peT
`WORLD INTELLECTUAL PROPERTY ORGAt\' IZAnON
`International Bun:au
`IN1T:RNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (pen
`wo 00106152
`(51) Internatio"al Patent Clnss ilicolion 7 :
`A61K 311337, 47/48, 47/42
`
`(43) International Publk:atlon OllIe:
`
`10 February 2000 (10,02.00)
`
`(1 1) International PUblication Numocr:
`
`Al
`
`(2 1) International AppJlcation Num ber:
`
`PCfruS9911 7179
`
`(22) International ~1liJlg Oate:
`
`29 July 1999 (29.07.99)
`
`(30) Priority Data:
`601094,687
`
`30 July 1'J98 (30.07.98)
`
`us
`
`except US):
`STales
`designmed
`0./1
`(for
`(?I) Applicant
`NOVOPHARM BIOTECH, INC. ICA/CAI: 30 Novopllarm
`Coun. Tororno. Ontario MJB 2K9 (CAl.
`
`(72) Innntor!1;; and
`(7S) InnntorYApplicants (for US only): KADiMA, Tenslluk, A.
`rCA/CAl; 7 Woodington Bay, Winnipeg. Manitoba R3P
`IM6 (CAl. KAPLAN, Howard. A. [CAlCA1; 18 H illhou~
`Road, Winni peg, Manitoba R2V '2V9 (CA). TlJ'TTIE.
`Koben, C. [USlCA]; 782 Allegheny Drive, Winnipeg,
`Maniloba K3T SL2 (CA).
`
`(74) Agents: WU, Frank et al.; Morrison & Foen;ter LU', 755 Page
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`patent (SF, SJ , CF, CO. 0, CM. GA, ON. GW. ML. MR,
`NE. SN, TD. TO).
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`I'ublished
`Wi,h intemotionol search reper/.
`8efore the expirtJIion of rhe Ii"", limit fnr amending tM
`cloim! o.nd /0 bt u publi$hed in the evtnt oj the receipt oj
`amendmtnt!.
`
`(54) Title: PHARMACElmCALLY ACCEPTAB I.E COfo,WOSITION COMPRISING AN AQUEOUS SOLlmON OF PACLITAXEL
`AND AI.BUMIN
`
`(57) AlJstract
`
`An optically clear. pharmaceutically nttcpl~ble aqueous composition CQ",pri~ing paclitaxd or ~ <.Icriv~tive thereof. serum albumin
`and a pharmaceutically acceplable vehicle, wherein the composition compri~s no more Illan 10 % organic solvent uruJ has a pH of about
`3.0 to about 4.8, is described. The serum album in can be failed or defalled, and the composition call optionall y be lyophilized or optionally
`lyophilizr:d and Tttonstiruted. At least 70 % of the paclllllxel is bound to seru m albumin, the ralio ()of paelitaxel to albumin is at least about
`1:5, anclthe corn:entration of paclitaxcl is al least about 2S /lglml. Methods of making and using this compo~ition are also provided,
`
`Apotex v. Abrax is - IPR20 18-00153, Ex. 1004, p.O I of 162
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT 011 the froot pages of pamphlets publishing international applications under the per.
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`Apotex v. Abrax is - IPR20 18-00 153 , Ex. 1004, p.02 of 162
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`

`

`WOOO/06 152
`
`PCT/US99/t 7t79
`
`PHARMACElTTICALLY ACCEPTABLe COMPOSITION COMPRIS ING AN AQUEOUS SOLUTION OF PACLlTAXEL
`AND ALBUMIN
`
`5
`
`10
`
`CROSS-REFERENCE TO RELATED APPLICATiONS
`
`(Not Applicable)
`
`STATEMENT OF RlGHTS TO INVENTiONS
`
`MADE UNDER FEDERALLY-S PONSORED RESEARCH
`
`(Not Applicable)
`
`TECHNICAL FIELD
`
`The present invention relates generally to aqueous formulations of paclitaxcl and
`
`methods of use thereof. More specifically, it pertains to phannaceutical compositions
`
`! 5
`
`comprifling p<!clitaxc\ (Pix) or a derivativc thereof and serum albumin or a fragment
`
`thereof, particularly human serum albumin, and more particularly recombinant human
`
`serum albumin, and a physiologically acceptable vehicle; methods of preparation of such
`phannaceutical compositions; and methods of use thereof. The vehicle can comprise an
`
`organic solvent, ami the composition lacks a toxic emulsifier such as Cremophor EL®
`
`20
`
`(polyoxyethylated castor oil).
