I IIIII
`
`1111111111111111111111111111111111111111111111111111111111111
`US007820788B2
`
`c12) United States Patent
`Desai et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7 ,820, 788 B2
`Oct. 26, 2010
`
`(54) COMPOSITIONS AND METHODS OF
`DELIVERY OF PHARMACOLOGICAL
`AGENTS
`
`(75)
`
`Inventors: Neil P. Desai, Los Angeles, CA (US);
`Patrick Soon-Shiong, Los Angeles, CA
`(US); Vuong Trieu, Calabasas, CA (US)
`
`(73) Assignee: Abraxis Bioscience, LLC, Los Angeles,
`CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 85 days.
`
`(21) Appl. No.: 11/553,339
`
`(22) Filed:
`
`Oct. 26, 2006
`
`(65)
`
`Prior Publication Data
`
`US 2010/0226996 AI
`
`Sep. 9, 2010
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 10/731,224, filed on
`Dec. 9, 2003.
`
`(60) Provisional application No. 60/432,317, filed on Dec.
`9, 2002, provisional application No. 60/526,544, filed
`on Dec. 3, 2003, provisional application No. 60/526,
`773, filed on Dec. 4, 2003, provisional application No.
`60/527,177, filed on Dec. 5, 2003.
`
`(51)
`
`Int. Cl.
`C07K 14176
`(2006.01)
`(52) U.S. Cl. ........................ 530/350; 977/779; 977/906
`(58) Field of Classification Search ............. 514/11-12;
`435/7.2; 424/178.1; 530/350; 977/779,
`977/906
`See application file for complete search history.
`
`(56)
`
`References Cited
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`FOREIGN PATENT DOCUMENTS
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`EP
`
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`
`OTHER PUBLICATIONS
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`
`(Continued)
`
`Primary Examiner-Maryam Monshipouri
`Assistant Examiner-Marsha M Tsay
`(74) Attorney, Agent, or Firm-Morrison & Foerster, LLP
`
`(57)
`
`ABSTRACT
`
`The present invention relates to a pharmaceutical composi(cid:173)
`tion comprising a pharmaceutical agent and a pharmaceuti(cid:173)
`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(cid:173)
`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(cid:173)
`ceutical composition, and methods for enhancing transport
`and binding of a pharmaceutical agent to a cell.
`
`12 Claims, No Drawings
`
`CIPLA EXHIBIT 1001
`Page 1 of 23
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`US 7,820,788 B2
`Page 2
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`U.S. PATENT DOCUMENTS
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`Page 3 of 23
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`US 7,820,788 B2
`Page 4
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`* cited by examiner
`
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`

`US 7,820,788 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(cid:173)
`tion Ser. No. 10/731,224, which claims the benefit of U.S.
`Provisional Patent Application No. 60/432,317 filed Dec. 9,
`2002, U.S. Provisional Patent Application 60/526,544 filed
`Dec. 3, 2003, U.S. Provisional Patent Application 60/526,773
`filed Dec. 4, 2003, and U.S. Provisional Patent Application
`60/527,177 filed 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
`
`20
`
`2
`reduced pH, drug degradation, and discoloration, thereby
`destabilizing the drug formulation and/or reducing shelflife.
`To circumvent the problems associated with administra(cid:173)
`tion-related side effects of drug formulations, alternate for(cid:173)
`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
`10 oflidocaine, the addition of cyclodextrin, and microfiltration
`(see, e.g., Mayer eta!., Anaesthesist, 45(11), 1082-4 (1996),
`Davies, eta!. Anaesthesia, 57, 557-61 (2002), Doenicke, et
`a!., Anaesth. Analg., 82, 472-4 (1996), Larsen eta!., Anaes(cid:173)
`thesitis 50, 842-5 (2001 ), Lilley eta!., Anaesthesia, 51, 815-8
`15 (1996), Bielen eta!., Anesth. Anal g., 82(5), 920-4 (1996), and
`Knibbe eta!., Br. J. Clin. Pharmacal., 47(6), 653-60 (1999)).
`These formulations, however, induce other side effects (e.g.,
`cardiovascular complications), or cause destabilization 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 sulfite-containing agents, or they have been have been
`formulated with a lower pH (see, e.g., U.S. Pat. Nos. 5,714,
`25 520, 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 99/39696). Since edetate and pentetate
`are metal ion chelators, however, they have the potential to be
`dangerous by scavenging the essential metal ions from the
`30 body system. Moreover, the addition of sulphites to drug
`formulations presents potential adverse effects to the pediat(cid:173)
`ric population and for those in the general population who are
`allergic to sulphur.
