`
`3DownloadedfrominformahealthearecombyMeGillUniversityon01/15/1For
`
`personaluseonly
`
`
`
`
`
`
`
`186
`
`VOLUME 7: FORMULATION AND PACKAGING
`
`commercializing new delivery modalities. It is therefore reasonable to expect that incremental
`improvementsin existing technologies will continue to dominate the near-term future of depot
`delivery. These improvements may include new manufacturing process techniques, new
`approachesto sterilization, novel packaging technologies, and novel combinations of existing
`technologies. Recent examples of these include the emerging use of supercritical fluid
`technologies to make polymeric microspheres (169), evaluation of electron-beam and ethylene
`oxide as methodsof sterilization (170), increasing use of delivery devices, such as the Lupron
`Depot-PED™ dual-chamber syringe, to enhance convenience during administration, and the
`integration of acid-neutralizing excipients in PLGA formulations to counteract acidification by
`hydrolysis products (44). Further value may be extracted from these technologies if leads are
`optimized during discovery specifically for sustained release, emphasizing potency and
`stability as key criteria.
`
`Introduction of New Excipients
`The acceptability of materials for parenteral use, from both the safety and regulatory points of
`view, continues to be a major constraint
`in the development of new depot delivery
`technologies. The hurdles to introduction of new excipients are significant, and few companies
`are willing to invest the significant time and money required to bring new or novel-use
`excipients through developmentto the market. PLGA enjoys the status of being a proven and
`well-accepted excipient, and continues to be the most common polymer used in parenteral
`sustained-release systems, further entrenching it
`in this application. Although PLGA is
`attractive in many respects, new polymeric materials are needed to provide a wider range of
`properties and potential release profiles, and to enhance the range of actives compatible with
`sustained-release approaches. In the short term,
`the most promising new candidates for
`approval are likely to be copolymers of currently-approved materials, such as copolymers of
`PLA and PEG, which can be expected to degrade to known materials. Longer-term, one
`approach to speed the introduction of new excipients could be the formation of jointly-funded
`industrial consortia, to advance the preclinical evaluation of novel materials.
`
`Enhanced Control over Drug Release
`Despite their many advances over the years, marketed depot delivery systems continueto offer
`a relatively limited ability to control release rate, relying on the intrinsic properties of the
`formulation (e.g., matrix degradation, AP] dissolution or partition, osmotic pressure, etc.) to
`govern drug release. The ability to rationally change drug release during dosing would
`represent a major step forward, and continues to comprise anactive area ofscientific inquiry.
`The ultimate goal is responsive systems, or smart delivery systems, which incorporate the
`ability to sense their surroundings and alter their function in response to specific signals
`generated in the body (171). Such systems will be particularly valuable in the treatment of
`diabetes and other metabolic disorders, and may also be useful in chronotherapy (172,173).
`Several approaches have been evaluated in the pursuit of
`this goal,
`including
`environmentally responsive polymers and microprocessor-based devices. Novel polymers
`have been synthesized, which are capable of changing their properties in response to changes
`in their environment,
`including pH,
`temperature,
`ionic strength, solvent composition or
`electromagnetic radiation (174 178). These include the pH-sensitive methacrylates, which
`changein their degree of swelling as pH changes, and temperature-sensitive systems such as
`poly (N-isopropylacrylamide) (174). Microelectromechanical solutions include an electro-
`thermally activated implantable silicon chip, under development by MicroCHIPsS (179). The
`device is segmented into multiple wells, which can be sealed prior to implantation and
`then opened on demand. Depot delivery systems of the future will likely include integrated
`sensing of biomarkers, metabolites, or actives, feedback-control over drug release, and real-
`time output of information relating to the underlying pathology and treatment (168).
`
`New Applications
`A numberof new applications for depot delivery are emerging, including targeted delivery,
`gene delivery, and tissue engineering. Fabrication of nanoparticles from PLGA offers a new
`platform for targeted delivery, amenable to IV administration (180). These systems are being
`
`Regeneron Exhibit 1015.201
`
`

`

`FORMULATION OF DEPOT DELIVERY SYSTEMS
`
`187
`
`developed and studied for the targeted delivery of a range of therapeutics, from small
`molecules to nucleic acids. Nucleic acid delivery via sustained-release systems is an
`increasingly active field of research given the recent advent of RNAi technology and continued
`interest in local gene delivery (181,182). Tissue engineering and regenerative medicine strategies
`often require controlled delivery of bioactive molecules, with particular sensitivity to spatial and
`temporal control of release (183), to a particular cell type or in a particular region of the body
`(184). There are many potent growth factors including nerve growth factor, bone morphogenic
`protein and vascular endothelial growth factor, which are underinvestigation (185). Approaches
`for regenerating nerve tissues, repairing bone defects from fractures, infections and cancers, and
`the ability to accelerate blood vessel formation are all areas of active research. The field of
`parenteral sustained release promises to be an exciting and active area of research for many years
`to come, offering the potential to significantly increase the value of both existing and new
`therapeutics and address important unmet medical needs.
