Page 1

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 I OI I i
USOO8 158 152B2
(12)
United States Patent
(10)
Palepu
(45)
(54)
LYOPHILIZATION PROCESS AND
PRODUCTS OBTAINED THEREBY
(75)
Inventor:
Nageswara R. Palepu, Mill Creek, WA
(US)
(73)
Assignee: SciDose LLC, Amherst, MA (US)
(*) Notice:
Subject to any disclaimer, the term of this
patent is extended or adjusted under 35
U.S.C. 154(b) by 1560 days.
(21)
Appl. No.: 11/282,507
(22)
Filed:
Nov. 18, 2005
(65)
Prior Publication Data
US 2007/0116729 Al
(51)
(52)
(58)
May
Y,
24, 2007
Int. Cl.
A61K 9/14
(2006.01)
U.S. Cl. .......... 424/489; 514/35; 514/291; 514/192;
514/200; 514/282
Field of Classification Search ........................ None
See application file for complete search history.
(56)
6,884,422 B1
6,900,184 B2
2002/0010357 Al
2002/0091270 Al
2002/0143038 Al
2002/0155097 Al
2003/0068416 Al
2003/0077321 Al
2003/0082236 Al
2003/0096378 Al
2003/0113316 Al
2003/0191157 Al
2003/0202978 Al
2003/0211042 Al
2003/0229027 Al
2004/0005351 Al
2004/0042971 Al
2004/0042972 Al
2004/0043042 Al
2004/0057927 Al
2004/0063792 Al
2004/0092587 Al
2004/0157789 Al
2004/0167173 Al
2004/0176357 Al
FOREIGN PATENT DOCUMENTS
WO
W099-30688
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Patent No.:
US 8,158,152 B2
Date of Patent:
Apr. 17, 2012
Jiang Guokun et al, Preparation of crystalline acyclovir sodium for
injection, Chinese Journal ofPharmaceuticals, 2002, 33(2):79-80).
Primary Examiner
Robert A Wax
Assistant Examiner
Hasan Ahmed
(74) Attorney, Agent, or Firm
Frommer Lawerence &
Haug LLP; Sandra Kuzmich, Esq.; Russell A. Garman
(57)
ABSTRACT
A lyophilization process which comprises dissolving a material in one or more solvents for said material to form a solution; forcing said material at least partially out of solution by
combining the solution and a non-solvent for the material,
which non-solvent is miscible with the solvent or solvents
used and wherein said non-solvent is volatilizable under
freeze-drying conditions. In addition, for hydrophobic and/or
lipophilic materials, the anti-solvent can be omitted, and the
solution of the material in the solvent can be subjected
directly to freeze drying. The lyophilizates can then be reconstituted with typical aqueous diluent in the case of hydrophilic materials. Hydrophobic and or lipophilic materials can
be initially reconstituted with propylene glycol and/or polyethyleneglycol to form a high concentration solution therein
and this is further diluted for use with a diluent of Intralipid,
plasma, serum, or even whole blood.
46 Claims, No Drawings
US 8,158,152 B2
Page 2
U.S. PATENT DOCUMENTS
2004/0197885 Al
2004/0234593 Al
2 004/023 59 03 Al
2005/0020509 Al
2005/0020610 Al
2005/0020615 Al
2005/0032775 Al
2005/0037067 Al
2005/0049209 Al
2005/0063912 Al
2005/0069578 Al
10/2004
11/2004
11/2004
1/2005
1/2005
1/2005
2/2005
2/2005
3/2005
3/2005
3/2005
Ueda
Kier! et al.
Khanna
Kiel et al.
Zhang et al.
Rubino
Gyollai et al.
Hovdal et al.
Chen
Montgomery et al.
Balasubramanian et al.
2005/0069584 Al
2005/0084530 Al
2005/0100598 Al
2005/0137265 Al
2005/0142190 Al
2005/0148597 Al
2005/0152962 Al
2005/0152980 Al
2005/0152981 Al
3/2005
4/2005
5/2005
6/2005
6/2005
7/2005
7/2005
7/2005
7/2005
Kiel et al.
Rao
Mizumoto et al.
Haley
Adin et al.
Kostanski et al.
Metselaar
Ausborn et al.
Gleeson et al.
FOREIGN PATENT DOCUMENTS
WO
W02004-039804
5/2004
US 8,158,152 B2
1
LYOPHILIZATION PROCESS AND
PRODUCTS OBTAINED THEREBY
CROSS-REFERENCE TO RELATED
APPLICATIONS
Not applicable.
STATEMENT REGARDING
FEDERALLY SPONSORED RESEARCH OR
DEVELOPMENT
Not Applicable
FIELD OF THE INVENTION
The present invention relates to methods of preparing lyophilizates, especially those free of undesired extra components. The invention further relates to obtaining lyophilizates
of amorphous/crystalline solids that are rapidly reconstitutable. The invention further relates to the materials resulting
from the novel lyophilization techniques presented herein.
BACKGROUND OF THE INVENTION
Freeze-drying or lyophilization has been widely used for a
number of decades in pharmaceutical, food, and chemical
industries. Freeze-drying is particularly desirable in situations where a pharmaceutical or other material is required to
be dried or dehydrated or desolvated, but is sensitive to the
application of heat for the purpose of drying. Many compounds, when exposed to the typically employed drying temperatures of non-freeze drying techniques, decompose,
degrade, or volatilize away, resulting in an undesirable product. To recognize the large number of applications to which
freeze-drying has been adapted, one need only run a simple
search of the US Patent and Trademark Office patent databases for the term "freeze drying" and/or "lyophilization",
which as of October 2005, returns over 3000 hits and covers
a wide range of active agents and other materials.
In general, the freeze-drying or lyophilization technique is
to dissolve, suspend, or emulsify a compound or formulation;
freeze the resultant solution, suspension, or emulsion; and
then to apply a vacuum thereto to sublimate/evaporate the
solvents and other liquids in the frozen mass used to dissolve,
suspend or emulsify the material. In many applications, the
use of auxiliary agents to create suitable solutions, suspensions, and emulsions is not of significant concern. This is
especially so where the auxiliary agent is acceptable to be
present in the end product, as in the use of auxiliary food
ingredients in freeze dried foods. Similarly, where pharmaceuticals are intended for oral ingestion, a wide range of
auxiliary pharmaceutically acceptable agents may be used to
aid in the preparation of lyophilized active compounds or
formulations containing such active compounds. In most
freeze-drying processes, a clear solution of the material to be
freeze dried is obtained, if possible. This is then usually
filtered aseptically to remove any extraneous solids and
microorganism, and the filtered solution is filled into glass
vials and cooled in a lyophilization chamber whereby the
dissolved solids generally freeze together with the freezable
liquid components, but may, depending upon concentration
and the rate of the freezing process, begin to come out of
solution during the process of cooling or freezing. For
example, if one were to prepare a solution at its saturation
concentration, the dissolved solid could precipitate during the
freezing process. Depending upon the solvent or solvent combination used, there may be some liquid portion that does not
freeze, but remains liquid and is distributed within the otherwise frozen mass. The application of vacuum pressures then
5 permits the removal of unfrozen liquids first, followed by the
sublimation of frozen liquid components, leaving behind a
purer, dried product. In some techniques, the freezing process
is done slowly so that crystallization takes place substantially
before the solvent is frozen. In other techniques, the freezing
io step is performed rapidly to freeze the solvent before appreciable crystallization has occurred. In still other techniques,
after freezing has taken place, addition of a small degree of
heat to warm the frozen mass slightly permits the frozen
liquid components to sublimate more readily. These same
15 techniques may be applicable to situations when suspensions,
emulsions, and complex formulations are involved, except
that the filtering step may not be suitable because it may
remove active or other auxiliary components which are
intended to be present.
20
Unfortunately, the range of acceptable materials for use in
pharmaceuticals that are intended for parenteral administration, is not as large and not so accommodating. For example,
emulsions where the freeze-drying process leaves the emulsifier and/or the oil phase present in the lyophilizate would
25 generally not be acceptable from an intravenous injection
point of view. Similarly, suspending agents would also not be
desirable. Thus, it is clear that an alternate lyophilization
procedure that could eliminate the use of undesirable auxiliary agents to a larger degree than is presently available is
3o desirable and sought after.
Although the prior art is replete with references to freezedrying and lyophilization, most literature refers to the technique in a general manner such as "the material is freeze-dried
as commonly practiced in the art" and other general state3 5 ments of similar description. Virtually all of the references
that do describe the details of the lyophilization process make
no mention of, nor suggestion of, the use of an anti-solvent or
non-solvent. Most references referto clear solutions, solvents
and co-solvents being used to obtain clarity or near clarity,
40 with the solution then being filtered. Most references involving lyophilization, when discussing solvents, refer to aqueous
materials.
Representative (non-exhaustive) patents and applications
which are of note include the following, all of which are
45 incorporated herein in their entirety. U.S. 2005/0049209 discusses freeze-drying of emulsions. U.S. Pat. No. 6,770,678
discusses that for freeze drying purposes it is desirable to have
the solution concentration as high as possible, but often the
high concentration leads to crystals forming during the cool50 ing step, which the reference states is undesirable. U.S. 2004/
0063792 mentions freeze-drying sertraline from a number of
solvent/co-solvent combinations. U.S. 2004/0043042 discusses micro-lyophilization. U.S. 2003/0229027 mentions
freeze-drying canabinoids from solvent mixtures in the pres55 ence of certain sugars. U.S. 2003/0202978 discusses spray
freeze-drying. U.S. 2002/0010357; U.S. Pat. Nos. 6,384,259;
6,407,278; 6,841,545; and 6,489,312 all relate to amifostine
lyophilizates. U.S. Pat. No. 6,566,329 discusses precipitating
human growth hormone out of solution by adjusting the pH to
60 the isoelectric point and then freeze-drying the result. U.S.
Pat. No. 5,731,291 discusses using a solvent (water) and a
second agent that sublimates at —40° C. in a lyophilization
process. W099/30688 discusses using an accelerant excipient to enhance the rate of solvent sublimation. W02004/
65 039804 discusses freeze-drying moxifloxacin from water.
The specification mentions that it can also be obtained by use
of an anti-solvent followed by filtration, decantation, or cen-
US 8,158,152 B2
3
4
trifugation. There is no suggestion that the moxifloxacin
obtained from the solution by use of an anti-solvent then be
subjected to freeze drying. U.S. 2003/082236 discusses use of
a supercritical anti-solvent.
rial in one or more solvents for said material to form a solution; forcing said material at least partially out of solution by
combining the solution and a non-solvent for the material,
which non-solvent is miscible with the solvent or solvents
used and wherein said non-solvent is volatilizable under
freeze-drying conditions or optionally seeding the solution
before or during the step of forcing it out of solution; freezing
the result thus far; and applying a vacuum to dry the frozen
result. For hydrophilic substances water is frequently the
primary solvent and forms the frozen mass while any cosolvent and the anti-solvent may or may not freeze during the
freezing step. For lipophilic or hydrophobic materials, water
is frequently the anti-solvent and it is the solvent and potential
co-solvent which may or may not freeze during the freezing
step. Either way, the dissolved material is forced out of solution by the anti-solvent, the result subjected to freezing temperatures to form a frozen mass, and the frozen mass subjected to vacuum pressures to result in a lyophilizate. In
addition, for hydrophobic and/or lipophilic materials, the
anti-solvent can be omitted, and the solution of the material in
the solvent can be subjected directly to freeze drying. The
lyophilizates can then be reconstituted with typical aqueous
diluent in the case of hydrophilic materials. Hydrophobic and
or lipophilic materials can be initially reconstituted with propylene glycol and/or polyethyleneglycol to form a high concentration solution therein and this is further diluted for use
with a diluent of Intralipid, plasma, serum, or even whole
blood.
OBJECTS OF THE INVENTION
5
It is therefore an object of the invention whereby a hydrophilic or a hydrophobic material may be lyophilized using a
minimum number of auxiliary materials.
It is another object of the invention to prepare lyophilizates 10
of water sensitive materials.
It is still another object of the invention whereby an amorphous material may be recovered via lyophilization with or
without the use of auxiliary agents.
Still another object of the invention is to provide a non- 15
aqueous lyophilization technique which includes several
organic solvents which have not been previously known for
use in the lyophilization process art.
It is still another object of the invention whereby a crystalline hydrate and/or amorphous material may be recovered via 20
lyophilization without the use of auxiliary agents while
simultaneously avoiding the use of ethanol.
An even further object of the invention is to provide a
method of obtaining a substantially pure, readily reconstitutable hydrophilic or hydrophobic or lipophilic material sub- 25
stantially free of auxiliary materials.
An even further object of the invention is to provide a
method of obtaining a substantially pure, readily reconstitutable hydrophilic or hydrophobic or lipophilic material substantially free of auxiliary materials which when reconstitutes
DETAILED DESCRIPTION OF THE INVENTION
with pharmaceutically acceptable diluent will result in either 30
a clear solution or a micellar solution or an emulsion or a
The present invention is directed to a method for freezesub-micron suspension.
drying or lyophilizing a material which may be (i) hydroAn even further object of the invention is to provide a
philic or (ii) hydrophobic and/or lipophilic. Generally when
method of obtaining a substantially pure, readily reconstitutable material containing a hydrophobic or lipophilic sub- 35 the material is hydrophilic, the material is also sensitive to the
presence of moisture. The material is usually a substantially
stance that further contains at least one of a solubilizer or a
pure compound, preferably a pure compound, but may also be
surfactant or combinations thereof which material, upon
a simple or complex mixture. The material is dissolved in a
reconstitution with pharmaceutically acceptable diluent will
solvent therefor, preferably without, but potentially with, one
result in either a clear solution or a micellar solution or an
40 or more co-solvents so as to obtain a substantially clear,
emulsion or a sub-micron suspension.
preferably clear, solution of said material therein. Solvent for
Yet another object of the invention is to provide a method
the material is one which can be removed in a freeze-drying
for obtaining an amorphous lyophilizate which is stable in the
process, i.e., one that is volatile or sublimates at the temperapresence of moisture.
ture and pressure used in the primary drying step with any
An even further object of the invention is to provide a
method of obtaining crystalline hydrate lyophilizates that are 45 residual amount being removable during a secondary drying
step. If desired, the solution may be filtered aseptically before
stable in the presence of moisture.
combining it with the anti-solvent which is also filtered asepYet another object of the invention is to prepare stable
tically, to remove any undesired (or undissolved) materials as
lyophilizates of water sensitive materials from a lyophilizawell as microorganisms from the material containing solution
tion process that includes water.
A further object of the invention is provide new, simplified so and anti-solvent. Alternatively, a pH adjustment can be
effected prior to the optional filtration in order to aid stability
lyophilization procedures for lipophilic and/or hydrophobic
and/or solubility, and/or post filtration to aid stability. Prefermaterials, with or without the use of anti-solvents.
ably, a pH adjustment for stability purposes, when used, is
An even further object of the invention is to provide novel
conducted before the optional filtration step. The pH adjustlyophilizates of lipophilic and/or hydrophobic materials.
Still a further object of the invention is to provide novel 55 ment can be accomplished by the addition of an acid or a base
or a buffer. Once the material to be lyophilized is in solution,
reconstitution methods for lyophilizates of lipophilic and/or
the solution is subjected to an anti-solvent for the material (or
hydrophobic materials.
a mixture of anti-solvents for the material). The anti-solvent
An even further object is to provide a rapidly dissolving
for the material is volatile or sublimates under lyophilization
end-used product that is suitable for use in delivering single
60 conditions (i.e., at the pressure and temperature used in the
unit dosages of in excess of hundreds of milligrams.
primary drying step). If the anti-solvent doesn't freeze under
Still other objects of the invention will be apparent to those
lyophilization conditions, special lyophilization techniques
of ordinary skill in the art.
are adopted (such as the inclusion of a liquid nitrogen trap
BRIEF SUMMARY OF THE INVENTION
between the condenser and vacuum pump, and the like) to
65 remove the anti-solvent. The anti-solvent is not a solvent for
These and other objects of the invention are surprisingly
the material and the material is essentially insoluble in the
achieved by a process which comprises dissolving the mateanti-solvent but is miscible with the solvent used to dissolve
US 8,158,152 B2
5
(and any co-solvent that is present to dissolve) the material so
parts water); "very slightly soluble" (1 part solute/1000 parts
that upon its addition, a substantial portion preferably subwater to 1 part solute/10000 parts water); and "practically
stantially all, most preferably all, of the material is forced out
insoluble" or "insoluble" (1 part solute/>10000 parts water).
of solution and forms a suspension or slurry of solid particuAll of the designations "very soluble", "freely soluble",
lates in the complex solvent/optional co-solvent/anti-solvent 5 "soluble", "sparingly soluble" and "slightly soluble" indicate
mixture. Optionally before or during, preferably before or at
materials which can be considered hydrophilic for the present
the beginning of, the step when the material is forced out of
invention. The designations "very slightly soluble", "practisolution, the solution may be seeded with a portion of the
cally insoluble", and "insoluble" can be considered hydromaterial that is in the desired solid form to enhance formation
phobic for purposes of the invention. The above classification
of the appropriate form of the material. Optionally, if desired, io system is used detailed in Remington: The Science and Practhe result can then be filtered, decanted, etc. to separate a
tice of Pharmacy 19th Ed., Mack Publishing co., Easton, Pa.
portion of the solvent/optional co-solvent/anti-solvent mix1995, Page 195, and is described in the United States Pharture from the precipitated solids. When such a separation
macopoeia. A second system is by a determination of the
technique is used, the separated solids are still wet with the
partition coefficient, P, defined as the ratio of the concentrasolvent/optional co-solvent/anti-solvent mixture. Whether or 15 tion of a material in octanol to the concentration in water in an
not the post precipitation separation technique is used, the
octanol/water system at equilibrium at 25° C. Generally, valresulting wet solids (suspension, slurry, etc.) are then frozen
ues for Pare given as log P (see Handbook of Chemistry and
and the frozen solid is dried by the application of vacuum to
Physics 86'h Ed. 2005-2006 at Pages 16-41 to 16-45 and
remove the solvent, the co-solvent, and the anti-solvent. In
Remington: The Science and Practice of Pharmacy 19th Ed.,
some embodiments, one or more (but not all) of the solvent/ 20 Mack Publishing Co., Easton, Pa. 1995, Pages 158-159).
optional co-solvent/anti-solvent of choice does not freeze at
Values of P«1 (log P is negative) are clearly hydrophilic.
the freezing step temperature allowed by the lyophilizer.
Values of P»1 are generally hydrophobic. However, since
When this is the case, special anti-solvent removal conditions
this measure is in the octanol/water system, it is not absoneed to be used. These special removal conditions include the
lutely controlling in the invention, but merely indicative of
use of a liquid nitrogen trap and other similar techniques 25 whether a particular material is a likely hydrophilic or likely
known in the art.
hydrophobic one for initial consideration of the solvent, coThe material may be selected from a wide range of comsolvent, and anti-solvent to use. Another guideline useful for
pounds and compositions, but is preferably a substantially
consideration of the hydrophilic or hydrophobic nature of the
pure compound, most preferably a pure compound, where
material is the hydrophilic-lipophilic balance (HLB) system.
"pure" indicates as reasonably pure as can be obtained using 30 (See Remington above, pages 287-288). Although the HLB
at least commercially reasonable standards and tolerances.
system was developed for surface active agents, it does give
Thus, a product is "pure" for purposes of this invention if (in
another guideline as to the hydrophilic nature or hydrophobic
the context of pharmaceutical materials) it is sufficiently pure
nature of a material, with hydrophilic materials having an
to meet Federal Food and Drug Administration purity stanHLB greater than about 10 and hydrophobic materials having
dards. If the product in question is other than an end use 35 an HLB value generally below about 10. Once a potential
pharmaceutical, the product is considered "pure" if it meets
solvent and potential anti-solvent are selected however, conthe relevant industry standard for purity. Such industry stanfirmation should be sought that the chosen anti-solvent does
dards include standards, such as "Reagent Grade", etc.
substantially push the material out of solution in the chosen
Compounds that can benefit from the present invention
solvent or solvent/co-solvent mixture. The more efficiently
include, but are not limited to, pharmaceutically active com- 4o and completely the anti-solvent pushes the material out of
pounds, veterinary compounds, food materials, dyes, housesolution, the better the invention should be expected to give
hold and industrial chemicals, etc. Selected, non-limiting,
the desired results.
representative compounds include hydrophilic materials as
Useful compounds which can be prepared in lyophilizate
well as hydrophobic/lipophilic materials. Various hydrates
form according to the invention (generally include, but are not
and solvates in various polymorphic forms of such materials 45 limited to, end use acceptable salts, amides thereof, sulfonaare also suitable. Conversion from hydrophilic to hydrophomides thereof, carbamates thereof, esters thereof and phosbic materials may often be accomplished by a pH change
phoesters thereof, hydrates and solvates thereof, and crystalbetween a charged species and an uncharged one, such as for
line polymorphs and amorphous forms thereof, and
example conversion between a free acid or base (less water
racemates, enantiomers, and diastereomers thereof). In the
soluble) and a salt thereof (more water soluble). If the solu- 50 following exemplary list, most of the compounds are pharbility shifts sufficiently, the solvents/co-solvents for one form
maceutically or veterinary acceptable compounds. Thus, the
can become the anti-solvent for the other form and the antisalt or ester is preferably those that are acceptable in these
solvents for the first form can become the solvents for the
uses. However, if the lyophilizate will be further modified
latter. Thus, the invention is applicable to free acids, free
before being used as a pharmaceutical or veterinary material,
bases, their salts, and zwitterionic species where appropriate, 55 the salt or ester is not so limited. In addition, the following
and those materials having a permanent charge such as
more extensive list, lists one moiety for the free base, the free
betains and sultanes, and other quaternium compounds. A
acid, and all salts thereof, so that the absence of a particular
general guideline as to the hydrophilic vs hydrophobic nature
salt or of the free acid or free base when another is present,
of compounds can be gleaned from a variety of methods
should be construed to include the listing of all such suitable
known in the art. A simple system is the simple solubility of 60 forms. Similarly, not all pharmaceutically acceptable esters
the compound in question in water and is designated by the
are indicated, and again, the listing of a non-esterified form
terms "very soluble" (1 part solute/less than 1 part water),
should be deemed to include the suitable esterified counter"freely soluble" (1 part solute/1 part water to 1 part solute/10
parts. In addition, compounds having a quaternary ammoparts water); "soluble" 1 part solute/10 parts water to 1 part
nium are listed only as the primary species without reference
solute/30 parts water); "sparingly soluble" (1 part solute/30 65 to the counterion (i.e., benzalkonium, rather than benzalkoparts water to 1 part solute/100 parts water); "slightly
nium chloride, etc), but all suitable counterions are deemed to
soluble" (1 part solute/100 parts water to 1 part solute/1000
be within the scope of the invention.
