; Irternazole;
Isalsteine; Isbogrel; Iseparnicin; Isofloxythepin; Isopropyl
Unoprostone; Itameline; Itopride; Ketoprofen, R--; Ketoprofen, S--;
Ketorolac; Lactitol; Lactivicin; Lactulose; Laennec; Lafutidine;
Lanoconazole; Lanperisone; Larnifiban; Lamotrigine; Latanoprost;
Lateritin; Laurocaprarn; Leflunomide; Lemefloxacin; Leminoprazole;
Lenercept; Lepirudin; Leptin; Lercanidipine; Lerisetron;
Lernildipine; Lesopitron; Letrazuril; Leucomyzin; Levalbuterol
Hydrochloride; Levallorphan Tartrate; Levamisole Hydrochloride;
Levetiracetam; Levobetaxolol; Levobunolol; Levobupivacaine;
Levobupivacaine Hydrochloride; Levocabastine; Levocarnitine;
Levodropropizine; Levofloxacin; Levopropoxyphene Napsylate,
Anhydrous; Levormeloxifene; Levornoprolol; Levosimendan;
Levosulpiride; Lindane; Linezolid; Linotroban; Linsidornine;
Lintitript; Lintopride; Lipase; Lirexapride; Lithium Carbonate;
Lithium Citrate; Lodoxamide; Lomerizine; Lonazolac; Lopinavir;
Lorglumide; Losartan; Losigamone; Loteprednol; Loviride; Loxapine
Hydrochloride; LpdR; Lubeluzole; Lutetium; Luzindole; Lydicamycin;
Lysostaphin; Magainin 2 Arnide; Magnesium Acetate; Magnesium
Acetate Tetrahydrate; Magnolol; Malathion; Mallotochromene;
Mallotojaponin; Mangafodipir; Mangafodipir Trisodium; Manidipine;
Maniwamycin A; Mannitol; Manurnycin E; Manurnycin F; Mapinastine;
Martek 8708; Martek 92211; Massetolide; Meglumine Metrizoate;
Meloxicam; Melphalan Hydrochloride; Menadiol Sodium Diphosphate;
Menadione; Meprednisone; Mequinol; Mersalyl Sodium; Mesna;
Metformin Hydrochloride; Methantheline Bromide; Metharbital;
Methoxamine Hydrochloride; Methoxatone; Methoxsalen;
Methscopolamine Bromide; Methyclothiazide; Methyldopa;
Methylhistamine, R-alpha; Methylinosine Monophosphate;
Methylprednisolone Aceponate; Methyprylon; Metiparnide;
Metipranolol Hydrochloride; Metolazone; Metoprolol Fumarate;
Metoprolol, S--; Metoprotol Tartrate; Metrifonate; Metrizoate
Magnesium; Metrizoic Acid; Mezlocillin Sodium Monohydrate;
Michellarnine B; Microcolin A; Midodrine; Miglustat; Milacernide;
Milarneline; Mildronate; Milnacipran; Milrinone Lactate;
Miokarnycin; Mipragoside; Mirfentanil; Mivazerol; Mixanpril;
Mizolastine; Mizoribine; Moexipril; Moexipril Hydrochloride;
Mofezolac; Mometasone; Mometasone Furoate Monohydrate; Monobenzone;
Montirelin; Moracizine; Moricizine Hydrochloride; Mosapramine;
Mosapride; Motilide; Moxifloxacin Hydrochloride; Moxiraprine;
Moxonidine; Mupirocin; Mupirocin Calcium; Mycophenolate Mofetil
Hydrochloride; Nadifloxacin; Nadroparin Calcium; Nafadotride;
Nafamostat; Naftopidil; Naglivan; Nalmefene Hydrochloride;
Naltrexone Hydrochloride; Napadisilate; Napsagatran; Naratriptan;
Nasaruplase; Nateglinide; Nateplasel; Nelfinavir Mesylate;
Nesiritide; Niacinamide; Nicotine; Nicotine Polacrilex;
Niperotidine; Niravoline; Nisin; Nitazoxanide; Nitecapone;
Nitisinone; Nitrendipine, S--; Nitrofurantoin Monohydrate;
Nitrofurantoin Sodium; Nitrofurantoin, Macrocrystalline;
Nitrofurazone; Nitroglycerin; Nonoxynol-9; Norelgestromin; Octyl
Methoxycinnamate; Olmesartan Medoxomil; Olopatadine; Olopatadine
Hydrochloride; Olprinone; Olsalazine; Omeprazole Magnesium;
Ondansetron, R--; Oral Hypoglyceremics; Orphenadrine Hydrochloride;
Oseltamivir Phosphate; Otenzepad; Oxamisole; Oxaprozin Potassium;
Oxcarbazepine; Oxiconazole; Oxiracetam; Oxodipine; Oxybenzone;
Oxybutynin; Oxyphencyclimine Hydrochloride; Oxyphenonium Bromide;
Ozagrel; Palauarnine; Palinavir; Palonosetron Hydrochloride;
Pamaparin Sodium; Panamesine; Pancrelipase; Panipenem; Panipenum;
