PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 99/00113
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`Intemational Bureau
`
`(51) International Patent Classification 6 :
`A61K 9/22
`
`Al
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`7 January 1999 (07.01.99)
`
`(21) International Application Number:
`
`PCT/US98/13272
`
`(22) International Filing Date:
`
`26 June 1998 (26.06.98)
`
`(30) Priority Data:
`60/051,021
`08/926,155
`
`27 June 1997 (27.06.97)
`9 September 1997 (09.09.97)
`
`us
`us
`
`(63) Related by Continuation (CON) or Continuation-in-Part
`(CIP) to Earlier Applications
`us
`Filed on
`us
`Filed on
`
`60/051,021 (CIP)
`27 June 1997 (27.06.97)
`08/926,155 (CIP)
`9 September 1997 (09.09.97)
`
`(71) Applicant (for all designated States except US): VIVORX
`PHARMACEUTICALS, INC. [US/US]; 2825 Santa Monica
`Boulevard, Santa Monica, CA 90404 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): DESAI, Neil, P. [IN/US];
`3633 Purdue Avenue, Los Angeles, CA 90066 (US).
`SOON-SHIONG, Patrick [US/US]; 11755 Chenault Street,
`Los Angeles, CA 90049 (US). MAGDASSI, Shlomo
`[IUIL]; Hanerd Street 36, Jerusalem (IL). SAHADEV AN,
`
`David, C. [US/US]; 13626 Franklin Street #3, Whittier, CA
`90602 (US).
`
`(74) Agent: RAYMER, Gregory, P.; Gray Cary Ware & Freidenrich,
`Suite 1600, 4365 Executive Drive, San Diego, CA 92121
`(US).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
`GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ,
`LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
`MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,
`TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO
`patent (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG).
`
`Published
`With international search report.
`
`(54) Title: NOVEL FORMULA TIO NS OF PHARMACOLOGICAL AGENTS, METHODS FOR THE PREPARATION THEREOF AND
`METHODS FOR THE USE THEREOF
`
`(57) Abstract
`
`In accordance with the present invention, there are provided compositions and methods useful for the in vivo delivery of substantially
`water insoluble pharmacologically active agents (such as the anticancer drug paclitaxel) in which the pharmacologically active agent
`In particular, protein and
`is delivered in the form of suspended particles coated with protein (which acts as a stabilizing agent).
`pharmacologically active agent in a biocompatible dispersing medium are subjected to high shear, in the absence of any conventional
`surfactants, and also in the absence of any polymeric core material for the particles. The procedure yields particles with a diameter of less
`than about 1 micron. The use of specific composition and preparation conditions (e.g., addition of a polar solvent to the organic phase),
`and careful selection of the proper organic phase and phase fraction, enables the reproducible production of unusually small nanoparticles
`of less than 200 nm diameter, which can be sterile-filtered. The particulate system produced according to the invention can be converted
`into a redispersible dry powder comprising nanoparticles of water-insoluble drug coated with a protein, and free protein to wJ:i.ich molecules
`of the pharmacological agent are bound. This results in a unique delivery system, in which part of the pharmacologically active agent is
`readily bioavailable (in the form of molecules bound to the protein), and part of the agent is present within particles without any polymeric
`matrix therein.
`
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`

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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`C<'.'>te d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
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`WO 99/00113
`
`PCT/US98/13272
`
`1
`
`NOVEL FORMULATIONS OF PliARMACOLOGICAL AGENTS.
`METHODS FOR THE PREPARATION THEREOF AND
`
`METHODS FOR THE USE THEREOF
`
`5
`
`FIELD OF THE INVENTION
`
`The present invention relates to methods for the
`
`production of particulate vehicles for the intravenous
`
`administration of pharmacologically active agents, as well as
`
`novel compositions produced thereby.
`
`In a particular aspect,
`
`10 the invention relates to methods for the in vivo delivery of
`
`substantially water insoluble pharmacologically active agents
`
`(e.g., the anticancer drug Taxol®).
`
`In another aspect,
`
`dispersible colloidal systems containing water insoluble
`
`pharmacologically active agents are provided. The suspended
`
`15 particles may be formed of 100% active agent, or may be encased
`
`in a polymeric shell formulated from a biocompatible polymer,
`
`and have a diameter of less than about 1 micron.
`
`Invention
`
`colloidal systems may be prepared without the use of
`
`conventional surfactant or any polymeric core matrix.
