(12) Ulllted States Patent
`Desai et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,923,536 B2
`*Apr. 12, 2011
`
`US007923536B2
`
`(54) COMPOSITIONS AND METHODS OF
`DELIVERY OF PHARMACOLOGICAL
`AGENTS
`
`(75) Inventors: Neil P. Desai, Los Angeles, CA (US);
`Patrick Soon-Shiong, Los Angeles, CA
`ms)’ Vuong Tneu’ Calabasas’ CA (Us)
`
`-
`
`.
`
`(73) Assignee: Abraxis BioScience, LLC, Los Angeles,
`CA (US)
`
`( * ) Notice:
`
`-
`
`Subject to any disclaimer, the term of this
`patent 1s extended or adjusted under 35
`U-S-C- 154(1)) by 0 days-
`-
`-
`-
`-
`-
`T1115 Patent 15 Sublect to a tenmnal ‘115'
`Clalmer'
`
`-
`
`21 A 1.NO.Z 12/758,413
`PP
`
`(22) Filed:
`
`API._ 12, 2010
`
`(65)
`
`.
`.
`.
`Pm" Pubhcatlon Data
`
`Us 2010/0196490 A1
`
`Aug‘ 5’ 2010
`_
`_
`Related U.S. APPllCatlOIl Data
`(63) Continuation of application No. 11/553,339, ?led on
`Oct. 26, 2006, noW Pat. No. 7,820,788, Which is a
`continuation of application No. 10/731,224, ?led on
`Dec. 9, 2003, noW abandoned.
`(60) Provisional application No. 60/432,317, ?led on Dec.
`9, 2002, provisional application No. 60/526,544, ?led
`on Dec. 3, 2003, provisional application No.
`60/526,773, ?led on Dec. 4, 2003, provisional
`application No. 60/527,177, ?led on Dec. 5, 2003.
`
`(51) Int_ CL
`(2006.01)
`C07K 14/76
`(52) US. Cl. ....... .. 530/350; 977/779; 977/906; 977/911
`(58) Field of Classi?cation Search ...................... .. None
`See application ?le for complete search history.
`
`(56)
`
`Ct 01
`R f
`e erences 1 e
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`
`Primary Examiner * Suzanne M Noakes
`Assistant Examiner i Marsha M Tsay
`74 Allorn , A enl, or Firm * Morrison & Foerster LLP
`ey g
`
`ABSTRACT
`(57)
`The present invention relates to a pharmaceutical composi
`tion comprising a pharmaceutical agent and a pharmaceuti
`cally acceptable carrier, Which carrier comprises a protein, for
`example, human serum albumin and/or deferoxamine. The
`human serum albumin is present in an amount effective to
`reduce one or more side effects associated With administra
`tion of the pharmaceutical composition. The invention also
`provides methods for reducing one or more side effects of
`administration of the pharmaceutical composition, methods
`for inhibiting microbial groWth and oxidation in the pharma
`ceutical composition, and methods for enhancing transport
`and binding of a pharmaceutical agent to a cell.
`
`16 Claims, N0 Drawings
`
`CIPLA EXHIBIT 1001
`Page 1 of 24
`
`

`

`US 7,923,536 B2
`Page 2
`
`U.S. PATENT DOCUMENTS
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`US 7,923,536 B2
`
`1
`COMPOSITIONS AND METHODS OF
`DELIVERY OF PHARMACOLOGICAL
`AGENTS
`
`CROSS-REFERENCE TO RELATED PATENT
`APPLICATIONS
`
`This patent application is a continuation of patent applica
`tion Ser. No. 11/553,339, ?led Oct. 26, 2006, noW issued as
`US. Pat. No. 7,820,788; Which is a continuation of patent
`application Ser. No. 10/731,224, ?led Dec. 9, 2003; Which
`claims the bene?t of US. Provisional Patent Application Ser.
`No. 60/432,317, ?led Dec. 9, 2002; US. Provisional Patent
`Application Ser. No. 60/526,544, ?led Dec. 3, 2003; US.
`Provisional Patent Application Ser. No. 60/526,773, ?led
`Dec. 4, 2003; and US. Provisional Patent Application Ser.
`No. 60/527,177, ?led Dec. 5, 2003.
`
`FIELD OF THE INVENTION
`
`This invention pertains to pharmaceutical compositions
`comprising pharmaceutically active agents for parenteral or
`other internal use, Which have the effect of reducing certain
`undesirable side effects upon administration When compared
`With available formulations of similar drugs.