`
`UW&Gh
`
`REFERENCES
`. Amylin Company Website.
`. Merriam Webster's Medical Dictionary. Vol. 2008.
`. Chien YW. Long acting parenteral drug formulations. J Parenter Sci Technol 1981; 35:106 139.
`. Langer R. Biodegradable polymers for drug delivery to the brain. ASAIO Trans 1988; 34:945 946.
`. Cole BJ, Schumacher HR Jr. Injectable corticosteroids in modern practice. J Am Acad Orthop Surg
`2005; 13:37 46.
`. Hughes DA. Estimation of the impact of noncompliance on pharmacokinetics: an analysis of the
`influence of dosing regimens. Br J Clin Pharmacol 2008; 65:871 878.
`- Pandarakalam JP. The long acting depot antipsychotic drugs. Hosp Med 2003; 64:603 608.
`8. Jann MW, Ereshefsky L, Saklad SR. Clinical pharmacokinetics of the depot antipsychotics. Clin
`Pharmacokinet 1985; 10:315 333.
`9. Shi Y, Li LC. Current advances in sustained release systems for parenteral drug delivery. Expert
`Opin Drug Deliv 2005; 2:1039 1058.
`10. Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol 2000;
`161:73 88.
`11. Kulkarni RK, Moore EG, Hegyeli AF, et al. Biodegradable polv(lactic acid) polymers. J Biomed Mater
`Res 1971; 5:169 181.
`12. Strickley RG. Parenteral formulations of small molecules therapeutics marketed in the United States
`(1999) Part 1. PDA J Pharm Sci Technol 1999; 53:324 349.
`13. Riffkin C, Huber R, Keysser CH. Castor oil as a vehicle for parenteral administration of steroid
`hormones. | Pharm Sci 1964; 53:891 895.
`14. Floyd AG,Jain S. Injectable emulsions and suspensions. In: Lieberman HA, Rieger MM, Banker GS,
`eds. Pharmaceutical Dosage Forms: Disperse Systems. Vol. 2. New York: Marcel Dekker, 1996:261 285.
`15. Chien YW. Novel Drug Delivery Systems. Drugs and the Pharmaceutical Sciences. Vol. 50. New
`York: Marcel Dekker, 1992.
`16. Wang Y. Parenteral products of peptides and proteins. In: Avis KE, Lieberman HA, Lachman L, ed.
`Pharmaceutical Dosage Forms, Parenteral Medications. New York: Marcel Dekker, 1992:283 320.
`17. Akers MJ, Fites AL, Robison RL. Formulation design and development of parenteral suspensions.J
`Parenter Sci Technol 1987; 41:88 96.
`18. Nail SL, Stickelmeyer MP. Coarse suspensions: design and manufacturing. In: Burgess DJ, ed.
`Injectable Dispersed Systems: Formulation, Processing, and Performance. Vol. 149. Boca Raton:
`Taylor & Francis Group, 2005:177 212.
`19. Liang Y, Hilal N, Langston P, et al. Interaction forces between colloidal particles in liquid: theory and
`experiment. Adv Colloid Interface Sci 2007; 134 135:151 166.
`20. Feldman S. Physicochemical factors influencing drug absorption from the intramuscular injection
`site. Bull Parenter Drug Assoc 1974; 28:53 63.
`21. Hirano K, Ichihashi T, Yamada H. Studies on the absorption of practically water insoluble drugs
`following injection. I]. Intramuscular absorption from aqueous suspensions in rats. Chem Pharm
`Bull (Tokyo) 1981; 29:817 827.
`22. Brittain HG. Effects of mechanical processing on phase composition. J PharmSei 2002; 91:1573 1580.
`23. Lee RW. Case study: development and scale up of NanoCrystal(R) particles. In: Burgess DJ, ed.
`Injectable Dispersed Systems: Formulation, Processing, and Performance. Vol. 149. Boca Raton:
`Taylor & Francis Group, 2005:355 370.
`24. Ober SS, Vincent HC, Simon DE, et al. A rheological study of procaine penicillin G depot
`preparations. } Am Pharm Assoc Am Pharm Assoc (Baltim) 1958; 47:667 676.
`
`a ~
`
`]
`
`Regeneron Exhibit 1015.202
`
`
`
`3DownloadedfrominformahealthearecombyMcGillUniversityon01/15/1For
`
`personaluseonly
`
`
`
`
`
`
`
`

`

`
`
`
`
`useonly
`
`
`
`3DownloadedfrominformahealthearecombyMeGillUniversityon01/15/1Forpersonal
`
`188
`
`VOLUME 1: FORMULATION AND PACKAGING
`
`25.