`
`In a
`
`20 presently preferred aspect of the invention, there is provided
`
`a method for preparation of extremely small particles which .can
`
`be sterile-filtered. The polymeric shell contains particles of
`
`pharmacologically active agent, and optionally a biocompatible
`
`dispersing agent in which pharmacologically active agent can be
`
`25 either dissolved or suspended. Thus, the invention provides a
`
`drug delivery system in either liquid form or in the form of a
`
`redispersible powder. Either form provides both immediately
`
`bioavailable drug molecules (i.e., drug molecules which are
`
`molecularly bound to a protein) , and pure drug particles coated
`
`30 with a protein.
`
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`PCT/US98/13272
`
`2
`
`FIELD OF THE INVENTION
`
`The invention also relates to the method of use and
`
`5 preparation of compositions (formulations) of drugs such as the
`
`anticancer agent paclitaxel.
`
`In one aspect, the formulation of
`
`paclitaxel, known as Capxol,
`
`significantly less toxic and
`
`more efficacious than Taxol®, a commercially available
`
`formulation of paclitaxel.
`
`In another aspect, the novel
`
`10 formulation Capxol, localizes in certain tissues after
`
`parenteral administration thereby increasing the efficacy of
`
`treatment of cancers associated with such tissues.
`
`15
`
`BACKGROUND OF THE INVENTION
`
`Intravenous drug delivery permits rapid and direct
`
`equilibration with the blood stream which carries the
`
`medication to the rest of the body. To avoid the peak serum
`
`levels which are achieved within a short time after
`
`20 intravascular injection, administration of drugs carried within
`
`stable carriers would allow gradual release of the drugs inside
`
`the intravascular compartment following a bolus intravenous
`
`injection of the therapeutic nanoparticles.
`
`25
`
`Injectable controlled-release nanoparticles can
`
`provide a pre-programmed duration of action, ranging from days
`
`to weeks to months from a single injection. They also can
`
`off er several profound advantages over conventionally
`
`administered medicaments, including automatic assured patient
`
`30 compliance with the dose regimen, as well as drug targeting to
`
`specific tissues or organs (Tice and Gilley, Journal of
`
`Controlled Release ~:343-352 (1985)).
`
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`3
`
`Microparticles and foreign bodies present in the
`
`blood are generally cleared from the circulation by the "blood
`
`filtering organs", namely the spleen, lungs and liver. The
`
`5 particulate matter contained in normal whole blood comprises
`
`red blood cells (typically 8 microns in diameter) , white blood
`
`cells (typically 6-8 microns in diameter), and platelets
`
`(typically 1-3 microns in diameter) . The microcirculation in
`
`most organs and tissues allows the free passage of these blood
`
`10 cells. When microthrombii (blood clots) of size greater than
`
`10-15 microns are present in circulation, a risk of infarction
`
`or blockage of the capillaries results, leading to ischemia or
`
`oxygen deprivation and possible tissue death.
`
`Injection into
`
`the circulation of particles greater than 10-15 microns in
`
`15 diameter, therefore, must be avoided. A suspension of
`
`particles less than 7 8 microns, is however, relatively safe
`
`and has been used for the delivery of pharmacologically active
`
`agents in the form of liposomes and emulsions, nutritional
`
`agents, and contrast media for imaging applications.
`
`20
`
`The size of particles and their mode of delivery
`
`determines their biological behavior. Strand et al. (in
`Microspheres-Biomedical Applications, ed. A. Rembaum, pp 193-.
`227, CRC Press (1988)) have described the fate of particles to
`
`25 be dependent on their size. Particles in the size range of a
`
`few nanometers (nm) to 100 nm enter the lymphatic capillaries
`
`following interstitial injection, and phagocytosis may occur
`
`within the lymph nodes. After intravenous/intraarterial
`
`injection, particles less than about 2 microns will be rapidly
`
`30 cleared from the blood stream by the reticuloendothelial system
`
`(RES) , also known as the mononuclear phagocyte system (MPS) .
`
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`4
`Particles larger than about 7 microns will, after intravenous
`
`injection, be trapped in the lung capillaries. After
`
`intraarterial injection, particles are trapped in the
`
`capillary bed reached.
`
`Inhaled particles are trapped by the
`
`5 alveolar macrophages.