`
`BACKGROUND OF THE INVENTION
`
`Paclitaxel, a structurally complex natural plant product, has demonstrated efficacy
`in the treatment of a wide variety of human malignancies. This drug shows strong
`
`25
`
`cytotoxicity in KB cell structures and in several orthe National Cancer Institute's in vivo
`
`screens, including the P-388, L·1 21O, and P·l S34 mouse leukemias, the B·16
`
`melanocarcinoma, the eX·1 colon xenograft, the LX-I lung xenograft, and the MX· J
`
`breast x~nograft. Further, studies by McGuire ct a1. [(1989) Ann. In!. Med. 111 :273-279]
`
`30
`
`found pacliraxel to be active against drug·refraetory ovarian cancer. Positive results were
`
`also seen with paclitaxel treatment of patients with other cancers, including melanoma.
`
`Apotex v. Abrax is - IPR20 18-00 153, Ex. 1004, p.03 of 162
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`Einsig Cl al. (1988) Proc. Am. Soc. C/in. Oncol. 7:249; Holmes (1991)J Nail. Cancer Insf.
`
`83 : 1797-1805; and Kohn el al. (\ 994) 1. Nat!' Cancer Ins/. 86: 18-24.
`
`]n addition to various cancers, pacl itaxel has been used in treating several other
`
`diseases, including malaria and babesiosis. U.S. Patent Nos. 5,356,927 and 5,631,278.
`
`5
`
`Paclitaxel can be used to treat indications characterized by chronic inflammation such as
`
`rheumatoid arthritis and auto-immune disease. U.S. Patent No. 5,583,1 53; and Song et al.
`
`(1996) Arthri/is Rheum. 39:S 178. Pac1itaxc1 can impair chronic inllammation by inhibiting
`
`the activity of white blood cells involved in the inflammatory response; reducing the
`
`production of matrix mctalloprOteiilllses that pennanently damage tissues ; blocking the
`
`10
`
`cancer-like growth of previously normal cells which respond to chronic inflammation by
`
`proliferating; and inhibiting the growth of blood vessels which lead to the formation of scar
`
`tissue. Paclitaxel is also a pOlent inhibitor of angiogenesis and other processes involved in
`
`the development of chronic inflammation. This activity is due, in part, to paclitaxel 's
`
`ability to inhibit the transcription factor AP- l . A P-\ is a key rcgulator of genes involved in
`
`15
`
`the production of (i) ma1rix metalloprotcinases, (ii) cytokines associated with chronic
`
`inflammation, and (iii) protei ns necessary for cell proliferation. Thercfore, pac1itaxel
`
`inhibits a regulator which plays an important role in chronic infl ammation and conditions
`
`that are dependent on angiogenesis (new blood vessel format ion), including tumor growth.
`
`Paclitaxel has shown strong anti-angiogenic activity when tested in the chorioallantoic
`
`20
`
`membrane of the developing chick embryo. The drug is a more potent angiogenesis
`
`inhibitor than approved anti-arthritic agents such as methotrexate, penicillam ine, and
`
`steroids.
`
`Atherosclerosis and reslenosis have also been treated with low paclitaxel dosages.
`
`U.S. Patent No. 5,616,608. Paclitaxel can alter several aspects ofthc process lcading to
`
`25
`
`restenosis, including inhibition of vascular smooth muscle cell ("VSMC") migration,
`
`inhibition ofVSMC proliferation, and inhibition of the effects of certain growth factors on
`
`these cells. Paditaxel also inhibits synoviocytc proliferation. Paclitaxel is capable of
`
`inhibiting proliferation of synovioc)1eS in vitro and inducing apoptosis (progmmmed cell
`death) at concentrations as low as 10-7 M, and is cytotoxic to the synoviocytes at slightly
`higher concentrations of \ 0-6 to 10-5 M. Paditaxc\ inhibits collagenase production by
`chondrocytes in vi/ro, but is not toxic to nonnal chondrocytes. A concentration of 10-7 M
`
`30
`
`paclitaxcl, for example, reduced collagenase expression by over 50% in cultured
`
`2
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`chondrocytes stimulated by tumor necrosis factor and interleukin-l. This inhibition occurs
`
`downstream from the transcription factor activity of c-fos and c-j un, apparently by
`
`disrupting the normal functioning of the AP-\ molecule, resulting in inhibition of
`
`transcription of the collagenase gene. As such, inhibition of collagenase secretion by
`
`5
`
`paclitaxel is not strictly d ue to interruption of the protein secretory pathway, which is
`
`dependent upon microtubule function for the movement of secretory granules. Paclitaxel
`
`also appears to act at the level of the genetic response to stimuli directing the cell to
`
`produce collagenase.