`
`26.
`
`27.
`
`29.
`
`Buckwalter FH, Dickison HL. The effect of vehicle and particle size on the absorption, by the
`intramuscular route, of procaine penicillin G suspensions. J Am Pharm Assoc Am Pharm Assoc
`(Baltim) 1958; 47:661 666.
`Miller LG, Fincher JH. Influence of drug particle size after intramuscular dosage of phenobarbital to
`dogs. J Pharm Sci 1971; 60:1733 1736.
`Brown WE, Wilder VM, Schwartz P. A study of oils used for intramuscular injections. J Lab Clin
`Med 1944; 29:259.
`. Murdan 5S, Florence AT. Non aqueous solutions and suspensions as sustained release injectable
`formulations.
`In: Senior J, ed. Sustained Release Injectable Products. Boca Raton:
`Informa
`HealthCare, 2000:71 108.
`Hirano K, Ichihashi T, Yamada H. Studies on the absorption of practically water insoluble drugs
`following injection. I. Intramuscular absorption from water immiscible oil solutions in rats. Chem
`Pharm Bull (Tokyo) 1981; 29:519 531.
`. Kulkarni RK, Pani KC, Neuman C,et al. Polylactic acid for surgical implants. Arch Surg 1966;
`93:839 843.
`. Cutright DE, Beasley JD 3rd, Perez B. Histologic comparison of polylactic and polyglycolic acid
`sutures. Oral Surg Oral Med Oral Pathol 1971; 32:165 173.
`route of elimination, and
`. Brady JM, Cutright DE, Miller RA, et al. Resorption rate, route,
`ultrastructure of the implant site of polylactic acid in the abdominal wall of the rat. ] Biomed Mater
`Res 1973; 7:155 166.
`. Boswell G, Seribner, R. Polylactide drug mixtures. U.S. patent 3773919. DuPont, 1973.
`. Yamamoto M, Okada H, OgawaY,et al. Polymer, production and use thereof. U.S. patent office,
`Takeda Chemical Industries, Ltd., 1989.
`. Tice T. Delivering with depot formulations. Drug Deliv Technol 2004; 4.
`. Jain RA. The manufacturing techniques of various drug loaded biodegradable poly(lactide
`co glycolide) (PLGA) devices. Biomaterials 2000; 21:2475 2490.
`. Omelczuk MO, McGinity JW. The influence of polymer glass transition temperature and molecular
`weight on drug release fromtablets containing poly(DL lactic acid). Pharm Res 1992; 9:26 32.
`. Okada H. One and three month release injectable microspheres of the LH RH superagonist
`leuprorelin acetate. Adv Drug Deliv Rev 1997; 28:43 70.
`Cohen S, Alonso MJ, Langer R. Novel approaches to controlled release antigen delivery.
`Technol Assess Health Care 1994; 10:121 130.
`In: Wise DL, ed.
`Wu X. Synthesis and properties of biodegradable lactic/glycolic acid polymers.
`Encyclopedic Handbookof Biomaterials and Bioengineering. New York: Marcel Dekker, 1995:1015 1054.
`Jalil R, Nixon JR. Biodegradable poly(lactic acid) and poly(lactide co glycolide) microcapsules:
`problems associated with preparative techniques and release properties.
`] Microencapsul 1990;
`7297 325,
`
`39.
`
`40.
`
`41.
`
`Int J
`
`42.
`
`43.
`
`46.
`
`47.
`
`48.
`
`49.
`
`Makino K, Ohshima H, Kondo T. Mechanism of hydrolytic degradation of poly(L lactide)
`microcapsules: effects of pH, ionic strength and buffer concentration. ] Microencapsul 1986; 3:203 212.
`Park TG. Degradation of poly(lactic ca glycolic acid) microspheres: effect of copolymer composition.
`Biomaterials 1995; 16:1123 1130.
`. LiL, SchwendemanSP. Mapping neutral microclimate pH in PLGA microspheres. J Control Release
`2005; 101:163 173.
`. Ding AG, Schwendeman SP. Determination of water soluble acid distribution in poly(lactide
`co glycolide). J PharmSci 2004; 93:322 331.
`Schakenraad JM, Hardonk MJ,Feijen J, et al. Enzymatic activity toward poly(L lactic acid) implants.
`] Biomed Mater Res 1990; 24:529 545.
`Anderson JM, Shive M5. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv
`Drug Deliv Rev 1997; 28:5 24.
`Tice T, Tabibi SE. Parenteral drug delivery: injectables. In: Kydonieus A, ed. Treatise on Controlled
`Drug Delivery. New York: Marcel Dekker, 1992:315 339.
`Beck L, Cowsar, DR, Lewis, DH. Systemic and local delivery of contraceptive steroids using
`biodegradable microspheres. In: Hafez E, Van Os WAA,eds. Biodegradables and Delivery Systems
`for Contraception. Vol. 1. MTP Press Limited, 1980:63 82.
