I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US008853260B2
`
`c12) United States Patent
`Desai et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,853,260 B2
`Oct. 7, 2014
`
`(54) FORMULATIONS OF PHARMACOLOGICAL
`AGENTS, METHODS FOR THE
`PREPARATION THEREOF AND METHODS
`FOR THE USE THEREOF
`
`(75)
`
`Inventors: Neil P. Desai, Santa Monica, CA (US);
`Patrick Soon-Shiong, Los Angeles, CA
`(US)
`
`(56)
`
`References Cited
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`U.S. PATENT DOCUMENTS
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`FOREIGN PATENT DOCUMENTS
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`(73) Assignee: Abraxis BioScience, LLC, Los Angeles,
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`OTHER PUBLICATIONS
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`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1070 days.
`
`(21) Appl. No.: 11/520,479
`
`(22) Filed:
`
`Sep.12,2006
`
`(65)
`
`Prior Publication Data
`
`US 2007/0093547 Al
`
`Apr. 26, 2007
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 09/446,783, filed as
`application No. PCT/US98/13272 on Jun. 26, 1998,
`and a continuation-in-part of application No.
`08/926,155, filed on Sep. 9, 1997, now Pat. No.
`6,096,331.
`
`(60) Provisional application No. 60/051,021, filed on Jun.
`27, 1997.
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`AOJN 43102
`AOJN25/00
`A61K 311335
`A61K 47100
`(52) U.S. Cl.
`USPC ........................................... 514/449; 514/776
`( 58) Field of Classification Search
`None
`See application file for complete search history.
`
`Vippagunta et al (Vippagunta et al. Crystalline solids. Advanced
`Drug Delivery Reviews. 2001;48:3-26.*
`(Continued)
`Primary Examiner - Trevor Love
`(74) Attorney, Agent, or Firm - Morrison & Foerster LLP
`ABSTRACT
`(57)
`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 is delivered in the form of
`suspended particles coated with protein (which acts as a sta(cid:173)
`bilizing agent). In particular, protein and pharmacologically
`active agent in a biocompatible dispersing medium are sub(cid:173)
`jected to high shear, in the absence of any conventional sur(cid:173)
`factants, and also in the absence of any polymeric core mate(cid:173)
`rial 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 nano(cid:173)
`particles of water-insoluble drug coated with a protein, and
`free protein to which molecules of the pharmacological agent
`are bound. This results in a unique delivery system, in which
`part of the pharmacologically active agent is readily bioavail(cid:173)
`able (in the form of molecules bound to the protein), and part
`of the agent is present within particles without any polymeric
`matrix therein.
`
`27 Claims, 4 Drawing Sheets
`
`4000~--------------7-1
`
`3500
`
`3000
`
`~ 2500
`~
`~ 2000
`~ 1500
`~
`~ 1000
`
`500
`
`12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34
`OaysPostlmplanl
`
`Actavis - IPR2017-01100, Ex. 1001, p. 1 of 42
`
`

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`acteristics and Stability of Three Novel Formulations of Paclitaxel:
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`ing_abstract/2008/ l_Annual_Meeting/ 5622?maxtoshow~&hitF
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`andorexacttitleabFand&searchid~ l&FIRSTINDEX ~O&sortspec~
`relevance&fdate~ 11l/2004&tdate~12/3 l/2009&resource-
`type~ HWCIT>, last visited on Sep. 30, 2010, 2 pages.
`Yao, J. H. et al. (Jun. 1, 1993). "Theory and Simulation of Ostwald
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`Burns, J.L. et al. ( 1997). "A Light Scattering Study of the Fractal
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`Kallay, N. et al. (2002). "Stability ofNanodispersions: A Model for
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`Schwarz, C. et al. (1997). "Freeze-Drying of Drug-Free and Drug(cid:173)
`Loaded Solid Lipid Nanoparticles (SLN)," International Journal of
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`10011099.8, filed on Jun. 26, 1998, nineteen pages.
`* cited by examiner
`
`Actavis - IPR2017-01100, Ex. 1001, p. 4 of 42
`
`

`

`U.S. Patent
`
`Oct. 7, 2014
`
`Sheet 1of4
`
`US 8,853,260 B2
`
`......
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`~
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`Actavis - IPR2017-01100, Ex. 1001, p. 5 of 42
`
`