`
`TIle drug is also known to be effective in treating a number of other indications.
`
`10
`
`l'aclitaxel is useful for treating surgical adhesions and post-surgical hyperplasias. 1n
`
`Alzheimer' s disease treatment, paclitaxel has been used to stabilize microtubules
`destabilized by insuflicicnt tau protein levels. U.S. Patent No. 5,580,898. Paclitaxel is also
`
`thought to be effective against polycystic kidney disease (PKD). Sommardahl et al. (1997)
`
`Pediatr. Nephrol. 11 :728-33. Paclitaxel derivatives are also effective in treating psoriasis.
`
`15
`
`EP 747385 and \VO 96 13494.
`
`Other therapeutic agents have been successfully co-administered with pacli taxeL
`
`For example, Vitamin C can be used to increase the efficacy of paclitaxel. Kurbacher et al.
`
`(1996) Cancer Lelf. 103: \ 83-189. EI) 781552 and EP 787716 describe additional
`
`compounds that enhance paclitaxel acti vity. U.S . Patent No. 5,565,478 describes
`
`20
`
`combinational therapy ofpaclita1(el with signal transduction inhibitors for cancer treatment.
`
`In treatment of autoimmune arthritis, paclitaxel has been administerro with other
`
`antiarthritic drugs. such as an angiogenesis inhibitor. U.S. Patent No. 5,583,153. Anilide
`
`derivatives have also been administered to sensitize multidrug-resistant cancer cells to
`
`paclitaxel. EP 649410. Paclitaxel can also be administered with antibodies specific to
`
`25
`
`cancerous cells. U.S. Patent No. 5,489,525. In breast cancer treatment, pac1itaxel has been
`
`administered in combination with estramustine phosphate. Keren-Rosenberg et al. (1997)
`
`Scm, Oncol. 24 (Supp!. 3):S3-26-29. Paclitaxel and IGF·I (Insulin-like growth fac tor I)
`
`have been used together to treat peripheral neuropathy. U.S. Patent Nos. 5,648,335,
`
`5,569,648 and 5,633,228. Paclitaxei has also been successfully administcred along with
`
`30
`
`doxorubicin, cyclophosphamide, and cisplatin. O'Shaughnessy ct al. (1995) Brea .... r Cancer
`
`Res. Treat. 33:27-37. P-glyeoprotein blocker SDZ PSC 833 , a cyclosporin derivative, has
`
`demonstrated a 1 O-fold increase in oral bioavailabi li ty ofpac1itaxcl in mice. Asperen et al.
`
`3
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`( 1997) Bri!. J Cancer 76: 1181-1 183 . Essential oils have also been suggested to increase
`
`paclitaxe!' s bioavailabilit y. U.S. Patent No. 5,716,928.
`
`The mechanism ofpaclitaxe l action has been extensively studied and is summarized
`
`by Honvitz (1984) Pharm. Ther. 25:S3-125. Paclitaxel can act by promoting tubulin
`
`5
`
`assembly into stable aggregated structures which resist depolymerization by dilution,
`
`calcium ion, cold, and several nUcrotubule-disrupting drugs. Tubulin depolymerization is
`
`cssential for cell division, and thus paclitaxel causes this process to cease. Schiff et al.
`
`(1979) Nature 277:665-667. Paclitaxel is unique in promoting tubulin polymer fomlation,
`
`whereas other anti-cance r drugs, such as vinblastine and colchicine, prevent this process.
`
`10
`
`As originall y described in Wani et al. [(1971) J. Amer. Chern. Soc. 93:2325-2327] ,
`
`paclitaxel can be purified via alcohol extraction from the Pacific yew tree. Tcuus brevifolia.
