PCT
`WORI_D INTELLECTIJAL PROPERTY O RGANIZATION
`International Bureau
`lNTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREAn' (PCT)
`wo 99100113
`(5 1) Inu.r nationa l Patent Clas.~ificalio n 6 :
`A61K 9122
`
`(43) lnternalionall'ubJ leatlon Dale:
`
`7 January ]999 (07.01.99)
`
`(H ) Internalional Publication Number:
`
`AI
`
`(21) International Application Number :
`
`PCf/US98113212
`
`(22) International Filing Date:
`
`261unc 1995 (26.06.98)
`
`(30) Priority Datil:
`601051,021
`08/926.155
`
`27 June 1997 (27.06.97)
`9 September 1997 (ffJJfl.97)
`
`us
`US
`
`(63) Related hy Cootlnuatlon (CON) or Continuation·ln,Part
`(CIP) to Earlier Applicatiomi
`US
`Fil.-.d on
`US
`Piled on
`
`601051,021 (CIP)
`27 Ju ne 1997 (27,06,97)
`08f926,155 (eIP)
`9 September 1997 (09.09.97)
`
`(7l) Applicant (jor all designated States except US): VIVORX
`PHARMACEUTICALS, INC. [US/US); 2825 Santa Monica
`Boulevard, Santa Monica, CA 90404 (US).
`
`(72) Inventors; a nd
`(75) inventorgApplicants (for US only): DESAI, Neil, P. [IN/US I;
`3633 Punlue Avenue. LOll Angeles, CA 9OQ6() (US).
`SOON-SHIONG, Patrick [US/US ); 11755 Chenault Street.
`Los Angeles, CA 90049 (US). MAGOASSI. Shlomo
`[lUll]; Hanerd Street 36, Jerusalem (IL). SAHADEVAN,
`
`David, C. [US/US]; 13626 Franklin SllUt #3, Whittier, CA
`90602 (US).
`
`(74) Agent: RAYMER , Gregory, P.; Gray Cary Ware & Flt'idenrich,
`Suite l6O(J, 4365 EllCClltive Drive, San Diego, CA 9212!
`(US),
`
`(81) Designated Stales: AL, AM, AT, AU, AZ, BA, BB, IlG, BR,
`BY, CA, CH, eN, CU, cz. DE, OK, BE, ES. FI, GR, OF"
`GIl, GM, ow, RU, [D, IL, IS, IP, KE, KG , KP, KR , K7~
`LC, LK. LR. LS, LT. LU. LV, MD, MG. MK, MN, MW,
`MX. NO, NZ. PI.. PT, RO. RU. SO. SE, SC . SI, SK. SL,
`'I'), TM, TR. 'IT , UA. UG. u s. UZ, VN. YU. ZW. ARIPO
`paLt:lU (CH. OM. KE. LS, MW. SO. SZ. UG, ZW), Eumian
`paLent(AM, AZ, BY, KG, KZ, MO, RU. TJ, Th1l. European
`patent (AT, BE, CH, C Y. DE, OK. £5, FI, FR. GB, GR,
`IE, IT. LU. MC, Nl , rT. SE), OArI patent (n F, OJ. CF.
`eG, CI, CM, GA, GN, ML, MR, NE, SN. TO, TO),
`
`Puhll~hed
`With inlernalit>TWl ,eo.fch r epor l.
`
`(54) Title: NOVEL FORMULA TIOKS OF PHARMACOLOGICA L AGEI'<iS, MUTIIODS FOR nm PREPARATION THEREOF AN D
`METIIODS FOR TIIE USE THEREOF
`
`(57) Abstract
`
`In IICCOrdance with the present invention. Ihere are provided compositions lind methods useful for the;n vivo delivery of substantially
`water insoluble phannacologically active agents (such as lhe anticancer drug paditaxel) in which lhe phannacologically active agenl
`is delivered in the fonn of s..spended particles coated with protein (which acts as a stabilizing agent).
`In particular, protein and
`phannacologically active agent in a biocOlllpa.lible dispersing medium are subject.-.d 10 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 I micron. The use of specific composition and preparntion conditiom (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 stetile-filtered. The pa.niculate Syslem produced accord ing 10 Ille invention can be converted
`inlo a redispersible dry powder comprising naooparticles of waler-insoluble drug coated with a protein, and free protein 10 wllich molecules
`of the phartnocological agent are bound. This lesulls in a un ique delivery system. in which part of the pharmacologically acl ive agent is
`read ily bioovailable (in the fonn of molecules bound 10 the protein). and part of the agent is present within particle~ without any polymeric
`matri~ therein.
`
`Apotex v. Abraxis - IPR20 I 8-00 I 5 I, Ex. 1006, p.OI of 175
`
`