US 8,158,152 B2
7
8
In light of the size of the more extensive list, the inventor
acetazolamide, acetiamine, acetiromate, acetohexamide,
presents his preferred compounds of interest, but this is only
acetophenazone, acetophenetidin, acetorphine, acetosulfone,
in the interest of clarity and should not be taken as a limitation
acetriozoic acid, acetylcysteine, acetyldigitoxin, acetylleuon the broader scope of the invention. Preferred compounds
cine, acetyltributyl citrate, acetyltriethyl citrate, acevaltrate,
for use as the material to be lyophilized according to the 5 acexamin acid, acifran, acipimox, acitazanolast, acitemate,
invention include antibiotics (including penicillins, cephaacitretin, acivicin, alcantate, aclarubicin, aclatonium napalosporins, tetracyclines, macrolides, etc) xanthines, anesthetdisilate, acolbifene, aconiazide, aconitine, acotiamide, acoxics (including barbiturates, narcotics, and the "caines"), antiatrine, acreozast, acridorex, acriflavine, acrihellin, acrisorcin,
emetics, anti-cancer agents, etc. A specifically preferred
acrivastine, acroinonide, acronine, actaplanin, actarit, actinogroup of compounds includes, but is not limited to, alfentanil io quinol, actisolide, actodigin, acyclovir, adafenoxate,
(particularly the hydrochloride especially the monohydrate),
adamexine, adapalene, adaprolol, adatanserin, adefovir, adeamifostine (particularly the amorphous and trihydrate forms),
kalant, adelmidrol, ademitrionine, adenosine, adibendal, adiaminophyllin (particularly the dehydrate form), amoxicillin
cillin, adimolol, adinazolam, adiphenine, aditeren, aditoprim,
(particularly the trihydrate form), ampicillin (especially the
adosopine, adozelesin, adrafinil, adrenalone, adrogolide,
trihydrate form), bupivacaine (especially the hydrochloride 15 afalanine, afeletecan, afloqualone, afovirsen, afurolol, aganosalt and particularly the monohydrate form), caffeine (espedine, aglepristone, agomelatine, aklomide, alacepril, alafoscially the monohydrate form), cefepime (especially the
falin, alagebrium, alamecin, alamifovir, alanine, alanosine,
hydrochloride salt and particularly the monohydrate form),
alaproclate, alatrofloxacin, alazanine triclofenate, albaconaceftazidime (especially the pentahydrate form), ceftriaxone
zole, albendazole, albuterol, albutoin, alclofenac, alclometa(especially the 3.5 hydrate form), cephradine (particularly the 20 Bone, alcloxa, alcuronium, aldioxa, aldosterone, alemcinal,
mono and di hydrate forms), chromic chloride (especially the
alendronic acid, alentemol, alepride, alestramustine, alehexahydrate form), clindamycin (especially the monohydrate
tamine, alexidine, alexitol, alexomycin, alfacalcidol, alfadex,
form), codeine, cyclophosphamide, cysteine, dextrose, doxalfidalone, alfaprostol, alfatradiol, aldaxalone, alfentranil,
apram (particularly the hydrochloride salt and especially the
alfluzosin, algeldrate, algestone, alibendol, aliconazole,
monohydrate form) doxycycline (especially the monohydrate 25 alifedrine, alifurane, alilusem, alimadol, alinastine, alinidine,
form), edetate (especially the dihydrate form), hyoscyamine
alipaminde, aliskiren, alitame, alitretinoin, alizapride, alle(especially the sulfate salt and the dihydrate form), levorphatorphine, allobarbitol, allocamide, allocupreide, allomethadinol (especially as the dihydrate form), lidocaine (particularly
one, allopurinol, allylestrenol, allylprodine, almecillin, almas the hydrochloride salt and especially as the monohydrate
estrone, alminoprofen, almitrine, almokalant, almotriptan,
form), lincomycin (particularly as the hydrochloride salt and 3o almoxatone, almurtide, alnespirone, alniditan, alonacic acid,
especially in the monohydrate form), menadiol (particularly
alonimid, aloracetam, alosetron, alovudine, aloxidone, aloxas the sodium diphosphate salt and especially in the hexhyiprin, aloxistatin, alozafone, alpertine, alphameprodine,
drate form), neropenam (especially as the trihydrate), metoalphamethadol, alphamethyldopa, alphaprodine, alpidem,
clopramide (particularly as the hydrochloride salt and espealpiropride,
alprafenone,
alprazolam,
alprenolol,
cially in the monohydrate form), morphine (particularly as 35 alprenoxime, alprostadil, alrestatin, altanserin, altapizone,
the sulfate salt and especially in the pentahydrate form),
alteconazole, althiazide, altinicline, altoqualiine, altrenogast,
nafcillin (particularly as the sodium salt and especially in the
altretamine, alvemeline, alverine, alvimopan, alvocidib, amamonohydrate form), norepinephrine (particularly as the bitardinone, amafalone, amanozine, amantadine, amantocillin,
trate salt and especially in the monohydrate form),
ambamustine, ambasilide, ambazone, ambenonium,
ondansetron (particularly as the hydrochloride salt and espe- 4o ambenoxan, ambomycin, ambrisentan, ambroxol, ambruticially in the dihydrate form), oxacillin (particularly as the
cin, ambucaine, ambucetamide, ambuphylline, ambuside,
sodium salt and especially as the monohydrate), oxytetracyambutonium, amcinafal, amcinafide, amcinonide, amdinocilcline (especially as the dihydrate), piperacillin (especially as
lin, amdoxovir, ambucort, amedalin, amelometasone, ameltthe monohydrate, scopolamine (particularly as the hydrobroolide, amelubant, amesergide, ametantrone, amethocaine,
mide salt and especially as trihydrate), spectinomycin (par- 45 amezapine, amezinium, amfenac, amfepentorex, amfetamiticularly as the dihydrochloride and especially as the pentahynil, amflutizole, amfonelic, amicarbalide, amicloral, amicydrate), succinylcholine (particularly as the chloride salt),
cline, anidantel, amidapsone, amidephrine, amiflamine, amitheophylline (especially as the monohydrate), thiothixene
floverine, amifloxacin, amifostine, amiglumide, amikacin,
(particularly as the dihydrochloride and especially as the
amikhelline, amiloride, amiloxate, aminacrine, amindocate,
dihydrate), tubocurarine (particularly as the hydrochloride 5o amineptine, aminoglutethimide, aminohippuric acid, amisalt and especially as the pentahydrate form), moxifloxacin,
nolevulinic acid, aminometradine, aminopentamide, amitacrolimus, itraconazole, argatroban, posaconazole, voranophenazone, aminophylline, aminopromazine, aminopconazole, docetaxel, fludarabine, glatiramer acetate, gemcitterin, aminopyrine, aminoquinol, aminoquinuride, aminorex,
abine, irinotecan, epoprostenol, and 7-ethyl-l0-hydroxy
aminosalicylic acid, aminothiazole, amiodarone, amiperone,
camptothecin.
55 amphenazole, amipizone, amiprolose, amiquinsin, amisomeA more complete list of compounds, most of which are
tradine, amisulprode, amiterol, amithiozone, amitivir, amipharmaceutical or veterinary, which can be utilized in the
traz, amitriptyline, amitriptyinoxide, amixetrine, amlexanox,
present invention includes, but is not limited to: abacavir,
amlintide, amlodipine, amocarzine, amodiaquine, amolabamectin, abanoquil, abaperidone, abarelix, abecamil, abianone, amonafide, amoproxan, amopyroquine, amorolfine,
raterone, abitesartan, ablukast, abunidazole, acadesine, 60 amoscanate, amosulatol, amotosalen, amotriphene, amoxapacamprosate, acaprazine, acebrochol, acebutolol, acecainide,
ine, amoxecaine, amoxicillin, amoxydramine, amperozide,
acecarbromal, aceclidine, aceclofenac, acedapsone, acediaanphechloral, amphenidone, amphetamine, amphomycin,
sulfone, acedoben, acefluranol, acefurtiamine, acefylline
amphotalide, amphotericin, ampicillin, ampiroxicam,
clofibrol, acefylline piperazine, aceglatone, aceglutaminde,
amprenavir, amprolium, ampyrimine, ampyzine, amquinate,
acemetacin, aceneuramicacid, acenocoumarol, acepeprone, 65 amrubicin, amsacrine. amtolmetin, amustaline, amylobaracepromazine, aceprometazine, acequinoline, acesulfame,
bital, angestone, anagrelide, anakinra, anaritide, anastrozole,
acetaminosalol, acetanilide, acetarsone, acetaminophen,
anatibant, anaxirone, anazocine, anazolene, ancarolol, ancit-
US 8,158,152 B2
9
10
abine, andolast, androstenediol, androstenedione, andulafunzocaine,
benzoclidine,
benzoctamine,
benzodepa,
gin, anecortave, anetholtrithion, angiotensin amide, andidoxbenzododecinium, benzonatate, benzopyrronium, benzoamine, anidulafungin, anilamate, anileridine, anilopam,
quinonium, benzotript, benzoxiquine, benzoxonium, benanipamil, aniracetam, anirolate, anisacril, anisindione,
zoylpas, benzphetamine, benzpiperylon, benzpyrinium, benanisopirol, anisotropine, anisperimus, anitrazafen, anpirto- 5 zquercin, benzquinamide, benzthiazide, benztropine,
line, ansoxetine, antafenite, antazoline, antazonite, anthelmybenzydamine, benzylhydrochlorothiazide, benzylpenicillin,
cin, anthralin, anthramycin, antipyrine, antrafenine, apadobenzylsulfamide, bepafant, beperidium, bephenium, bepiasline, apafant, apalcillin, apaxafylline, apaziquone, apazone,
tine, bepridil, beractant, beraprost, berberine, berefrine, berapicycline, aplindore, apomorphine, apovincamine, apragenin, berlafenone, bermoprofen, bertosamil, berupipam,
clonidine, apramycin, aprepitant, aprakalim, aprindine, io bervastatin, berythromycin, besigomsin, besipirdine, besonaprinocarsine, apofene, aprosulate, aptazapine, aptiganel,
prodil, besulpamide, besunide, beta carotene, betacetylmethaptocaine, aranidipine, aranotin, arbaprosil, arbekacin, arbadol, betahistine, betaine, betameprodine, betamethadol,
utamine, arclofenin, ardacin, ardeparin, arecoline, arfalasin,
betamethasone, betamicin, betamipron, betaprodine, betaxarfendazam, arformoterol, argatroban, argimesna, argipresolol, betazole, bethanacol, bethanidine, betiatide, betoxsin, argiprestocin, arlidone, arimoclomol, aripiprazole, 15 ycaine, bevantolol, bevonium, bexarotene, bexlosteride,
armodafinil, amolol, arofylline, artinolol, arprinocid, arprobezafibrate, beztiramide, bialamicol, biapenem, bibezonium,
midine, arsanilic acid, arteflene, artemether, artemisinin, artebibrocathol, bilcalutamide, bicifadine, bicoldil, biclofibrate,
motil, artenimol, artesunate, articaine, artilide, arundic acid,
biclotymol, bicozamycin, bidimazium, bidisomide,
arzoxifene, ascorbic acid, arsenapine, aseripide, asimadoline,
bietamiverine, bietaserpine, bifemelane, bifepramide,
asobamast, asocainol, asoprisnil, aspartame, aspartocin, 20 bifeprofen, bifeprunox, bifluranol, bifonazole, bilastine,
asperlin, aspirin, aspoxicillin, astemizole, astromicin, asulabimakalim, bimatoprost, bimoclomol, bimosiamose, bincrine, atamestane, ataprost, ataquimast, atavanavir, atenolol,
darit, binedaline, binfloxacin, binfibrate, biniramycin, biniatevirdine, atibeprone, atilmotin, atipamezole, atipromod,
zolast, binodenosine, binospirone, bioallethrin, botin, bipenatiprosin, atizoram, atliprofen, atocalcitol, atolide, atomoxetamol, biperiden, biphenamine, biricodar, biriperone,
ine, atorvastatin, atosiban, atovaquone, atracurium, atrasen- 25 bisacodyl, bisantrene, bisaramil, bisbendazole, bisbentan, atraleuton, atrimustine, atrinositol, atromepane, atropine,
tiamine, bisbutiamine, bisdequilinium, bisfenazone, bisfentiatropine oxide, auranofin, aurothioglucose, avanafil, avadine, bisnafide, bisorbin, bisoctriazole, bisoprolol, bisorcic,
simibe, avicatonin, avalamycin, aviptadil, avitriptan,
bisoxatin, bispyrithione, bithonol, bithionoloxide, butipaavizafone, avobenzone, azoparcin, avorelin, avridine, axamzone, bitolterol, bitoscanate, bivalirudin, bizelesin, bleomyozide, axitirome, axomadol, azabon, azabuperone, azaciti- 30 cin, blonanserine, bluensomycin, bofumustine, bolandiol,
dine, azacitidine, azaclorzine, azaconazole, azacosrterol, azabolasterone, bolazine, boldenone, bolenol, bolmantalate,
cyclonol, azaftozine, azalanstat, azalomycin, azaloxan,
bometolol, bopindolol, bomaprine, bomaprolol, borelone,
azamethiphos, azamethonium, azamulin, azanator, azanidaborocaptane, bortezomib, bosentan, botiacrine, boxidine,
zole, azaperone, azapetine, azaquinzole, azaribine, azarole,
brallobarbital, brasofensine, brazergoline, brefonalol, bremaazaserine, azasetron, azaspirium, azastene, azatadine, aza- 35 zocine, brequinar, bretazenil, bretyllium, brifentanil, brithioprine, azelaic acid, azelastine, azelinnidipine, azepexole,
monidine, brinazaprone, brindoxime, brinzolamide, brivuazepindole, azetepa, azetirelin, azidamfenicol, azidocillin,
dine, brobactam, broclepride, brocrestine, brocrinat,
azimexon, azimilide, azintamide, azipramide, azithromycin,
brodimoprim, brofaromine, brofoxine, brolaconazole, brolaazlocillin, azlocillin, azolimine, azosemide, aztomycin,
mfetamine, bromadoline, bromamid, bromazepam, broaztreonam, azumolene, bacampicillin, bacitracin, baclofen, 40 mchlorenone, bromebric acid, bromerguride, brometebacmecillinam, bakeprofen, balaglitazone, balazipone, balonamine, bromfenac, bromhexene, bomindione,
floxacin, balsalazide, bamaluzole, bamaquimast, bambermybromisovalum, bromociclen, bromocriptine, bromodiphecin, bambuterol, bamethan, bamifylline, bamipine, bamirasnylhydramine, bromofenfos, bromofos, bromopride, brotine, bamidazole, banoxantrone, baquiloprim, barbexaclone,
moxanide, bromperidol, brompheniramine, broparestrol,
barbital, barixibat, barmastine, barnidipine, barucainide, 45 broperamol, bropirimine, broquinaldol, brosotaminde, brosbarusiban, basifangin, batalbulin, batanopride, batebulast,
tallicin, brosuximide, brotianide, brotizolam, brovanexine,
batelapine, batilol, batimastat, batoprozine, baxitoizine,
brovincamine, broxaldine, broxaterol, broxitalamide, broxubazedoxifene, bazinaprine, becanthone, becatecarin, beciparridine, broxyquinoline, bucainide, bucetin, buciclovir, bucilcil, beclamide, becliconazole, beclobrate, beclomethasone,
lamine, bucindolol, bucladesine, buclizine, buclosaminde,
beclotiamine, befetupitant, befiperide, befloxatone, 5o bucloxic acid, bucolme, bucricaine, bucromarone, bucubefunolol, befuraline, bekanamycin, belaperidone, belarizmolol, budesonide, budipine, budotitane, budralazine,
ine, belfosdil, belotecan, beloxamide, beloxepin, bemarbufenadrine, bufeniode, bufetolol, bufexamac, bufezolac,
inone, bemegride, bemesetron, bemetizide, beminafil, bemibuflomedil, bufogentin, buformin, bufrolin, bufuralol, bufylparin, bemetradine, bemoradan, bemotrizinol, benactyzine,
line, bulaquine, bumadizone, bumecaine, bumepidil, bumetbenafentrine, benapryzine, benaxibine, benazepril, ben- 55 anide, bumetriazole, bunaftine, bunamidine, bunamiodyl,
cianol, bencisteine, benclonidine, bencyclane, bendacalol,
bunaprolast, bunazosin, bunitrolol, bunolol, buparvaquone,
bendamustine, bendazac, bendazol, benderizine, bendroflubupicomide, bupivacaine, bupranolol, buprenorphine, bupromethazide, benethamine penicillin, benexate, benfluorex,
pion, buquinerin, buquinolate, buquiterine, buramate,
benfosformin, benfotiamine, benflurodil, benhepazone, beniburodiline, buserelin, buspirone, busulfan, butobarbital,
dipine, benmoxin, benolizime, benorilate, benorterone, 6o butacaine, butacetin, butaclamol, butadiazamide, butafosfan,
benoxifos, benoxaprofen, benoxinate, benpenolisin, benpeributalamine, butalbital, butamben, butamirate, butamisole,
dol, benproperine, benrixate, bensalan, benserazide, bensulbutamoxane, butanilicaine, butanserin, butantrone, butaperadazic acid, bentazepam, bentemazole, bentiamine, bentipizinc, butaprost, butaverine, butedronate, bytenafine, buterizmine, bentiromide, bentoquatam, benurestat, benzalkonium,
ine, butenamate, buthiazide, butibufen, butifrine, butikacin,
benzarone, benzbromarone, benzestrol, benzethidine, benze- 65 butilfenin, butinazocine, butinoline, butirosin, butixirate,
thonium, benzetimide, benzilonium, benzindopyrine, benbutixocort, butobendine, butoconazole, butocrolol, butoctaziodarone, benzmalecene, benznidazole, benzobarbital, benmide, butofiolol, butonate, butopamine, butopiprine, buto-
US 8,158,152 B2
11
12
prozine, butopyrammonium, butorphanol, butoxamine,
terol, choline alfoscerate, choline, chromic chloride, chromobutoxylate, butriptyline, butropium, butylscopolamine,
nar, ciadox, ciaftalan, ciamexon, cianergoline, cianidanol,
butynamine, buzepide, cabastine, cabergoline, cactinomycin,
cianopramine, ciapilome, cicaprost, cicarperone, ciclactate,
cadralazine, cadrofloxacin, cafaminol, cafedrine, caffeine,
ciclafrine, ciclazindol, ciclesonide, cicletanine, cicliomenol,
calcifediol, calciprotriene, calcitriol, calcobutrol, caldaret, 5 ciclonicate, ciclonium, ciclopirox, ciclopramine, cicloprocaldiamine, caloxetic acid, calteridol, clausterone,
fen, cicloprolol, ciclosidomine, ciclotizolam, ciclotropium,
camazepam, cambendazole, camaglibose, camiverine, campcicloxilic acid, cicloxolone, cicortonide, cidofovir, cidoxtothecin and its analogues such as 9-amino camptothecin,
epin, cifenline, cifostodine, ciglitazone, ciheptolane, cila10-hydroxy camptothecin, 7-ethyl-l0-hydroxy camptothdopa, cilansertron, cilastatin, cilazapril, cilengitide, cilexin,
ecin, 9-nitro camptothecin and all other camptothecin ana- io cilnidipine, cilobamine, cilobradine, cilofungin, cilomilast,
logues with six, seven and eight membered lactone rings,
cilostamide, cilostazol, ciluprevir, cilutazoline, cimaterol,
camonagrel, camostat, camylofin, canbisol, candesartan, cancimemoxin, cimetidine, cimetropium, cimicoxib,
dicidin, candocuronium, candoxatril, candoxatrilat, canercimoxatone, cinacalcet, cinalukast, cinametic acid,
tinib, canfosfaminde, cangrelor, cannabinol, canrenoate, cancinamolol, cinanserin, cinaproxen, cinchophen, cinecromen,
renone, capectitabine, capobenate, capobenic acid, 15 cinepazet, cinepazide, cinfenine, cinfenoac, cinflumide,
capravirine, capreomycin, capromorelin, caproxamine, capcingestol, cinitapride, cinmetacin, cinnamaverine, cinnamedsaicin, captamine, captodiame, captopril, capuride, caraberrine, cinnarizine, cinnofuradione, cinoctramide, cinodine,
sat, caracemide, carafiban, caramiphen, carbachol, carbadox,
cinolazepam, cinoquidox, cinoxacin, cinoxate, cinoxolone,
carbamazepine, carbentel, carbasone, carbaspirin, carbazcinoxopazide, cinperene, cinprazole, cinpropazide, cinpromeran, carbazochrome, carbazocine, cabenicillin, carbenox- 20 ide, cintazone, cintriamide, cinuperone, cioteronel, cipamfylolone, carbenzide, carbetapentane, carbetocin, carbidopa,
line, cipemastat, ciprafamide, cipralisant, ciprazafone,
carbimazole, carbinoxamine, carbiphene, carbofenotion, carciprefadol, ciprocinonide, ciprofibrate, ciprofloxacin,
boplatin, carboprost, carboquone, carbubarb, carburazepam,
ciprokiren, cipropride, ciproquazone, ciprestene, ciramadol,
carbutamide, carbuterol, carcainium, carebastine, carfentacirazoline, cirolemycin, cisapride, cisatracurium, cinconanil, carfimate, cargutocin, cariporide, carisoprodol, carman- 25 tole, cismadinone, cisplatin, cistinexine, citalopram,
tadine, carmofur, carmoterol, carmustine, camidazole, carcitatepine, citenamide, citenazone, citicoline, citiolone, cizonitine, carocainide, caroverine, caroxazone, carperidine,
lirtine, cladribine, clamidoxic acid, clamikalant, clamoxcarperitide, carperone, carphenazine, carpindolol,
yquin, clanfenur, clanobutin, clantifen, clarithromycin, clacarpipramine, carprazidil, carprofen, capronium, carsalam,
vulanate, clazolam, clazolimine, clazuril, clebopride,
carsatrin, cartasteine, cartazolate, carteolol, carubicin, cara- 30 clefamide, clemastine, clemeprol, clemizole, clenbuterol,
monam, carvedilol, carvotroline, carzelesin, carzenide, casclenpirin, clentiazem, cletoquine, clevidipine, clevudine,
anthranol, casokefaminde, caspofungin, cathine, cathinone,
clibucaine, clidafidine, clidanac, clindium, climazolam,
cebaracetam, cedefingol, cefaclor, cefadroxil, cefalonium,
climbazole, climiqualine, clinafloxacin, clindamycin, clicefaloram, cefamandole, cefaparole, cefatriazine, cefazaflur,
nofibrate, clinolamide, clinprost, clioquinol, clioxanide, clipcefazedone, cefazolin, cefbuperazone, cefanel, cefcapene, 3 5 rofen, cliropamine, clobazam, clobenoside, clobenzepam,
cefclidin, cefdaloxime, cefdinir, cefditoren, cefedrolor,
clobenorex, clobenztropine, clobetasol, clobetasone, clobuticefempidone, cefepime, cefetamet, cefetecol, cefetriaole,
nol, clobuzarit, clocanfamide, clocapramine, clociguanil,
cefivtril, cefixime, cefmatilen, cefinenoxine, cefinepidium,
clocinizine, clocortolone, clocoumarol, clodacaine,
cefmetazole, ceminox, cefodizime, cefonicid, cefoperazone,
clodanolene, clodazon, clodoxopone, clodronate, clofaraceforanide, cefoselis, cefotaxime, cefotetan, cefotiam, 4o bine, clofazimine, clofenamic acid, clofeniclan, clofencefovecin, cefoxazole, cofoxitin, cefozopran, cefpimizole,
etamine, clofenoxyde, clofevine, clofexamine, clofezone,
cefpiramide, cefpodoxime, cefprozil, cefquinome, cefrotil,
clofibrate, clofibric acid, clofibride, clofilium, clofucarba,
cefroxadine, cefsulodin, cefsumide, ceftazidime, cefteram,
clofoctol, cloforex, clofurac, clogestone, cloguanamil, cloceftezole, ceftibuten, ceftioflur, ceftiolene, ceftioxide, ceftmacrin, clomegestone, clometacin, clometherone, clomethiaioxime, ceftriaxone, cefuracetamime, cefuroxime, cefu- 45 zole, clometocillin, clomifenoxide, clominorex, clomiphene,
zonam, celecoxib, celgosivir, celiprolol, cemadotin, cephclomipramine, clomocycline, clomoxir, clonazepam, clonaacetrile,
cephadrine,
cephalexin,
cephaloglycin.