`
`Pharmaceuticals that are water-insoluble or poorly
`
`water-soluble and sensitive to acid environments in the stomach
`
`cannot be conventionally administered (e.g., by intravenous
`
`10 injection or oral administration). The parenteral
`
`administration of such pharmaceuticals has been achieved by
`
`emulsification of the oil solubilized drug with an aqueous
`
`liquid (such as normal saline) in the presence of surfactants
`
`or emulsion stabilizers to produce stable microemulsions.
`
`15 These emulsions may be injected intravenously, provided the
`
`components of the emulsion are pharmacologically inert. US
`
`Patent No. 4,073,943 describes the administration of water(cid:173)
`
`insoluble pharmacologically active agents dissolved in oils and
`
`emulsified with water in the presence of surfactants such as
`
`20 egg phosphatides, pluronics (copolymers of polypropylene glycol
`
`and polyethylene glycol), polyglycerol oleate, etc. PCT
`
`International Publication No. WOBS/00011 describes
`
`pharmaceutical microdroplets of an anaesthetic coated with a -
`
`phospholipid such as dimyristoyl phosphatidylcholine having
`
`25 suitable dimensions for intradermal or intravenous injection.
`
`An example of a water-insoluble drug is Taxol®, a
`
`natural product first isolated from the Pacific Yew tree, Taxus
`
`brevifolia, by Wani et al. (J. Am. Chem. Soc. ~:2325 (1971)).
`
`30 Among the antimitotic agents, Taxol, which contains a diterpene
`
`carbon skeleton, exhibits a unique mode of action on
`
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`microtubule proteins
`
`5
`responsible for the formation
`
`of the mitotic spindle.
`
`In contrast with other antimitotic
`
`agents such as vinblastine or colchicine, which prevent the
`
`assembly of tubulin, Taxol is the only plant product known to
`
`5 inhibit the depolymerization process of tubulin, thus
`
`preventing the cell replication process.
`
`Taxol, a naturally occurring diterpenoid, has been
`
`shown to have significant antineoplastic and anticancer effects
`
`IO in drug-refractory ovarian cancer. Taxol has shown excellent
`
`antitumor activity in a wide variety of tumor models such as
`the B16 melanoma, Ll210 leukemias, MX-1 mammary tumors, and cs-
`1 colon tumor xenografts. Several recent press releases have
`
`termed Taxol as the new anticancer wonder-drug.
`
`Indeed, Taxol
`
`15 has recently been approved by the Federal Drug Administration
`
`for treatment of ovarian cancer. The poor aqueous solubility
`
`of Taxol, however, presents a problem for human administration.
`
`Indeed, the delivery of drugs that are inherently insoluble or
`
`poorly soluble in an aqueous medium can be seriously impaired
`
`20 if oral delivery is not effective. Accordingly, currently used
`
`Taxol formulations require a cremaphor to solubilize the drug.
`
`The human clinical dose range is 200-500 mg. This dose is
`
`dissolved in a 1:1 solution of ethanol:cremaphor and diluted
`
`with saline of about 300-1000 ml of fluid given intravenously.
`
`25 The cremaphor currently used is polyethoxylated castor oil. The
`
`presence of cremaphor in this formulation has been linked to
`
`severe hypersensitivity reactions in animals (Lorenz et al.,
`
`Agents Actions 1987, 7, 63-67) and humans (Weiss et al., J.
`
`Clin. Oncol. 1990, 8, 1263-68) and consequently requires
`
`30 premedication of patients with corticosteroids (dexamethasone)
`
`and antihistamines. The large dilution results in large
`
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`volumes of infusion (typical
`
`6
`dose 175 mg/m2
`and infusion times ranging from 3 hours to 24 hours. Thus,
`
`) up to 1 liter
`
`there is a need for an alternative less toxic formulation for
`
`paclitaxel.
`
`5
`
`®
`In phase I clinical trials, Taxol
`
`itself did not
`
`show excessive toxic effects, but severe allergic reactions
`
`were caused by the emulsifiers employed to solubilize the drug.
`
`The current regimen of administration involves treatment of the
`
`IO patient with antihistamines and steroids prior to injection of
`
`the drug to reduce the allergic side effects of the cremaphor.