`Thus, there remains a need for a composition and method
`35 that reduce or eliminate the side effects associated with the
`parenteral or in vivo administration of drugs. There also is a
`need for a pharmaceutical composition that is sterile, and
`methods of preparing such a composition. In addition, there is
`a need for a pharmaceutical composition and method that
`reduce or eliminate oxidation of pharmaceutical formulations
`to prevent drug destabilization.
`The invention provides such compositions and methods.
`These and other advantages of the invention, as well as addi(cid:173)
`tional inventive features, will be apparent from the descrip-
`45 tion of the invention provided herein.
`
`It is well recognized that many drugs for parenteral use,
`especially those administered intravenously, cause undesir(cid:173)
`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(cid:173)
`lizing agents, surfactants, solvents, and/or emulsifiers that are
`irritating, allergenic, or toxic when administered to patients
`(see, e.g., Briggs et a!., Anesthesis 37, 1099 (1982), and
`Waugh eta!., Am. J. Hasp. 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 first-line che- 40
`motherapy for advanced non-small cell lung carcinoma. (see,
`e.g., Vallejo eta!., Am. J. Clin. Oneal., 19(6), 584-8 (1996)).
`Moreover, vancomycin has been shown to induce side effects
`such as phlebitis (see, e.g., Lopes Rocha eta!., Braz. J. Infect.
`Dis., 6( 4), 196-200 (2002)). The use of cisplatin, gemcitab(cid:173)
`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 a!., J. Clin. Oneal., 20(6), 1657-67
`(2002) ). In addition, propofol, an anesthetic agent, can induce
`pain on injection, burning and vein irritation, particularly 50
`when administered as a lecithin-stabilized fat emulsion (see,
`e.g, Tan eta!., Anathesia, 53, 468-76, (1998)). Other drugs
`that exhibit administration-associated side effects include, for
`example, Taxol (paclitaxel) (see, e.g., package insert for
`Taxol I.V.), codarone (amiodarone hydrochloride) (see, e.g., 55
`package insert for Codarone I.V.), 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(cid:173)
`ance of sterility. Sterile manufacturing of drug emulsions/
`dispersions can be accomplished by absolute sterilization of
`all the components before manufacture, followed by abso(cid:173)
`lutely aseptic technique in all stages of manufacture. How(cid:173)
`ever, such methods are time consuming and expensive. In
`addition, the oxidation of drug formulations by exposure to
`air during manufacture or storage can lead to, for example,
`
`BRIEF SUMMARY OF THE INVENTION
`
`The invention provides various embodiments of pharma(cid:173)
`ceutical compositions. One, some, or all of the properties of
`the various embodiments can be found in different embodi(cid:173)
`ments of the invention and still fall within the scope of the
`appended claims.
`The invention provides a pharmaceutical composition
`comprising a pharmaceutical agent and a pharmaceutically
`acceptable carrier, wherein the pharmaceutically acceptable
`carrier comprises a protein, such as albumin, more preferably
`human serum albumin, in an amount effective to reduce one
`or more side effects of administration of the pharmaceutical
`60 composition into a human, and wherein the pharmaceutically
`acceptable carrier comprises deferoxamine in an amount
`effective to inhibit microbial growth in the pharmaceutical
`composition. The invention also provides a pharmaceutical
`composition comprising a pharmaceutical agent and a phar-
`65 maceutically acceptable carrier, wherein the pharmaceuti(cid:173)
`cally acceptable carrier comprises a protein, such as albumin,
`in an amount effective to reduce one or more side effects of
`
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`

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`US 7,820,788 B2
`
`3
`administration of the pharmaceutical composition into a
`human, and wherein the pharmaceutically acceptable carrier
`comprises deferoxamine in an amount effective to inhibit
`oxidation in the pharmaceutical composition.
`The invention provides a method for reducing one or more
`side effects associated with administration of a pharmaceuti(cid:173)
`cal composition to a human comprising (a) administering to a
`human a pharmaceutical composition comprising a pharma(cid:173)
`ceutical agent and a pharmaceutically acceptable carrier,
`wherein the pharmaceutically acceptable carrier comprises
`albumin and deferoxamine. Also provided are methods for
`inhibiting microbial growth, or for inhibiting oxidation, or for
`inhibiting microbial growth and oxidation in a pharmaceuti(cid:173)
`cal composition. These methods comprise preparing a phar(cid:173)
`maceutical composition comprising a pharmaceutical agent
`and a pharmaceutically acceptable carrier, wherein the phar(cid:173)
`maceutically acceptable carrier comprises deferoxamine in
`an amount effective for inhibiting microbial growth or in an
`amount effective for inhibiting oxidation in the pharmaceu(cid:173)
`tical composition.