zoline, clonidine, clonitazine, clonixeril, clonixin, clopamCephaloridine, cephalothin, cephapirin, cepharanthine, cephide, clopenthixol, cloperastine, cloperidone, clopidogrel, cloradine, cericlamine, cerivastatin, ceronapril, ceruletide, cetapidol, clopimozide, clopipazan, clopirac, cloponone,
ben, cetalkonium, cetamolol, cetefloxacin, cethexonium, 50 cloprendol, cloprostenol, cloprothiazole, cloquinate, clocethromycin, cetiedil, cetilistat, cetirizine, cetocycline,
quinozine, cloracetadol, cloranolol, clorazepate, clorazepic
cetopheincol, cetotiamine, cetoxime, cetraxate, cetrimoacid, clorethane, chlorexolone, clorfenvinos, clorgiline, clonium, cetylpyridinium, cevimeline, chaulmosulfone, chenoricromen, cloridarol, clorindanic acid, clorindione, clodiol, chinofon, chlofibrate, chlophendianol, chloracyzine,
rmecaine, cloroperone, clorophene, cloroqualone, clochloralose, chlorambusil, chloramines-T, chloramphenicol, 55 rotepine, clorprenaline, clorsulon, clortermine, closantel,
chlorazanil, chlorbenoxamine, chlorbetamide, chlorcyclizclosiramine, clostebol, clothiapine, clothixamide, clotiazine, chlordantoin, chlordiazepoxide, chlordimorine, chloepam, cloticasone, clotioxone, clotixamide, clotrimazole,
rhexidine, chlorindanol, chlorisondamine, chloramadione,
clovoxamine, cloxacepride, cloxacillin, cloxazolam, cloxchlormerodrin, chlormezanone, chlormidazole, chlornaphazestradiol, cloximate, cloxotestosterone, cloxypendyl, cloxine, chloroazodin, chloroprednisone, chloroprocaine, chloro- 60 yquin, clozapine, cobalamide, cocaine, codeine, codoxime,
pyramine, chloroquine, chloroserpidine, chlorothen, chlocofistatin, cogazocine, colchicines, colestolone, colfenamate,
rothiazide, chlorotrianisene, chloroxine, chloroxylenol,
colforsin, colfosceril, colimecycline, colterol, coluracetam,
chlorphenesin, chlorpheniramine, chlorphenoctium, chlorconessine, congazone, conivaptan, conorphone, cormethaphenoxamine, chlorphentermine, chlorproethazine, chlorsone, corticorelin, cortisone, cortisuzol, cortivazol, cortodoxproguanil, chlorpromazine, chlorpropamide, chlorprothix- 65 one, cotinine, cotriptyline, coumaphos, coumazolin, coumerene, chlorpyrifos, chlortetracycline, chlorthalidone,
mycin, coumetarol, creatinine, creatinolfosfate, cresotamide,
chlorthenoxazine, chlorzoxazone, cholecalciferol, cholescridanimod, crilvastin, crisnatol, crobenetine, croconazole,
US 8,158,152 B2
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14
cromakalim, cromitrile, cromoglicate lisetil, cromolyn, crodibenzothiophene, dibrompropamidine, bibromsalan,
lom, cronidipine, cropropamide, crotamiton, crotetamide,
dibrospidium, dibucaine, dibuprol, dibupyrone, dibusadol,
crotoniazide, crotoxyfos, crufomate, cuprimyxin, cuproxodicarbine, dicarfen, dichloralphenazone, dichloramine,
line, cyacetacide, cyamemazine, cyanocobalamine, cyclacildichlorisone, dichlormezanone, dichlorophen, dichlorphelin, cyclamate, cyclamic acid, cyclandelate, cyclarbamate, 5 narsine, dichloroxylenol, dichlorphenamide, dichlovos, dicicyclazocine, cyclazodone, cyclexanone, cyclindole, cycferron, dicirenone, diclazuril, diclofenac, diclofenamide,
liramine, cyclizine, cyclobarbital, cyclobendazole, cyclobendiclofensine, diclofutrime, diclometide, diclonixin, diclozaprine, cyclobutoic acid, cyclobutyrol, cyclocumarol,
ralurea, dicloxacillin, diclolinium, dicumrol, dicyclomine,
cyclofenil, cycloguanil, cycloheximide, cyclomenol, cyclomdidanosine, didrovaltrate, dieldrin, dienestrol, dienogest,
ethycaine, cyclopentamine, cyclopenthiazide, cyclopento- io diethadione, diethylphthalate, diethylcarbamazine, dietyllate, cyclophenazine, cyclophosphamide, cyclopregnol,
propion, diethylstilbestrol, dethylthambutene, dietyltoluacyclopyrronium, cycloserine, cyclothiazide, cyclovalone,
mide, dietifen, difebarbamate, difemerine, difemetorex, difecycotiamine, cycrimine, cyfluthrin, cyhalothrin, cyheptanamizole, difencloxazine, difenoximide, difenoxin,
mide, cyheptropine, cynarine, cypenamine, cypermethrin,
difetarsone, difeterol, diflomotecan, diflorasone, difloxacin,
cypothrin, cyprazepam, cyprenorphine, cyprodenate, cypro- 15 difluanine, diflucortolone, diflumidone, diflunisal, diflupredheptadine, cyprolidol, cyproquinate, cyproterone, cyproximnate, diftalone, digitalis, digitoxin, digoxin, dihexyverine,
ide, cyromazine, cysteamine, cysteine, cystine, cytarabine,
dihydralazine, dihydrocodeine, dihydroergotamine, dihycythiolate, dabelotine, dabigatran, dabuzalgron, dacarbazine,
drostreptomycin, dihydrotachysterol, diisobutylaminobendacemazine, dacinostat, dacisteine, dacopafant, dactinomyzoyloxypropyl theophylline, diisopromine, diisopropanolacin, dacuronium, dagapamil, dagluril, dalbavancin, dalbrami- 20 mine, diisopropylamine, dilazep, dilevalol, dilmefone,
nol, dalcotidine, daledalin, dalfopristin, dalteparin, daldiloxanide, diltiazem, dimabefylline, dimadectin, dimecamtroban, dalvastatin, dametralast, damotepine, danazol,
ine, dimeclonium, dimecrotic acid, dimefadane, dimefline,
daniquidone, danittracen, danofloxacin, danosteine, dandimelazine, dimenhydrinate, dimenoxadol, dimepheptanol,
thron, dantrolene, dapiprazole, dapitant, dapivirine, dapoxetdimepranol, dimepregnen, dimepropion, dimeprozan, dimeine, dapsone, daptomycin, darbufelone, darenzepine, dargli- 25 sna, dimesone, dimetacrine, dimetamfetamine, dimethaditazone, darifenacin, darodipine, darunavir, darusentan,
one, dimethazan, dimethisoquin, dimethisterone, dimetholizdasantafil, dateliptium, daunorubicin, daxalipram, dazadrol,
ine, dimethothizine, dimethoxanate, dimethylaminoethyl
dazepinil, dazidamine, dazmegrel, dazolicine, dazopride,
reserpilinate, dimethylthambutene, dimethyltubocurarinium,
dazoquinast, dazoxiben, deboxament, debrisoquin, decamedimetipirium, dimetofrine, dimetridazole, diminazene,
thonium, decimemide, decitabine, decitropine, declenper- so dimiracetam, dimoxamine, dimoxaprost, dimoxyline,
one, declopramide, decloxizine, decominol, decoquinate,
dimpylate, dinaline, dinazafone, diniprofylline, dinitolmide,
dectaflur, deditonium, deferasirox, deferiprone, deferoxamdinoprost, dinoprostone, dinsed, diohippuric acid, diosmin,
ine, deflazacort, defosfamine, defoslimod, degarelix, dehydiotyrosine, dioxadrol, dioxamate, dioxaphetyl butyrate,
droacetic acid, dehydrocholic acid, dehydroemetine,
dioxation, dioxethedrin, dioxifedrine, dioxybenazone, dioxydelanterone, delapril, delavirdine, delquamine, deergotrile, 35 line, dipenine, diperodon, diphemanil, diphenadione,
delfantrine, delfaprazine, selmadinone, delmetacin, delmpidiphenan, diphenchloxazine, diphenhydramine, diphenidol,
nol, delorazepam, deloxolone, delprostenate, delucemine,
diphenoxylate, diphenylpiperidinomethyldioxolan, diphedembrexine, demecarium, demeclocycline, demecolcine,
nylpyraline, diphenoxazide, dipipanone, dipiproverine,
demecycline, demegestone, demelverine, demexiptiline,
dipivefrin, diprafenone, diprenorphine, diprobutine, diprodemoconazole, demoxepam, demoxytocin, denatonium, 40 fene, diprogulic acid, diproleandomycin, diprofylline, diprodenaverine, denbufylline, denipride, denofungin, denopamqualone, diproteverine, diprotrizoate, diproxadol, dipyine, denotivir, denpidazone, denufosol, denzimol, depelestat,
ridamole, dipyrithione, dipyrocetyl, dipyrone, diquafosol,
depramine, depreotide, deprodone, deprostil, deptropine,
dirithomycin, dirlotapide, disermolide, disquonium, disobdequalinium, deracoxib, deramciclane, deriglidole, derpanutamide, sidofenin, sdisogluside, disopyramide, disoxaril,
icaine, dersalazine, desapidin, desciclovir, descinolone, 45 distigmine, disufenton, disulergine, disulfamide, disulfiram,
deserpidine, desipramine, deeslanoside, desloratidine,
disuprazoole, ditazole, ditekiren, ditercalinium, dithiaanine,
deslorelin, desmeninol, desmethylmoramide, desmopressin,
ditiocade, ditiocarb, ditiomustane, ditolamide, ditophal, divdesocriptine, desogestrel, desmorphine, desonide, desabuterol, divalproex, divaplon, dixanthogen, dizatrifone,
oximetasone, desoxycorticosterone, desvenlafaxine, detajdizcilpine, dobesilate, dobupride, dobutamide, dobutamine,
mium, detanosal, deterenol, detirelix, detiviciclovir, detromi- 5o docarpamine, docebenone, docetaxel, doconazole, doconexdine, detorubicin, detrothyronine, devapamil, devazepide,
ent, docosanol, docusate, dodeclonium, dodicin, dofamium,
dexamethasone, dexamisole, dexbrompheniramine, dexdofequidar, dofetilide, dolasetron, doliracetam, domazoline,
budesonide, dexchlorpheniramine, dexclamol, dexecadotril,
domiodol, domiphen, domipizone, domitroban, domopreddexefaroxan, dexetimide, dexetozoline, dexfenfluramine,
nate, domoxin, domperidone, donepezil, donetidine, donidexfosfoserine, dexibuprofen, deximafen, dexindoprofen, 55 triptan, dopamantine, dopamine, dopexamine, dopropidil,
dexivacaine, dexketoprofen, dexlofexidine, dexloxiglumide,
doqualast, dorampimod, doramectin, doranidazole, dorasdexmedetomidine, dexmethylphenidate, dexnafenodonee,
tine, soreptide, doretinel, doripenem, dorzolamide. dosergodexniguldipine, dexnorgestrel, dexormaplatin, dexoxadrol,
side, dosmalfate, dotarizine, dotefonium, dothiepin, doxacudexpanthenol, dexpemedolac, dexpropranolol, dexproxibrium, doxapram, doxaprost, doxazosin, doxefazepam,
utene, dexrazoxane, dexsecoverine, dexsotalol, dextilidine, 6o doxenitoin, doxepine, doxergocalciferol, doxibetasol, doxidextiopronin, dextofisopam, dextroamphetamine, dextrofluridine, doxofylline, doxorubicin, doxpicomine, doxycyfemine, dextromethorphan, dextromoramide, dextrorphan,
cline, doxylamine, draflazine, dramedilol, draquinolo, drazidextrothyroxine, dexcerapimil, sezaguanine, dezinamide,
dox, dribendazolew, drimidene, drobuline, drocinonide,
dezocine, diacerein, diacetamate, diacetolol, diamfenetide,
droclidinium, drofenine, droloxifene, drometrizole, dromodiamocaine, diampromide, diamthiazole, diapamide, diar- 65 stanolone, dronabinol, drinedarone, dropempine, droperidol,
barone, diathymosulfone, diatrizoate, diaveridine, diazepam,
droprenilamine, dropropizine, drospirenone, drotaverine,
diaziquone, diazoxide, dibekacin, dibemethine, dibenzepin,
drotebanol, droxacin, droxicainide, droxicam, droxidopa,
US 8,158,152 B2
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16
droxinavir, droxypropine, duazomycin, dulofibrate, duloxetzole, etisomicin, etisulergine, etizolam, etocarlide, etocine, dulozafone, dumorelin, dumetacin, duoperone, dupracrylene, etodolac, etodroxizine, etofamide, etofenamate,
etam, dutasteride, dyclonine, dyhydrogestrone, dymanthine,
etofenprox, etofibrate, etofermin, etofuradine, etofylline, etodyphylline, ebalzotan, ebastine, eberconazole, ebiratide,
glucid, eorolex, etolotifen, etoloxamine, etomidate, etomidoebrotidine, ebselen, ecabapide, ecabet, ecadotril, ecalcidene, 5 line, etomoxir, etomitazene, etonogestrel, etoperidone, etoecamsule, ecastolol, ecenofloxacin, echothiophate, ecipramiposide, etoprindole, etoprine, etoricoxib, etorphine,
dil, eclanamine, eclazolast, ecomustine, econazole, ecopietosalamide, etoxadrol, etoxeridine, etozolin, etrabamine,
pam, ecraprost, ectylurea, edaglitazone, edaravone, edatrexetravirine, etretinate, etriciguat, etryptamine, etymemazine,
ate, edelfosine, edetol, edifolone, edogestrone, edonentan,
eucaine, eucalyptol, eugenol, euprocin, evandamine, evemedotecarin, edotreotide, edoxudine, edratide, edronocaine, io imicin, everolimus, evicromil, exalamide, exametazime,
edrophonium, efaproxiral, efaroxan, efavirenz, efegatran,
examorelin, exaprolol, exatecan, exemestane, exepanol, exiefepristin, efetozole, efletirizine, eflomithine, efloxate, eflufone, exiprofen, exisulind, ezetimibe, ezlopitant, fadolmicimibe, elfumast, efonidipine, efrotomycin, eganoprost,
dine, fadrozole, falecalcitriol, falintolol, falipamil,
eglumetad, egtazic acid, equalen, elacridar, elantrine, elanfalnidamol, famciclovir, famirapinium, famotidine, famozepine, elaarofiban, elbanizine, eldacimibe, eletriptan, elf- 15 tine, fampridine, famprofazone, fampronil, fananserin,
azepam, elgotipine, elinafide, eliprodil, elisartan, ellagic acid,
fanapanel, fandofloxacin, fandosentan, fanetizole, fantofarelliptinium, elmustine, elnadipine, elopiprazole, elsamitruone, fantridone, farglitazar, fasidotril, fasiplon, fasoracetam,
cin, eltanolone, eltenac, eltoprazine, elucaine, elvucitabine,
faudil, fazadinium, fazarabine, febantel, febarbamate, febuelzasonan, elziverine, emakalim, emapunil, embramine,
prol, febuverine, febuxostat, feclemine, feclobuzone, fedotembusartan, embutramide, emedastine, emepronium, emet- 20 ozine, fedrilate, felbamate, felbinac, felipyrine, felodipine,
ine, emeglitate, emilium, emiteflur, emiverine, emodepside,
feloprentan, felypressin, femoxetine, fenabutene, fenaceemopamil, emorfazone, emtricitabine, emylcamate, enadotinol, fenaclon, fenadiazole, fenaftic acid, fenalamide, femalline, enalapril, enalaprilat, enalkiren, enazadrem, enbucrilate,
comine, fenamifuril, fenamole, fenaperone, fenbendazole,
encainide, enciprazine, enclomiphene, encyprate, endixfenbenicillin, fenbufen, fenbutreazate, fencamfamin, fenciaprine, endomide, endralazine, endrysone, enecadin, enefex- 25 butirol, fenclexonium, fleclofenac, fenclonine, fenclorac,
ine, enestebol, enfenamic acid, enfluvirtide, englitazone, enifenclozic acid, fendiline, fendizoate, fendosal, feneritrol,
clobrate, enilconazole, enilospirone, eniluracil, eniporide,
fenestrel, fenethazine, fenethylline, fenetradil, fenflumizole,
enisoprost, enloplatin, enocitabine, enofelast, enolicam,
fenfluramine, flenfluthrin, fengabine, fenharmane, fenimide,
enoxacin, enoxamast, enoxaparin, enoximone, enoxolone,
feniodium, fenipentol, fenirfibrate, fenisorex, fenitrothion,
enipiprazole, enpiroline, enprazepine, enprofylline, enpro- 30 fenleuton, fenmetozole, fenmetraminde, fenobam, fenocinol,
mate, enprostil, enramycin, enrasentan, enrofloxacin,
fenocitimine, fenofibrate, fenoldopam, fenoprofen, fenotensacillin, ensulizole, entacapone, entecavir, entsufon, envioerol, fenoerine, fenoxazoline, fenoxedil, fenozolone, fenpenmycin, enviradene, enviroxime, enzacamene, anzastaurin,
tadiol, fenperate, fenprpalone, fenpipramide, fenpiprane, fenepalrestat, epanolol, eperezolid, eperisone, epervudine, ephepiverinium, fenprinast, fenproporex, fenprostalene,
drine, epicainide, epicillin, epicriptine, epiestriol, epimestrol, 35 fenquiaone, fenretinide, fenspiride, fentanyl, fenthion, fenepinastine, epinephrine, epinepheryl, epipropidine, epirizole,
tiazac, fenticlor, fenticonazolem, fentonium, fenvalerate,
apiroprim, epirubicin, epitetracycline, epithiazide, epifenyripol, fepentolic acid, fepitrizol, fepradinol, feprazone,
tiostanol, eplerenone, elivanserin, epoprostenol, epostane,
fepromide, feprosidnine, ferpifosate, fesoterodine, fetoxyeprazinone, eprinomectin, epristeride, eprobemide, eprosarlate, fexicaine, fexinidazole, fexofenadine, fezatione, fezolatan, eprovafen, eproxindine, eprozinol, epsipranel, epalo- 40 mine, fiacitabine, fialuridine, fibracillin, fidarestat, fidexaban,
prost, eptapirone, eptaplatin, eptastigmine, eptazocin, eptififiduxosin, figopitant, filaminast, filenadol, filipin, finafloxabatide, equillin, erbulozole, erdosteine, ergocalciferol,
cin, finasteride, fingolimod, fipamezole, fipexide, fipronil,
ergonovine, ergotamine, eritoran, erizepine, erlotinib, ercainfirocoxib, flavamine, flavodic acid, flavodilol, flavoxate,
ide, ersentilide, ertapenem, ertiprotafib, erythrity tetmitrate,
flazalone, flecainide, flerobuterol, fleroxacin, flesinoxan,
erythromycin, esafloxacin, esaprazole, esatenolol, escitalo- 45 flestolol, fletazepam, flezelastine, flibanserin, flindokalner,
pram, esculamine, eseridine, esflurbiprofen, esketamine,
flocalcitriol, floctafenine, flomoxef, floptopione, florantyescarbazepine, esmolol, esomeprazole, esonarimod, esorubirone, flordipine, floredil, florfenicol, florifenine, flosatidil,
cin, esoxybutynin, espatropate, esproquin, estazolam, estraflosequinan, flosulide, flotrenizine, floverine, floxacillin,
diol, estramustine, estrazinol, estriol, estrofurate, estrone,
floxacrine, floxuridine, flucizine, flualamine, fluanisone, fluestropipaten esupone, eszopclone, etabenzarone, etacepride, 5o azacort, fluazuron, flubanilate, flubendazole, flubepride, fluetafedrine, etafenone, etalocib, etamestrol, etaminile, etamicarbril, flucetorex, flucindole, flucinprazine, flucloronide,
phylline, etamocycline, etanidazole, etanterol, etaqualone,
fluconazole, flucrylate, flucytosine, fludalanine, fludarabine,
etarotene, etasuline, etazepine, etazolate, etebenecid, eterfludazonium, fludeoxyglucose, fludiazepam, fludorex, fluobarb, etersalate, ethacridine, ethacrynic acid, ehtambutol,
doxopone, fludrocortisone, flufenamic acid, flufenisal, fluethamivan, ethamsylate, ethaverine, ethenzameide, ethiazide, 55 fosal, flufylline, flugestone, fluindarol, fluindione, flumazeethinamate, ethinyl estradiol, ethionamide, ethisterone, ethonil, flimecinol, flumedroxone, flumequine, flumeridone,
heptazine, ethomoxane, ethonam, ethopabate, ethoproflumethasone, flumethiazole, flumetramide, flumexadol,
pazine, ethosuximide, ethotoin, ethoxazene, ethoxazorutoflumezapine, fluminorex, flumizole, flumoxonide, flunamine,