`
`In an effort to improve the water solubility of
`
`Taxol, several investigators have modified its chemical
`
`15 structure with functional groups that impart enhanced water(cid:173)
`
`solubility. Among them are the sulfonated derivatives
`
`(Kingston et al., U.S. Patent 5,059,699 (1991)), and amino acid
`
`esters (Mathew et al., J. Med. Chem . .15.:145-151 (1992)) which
`
`show significant biological activity. Modifications to produce
`
`20 a water-soluble derivative
`
`the intravenous delivery
`
`of Taxol dissolved in an innocuous carrier such as normal
`
`saline. Such modifications, however, add to the cost of drug
`
`preparation, may induce undesired side-reactions and/or
`
`allergic reactions, and/or may decrease the efficiency of the
`
`25 drug.
`
`Protein microspheres have been reported in the
`
`literature as carriers of pharmacological or diagnostic agents.
`
`Microspheres of albumin have been prepared by either heat
`
`30 denaturation or chemical crosslinking. Heat denatured
`
`microspheres are produced from an emulsified mixture (e.g.,
`
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`albumin, the agent to be
`
`7
`incorporated, and a suitable
`
`oil) at temperatures between 100°c and 150°C. The microspheres
`
`are then washed with a suitable solvent and stored. Leucuta et
`
`al. (International Journal of Pharmaceutics 41:213-217 (1988))
`
`5 describe the method of preparation of heat denatured
`
`microspheres.
`
`The procedure for preparing chemically crosslinked
`
`microspheres involves treating the emulsion with glutaraldehyde
`
`JO to crosslink the protein, followed by washing and storage. Lee
`
`et al. (Science 2.U:233-235 (1981)) and U.S. Patent No.
`
`4,671,954 teach this method of preparation.
`
`The above techniques for the preparation of protein
`
`15 microspheres as carriers of pharmacologically active agents,
`
`although suitable for the delivery of water-soluble agents, are
`
`incapable of entrapping water-insoluble ones. This limitation
`
`is inherent in the technique of preparation which relies on
`
`crosslinking or heat denaturation of the protein component in
`
`20 the aqueous phase of a water-in-oil emulsion. Any aqueous(cid:173)
`
`soluble agent dissolved in the protein-containing aqueous phase
`
`may be entrapped within the resultant crosslinked or
`
`heat-denatured protein matrix, but a poorly aqueous-soluble or
`
`oil soluble agent cannot be incorporated into a protein matrix
`
`25 formed by these techniques.
`
`One conventional method for manufacturing
`
`drug-containing nanoparticles comprises dissolving polylactic
`
`acid (or other biocompatible, water insoluble polymers) in a
`
`30 water-immiscible solvent (such as methylene chloride or other
`
`chlorinated, aliphatic, or aromatic solvent), dissolving the
`
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`pharmaceutically active agent
`
`8
`in the polymer solution, adding
`
`a surfactant to the oil phase or the aqueous phase, forming an
`
`oil-in-water emulsion by suitable means, and evaporating the
`
`emulsion slowly under vacuum.
`
`If the oil droplets are
`
`5 sufficiently small and stable during evaporation, a suspension
`
`of the polymer in water is obtained. Since the drug is
`
`initially present in the polymer solution, it is possible to
`
`obtain by this method, a composition in which the drug
`
`molecules are entrapped within particles composed of a
`
`10 polymeric matrix. The formation of microspheres and
`
`nanoparticles by using the solvent evaporation method has been
`
`reported by several researchers (see, for example, Tice and
`
`Gilley, in Journal of Controlled Release 2:343-352 (1985);
`
`Bodmeier and McGinity, in Int. J. Pharmaceutics ~:179 (1988);
`
`15 Cavalier et al., in J. Pharm. Pharmacol. 1..6.:249 (1985); and
`
`D'Souza et al., WO 94/10980) while using various drugs.
`
`Bazile et. al., in Biomaterials .l.3.:1093 (1992), and
`
`Spenlehauer et al., in Fr Patent 2 660 556, have reported the
`
`20 formation of nanoparticles by using two biocompatible polymers,
`
`one (e.g., polylactide) is dissolved in the organic phase,
`
`together with an active component such as a drug, and the other
`
`polymer, such as albumin, is used as the surface active agent.
`
`After emulsification and removal of the solvent, nanoparticles
`
`25 are formed, in which the drug is present inside the polymeric
`
`matrix of the polylactide particles.