`It is also present in other Taxus species, such as T. baccata and T. cuspidata. However,
`
`pacli taxel is found only in minute quantiti es in the bark of these slow-growi ng trees,
`
`causing concern that the limited paclitaxel supply will not meet the demand. Consequently,
`
`15
`
`chemists in recent years have attempted to find alternative or synthetic routes for producing
`
`paclitaxcl. U.S. Patent No. 5,019,504 describes the puri fi cation of paclitaxcl from tis~ucs
`
`of1~ brevifolia grown in vitro. U.S. Patent No. 5,322,779 describes the production of
`
`paclitaxd from a fungus , Taxomyces andreanae, found in association with the yew tree.
`
`More recently, novcl compounds have been suggested for use in enhanc ing plant
`
`20
`
`production ofpaclitaxel. U.S. Patent No. 5,710,099.
`
`Paclitaxel has also been synthesized from related compounds found in higher
`
`quantities in Taxus trees. These compounds include baccatin Ill, obtained from Taxus
`
`wood, and lO-deacctyl baccatin 111, fro m Taxu.\·leaves. Methods of preparing paclitaxc1
`
`from these precursor compounds, which themselves lack antitumor activity, have been
`
`25
`
`described. Greene et al. (1988) JACS 110:5917-5919; U.S. Patent Nos. 5,7 17,103,
`
`4,857,653 , "nd 4,924,01 1 (Re. 34,277).
`
`Various synthetic routes and intermediates in paclitaxel syntllesis have been
`
`described, including a route directed to the synthesis of the tricyclic taxane nucleus from
`
`commodity chemicals. Hol ton et al. (1994) J. Am. Chen/. Soc. 116: 1597~ 1598, 1599-1600;
`
`30
`
`Nicolaou et al . (1994) Nature 367:630-634; anti Dan ishefsky et al. (\996) 1. Am. Chern
`Soc. 118:2843-59; and U.S. Patent Nos. 5,723 ,635 and 5,726,318. Additional compounds
`
`useful in paclitaxel synthesis have also been described. U.S. Patent No. 5,015,744
`
`4
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`describes the use of an oxazinone as a side-chain precursor for paclitaxel synthesis. U.S.
`
`Palent No. 4,876,399 describes an intcnnediate, 2,5-dihydroxy-2-patchoulenc. U.S. Patent
`
`Nos. 5,523,219 and 5,705,671 describe additional intennediates.
`
`Pacl itaxel itself has been chemically modified, sometimes producing compounds
`
`5
`
`with even greater antitumor activity than paclitaxel itself. U.S. Patent No.4, 814,470.
`
`Cephalomannine, which differs from paclitaxc! and baccatinlll in the C-13 ester
`
`functionality, demonstrates activity against leukemia in animals. U.S. Patent No.
`
`4,206,22 1. Other paclitaxe\ derivatives include prodrug fonns, in which paclitaxel is
`
`conjugated to cleavage spacer and sugar groups. EP 78 1778.
`
`10
`
`Some paclitaxel derivatives have been produced in attempts to address a significant
`
`problem limiting the util ity of paclitaxel: pacl itaxel is largely insoluble in water. This has
`
`created significant problems in developing suitable pharmaceutical formulations for human
`
`therapy both in tenns of formulation and side effects. The problem is also a serious
`
`impediment for experimental research on paclitaxei and its cl inical effectiveness.
`
`15
`
`Derivatives of paclitaxel, designed to havc increased water solubility, includc 2' - and/or 7-
`
`position paclitaxel esters, as described in U.S. Patent No. 4,960,790. Additional
`
`substitutions at the C-2' and C-7 positions were described by Magri et al. (1988) J. Nalural
`
`Products 51 :298-306. 2' -succin)'! paclitaxels are described in U.S. Patent No. 4,942,184;
`
`and sulfonated 2' -acryloyltaxol and sulfonated 2' -O-acyl acid paclitaxel derivatives, in
`
`20
`
`U.S. Patent No. 5,059,699.