side, ethoxzolamide, ethybenztropine, ethyl biscoumacetate,
flunarizine, flunidazole, flunisolide, flunitrazepam, flunixin,
ethyl carfluzepate, ethyl cartrizoate, ethyl dibunate, ethyl 60 flunoprost, flunoxaprofen, fluocinolone, fluocinonide, fluodirazepate, ethyl loflazepate, ethylestrenol, ethylhydrocucortin butyl, fluocortolone, fluorescein, fluoresone, fluoropreine, ethylmethylthiambutene, ethylmorphine, ethylnoredopa, fluorometholone, fluorosalan, fluorouracil, fluotracen,
pinepherine, ethylstilbamine, ethylnerone, ethylnodil,
fluoxetine, fluoxymesterone, fluparoxan, flupentixol, fluethypicone, etibendazole, eticlopride, eticyclidine, etiperamide, fluperlapine, fluperolone, flupheazine, flupidocaine, etidronate, etidronic acid, etifelmine, etifenin, eti- 65 mazine, flupirtine, flupranone, fluprazine, fluprednidene, flufoxine, etilamfetamine, etilefrine, etilevodopa, etinidine,
prednisolone, fluprofen, fluprofylline, fluproquazone,
etipirium, etiprendol, etiproston, etiracetam, etiroxate, etisafluprostenol, fluquazone, fluradoline, flurandrenolide, fluran-
US 8,158,152 B2
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18
tel, flurazepam, flurbiprofen, fluretofen, flurithromycin,
hexaprofen, hexapropymate, hexasonium, hexazole, hexeflurocitabine, flurofamide, flurogestone, flusoxolol, fluspipdine, hexestrol, hexetidine, hexobarbital, hexobendine, hexoerone, fluspirilene, flutamide, flutazolam, flutemazepam, flucyclium, hexoprenaline, hexopyrronium, heylcaine, histatiazin, fluticasone, flutizenol, flutomidate, flutonidine, flutomine, histapyrrodine, histidine, homarylamine, homatropine,
prazepam, flutrimazole, flutroline, flutropium, fluvastatin, 5 homidium,
homochlorcyclizine,
homofenazine,
fluvoxamine, fluzinamide, fluzoperine, fodipir, folic acid,
homopipramol, homosalate, homprenorphine, hopantenic
fomepizole, fomidacillin, fominoben, fomiversen,
acid, hoquizil, hycanthone, hydracarbazine, hydralazine,
fomocaine, fonazine, fondaparinux, fopirtoline, forasartan,
hydragaphen, hydrobentizide, hydrochlorothiazide, hydrocforfenimex, formebolone, formestane, formetorex, forminiodone, hydrocortisone, hydroflumethiazide, hydromadinone,
trazole, formocortal, formoterol, forodesine, foropafant, fos- io hydromorphinol, hydromorphone, hydroquinone, hydroxyamprenavir, fosarilate, fosazepam, fosenazide, fosfluconaindasate, hydroxyindasol, hydroxocobalamin, hydroxyamzole, fosfocreatinine, fosfomycin, fosfonet, fosfosal,
phetamine, hydroxychloroquin, hydroxydione, hydroxyfosfructose, fosinopril, fosinoprilat, fosmenic acid, fosmidopethidine,
hydroxyphenamate,
hydroxyprocaine,
mycin, fosopamine, fosphenyloin, fospirate, fosquidone,
hydroxyprogesterone, hydroxypyridine tartrate, hydroxysfostedil, fosrtriecin, fosveset, fotemustine, fortrenamine, 15 tenozole, hydroxystilbamidine, hydroxytetracaine, hydroxfozivudine, frabuprofen, fradafiban, frakefamide, framycetin,
yzine, hymecromone, hyoscyamine, ibafloxacin, ibandrfrentizole, freselestat, fronepidil, fropenem, frovatriptan,
onate, ibazocine, ibopamine, ibrolipim, ibrotamide,
froxiprost, ftaxilide, ftivazide, ftormetazine, ftorpropazine,
ibudalast, ibufenac, ibuprofen, ibuproxam, ibutamoren,
fubrogonium, fudosteine, fuladectin, fulvestrant, fumagillin,
ibuterol, ibutilide, ibuverine, icaridin, icatibant, iclaprim,
fumoxicillin, fungimycin, fuprazole, furacrinic acid, furafyl- 20 icazepam, icodulinium, icofangipen, ifometasone, icopezil,
line, furalazine, furaltadone, furaprofen, furazabol, furazoliicosapent, icospiramide, icotidine, icrocaptide, idarubicin,
done, furazolium, furbicillin, furcloprofen, furegrelate, fureidaverine, idazoxan, idebenone, idenast, idoxifene, idoxurithidine, furfenorex, furidarone, furmethoxadone, fumidipine,
dine, idralfidine, idramantone, idraparinux, idrapril, idremcifurobufen, furodazole, furofenac, furomazine, furomine,
nal, idrociliamide, idronoxil, idropranolol, iferanserin,
furosemide, furostilbestrol, fursalan, fursultiamine, fur- 25 ifetroban, ifosfamide, ifoxetine, iganidipine, igmesine, iguterene, furtrethonium, fusafungine, fusidate, fusidic acid,
ratimod, ilaprazole, ilatreotide, ilepcimide, iliparcil, ilmofosfuzlocillin, gabapentin, gabapexate, gaboxadol, gacyclidine,
ine, iloomastat, ilonidap, iloperidone, imafen, imanixil, imagadobenate, gadobutrol, gadocolectic acid, gadodiamine,
tinib, imazodan, imcarbofos, imiclopazine, imidafenacin,
gadofosveset, gadomelitol, gadopenamide, gadopentetate,
imidapril, imidaprilat, imidocarb, imidoline, imidurea, imigadoteric acid, gadoteridol, gadoversetamide, gadoxetate, 30 glitazar, imiloxan, iminophenimide, imipenem, imipramine,
gadoxeticaicid, galamustine, galntamine, galarubicin, galaimipraminoxide, imiquimod, imirestat, imitrodast, imolasomite, galdansetron, gallamine triethiodide, gallopamil,
mine, imoxiterol, impacarzine, implitapide, impromidine,
galocitabine, galosemide, galtifenin, gamfexine, gamolenic
improsulfan, imuracetam, inamirone, inaperisone, incadacid, gamaxolone, ganciclovir, ganefromycin, ganglefene,
ronic acid, indacaterol, indacrinone, indalpine, indanazoline,
ganstigmine, gantacurium, gantofiban, gapicomine, gapro- 35 indanidine, indanorex, indapamide, indatraline, indecainide,
midine, garenoxacin, gatifloxacin, gavestinel, geclosporin,
indeloxazine, indenolol, indibulin, indigotindisulfonate,
gedocarnil, gefarnate, gefitinib, gemazocine, gemcabene,
indinavir, indiplon, indisetron, indobufen, indocate, indocyagemcadiol, gemcitabine, gemeprost, genfibtrozil, gemifloxanine green, indolapril, indolidan, indomethacin, indopanolol,
cin, gemopatrilat, gentamicin, gepefrine, gepirone, geroindopine, indoprofen, indoramin, indorenate, indoxole,
quinol, gestaclone, gestadienol, gestodene, gestonorone, 40 indriline, inecalcitol, ingliforib, inicarone, inocterone
gestrinone, gevotroline, gimatecan, gimeracil, giparmen,
acetate, inogatran, inosine, inositol, improquoone, intopligiracodazole, giractide, girisopam, gitaloxin, gitoformate,
cine, intrazole, intriptyline, inulin, iobenguane, iobenzamic
glafenine, glaspimod, glatiramer acetate. glemanserin, glenacid, iobitridol, iobutoic acid, icanlidic acid, iocarmic acid,
vastatin, gliamilide, glibotnuride, glibutimine, glicaramide,
iocetamic acid, iodamine, iodipamide, iodixanol, iodoantipyglicetanide, gliclazide, glicondamine, glidazamide, gliflu- 45 rine, iodocholesterol, iodohippurate, iodoquinol, iodothioumide, glimepiride, glipalamide, glipizide, gliquidone,
racil, idoxamic acid, iofetamine, ioflupane, iofratol, ioglicic
glisamuride, glisentide, glisindamine, glisolamide, glisoxacid, ioglucol, ioglunide, ioglycamic acid, iogulaamide,
epide, gloxazone, gloximonam, glucametacin, glucosamine,
iohexol, iolidonic acid, iolixanic acid, iolopride, iomazenil,
gluronolactone, glucuronamide, glunicate, glyburide, glyiomeglamic acid, iomeprol, iomethin, iometopane, iomorinic
buthiazole, glubuzole, gycopyrrolate, glycylamide, glyhexa- 5o acid, iopamidol, iopanoic acid, iopentol, iophendylate, iophemide, glymidine, glyoctamide, glyparamide, glypinamide,
noxic acid, iopromide, iopronic acid, iopydol, iopydone, iosaglyprothiazole, glysobuzole, goralatide, goserelin, gramicircol, isofenamic acid, ioseric acid, iosimenol, iosimide, iosudin, granisetron, grepafloxacin, griseofulvin, guabenxan,
lamide, iosumetic acid, iotasul, ioteric acid, iothalamate,
guacetisal, guafecainol, guaiactamine, guaiapate, guaietolin,
iothalamic acid, iotranic acid, iotriside, iotrizoic acid, iotroguaifenesin, guaimesal, guaisteine, guaithylline, guanabenz, 55 lan, iotroxic acid, iotyrosine, iovesol, ioxabrolic acid, ioxaguanacline, guanadrel, guanazodine, guanclofine, guancyglic acid, ioxilan, ioxitalamic acid, ioxotrizoic acid, iozomic
dine, guanethidine, guanfacine, guanisoquin, guanoclor, guaacid, ipamorelin, ipazilide, ipenoxazone, ipexidine, ipidanoctine, guanoxabenz, guanoxan, guanoxyfen, gusperimus,
crine, ipodate, iprgratine, ipramidil, ipratropium, iprahalazepam, halazone, halcinonide, halethazole, halobetasol,
vacaine, iprazochrome, ipriflavone, iprindole, ipocinidine,
halocortolone, halofantrine, halofenate, halofuginone, 60 iproclozide, iprocrodol, iprofenin, iproheptine, iproniazide,
halometasone, halonamine, halopemide, halopenium, haloipronidazole, iproplatin, iprotiazem, iproxamine, iprozilperidol, halopredone, haloprogesterone, haloprogin, haloxamine, ipsalazide, ipsapirone, iquindamine, iralukast, iramazolam, haloxon, haloqionol, hamycin, hedaquinium, heliopanel, irbesartan, irindalone, irinotecan, irloxacin, irofulven,
mycin, hepronicate, heptabarbital, heptaverine, heptolamide,
irolapride, iroxanadine, irsogladine, irtemazole, isalidole,
hepzidine, heroin, hetacillin, hetaflur, heteronium, hexachlo- 65 isalsteine, isamfazone, isamoltan, isamoxole, isatoribine,
rophene, hexacyclonate, hexacyprone, hexadiline, hexafluoisaxonine, isbogrel, isbufylline, ispamicin, isoamilinile, isorenium, hexamethonium, hexaminolevulinate, hexapradol,
bromindione, isobucaine, isobutamben, isocarboxazid, iso-
US 8,158,152 B2
19
20
conazole, isocromil, isoetharine, isoflupredone, isoffen, losoxantrone, losulazine, loteprednol, lotrafiban, lotlurophate,
isomazole,
isomerol,
isometamidium,
rifen, lotucaine, lovastatin, loviride, loxanast, loxapine,
isomethadone, isometheptene, isomolpan, isoamylamine,
loxiglumide, loxoprofen, loxoribine, lozilurea, lubazodone,
isoniazid,isonixin,isoprazole,isoprednidene,isoprofen,isolubeluzole, lubiprostone, lucanthone, lucartamide, lucimypropamide, isopropicillin, isoproterenol, isosrbide, isospa- 5 cin, lufenuron, lufironil, lufuradom, luliconazole, lumiraglumic acid, isosulfan blue, isosulpride, isothipendyl, isocoxib, lupitidine, luprostiol, lurasidone, lurosetron, lurototetiquimide, isotretinoin, isoxaprolol, isoxepac, isoxicam,
can, lusaperidone, luxabendazole, lydimycin, lymecycline,
isoxsuprine, isradipine, israpafant, istrdefylline, itameline,
lynestrenol, lypressin, mabuprofen, mabuterol, maduramiitanoxone, itasetron, itazigrel, itopride, itraconazole, itriglucin, mafenide, mafoprazine, mafosfamide, malathion, maleymide, itrocainide, itrocinonide, iturelix, ivbradine, ivarimod, io lsulfathiazole, malotilate, mangafodipir, manidipine, maniivermectin, ivoqualine, ixabepilone, izonsteride, josamycin,
faxine,
mannomustine,
manozodil,
mantabegron,
kainic acid, kalafungin, kanamycin, kebuzone, keracyanin,
mapinastine, maprotiline, maraviroc, marbofloxacin, maribketamine, ketanserin, ketazocine, ketazolam, kethoxal,
avir, maridomycin, marimastat, mariptiline, maropitant, marketipramine, ketobemidone, ketocaine, ketocainol, ketoconaoxepin, masoprocol, maxacalcitol, maytansine, mazapertine,
zole, ketoprofen, ketorfanol, ketorolac, ketotifen, ketotrexate, 15 mazaticol, mazindol, mazipredone, mazokalim, mebanazine,
khellin, khelloside, kitasamycin, labetalol, labradimil,
mebendazole, menbenoside, mebeverine, mebezonium, meblachesine, lacidipine, lacosamide, lactalfate, lactilol, lactuhydrolin, mebiquine, mebolazine, mebrofenin, mebutamate,
lose, ladirubicin, ladostigil, laflunimus, lafutiine, laidlomycin
mebutizide, mecamylamine, mecarbinate, mecetronium,
propionate, lamifiban, lamivudine, lamotrigine, lamitidine,
meciadanil, mecinarone, meclinertant, meclizine, meclocylanatoside, landiolol, lanepitant, lanicemine, laniquidar, 20 cline, meclofenamaic acid, meclofenoxate, meclonazepam,
lanoconazole, lanperisone, lanproston, lanreotide, lansopramecloqualone, meclorisone dibutyrate, mecloxamine, mecozole, lapatinib, lapisteride, laprafylline, lapyrium, laquinibalamin, medazepam, medazomide, medetomidine, medibamod, lasalocid, lasinavir, lasofoxifene, latanoprost, lauzinc,
medifoxamine,
medorinone,
medorubicin,
dexium, laurcetium, laurocapram, lauroguadine, laurolinium,
medrogestrone, medronic acid, medroxalol, medroxyprogeslauryl isoquinolinium, lavoltidine, lazabemide, lecimibide, 25 terone acetate, medrylamine, medrysone, mefeclorazine,
ledazerol,
ledoxantrone,
lefetamine,
leflunomide,
mefenamic acid, mefenidil, mefenidramium, mefenorex,
lefradafiban, leiopyrrole, lemidosul, lemidipine, leminopramefeserpine, mefexamide, mefloquine, mefruside, megalozole, lemoxinol, lemuteporfin, lanalidomine, lenampicillin,
myciin, megestrol, megace, meglitinide, meglucycline,
lenapenem, leniquisin, leuperone, leptacline, lercanidipine,
meglumine, meglutol, meladrizine, melagatran, melarsomlergotrile, lerisetron, lesoptiron, lestaurtinib, leteprinim, lete- 30 ine, melarsonyl, melarsoprol, meldonium, melengestrol
prinim, letimide, letosteine, letrazuril, letrozole, leucinoacetate, meletimide, melevodopa, melinamide, melitracen,
caine, leucocianidol, leucovorin, leurubicin, levalbuterol,
melizame, meloxicam, melperone, melphalan, melquinast,
levallorphan, levamfetamine, levamisole, levcromakalim,
meluadrine, mamantine, memotine, menabitan, menadiol,
levcycloserine, levdobutamine, levemoamil, levetiracetam,
menadione, menadoxime, menatetrenone, menbutone, menlevisoprenaline, levlofexidine, levmetamfetamine, levobe- 35 fegol, menglytate, menitrazepam, menoctone, menogaril,
taxolol, levobunolol, levobupiacaine, levocabastine, levomenobentine, mepazine, mepenzolate, meperidine, mephencamitine, levodopa, levodropropizine, levofacetoperane,
esin, mephenoxalone, mephentermine, mephenyloin,
levofenfluramine, levofloxacin, levofluraltadone, levoleucomephobarbital, mebaral, mepindolol, mepiperphenidol,
vorin, levomenol, levomepromazine, levomethadone,
mepiprazole, mepiroxol, mepitiostane, mepivacaine, mepixlevomethadyl acetate, levomethorphan, levometiomeprazine, 4o anox, mepramidil, meprednisone, meprobamate, meprochol,
levomoprolol, levomoramide, levonantradol, levonordefrin,
meproscillarin, meprotixol, meprylcaine, meptazinol, mequilevonorgestrel, levophenacylmorphan, levopropoxyphene,
dox, mequinol, mequitamium, mequitazine, meradimqate,
levopropylcilline, levopropuylhexedrine, levoprotiline,
menthyl anthranilate, merafloxacin, meralein, meralluride,
levorin, levormeloxifene, levorphanol, levosalbutamol,
merbaphen, merbromin, mercaptomerin, mercaptopurine,
levosemotiadil, levosimendan, levosulpiride, levothyroxine, 45 mercuderamide, mercufenol, mercumatilin, mergocriptine,
levotofisopam, levoxadrol, lexipafant, lexithromycin, lexmeribendan, merimepodib, meropenem, mersalyl, merofenac, liarozole, libecillide, libenzapril, licarbazepine,
tialide, mesabolone, mesalamine, meseclazone, mesocarb,
licofelone, licostinel, lidadronic acid, lidamine, lidanserin,
mesoridazine, mesipiperone, mespirenone, mestanolone,
lidocaine, lidoferin, lidorestat, lifariaine, lifibrate, lifibrol,
mesterolone, mestranol, mesudipine, mesulergine, mesulfalilopristone, limaprost, limazocic acid, linarotene, lincomy- 50 wide, mesulfen, mesuprine, metabromsalan, metcin, lindane, linetastine, linezolid, linogliride, linopirdine,
butethamine, metabutoxycaine, metacetamol, metalinotroban, lisinidomine, lintitript, lintopride, liothyronine,
clazepam, metacresol, metaglycodol, metahexamide,
lipoic acid, liraglutide, liranaftate, lirequinil, lirexapride, lirmetalkonium, metalol, metamelfalan, metamfazone, metamimilast, liroldine, lisadimate, lisinopril, lisofylline, lisuride,
fenpramone, metampicillin, metanixin, metapramine, metaplitomeglovir, litoxetine, litracen, lividomycin, lixazinone, lix- 55 roterenol, metaraminol, metaxalone, metazamide, metazide,
ivaptan, lobapolatin, lobeline, lobendazole, lobenzarit, lobumatazocine, metbufen, meteneprost, metergoline, metergotacavir, lobuprofen, locicortolone, lodaxaprine, lodazecar,
mine, metescufylline, metesculetol, metesind, metethoheplodelaben, lodenosine, Iodinixil, lodiperone, Iodoxamide,
tazine, metformin, methacholine, methacycline, methadone,
lofemizole, lofendazam, lofentanil, lofepramine, lofexidine,
methadyl acetate, methallenestril, methallibure, methalthiazloflucarban, lombazole, lomefloxacin, lomeguarib, lomeriz- 60 ide, methamphetamine, methandriol, methandrostenolone,
ine, lometraline, lometrexol, lomevactone, lomifylline, lomomethaniazide, methantheline, methaphenilene, methapyfungin, lomustine, lonafamib, lonapalene, lonaprofen, lonarilene, methaqualone, metharbital, methastyridone, methzolac, lonidamine, loperamide, lopinavir, lopirazepam,
azolamide, methdilazine, methenamine, methenolone, methlopobutan, loprazolam, loracarbef, lorajmine, lorapride,
eptazine, methestrol, methetoin, methikcillin, methimazole,
lorazepam, lorbamate, lorcainide, lorcinadol, loreclezole, 65 methiodal, methiomeprazine, methionine, methisazone,
lorglumide, lormetazepam, lornoxicam, lopiprazole, lortamethitural, methixene, methocarbamol, methocidin, metholamine, lorzafone, losartan, losigamone, losindole, losmiprohexital, methopholone, methoprene, methoserpidine, meth-
US 8,158,152 B2
21
otrexate, methotrimeprazine, methoxamine, methoxsalen,
nafronyl, naftalofos, naftazone, naftifine, naftopidil, naftoxmethoxyphedrine, methoxyphenamine, methoxypromazine,
ate, naftypamide, naglivan, nalbuphine, nalfurafine, nalidixic
methscopolamine, methsuximide, methyclothiazide, methyl
acid, nalmefene, nalmexone, nalorphine, naloxone, naltrexaminolevulinate, methyl palmoxirate, methyl salicylate,