`
`The properties of the polymer solution from which the
`
`polymeric matrix is formed are very important to obtain the
`
`30 proper emulsion in the first stage. For example, polylactide
`
`(the polymer commonly used in the preparation of injectable
`
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`nanoparticles), has a surface
`
`9
`activity which causes the rapid
`
`adsorption thereof at the dichloromethane-water interface,
`
`causing reduced interfacial tension (see, for example, Boury et
`
`al., in Langmuir l..1.:1636 (1995)), which in turn improves the
`
`5 emulsification process.
`
`In addition, the same researchers
`
`found that Bovine Serum Albumin (BSA) interacts with the
`
`polylactide, and penetrates into the polylactide monolayer
`
`present at the oil-water interface. Therefore, it is expected,
`
`based on the above reference, that emulsification during the
`
`10 conventional solvent evaporation method is greatly favored by
`
`the presence of the surface active polymer (polylactide) in the
`
`nonaqueous organic phase.
`
`In fact, the presence of polylactide
`
`is not only a sufficient condition, but it is actually
`
`necessary for the formation of nanoparticles of suitable
`
`15
`
`Another process which is based on the solvent
`
`evaporation method comprises dissolving the drug in a
`
`hydrophobic solvent (e.g., toluene or cyclohexane), without any
`
`polymer dissolved in the organic solvent, adding a conventional
`
`20 surfactant to the mixture as an emulsifier, forming an oil in(cid:173)
`
`water emulsion by use of sonication on high-shear equipment,
`
`and then evaporating the solvent to obtain dry particles of the
`
`drug (see, for example, Sjostrom et al., in J. Dispersion
`
`Science and Technology .l.5.:89-117 (1994)). Upon removal of the
`
`25 nonpolar solvent, precipitation of the drug inside the solvent
`
`droplets occurs, and submicron particles are obtained.
`
`It has been found that the size of the particles is
`
`mainly controlled by the initial size of the emulsion droplets.
`
`30 In addition, it is interesting to note that the final particle
`
`size is reported to decrease with a decrease in the drug
`
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`concentration in the organic
`
`10
`phase. This finding is
`
`contrary to the results reported herein, wherein no
`
`conventional surfactant is used for the preparation of
`
`nanoparticles (in same embodiments of the invention) .
`
`In
`
`5 addition, it is noted by the authors of the Sjostrom paper that
`
`the drug used, cholesteryl acetate, is surface active in
`
`toluene, and hence may be oriented at the oil-water interface;
`
`therefore the concentration of drug at the interface is higher,
`
`thus increasing the potential for precipitation.
`
`10
`
`Formation of submicron particles has also been
`
`achieved by a precipitation process, as described by Calvo et
`
`al. in J. Pharm. Sci . .8.5.:530 (1996). The process is based on
`
`dissolving the drug (e.g., indomethacin) and the polymer (poly-
`
`15 caprolactone) in methylene chloride and acetone, and then
`
`pouring the solution into an aqueous phase containing a
`
`surfactant (Poloxamer 188), to yield submicron size particles
`
`(216 nm). However, the process is performed at solvent
`
`concentrations at which no emulsion is formed.
`
`20
`
`BACKGROUND OF THE INVENTION
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`Taxol is a naturally occurring compound which has
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`shown great promise as an
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`-cancer drug. For example, Taxol
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`25 has been found to be an active agent against drug-refractory
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`ovarian cancer by McGuire et al. See "Taxol: A Unique Anti(cid:173)
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`Neoplastic Agent With Significant Activity Against Advanced
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`Ovarian Epithelial Neoplasms." Ann. Int. Med., 111, 273-279
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`(1989) . All patents, scientific articles, and other documents
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`30 mentioned herein are incorporated by reference as if
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`reproduced in full below.
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`Unfortunately, Taxol has extremely low solubility in
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`water, which makes
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`difficult to provide a suitable dosage
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`form. In fact, in Phase I clinical trials, severe allergic
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`5 reactions were caused by the emulsifiers administered in
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`conjunction with Taxol to compensate for Taxol's low water
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`solubility; at least one patient's death was caused by an
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`allergic reaction induced by the emulsifiers. Dose limiting
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`toxicities include neutropenia, peripheral neuropathy, and
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`10 hypersensitivity reactions.