Pannorin; Panornifene; Pantethine; Pantoprazole Sodium; Pantothenic
Acid; Paramethadione; Paricalcitol; Parnaqueside; Parnicogrel;
Paroxetine Hydrochloride; Paroxetine Mesylate; Parthenolide;
Pazufloxacin; Pegademase Bovine; Pegvisomant; Pemirolast;
Pemirolast Potassium; Penciclovir Sodium; Penicillamine;
Pentafuside; Pentagastrin; Pentamidine; Pentamidine Isethionate;
Pentetate Calcium Trisodium Yb-169; Pentigetide; Pentolinium
Tartrate; Pentosan; Perflexane; Perfluoropolymethylisopropyl Ether;
Perflutren; Pergolide; Pergolide Mesylate; Perindoprilat;
Pernedolac; Perospirone; Phenaridine; Phenindione; Pheniramine
Maleate; Phenmetrazine Hydrochloride; Phenotoxifvline; Phenserine;
Phensuccinal; Phentermine Resin Complex; Phentolamine Mesilate;
Phenylalanyl Ketoconazole; Phenylephrine Bitartrate; Phenytoin
Sodium, Extended; Phenytoin Sodium, Prompt; Phosphoric Acid;
Phytonadione; Picenadol; Picroliv; Picumeterol; Pidotimod;
Pilsicainide; Pimagedine; Pimecrolimus; Pimilprost; Pinocebrin;
Pioglitazone; Piperonyl Butoxide; Pirlindole; Pirmenol;
Pirodornast; Polyestradiol Phosphate; Polyethylene Glycol 3350;
Polytetrafluoroethylene; Poractant Alfa; Potassium Chloride;
Pramipexole Dihydrochloride; Praziquantel; Prazosin; Prilocaine;
Procaine Merethoxylline; Proguanil Hydrochloride; Propagermanium;
Propentofylline; Propiolactone; Propiomazine Hydrochloride;
Propionylcamitine, L-; Propiram; Propiram+Paracetamol; Propiverine;
Prostratin; Protegrin; Protein Hydrolysate; Protokylol
Hydrochloride; Protosufloxacin; Prulifloxacin; Pyrethrins;
Pyridoxine; Pyridoxine Hydrochloride; Quazepam; Quetiapine;
Quetiapine Fumarate; Quiflapon; Quinagolide; Quinapril;
Quinethazone; Quinidine Polygalacturonate; Raloxifene; Ramatroban;
Ranelic Acid; Ranolazine; Rapacuronium Bromide; Recainarn;
Regavirumab; Repaglinide; Rescinnamine; Resinferatoxin; Reticulon;
Reviparin Sodium; Revizinone; Riboflavin; Riboflavin Phosphate
Sodium; Ricasetron; Rilopirox; Rimantadine; Rimexolone; Rimoprogin;
Riodipine; Ripisartan; Risedronic Acid; Rispenzepine; Ritipenem
Acoxil; Ritipenern; Ritonavir; Rivastigmine Tartrate; Rizatriptan
Benzoate; Rnibefradil; Rnivacurium Chloride; Rofecoxib;
Rokitamycin; Ropinirole; Ropivacaine; Ropivacaine Hydrochloride
Monohydrate; Roquinimex; Rose Bengal Sodium, 1131; Rosiglitazone
Maleate; Roxatidine; Roxindole; Rubidium Chloride Rb-82;
Rufloxacin; Rupatidine; Ruzadolane; Sacrosidase; Safflower Oil;
Safironil; Salbutamol, R--; Salnacedin, R--; Samarium Sm 153
Lexidronam Pentasodium; Sanfetrinem; Saprisartan; Sapropterin;
Saquinavir; Sarcophytol A Sargramostim; Sarneridine; Sarnpatrilat;
Sarpogrelate; Saruplase; Saterinone; Satigrel; Satumomab Pendetide;
Scopolamine; Secretin; Selenomethionine, Se-75; Sematilide;
Sermorelin; Sernotiadil;
Sertaconazole; Sertraline; Sertraline-HCl; Setiptiline; Sevelamer
Hydrochloride; Sevirurnab; Sezolamide; Sildenafil Citrate;
Silipide; Silteplase; Silver Sulfadiazine; Simendan; Simethicone;
Simethicone-Cellulose; Sinitrodil; Sinnabidol; Sipatrigine;
Sirnvastatin; Somatomedin C; Somatropin Recombinant; Sorbitol;
Somatomedin B; Sornatrem; Somatropin; Sotalol; Staurosporine;
Stepronin; Stobadine; Strontium Chloride, Sr-89; Succibun;
Sulfanilamide; Sulfaphenazole; Sulfapyridine; Sulfoxamine;
Sulfoxone Sodium; Sulfur; Sultamicillin; Sultopride; Sumatriptan;
Sutilains; Symakalim; Talbutal; Tandospirone; Tannic Acid; Tapgen;
Taprostene; Tartaric Acid; Tazanolast; Tegaserod Maleate;
Telenzepine; Telmesteine; Telmisartan; Temocapril; Tenofovir
Disoproxil Fumarate; Tenosal; Tepirindole; Terazosin; Terbinafine