`

`liOR TilE PURPOSES OF INFORMATION ONLY
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`Apotex y, Abrax is - IPR20 I 8-00 I 5 I, Ex, 1006, p,02 of 175
`
`

`

`wo 99/00113
`
`PCfIUS98/13272
`
`NOVEL FORMULATIONS OF PHlIBMACOI,OGICAJ. AGENTS
`
`METHOPS FOR THE pREpARATION THEREOF AND
`
`METHonS FOR TIlE USE THEREOF
`
`,
`
`FIETrD 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 re la tes 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 i n soluble
`
`pharmacologically act ive 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
`
`convent ional surfactant or any polymeric core matrix.
`
`In a
`
`20 presently preferred aspect of the invention, there is provided
`
`a method for preparation of extremely smal l particles which ,can
`
`be sterile-filtered. The polymer ic shell contains partic l es 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 i n the form o f 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.
`
`Apotex v. Abrax is - IPR20 I 8-00 I 5 I, Ex. 1006, p.03 of 175
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`

`

`WO 99fO011 3
`
`PCTIUS98113272
`
`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
`
`an ticancer agent paclitaxel.
`
`In one aspect, the formulation of
`
`pacl itaxel , known as Capxol. is significantly less toxic and
`
`more efficacious than Taxol®, a commercially available
`
`formulation of pac l itaxel.
`
`In another aspect, the novel
`
`10 f ormulation Capxol. localizes in certain tissues after
`
`parenteral administration thereby increasing the efficacy of
`
`treatment of cancers associated with such t issues.
`
`BAc}{GRmIND QF TIm INVENTION
`
`15
`
`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 s erum
`
`levels which are achieved within a short time after
`
`20 intravascular injection , administration of drugs carried within
`
`stable car riers would allow gradual release of the d rugs inside
`
`the intravascular compartment f ollowing a bolus intravenous
`
`injection of the therapeutic nanoparticles .
`
`25
`
`Inj ectable 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
`
`offer several profound advantages over conventionally
`
`administered medicaments, including automatic assured patient
`
`30 compl iance with the dose regimen, as well as drug targeting to
`
`specific tissues or organs (Tice and Gi l ley, Journal of
`
`Controlled Release 2:343 - 352 (1 985).
`
`Apotex v. Abrax is - IPR20 I 8-00 I 5 I, Ex. 1006, p.04 of 175
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`

`

`W0 99fOOl13
`
`PCfIUS98/13272
`
`3
`
`Microparticles and foreign bodies present in the
`
`blood are generally cleared from the circulation by the "blood
`
`filtering organs" J 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
`
`(typica lly 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 p resent 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 circulat i on 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. a n d contrast media f o r
`
`imaging applications.
`
`20
`
`The size of particles and their mode of delivery
`
`determines t heir 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
`
`i njection, particles less than about 2 microns will be rapidly
`
`30 cleared from the blood stream by the reticuloendothelia l system
`
`(RES), also known as the mononuclear phagocyte system (MPS) .
`
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`WO 99/00113
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`PCTIUS98/13272
`
`4
`Particles larger than about 7 microns will, after intravenous
`
`injec t ion, be trapped in the lung capillaries. After
`
`intraarterial in jection, particles are trapped in the fir st
`
`c apil lary bed reached .
`
`I nhal ed particles are trapped by the
`
`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 i ntravenous
`
`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
`
`o r emulsion stabilizers to produce stable microemulsions.
`
`15 These emulsions may be injected intravenously, provided the
`
`components of the emuls ion are pharmacologically inert. US
`
`Patent No . 4,073,943 describes the administration of water(cid:173)
`
`insoluble pharmacolog ical l y 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.
`
`peT
`
`I nternat ional Publication No. W085/0DD11 describes
`
`pharmaceutical microdropl ets of an anaes thetic coated with a
`
`phospholipid such as dimyri stoy l phosphatidylcholine having
`
`25 suitable dimens i ons f or i ntradermal or intravenous injection.
`
`An example of a water -insoluble drug is Taxol ®, a
`
`natural product first isolated from the Pacific Yew tree, Taxus
`
`brevi folia , by Wan i et al. {J . Am . Chern, Soc, ~;232 5 (1 9 71)).
`
`30 Among the antimitot ic agents, Taxol. which contains a diterpene
`
`carbon skeleton, exhibits a unique mode o f action on
`
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`