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`Brown et al., in "A Phase I Trial of Taxol Given by
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`A 6-Hour Intravenous Infusion" J of Clin Oncol, Vol. 9 No. 7,
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`pp. 1261-1267 (July 1991) report on a Phase I Trial in which
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`15 Taxol was provided as a 6-hour IV infusion every 21 days
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`without premedication. 31 patients received 64 assessable
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`courses of Taxol. One patient had a severe (or acute)
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`hypersensitivity reaction, which required discontinuation of
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`the infusion and immediate treatment to save the patient's
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`20 life. Another patient experienced a hypersensitivity reaction,
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`but it was not so severe as to require discontinuing the
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`infusion. Myelosuppression was dose-limiting, with 2
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`fatalities due to sepsis. Non-hematologic toxicity was of
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`Grade 1 and 2, except for one patient with Grade 3 mucositis
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`25 and 2 patients with Grade 3 neuropathy. The neuropathy
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`consisted of reversible painful paresthesias, requiring
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`discontinuation of Taxol in two patients. Four partial
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`responses were seen (3 in patients with non-small-cell lung
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`cancer, and one
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`a patient with adenocarcinoma of unknown
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`30 primary). The maximum tolerated dose reported was 275 mg/m2,
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`and the recommended Phase II starting dose was 225 mg/m2. The
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`incidence of hypersensitivity
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`12
`reaction was reported to be
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`schedule-dependent, with 6 to 24-hour infusions of drug having
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`a 0% to 8% incidence of hypersensitivity reactions. It was
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`also reported that hypersensitivity reactions persist with or
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`5 without premedication despite prolongation of infusion times.
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`Since these Phase I studies were conducted on terminally ill
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`patients suffering from a variety of cancers, the efficacy of
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`the Taxol treatments could not be determined.
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`IO
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`In a study by Kris et al., Taxol formulated with
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`Cremaphor EL in dehydrated alcohol was given as a 3-hour IV
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`infusion every 21 days, with the administered dosage ranging
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`from 15 to 230 mg/m2 in nine escalation steps. Kris et al.
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`concluded that "with the severity and unpredictability of the
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`15 hypersensitivity reactions, further usage of Taxol is not
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`indicated with this drug formulation on this administration
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`schedule." See Cancer Treat. Rep., Vol. 70, No. 5, May 1986.
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`Since early trials using a bolus injection or short
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`20 (1 3 hour) infusions induced anaphylactic reactions or other
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`hypersensitivity responses, further studies were carried out
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`in which Taxol was administered only after premedication with
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`steroids (such as dexamethasone), antihistamines (such as
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`diphenhydramine), and H2-antagonists (such as cimetidine or
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`25 ranitidine) , and the infusion time was extended to 24 hours in
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`an attempt to eliminate the most serious allergic reactions.
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`Various Phase I and Phase II study results have been published
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`utilizing 24-hour infusions of Taxol with maximum total
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`dosages of 250 mg/m2, generally with the course being repeated
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`30 every 3 weeks. Patients were pre-treated with dexamethasone,
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`diphenhydramine, and cimetidine to offset allergic reactions.
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`See Einzig, et al., "Phase II
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`13
`Trial of Taxol in Patients
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`with Metastatic Renal Cell Carcinoma," Cancer Investigation,
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`9(2) 133-136 (1991), and A. B. Miller et al., "Reporting
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`Results of Cancer Treatment," Cancer, Vol 47, 207-214 (1981).
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`5
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`Koeller et al., in "A Phase I Pharmacokinetic Study
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`of Taxol Given By a Prolonged Infusion Without Premedication,"
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`Proceedings of ASCO, Vol. 8 (March, 1989), recommends routine
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`premedication in order to avoid the significant number of
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`10 allergic reactions believed to be caused by the cremophor
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`(polyethoxylated castor oil) vehicle used for Taxol infusions.
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`Patients received dosages ranging from 175 mg/m2 to 275 mg/m2.
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`Wiernik et al. in "Phase I Cl
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`and
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`15 Pharmacokinetic Study of Taxol," Cancer Research, 47, 2486-
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`2493
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`(May 1, 1987), also report the administration of Taxol in
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`a cremophor vehicle by IV infusion over a 6-hour period in a
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`Phase I study. Grade 3-4 hypersensitivity reactions incurred
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`in 4 of 13 courses. The starting dose for the study was 15
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`20 mg/m2 (one third of the lowest toxic dose in dogs) . Doses were
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`escalated, and a minimum of 3 patients were treated at each
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`dose level unt
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`toxicity was identified, and then 4-6
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`patients were treated at each subsequent level. The study
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`concluded that neurotoxicity and leukopenia were
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`25 dose-limiting, and the recommended Phase II trial dose was 250
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`mg/m2 with premedication.