Hydrochloride; Terflavoxate; Terguride; Terlipressin; Terodiline;
Tertatolol; Testosterone Buciclate; Thallous Chloride, Tl-201;
Thiamine; Thiamine Hydrochloride; Thiofedrine; Thiomarinol;
Thioperamide; Thiosemicarbazone; Thonzonium Bromide; Thyroglobulin;
Thyrotropin; Thyrotropin Alfa; Tiagabine; Tiagabine Hydrochloride;
Tianeptine; Tiapafant; Ticlopidine; Tienoxolol; Tilisolol;
Tilnoprofen Arbamel; Tiludronic Acid; Tiopronin; Tiotropium
Bromide; Tirandalydigin; Tirilazad; Tirofiban; Tiropramide;
Tocopherol Acetate; Tolterodine Tartrate; Torasemide; Trafermin;
Trandolapril; Tranylcypromine Sulfate; Travoprost; Traxanox;
Trazodone-HCl; Treprostinil Sodium; Tretinoin Tocoferil;
Triarntevene; Tricaprilin; Trichohyalin; Trichosanthin, Alpha;
Triclosan; Tridihexethyl Chloride; Trientine; Trientine
Hydrochloride; Triflavin; Trimegestone; Trimethoprim Hydrochloride;
Trioxsalen; Triptorelin Pamoate; Trolamine Polypeptide Oleate
Condensate; Trombodipine; Trometamol; Tromethamine; Tropine Ester;
Trospectomycin; Trovafloxacin; Trovafloxacin Mesylate; Trovirdine;
Tucaresol; Tulobuterol; Tylogenin; Tyloxapol; Undecoylium Chloride;
Undecoylium Chloride Iodine Complex; Unoprostone Isopropyl;
Urapidil; Urea, C-13; Urea, C-14; Uridine Triphosphate;
Valaciclovir; Valdecoxib; Valganciclovir Hydrochloride; Valproate
Magnesium; Valproate Semisodium; Valrubicin; Valsartan; Vamicamide;
Vanadeine; Vaninolol; Vasopressin Tannate; Venlafaxine; Verapamil,
(S); Veratrum Viride; Veroxan; Vexibinol; Vinburnine Citrate;
Vinburnine Resinate; Vinconate; Vinpocetine; Vinpocetine Citrate;
Vintoperol; Viomycin Sulfate; Vitamin A; Vitamin A Palmitate;
Vitamin E; Vitamin K; Voriconazole; Voxergolide; Warfarin
Potassium; Xemilofiban; Ximoprofen; Yangarnbin; Zabicipril;
Zacopride; Zacopride, R--; Zafirlukast; Zalospirone; Zaltoprofen;
Zanamivir; Zanarnivir; Zankiren; Zatebradine; Zatosetron;
Zenarestat; Zinostatin Stimalarner; Ziprasidone; Ziprasidone
Mesylate; Zoledronic Acid; Zolmitriptan; Zolpidem; Zopiclone;
Zopiclone, S--; Zopolrestat; and Zotepine. Still other examples of
therapeutically active agents are listed in 2000 MedAd News
19:56-60 and The Physicians Desk Reference, 53rd. Edition, pages
792-796, Medical Economics Company (1999).
[0258] Embodiments of the present disclosure will be described with
reference to the following Examples which are provided for
illustrative purposes only and should not be used to limit the
scope of or construe the invention.
EXAMPLES
Example 1--Transdermal/Topical Delivery Formulations
[0259] Several formulations were prepared according to embodiments
of the present disclosure utilizing the compositional components
set forth in Tables 1A and 1B. Each of the formulations was
prepared in a batch at a batch size of 2 kg. All raw materials were
stored at ambient conditions prior to manufacturing of the
formulations. Generally, all formulations were manufactured as
described below.
[0260] The organic phase, containing isopropyl alcohol,
di-isopropyl adipate, hexylene glycol, halobetasol propionate was
added into an aqueous phase containing purified water, anhydrous
citric acid, di-hydrate sodium citrate, and if present in the
formulation SLSA. This mixture was then combined with any other
MMPE.TM.s found in the formulation and if present in the
formulation polyoxyl 35 castor oil. A bench top mixer was used to
ensure complete dissolution after each component addition. The
order of ingredients combined may vary depending on the preparation
of laboratory vs. GMP batches.