one, naminidil, naminterol, namirotene, namoxyrate, nanamethylatropine, methylbenactyzium, methylbenzethonium, 5 frocin, nandrolone, nanterinone, nantradol, napactadine,
methylcromone, methyldesorphine, methyldihydromornapamezole, naphazaoline, naphthonone, napirimus, napiphine, methyldopa, methylene blie, methylephedrine, methtane, naproxime, naproxen, naproxol, napsagatran, naranol,
ylergometrine, methylergonovine, methyllparaben, methnarasin, naratriptan, nardetoterol, naroparcil, natamycin,
ylphenidate,
methylprednisolone,
methyltestosterone,
nateglinide, navuridine, naxagolide, naxaprosteine, naxifylmethylthiouracil, methynodiol, methyprylon, methysergide, io line, nealbarbital, nebantan, nebidrazine, nebivolol,
metiamide, metiapine, metiazinic acid, metibride, meticrane,
neboglamine, nebracetam, nebramycin, necopidem, nedaplmetildigoxin, metindizate, metioprim, metioxate, metipirox,
atin, nedocromil, nefazodone, nefiracetam, neflumozide,
metiprenaline, metitepine, metizoline, metkephamid,
nefopam, nelarabine, neldazosin, nelezaprine, nelfinavir,
metochalcone, metocinium, metoclopramide, metocurine,
neltenexine, nelzarabine, nemadectin, nemazoline, nemimetofenazate, metogest, metolazone, metomidate, metopi- 15 fitide, nemonapride, nemorubicin, neocinchophen, neomymazine, metopon, metoprine, metoprolol, metoquizine,
cin, neostigmine, nepadutant, nepafenac, nepaprazole, nepimetoserpate, metostilenol, metoxepin, metrafazoline, metralcastat, nepinalone, nequinate, neramexane, neraminol,
indole, metrazifone, metrenperone, metribolone, metrinerbacadol, neridronic acid, nerisopam, nesapidil, nesiritide,
fonate, metrifudil, metrizamide, metrizoate, metronidiazole,
nesosteine, nestifylline, neticonazole, netilmicin, netivudine,
meturedepa, metyrapone, metyrosine, mevastatin, mexafyl- 20 netobimin, netoglitazone, netupitant, neutramycin, neviline, mexazolam, mexenone, mexiletine, mexiprosil, mexoparine, nexeridine, nexopamil, niacin, niacinamide, nialaprofen, mexrenoate, mezacopride, mezepine, mezilamine,
mide, niaprazine, nibroxane, nicafenine, nicainoprol, nicamezlocillin, miaanserin, mibefradil, mibolerone, miboplatin,
metane, nicanartine, nicaraven, nicarbazin, nicardipine,
micafungin, miconazole, micronomicin, midaflur, midafotel,
nicergoline, niceritol, niceverine, niclofolan, niclosamide,
midaglizole, midamaline, midaxifylline, midazogrel, mida- 25 nicoboxil, nicoclonate, nicocodine, nicocortonide, nicocidozolam, midecamycin, midestein, midodrine, midostaurin,
dine, nicoduozide, nicofibrate, nicofuranose, nifurate,
mifentidine, mifepristone, mifobate, miglitol, miglustat,
nicogrelate, nicomol, nicomorphine, nicopholine, nicoracmikamycin, milacainide, milacemide, milameline, milataxel,
etam, nicorandil, nicothiazone, nicotredole, nicoxamat, nicmilenperone, milfasartan, milipertine, miloxacin, milrinone,
tiazem, nictindole, nidroxyzone, nifedipine, nifekalant, nifemiltefosine, milverine, mimbane, minalrestat, minamestane, to nalol, nifenazone, niflumic acid, nifungin, nifiradene,
minaprine, minaxolone, mindodilol, mindoperone, minepennifuraldezone, nifuralide, nifuratel, nifuratrone, nifurdazil,
tate, minocromil, minocycline, minodronic acid, minopafant,
nifurethazone, nifurfoline, nifurimide, nifurizone, nifurmaminoxidil, mioflaazine, mipitroban, mipragoside, miproxzole, nifurmerone, nifuroquine, nifuroxazide, nifuroxime,
ifene, mirfentanil, mirincamycin, miripirium, miriplatin,
nifurpipone, nifurpirinol, nifirprazine, nifurquinazol,
mirisetron, miristalkonium, miroprofen, mirosamicin, 35 nifursemizone, nifursol, nifurthiazole, nifurtimox, nifurtoimirostipen, mirtazapine, misonidazole, misoprostol, mitemnol, nifurvidine, nifurzide, nigludipine, nihydrazone,
cinal, mitiglinide, mitindomine, mitobronitol, mitocarcin,
nikethamide, nileprost, nilprazole, niludipine, nilutamide,
mitoclomine, mitocromin, mitoflaxone, mitogillin, mitoguanilvadipine, nimazone, nimesulide, nimetazepam, nimidane,
zone, mitolactol, mitomalcin, mitomycin, mitonafide, mitonimodipine, nimorazole, nimustane, neometacin, niperotipodozide, mitoquidone, mitosper, mitolane, mitotenamine, 4o dine, nipradilol, niprofazone, nitavoline, nirdazole, nismitoxantrone, mitozolomide, mitradipide, mivacurium,
buterol, nisobamate, nisoldipine, nisoxetine, nisterime, nitarmivobulin, mivotilate, mixidine, mizolastine, mizoribine,
sone, nitazoxanide, nitecapone, nithiamide, nitisinone,
mobecarb, mobenzoxamine, mocimycin, mociprazine,
nitracrine, nitrafudan, nitralamine, nitramisole, nitraquamoclonemide, moctamide, modafinil, modaline, modecainzone, nitrazepam, nitrefazole, nitrendipine, nitrocefin, nitroide, modipafant, moexipril, moexiprilat, mofarotene, 45 clofene, nitrocycline, nitrodan, nitrofurantoin, nitrofurazone,
mofebtazone, mofegiline, mofezolac, mofloverine, mofoxnitromersol, nitromide, nitromifene, nitroscanate, nitrovin,
ine, mofuisteine, molfamate, molinazone, molindone, molnitroxinil, nitroxoline, nivazol, nivimedone, nizatidine,
racetam, molsidomine, mometasone, monalazone,
nizofenone, noberastine, nocloprost, nocodazole, nofecainmonatepil, monesin, monobenzone, monoctanoin,
ide, nogalamycin, nolatrexed, nolinium, nolomirole, nolpimonometacrine, monophosphothiamine, monoxeratin, mon- 50 tantium, nomegestrol, nomelidine, nomifensine, nonabine,
telukast, monterelin, moperone, mopidamol, mopidralazine,
nonaperone, nonapyrimine, nonathymulin, nonivamide,
moprolol, moquizone, morantel, morazone, morclofone,
noracymethadol, norbolethone, norbudroine, norcholestenol,
morforex, moricizine, morinamide, momiflumate, moronorclostebol, norcodeine, nordazepam, nordefrin, nordinone,
cromen, moroxydine, morpheridine, morphine, morsuximnorelgestromin, norepinepherine, norethandrolone, noethinide, mosapramine, mosapride, motapizone, motexafin, 55 drone, norethynodrel, noreximide, norfenefrine, norfloxacin,
motrazepam, motrtinide, moveltipril, moxadolen, moxalacnorgesterone, norgestimate, norgestomet, norgestrel, norgtam, moxaprindine, moxastine, moxaverine, moxazocine,
estrieneone, norletimol, norlevorphenol, normethadone, normoxestrol, moxicoumone, moxidectin, moxifloxacin, moximorphine, norpipanone, nortetrazepam, nortopixantrone,
lubant, moxipraquine, moxirapine, moxisylate, moxnidanortriptyline, norvinisterone, nosantine, noscapine, nosihepzole, moxonidine, mozavaptan, mozenavir, mubritnib, mupi- 60 tide, novobiocin, noxiptiline, noxytiolin, nuclomedone,
rocin, murabutide, muraglitazar, mureletecan, murocainide,
nuclotixene, nufenoxole, nupafant, nuvenzepine, nylestriol,
muzolimine, mycophenolic acid, myfadol, myrophine,
nylidrin, nystatin, obidoxime, ocaperidone, ocfentanil, ociltmyrtecaine, nabazenil, nabilone, nabitan, naboctate, nabumeide, ocinaplon, octacaine, octafonium, octamoxin, octapinol,
tone, nacartocin, nadide, nadiofloxacin, nadolol, nadoxolol,
octatine, octaverine, octazamide, octenidine, octicizer,
nafagrel, nafamostat, nafarelin, nafazatrom, nafcaproic acid, 65 octimibate, octinoxate, octisalate, octocrylene, octodrine,
nafcillin, nafenodone, nafenopin, nafetolol, nafimidone,
octopamine, octotiamine, octreotide, octriptyline, octriazole,
nafiverine, naflocort, nafomine, nafoxadol, nafoxidine,
odalprofen, odapipam, odiparcil, ofloxacin, ofomine, oftas-
US 8,158,152 B2
23
ceine, oglufanide, olaflur, olamufloxacin, olanexidine, olantigetide, pentisomicin, pentisomeide, pentizidone, pentobarzapine, olaquindox, olcegepant, oleandomycin, oletimol,
bital, pentolinium, pentolonium, pentomone, pentopril, penolmesartan, olopatadine, olpadronic acid, olpimedone,
torex, pentosalen, pentostatin, pentoxifylline, pentoxyverine,
olprinone, olradipine, olsalazine, oltipraz, olvanil, omaciclopentrinitrol, pentylenetetrazol, peplomycin, pepstatin, peravir, omapartrilat, omeprazole, omidoline, omigapil, omilox- 5 clopone, peradoxime, perafensine, peralopride, peramivir,
etine, omoconazole, omonasteine, onapristone, ondansetron,
peraquisin, perastine, peratizole, perazine, perbufylline, perontazolast, ontianil, opanixil, opaviraline, opiniazide,
fomedil, perfosfamide, pegolide, perhexiline, periciazine,
opipramol, opratonium, orazamide, orazipone, orbofiban,
perifosine, perimetazine, perindopril, perindoprilat,
orbutopril, orconazole, orientiparcin, oritavancin, orlistat,
perisoxal, perlapine, permethrin, perospirone, perphenazine,
ormaplatin, ormeloxifene, ormetoprin, ornidazole, orni- io persilic acid, perzinfotel, petrichloral, pexantel, phanquone,
preessin, omithine, omoprostil, orotic acid, orotirelin, orpanphenacaine, phenacemide, phenacetin, phenactropinium,
oxin, orphenadrine, ortataxel, orteteamine, osanetant, osaterphenadoxone, phenaglycodol, phenamazoline, phenamproone, oseltamivir, osemozotan, osmadizone, ospemifene,
mide, phenaphthazine, phenarsone, phenazocine,
ostreogrycin, osutidine, otamixaban, otenzepad, oteracil,
phenazopyridine, phenbutazone, phencarbamide, phencycliotilonium, otimerate, ouabain, oxabolon, oxabrexine, 15 dine, phendimetrazine, phenelzine, pheneridine, phenethiciloxaceprol, oxacillin, oxadimedine, oxaflozane, oxaflulin, pheneturide, phenylglutarimide, phenicarbazide, pheninmazine, oxagrelate, oxalinast, oxaliplatin, oxamarin, oxamdamine, phenindione, pheniprazine, pheniramine,
etacin, oxamisole, oxaminiquinem oxanamide, oxandrolone,
phenisonone, phenmetrazine, phenobarbital, phenobutiodil,
oxantel, oxapadol, oxapium, oxaprazine, oxaprotiline,
phenomorphan, phenothiazine, phenothrin, phenoxybenoxaprozin, oxcarbazole, oxatomide, oxazafone, oxazepam, 20 zamine, phenoxypropazine, phenprobamate, phenprocouoxazidone, oxazolam, oxazorone, oxcarbazepine, oxdralamon, phenpromethamine, phensuximide, phentermine, phenzinc, oxeclosporin, oxedrine, oxeglitazar, oxeladin, oxentolamine, phenyl aminosalicylic acid, phenylalanine,
dolone, oxepinac, oxetacillin, oxethazine, oxetorone,
phenylbutazone, phenylephrine, phenylpropanolamine, pheoxfendazole, oxfenicine, oxibendazole, oxibetaine, oxiconinylthiolone, phenyltoloxamine, phenyracillin, phenyramidol,
zole, oxidapamine, oxidronic acid, oxfentorex, oxifangin, 25 phenyloin, pnetharbital, pholcodine, pholedrine, phoxim,
oxigluttione, oxilofrine, oxilorphan, oximonam, oxindanac,
phthalofyne, phthylsulfacetamide, phthalylsulfamethiazole,
oxiniacic acid, oxperomide, oxiracetam, oxiramide, oxisophthalylsulfathiazole, physostigmine. Phytic acid, phytonapred, oxisuran, oxitefonium, oxitriptan, oxitriptyline, oxtridione, pibaxizine, pibecarb, piberaline, piboserod, pibrozeponium, oxmetidine, oxodipine, oxogestone, oxolamine,
lesin, pibutidien, picafibrate, picartamide, picenadol, piciloxolinic acid, oxomermazine, oxonazine, oxophenarsine, 30 orex, piclamilast, piclonidine, piclopastine, picloxydine,
oxoprosto;l, oxpheneridine, oxprenoate, oxprenolol, oxtriphpicobenzide, picodralazine, picolamine, piconol, picoperine,
ylline, oxbenzone, oxybutynin, oxychlorosene, oxycinpicoplatin, picoprazole, picotamide, picotrin, picumast, picuchophen, oxyclipine, oxyclozanide, oxycodone, oxydipentometerol, pidobenzone, pidolacetamol, pidolicaicd, pidotinium, oxyfedrine, oxymesterone, oxymetazoline,
mod, pifarnine, pifinate, pifexole, piflutixol, piketoprofen,
oxymethalone, oxymorphone, oxypendyl, oxypertine, 35 pildralazine, pilocarpine, pilsicainide, pimagedine, pimeoxyphenbutazone, oxyphencyclimine, oxyphenisatin,
clone, pimecrolimus, pimefylline, pimelautide, pimetacin,
oxyphenonium, oxypurinol, oxypurronium, oxyquinoline,
pimethixene, pimetine, imetremide, pimilprost, piminodine,
oxyridazine, oxysonium, oxytetracycline, oxytocin, ozagrel,
pimobendan, pimonidazole, pimozide, pinacidil, pinadoline,
ozagamicin, ozolindone, paclitaxel, pacrindolol, pactimibe,
pinafide, pinaverium, pinazepam, pincainide, pindolol,
padimate A, padimate Q, pafenolol, pagoclone, paldimycin, 40 pinokalant, pinolcaine, pinoxepine, pioglitazone, pipacypalinavir, paliperidone, palmidrol, palmoxirate, palonidcline, pipamazine, pipamperone, pipazethate, pipebuzone,
ipine, palonosertron, palosuran, pamabron, pamaqueside,
pipecuronium, pipemidicacid, pipendoxifene, pipenzolate,
pamaquin, pamicogrel, pamidronic acid, panadiplon, panpipequaline, piperacetazine, piperacillin, piperamide, piperiamesine, pancopride, pancuronium, panipenem, panomifene,
dolate, piperilate, piperocaine, piperonyl butoxide, piperpantenicate, pantethine, panthenol, pantoprazole, 45 oxan, piperphenidol, piperylone, pipobroman, pipoctanone,
panuramine, papverine, papveroline, parachlorphenol,
pipofezine, piposulfan, pipotiazine, pipoxizine, pipoxolan,
paraflutizide, paramethadione, paramethasone acetate,
pipradimadol, pipradrol, pipramadol, pipratecol, piprinhydriparanitrosulfathiazole, paranyline, parapenzolate, paranate, pipocurarium, piprofurol, piprozolin, piquindone,
propamol, pararosaniline, paraxazone, parbendazole, parcpiquizil, piracetam, pirandamine, pirarubicin, piraxelate,
etasal, parconazole, parecoxib, pareptide, parethoxycaine, 50 pirzmonam, pirazolac, pirbenicillin, pirbuterol, pirdonium,
pargeverine, pargolol, pargyline, paricalcitol, paridocaine,
pirenoxine, pirenperone, pirezepine, pirepolol, piretanide,
parodilol, paromomycin, paroxetine, paroxypropione,
pirfenidone, pirbendil, piridicillin, piridocaine, piridoxilate,
parsalmide, particin, parvaquone, pasiniazid, pasireotide,
piridronic acid, pirifibrate, pirimiphos-ethyl, pirindazole,
patamostat, patupilone, paulomycin, paxamate, pazelliptine,
pirinixic acid, pirinixil, piriprost, piriqualone, pirisudanol,
pazinaclone, pazoxide, pazufloxacin, pecilocin, pecocycline, 55 piritramide, piritrexin, pirlimycin, pirlindole, pirmagrel, pirpefloxocin, pelanserin, peldesine, peliomycin, pelitinib, pelimenol, pirnabine, piroctone, pirodavir, priodomast, pirogtrexol, pelretin, pelrinone, pelubiprofen, pemedolac,
liride, piroheptine, pirolate, pirolazamide, piromidic acid,
pemerid, pemetrexed, pemirolast, pemoline, penamecillin,
piroxantrone, piroxicam, piroxicillin, piroximone, pirozadil,
penbutolol, penciclovir, pendecamine, pendetide, penfluripirprofen, pirquinozol, pirralkonium, pirsidomine, pirtenidol, penflutizide, pengitoxin, penicillamine, penicillin G, 6o dine, pitenodil, pitofenone, pituxate, pivagabine, pivampicilpenicillin V, penimepicycline, penimocycline, penirolol, penlin, pivenfrine, pivopril, pivoxazepam, pixantrone, pizotymesterol, penoctonium, penprostene, pentabamate, pentaline, plafbride, plaunotol, plauracin, pleconaril, pleuromulin,
cynium, pentfluranol, pentagastrin, pentagestrone, pentalaplevitrexed, plicamuycin, plomestane, pobilukast, podilfen,
mide, pentamethonium, pentamidine, pentamorphone,
podofilox, poldine, polymixin, polythiazide, pomisartan,
pentamoxane, pentamustine, pentapiperide, pentapiperium, 65 ponalrestat, ponazuril, ponfibrate, porfiromycin, posaconapentaquine, pentazocine, pentetic acid, pentreotide,
zole, posatirelin, posizolid, poskine, practolol, pradolfoxapenthienate, penthrichloral, pentiapine, pentifylline, pencin, prajmalium, pralatrexate, pralidoxime, pralmorelin, pral-
US 8,158,152 B2
nacasan, pramipexole, pramiracetam, pramoxine, prampine,
tazar, relcovaptan, relomycin, remacemide, remifentanil,
pranazepide, pranidipine, prankulast, pranolium, pranoproremikiren, remiprostol, remoxipride, renanolone, rentiapril,
fen, pranosal, prasterone, prasugrel, pratosartan, pravadoline,
renzapride, repaglinide, reparixin, repinotan, repirinast,
pravastatin, praxadine, prazarelix, prazepam, prazepine,
repromicin, reproterol, rescimetol, rescinnamine, resequinil,
praziquantel, prazitone, prazocillin, prazosin, preclamol, 5 reserpine, resiquimod, resocortol butyrate, resorantel, resorprednazate, prednazoline, prednicarbate, prednimustine,
cinol, retapamulin, retelliptine, retigabine, retinol, revapraprednisolamate, prednisolone, prednisone, prednival, predzan, revatropate, revenast, reviparin, revizinone, revospirone,
nylidene, pregabalin, pregnadiol, pregnenolone, premafloxaribavirin, riboflavin, riboprine, ribostamuycin, ricasetron,
cin, premazepam, prenalterol, prenisteine, prenoverine,
ridazolol, ridogrel, rifabutin, rifalazil, rifametane, rifamexil,
prenoxdiazine, prenylamine, pretamazium, pretiadoil, preza- io rifamide, rifampin, rifapentine, rifaximin, rilapine, riltide, pribecaine, pridefine, prideperone, pridinol, prifelone,
makalim, rilmazafone, rilmenidine, rilopirox, rilozarone,
prifinium, prifuroline, pilocalne, primaperone, primaquine,
rilpovorine, riluzole, rimantadine, rimazolium, rimcazole,
primidolol, primidone, primycin, prinomastat, prinomide,
rimexolone, rimiterol, rimonabant, rimoprogin, riodipine,
prinoxodan, pristinol, pristinamycin, prizidilol, proadifen,
rioprostil, ripazepam, ripisartan, risarestat, risedronicacid,
probarbital, probenecid, probicromil, probucol, procaina- 15 risocaine, risotilide, rispenzepine, risperidone, ristianol, rismide, procaine, procarbazine, procaterol, prochlorperazine,
tocetin, ritanserin, ritometan, ritipenem, ritobegron, ritoprocinolol, procinonide, proclonol, procromil, procyclidine,
drine, ritolukast, ritonavir, ritropirronium, ritrosulfan, rivarprocymate, prodeconium, prodilidine, prodipine, prodolic