`
`Unfortunately, many of these more soluble derivatives reduce paclitaxel antitumor
`
`activity_ A 2' -succinyltaxol, prepared hy the treatment ofpaclitaxel with succ inic
`
`anhydride, had decreased in vivo activity compared with paci itaxel , and a 2' -(t(cid:173)
`
`butyldimethylsilyl)taxol was essentially inactive. Magri et al. ( 1988). Other derivatives,
`
`25
`
`such as 2'-(~-alanyl)taxol, are unstable. Magri et at. (1988). Attempts to derivatize
`
`paclitaxel generally increase the molecule's size, which decreases its ability to passively
`
`diffuse through the cel lular and nuclear membranes of cancerous cells.
`
`The insolubility of paclitaxel itsdfhas yidded a further complication: it has elicited
`
`the widespread use of a toxic carrier. Paclitaxel is generally supplied through CTEP
`
`30
`
`(Cancer Therapy Evaluation Program), DCT (Division of Cancer Treatment), and NCI
`
`(National Canccr Institute, IND#2280) as a concentrated solution in 50% polyoxyethylated
`
`castor oil [Cremophor EL® (BAS F)] and 50% dehydrated alcohol. 111is is then mixed with
`
`,
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`either a dextrose or sodium chloride solution prior to administration. Although Cremophor
`
`EL® is the industry-standard administration vehicle for paclitaxel, Cremophor EL® is
`
`itsclftoxic, causing idiosyncratic histami ne release and anaphylactoid-like response.
`
`Crcmophor EL® is also likely to be 1he cause of several side effects associated with
`
`5
`
`pac1itaxel treatment, including cutaneous flushing, urticaria, dyspnea, bronchospasm, and
`hypotension. Runowicz ct al. (1993) Cancer 71: 1591-1 596; and Weiss et a!. (1990) J.
`
`Clin. Oneol. 8: 1263-126. In studies with dogs, Cremophor EL® and its fatty acid
`
`constituents induced histamine release and hypotension within [0 minutes of
`
`administration. Lorenz ct al. (1977) Agents AClions 7:63-67. Some tested animals died as a
`
`10
`
`result of this hypotension.
`
`Other organic carriers have been proposed for pac1itaxel administration or used in in
`
`vitro pac1itaxcl preparations. Polyethy lene glycol (PEG) has bcen suggested as a substitute
`
`emul sifier for paclitaxel, but PEG decreases the antitumor activity ofpaclitaxel in murine
`
`tumor studies. Weiss et al. (1990) J. Clin. Oneal. 8: 1263-1268. Paclitaxel has also been
`
`15
`
`prepared in sol Ulion with dimethylsulfoxide [Kumar et al. (1993) Res. Comm. Chern. Palh
`
`Pharm. 80:337-344}, which is itself toxic [Kamiya el a!. (1967) Nippon Ganka Kiyo
`
`18:387-9; Sperling et aL (1979) ACla Ophtha/mol. 57:891-8}. Polysorbate-8 0 was used in
`
`in vilro mixtures containing very low concentrations of docetaxel [Urien et al. (1996)
`
`invest. New Drugs 14: 147- 151}, but polysorbates are toxic , reducing locomotor activity,
`
`20
`
`inducing ataxia and hypotension, and increasing the activity of various carcinogens. Pesce
`
`et al. (I 989) Ann. Clin Lab. Sci. 19:70-3; (1984) J. Am. Call. Toxicol. 3/5:1 -82; and Varma
`
`ct al. (1985) Arzneimilteljorschung 35 :804-8. Therefore, the sole nse of these carriers to
`
`solubi lize paclitaxel is not a desirable solution to the problem of developing therapeutically
`
`effective pacl itaxel formulations.
`
`25
`
`In lhe absence of workable aliernativcs, and despite its tox icity, Crcmophor EL®
`
`remains the standard vehicle used for pacl itaxel administration to human patients.
`
`Documents demonstrating the universal use ofCremophor EL® in paclitaxel preparations
`
`and paciitaxei administration include: Ein:cig et a1. (1991) Cancer Jnve~·1. 9: 133-136;
`
`O'Shaughnessy etal. (1994) Breast Cancer Res. Treal. 33 :27-37; Kawano ct a1. (1994).1.
`
`30
`
`1'oxi(;ol. Sci. 19 (suppl. 1): 113-122; Aspercn et al. (1997) Brit. .I. Cancer 76:1181- 118 3;
`
`Sparreboom et al. (1998) Anti-Cancer Drugs 9:1-17; Runowicz et al. (1993) Cancer
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`71: 1591 -1 596; Sparreboom el a1. ( 1998) Anal. Biochemistry 255: 171-175; Plasswilm et al.