TABLE-US-00003 TABLE 1A Example Formulations Control and F1-F6 (wt
%) C1 Ingredient Control F1 F2 F3 F4 F5 F6 Halobetasol Propionate
0.05 0.05 0.05 0.05 0.05 0.05 0.05 Isopropyl Alcohol (IPA) 35.0
35.0 35.0 35.0 35.0 35.0 35.0 Di-Isopropyl Adipate (DIA) 3.0 3.0
3.0 3.0 3.0 3.0 3.0 Hexylene Glycol 7.5 7.5 7.5 7.5 7.5 7.5 7.5
Citric Acid, anhydrous 0.09 0.09 0.09 0.09 0.09 0.09 0.09 Sodium
Citrate, dihydrate 0.07 0.07 0.07 0.07 0.07 0.07 0.07 Purified
Water 54.29 47.79 47.79 47.79 52.79 47.29 47.29 Polyoxyl 35 Castor
Oil -- 5.0 5.0 5.0 0 5.0 5.0 Methyl Laurate (ML) -- 0.5 0.5 0.5 0.5
-- -- Isopropyl Myristate (IM) -- 1.0 -- -- -- 1.0 1.0 Oleic Acid
(OA) -- -- 1.0 -- -- 1.0 -- Glyceryl Oleate (GO) -- -- -- 1.0 -- --
1.0 Sodium Lauryl Sulfoacetate (SLSA) -- -- -- -- 1.0 -- --
TABLE-US-00004 TABLE 1B Example Formulations F7-F11 (wt %)
Ingredient F7 F8 F9 F10 F11 Halobetasol Propionate 0.05 0.05 0.05
0.05 0.05 Isopropyl Alcohol (IPA) 35.0 35.0 35.0 35.0 35.0
Di-Isopropyl Adipate (DIA) 3.0 3.0 3.0 3.0 3.0 Hexylene Glycol 7.5
7.5 7.5 7.5 7.5 Citric Acid, anhydrous 0.09 0.09 0.09 0.09 0.09
Sodium Citrate, dihydrate 0.07 0.07 0.07 0.07 0.07 Purified Water
47.29 47.29 47.29 47.29 47.79 Polyoxyl 35 Castor Oil 5.0 5.0 5.0
5.0 5.0 Methyl Laurate (ML) -- -- -- -- 0.5 Isopropyl Myristate
(IM) 1.0 -- -- -- -- Oleic Acid (OA) -- 1.0 1.0 -- -- Glyceryl
Oleate (GO) -- 1.0 -- 1.0 -- Sodium Lauryl 1.0 -- 1.0 1.0 1.0
Sulfoacetate (SLSA)
Example 2--Physical Stability of the Formulations of Example 1
[0261] Each of the formulations and the control described in
Example 1 were stored at ambient conditions (25.degree. C.). The
physical stability (i.e. the phase separation of the formulations)
of each of the formulations was tested at weeks one, two, three,
four, eight, and twelve. The phase separation was measured by
placing each of the formulations in a 10 ml graduated glass
container. The cylinders were stopped and the phase separation was
measured in terms of millimeters at the indicated time intervals.
The containers were not moved during the course of this study.
[0262] The phase separation for each of the formulations is
provided in Table 2. None of the formulations experienced any
visible phase separation during the testing period.
TABLE-US-00005 TABLE 2 Phase Separation (ml) C1 Week Control F1 F2
F3 F4 F5 F6 F7 F8 F9 F10 F11 1 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0
0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 0 0 4 0 0 0 0 0 0 0 0 0 0 0 0 8
0 0 0 0 0 0 0 0 0 0 0 0 12 0 0 0 0 0 0 0 0 0 0 0 0
Example 3--pH of the Formulations of Example 1
[0263] Each of the formulations and the control described in
Example 1 were stored at ambient conditions (25.degree. C.). The pH
of each of the formulations was tested following U.S. Pharmacopeial
Convention (USP) procedure 791 as of the date of the present patent
application filing. The pH of each of the formulations was tested
at zero, four, eight, and twelve weeks. The pH for each of the
formulations are provided in Table 3 and graphed in FIG. 1. All
test formulations (F1 to F11) showed improved pH stability over the
control formulation following 12 weeks of storage. The improvement
in pH stability over the control formulation may become more
pronounced for the test formulations at extended time intervals
e.g. 6 months, 12 months, 24 months.
TABLE-US-00006 TABLE 3 pH C1 Week Control F1 F2 F3 F4 F5 F6 F7 F8
F9 F10 F11 0 4.74 4.98 4.86 5.07 4.78 4.91 5.07 4.90 4.92 4.84 4.93
4.92 4 4.75 4.95 4.91 5.09 4.79 4.91 5.06 4.91 4.95 4.83 4.92 4.90
8 4.73 5.02 4.90 5.07 4.79 4.93 5.07 4.89 4.95 4.84 4.93 4.90 12
4.80 5.02 4.91 5.06 4.79 4.90 5.07 4.88 4.95 4.83 4.94 4.90 Total
0.06 0.04 0.05 0.01 0.01 0.01 0 0.02 0.03 0.01 0.01 0.02 Change*
*Calculated as change in pH between 0-week timepoint and 12-week
timepoint.
Example 4--Viscosity of the Formulations of Example 1
[0264] Each of the formulations and the control described in
Example 1 were stored at ambient conditions (25.degree. C.). The
viscosity of each of the formulations was tested following U.S.
Pharmacopeial Convention (USP) procedure 911 as of the date of the
present patent application filing. The viscosity of each of the
formulations was tested at zero, four, eight, and twelve weeks. The
viscosity for each of the formulations is provided in Table 4.
TABLE-US-00007 TABLE 4 viscosity (cps) C1 Week Control F1 F2 F3 F4
F5 F6 F7 F8 F9 F10 F11 0 4.11 5.61 5.49 5.94 4.26 6.51 6.21 5.94
5.94 5.76 5.76 5.46 4 3.96 5.64 5.76 5.82 3.99 5.61 5.58 5.28 5.85
5.61 5.70 5.55 8 3.90 5.64 6.39 5.67 3.69 6.39 5.70 5.64 5.94 5.28
5.73 5.34 12 3.72 5.13 5.04 5.19 3.57 5.91 5.79 5.55 5.64 5.34 5.64
5.31 Total 0.39 0.48 0.45 0.75 0.69 0.60 0.42 0.39 0.30 0.42 0.12
0.15 Change* *Calculated as change in cps between 0-week timepoint
and 12-week timepoint.