`
`BACKGROUND OF THE INVENTION
`
`It is Well recognized that many drugs for parenteral use,
`especially those administered intravenously, cause undesir
`able side effects such as venous irritation, phlebitis, burning
`and pain on injection, venous thrombosis, extravasation, and
`other administration related side effects. Many of these drugs
`are insoluble in Water, and are thus formulated With solubi
`liZing agents, surfactants, solvents, and/or emulsi?ers that are
`irritating, allergenic, or toxic When administered to patients
`(see, e.g., Briggs et al., Anesthesis 37, 1099 (1982), and
`Waugh et al., Am. J. Hosp. Pharmacists, 48, 1520 (1991)).
`Often, the free drug present in the formulation induces pain or
`irritation upon administration. For example, phlebitis Was
`observed in 50% of patients Who received peripheral vein
`administration of ifosfamide and vinorelbine as ?rst-line che
`motherapy for advanced non-small cell lung carcinoma. (see,
`e.g., Vallejo et al., Am. J Clin. Oncol., 19(6), 584-8 (1996)).
`Moreover, vancomycin has been shoWn to induce side effects
`such as phlebitis (see, e. g., Lopes Rocha et al., Braz. J Infect.
`Dis., 6(4), 196-200 (2002)). The use of cisplatin, gemcitab
`ine, and SU5416 in patients With solid tumors has resulted in
`adverse events such as deep venous thromboses and phlebitis
`(see, e.g., Kuenen et al., J. Clin. Oncol., 20(6), 1657-67
`(2002)). In addition, propofol, an anesthetic agent, can induce
`pain on injection, burning and vein irritation, particularly
`When administered as a lecithin-stabilized fat emulsion (see,
`e.g, Tan et al., Anathesia, 53, 468-76, (1998)). Other drugs
`that exhibit admini stration-as sociated side effects include, for
`example, Taxol (paclitaxel) (see, e.g., package insert for
`Taxol I.V.), codarone (amiodarone hydrochloride) (see, e.g.,
`package insert for Codarone IV), the thyroid hormone T3 or
`liothyronine (commercially available as Triostat), thiotepa,
`bleomycin, and diagnostic radiocontrast agents.
`Another problem associated With the manufacture of drugs
`for injection, particularly Water insoluble drugs, is the assur
`ance of sterility. Sterile manufacturing of drug emulsions/
`dispersions can be accomplished by absolute sterilization of
`all the components before manufacture, folloWed by abso
`lutely aseptic technique in all stages of manufacture. HoW
`ever, such methods are time consuming and expensive. In
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`addition, the oxidation of drug formulations by exposure to
`air during manufacture or storage can lead to, for example,
`reduced pH, drug degradation, and discoloration, thereby
`destabiliZing the drug formulation and/or reducing shelf life.
`To circumvent the problems associated With administra
`tion-related side effects of drug formulations, alternate for
`mulations have been attempted. With respect to propofol, for
`example, methods for reducing propofol-induced pain
`include increasing the fat content of the solvent (e.g., long
`chain triglycerides (LCT)), premedication, pretreatment With
`non-steroidal drugs, local anaesthetics, opioids, the addition
`of lidocaine, the addition of cyclodextrin, and micro?ltration
`(see, e.g., Mayer et al., Anaesthesist, 45(11), 1082-4 (1996),
`Davies, et al. Anaesthesia, 57, 557-61 (2002), Doenicke, et
`al., Anaesth. Analg, 82, 472-4 (1996), Larsen et al., Anaes
`thesitis 50, 842-5 (2001), Lilley et al., Anaesthesia, 51, 815-8
`(1996), Bielen et al., Anesth. Analg, 82(5), 920-4 (1996), and
`Knibbe et al., Br. J. Clin. Pharmacol., 47(6), 653-60 (1999)).
`These formulations, hoWever, induce other side effects (e. g.,
`cardiovascular complications), or cause destabilisation of
`propofol emulsions.
`To overcome the problem of bacterial contamination, pro
`pofol formulations have been developed With antibacterial
`agents, such as an EDTA equivalent (e. g., edetate), pentetate,
`or sul?te-containing agents, or they have been have been
`formulated With a loWer pH (see, e.g., US. Pat. Nos. 5,714,
`520, 5,731,355, 5,731,356, 6,028,108, 6,100,302, 6,147,122,
`6,177,477, 6,399,087, 6,469,069, and International Patent
`Application No. WO 99/