`

`WO 99/001 13
`
`PCTfUS98J13272
`
`microtubule proteins
`
`5
`responsible for t he formation
`
`of the mitotic spindle.
`
`In contr ast with other antimitotic
`
`agents such as vinblastine or colchicine, which prevent the
`
`assembly of tubulin, Taxol is the only p lan t product known to
`
`5 inhibit the depolymerization process of tubulin, thus
`
`preventing t he cell replication process .
`
`Taxol, a naturally occurring diterpenoid, has been
`
`shown to have significant ant ineoplastic and anticancer effects
`
`10 in drug-refractory ovarian cancer. Taxol has shown excellent
`
`antitumor activity in a wide variety of tumor models such as
`
`the B16 melanoma, L12l0 leukemias, MX-1 mammary tumors, and cs-
`
`1 colon tumor xenografts. Several recent press releases have
`
`termed Tax ol as the new anticancer wonder - drug.
`
`Indeed, Taxol
`
`15 has recently been approved by the Federal Drug Admi nistration
`
`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 de l ivery is not effective . Accordingly, current l y 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 sol ution of etha nol:cremaphor and diluted
`
`with saline of about 300 - 1000 ml of fluid giv en i ntrav enous l y.
`
`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 (Loren z et al.,
`
`Agents Act ions 1987, 7, 63-67) and humans (Weiss et al., J.
`
`Clin . Oncol . 1990, 8, 1263-68) and consequently requires
`
`30 p r emedication of patients with corticosteroids (dexamethasone)
`
`and antihistamines. The large di lut ion results in large
`
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`WO 99/00113
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`PCTIUS98/ t3272
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`volumes of infusion (typical
`
`6
`dose 175 mg/m2) up to 1 liter
`
`and infusion times ranging from 3 hours to 2 4 hours. Thus,
`
`there is a need for an a l ternative less toxic formulation for
`
`paclitaxel .
`
`,
`
`•
`In phase I clinical trials, Taxol
`
`i'tself did not
`
`show excess ive 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
`
`10 patient with antihistamines and steroids prior to injection of
`
`the drug to reduce the al l ergic 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)
`
`sol ubility . Among t hem are the sulfonated derivatives
`
`(Kingston et aI " U , S, Patent 5,059,699 (1991 )) , and amino acid
`
`esters (Mathew et al., J . Med. Chern. ~ :14 5 - 151 (1 992)) which
`
`show significant biological activity. Modifications to produce
`
`20 a water-sol uble derivative facilitate the intravenous delivery
`
`of Taxol dissolved in an innocuous car rier such as normal
`
`saline. Such modifications, however, add to the cost o f 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 i n the
`
`literature as carriers of pharmacological or diagnost i c agents.
`
`Microspheres of albumin have been prepared by either heat
`
`30 denaturation or chemical crossl i nking. Heat denatured
`
`microspheres are produced from a n e muls i fied mixture {e.g .,
`
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`

`WO 99fOOl13
`
`PCflUS98f13171
`
`a l bumin, the agent to be
`
`7
`incorporated, and a suitable
`
`oil) at temperatures be t ween 100°C and 150°C. The microspheres
`
`are then washed with a suitable solvent and stored . Leucuta et
`
`al. (International Journal of Pharmaceutics li : 213-217 (1988))
`
`5 describe the method of preparation of heat denatured
`
`microspheres .
`
`The procedure for preparing chemically cross l inked
`
`microspheres involves treating the emulsion with g l utaraldehyde
`
`10 to crosslink the protein, fo llowed by washing and storage . Lee
`
`et al. (Science 2.ll: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 o r heat denaturation of the protein component
`20 the aqueous phase of a water - in - oil emulsion . Any aqueous(cid:173)
`
`in
`
`soluble agent dissolved in the protein - conta i ning 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
`
`d r ug-containing nanoparticles comprises disso l ving polylactic
`
`acid (or other biocompatible, wate r 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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`wo 99/00 113
`
`PCT/uS98JI3272
`
`pharmaceutically active agent
`
`8
`in the polymer solution, adding
`
`a surfactant to the oil phase or the aqueous phase, forming an
`
`oil-in- wate r emu l sion by sui tabl e means, and evaporating the
`
`emulsion slowly under vacuum.
`
`If the oil droplets are
`
`S suff i c i ent l y small and stabl e duri ng evaporation, a suspension
`
`of the polymer in water is obtained . Since the drug is
`
`initially present i n the polymer solution, it is possible t o
`
`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
`
`nanopart i cles by using the solvent evaporation method has been
`
`repo r ted by several
`
`r esearchers (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 . la:249 (1985); and
`
`D'Souza et al., WO 94/10980) while using various drugs.
`
`Bazile et. a l ., in Biomaterials ~:1093 (1992), and
`
`Spenl ehauer et al., i n Fr Patent 2 660 556, have reported the
`
`20 format ion of nanoparticles by usin9 .two biocompatibl e 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 emuls i fication and removal of the solvent, nanoparticles
`
`2S are formed,
`
`i n which the drug is present inside the polymeric
`
`matrix of the pol ylactide particles .
`
`The p r operties of the polymer sol ution from which the
`
`pol ymer i c matrix is formed are very important to obt ain the
`
`30 proper emulsion in the first stage. For example, polylactide
`
`(the polymer commonly used in the preparation o f injectable
`
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`