The viscosity at 25.degree. C. for each of the formulations is
plotted and shown in FIG. 2. Formulations F8, F10 and F11 showed
improved consistency of viscosity over the control formulation
following 12 weeks of storage. The consistency of viscosity over
the control formulation may become more pronounced for certain test
formulations at extended periods of time, e.g. 6 months, 12 months,
24 months.
Example 5--Active Pharmaceutical Ingredient Assay of the
Formulations of Example 1
[0265] Each of the formulations and the control described in
Example 1 were stored at ambient conditions (25.degree. C.). An
active pharmaceutical ingredient (API) assay for each of the
formulations was tested using High Performance Liquid
Chromatography (HPLC) equipped with a Synergi.TM. Hydro-RP (4
.mu.m, 100.times.3.0 mm) column. The API of each of the
formulations was tested at zero, four, eight, and twelve weeks. The
API assay results for each of the formulations are provided in
Table 5.
TABLE-US-00008 TABLE 5 Active Pharmaceutical Ingredient (API) (%)
C1 Week Control F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 0 102.5 102.3
102.2 102.4 102.4 101.5 101.6 101.1 102.2 101.9 101.3 101.3 4 99.8
100.3 100.5 100.5 100.0 100.4 100 99.1 100.1 100.3 100.1 98.9 8
102.6 102.2 101.4 102.1 102.0 101.8 101.9 100.5 102.3 102.2 101.9
101.7 12 101.0 101.5 101.1 101.3 101.1 101.2 98.8 98.0 101.0 99.3
100.5 100.3 Total 1.5 0.8 1.1 1.1 1.3 0.3 2.8 3.1 1.2 2.6 0.8 1
Change* *Calculated as change in API between 0-week timepoint and
12-week timepoint.
The API assay results for each of the formulations is plotted and
shown in FIG. 3. Formulations F1, F2, F3, F4, F5, F8, F10 and F11
showed reduced active degradation over the control formulation
following 12 weeks of storage. The reduction in degradation of API
over the control formulation may become more pronounced in certain
test formulations at extended periods of time, e.g. 6 months, 12
months, 24 months.
Example 6--Delivery Through Durapore.RTM. Membrane of the
Formulations of Example 1
[0266] Select formulations and the control described in Example 1
were tested for penetration through the Durapore.RTM. membrane. A
total of 10 formulations were tested. The Durapore.RTM. membrane is
a hydrophilic polyvinylidene fluoride membrane with a 0.45 .mu.m
pore size. The amount of halobetasol propionate that diffused
through the Durapore membrane into the receptor fluid was
quantified at hours 2, 4, 6, 8, 10, 24, and 30. The results are
included in Table 6A.
TABLE-US-00009 TABLE 6A Diffusion of Halobetasol Propionate through
Durapore .RTM. Membrane Time (hours) Control F1 F2 F3 F4 F5 F7 F9
F10 F11 2 16.65 228.81 128.1 10.56 57.22 15.26 46.74 58.38 218.01
786.64 4 15.39 544.73 261.09 135.37 131.91 72.88 735.87 183.14
655.06 1392.31 6 50.64 1048.57 774.24 404.35 229.19 343.75 1923.86
1414.31 1813.25 2009.5 8 156.67 1654.93 1475.49 1001.02 336.98
1034.7 3325.24 3219.19 3265.42 2917.09 10 231.19 2296.47 2116.4
3664.81 415.6 3668.02 4528.02 4941.46 5142.33 3797.72 24 348.98
3828.18 3757.6 4295.24 526.23 4501.34 5028.3 5853.46 5648.37
4216.92 30 519.22 3916.49 3823.75 4395.79 511.34 4536.92 5085.83
5874.12 5509.76 4211.38 Total 1338.73 13518.18 12336.67 13907.13
2208.46 14172.86 20673.85 21544.07 22252.19 19331.57
The total amount of halobetosal propionate delievered during the
treatment period and percent increase compared to the control is
included in Table 6B. The presence of the MMPE.TM.s in the test
formulations improved penetration of the halobetasol propionate by
as much as 1,600%.
TABLE-US-00010 TABLE 6B Percent Increase of Total Diffusion During
the Testing Period Control F1 F2 F3 F4 F5 F7 F9 F10 F11 Amount
1338.73 13518.18 12336.67 13907.13 2208.46 14172.86 20673.85
21544.07 22252.19 19331.57 % Increase 1009.78 921.52 1038.83 164.97
1058.68 1544.29 1609.29 1662.19 1444.02
Examples 7-14
Materials and Methods for Examples 7-14
[0267] A number of formulations (described in Examples 7-14 below)
containing diclofenac sodium (a non-steroidal anti-inflammatory
drug or NSAID) were tested for permeation through porcine skin
using the Franz diffusion cells [as generally described in Franz
TJ: Percutaneous absorption. On the relevance of in vitro data. J.
Invest Dermatol 1975; 64:190-195].