`. Tice T, Lewis, DH, Dunn, RL, et al. Biodegradation of microspheres and biomedical devices
`prepared with resorbable polyesters, 9th International Symposium on Controlled Release of
`Bioactive Materials, 1982. The Controlled Release Society, Inc.
`. Varde NK, Pack DW. Microspheres for controlled release drug delivery. Expert Opin Biol Ther 2004;
`4:35 51.
`
`. Tice T, Tabibi ES. Parenteral drug delivery: injectables. In: Kydonieus A, ed. Treatise on Controlled
`Drug Delivery: Fundamentals, Optimization, Applications. New York: Marcel Dekker, 1991:315 339.
`
`Regeneron Exhibit 1015.203
`
`

`

`
`
`3DownloadedtrominformahealthearecombyMeGillUniversityon01/15/1For
`
`personaluseonly
`
`
`
`
`
`
`
`FORMULATION OF DEPOT DELIVERY SYSTEMS
`
`189
`
`53.
`
`54.
`
`55.
`
`56.
`
`57,
`
`s
`
`6l.
`
`62.
`
`63.
`
`Lewis D. Controlled release of bioactive agents from lactide/glycolide polymers. In: Chasin M, Langer
`R, ed. Biodegradable Polymers as Drug Delivery Systems. New York: Marcel Dekker, 1990:1 41.
`Wu X. Preparation, characterization, and drug delivery applicaitons of microspheres based on
`biodegradable lactic/glycolic acid polymers.
`In: Wise DL, ed. Encyclopedic Handbook of
`Biomaterials and Bioengineering. New York: Marcel Dekker, 1995:1151 1200.
`Fong J. Microencapsulation by solvent evaporation and organic phase separation process. In: Hsieh D,
`ed. Controlled Release Systems: Fabrication Technology. Vol. 1. Boca Raton: CRC Press, 1988:81 108.
`Vrancken M, Claeys DA. Process for encapsulating water and compounds in aqueous phase by
`evaporation. U.S. patent office, 1970.
`Wang J, Schwendeman SP. Mechanisms of solvent evaporation encapsulation processes: prediction
`of solvent evaporation rate. J Pharm Sci 1999; 88:1090 1099.
`. Vrancken M, Claeys DA. Process for encapsulating water and compounds in aqueous phase by
`extraction. U.S. patent office, 1970.
`. Albayrak C. Induced phase transition method for the production of microparticles containing
`hydrophobic active agents. US 6899898. USA, 2005.
`. Arshady R. Preparation of biodegradable microspheres and microcapsules: 2. Polylactides and
`related polyesters. J Control Release 1991; 17:1 22.
`Wischke C, Schwendeman SP. Principles of encapsulating hydrophobic drugs in PLA/PLGA
`microparticles. Int J Pharm 2008.
`Wang SH, Zhang LC,LinF, et al. Controlled release of levonorgestrel from biodegradable poly(D,
`Llactide co glycolide) microspheres: in vitro and in vivo studies. Int J Pharm 2005; 301:217 225.
`Birnbaum DT, Kosmala JD, Henthorn DB, et al. Controlled release of beta estradiol from PLAGA
`microparticles: the effect of organic phase solvent on encapsulation and release. J] Control Release
`2000; 65:375 387.
`. Kino 5, Osajima, T, Minuta, H. Sustained release microsphere preparation containing antipsychotic
`drug and production process thereof. US patent office. USA, 1997.
`Shenderova A, Burke TG, Schwendeman 5P. Stabilization of 10 hydroxycamptothecin in poly
`(lactide co glycolide) microsphere delivery vehicles. Pharm Res 1997; 14:1406 1414.
`. Cong H, Beck LR. Preparation and pharmacokinetic evaluation of a modified long acting injectable
`norethisterone microsphere. Adv Contracept 1991; 7:251 256.
`Alpar H, Conway, BR, Bowen, JC. The effects of formulation of PLA microspheres on immune
`responses: an in vivo study. International Symposium on Controlled Release Bioactive Materials,
`1995, 22.
`. Alonso MJ, Gupta RK, Min C, et al. Biodegradable microspheres as controlled release tetanus toxoid
`delivery systems. Vaccine 1994; 12:299 306.
`. Cohen S, Yoshioka T, Lucarelli M, et al. Controlled delivery systems for proteins based on poly
`(lactic/ glycolic acid) microspheres, Pharm Res 1991; 8:713 720.
`Conway B, Alpar, HO, Lewis, DA. Studies on the optimisation of loading and release kinetics of
`interferon gamma from polylactide microspheres. International Symposium on Controlled Release
`of Bioactive Materials, 1994, 21.