`WO 99/00113
`
`PCTIUS981132?2
`
`nanoparticles), has a surface
`
`9
`activity which causes the rapid
`
`adsorption the r eof at the dichloromethane-water interface,
`
`causing reduced interfacial tension (see, for example, Boury et
`
`al . , in Langmuir ~ : 1636 (1995», which in turn improves the
`
`5 emulsif ication process.
`
`In addition, the same researchers
`
`found that Bovine Serum Albumin (BSA) interacts wi th the
`
`polyl actide, and penetrates into the polyl actide 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 polyl actide
`
`is not only a sufficient condition, but i t is actual l y
`
`necessary f or the formation of nanoparticles of suitable size .
`
`15
`
`Another process which is based on the solvent
`
`ev aporation method comprises dissolving the drug in a
`
`hydrophobic solvent
`
`(e .g., toluene or cyclohexane), without any
`
`pol ymer dissolved in the organic so l vent, 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 evapora ting the solvent to obtain dry particles of the
`
`drug (see, for example, Sjostrom et al., in J . Dispersion
`
`Science and Technology ~:89-117 (1994». Upon removal of the
`
`25 nonpolar solvent, preci pitation of the drug i nside the sol vent
`
`drop l ets occurs, and submicron particles are obta ined.
`
`It has been found that the size of the particles is
`
`mainly controlled by the init i al size of the emulsion droplets.
`
`30 I n 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 her ein, wherein no
`
`convent j onal 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, i s surface active in
`
`toluene, and hence may be oriented at the oil-water interface;
`
`therefore t he concentration of drug at the interface is higher,
`
`thus increasing the potential for precipitation .
`
`10
`
`Formation of suhmicron particles has also been
`
`achieved by a precipitation process, as described by Calvo et
`
`al . in J . Pharm . Sci . a2:530 (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
`
`BACKGROlJNDOE TIlE INyENTION
`
`Taxol is a naturally occurring compound which has
`
`shown great promise as an anti-cancer drug. For example, T~xol
`
`25 has been found to be an active agent against drug-refractory
`
`ovar i an cancer by McGuire et al. See "Taxol: A unique Anti(cid:173)
`
`Neoplastic Agent With Significant Activity Against Advanced
`
`OVarian Epithelial Neoplasms ." Ann. Int. Med., 111, 273-279
`
`(1989). All patents, scientific articles, and other documents
`
`30 mentioned herein a re incorporated by reference as if
`
`reproduced in full below.
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`
`Unfortunately, Taxol has extremely low solubility in
`
`water, wh ich makes it difficult to provide a suitable dosage
`
`form. In fact, in Phase I clinical trials, severe allergic
`
`5 reactions were caused by the emulsifiers administered in
`
`conjunction with Taxol to compensate for Taxol's low water
`
`solubility ; at least one patient's death was caused by an
`
`allergic reaction induced by the emulsifiers . Dose limi t ing
`
`toxi cit ies include neutropenia, peripheral neuropathy, and
`
`10 hypersensitivity re actions.
`
`Brown et al., in "A Phase I Trial of Taxol Given by
`
`A 6 - Hour Intravenous Infusion" J of Clin Oneal, Vol. 9 No . 7,
`
`pp. 1261-1267 (July 1991) report on a Phase I Trial in wh i ch
`
`15 Taxo l was provided as a 6-hour IV infusion every 21 days
`
`wjthollt premedjcation. 31 patients received 64 assessable
`
`courses of Taxol . One patient had a severe (or acute)
`
`hypersensitivity reaction, which required discontinuation of
`
`the infusion and immediate treatment to save the patient's
`
`20 life. Another patient experienced a hypersensitivity reaction,
`
`but i t was n ot so severe as to require discontinuing the