[0268] More specifically, Franz cells with a 5 ml receptor well
volume were used in conjunction with full-thickness porcine skin
harvested at Perry Scientific (San Diego, Calif.). The porcine skin
was shaved free of hair, washed with water and subcutaneous fat was
removed. The donor well had an area of .about.0.5 cm.sup.2.
Receptor wells were filled with isotonic phosphate buffered saline
(PBS) doped with 0.01% sodium azide. The flanges of the Franz cell
were coated with vacuum grease to ensure a complete seal and were
clamped together with uniform pressure using a pinch clamp (SS #18
VWR 80073-350).
[0269] After the Franz cells were assembled, the porcine skin was
allowed to pre-hydrate for 45 minutes with isotonic PBS. Isotonic
PBS was then removed and 200 ml of the formulation was applied to
the donor well. Receptor wells of the Franz cells were maintained
at 37.degree. C. (temperature on the surface of the skin is
.about.30.degree. C.) in a stirring block with continual agitation
via a stir bar.
[0270] The flux rates were calculated by assuming a radius of 0.4
cm in the donor well (i.e., an area of 0.503 cm.sup.2). The HPLC
calibration curve for diclofenac was determined to have a slope of
115.6 AUC/(.mu.g diclofenac/ml).
[0271] Samples were drawn from the receptor wells at t=24 hours and
t=46 hours for all formulations. Franz diffusion cell measurements
were made in five-fold replicates for each formulation.
[0272] The concentration of diclofenac in the samples was measured
using HPLC analysis. Specifically, HPLC was carried out with C18
column and using acetonitrile and water as the mobile phase. Flux
rates were calculated using standard equations based on the total
transference of diclofenac across the skin after 46 hours. Thus,
flux rates, F, were computed according to
F = D * V t * A , ##EQU00001##
wherein: D is the concentration of the drug in the receptor well
after incubation time t, V is the volume of the receptor well and A
is the surface area of skin.
[0273] Individual penetration enhancers in the Examples discussed
below were obtained from the following sources: [0274] glyceryl
oleate (glycerol monooleate) from TCI (VWR), product code TCG0082
[0275] isopropyl myristate from Sigma product code M0757 [0276]
methyl laurate from Chem Service product code CS0426 [0277]
N-lauroyl sarcosine from Sigma product code L5000 [0278] oleic acid
(octadecenoic acid) from Mallinckroft (VWR) product code MK274404
[0279] sodium lauryl sulfoacetate from Stepan (65-72%) product code
Lathanol LAL [0280] sodium octyl sulfate from Alfa Aesar (VWR)
product code AA43750-06
[0281] The base composition used for each formulation of a carrier
composition comprised isotonic PBS, ethanol, propylene glycol and
propylene glycol 300 in a volume ratio of 2:2:1:1. The base
formulation further comprised diclofenac sodium in a concentration
of 1.5 wt % per unit volume of the base composition. In the
Examples below, various combinations of the MMPE.TM.s detailed
below were added to the base composition.
Example 7--NLS and IM
[0282] In this Example, N-lauroyl sarcosine (NLS) and isopropyl
myristate (IM) were added to the base formulation. The details of
each formulation and the results of the Franz diffusion cell
experiments are set out in Table 7 below.
TABLE-US-00011 TABLE 7 [NLS + IM] Formulation (wt %/vol) Weight
Ratio of NLS:IM Flux (.mu.g/hr/cm.sup.2) A 3.0 1:1 3.80 B 5.0 1:1
0.53 C 5.0 1:0 0.26 D 5.0 0:1 0.02
[0283] With reference to Table 7, it can be seen that Formulation B
(containing a mixture of NLS and IM each at a concentration 2.5%
wt/vol) was more effective at enhancing diclofenac sodium flux
rates through the skin when compared to either of Formulation C
(containing 5% wt/vol NLS and no IM) or Formulation D (containing
5% wt/vol IM and no NLS). Further and surprisingly, Formulation A
(containing a mixture of NLS and IM each at a concentration of 1.5%
wt/vol) was approximately seven times more effective at enhancing
the flux rate of the diclofenac sodium when compared to Formulation
B.
Example 8
[0284] In this Example, N-lauroyl sarcosine (NLS) and oleic acid
(OA) were added to the base formulation. The details of each
formulation and the results of the Franz diffusion cell experiments
are set out in Table 8.
TABLE-US-00012 TABLE 8 Weight Ratio Formulation [NLS + OA] (wt
%/vol) of NLS:OA Flux (.mu.g/hr/cm.sup.2) E 3.0 1:1 3.29 F 5.0 1:0
0.26 G 5.0 0:1 2.70
[0285] With reference to Table 8, it can be seen that Formulation E
(containing a mixture of NLS and OA each at a concentration 1.5%
wt/vol) was more effective at enhancing diclofenac sodium flux rate
through the skin when compared to either of Formulation F
(containing 5% wt/vol NLS and no OA) or Formulation G (containing
5% wt/vol OA and no NLS).
[0286] It is notable that the flux rate of the NSAID in Formulation
E was higher than that achieved by either of Formulation F or
Formulation G in spite of the fact that the total concentration of
the molecular penetration enhancers in Formulation E was lower than
that in Formulation F and Formulation G.