`Singh M, Singh O, Talwar GP. Biodegradable delivery system for a birth control vaccine:
`immunogenicity studies in rats and monkeys. Pharm Res 1995; 12:1796 1800.
`Edelman R, Russell RG, Losonsky G, et al. Immunization of rabbits with enterotoxigenic E. coli
`colonization factor antigen (CFA/JI) encapsulated in biodegradable microspheres of poly (lactide
`co glycolide). Vaccine 1993; 11:155 158.
`Wagenaar BW, Muller BW. Piroxicam release from spray dried biodegradable microspheres.
`Biomaterials 1994; 15:49 54,
`Takada 5, Uda Y, Toguchi H, Ogawa Y. Application of a spray drying technique in the production of
`TRHcontaining injectable sustained release microparticles of biodegradable polymers. PDA J
`Pharm Sci Technol 1995; 49:180 184.
`NykampG, Carstensen U, Muller BW. Jet milling a new technique for microparticle preparation. Int
`J Pharm2002; 242:79 86.
`Tipton A, Dunn, RL.Insitu gelling systems. In: Senior J, ed. Sustained Release Injectable Products.
`Boca Rota: Interpharm Press, 2000:241 278.
`. Packhaeuser CB, Schnieders J, Oster CG, et al. In situ forming parenteral drug delivery systems: an
`overview. Eur J Pharm Biopharm 2004; 58:445 455.
`78.
`Sartor O. Eligard: leuprolide acetate in a novel sustained release delivery system. Urology 2003;
`61:25 31.
`
`65.
`
`67.
`
`70.
`
`71.
`
`72.
`
`73.
`
`74.
`
`75.
`
`76.
`
`79.
`
`Zentner GM, Rathi R, Shih C, et al. Biodegradable block copolymers for delivery of proteins and
`water insoluble drugs. J Control Release 2001; 72:203 215.
`
`Regeneron Exhibit 1015.204
`
`

`

`
`
`
`
`useonly
`
`
`
`3DownloadedfrominformahealthearecombyMeGillUniversityon01/15/1Forpersonal
`
`190
`
`VOLUME 1: FORMULATION AND PACKAGING
`
`81.
`
`82.
`
`83.
`
`85.
`
`87.
`
`89.
`
`91,
`
`92.
`
`93.
`
`94.
`
`. Pasut GGA, Veronese FM. Protein, peptide and non peptide drug PEGylation for therapeutic
`application. Expert Opin Ther. Patents 2004; 14:859 894.
`Basu SK, Govardhan CP, Jung CW,et al. Protein crystals for the delivery of biopharmaceuticals.
`Expert Opin Biol Ther 2004; 4:301 317.
`Tamilvanan 5, Venkatesh Babu R, Kannan K,et al. Manufacturing techniques and excipients used
`during the design of biodegradable polymer based microspheres containing therapeutic peptide /
`protein for parenteral controlled drug delivery. PDA J Pharm Sci Technol 2008; 62:125 154.
`Lai MC, Topp EM. Solid state chemical stability of proteins and peptides. J Pharm Sci 1999; 88:
`489 500.
`. van de Weert M, Hennink WE, Jiskoot W. Protein instability in poly(lactic co glycolic acid)
`microparticles. Pharm Res 2000; 17:1159 1167.
`Perez C, Castellanos IJ, Costantino HR, et al. Recent trends in stabilizing protein structure upon
`encapsulation and release from bioerodible polymers. J] Pharm Pharmacol 2002; 54:301 313.
`. Jones AJ, Putney S, Johnson OL, et al. Recombinant human growth hormone poly(lactic co glycolic
`acid) microsphere formulation development. Adv Drug Deliv Rev 1997; 28:71 84.
`Johnson OL, Jaworowicz W, Cleland JL, et al. The stabilization and encapsulation of human growth
`hormone into biodegradable microspheres. Pharm Res 1997; 14:730 735.
`. Herbert P, Murphy K, Johnson O,et al. A large scale process to produce microencapsulated proteins.
`Pharm Res 1998; 15:357 361.
`Gombotz W, Healy M, Brown L. Very low temperaturecasting of controlled release microspheres. U.
`S. patent office. Vol. 5019400, Enzytech, Inc., Cambrige, 1991.
`. Tay B, Zhang, SX, Myint, MH,et al. Processing of polycaprolactone porous structure for scaffold
`development. J Mater Process Technol 2007; 182:117 121.
`Sinha VR, Bansal K, Kaushik R, et al. Poly epsilon caprolactone microspheres and nanospheres: an
`overview. Int J Pharm 2004; 278:1 23.
`Shenoy DB, D'Souza RJ, Tiwari SB,et al. Potential applications of polymeric microsphere suspension
`as subcutaneous depotfor insulin. Drug Dev Ind Pharm 2003; 29:555 563.