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`Other exemplary studies on Taxol include: Legha et
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`al., "Phase II Trial of Taxol in Metastatic Melanoma," Vol. 65
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`30 (June 1990) pp. 2478-2481; Rowinsky et al., "Phase I and
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`Pharmacodynamic Study of Taxol in Refractory Acute Leukemias,"
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`Cancer Research, 49, 4640 4647
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`14
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`(Aug. 15, 1989); Grem et al.,
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`"Phase I Study of Taxol Administered as a Short IV Infusion
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`Daily For 5 Days," Cancer Treatment Reports, Vol. 71 No. 12,
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`(December, 1987); Donehower et al., "Phase I Trial of Taxol in
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`5 Patients With Advanced Cancer," Cancer Treatment Reports, Vol.
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`71, No. 12,
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`(December, 1987); Holmes et al., "Phase II Study
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`of Taxol in Patients (PT) with Metastatic Breast Cancer
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`(MBC) ," Proceedings of the American Society of Clinical
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`Oncology, Vol. 10,
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`(March, 1991), pp. 60. See also Suffness.
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`IO "Development of Antitumor Natural Products at the National
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`Cancer Institute," Gann Monograph or Cancer Research, 31
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`(1989) pp. 21-44 (which recommends that Taxol only be given as
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`a 24-hour infusion).
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`15
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`Weiss et al., in "Hypersensitivity Reactions from
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`Taxol," Journal of Clinical Oncology, Vol. 8, No. 7 (July
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`1990) pp. 1263-1268, reported that it was difficult to
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`determine a reliable overall incidence of hypersensitivity
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`reactions, HSRs, because of the wide variations in Taxol doses
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`20 and schedules used, and the unknown degree of influence that
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`changing the infusion schedule and using premedication has on
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`HSR incidents. For example, of five patients who received
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`Taxol in a 3-
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`hour infusion at greater than 190 mg/m2 with no premedication,
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`25 three had reactions, while only one out of 30 patients
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`administered even higher doses over a 6 hour infusion with no
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`premedication had a reaction. Therefore, this suggests that
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`prolonging the infusion to beyond 6 hours is sufficient to
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`reduce HSR incidents. Nevertheless, Weiss et al. found that
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`30 patients receiving 250 mg/m2 of Taxol administered via a 24-
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`hour infusion still had definite HSRs. Thus, while prolonging
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`drug infusion to 6 or 24-hours may reduce the risk for an
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`acute reaction, this conclusion can not be confirmed, since
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`78% of the HSR reactions occurred within ten minutes of
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`initiating the Taxol infusion, which indicates that the length
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`5 of time planned for the total infusion would have no bearing.
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`Further, concentration of Taxol in the infusion may also not
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`make a difference since substantial numbers of patients had
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`reactions to various small Taxol dosages. Finally, not only is
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`the mechanism of Taxol HSR unknown, it is also not clear
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`IO whether Taxol itself is inducing HSRs, or if the HSRs are due
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`to the excipient (Cremaphor EL; Badische Anilin und Soda
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`Fabrik AG
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`[BASF] , Ludwigshafen, Federal Republic of Germany) .
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`Despite the uncertainty as to whether or not premedication had
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`any influence on reducing the severity or number of HSRs,
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`15 prophylactic therapy was recommended, since there is no known
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`danger from its use.
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`The conflicting recommendations in the prior art
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`concerning whether premedication should be used to avoid
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`20 hypersensitivity reactions when using prolonged infusion
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`durations, and the lack of efficacy data for infusions done
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`over a six-hour period has led to the use of a 24 hour
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`infusion of high doses (above 170 mg/m2) of Taxol in a
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`Cremaphor EL emulsion as an accepted cancer treatment
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`25 protocol.
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`Although it appears possible to minimize the side
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`effects of administering Taxol in an emulsion by use of a long
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`infusion duration, the long infusion duration is inconvenient
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`30 for patients, and is expensive due to the need to monitor the
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`patients for the entire 6 to 24-hour infusion duration.
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`Further, the long infusion
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`16
`duration requires that
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`patients spend at least one night in a hospital or treatment
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`clinic.
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`5
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`Higher doses of paclitaxel have also been described
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`in the literature. To determine the maximal-tolerated dose
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`(MTD) of paclitaxel in combination with high-dose
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`cyclophosphamide and cisplatin