Example 9
[0287] In this Example, sodium octyl sulfate (SOS) and oleic acid
(OA) were added to the base formulation. The details of each
formulation and the results of the Franz diffusion cell experiments
are set out in Table 9.
TABLE-US-00013 TABLE 9 Flux Formulation [SOS + OA] (wt %/vol)
Weight Ratio of (.mu.g/hr/cm.sup.2) H 5.0 3:7 4.73 I 5.0 1:0 2.70 J
5.0 0:1 0.02
[0288] With reference to Table 9, it can be seen that Formulation H
(containing a mixture of SOS and OA each at a concentration 1.5%
wt/vol and 3.5% wt/vol, respectively) was more effective at
enhancing diclofenac sodium flux rate through the skin when
compared to either of Formulation I (containing 5% wt/vol OA and no
SOS) or Formulation J (containing 5% wt/vol SOS and no OA).
Example 10
[0289] In this Example, glyceryl oleate (GO) and sodium octyl
sulfate (SOS) were added to the base formulation. The details of
each formulation and the results of the Franz diffusion cell
experiments are set out in Table 10.
TABLE-US-00014 TABLE 10 Formu- [GO + SOS] Weight Flux lation (wt
%/vol) Ratio of (.mu.gl/hr/cm.sup.2) K 3.0 1:1 0.30 L 5.0 1:0 0.34
M 5.0 0:1 0.02
[0290] With reference to Table 10, it can be seen that Formulation
K (containing a mixture of GO and SOS each at a concentration 1.5%
wt/vol) was approximately as effective at enhancing diclofenac
sodium flux rate through the skin as Formulation L (containing 5%
wt/vol GO and no SOS) and was substantially improved over that of
Formulation M (containing 5% wt/vol SOS and no GO).
Example 11
[0291] In this Example, glyceryl oleate (GO) and methyl laurate
(ML) were added to the base formulation. The details of each
formulation and the results of the Franz diffusion cell experiments
are set out in Table 11.
TABLE-US-00015 TABLE 11 Formu- [GO + ML] Weight Flux lation (wt
%/vol) Ratio of (.mu.g/hr/cm.sup.2) N 5.0 1:1 0.54 O 5.0 1:0 0.34 P
5.0 0:1 0.32
[0292] With reference to Table 11, it can be seen that Formulation
N (containing a mixture of GO and ML each at a concentration 2.5%
wt/vol) was more effective at enhancing diclofenac sodium flux rate
through the skin when compared to either of Formulation 0
(containing 5% wt/vol GO and no ML) or Formulation P (containing 5%
wt/vol ML and no GO).
Example 12
[0293] In this Example, sodium lauryl sulfoacetate (SLSA) and
methyl laurate (ML) were added to the base formulation. The details
of each formulation and the results of the Franz diffusion cell
experiments are set out in Table 12.
TABLE-US-00016 TABLE 12 Formu- [SLSA + ML] Weight Ratio Flux lation
(wt %/vol) of SLSA:ML (.mu.g/hr/cm.sup.2) Q 5.0 3:7 0.52 R 5.0 1:0
0.22 S 5.0 0:1 0.32
[0294] With reference to Table 12, it can be seen that Formulation
Q (containing a mixture of SLSA and ML each at a concentration 2.5%
wt/vol) was more effective at enhancing diclofenac sodium flux rate
through the skin when compared to either of Formulation R
(containing 5% wt/vol SLSA and no ML) or Formulation S (containing
5% wt/vol ML and no SLSA).
Example 13
[0295] In this Example, sodium lauryl sulfoacetate (SLSA) and
isopropyl myristate (IM) were added to the base formulation. The
details of each formulation and the results of the Franz diffusion
cell experiments are set out in Table 13.
TABLE-US-00017 TABLE 13 Formu- [SLSA + IM] Weight Ratio Flux lation
(wt %/vol) of SLSA:IM (.mu.g/hr/cm.sup.2) T 5.0 1:1 0.52 U 5.0 1:0
0.22 V 5.0 0:1 0.02
[0296] With reference to Table 13, it can be seen that Formulation
T (containing a mixture of SLSA and IM each at a concentration 2.5%
wt/vol) was more effective at enhancing diclofenac sodium flux rate
through the skin when compared to either of Formulation U
(containing 5% wt/vol SLSA and no IM) or Formulation V (containing
5% wt/vol IM and no SLSA).
Materials and Methods for Example 14
[0297] Using methodology similar to that described in Examples
8-13, a number of formulations containing other active agents (as
described in greater detail below) were tested for permeation
through porcine skin using Franz diffusion cells.
Franz Cell Guidelines:
[0298] Skin Preparation:
[0299] Porcine skin was sourced from Lampire Biological
Laboratories (Pipersville, Pa.). The skin was then dermatomed in
house to a set thickness.