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`6
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`PCTIUS99JI 7179
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`(1998) Strahlentherapie und Onkologie 174:37-42; Xu et a1. (1997) Hospital Pharmacy
`
`32: 1635- 1638; Khan ci a!. (l997) Ann. Pharmacotherapy 31: 1471-1474; Michaud et al.
`
`(1997) Ann. Pharmacotherapy 31: 1402-1404; Zhang et al. (1997) Anti-Canccr Drugs
`
`8:696-701; Wilson et al. (1997) Ann. Pharmacotherapy 31 :873-875; Reinecke ct al. ( 1997)
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`5
`
`£ur. J. Cancer Pari A :Uniled Kingdom 33:1 122-1 129; Kuangj ing Shao et al. (1997) Anal.
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`Chemi.~try 69:2008-2016; S onfrer et al. (1997) Tumor Biology; Swilzerland 18:232·240;
`
`Decorti et al . (1997) Cancer Chemother. Pharmacology 40:363-366; Ho et a1. (1997)
`
`Neurosurgery 40/6 :1260-1268; Terzis et al. (1997) Brihsh J. Cancer 75: 1744-1752;
`
`Kilbourn et al. (1997) Disease-a-Month 43:282-348; Frasci et al. (1997) J. Clinical
`
`10
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`Oncology 15: 1409- 14 17; Sharma et a1. (1997) international J Cancer 71: 1 03 -107;
`
`Georgiadis et al. (1997) Clinical Cancer Re~·earch 3:449-454; Zhang et al. (1997) Cancer
`
`Chemo/her. Pharmacology 40:81-86; EP 694303; WO 94/12031 ; and U.S. Patent Nos.
`
`5,733 ,888,5,731,334,5,7 19,265,5,714,5 12, 5,703,1 17, 5,698,582, 5,696,153, 5,686,488,
`
`5,683,715,5,681 ,846,5,670,537,5,665,761, 5,648,335, 5,648,090, 5,641,803 , 5,63),228,
`
`15
`
`5,621 ,001 , 5,616,608, 5,6 16,330, 5,614,549, 5,608,087, 5,604,202, 5,569,648, 5,583,153,
`
`5,580,899, 5,569,720, 5,565,478,5,504,102, 5,496,846, 5,496,804, 5,478,860, 5,403,858,
`
`Numerous attempts have been made to produce aqueous solutions of hydrophobic
`
`drugs. For instance, fomlU larions of cisplatin combined with dextran, polyglutamic acid,
`
`DNA, proteins, hyaluronic acid, etc. were compared. It was found that many of these
`
`20
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`excipicnts were unacceptable as they bound the drug too tightly and did not release it on
`
`administration or did not bind enough drug to produce a phannaceuti cally acceptable
`
`fonnulation. DNA was in the category of excipients which bound too tightly. Proteins,
`
`including serum albumin, were found to bind limited amounts of drug, only a portion of
`
`which was reversibly bo und.
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`25
`
`Albumins have been used as excipients as bulk stabilizers fo r a number of drug
`
`formulations, particularly biologicals such as interleukins and cytokines. Human serum
`
`albumin is a large component ofinterleukin-4 preparations. Meyer et al. (1994) Pharm.
`
`Res. 11: 1492-1495. Albumin has also been conjugated to drugs to increase uptake of the
`
`drug and derivatized albumins have been used to couple drugs and enhanee uptake through
`
`30
`
`the blood-brain barrier. SiJUl et al. (1990) Nllci. Mcd. BioI. 17:8 19-827; Pardridge et al.
`
`(1990) J. Plwrml1col. Exp. Ther. 255:893-899; Flume et a1. (1989) Pharm. Ac/a He/v.
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`64:351-352; and JP 61001622. WO 94/0 1090 describes broad formulations of hydrophilic
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`peptides and "sparingly water soluble" active compounds. Album in is a cost-limiting
`
`component for use in drug stabilization. Thus, unless an unstable drug can be stabilized in
`
`some other fashion. albumin is nOl ideal as a bulk stabilizing agent. Further, nalive
`
`albumin is being phased out of use as it may contain infectious agents such as prions.
`
`5
`
`Replacement with recombinant albumin may result in an even more costly product.