oxaban, rivastigmine, rivoglitazone, rizatriptan, robalzotan,
acid, profadol, profexalone, proflavine, proflazepam, progarobenidine, rocastine, rocepafant, rociclovir, rocuronium,
bide, progesterone, proglumetacin, proglumide, prohep- 20 rodocaine, rodorubicin, rofecoxib, rofelodine, rofleponide,
tazine, proligestone, praline, prolintane, prolonium, proroflumilast, rogletimide, rokitamycin, rolafagrel, roletamide,
mazine, promegestone, promestriene, promethazine,
rolgamidine, rolicyclidine, rolicyprine, rolipram, rolitetracypromolate, promoxolane, prontalol, propacetamol, procline, rolodine, rolziracetam, romazarit, romergoline,
pafenone, propagermanium, propamidine, propanidid, proromifenone, romifidine, romurtide, ronactolol, ronidazole,
panocaine, propantheline, proparacaine, propatyl nitrate, 25 ronifibrate, ronipamil, runnel, ropinirole, ropitoin, ropivpropazolamide, propenidazole, propmtofylline, propenacaine, ropizine, roquinimex, rosaprostol, rosaramicin, rose
zolate, properidine, propetamide, propetamfos, propetandrol,
bengal, rosiglitazone, rosoxacin, rostafuroxin, rostaporfin,
propicillin, propikacin, propinetidine, propiomazine, propirosterolone, rosuvastatin, rotamicillin, rotigotine, rotoxamocaine, propiram, propisergide, propiverine, propizepine,
ine, rotaxate, roxadimate, roxarsone, roxatidine acetate, roxipropofol, propoxate, propoxur, propoxycaine, pro- so bolone, roxifiban, roxindole, roxithromycin, roxolonium,
poxyphene, propranolol, propyl docetrizoate, propyl gallate,
roxoperone, rubitecan, ruboxistaurin, rufinamide, rufloxacin,
propylhexedrine, propyliodone, propylthiouracil, propyperrupatadine, rupintrivir, rutamycin, ruvazone, ruzadolane,
one, propyphenazone, propyromazine, proquazone, prosabarubicin, sabcomeline, sabeluzole, sabiporide, saccharin,
quinolate, prorenoate, proroxan, prscillardin, prospidium,
safingol, safirinol, sagandipine, salacetamide, salafibrate, salprostalene, prosulpride, prosultiamine, proterguride, pro- 35 antel, salazodine, salazosulfadimidine, salazosulfamide,
theobromine, prothipendyl, prothixene, protiofate, protionasalazosulfathiazole, salcaprozoic acid, salcolex, salethamide,
mide, protirelin, protizinic acid, protokylol, protoporphyrin,
salflucerine, salicyl alcohol, salicylamide, salicylic acid, saliprotriptyline, proxzole, proxibarbal, proxibutene, proxicronazid, salinomycin, salmefamol, salmeterol, salmisteine, salmil, proxifezone, proxorphan, proxymetacaine, proxyphylnacedin, salprotoside, salsalate, sameridine, samixogrel,
line, prozapine, prucalopride, prulifloxacin, pruvanserin, 40 sampatrilat, sampirtine, sancycline, sanfetrinem, sanguipseudoephedrine, pumafentrine, pumaprazole, pumitepa,
narium, saperconazole, saprisartan, sapropterin, saquinavir,
pumosetrag, puromycin, pyrabrom, pyrantel, pyrathiazine,
sarafloxacin, sarakalim, saralasin, sarcolysin, sardomozide,
pyrazinamide, pyrazofurin, pyricarbate, pyridarone, pyridisaredutant, saripedem, sarizotan, sarmazenil, samoxicillin,
nol, pyridofylline, pyridostigmine, pyridoxal, pyridoxamine,
sarpicillin, sarpogrelate, saterinone, satigrel, satranidazole,
pyridoxine, pyrilamine, pyrimethamine, pyrimate, pyrino- 45 satraplatin, saviprazole, savoxepin, scopafungin, scopinast,
line, pyrithione, pyrithyldione, pyritidium, pyritinol,
scopolamine, secalciferol, seclazone, secnidazole, secobarpyrophenindane, pyrovalerone, pyroxamine, pyrrobutamine,
bital, securinine, sedecamycin, sedoxantrone, seganserin,
pyrrocaine, pyrrolifene, pyrroliphene, pyrrolnitrin, pyrroxsegesterone, seglitide, selamectin, selgiline, selfotel, soldeane, pyrvinium, pytamine, quadazocine, quadrosilan,
noson, selprazine, sampimod, sematilide, semaxanib, semduquatacaine, quazepam, quazinone, quazodine, quazolast, 5o ramicin, semorphone, semotiadil, semustine, senazodan, seoquetiapine, quifenadine, quiflapon, quillifoline, quilostigcalcitol, sepazonium, seperidol, sepimostat, seprilose,
mine, quinacainol, quinacillin, quinacrine, quinagolide,
seproxetine, sequifenadine, seratrodast, serazapine, serfiquinaldine blue, quinapril, quinaprilat, quinazosin, quibrate, sergolexole, sermetacin, sertindole, sertraline, setastbolone, quincarbate, quindecamine, quindonium, quindoxin,
ine, setzindol, setipafant, setiptiline, setoperone, sevitropium,
quinelorane, quinestradol, quinestrol, quinethazone, quineto- 55 sevopramide, sezalamide, sagoside, sibenadet. Sibopirdine,
late, quinezamide, quinfamide, quingestanol acetate,
sibrafiban, sibutramine, siccanin, sifrprazine, siguazodan,
quingestrone, quinidine, quinine, quinotolast, quinpirole,
silandrone, sildenafil, silibinin, silcristin, sildianin, silodosin,
quinterenol, quitiofos, quinuclium, quinupramine, quinuprissilodrate, silperisone, siltenzepine, simendan, simetride, simtin, quipazine, quisultazine, rabeprazole, raclopride, ractofibrate, simtrazene, simvastatin, sincalide, sinefungin, sinipamine, radafaxine, rafoxanide, ragaglitazar, ralitoline, ral- 60 trodil, sintropium, sipatrigine, siramesine, siratiazem, sirolioxifene, raltitrexed, raluridine, ramatroban, ramciclane,
mus, sisomicin, sitafloxacin, sitalidone, sitamaquine,
ramelteon, ramifenazone, ramipril, ramiprilat, ramixotidine,
sitaxentan, sitofibrate, sitoglusoide, sivelestat, soblidotin,
ramnodigin, ramnoplanin, ramorelix, ramosetron, ranelic
sobuzoxane, solabegron, solifenasin, solimastat, solpecainol,
acid, ranimustine, ranimycin, ranirestat, ranitidine, ranolaine,
solypertine, somatadine, soneclosan, sonepiprazole, sopirapacuronium, rasagiline, rasburicase, rathyronine, ravu- 65 tazine, sopromidine, soquinolol, sorafenib, soraprazan, sorbconazole, razaxaban, razinodil, razobazam, razoxane, rebiminicate, sorbinil, sorivudine, somidipine, sotalol, soterenol,
astat, reboxetine, recainam, reclazepam, regadenoson, reglispaglumic acid, sparfloxacin, sparfosate, sparsomycin,
US 8,158,152 B2
WA
28
sparteine, spectinomycin, spiclamine, spiperone, spiradoline,
zole, tendamistat, tenidap, tenilapine, teniloxazine,
spiramide, spiramycin, spirapril, spiraprilat, spirendolol,
tenilsetam, teniposide, tenivastatin, tenocyclidine, tenofovir,
spirgetine, spirilene, spiriprostil, spirofylline, spirogermatenofovir disoproxil, tenonitrozole, tenosal, tenosiprol,
nium, spiroglumide, spiromustine, spironolactone, spiropltenoxicam, tenylidone, teoprantil, teoprolol, tepirindole, tepatin, spirorenone, spirotriazine, spiroxasone, spiroxatrine, 5 oxalin, teprenone, teprotide, terazosin, terbequinil, terbinspiroxepin, spizofurone, sprodiamine, squalamine, squalane,
afine, terbogrel, terbucromil, terbufirol, terbuficin, terbuprol,
stacofylline, stllimycin, stannsoprfin, stanolone, stanoaolol,
terbutaline, terciprazine, terconazole, terdecamycin, teeresstavudine, stearylsufamide, steffimycin, stenbolone, strprotigmine, terfeadine, terflavoxate, terfluranol, terguride, terinin, stercuronium, stevaladil, stibamine, stibophen, stilbamiflunomide, terikalant, terizidone, terlakiren, terlipressin,
dine, stilbazium, stilonium, strimazole, stiripentol, stirocain- io ternidazole, terodiline, terofenamate, teroxalene, teroxirone,
ide, stirofos, streptomycin, streptonicozid, streptonigrin,
tertatolol, tesaglitazar, tesicam, tesimide, tesimilifene,
streptozocin, styramine, subathiazone, subendazole, succitesofensine, testolactone, testosterone, tetomilst, tetrabarnylcholine, succinylsulfathiazole, succisulfone, suclofenide,
bital, tetrabenazine, tetracaine, tetracycline, tetrahydrozosucralfate, sucralose, sucrose octaacetate, sucrosufate, sudexline, tetramethrin, tetramisole, tetraxetan, tetrazepam, tetraanox, sudoxicam, sufenatil, sufotidine, sufugolix, sugamma- 1 5 zolast, tetriprofen, tetrofosmin, tetronasin, tetroquinone,
dex, sulamserod, sulazepam, sulazuril, sulbactam, sulbeniciltetroxoprin, tetrydamine, teverelix, texacromil, tezacitabine,
lin, sulbenox, sulbentine, sulbutiamine, sulclamine,
tezosentan, thalidomide, thebacon, thenalidine, thenium, thesulconazole, sulfabenz, sulfabenzamide, sulfabromomethaznyldiamine, theobromine, theodrenaline, theofibrate, theoine, sulfacarbamide, sulfacecole, sulfacetamide, sulfachlophylline, thiabendazole, thiacetarsamide, thialbarbital, thiarpyridazine, sulfachrysoidine, sulfaclomide, sulfaclorazole, 20 mazole, thiamine, thiamiprine, thiamphenicol, thamylal,
sulfaclozine, sulfacytine, sulfadiazine, sulfadimethoxine,
thiazesim, thiazinamium, thiazolsulfone, thiethyperazine,
sulfadoxine, sulfaethidole, sulfaguanidine, sulfaguanole, sulthihexinol ethylbromide, thimerfonate, thimerosal, thiofalene, sulfaloxic acid, sulfamazone, sulfamerazine, sulfamecolchicoside, thioctic acid, thiofuradene, thioguanine, thioter, sulfamethaziine, sulfamethizole, sulfamethoxazole, sulhexamide, thioinosine, thiopental, thiophanate, thioprofamethoxypyridazine, sulfametmidine, sulfametrole, 25 pazate, thioproperazine, thioridazine, thiosalan, thiostrpton,
sulfamonomethoxine, sulfamoxole, sulfanilamide, sulfathiotepa, thiotetrabarbital, thiothixene, thiphenamil, thiphennilate, sulfaanitran, sulfaperin, sulfaphenazole, sulfaproxycillin, thiram, thonzonium, thonzylamine, thozalinone, threoline, sulfapyridine, sulfaquinoxaline, sulfarsphenamine, sulnine, thymocartin, thymoctonan, thymol, thymopentin, thyfasalazine, sulfasomizole, sulfasuccinamide, sulfasymazine,
motrinan, thyromedan, thyropropic acid, thyroxin, tiacrilast,
sulfathiazole, sulfathiourea, sulfatolamide, sulfatroxazole, 30 tiadenol, tiafibrate, tiagabine, tiamenidine, tiametomnium,
sulfatrozole, sulfazamet, sulfinaolol, sulfinpyrazone, sultiamulin, tianafac, tianeptine, tiapamil, tiapirinol, tiapride,
firam, sulfisomidine, sulfisoxazole, sulfobromophthalein,
tiaprofenic acid, tiaprost, tiaramide, tiazofurin, tiazuril, tiasulfonterol, sulforidazine, sulfosalicylic acid, sulfoxone, sulbalosin, tibeglisene, tibenelast, tibenzate, tibezonium,
crinat, sulindac, sulisatin, sulisobenzone, sulmarin, sulmatibolone, tibric acid, tibrofan, ticabesine, ticalopride, ticarbozole, sulmepride, sulnidazole, sulocarbilate, suloctidil, sulo- 35 dine, ticarcillin, ticlatone, ticlopidine, ticolubant, ticrynafen,
dexide, sulofenur, sulopenem, sulosemide, sulotroban,
tidembersat, tidiacic acid, tiemonium, tienocarbine, tienosuloxifen, sulpiride, sulprosal, sulprostone, sultamicillin, sulpramine, tienoxolol, tifemoxone, tifenazoxide, tiflamizole,
tiame, sultopride, sultosilic acid, sultroponium, sulukast, sultiflorex, tifluadom, tiflucarbine, tiformin, tifurac, tigecycline,
verapride, sumacetamol, sumanirole, sumarotene, sumatriptigemonam, tigestol, tigloidine, tilargenine, tiletamine, tilitan, sumetizide, sunagrel, suncillin, sunepitron, supidimide, 4o dine, tiliquinol, tilisolol, tilmacoxib, tilmicosin, tilnoprofen,
supalast, suproclone, suprofen, suramin, suricainide, suntilomisole, tilorone, tilozepine, tilsuprost, tiludonic acid, timclone, suritozole, suronacrine, susalimod, suxemerid, suxcodar, timefurone, timegadine, timelotem, timepidium, timiethonium, suxibuzone, symclosene, synetine, tabilautide,
perone, timirdine, timobesone acetate, timofibrate, timolol,
tabimorelin, tacalcitol, tacapenem, tacedinaline, taclamine,
timonacic, timoprazole, tinabinol, tinazoline, tinidazole,
tacrine, tacrolimus, tadalafil, tafluposide, taglutamine, tago- 45 tinisulpride, tinofedrine, tinoridine, tiocarlide, tioclomarol,
rizine, talampanel, talampicillin, talaporfin, talastine, talbtioconazole, tioctilate, tiodazosin, tiodonium, tiomergine,
utal, taleranol, talibegron, talinolol, talipexole, talisomycin,
tiomesterone, tioperidone, tiopinate, tiopronin, tiopropamtallimustine, talmetacin, talmetoprim, talnetant, talniflumate,
ine, tiospirone, tiotidine, tiotropium, tioxacin, tioxamast,
talopram, talsalate, toloximine, talsaclidine, talsupram,
tioxaprofen, tioxidazole, tioxolone, tipentosin, tipepidine,
taltirelin, taltobulin, taltrimide, taludipine, talviraline, 50 tipetropium, tipifamib, tipindole, tipranavir, tipredane, tipretameridone, tameticillin, tametraline, tamibarotene, tamitinolol, tiprinast, tiprodil, tiprostanide, tiportimod, tiqueside,
nol, tanolarizine, tamoxifen, tampramine, tamsulosin,
tiquinamide, tiquizium, tiracizine, tirapazamine, tiratricol,
tanaproget, tandamine, tandospirone, tandutinib, taniplon,
tirilazad, tirofiban, tiropramine, tisartan, tisocalcitate,
tanomastat, tapentadol, taprizosin, taprostene, tarazepide,
tisocromide, tisopurine, tisoquone, tivanidazole, tiviciclovir,
tariquindar, tasosartan, tasuldine, taurolidine, tauromustine, 55 tivirapine, tixadil, tixanox, tixocortol, tizabrin, tizanidine,
tauroselcholic acid, taurosteine, tazadolene, tazanolast, taztizolemide, tizoprolic acid, tobicillin, toborinone, tobramyarotene, tazasubrate, tazeprofen, tazifylline, taziprinone,
cin, tocainide, tocamphyl, tocladesine, tocofenoxate, tocofitazobactam, tazofelone, tazolol, tazometine, tebanicline,
brate, tocophersolan, todralazine, tofenacin, tofetridine,
tebatizole, tebipenem, tebufelone, tebuquine, tecadenoson,
tofimilast, tofisoline, tofisppam, tolafentrine, tolamolol,
tecalcet, tecastemizole, teclthiazide, teclozan, tedisamil, tefa- 60 tolazamide, tolboxane, tolbutamide, tolvapone, tolciclate,
zoline, tefenperate, teflufazine, teflutixol, tegafur, tegaserod,
toldimfos, tolfamide, tolfenamic acid, tolgabide, tolimidone,
teglicar, teicopanin, telavancin, telbivudine, telenzepine,
tolindate, toliodium, toliprolol, tolmesoxide, tometin, tolnaftelinavir, telithromycin, telmesteine, telmisartan, teloxtate, tolnapersine, tolnidamine, toloconium, tolonidine, toloantrone, teludipine, temafloxacin, temarotene, tematropium,
nium, toloxatone, toloxychlorinol, tolpadol, tolpentamide,
temazepam, temefos, temelastine, temiverine, temocapril, 65 tolperisone, tolpiprazole, tolpronine, tolpropamide, tolpyrratemocaprilat, temocillin, temodox, temoporfin, temozolomide, tolquinzole, tolrestat, tolterodine, toltrazuril, tolumide, temisirolimus, temurtide, tenamfetamine, tenatoprafazepam, tolvaptan, tolycaine, tomeglovir, tomelukast, tomo-
US 8,158,152 B2
30
glumide, tomoxiprole, tonabersat, tonazocine, topilutamide,
viroxime, visnadine, visnafylline, vofopitant, voglibose,
topiramate, topixantrone, topotecan, toprilidine, topterone,
volazocine, volpristin, voriconazole, vorozole, voxergolide,
toquizine, torbafylline, torcetrapib, torcitabine, toremifene,
xaliproden, xamoterol, xanomeline, xanoxic acid, xanthinol,
toripristone, torsemide, tosagestin, tosifen, tosufloxacin,
xantifibrate, xantocillin, xantofyl palmitate, xemilofiban,
tosulur, trabectedin, traboxopine, tracazolate, tradecamide, 5 xenalipin, xenazoic acid, xenbucin, xenipentone, xenothiotralonide, tramadol, tramazoline, trandolapril, trandolaprilat,
rate, xenygloxal, xenylhexenicacid, xenylropium, xibenolol,
tranexamic acid, tranilast, transcainide, trantelinium, tranyxibornol, xidecaflur, xilobam, ximelagatran, ximoprofen,
cypromine, trapencaine, trapidil, travoprost, traxanox, traxoxinidamine, xinomiline, sipamide, xipranolol, xorphanol,
prodil, trazitiline, trazium, trazodone, trazolopride, trebenxylamidine, xylazine, xylocoumarol, xylometazoline, xyloxzomine, trecadrine, trecetilide, trefentanil, trelnarizine, io emine, yohimbic acid, zabicipril, zabiciprilat, zacopride,
treloxinate, trenbolone, trengestone, trenizine, treosulfan,
zafirlukast, zafuleptine, zalcitabine, zalderide, zaleplon,
trepibutone, trepipam, trepirium, treprostinil, treptilamine,
zalospirone, zalitidine, zaltoprofen, zamifenacin, zanamivir,
terquisin, tresperimus, trestolone, trethinium, trethocanoic
zanapezil, zankiren, zanoterone, zapizolam, zaprinast, zardacid, tretinoin, tretinoin tocoferil, tretoquinol, triacetin, triaverine, zatebradine, zatosetron, zelandopam, zenarestat,
afungin, triamcinolone, triamcinolone acetonide, triamcino- 15 zenazocine, zeniplatin, zepastine, zeranol, zetidoline, zidapalone benetonide, triamcinolone furetonide, triampyzine, trimide, zidometacin, zidovudine, zifrostilone, zilantel, zilasamtemem triaziquone, triazolam, tribendilol, tribenoside,
corb, zileuton, zilpaterol, zimeldine, zimiidoben, zindotrine,
tribromsalan, tribuzone, tricaprilin, tricetamide, trichlorfon,
zindoxifene, zinconazole, zinostatin, zinterol, zinviroxime,
trichlormethiazide, trichlomethine, triciribine, triclabendazipeprol, ziprsidone, zocainone, zofenopril, zofenoprilat,
zole, triclacetamol, triclazate, triclobisonium, triclocarban, 20 zoficonazole, zolamine, zolasartan, zolazepam, zolendronic
triclodazol, triclofenol, triclofos, triclofyllin, triclonide, triacid, zolenzepine, zolertine, zolimidine, zoliprofen, zolmiclosan, tricyclamol, tridihexethyl, tridolgosir, trientine, tritriptan, zoloperone, zolpidem, zomebazam, zomepirac,
ethylenemelamine, trifenagrel, trifezolac, triflocin, triflubazometapine, zonampanel, zoniclezole, zoniporide, zonisazam, triflumidate, triflomeprazine, trifluperazine,
mide, zopiclone, zopolrestat, zorbamycin, zorubicin, zosutrifluperidol, triflupromazine, trifluidine, triflusal, trifosmin, 25 quidar, zotepine, zoticasone, zoxazolamine, zucapsaicin,
trigevolol, trihexylpheidyl, triletide, trilostane, trimazosin,
zuclomiphene, zuclopenthixol, and zylofuramine.