Diffusion Cell Assembly:
[0300] Diffusion cells were assembled using dermatomed porcine skin
as the substrate. Cell assembly was carried out by clamping the
skin between a donor well (the flange was coated with a thin
coating of vacuum grease to ensure a proper seal) and a receptor
well. The wells were clamped together and held in place using a
spring clamp. The receptor wells had a volume of 3.3 ml and the
clamped skin had an available surface area of .about.0.55 cm.sup.2
for the diffusion study. Once the cell was assembled, the receptor
well was filled with PBS containing 0.01 wt % NaN.sub.3 (to help
prevent skin degradation). Care was taken to ensure all bubbles are
removed from the receptor solution. The skin was allowed to
pre-hydrate for 20 minutes before the formulations were applied to
the skin.
[0301] Diffusion Cell Testing:
[0302] After the skin was prehydrated, 40 .mu.l of the test
formulation was applied to the skin with a positive displacement
pipettor and the applied dose then rubbed gently across the skin
with a glass stir rod. Once the formulation was applied, a stir bar
was added to the receptor well. The receptor well was maintained at
32.degree. C. and continuously agitated throughout the experiment.
Sample aliquots were drawn from the receptor well at varying time
points and replaced with fresh PBS buffer. Sample aliquots were
filtered and analyzed for concentration of the active using HPLC
analysis. Measurements for each formulation were carried out in
six-fold replicates.
[0303] The individual penetration enhancers used in Example 7 are
provided in the following table along with their abbreviation
(Abbr) and Chemical Abstract Service (CAS) registry number:
TABLE-US-00018 Abbr. Chemical CAS No. IM Isopropyl Myristate
110-27-0 SLSA Sodium Lauryl Sulfoacetate 1847-58-1 OA Oleic Acid
112-801-1 ML Methyl Laurate 111-82-0 GO Glyceryl Monooleate
31566-31-1 NLS N-lauroyl Sarcosine 97-78-9
[0304] Numerous formulations were prepared with the MMPE.TM.s used
in conjunction with varying active agents. MMPE.TM.s tested were
SLSA/IM, SLSA/ML, IM/NLS, GO/ML, and NLS/OA in a hydroalcoholic
solution. These MMPE.TM.s were tested with the active agents
ibuprofen, buproprion HCl, ketoprofen, and testosterone. Tables
14A-14J list the MMPE.TM.s that showed a significant increase in
flux when compared to flux from the analogous formulations
containing only one of the MMPE.TM.s.
TABLE-US-00019 TABLE 14A Formu- Ibuprofen SLSA IM Flux lation
(wt/wt %) (wt/wt %) (wt %/wt %). (.mu.g/hr/cm.sup.2) W 5 3 42.1 X 5
3 28.5 Y 5 1.5 1.5 66.5
TABLE-US-00020 TABLE 14B Formu- Ibuprofen SLSA ML Flux lation (wt
%/wt %). (wt %/wt %). (wt %/wt %). (.mu.g/hr/cm.sup.2) Z 5 3 42.1
AA 5 3 25.2 BB 5 1.5 1.5 53.9
TABLE-US-00021 TABLE 14C Formu- Ibuprofen IM NLS Flux lation (wt
%/wt %). (wt %/wt %). (wt %/wt %). (.mu.g/hr/cm.sup.2) CC 5 3 28.5
DD 5 3 10.0 EE 5 1.5 1.5 31.0
TABLE-US-00022 TABLE 14D Formu- Ibuprofen GO ML Flux lation (wt
%/wt %). (wt %/wt %). (wt %/wt %). (.mu.g/hr/cm.sup.2) FF 5 3 14.4
GG 5 3 25.2 HH 5 1.5 1.5 53.6
TABLE-US-00023 TABLE 14E Bupropion Formu- HCl NLS OA Flux lation
(wt %/wt %). (wt %/wt %). (wt %/wt %). (.mu.g/hr/cm.sup.2) II 5 3
14.3 JJ 5 3 9.1 KK 5 1.5 1.5 18.8
TABLE-US-00024 TABLE 14F Bupropion Formu- HCl SLSA IM Flux lation
(wt %/wt %). (wt %/wt %). (wt %/wt %). (.mu.g/hr/cm.sup.2) LL 5 3
34.3 MM 5 3 14.5 NN 5 1.5 1.5 45.6
TABLE-US-00025 TABLE 14G Bupropion Formu- HCl SLSA ML Flux lation
(wt %/wt %). (wt %/wt %). (wt %/wt %). (.mu.g/hr/cm.sup.2) OO 5 3
34.3 PP 5 3 14.8 QQ 5 1.5 1.5 51.3
TABLE-US-00026 TABLE 14H Bupropion Formu- HCl IM NLS Flux lation
(wt %/wt %). (wt %/wt %). (wt %/wt %). (.mu.g/hr/cm.sup.2) RR 5 3
14.5 SS 5 3 14.3 TT 5 1.5 1.5 55.9
TABLE-US-00027 TABLE 14I Formu- Ketoprofen NLS OA Flux lation (wt
%/wt %). (wt %/wt %). (wt %/wt %). (.mu.g/hr/cm.sup.2) UU 5 3 14.3
VV 5 3 9.1 WW 5 1.5 1.5 18.8
TABLE-US-00028 TABLE 14J Formu- Testosterone SLSA IM Flux lation
(wt %/wt %). (wt %/wt %). (wt %/wt %). (.mu.g/hr/cm.sup.2) XX 5 3
14.3 YY 5 3 9.1 ZZ 5 1.5 1.5 18.8
* * * * *
References