`
`infusion. Myelosuppression was dose- limi ting, with 2
`
`fatal i ties due to sepsis. Non-hematologic toxicity was of
`
`Grade 1 and 2, except for one patient with Grade 3 mucositis
`
`25 and 2 patients with Grade 3 neuropathy. The neuropathy
`
`consisted of reversible painful paresthesias, requiring
`
`d iscontinuation of Taxol in two patients. Four partial
`
`responses were seen (3 in patients with non-smaIl-cell lung
`
`cancer, and one in a patient with adenocarcinoma of unknown
`
`30 primary). The maximum tolerated dose reported was 275 mg/m2,
`
`and the recommended Phase II starting dose was 225 mg/m2. The
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`incidence of hypersensitivity
`
`12
`reaction was reported to be
`
`schedule-dependent, wi th 6 to 24-hour i nfus ions of drug having
`
`a 0% to at incidence of hypersensitivity reactions. It was
`
`also reported that hypersensitivity reactions persist with or
`
`5 without premedication despite prolongation of infusion times.
`
`Since these Phase I studies were conducted on term i na l ly ill
`
`patients suffering from a variety of cancers, the e ff icacy of
`
`the Taxal treatments could not be determined .
`
`10
`
`In a study by Kris et al ., Tax ol formulated with
`
`Cremaphor EL in dehydrated alcohol was given as a 3-haur IV
`
`infusion every 21 days, with the administered dosage ranging
`
`from 15 to 230 mg/m2 in nine escalation steps. Kris et a l .
`
`concluded that "with the severity and unpredic t ability of t h e
`
`15 hypersensitivi ty reactions, further usage of Taxol is not
`
`indicated with this drug formulation on this administration
`
`schedule ." See Cancer Treat. Rep., Vol . 70, No.5, May 1986.
`
`Since early trials using a bolus injection or short
`
`20 (1 - 3 hour ) infusions induced anaphylactic reactions or other
`
`hypersensitivity responses , further studies were carried out
`
`in which Taxol was administered only after premedication with
`
`steroids (such as dexamethasone), antihistamines (such as
`
`diphenhydramin e), and H2 - antagonists (such as cimetidine or
`
`25 ranitidine), and the infusion t ime wa s extended to 24 hours in
`
`an a t tempt to eliminate t he most serious al lergic reactions.
`
`Various Phase I and Phase II study results have been published
`
`utili zing 24-hour infusions of Taxol wi th maximum total
`
`dosages of 250 mg/m2, generally with the couree being repeated
`
`30 every 3 weeks. Patients were pre-treated with dexamethasone,
`
`diphenhydramine, a n d cimetidine to offset allergic reactions.
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`See Einzi9, et al., "Phase II
`
`1 3
`Trial of Taxol in Patients
`
`wit h Metastatic Renal Cell Carcinoma," Cancer Investigation,
`
`9(2) 133-136 (1991 ) , and A. B. Miller et a!., "Reporting
`
`Results of Cancer Trea t ment," Cancer, Vol 47, 207-214 (1 981).
`
`5
`
`Koeller et al., in "A Phase I Pharmacokinetic Study
`
`of Taxo l Given By a prolonged Infusion Without Premedication,"
`
`Proceedings of ABCO, Vol. 8 (March, 1989), recommends rout ine
`
`premedication i n order to avoid the significant number of
`
`10 a ll ergic r eac t ions believed to be caused by the cremophor
`
`(pol yethoxyl ated castor oi l ) vehicle used for Taxo l infusions .
`
`Patients received dosages ranging from 175 mg/m2 t o 275 mg/m2.
`
`Wiernik et al. in "Phase I Clinical and
`
`IS Pharmacokinetic Study of Taxol," Cancer Research, 47, 2486 -
`
`2493 (May 1, 1987), also report the admi nistration of Taxol in
`
`a cremophor vehic l e by I V i nfus i on over a 6 -hour per iod i n a
`
`Phase I study . Gr ade 3-4 hypersensit i vity reactions incurred
`
`in 4 of 13 courses. The starting dose for the study was 1 5
`
`20 mg/m2
`
`(one - third of the lowest toxic dose in dogs). Doses were