`Martini LG, Collett JH, Attwood D. The release of 5 fluorouracil from microspheres of poly(epsilon
`caprolactone co ethylene oxide). Drug Dev Ind Pharm2000; 26:7 12.
`Zhou $, Deng X, Yang H. Biodegradable poly(epsilon caprolactone) poly(ethylene glycol) block
`copolymers: characterization and their use as drug carriers for a controlled delivery system.
`Biomaterials 2003; 24:3563 3570.
`. Dong CM, Guo YZ, Qiu KY, et al. In vitro degradation and controlled release behavior of D,
`L PLGA50 and PCL b D,L PLGA50 copolymer microspheres. J] Control Release 2005; 107:53 64.
`. Zhao Z, Wang J, Mao HQ,et al. Polyphosphoesters in drug and gene delivery. Adv Drug Deliv Rev
`2003; 55:483 499,
`. Harper E, Dang W, Lapidus RG, et al. Enhanced efficacy of a novel controlled release paclitaxel
`formulation (PACLIMERdelivery system) for local regional therapy of lung cancer tumor nodules
`in mice. Clin Cancer Res 1999; 5:4242 4248.
`Xu X, Yu H, Gao 5,et al. Polyphosphoester microspheres for sustained release of biologically active
`nerve growth factor. Biomaterials 2002; 23:3765 3772.
`. Wang J, Mao HQ, Leong KW. A novel biodegradable gene carrier based on polyphosphoester. ] Am
`Chem Soc 2001; 123:9480 9481.
`100.
`Jain JP, Modi $, DombAJ,et al. Role of polyanhydridesas localized drugcarriers. J Control Release
`2005; 103:541 563.
`Kumar N, Langer RS, Domb AJ. Polyanhydrides: an overview. Adv Drug Deliv Rev 2002; 54:
`889 910.
`Jain JP, Chitkara D, Kumar N. Polyanhydrides as localized drug delivery carrier: an update. Expert
`Opin Drug Deliv 2008; 5:889 907.
`Heller J, Barr J. Biochronomer technology. Expert Opin Drug Deliv 2005; 2:169 183.
`Rothen Weinhold A, Schwach Abdellaoui K, Barr J, et al. Release of BSA from poly(ortho ester)
`extruded thin strands. J] Control Release 2001; 71:31 37.
`Ng SY, Shen HR, Lopez E, et al. Development of a poly(ortho ester) prototype with a latent acid in
`the polymer backbone for 5 fluorouracil delivery. ] Control Release 2000; 65:367 374.
`Deng J5, Li L, Tian Y, et al. In vitro characterization of polyorthoester microparticles containing
`bupivacaine. Pharm Dev Technol 2003; 8:31 38.
`Fournier E, Passirani C, Colin N, et al. Development of novel 5 FU loaded poly(methylidene
`malonate 2.1.2) based microspheres for the treatment of brain cancers. Eur J Pharm Biopharm2004;
`57:189 197.
`
`98.
`
`101.
`
`102.
`
`103.
`104.
`
`105.
`
`106.
`
`107.
`
`108.
`
`Bai X, Yang, YY, Chung, TS,et al. Effect of Polymer Compositions onthe fabrication of poly(ortho ester)
`microspheres for controlled release of protein. J Appl PolymSci 2001; 80:1630 1642.
`
`Regeneron Exhibit 1015.205
`
`

`

`
`
`3DownloadedfrominformahealthearecombyMcGillUniversityon01/15/1For
`
`personaluseonly
`
`
`
`
`
`
`
`FORMULATION OF DEPOT DELIVERY SYSTEMS
`
`191
`
`109.
`
`110.
`
`111.
`
`whee
`
`113.
`
`114.
`
`115.
`
`116.
`
`LL.
`
`118.
`119.
`
`120.
`
`121.
`‘122.
`123.
`124.
`
`125.
`
`Yang YY, Wan JP, Chung TS, et al. POE PEG POEtriblock copolymeric microspheres containing
`protein. I. Preparation and characterization. J Control Release 2001; 75:115 128.
`Jansen JA, de Ruijter JE, Janssen PT, et al. Histological evaluation of a biodegradable Polyactive/
`hydroxyapatite membrane. Biomaterials 1995; 16:819 827.
`Deschamps A, Grijpma, DW, Geijen,
`J. Poly(ethylene oxide)/poly(butylenes terephthalate)
`segmented block copolymers:
`the effect of copolymer composition on physical properties and
`degradation behavior. Polymer 2001; 42:9335 9345.
`De Groot CJ, Van Luyn MJ, Van Dijk Wolthuis WN, et al. In vitro biocompatibility of biodegradable
`dextran based hydrogels tested with human fibroblasts. Biomaterials 2001; 22:1197 1203.
`Cadee JA, van Luyn MJ, Brouwer LA,et al. In vivo biocompatibility of dextran based hydrogels.