`

`140%
`
`Paw Size Pre- & Post- Treatment
`
`FIGURE 2
`
`120%
`I
`I
`
`I I
`100%1 I
`I
`I
`80%1
`
`60%
`
`ClJ
`N
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`.2: 0
`12 ~
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`
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`
`Prednisone 0.2 mg/kg+
`Paclitaxel Nanoparticles 0.5 mg/kg
`
`~
`00
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`Pre-Arthr. Day 0
`
`Paclitaxel Nanoparticles 1.0 mg/kg
`
`Day 3
`
`Days
`
`Day8
`
`DaylO
`
`Day12
`
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`
`Day32
`
`Day49
`
`Days After Treatment
`
`d
`rJl
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`tit w
`'N
`
`0--, = = N
`
`Actavis - IPR2017-01100, Ex. 1001, p. 6 of 42
`
`

`

`U.S. Patent
`
`Oct. 7, 2014
`
`Sheet 3 of 4
`
`US 8,853,260 B2
`
`Figure 3
`
`_.,.._eapxol 5 rrglkg
`. . . . . BMS 5 n9'kg
`
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`40.00
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`£· T
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`0
`2
`3
`4
`5
`6
`7
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`9
`10
`11
`12 13 14
`Daya post-Injection
`
`Actavis - IPR2017-01100, Ex. 1001, p. 7 of 42
`
`

`

`U.S. Patent
`
`Oct. 7, 2014
`
`Sheet 4 of 4
`
`US 8,853,260 B2
`
`Figure 4
`
`Treatment initiated after s.c. tumors reach 200 mm3 or 200 mg
`Treatment days 13-17; n = 5 mice in each group
`
`.. -. -·•
`
`' \
`
`\ •
`
`>4500mg
`
`-+--Control (Saline iv)
`
`•• • •• VN-1 (20 mg/kg/dose, qd1-5, iv)
`
`10000.
`
`1000
`
`100
`
`10
`
`0.1
`
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`
`* • * • •
`+---~~--+---t---1---1-.._1----9-_
`12
`14
`16
`18
`20
`22
`24
`26
`28
`Days Postimplant
`* Treatment days
`
`30
`
`•-+-•
`
`32
`
`34
`
`Actavis - IPR2017-01100, Ex. 1001, p. 8 of 42
`
`