`
`escalated, and a minimum of 3 patients were t reated at each
`
`dose leve l unt i l toxicity was i dent i fied, and then 4 -6
`
`patients were treated at each subsequent level . The study
`
`concluded that neurotoxicity and leukopenia were
`
`25 dose - limiting, and the recommended Phase II trial dose was 250
`
`mg/m2 with premedication .
`
`Other exemplary studies on Taxol i nclude: Legha e t
`
`al . , "Phase II Trial of Taxol i n Metastatic Melanoma," Vol. 65
`
`30 (June 1990) pp. 2478-2481; Rowinsky et a!., "Phase I and
`
`Pharmacodynamic Study of Taxol in Refractory Acute Leukemi as I
`
`"
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`Cancer Research, 49, 4640 - 4647
`
`14
`
`(Aug. 15, 1989); Grem et al.,
`
`"Phase I study of Taxol Administered as a Short IV Infusion
`
`Daily For 5 Days," Cancer Treatment Reports, Vol. 71 No. ~2,
`
`(December, 1987) i Donehower et al., "Phase I Trial of Taxol in
`
`5 Patients With Advanced Cancer," Cancer Treatment Reports, Vol.
`
`71, No. 12 ,
`
`(December , 1987); Holmes et al., "Phase II Study
`
`of Taxol in Patients (PT) with Metastatic Breast Cancer
`
`(MBC) ," Proceedings of the American Soc i ety of Clinica l
`
`Oncology, Vol. 10,
`
`(March, 1991), pp. 60. See also Suffness .
`
`10 "Development of Antitumor Natural Products at the National
`
`Cancer Institute," Gann Monograph or Cancer Research, 31
`
`(1989) pp. 21-44 (which recommends that Taxol onl y be given as
`
`a 24-hour i nfusion) .
`
`15
`
`Weiss et al., in "Hypersensitivity Reactions from
`
`TaxoI," Journal of Clinical Oncology, Vol. 8, NO.7 (July
`
`1990) pp . 1263 - 1268, reported that it was difficult to
`
`determine a reliable overall incidence of hypersensitivit y
`
`reactions, HSRs, because of the wide variations in Taxol doses
`
`20 and schedules used, and the unknown degree of influence that
`
`changing the infusion schedule and using premedication has on
`
`HSR incidents. For example, of five patients who received
`
`Taxol in a 3-
`
`hour infusion at greater than 190 mg/m2 with no premedication,
`
`25 three had reactions, whi le only one out of 30 patients
`
`administered even higher doses over a 6-hour infusion with no
`
`premedication had a reaction. Therefore, t h is suggests that
`
`prol onging the infusion to beyond 6 hours is sufficient to
`
`reduce HSR inciden~s. Nevertheless , Weiss et al. found that
`
`30 patients receiving 250 mg/m2 of Taxol adminis t ered via a 24-
`
`hour i nfusion still had definite HSRs. Thus, while prolonging
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`15
`drug infusion to 6 or 24-hours may reduce the risk for an
`
`acute reaction, this conclusion can not be confirmed, since
`
`78% of the HSR reac tions occurred within ten minutes of
`
`initiating the Taxol infusion, which indicates that the length
`
`5 of time planned for the total infusion would have no bearing.
`
`Further, concentration of Taxol in the infusion may also not
`
`make a difference since subs tantial numbers of patients had
`
`reactions to various small Taxol dosages. Finally, not only is
`
`the mechanism of Taxol HSR unknown, it is also not clear
`
`10 whether Taxol itself is inducing HSRs, o r
`
`i f
`
`t h e HSRs are due
`
`t o the excipient (Cremaphor ELi Badische Anilin und Soda
`
`Fabrik AG
`
`[BASF ] , Ludwigshafen, Federal Repub l ic of Germany)
`
`Despite the uncertainty as to whether or not premedication had
`
`any influence on reducing the severity or number of HSRs,
`
`15 prophyl actic therapy was recommended, since there is no known
`
`danger from its use .
`
`The conflicting recommendations in the prio r a rt
`
`concerning whether p remedication should be used to avoid
`
`20 hypersensitivity reactions when using prolonged infus ion
`
`du