`J Biomed Mater Res 2000; 50:397 404.
`Stenekes RJ, Franssen O, van Bommel EM,et al. The use of aqueous PEG/ dextran phase separation
`for the preparation of dextran microspheres. Int J Pharm 1999; 183:29 32.
`Franssen O, Vandervennet L, Roders P, et al. Degradable dextran hydrogels: controlled release of a
`model protein from cylinders and microspheres. J Control Release 1999; 60:211 221.
`Cadee JA, de Groot CJ, Jiskoot W, et al. Release of recombinant humaninterleukin 2 from dextran
`based hydrogels. J Control Release 2002; 78:1 13.
`Constancis A, Meyrueix R, Bryson N, et al. Macromolecular colloids of diblock poly(amino acids)
`that bind insulin. J Colloid Interface Sci 1999; 217:357 368.
`Flamel Technologies webpage.
`Koch M, Steidle C, Brosman 5, et al. An openlabel study of abarelix in men with symptomatic
`prostate cancerat risk of treatment with LHRH agonists. Urology 2003; 62:877 882.
`Gefter M, Barker N, Musso G, et al. Pharmaceutical formulations for sustained drug delivery. U.S.
`patent and trademark office (US 6180608 B1). Praecis Pharmaceuticals, Inc., 2001.
`Praecis home page (http://www.praecis.com).
`Baxter BioPharma Solutions home page. Available at: http:/ /www-.baxterbiopharmasolutions.com.
`Durect home page. Available at: http://www-durect.com.
`Okumu FW, Dao le N, Fielder PJ, et al. Sustained delivery of human growth hormone froma novel
`gel system: SABER. Biomaterials 2002; 23:4353 4358.
`Qiu B, Stefanos 5, Ma J, et al. A hydrogel prepared byin situ crass linking of a thiol containing poly
`(ethylene glycol) based copolymer: a new biomaterial for protein drug delivery. Biomaterials 2003;
`24:11 18.
`injectable neutral solutions of chitosan form
`Chenite A, Chaput C, Wang D, et al. Novel
`biodegradable gels in situ. Biomaterials 2000; 21:2155 2161.
`Ruel Gariepy E, Chenite A, Chaput C, et al. Characterization of thermosensitive chitosan gels for the
`sustained delivery of drugs. Int J Pharm 2000; 203:89 98.
`Berrada M, Serreqi A, Dabbarh F, et al. A novel non toxic camptothecin formulation for cancer
`chemotherapy. Biomaterials 2005; 26:2115 2120.
`Yong CS, Choi J5, Quan QZ,et al. Effect of sodium chloride on the gelation temperature, gel strength
`and bioadhesive force of poloxamer gels containing diclofenac sodium. Int J Pharm 2001; 226:195 205.
`Wasan KM,Subramanian R, KwongM,et al. Poloxamer 407 mediated alterations in the activities of
`enzymes regulating lipid metabolismin rats. J Pharm PharmSci 2003; 6:189 197.
`Knight CG. Hydrophobic prodrugs in liposomes.In: Knight C, ed. Liposomes: from Physical Structure
`to Therapeutic Applicaiton. New York: Elsevier/North Holland Biomedical Press, 1981:381 390.
`In:
`Oussoren C, Storm G, Crommelin DJ, el al. Liposomes for local sustained drug release.
`Oussoren C, Storm G, Crommelin DJ, et al., eds. Sustained Release Injectable Products. Boca Raton:
`Interpharm/ CRC Press, 2000:137 180.
`Pacira Pharmaceuticals home page. Available at: http: / /www.pacira.com.
`. Mantripragada 5S. A lipid based depot (DepoFoamtechnology) for sustained release drug delivery.
`Prog Lipid Res 2002; 41:392 406.
`Ye Q, Asherman J, Stevenson M, et al. DepoFoamtechnology: a vehicle for controlled delivery of
`protein and peptide drugs. J Control Release 2000; 64:155 166.
`Westesen K, Bunjes, H, Koch, MHJ. Physicochemical characterization of lipid nanoparticles and
`evaluation of their drug loading capacity and sustained release potential. J] Control Release 1997;
`48:223 236.
`
`126.
`
`127.
`
`128.
`
`129.
`
`130.
`
`131.
`
`132.
`
`133.
`
`135.
`
`136.
`
`137.
`
`138.
`
`139.
`
`Del Curto MD, Chicco D, D’Antonio M,etal. Lipid microparticles as sustained release systemfor a
`GnRH antagonist (Antide}. J Control Release 2003; 89:297 310.
`Engwicht A, Girreser U, Muller BW. Characterization of co polymers oflactic and glycolic acid for
`supercritical fluid processing. Biomaterials 2000; 21:1587 1593.
`Reithmeier H, Herrmann J, Gopferich A. Lipid microparticles as a parenteral controlled release
`device for peptides. J Control Release 2001; 73:339 350.