`

`US 8,853,260 B2
`
`1
`FORMULATIONS OF PHARMACOLOGICAL
`AGENTS, METHODS FOR THE
`PREPARATION THEREOF AND METHODS
`FOR THE USE THEREOF
`
`FIELD OF THE INVENTION
`
`2
`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 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
`10 diameter, therefore, must be avoided. A suspension of par(cid:173)
`ticles 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.
`The size of particles and their mode of delivery determines
`their biological behavior. Strand et al. (in Microspheres-Bio(cid:173)
`medical Applications, ed. A. Rembaum, pp 193-227, CRC
`Press (1988)) have described the fate of particles to be depen(cid:173)
`dent on their size. Particles in the size range of a few nanom-
`20 eters (nm) to 100 nm enter the lymphatic capillaries following
`interstitial injection, and phagocytosis may occur within the
`lymph nodes. After intravenous/intraarterial injection, par(cid:173)
`ticles less than about 2 microns will be rapidly cleared from
`the blood stream by the reticuloendothelial system (RES),
`25 also known as the mononuclear phagocyte system (MPS).
`Particles larger than about 7 microns will, after intravenous
`injection, be trapped in the lung capillaries. After intraarterial
`injection, particles are trapped in the first capillary bed
`reached. Inhaled particles are trapped by the alveolar mac-
`30 rophages.
`Pharmaceuticals that are water-insoluble or poorly water(cid:173)
`soluble and sensitive to acid environments in the stomach
`cam10t be conventionally administered (e.g., by intravenous
`injection or oral administration). The parenteral administra-
`35 tion of such pharmaceuticals has been achieved by emulsifi(cid:173)
`cation 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. These emul(cid:173)
`sions may be injected intravenously, provided the compo-
`40 nents of the emulsion are pharmacologically inert. U.S. Pat.
`No. 4,073,943 describes the administration of water-in(cid:173)
`soluble pharmacologically active agents dissolved in oils and
`emulsified with water in the presence of surfactants such as
`egg phosphatides, pluronics (copolymers of polypropylene
`45 glycol and polyethylene glycol), polyglycerol oleate, etc.
`PCT International Publication No. W085/00011 describes
`pharmaceutical microdroplets of an anaesthetic coated with a
`phospholipid such as dimyristoyl phosphatidylcholine hav(cid:173)
`ing suitable dimensions for intradermal or intravenous injec-
`50 tion.
`An example of a water-insoluble drug is Taxol®, a natural
`product first isolated from the Pacific Yew tree, Taxus brevi(cid:173)
`folia, by Wani et al. (J. Am. Chem. Soc. 93:2325 (1971)).
`Among the antimitotic agents, Taxol, which contains a diter-
`55 pene carbon skeleton, exhibits a unique mode of action on
`microtubule proteins 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 inhibit the
`60 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 in drug(cid:173)
`refractory ovarian cancer. Taxol has shown excellent antitu-
`65 mor activity in a wide variety of tumor models such as the B 16
`melanoma, L1210 leukemias, MX-1 mammary tumors, and
`CS-1 colon tumor xenografts. Several recent press releases
`
`The present invention relates to methods for the production
`of particulate vehicles for the intravenous administration of
`pharmacologically active agents, as well as novel composi(cid:173)
`tions produced thereby. In a particular aspect, 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 col(cid:173)
`loidal systems containing water insoluble pharmacologically 15
`active agents are provided. The suspended particles may be
`formed of 100% active agent, or may be encased in a poly(cid:173)
`meric shell formulated from a biocompatible polymer, and
`have a diameter of less than about 1 micron. Invention col(cid:173)
`loidal systems may be prepared without the use of conven(cid:173)
`tional surfactant or any polymeric core matrix. In a 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 biocompat(cid:173)
`ible dispersing agent in which pharmacologically active agent
`can be 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 mol(cid:173)
`ecules which are molecularly bound to a protein), and pure
`drug particles coated with a protein.
`
`FIELD OF THE INVENTION
`
`The invention also relates to the method of use and prepa(cid:173)
`ration of compositions (formulations) of drugs such as the
`anticancer agent paclitaxel. In one aspect, the formulation of
`paclitaxel, known as Capxol, is significantly less toxic and
`more efficacious than Taxol®, a commercially available for(cid:173)
`mulation of paclitaxel. In another aspect, the novel formula(cid:173)
`tion Capxol, localizes in certain tissues after parenteral
`administration thereby increasing the efficacy of treatment of
`cancers associated with such tissues.
`
`BACKGROUND OF THE INVENTION
`
`Intravenous drug delivery permits rapid and direct equili(cid:173)
`bration 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 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.
`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 offer
`several profound advantages over conventionally adminis(cid:173)
`tered medicaments, including automatic assured patient com(cid:173)
`pliance with the dose regimen, as well as drug targeting to
`specific tissues or organs (Tice and Gilley, Journal of Con(cid:173)
`trolled Release 2:343-352 (1985)).
`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 particulate
`matter contained in normal whole blood comprises red blood
`
`Actavis - IPR2017-01100, Ex. 1001, p. 9 of 42
`
`

`

`US 8,853,260 B2
`
`3
`have termed Taxol as the new anticancer wonder-drug.
`Indeed, Taxol has recently been approved by the Federal Drug
`Administration for treatment of ovarian cancer. The poor
`aqueous solubility ofTaxol, 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 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. The cremaphor cur(cid:173)
`rently 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.
`Oneal. 1990, 8, 1263-68) and consequently requires premedi(cid:173)
`cation of patients with corticosteroids ( dexamethasone) and
`antihistamines. The large dilution results in large volumes of
`infusion (typical dose 175 mg/m2
`) up to 1 liter and infusion
`times ranging from 3 hours to 24 hours. Thus, there is a need
`for an alternative less toxic formulation for paclitaxel.
`In phase I clinical trials, Taxol® itself did not show exces(cid:173)
`sive toxic effects, but severe allergic reactions were caused by
`the emulsifiers employed to solubilize the drug. The current
`regimen of administration