(19) *EP002515942B1* (11) EP 2 515 942 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/22 (2006.01) A61K 9/127 (2006.01) (2006.01) (2006.01) 12.02.2020 Bulletin 2020/07 A61K 47/30 A61K 31/573 A61K 31/56 (2006.01) (21) Application number: 10842554.7 (86) International application number: (22) Date of filing: 15.12.2010 PCT/US2010/060564 (87) International publication number: WO 2011/084513 (14.07.2011 Gazette 2011/28) (54) THERAPEUTIC POLYMERIC NANOPARTICLE COMPOSITIONS WITH HIGH GLASS TRANSITION TEMPERATURE OR HIGH MOLECULAR WEIGHT COPOLYMERS THERAPEUTISCHE POLYMERNANOPARTIKELZUSAMMENSETZUNGEN MIT HOHER GLASÜBERGANGSTEMPERATUR ODER COPOLYMEREN VON HOHEM MOLEKULARGEWICHT COMPOSITIONS DE NANOPARTICULES POLYMÈRES À VISÉE THÉRAPEUTIQUE À BASE DE COPOLYMÈRES À TEMPÉRATURE DE TRANSITION VITREUSE ÉLEVÉE OU POIDS MOLÉCULAIRES ÉLEVÉS (84) Designated Contracting States: • TROIANO, Greg AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Pembroke GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO MA 02359 (US) PL PT RO RS SE SI SK SM TR • WRIGHT, James Designated Extension States: Lexington BA ME MA 02421 (US) • FIGUEIREDO, Maria (30) Priority: 16.12.2009 US 286897 P Somerville 22.10.2010 US 405778 P MA 02143 (US) 15.12.2009 US 286559 P • FIGA, Michael 22.02.2010 US 306729 P Allston 16.12.2009 US 286831 P MA 02134 (US) • VAN GEEN HOVEN, Tina (43) Date of publication of application: Danvers 31.10.2012 Bulletin 2012/44 MA 01923 (US) • SONG, Young-Ho (73) Proprietor: Pfizer Inc. Natick New York, NY 10017-5755 (US) MA 01760 (US) • AUER, Jason (72) Inventors: Cambridge • ALI, Mir, Mukkaram MA 02139 (US) Woburn • CAMPBELL, Tarikh, Christopher MA 01801 (US) Boston • SABNIS, Abhimanyu MA 02115 (US) Arlington MA 02474 (US) (74) Representative: Pfizer • DEWITT, David European Patent Department Allston 23-25 avenue du Docteur Lannelongue MA 02134 (US) 75668 Paris Cedex 14 (FR) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 515 942 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 515 942 B1 (56) References cited: • GREF, R. ET AL.: ’Development and WO-A2-2004/089291 WO-A2-2010/005725 chracterization of CyA-loaded poly(lactic WO-A2-2011/072218 WO-A2-2011/084521 acid)-poly(ethylene glycol)PEG micro- and US-A- 5 766 635 US-A1- 2006 034 925 nanoparticles. Comparision with conventional US-A1- 2009 306 120 PLA particluate carriers.’ EUROPEAN JOURNAL OF PHARMACEUTICS AND • MURUGESAN,S. ET AL.: ’Pegylated BIOPHARMACEUTICS. vol. 51, 2001, pages 111 - poly(lactide-co-glycolide) (PLGA) 118 nanoparticulate delievery of docetaxel: synthesis of diblock copolymers, optimization of preparation variables on formulation characteristics and in vitro release studies.’ JOURNAL OF BIOMEDICAL NANOTECHNOLOGY. vol. 3, 2007, pages 52 - 60 • OMELCZUK,M. ET AL.: ’The influence of polymer glass transition temperature and molecular weight on drug release from tablets containing poly(DL-lactic acid).’ PHARMACEUTICAL RESEARCH. vol. 9, no. 1, 1992, pages 26 - 32 2 EP 2 515 942 B1 Description BACKGROUND 5 [0001] Systems that deliver certain drugs to a patient (e.g., targeted to a particular tissue or cell type or targeted to a specific diseased tissue but not normal tissue), or that control release of drugs has long been recognized as beneficial. For example, therapeutics that include an active drug and that are capable of locating in a particular tissue or cell type e.g., a specific diseased tissue, may reduce the amount of the drug in tissues of the body that do not require treatment. This is particularly important when treating a condition such as cancer where it is desirable that a cytotoxic dose of the 10 drug is delivered to cancer cells without killing the surrounding non-cancerous tissue. Further, such therapeutics may reduce the undesirable and sometimes life threatening side effects common in anticancer therapy. For example, nano- particle therapeutics may, due the small size, evade recognition within the body allowing for targeted and controlled delivery while e.g., remaining stable for an effective amount of time. [0002] Therapeutics that offer such therapy and/or controlled release and/or targeted therapy also must be able to 15 deliver an effective amount of drug. It can be a challenge to prepare nanoparticle systems that have an appropriate amount of drug associated with each nanoparticle, while keeping the size of the nanoparticles small enough to have advantageous delivery properties. For example, while it is desirable to load a nanoparticle with a high quantity of ther- apeutic agent, nanoparticle preparations that use a drug load that is too high will result in nanoparticles that are too large for practical therapeutic use. Further, it may be desirable for therapeutic nanoparticles to remain stable so as to e.g. 20 substantially limit rapid or immediate release of the therapeutic agent. [0003] Accordingly, a need exists for new nanoparticle formulations and methods of making such nanoparticles and compositions, that can deliver therapeutic levels of drugs to treat diseases such as cancer, while also reducing patient side effects. [0004] WO-2010/005725 discloses therapeutic polymeric nanoparticles comprising vinca alkaloids. 