`The invention also provides a method for enhancing trans(cid:173)
`port of a pharmaceutical agent to the site of an infirmity,
`which method comprises administering to a human a phar(cid:173)
`maceutical composition comprising a pharmaceutical agent
`and a pharmaceutically acceptable carrier, wherein the phar(cid:173)
`maceutically acceptable carrier comprises albumin, and
`wherein the ratio of albumin to pharmaceutical agent in the
`pharmaceutical composition is about 18:1 or less. The inven(cid:173)
`tion further provides a method for enhancing binding of a
`pharmaceutical agent to a cell in vitro or in vivo, which
`method comprises administering to said cell in vitro or in vivo
`a pharmaceutical composition comprising a pharmaceutical
`agent and a pharmaceutically acceptable carrier, wherein the
`pharmaceutically acceptable carrier comprises albumin, and
`wherein the ratio of albumin to pharmaceutical agent in the
`pharmaceutical composition is about 18:1 or less.
`The invention also provides a pharmaceutical composition
`comprising a pharmaceutical agent and a pharmaceutically
`acceptable carrier, wherein the pharmaceutically acceptable
`carrier comprises albumin in an amount effective to increase
`transport of the drug to the site of infirmity in a human, and
`wherein the ratio of albumin to pharmaceutical agent is about
`18:1 or less.
`The invention further provides a method for increasing the
`transport of a pharmaceutical agent to a cell in vitro or in vivo
`by combining said agent with a protein, wherein said protein
`binds a specific cell-surface receptor on said cell, wherein
`said binding of the protein-pharmaceutical agent combina(cid:173)
`tion with the said receptor causes the transport to occur, and
`wherein the ratio of protein to pharmaceutical agent is about
`18:1 or less.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The invention provides a pharmaceutical composition
`comprising a pharmaceutical agent and a pharmaceutically
`acceptable carrier, wherein the pharmaceutically acceptable
`carrier comprises a protein such as albumin, preferably
`human serum albumin, in an amount effective to reduce one
`or more side effects of administration of the pharmaceutical
`composition to a human, and wherein the pharmaceutically
`acceptable carrier comprises deferoxamine in an amount
`effective to inhibit microbial growth in the pharmaceutical
`composition. The invention also provides a pharmaceutical
`composition comprising a pharmaceutical agent and a phar(cid:173)
`maceutically acceptable carrier, wherein the pharmaceuti(cid:173)
`cally acceptable carrier comprises a protein such as albumin
`
`4
`in an amount effective to reduce one or more side effects of
`administration of the pharmaceutical composition to a
`human, and wherein the pharmaceutically acceptable carrier
`comprises deferoxamine in an amount effective to inhibit
`oxidation in the pharmaceutical composition.
`Any suitable pharmaceutical agent can be used in the
`inventive pharmaceutical composition. Suitable pharmaceu(cid:173)
`tical agents include, but are not limited to, anticancer agents
`or antineoplastics, antimicrotubule agents, immunosuppres-
`10 sive agents, anesthetics, hormones, agents for use in cardio(cid:173)
`vascular disorders, antiarrythmics, antibiotics, antifungals,
`antihypertensives, antiasthmatics, analgesics, anti-inflamma(cid:173)
`tory agents, anti-arthritic agents, and vasoactive agents. The
`invention is useful with many other drug classes as well. More
`15 specifically, suitable pharmaceutical agents include, but are
`not limited to, taxanes, (e.g., Taxol® (paclitaxel), and Taxo(cid:173)
`tere™ ( docetaxel)), epothilones, camptothecin, colchicine,
`amiodarone, thyroid hormones, vasoactive peptides (e.g.,
`vasoactive intestinal peptide), amphotericin, corticosteroids,
`20 propofol, melatonin, cyclosporine, rapamycin (sirolimus),
`tacrolimus, mycophenolic acids, Ifosfamide, vinorelbine,
`vancomycin, gemcitabine, SU5416, thiotepa, bleomycin,
`diagnostic radiocontrast agents, and derivatives thereof.
`Other drugs that are useful in the inventive composition are
`25 described in, for example, U.S. Pat. No. 5,916,596 and co(cid:173)
`pending U.S. patent application Ser. No. 09/446,783. Prefer(cid:173)
`ably, the pharmaceutical agent is propofol, paclitaxel, or doc(cid:173)
`etaxel. More preferably, the pharmaceutical agent is propofol
`or paclitaxel. Most preferably, the pharmaceutical agent is
`30 propofol.
`Taxol® (paclitaxel) (Bristol-Myers Squibb) is active
`against carcinomas of the ovary, breast, lung, esophagus and
`head and neck. Taxol, however, has been shown to induce
`toxicities associated with administration, as well significant
`35 acute and cumulative toxicity, such as myelosuppression,
`neutropenic fever, anaphylactic reaction, and peripheral neu(cid:173)
`ropathy. Because paclitaxel is po