`
`Regeneron Exhibit 1015.206
`
`

`

`
`
`3DownloadedfrominformahealthearecombyMeGillUniversityon01/15/1For
`
`personaluseonly
`
`
`
`
`
`
`
`192
`
`VOLUME 1: FORMULATION AND PACKAGING
`
`140.
`
`141.
`
`142.
`
`143.
`
`144.
`145.
`
`146.
`
`147.
`
`148.
`
`149.
`
`150).
`151.
`
`152.
`
`153.
`
`154.
`
`155.
`
`Reithmeier H, Herrmann J, Gopferich A. Development and characterization of lipid microparticles
`as a drug carrier for somatostatin. Int J Pharm 2001; 218:133 143,
`Scholer N, Krause K, Kayser O, et al. Atovaquone nanosuspensions show excellent therapeutic effect in
`a new murine modelof reactivated toxoplasmosis. Antimicrob Agents Chemother 2001; 45:1771 1779.
`Li LC, Zhu L, Song JF, Deng JS, et al. Effect of solid state transition on the physical stability of
`suspensions containing bupivacaine lipid microparticles. Pharm Dev Technol 2005; 10:309 318.
`Papahadjopoulos D, Vail WJ, Jacobson K, et al. Cochleate lipid cylinders: formation by fusion of
`unilamellar lipid vesicles. Biochim Biophys Acta 1975; 394:483 491.
`Zarif L. Drug delivery by lipid cochleates. Methods Enzymol 2005; 391:314 329.
`intravenous
`Segarra I, Movshin DA, Zarif L. Pharmacokinetics and tissue distribution after
`administration of a single dose of amphotericin B cochleates, a new lipid based delivery system. J
`Pharm Sei 2002; 91:1827 1837.
`Zarif L, Graybill JR, Perlin D, et al. Antifungal activity of amphotericin B cochleates against Candida
`albicans infection in a mouse model. Antimicrob Agents Chemother 2000; 44:1463 1469.
`Gould Fogerite 5, Kheiri, MT, et al. Cochleate delivery vehicles: applications in vaccine delivery.
`J Liposome Res 2001; 10:339 356.
`Bracho G, Lastre M, del CampoJ, et al. Proteoliposome derived cochleate as novel adjuvant. Vaccine
`2006; 24(suppl 2):52 530 31.
`Gould Fogerite 5, Mannino, RJ. Cochleate delivery vehicles: applications to gene therapy. Drug
`Deliv Technol 2003; 3.
`Croxatto HB. Progestin implants. Steroids 2000; 65:681 685.
`Chertin B, Spitz IM, Lindenberg T, et al. An implant releasing the gonadotropin hormonereleasing
`hormone agonist histrelin maintains medical castration for up to 30 months in metastatic prostate
`cancer. J Urol 2000; 163:838 844.
`WrightJ, Chester, AE, Skowronski, RJ, et al. Long term controlled delivery of therapeutic agents via
`an implantable osmotically driven system: the DUROS implant.
`In: Rathbone M, ed. Modified
`Release Drug Delivery Technology. New York: Marcel Dekker, 2003:657 669.
`Fowler JE Jr., GottesmanJE, Reid CF, et al. Safety and efficacy of an implantable leuprolide delivery
`system in patients with advanced prostate cancer. J Urol 2000; 164:730 734.
`Burgess DJ, Hussain AS, Ingallinera TS, et al. Assuring quality and performance of sustained and
`controlled release parenterals: AAPS workshop report, co sponsored by FDA and USP. Pharm Res
`2002; 19:1761 1768.
`Burgess DJ, Crommelin DJ, Hussain AS, et al. Assuring quality and performance of sustained and
`controlled released parenterals. Eur J Pharm Sci 2004; 21:679 690.
`. D'Souza SS, DeLuca PP. Methods to assess in vitro drug release from injectable polymeric
`particulate systems. Pharm Res 2006; 23:460 474.
`D'Souza 5S, Faraj JA, DeLuca PP. A model dependent approach to correlate accelerated with real
`time release from biodegradable microspheres. AAPS PharmSciTech 2005; 6:E553 E564.
`Gido C, Langguth P, Kreuter J, et al. Conventional versus novel conditions for
`the in vitro
`dissolution testing of parenteral slow release formulations: application to doxepin parenteral dosage
`forms. Pharmazie 1993; 48:764 769.
`Iyer SS, Barr WH, Karnes HT.Profiling in vitro drug release from subcutaneous implants: a review
`of current status and potential implications on drug product development. Biopharm Drug Dispos
`2006; 27:157 170.
`Giteau A, Venier Julienne MC, Aubert Pouessel A, et al. How to achieve sustained and complete
`protein release from PLGA based microparticles? Int J Pharm 2008; 350:14 26.
`UppoorVR. Regulatory persp