trimebutine, trimecain, trimedoxime, trimegestone, trimepThe solvent, as mentioned, can be any liquid in which the
eridine, trimeprazine, trimetazidine, trimethadone, trimethamaterial dissolves; the solvent can be a single substance or a
mide, trimethaphan, trimethidinium, trimethobenzamide, trimixture of co-solvents, the important point being that the
methoprim, trimetozine, trimetrexzate, trimexiline, 30 material to be lyophilized goes into solution. Solvents useful
trimipramine, trimoprostil, trimoxamine, trioxifene, trioxin the invention include materials that are liquid at room
salen, tripalmitin, tripamide, triparanol, tripelennamine, tritemperature, dissolve the material, and are volatilizable or
platin, triprolidine, triptorelin, tritoqualine, trixolane, trisublimatable at the temperature and pressure conditions of
zoxime, trocimine, troclosene, trodusquemine, trofosfamide,
the primary drying step discussed below. Since not all soltroglitazone, troleandomycin, tromanttadine, tropabazate, 35 vents dissolve all materials, some of the potential solvents
tropanserin, tropapride, tropatepine, tropenziline, tropicamwill not be solvents in particular cases. Those of ordinary skill
ide, tropigline, tropirine, tropisetron, tropodifene, troquidawill know which liquids are suitable as solvents once the
zole, trospectomycin, trospium, trovafloxacin, trovirdine,
material to be lyophilized has been selected, by reference to
troxacitabine, troxeratin, troxipide, troxolamide, troxonium,
standard texts in the field or by the conduct of simple dissotroxypyrrolium, truxicurium, truxipicurium, tryparsamide, 40 lution testing of the material with the potential solvent. The
tubocurarine, tubulozole, tucaresol, tuclazepam, tulathromychosen solvent will either alone dissolve the material or
cin, tulobuterol, tulopafant, turosteride, tuvatidine, tybamate,
together with a co-solvent will dissolve the material in questylosin, tymazolin, tyropanoate, tyrosine, tyrothricin, ubention. Co-solvents are selected from the same class as solvents,
imex, ubidecarenone, ubisindine, ufenamate, ufiprazole,
are miscible with the chosen solvent, and generally aid the
uldazepam, ulifloxacin, uliprisnil, umespirone, undecylenic 45 dissolution of the material in the solvent. Once the material in
acid, unoprostone, upenazime, upidosin, uracil, uracil musquestion is selected and the solvent and any co-solvent is
tard, urapidil, uredepa, uredofos, urefibrate, ursodiol,
selected, the anti-solvent is also selected from the same set of
urulcholic acid, utibapril, utibaprilat, vadocaine, valaciclovir,
substances, but limited to those which do not significantly
valconazole, valdecoxib, valdetamide, valdipromide, valedissolve the material, preferably do not dissolve the material
thamate, vlaganiciclovir, valine, valnemulin, vlanoctamide, 5o at all, and yet are miscible with the chosen solvent/optional
valofane, valomaciclovir, valperinol, valproate, vlaproicacid,
co-solvent system previously selected. For purposes of the
valpromide, valrocemide, valrubicin, valsartan, valorcitabpresent invention, solubility of the material in the solvent or
ine, valtrate, vamicamide, vancomycin, vandetanib, vanepsolvent/cosolvent mixture is critical only in that the material
rim, vanitiolide, vanoxerine, vanyldisulfamide, vapiprost,
needs to be dissolved. The concentration of the material in the
vapreotide, vardenfanil, varenicline, varespladib, vatalanib, 55 solvent or solvent/co-solvent mixture is only of concern in
vatanidipine, vebufloxacin, vecuronium, vedaclidine,
certain situations. For example, in pharmaceutical injectable
vedaprofen, velaresol, velnacrine, venlafaxine, venritidine,
formulations, where the material is lyophilized in containers
verodoline, veralipride, verapamil, verazide, verilopam, verthat, once reconstituted in the container contain unit dosage of
lukast, verofylline, versetamide, vertepozfin, vesnarinone,
the material for administration, materials requiring a small
vestipitant, vetrabutine, vidarabine, vigabatrin, vilazodone, 60 unit dose may utilize a significant volume of "solvent" in the
vildaglipin, viloxazine, vinbarbital, vinblastine, vinbuznine,
lyophilization procedure. However, where the material
vincamine, vincanol, vincofos, vinconate, vincristine, vinderequires a large unit dose, the liquid chosen as the solvent
burnol, vindesine, vinpidine, vinflunine, vinformide, vinfosmust necessarily be a much better solvent for the material so
iltine, vinglycinate, vinleucinol, vinleurosine, vinmegallate,
that the amount of solvent needed to dissolve the unit dose is
vinorelbine, vinpocetine, vinpoline, vinrosidine, vintiamol, 65 amenable to being placed in the lyophilization container for
vintoperol, vintriptol, vinylbital, vinzolidine, viomycin,
processing economically. While these same concerns are
viprostol, viqualine, viquidil, virginiamycin, viridofulvin,
important to bulk lyophilization procedures as well, they are
US 8,158,152 B2
31
less stringent than where the lyophilization containers are
intended as the reconstitution container having unit doses.
Thus, the choice of a liquid as a solvent or a co-solvent not
only depends upon the intrinsic ability to dissolve the material
in question, but on its relationship to the amount of the solution that can be placed in the lyophilization container
intended to have a specific amount of end lyophilizate. Those
of ordinary skill in the art will appreciate these concerns and
be able to readily modify their particular choices to accommodate these concerns. Similar concerns apply to the choice
of anti-solvent.
The lyophilization procedures herein can also be used to
prepare rapidly disintegrating tablets that dissolve in the
mouth without the need for water to swallow the tablet. Currently available rapidly dissolving tablets (technology owned
by Zydus) is only applicable to hydrophilic molecules having
a low unit dose requirement (generally less than about 15 mg
per dose) which do not require taste-masking. The current
invention, on the other hand, permits creating a lyophilizate in
a tablet mold so that the lyophilizate takes the shape of a
tablet. Since the present lyophilization method can omit virtually all auxiliary materials if the drug doesn't require taste
masking, it is applicable to materials having a high unit dose
amount (hundreds to more than 1 gram per unit dose), as well
as to those having small unit dosage amounts. Furthermore,
while the Zydus technology is available only with respect to
hydrophilic materials, the present invention is applicable to
both hydrophilic and hydrophobic materials.
Suitable, non-limiting, liquids for use as solvents, co-solvents, or anti-solvents, depending on the circumstances as
outlined elsewhere in this specification include, but are not
limited to water, 5-7 membered heteroring systems (the heteroring systems having 1-3 heteroatoms, where the heteroatoms are oxygen or sulfur, the sulfur atoms being unsubstituted or further carrying one or two oxygen substituents,
except that two oxygen atoms cannot be in adjacent ring
positions, for example tetrahydrofuran (THF), tetrahydropyran, dioxane, trioxane and other cyclic mono-, di- and triethers), lower alkanols (such as ethanol, propanol, isopropanol, sec-butanol, t-butyl alcohol, and n-butyl alcohol), or
other organic solvents that freeze in the range of a lower
temperature of about —100° C., preferably —90° C., more
preferably —80° C., and an upper temperature of not more
than about 250 C., preferably not more than about 20° C., even
more preferably not more than about 15° C., still more preferably not more than about 10° C., In addition, PEG 600-6000
and tocopherol succinate and acetate can also be used.
Preferably, the solvent is water, especially for hydrophilic
materials. Water is preferred in the context of pharmaceuticals, veterinary products, and foodstuffs because any residual
solvent that remains with the solid is innocuous once the
lyophilizate is reconstituted with water. In applications in
industries other than the above or where the freeze dried
product is desired as a reactant in further reactions, other
solvents, both within and beyond those set forth above may be
preferred as well and will be well within the ordinary skill of
those in the art. Nonetheless, the solvent must be one that is
volatile or sublimates under the primary drying step conditions. Other preferable liquids for use in the invention as the
solvent or as the co-solvent or as the anti-solvent as dictated
by the particulars of the material in question include ethanol,
tetrahydrofuran, and dioxane.
If desired, a co-solvent may be used to aid in the dissolution
of the material in the solvent. As stated above, such cosolvents are selected from the same group of liquids above, as
long as the co-solvent is different from the solvent in question
in the particular embodiment in question and miscible with
5
10
15
20
25
3o
35
40
45
50
55
60
65
the primary solvent so as to effect dissolution of the material.
Such co-solvents should be used as minimally as possible so
as to avoid unnecessarily complicating the solid product (potentially mixed solvate crystal forms or mixed solvent amorphous associations, etc.), but there is no other reason to avoid
them and their use is within the scope of the present invention.
Where a co-solvent is utilized, it must also be one that is
volatile or sublimates under the primary drying step conditions.
If desired, the solution pH may be adjusted within a range
either to facilitate the solubility of the compound or to provide
a particular pH environment for optimum stability that is
compatible with the end use of the lyophilizate. Thus, for
product that will be reconstituted with water for injection,
with or without tonicity modifiers therein, the pH should be
such that on reconstitution, a physiologically tolerated compatible pH is achieved. This is less of concern with materials
that will be incorporated into more complex formulations or
that will be used as reagents for further reactions. In these
latter situations, the pH of the lyophilizate does not necessarily correlate with its end pH so that a larger latitude of pH
values in the lyophilizate are acceptable.
In one embodiment of the invention, once the solution is
obtained (and any desired pH adjustment and any desired
filtration pre-material precipitation has taken place), the solution can be added to an anti-solvent for the material or can
have such anti-solvent added to it. The purpose of this step is
to force the material out of solution in a manner which will
permit recovery of the desired form of the material. The
anti-solvent is a substance which is not a solvent for the
material, but is miscible with the solvent and, if present, any
co-solvent, used. The anti-solvent must also be a substance
that can be removed in the context of the freeze-drying itself.
Thus, it is a substance which is volatile or sublimes at the
temperature and pressure used in the primary drying step of
the freeze-drying process. As stated above, the anti-solvent is
selected from the same group of liquids set forth above,
except that for use as an anti-solvent, the liquid must adhere to
the constraints of this paragraph with respect to the particular
material/solvent/optional co-solvent system in question.
In another embodiment of the invention, in which the material is hydrophobic or lipophilic, the solvent is selected from,
5-7 membered heteroring systems (the heteroring systems
having 1-3 heteroatoms, where the heteroatoms are oxygen or
sulfur, the sulfur atoms being unsubstituted or further carrying one or two oxygen substituents, except that two oxygen
atoms cannot be in adjacent ring positions, for example tetra
hydrofuran (THF), tetrahydropyran, dioxane, trioxane and
other cyclic mono-, di- and tri-ethers). The use of these liquids as solvents in the lyophilization process is new to the
lyophilization art. In addition, in the lyophilization of hydrophobic or lipophilic materials according to the invention,
lower alkanols (methanol, ethanol, propanol, isopropanol,
n-butanol, sec-butanol, or t-butanol), liquid ketones, liquid
(oxygen or sulfur) ethers, liquid (oxygen or sulfur) ketones,
liquid (oxygen or sulfur) esters or thioesters may also be used
as the liquid solvent. In these embodiments, in addition to
utilizing the anti-solvent as indicated above, the system can
omit the anti-solvent and directly lyophilize the solution of
the material in these liquids, in a manner completely analogously to completely aqueous lyophilization techniques.
When omitting the anti-solvent, the preferred solvents are the
heteroring solvents discussed above. The lyophilizate here as
with the resultant lyophilizate of hydrophobic and lipophilic
embodiments when using the anti-solvent process above do,
however, require different reconstitution techniques than
those for the hydrophilic materials.
US 8,158,152 B2
33
Again, it should be noted that for any given material, not all
anti-solvent to solvent/co-solvent utilized as well as the speed
of the liquids listed above will be solvents for the specific
of the addition when adding anti-solvent to the solvent/comaterial, however, a mere solubility test will determine if the
solvent/material solution as well as freezing conditions. The
particular solvent is suitable for a particular material. If the
reverse addition of solvent/co-solvent/material to anti-solmaterial is soluble in the particular liquid, then the liquid is 5 vent results in a very rapid precipitation since the ratio of
suitable as a solvent and/or co-solvent. If the material is not
anti-solvent to solvent/co-solvent is always very high during
soluble in the liquid, then that is a potential anti-solvent for
the addition.
that system if and only if it is also miscible with the solvent or
Once the precipitation is effected (or once the dissolution is
solvent/co-solvent system being used. Suppose a material has
effected in the embodiments that omit the anti-solvent), the
a solubility in a liquid A of 1000 mg/ml, in liquid B of 100 io mixture is frozen in a cooling step that is typically over a
mg/ml, in liquid C of 10 mg/ml, and in liquid D of 0.01
period of about 30 min to 10 hours, preferably about 1 our to
mg/ml. Further, suppose that the material has a unit adult dose
about 8 hours, more preferably about 2 hours to about 7 hours,
of 300 mg, a unit pediatric dose of 60 mg, and an infant unit
typically about 4 to about 6 hours to result in a frozen mass. A
dose of 12 mg. To prepare a suitable adult dose of the invenquick freezing generally favors amorphous product, while a
tion, one would use liquid A (and possibly liquid B) as the 15 slow cooling generally favors a more crystalline product;
solvent. Liquid D is an clearly suitable as an anti-solvent, but
however, this is only a general guideline, and particular
liquid C might also be suitable as the anti-solvent. To prepare
results can vary depending on a number of conditions. If
a suitable pediatric unit dose of the invention, one might use
desired, prior to freezing, the mixture can be filtered so that
liquidA, but liquid B might be a better choice depending upon
the bulk of the solvent/co-solvent/anti-solvent is removed/
available equipment precision. Liquid C, while it can be used 20 recovered leaving behind a precipitate wet with some of the
as the anti-solvent, since it can still dissolve an appreciable
solvent/co-solvent/anti-solvent mixture, which is then subamount of the unit dose amount, it is preferably not so used,
jected to the freezing step. (This procedure applies especially
and the better choice as the anti-solvent is liquid D. In prewhen preparing sterile bulk, not unit dose vials for parenteral
paring a suitable infant unit dosage of the invention, liquid C
administration).
is not only not suitable as the anti-solvent (since it is capable 25
Once frozen, the mass is subjected to a vacuum pressure
of dissolving virtually the entire unit dosage amount, but
whereby a substantial portion, if not all of the remaining
precisely because of this, it might actually be suitable for use
solvent/co-solvent/anti-solvent is volatilized off during prias the solvent while liquid D would be the anti-solvent. Thus,
mary drying. Remaining residual amounts of one or more of
given the particulars of the individual situation of the various
solvent and/or co-solvent and/or anti-solvent are removed in
solubilities in the various liquids as potential solvent and 3o a secondary drying step. Generally, during the primary drying
anti-solvents, and the specifics of the unit dosage amounts
the product temperature is maintained below 0°C while in the
needed to be in the lyophilized product, a single liquid may be
secondary drying the product temperature will be maintained
a solvent in some cases and yet an anti-solvent in others even
at about 25 to 40° C., although other primary and secondary
for the same material intending to be lyophilized. Thus, while
drying temperatures may be suitably found in the ordinary
some testing is necessary to determine the specifics of the 35 course by those of ordinary skill in the art.
systems within the invention, such is well within the abilities
The lyophilizates prepared according to the invention can
of one of ordinary skill in the art. Generally, liquids that are
be prepared in situ in the container that will be used for
suitable as solvent or co-solvents for hydrophilic materials
reconstitution; in molds (or blister packs) for preparing rapare likely to be anti-solvents for hydrophobic or lipophilic
idly dissolving tablets; or can be prepared in bulk for use in
materials, while anti-solvents for hydrophilic materials are 4o any other processes or reactions as desired. Thus, bulk chemilikely to be solvents and co-solvents for hydrophobic and/or
cals can be prepared and packaged for blending with other
lipophilic materials. Similarly, liquids that are solvents and/or
components at a user's convenience or need. Similarly small
co-solvents for hydrophobic and/or lipophilic materials are
portions of lyophilizates of the invention may be prepared in
likely to be anti-solvents for hydrophilic materials, while
unit of use containers and packed with dissolution media in
carriers that are anti-solvents for hydrophobic and/or lipo- 45 suitable kits for ease of preparing single units of use.
philic materials are likely to solvents or co-solvents for
In one particularly preferred embodiment, amifostine (a
hydrophilic materials.
highly water soluble material) is the hydrophilic material,
The material/solvent/co-solvent (if present)/anti-solvent
water is selected as the solvent, and tetrahydrofuran is
(if present) system is then frozen and the frozen product is
selected as the anti-solvent. Also, tetrahydropyran, dioxane,
subjected to vacuum to sublimate or volatilize the solvent, 50 trioxane and the other liquid heteroring compounds menso-solvent/anti-solvent components.
tioned in paragraphs 0034-0036 can be used as anti-solvents
In general, in the embodiments in which anti-solvent is
for amifostine when water is the solvent. Of the aforemenutilized, once the solution of the material is formed in the
tioned solvents, dioxane offers special advantages over other
solvent or solvent/co-solvent mixture, the solution is mixed
organic solvents. Dioxane freezes below 15° C and subliwith anti-solvent in a proportion in the range of about 5:1 to 55 mates rapidly under vacuum. Use of dioxane as an antiabout 1:5, preferably about 4:1 to about 1:4, more preferably
solvent does not require any solvent trap and can be lyoabout 3:1 to about 1:3; even more preferably about 2:1 to
philized similar to completely aqueous lyophilization.
about 1:2, still more preferably about 1.5:1 to about 1:1.5, still
Similarly trioxane also has a low meting point and can be
even more preferably about 1:1 on a volume/volume basis of
easily removed during the lyophilization. Optionally, the pH
(solvent and/or-solvent): (anti-solvent).
60 can be adjusted to into the range of about 7 to about 8 prior to
The addition of the anti-solvent causes the material to come
adding the anti-solvent.
out of solution. This precipitation can be allowed to continue
In another preferred embodiment, a slurry is made using
for as long as desired before the freezing step takes place, but
ceftazadime and water. The pH is adjusted to about 5 to about
the slower the precipitation, the greater the likelihood that the
7 using NaOH to facilitate the dissolution of ceftazidime.
precipitated material will adopt a crystalline conformation. 65 Once solution is effected, an anti-solvent, such as THF, dioxThe speed of precipitation and thus the degree of crystallinity
ane or one of the other liquid heteroring compounds is added
or amorphous character can be controlled by the ratio of
to precipitate the ceftazadime, which is then frozen and dried.
US 8,158,152 B2
35
In this embodiment, lower alkanols, such as ethanol, n- or
iso-propanol, or n-, sec-, or t-butanol may also be used as the
anti-solvent. The same procedure is generally applicable to
other cephalosporins, especially to ceftrioxone and cephradine.
In another embodiment, a slurry of cefapime is made in
water. The pH is adjusted to about 1 to about 3 with HCl (or
other suitable inorganic acid) to facilitate dissolution. Once
dissolved, anti-solvent (liquid herteroring compounds) is
added to precipitate the cefapime, and the result is freeze
dried.