25 [0005] WO-2011/072218 discloses lyophilised pharmaceutical compositions comprising polymeric nanoparticles which, upon reconstitution, have low levels of particles over 10 microns in size. [0006] US-2006/034925 and WO-2004/089291 both disclose a composition for delivering a tumor therapeutic agent to a patient which includes a fast-release formulation of a tumor apoptosis inducing agent, a slow-release formulation of a tumor therapeutic agent and a pharmaceutically acceptable carrier. 30 [0007] WO-2011/084521 discloses therapeutic nanoparticles comprising epothilone and a biocompatible polymer. SUMMARY [0008] Provided herein is a method for screening nanoparticle suspensions to identify a suspension having a specific 35 drug release rate, comprising: (a) separately preparing a plurality of suspensions having nanoparticles comprising a therapeutic agent, and 10 to 99 weight percent of one or more a block copolymers having at least one hydrophobic portion selected from poly(D,L- lactic) acid or poly(lactic) acid-co-poly(glycolic) acid and at least one hydrophilic portion which is a poly(ethylene)gly- 40 col, and optionally 0 to 75 weight percent of a homopolymer selected from poly(D,L-lactic) acid; wherein each suspension is in a separate compartment, each suspension comprises nanoparticles having a pre-determined mo- lecular weight of the block copolymer and if present, a pre-determined molecular weight of the homopolymer; (b) determining the glass transition temperature of the drug loaded nanoparticles in each of the suspensions; and (c) identifying the suspension having drug-loaded nanoparticles with a pre-determined glass transition temperature 45 of between 37°C to 39.5°C, 39.5°C to 41°C or 42°C to 50°C, thereby identifying a suspension with the specific drug release rate. BRIEF DESCRIPTION OF THE DRAWINGS 50 [0009] Figure 1 is a flow chart for an emulsion process for forming disclosed nanoparticles. Figure 2 is a flow diagram for a disclosed emulsion process. 55 Figure 3 is a DSC curve of poly(D,L-lactide)-block-poly(ethylene glycol) (PLA- PEG, Mn PLA block = 16 kDa; Mn PEG block = 5 kDa) when recovered from a melt polymerization and having been cooled at an unknown cooling rate. 3 EP 2 515 942 B1 Figure 4A is a DSC curve of poly(D,L-lactide)-block-poly(ethylene glycol) (PLA-PEG, Mn PLA block = 16 kDa; Mn PEG block = 5 kDa) when recovered from a precipitation of polymer solution (100 mg/mL in dichloromethane) into a binary non-solvent mixture (diethyl ether/hexane = 70/30 (v/v); Figure 4B are DSC curves showing glass transitions observed in PLA-PEG block copolymers of increasing molecular weights. PLA block number average molecular 5 weight, Mn = 10KDa (lower curve), 15KDa, 30KDa and 50KDa; Figure 4C shows the dependence of Tg on the molecular weight (Mn) of PLA in PLA-PEG block copolymers. Figure 5 is a DSC curve of poly(D,L-lactide) (PLA, Mn = 6 kDa) when recovered from a precipitation process. 10 Figure 6A depicts a DSC curve of poly(D,L-lactide) (PLA, Mn = 75 kDa) when recovered from a precipitation process; Figure 6B depicts modulated DSC curves showing the glass transition temperatures in homopolymer poly(D,L- lactide) of number average molecular weights (Mn) 1.7KDa (lower), 4.3KDa, 6KDa, 10KDa, 22KDa, and 120 KDa; Figure 6C shows the dependence of Tg on the number average molecular weight (Mn) of PLA homopolymers 15 Figure 7 is an illustration of the five points used to define the endothermic transitions observed in the DSC analysis of nanoparticles. Figure 8 is a DSC curve showing the endothermic glass transition observed in nanoparticles composed of a mixture of PLA-PEG (Mn PLA block = 16 kDa; Mn PEG block = 5 kDa) and low molecular weight PLA homopolymer (Mn = 20 6.5 kDa). Figure 9 is a DSC curve showing the endothermic glass transition observed in nanoparticles composed of PLA- PEG (Mn PLA block = 16 kDa; Mn PEG block = 5 kDa) as the only polymeric component of the particle. 25 Figure 10 is a DSC curve showing the endothermic glass transition observed in nanoparticles composed of a mixture of PLA-PEG (Mn PLA block = 16 kDa; Mn PEG block = 5 kDa) and high molecular weight PLA homopolymer (Mn = 75 kDa).