`
`Therefore, in order to produce a commercially available, phannaceutically acceptable
`
`albumin-bound drug, the drug must be bound reversibly to the albumin in a high molar
`
`ratio.
`
`The need remains for aqueous phannaceu1ically acceptable fonnlliations of
`
`JO
`
`paclitaxc] which are easy and inexpensive to prepare, produce fewer side effects, and in
`
`which the drug retains high \vater solubility and activity.
`
`SUMMARY AND OBJECTS OF THE INVENTION
`
`In one embodiment, the invention provides an optically clear, phannacelltically
`
`15
`
`acceptable aqueous composition comprising paclitaxcl or a derivative thereof, serum
`
`albumin or a fragment thereof, and a pharmaceutically acceptable vehicle. In various
`
`embodiments, the composition comprises no morc than 10% organic solvent, and has a pH
`
`of about 3.0 to about 4.8 (the pi of albumin). In various embodiments, the composition
`
`comprises about 1 to about 10%, about 2 to about 8%, or about 4 to about 6% vlv
`
`20
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`(volume/volume) organic solvent. In a preferred cmbodiment, the composition is essential
`
`free of organic solvent. The organic solvent is prefcrably an alcohol, most preferably
`
`ethanol. In various embodiments, the pH is about 3.0 to about 4.8, about 4.0 or less, about
`
`3.0 to about 4.0, or about 3.4 to about 3.8. In various embodiments, the ratio ofpaclitaxel
`
`or derivative thereof to albumin is at least about 1 :5, at least about J:4, at least about I :2, at
`
`25
`
`least about 1: I, or at least about 2:1. In various embodiments, the serum albumin is
`
`defatted, undefatted or a mixture of defatted and undefatted fonns. In various
`
`embodiments, the serum albumin is mammalian, preferably human. In various
`
`embodimcnts, the serum albumin is at least about 50%, at least about 60%, at least about
`
`70%, at least about 80%, or at lea"t about 90% monomeric. In various embodiments, at
`
`30
`
`least about 70%, at least about 80%, at least about 85%, or at least about 90% ofthe
`
`paclitaxel or derivative thereof is bound to albumin. In another embodiment, the
`
`composition is lyophilized. In another embodiment, the composition is reconstituted trom a
`
`,
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`lyophili.zed formu lation. In various embodiments, the concentration ofpaclitaxel is greater
`
`than about 25 ~gJml, greater than about 50 ~glm l, greater than about I 00 ~g/ml, greater
`
`than about 200 Ilg/ml, grealer than about 300 flg/ml, greater than about 400 Ilglm1 , or
`
`greater than about 500 f.lg/ml. In another embodiment, the composition is coated onto an
`
`5
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`implantable device such as a stent or wrap. In some embodiments, the device is catheter(cid:173)
`
`based and/or used in conj unction with surgery. In some embodiments, the coating prevenrs
`
`rcstenosis, local tumor growth or tissue over-growth and/or chronic inflammation.
`
`The composition is characterized by having optical clarity for a length of time
`
`sufficient to administer to a patient or to process further (e.g., subject to drying). In another
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`10
`
`embodiment, the composition is optionally dried and stored as a dried "storage-stable"
`
`composition. The dried preparation oCthe composition is resolubilized prior to
`
`administration. In a preferred embodiment, the drying process is lyophilization. In one
`
`embodiment , the composition prior to drying comprises McIlvaine buffer. In another
`
`embodiment, the lyophilized preparation of the composition is optionally reconstituted with
`
`15
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`a physiologically acceptable vehicle, such as McIlvaine buffer, water, a sugar solution such
`
`as dextrose or glucosc, or ccrtain saline solutions. including dilutions ofsalinc. The
`
`reconstituted compositions can be essentially free of solvent, which can be removed in the
`
`lyophilization step. The resolubilized composition can be 2- 10 times more concentrated
`
`than the original pharmaceutically acceptable composition, depcnding on the concentration
`
`20
`
`of pac lit axel in the pre- lyophili7.ed composition. Thus, the invention encompasses a
`
`resolubilized composition wh ich is optically clear for at least 8 hours after reconstitution.