In a further embodiment, cyclophosphamide (sparingly
soluble in water but highly soluble in ethanol) is dissolved in
one or more of the liquid hetero-ring compounds and/or lower
alkanols to form a concentrated solution. Water is then added
as an anti-solvent to precipitate the crystalline cyclophosphamide monohydrate or anhydrate. The result is then freezedried.
In another particularly preferred embodiment, itraconazole
is the hydrophobic/lipophilic material and a non-aqueous
liquid is selected as a solvent to dissolve it. An anti-solvent is
not needed to lyophilize the hydrophobic/lipophilic molecule. The non-aqueous solvents to dissolve lipophilic molecules are listed in paragraph 0034-0036. In addition ethanol
and PEG 600-6000 and tocopherol succinate and acetate can
also be used as solvents to solubilize lipophilic materials.
Once the material is dissolved in the non-aqueous solvent, it
is filtered asceptically to remove any undesired components
and microorganisms and filled into vials and lyophilized
either using the conventional lyophilization procedures or
special procedures depending on the nature and amount of
non-aqueous solvents used to dissolve the material. The lyophilizate can be reconstituted with minimum volume of pharmaceutically acceptable solvent (typically polyethylene glycol or liquid PEGs) to prepare a liquid concentrate. The liquid
concentrate is further diluted to a desirable concentration in a
special diluent or commercially available Intralipid fat emulsions, or plasma or serum or in whole blood prior to administering to patients. One aspect of the novelty of this embodiment of the invention is that patient's blood can be used to
dilute the liquid concentrate and administer back into the
patients blood stream. Since these molecules are lipophilic,
they will partition into the lipid layer of the fat emulsion or
blood.
In a still further embodiment, itraconazole is dissolved in
non-aqueous liquid such as THE at a very high concentration.
Itraconazole is generally considered soluble in methylene
chloride only. We surprisingly found that high concentrations
of itraconazole can be dissolved in the non-aqueous solvents
listed in the paragraph 0034-0036 in the presence of small
quantities of HCl. The itraconazole thus dissolved in the non
aqueous solvent is lyophilized. The lyophilizate is reconstituted to 100 mg/ml solution using pharmaceutically acceptable solvent, typically propylene glycol. The liquid concentrate is further diluted with 25 ml or more of 10% Intralipid fat
emulsion. The aqueous and oil phase of the emulsion is separated by using an ultracentrifuge and it is observed that all the
itraconazole is partitioned into the fat layer of the emulsion.
While some embodiments seek to eliminate auxiliary components in the lyophilization process, not all auxiliaries need
be eliminated. Thus, as desired, the solution prepared prior to
any precipitation of the material and prior to any freezing step
can have suitable auxiliary materials such as building agents,
buffers, and anti-oxidizing agents. Each of the auxiliary
agents must be compatible with the end use or be capable of
being removed prior to use (as when the lyophilizate is being
used in further reactions or where the subsequently purified
5
10
15
20
25
30
35
40
45
50
product will have the non-acceptable material removed prior
to that product being used). Bulking agents that are generally
suitable are those which raise the glass transition temperature
of the material being lyophilized. For pharmaceuticals these
generally include, but are not limited to, saccharides (such as
fructose, sucrose, lactose, trehalose, and others), polyvinylpyrrolidone, and cyclodextrins, the saccharides being preferred, and trehalose being a particularly suitable material.
Complexing/solubilizing agents include niacinamide and
other cyclic amide, gentisic acid, cyclodextrins and surfactants with HLB values ranging from 1 to 16. Nonetheless, in
most instances, the invention permits the omission of the
bulking agent, and the absence of bulking agent is a preferred
embodiment. For pharmaceutical purposes, buffers can be,
but are not limited to, amino acids, inorganic buffers, monoand di-carboxylic acid buffers, hydroxyl-mono- and di-carboxylic acid buffers, amines, and sulfonamides. The antioxidants include, but are not limited to, different class of
bisulfites, ascorbic acid, disodium- and tetrasodium EDTA,
citrates as metal ion chelators, BHA, BHT, sulfoxylates, propyl gallate, amino acids containing thio group such as
methionine, and thiols as well as other antioxidants listed in
the FDA website for inactive ingredients used in pharmaceutical dosage forms.
Lyophilizates of the present invention have significantly
improved stability over materials prepared without lyophilization or prepared via current lyophilization techniques
other than those of the invention. For example, a completely
water lyophilization of amifostine results in a material that
degrades to 80% of its initial amifostine amount in 30 days,
when stored at 40° C. Amorphous amifostine lyophilizate of
the invention using water as the solvent and tetrahydrofuran
as the anti-solvent, stored under the same conditions, results
in degrading to only 98% of its initial amount in 30 days and
to 90% of its initial amount in 90 days.
The lyophilizates of the present invention (when limited to
pharmaceutical and veterinary active agents, as previously
discussed, can be utilized in the preparation of injectable final
products as well as in rapidly dissolving oral dosage forms. In
addition, they can be utilized in the preparation of other oral
dosage forms (tablets, capsules, powders, etc) for ingestion as
is or for rapid dissolution in liquids for ingestion. Still further,
the lyophilizates can be applied topically as is to wet or
"weeping/oozing" surfaces for administration. These
include, without limitation topical application to open or
oozing wounds, as well as to mucous membranes. Inhalation
of lyophilizate powder for application to the nose and bronchial tree, as well as instillation of the powder to the eye, oral
mucosa, rectum, vaginal, uterine, urethral, and urinary bladder tissues are contemplated by the present invention. In
addition, the lyophilzates can be rapidly dissolved in appropriate liquid media for administration to these tissues as well.
EXAMPLES
55
Example 1
60
65
A sufficient amount of amifostine is dissolved in water to
result in a concentration in the range of 100 to 500 mg/ml. The
solution is asceptically filtered through a 0.2 micron filter
(Pall filter membrane Nylon 66 or any compatible filter).
Separately, tetrahydrofuran is asceptically filtered using a
Pall filter membrane Nylon 66.2 ml of the filtered amifostine
solution is placed in a 5 ml USP type 1 pre-sterilized and
depyrogenated flint vial and 1 ml of the filtered THE is added
thereto. The vial contents become cloudy. The vials having
the amifostine, water, and THE are placed onto a lyophiliza-
US 8,158,152 B2
37
38
tion tray, which is then introduced into a lyophilization chamber. The chamber temperature is set to —30° C. When the
product temperature reaches —25° C., the condenser is turned
on at a setting of —50° C. or below. When the condenser
temperature reaches —40° C., the vacuum pump is turned on
and the vacuum monitor gauge is adjusted to 200 microns.
When the vacuum reaches 200 microns, the shelf temperature
is set to —5° C. and the product is dried for 12 hours. At the
conclusion of the 12 hours, the shelf temperature is reset to
30° C. and the product is dried for an additional 15 hours. The
equipment is bleeded with nitrogen to bring the pressure back
to atmospheric pressure, the vials are stoppered, and sealed
with aluminum caps.
Example 8
Example 2
5
10
15
Example 1 is repeated with the following variations as set
forth in Table I
A sufficient amount of itraconazole is dissolved in acidified
tetrahydrofuran to result in a concentration in the range of 100
to 500 mg/ml. The solution is asceptically filtered through a
0.2 micron filter (Pall filter membrane Nylon 66 or any compatible filter). Separately, water is asceptically filtered using a
Pall filter membrane Nylon 66 (or any compatible filter). 2 ml
of the filtered itraconazole solution is placed in a 5 ml USP
type 1 pre-sterilized and depyrogenated flint vial and 1 ml of
the filtered water is added thereto. The vial contents become
cloudy. The vials having the itraconazole, water, and THE are
placed onto a lyophilization tray, which is then introduced
into a lyophilization chamber. The chamber temperature is set
to —30° C. When the product temperature reaches —25° C., the
condenser is turned on at a setting of —50° C. or below. When
the condenser temperature reaches —40° C., the vacuum
pump is turned on and the vacuum monitor gauge is adjusted
TABLE I
SAMPLE
AMIFOSTINE
AMOUNT
A
B
C
D
E
F
G
H
I
J
K
L
M
N
0
P
Q
R
S
T
U
V
W
X
Y
100mg
200 mg
300 mg
400 mg
500 mg
100mg
200 mg
300 mg
400 mg
500 mg
100mg
200 mg
300 mg
400 mg
500 mg
100mg
200 mg
300 mg
400 mg
500 mg
100mg
200 mg
300 mg
400 mg
500 mg
THE
AMOUNT
0.1 ml
0.1 ml
0.1 ml
0.1 ml
0.1 ml
0.25 ml
0.25 ml
0.25 ml
0.25 ml
0.25 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
0.5 ml
1 ml
1 ml
1 ml
1 ml
1 ml
2 ml
2 ml
2 ml
2 ml
2 ml
FREEZE
TEMP
PRIMARY
DRY TIME
SECONDARY
DRY TIME
-40°
-40°
-40°
-40°
-40°
-30°
-30°
-20°
-20°
-40°
-35°
-350°
-20°
-25°
-25°
-20°
-30°
-30°
-20°
-20°
-40°
-35°
-350°
-20°
-25°
12 HOURS
20 HOURS
12 HOURS
12 HOURS
12 HOURS
15 HOURS
15 HOURS
18 HOURS
18 HOURS
20 HOURS
20 HOURS
14 HOURS
14 HOURS
13 HOURS
13 HOURS
12 HOURS
15 HOURS
15 HOURS
18 HOURS
18 HOURS
20 HOURS
20 HOURS
14 HOURS
14 HOURS
13 HOURS
12 HOURS
20 HOURS
12 HOURS
12 HOURS
12 HOURS
15 HOURS
15 HOURS
15 HOURS
15 HOURS
15 HOURS
15 HOURS
18 HOURS
18 HOURS
18 HOURS
18 HOURS
18 HOURS
15 HOURS
15 HOURS
15 HOURS
15 HOURS
15 HOURS
15 HOURS
18 HOURS
18 HOURS
18 HOURS
45
whereby suitable lyophilizates can be obtained.
Example 3
Example 2 is repeated using dioxane as the anti-solvent,
whereby suitable lyophilizates can be obtained.
50
to 200 microns. When the vacuum reaches 200 microns, the
shelf temperature is set to —5° C. and the product is dried for
12 hours. At the conclusion of the 12 hours, the shelf temperature is reset to 30° C. and the product is dried for an
additional 15 hours. The equipment is bleeded with nitrogen
to bring the pressure back to atmospheric pressure, the vials
are stoppered, and sealed with aluminum caps.
Examples 4-7
Examples 2-3 are repeated except that amifostine is
replaced (a) with ceftazadine with the water having a pH of
5-7 (Examples 4-5) or (b) with cefapine with the water having
a pH of 1-3, whereby suitable lyophilizates can be obtained.
Example 9
55
Example 8 is repeated with the following variations as set
forth in Table II
TABLE II
SAMPLE
INTRACONAZOLE
AMOUNT
THE
AMOUNT
FREEZE
TEMP
PRIMARY
DRY TIME
SECONDARY
DRY TIME
A
B
C
100mg
200 mg
300 mg
1 ml
2 ml
3 ml
-40°
-40°
-40°
12 HOURS
20 HOURS
12 HOURS
12 HOURS
20 HOURS
12 HOURS
US 8,158,152 B2
39
40
TABLE II-continued
SAMPLE
INTRACONAZOLE
AMOUNT
D
E
F
G
H
I
1
K
L
M
N
0
P
Q
R
S
T
U
V
W
X
Y
400 mg
500 mg
100 mg
200 mg
300 mg
400 mg
500 mg
100 mg
200 mg
300 mg
400 mg
500 mg
100 mg
200 mg
300 mg
400 mg
500 mg
100 mg
200 mg
300 mg
400 mg
500 mg
THE
FREEZE
AMOUNT TEMP
4m1
5 ml
1 ml
2 ml
3 ml
4 ml
5 ml
1 ml
2 ml
3 ml
4 ml
5 ml
1 ml
2 ml
3 ml
4 ml
5 ml
1 ml
2 ml
3 ml
4m1
5 ml
-40°
-40°
-30°
-30°
-20°
-20°
-40°
-35°
-350°
-20°
-25 °
-25°
-20°
-30°
-30°
-20°
-20°
-40°
-35 °
-350°
-20°
-25°
PRIMARY
DRY TIME
SECONDARY
DRY TIME
12 HOURS
12 HOURS
15 HOURS
15 HOURS
12 HOURS
12 HOURS
15 HOURS
15 HOURS
15 HOURS
15 HOURS
15 HOURS
15 HOURS
18 HOURS
18 HOURS
20 HOURS
20 HOURS
14 HOURS
14 HOURS
13 HOURS
13 HOURS
12 HOURS
15 HOURS
15 HOURS
18 HOURS
18 HOURS
20 HOURS
20 HOURS
14 HOURS
14 HOURS
13 HOURS
whereby suitable lyophilizates can be obtained.
Example 10
Example 9 is repeated using dioxane as the solvent w
whereby suitable lyophilizates can be obtained.
Examples 11-12
Examples 9-10 are repeated except that the water antisolvent is omitted, whereby suitable lyophilizates can be
obtained.
Example 13-17
Example 9 is repeated using ethanol (Example 13), tetrahydropyrane (Example 14), isopropanol (Example 15), tocopherol acetate (Example 16), or tocopherol succinate (Example 17) as the solvent whereby suitable lyophilizates can
be obtained.
I claim:
1. A method of lyophilizing a hydrophilic pharmaceutical
compound comprising:
(a) dissolving the hydrophilic pharmaceutical compound
in one or more hydrophilic solvents to form a solution,
wherein the one or more hydrophilic solvents is a liquid
in which the hydrophilic pharmaceutical compound dissolves;
(b) adding one or more lipophilic non-solvents for the
hydrophilic pharmaceutical compound to the solution,
wherein:
(i) the one or more lipophilic non-solvents is a liquid in
which the hydrophilic pharmaceutical compound is
essentially insoluble,
(ii) the one or more lipophilic non-solvents is miscible
with the one or more hydrophilic solvents,
(iii) the one or more lipophilic non-solvents is volatilizable under freeze-drying conditions, and
(iv) the hydrophilic pharmaceutical compound at least
partially precipitates;
(c) freezing the hydrophilic pharmaceutical compound, the
one or more hydrophilic solvents and the one or more
18 HOURS
18HOURS
18 HOURS
18 HOURS
18 HOURS
15 HOURS
15 HOURS
15 HOURS
15 HOURS
15 HOURS
15 HOURS
18 HOURS
18HOURS
18 HOURS
25
lipophilic non-solvents of step (b) to yield a frozen
result, the frozen result comprising a frozen portion; and
(d) vacuum drying the frozen result of step (c) to yield a
lyophilizate.
2. The method of claim 1 wherein the hydrophilic pharma30
ceutical compound is crystalline.
3. The method of claim 1 wherein the hydrophilic pharmaceutical compound is amorphous.
4. The method of claim 1 wherein the lyophilizate is crys35 talline.
5. The method of claim 1 wherein the lyophilizate is amorphous.
6. The method of claim 1, further comprising at least one of
(i) aseptically filtering the solution of step (a) prior to the
40 addition of the lipophilic non-solvent thereto; and (ii) aseptically filtering the lipophilic non-solvent prior to the addition
of the lipophilic non-solvent to the solution of step (a).
7. The method of claim 1 wherein the hydrophilic solvent
is water.
45
8. The method of claim 1 wherein the hydrophilic solvent
is a lower alkanol.
9. The method of claim 8 wherein the lower alkanol is
ethanol, propanol, isopropanol, sec-butanol, t-butyl alcohol,
or n-butyl alcohol.
50
10. The method of claim 1 wherein the lipophilic nonsolvent is a cyclic mono-, di-, or tri-ether.
11. The method of claim 10 wherein the cyclic mono-, di-,
or tri-ether is tetrahydrofuran, tetrahydropyran, dioxane, or
trioxane.
55
12. The method of claim 1, further comprising adding a
co-solvent to the hydrophilic solvent.
13. The method of claim 12 wherein the co-solvent is
selected from the group consisting of polyethylene glycol
60 600-6000.
14. The method of claim 1, further comprising adding a
bulking agent.
15. The method of claim 14 wherein the bulking agent is
selected from the group consisting of a saccharide, polyvi65 nylpyrrolidone, a cyclodextrin, and trehalose.
16. The method of claim 1, further comprising adding a
solubilizer, a surfactant or a combination thereof.
US 8,158,152 B2
41
17. The method of claim 16 wherein the solubilizer is
selected from the group consisting of a cyclic amide, gentisic
acid, and a cyclodextrin.
18. The method of claim 16, wherein the surfactant comprises a hydrophilic-lipophilic balance (HLB) value ranging
from Ito 16.
19. The method of claim 1, further comprising adding a
buffer.
20. The method of claim 19, wherein the buffer is selected
from the group consisting of an amino acid, an inorganic
buffer, a mono- or di-carboxylic acid buffer, a hydroxylmono- or di-carboxylic acid buffer, an amine, and a sulfonamide.
21. The method of claim 1, further comprising adding an
antioxidant.
22. The method of claim 21 wherein the antioxidant is
selected from the group consisting of a bisulfite, ascorbic
acid, disodium- or tetrasodium ethylenediaminetetraacetic
acid, a citrate as metal ion chelator, butylatedhydroxyanisole,
butylated hydroxytoluene, a sulfoxylate, propyl gallate, an
amino acid containing a thio group, and a thiol.
23. The method of claim 1 wherein the frozen result further
comprises an unfrozen portion.
24. A method of lyophilizing a lipophilic pharmaceutical
compound comprising:
(a) dissolving the lipophilic pharmaceutical compound in
one or more lipophilic solvents to form a solution,
wherein the one or more lipophilic solvents is a liquid in
which the lipophilic pharmaceutical compound dissolves;
(b) adding one or more hydrophilic non-solvents for the
lipophilic pharmaceutical compound to the solution,
wherein:
(i) the one or more hydrophilic non-solvents is a liquid in
which the lipophilic pharmaceutical compound is
essentially insoluble,
(ii) the one or more hydrophilic non-solvents is miscible
with the one or more lipophilic solvents,
(iii) the one or more hydrophilic non-solvents is volatilizable under freeze-drying conditions, and
(iv) the lipophilic pharmaceutical compound at least
partially precipitates;
(c) freezing the lipophilic pharmaceutical compound, the
one or more lipophilic solvents and the one or more
hydrophilic non-solvents of step (b) to yield a frozen
result, the frozen result comprising a frozen portion; and
(d) vacuum drying the frozen result of step (c) to yield a
lyophilizate.
25. The method of claim 24 wherein the lipophilic pharmaceutical compound is crystalline.
26. The method of claim 24 wherein the lipophilic pharmaceutical compound is amorphous.
27. The method of claim 24 wherein the lyophilizate is
crystalline.
42
28. The method of claim 24 wherein the lyophilizate is
amorphous.
29. The method of claim 24, further comprising at least one
of (i) aseptically filtering the solution of step (a) prior to the
5 addition of the hydrophilic non-solvent thereto; and (ii) aseptically filtering the hydrophilic non-solvent prior to the addition of the lipophilic non-solvent to the solution of step (a).
30. The method of claim 24 wherein the hydrophilic nonsolvent is water.
10 31. The method of claim 24 wherein the hydrophilic nonsolvent is a lower alkanol.
32. The method of claim 31 wherein the lower alkanol is
ethanol, propanol, isopropanol, sec-butanol, t-butyl alcohol,
or n-butyl alcohol.
33. The method of claim 24 wherein the lipophilic solvent
15
is a cyclic mono-, di-, or tri-ether.
34. The method of claim 33 wherein the cyclic mono-, di-,
or tri-ether is tetrahydrofuran, tetrahydropyran, dioxane, or
trioxane.
35. The method of claim 24, further comprising adding a
20
co-solvent to the lipophilic solvent.
36. The method of claim 35 wherein the co-solvent is
selected from the group consisting of polyethylene glycol
600-6000.
37. The method of claim 24, further comprising adding a
25 bulking agent.
38. The method of claim 37 wherein the bulking agent is
selected from the group consisting of a saccharide, polyvinylpyrrolidone, a cyclodextrin, and trehalose.
39. The method of claim 24, further comprising adding a
30
solubilizer, a surfactant or a combination thereof.
40. The method of claim 39 wherein the solubilizer is
selected from the group consisting of a cyclic amide, gentisic
acid, and a cyclodextrin.
35
41. The method of claim 39, wherein the surfactant comprises a hydrophilic-lipophilic balance (HLB) value ranging
from Ito 16.
42. The method of claim 24, further comprising adding a
buffer.
43. The method of claim 42, wherein the buffer is selected
40
from the group consisting of an amino acid, an inorganic
buffer, a mono- or di-carboxylic acid buffer, a hydroxylmono- or di-carboxylic acid buffer, an amine, and a sulfonamide.
44. The method of claim 24, further comprising adding an
45
antioxidant.
45. The method of claim 44 wherein the antioxidant is
selected from the group consisting of a bisulfite, ascorbic
acid, disodium- or tetrasodium ethylenediaminetetraacetic
acid, a citrate as metal ion chelator, butylatedhydroxyanisole,
50
butylated hydroxytoluene, a sulfoxylate, propyl gallate, an
amino acid containing a thio group, and a thiol.
46. The method of claim 24 wherein the frozen result
further comprises an unfrozen portion.