`
`Thc composition comprises less than 10% organic solvent and has a pH of about 3.0 to
`
`about 4.8 upon reconstitution, at least about 70% ofthc paclitaxcl introduced into the
`
`composition is bound to the serum albumin, and the paclitaxei concentration in the
`
`25
`
`composition is at least SO ~gJml. The invention further cneompasses methods of
`
`administration of the reconstitutcd composition whcrein a therapeutically cffeetive amount
`
`ofpacJitaxel can be administered as a I to 3 hour (or greater) injcction or as a bolus.
`
`In another embodiment, the invention encompasses a method of treatment,
`
`comprising administering to a patient a therapeutically effective amount of an optically
`
`30
`
`clear, pharmaceutically acceptable aqueous compo!!ition comprising paclitaxel or a
`
`derivative thereof, serum albumin and a pharmaceutically acceptable vehicle, as described
`
`above. The indication to be treated with the composition can include any indication known
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`in the art to be treatable wilh paclitaxel, including, but not limited to, cancer. Preferably,
`
`the cancer afleet~ ce lls of the bladder, blood, bone, brain , breast, cervix, colon, epithelium,
`
`digestive tract , head/neck, kidneys, liver, lung, mouth , ovaries, pancreas, prostate gland ,
`
`skin. stomach, testicles, or tongue. The indi cation can also include, but is not limited to,
`
`5
`
`paclitaxcl~trcatablc indications such as Alzheimer's disease, kidney disease, peripheral
`
`neuropathy, psoriasis, restenosis, rheumatoid arthritis, systemic lupus erythematosus,
`
`surgical adhesions, or tissue overgrowth after surgery. Preferably, the patient is a mammaL
`
`More preferably, the mammal is a human.
`
`The composition and methods of use thereof can optionatly umher comprise an
`
`10
`
`additional biologically active ingredient, including but not limited to those known to
`
`function synergistically with paclitaxcL In various embodiments, the additional agent
`
`includes, but is not limited to, G~CSF (granulocyte colony-stimulating factor) , GM-CSF
`
`(granulocyte macrophage colony-stimulating factor), IL-4 (interleukin4), IGF-I, analide
`
`derivatives, antiarthrities (e.g., an angiogenesis inhibitor), antibodie~ specific to cancer
`
`15
`
`cells, anlineopla."ti es (e.g., carboplatin, cyclophosphamide, estram u~ine phosphate, and
`
`etoposide), doxorubicin, immunosu ppressants (e.g., eisplatin and cyclophosphamide),
`
`steroidal and non-steroidal hormone (e.g., cortisone), transduction inhibitors, and vitamins
`
`(e.g. , vitamin C). The composition can fu rther comprise low concentrations of cxcipients
`
`such as polyethy lene glycol, detergents, organic solvents, or organic or inorganic acids.
`
`20
`
`In another embodiment, the invention encompasses a method of making an optically
`
`clear, pharmaceuti cally acceptable aqueous composition comprising pacli taxc1 or a
`
`derivative thereof, serum albwnin and a phannaceutically acceptable vehicle, as described
`
`above, comprising the steps of preparing a solution of the paclitaxel or a derivative thereof,
`
`preparing a solution of serum albumin, and slowly combining the solutions. Due to stable
`
`25
`
`binding of Ptx to serum albumin, the rate of addition of lhe Ptx solution to the albumin
`
`solution can be decreased to assist in more optimal loading of PIx onto albumin. The
`
`paclitaxcl solution can, for example, be added dropwise at a controlled rate; this rate can
`
`be, for example, at about 0.1 to 10 mUmin, e.g., I mllmin or slower, and the drop size can
`
`be 8 to 20 fll. In various embodiments, the ratio ofpacIitaxcl or derivative thereof to
`
`)0
`
`albumin is al least about I: I or al least about 2: I , and the solutions are combined at a
`
`temperature below room lemperature, about 2°C to 8°C, or about 4°C. In various
`
`embodiments, the ratio ofpaclitaxel or derivative thereof to album in is at least about 1 :5, at
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`10
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`least about 1:4, at least about 1 :2, at least about 1: I, or at least about 2:1. It is anticipated
`that ratios of J: I and possibly even 4:1 can be achieved according to the invcntion
`
`dc.~crihed hcrcin , by controlling the rate of addition of the paelitaxel to the albumin solution
`
`to a degree that does not interfere with continued stability during p rocessing.
`
`5
`
`Preferably the paclitaxel is "optimally concentrated." This lenn means that the
`
`pac1itax