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`©Wright,JeremyC.;Burgess,DianeJ.,Jan29,2012,LongActingInjectionsandImplantsSpringer,
`
`
`
`Jeremy C. Wright - Diane J. Burgess
`Editors
`
`Long Acting Injections
`and Implants
`
`@ Springer
`
`AstraZeneca Exhibit 2157 p. 1
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`Editors
`
`Jeremy C. Wright
`DURECT Corporation
`Cupertino, CA, USA
`jeremy.wright@durect.com
`
`Diane J. Burgess
`Department of Pharmaceutical Sciences
`School of Pharmacy
`University of Connecticut
`Storrs, CT, USA
`d .burgess @ uconn.edu
`
`ISSN 2192-6204
`ISBN 978-1—4614—0553-5
`DOI 10.1007/978—1-4614—0554-2
`
`e-ISBN 978-1-4614-0554-2
`
`Springer New York Dordrecht Heidelberg London
`
`Library of Congress Control Number: 2011937763
`
`© Controlled Release Society, 2012
`All rights reserved. This work may not be translated or copied in whole or in part without the written
`permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York,
`NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in
`connection with any form of information storage and retrieval, electronic adaptation, computer software,
`or by similar or dissimilar methodology now known or hereafter developed is forbidden.
`The use in this publication of trade names, trademarks, service marks, and similar terms, even if they
`are not identified as such, is not to be taken as an expression of opinion as to whether or not they are
`subject to proprietary rights.
`
`Printed on acid—free paper
`
`Springer is part of Springer Science+Business Media (www.springer.com)
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`©Wright,JeremyC.;Burgess,DianeJ.,Jan29,2012,LongActingInjectionsandImplantsSpringer,
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`

`

`Contents
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`11
`
`An Introduction to Long Acting Injections and Implants ............... ..
`Diane J. Burgess and Jeremy C. Wright
`
`Historical Overview of Long Acting Injections and Implants ......... ..
`Jeremy C. Wright and Allan S. Hoffman
`
`Host Response to Long Acting Injections and Implants .................. ..
`James M. Anderson
`
`Anatomy and Physiology of the Injection Site:
`Implications for Extended Release Parenteral Systems ................... ..
`Arlene McDowell and Natalie J. Medlicott
`
`Drugs for Long Acting Injections and Implants ............................... ..
`Jie Shen and Diane J. Burgess
`
`Diseases and Clinical Applications that Can Benefit
`from Long Lasting Implants and Injections ...................................... ..
`Roshan James, Udaya S. Toti, Sangarnesh G. Kumbar,
`and Cato T. Laurencin
`
`Oily (Lipophilic) Solutions and Suspensions ..................................... ..
`Susan W. Larsen, Mette A. Thing, and Claus Larsen
`
`Aqueous Suspensions ........................................................................... ..
`Susan M. Machkovech and Todd P. Foster
`
`In Situ Forming Systems (Depots) ...................................................... ..
`Jeremy C. Wright, Michael Sekar, William van Osdol,
`Huey Ching Su, and Andrew R. Miksztal
`
`Microsphere Technologies ................................................................... ..
`Yan Wang and Diane J. Burgess
`
`Liposomes as Carriers for Controlled Drug Delivery ...................... ..
`Xiaoming Xu and Diane J. Burgess
`
`1
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`11
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`25
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`57
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`73
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`93
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`113
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`137
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`153
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`167
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`195
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`xi
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`

`xii
`
`Contents
`
`12 Micro- and Nanoemulsions (Controlled Release Parenteral
`Drug Delivery Systems) ....................................................................... ..
`Jacqueline M. Morais and Diane J. Burgess
`
`13 Nanosuspensions .................................................................................. ..
`Sumit Kumar and Diane J. Burgess
`
`14 PEGylated Pharmaceutical Nanocarriers ......................................... ..
`Vladimir Torchilin
`
`15 Protein PEGylation .............................................................................. ..
`Francesco M. Veronese and Gianfranco Pasut
`
`16 Self-Assembling Lipid Formulations .................................................. ..
`Fredrik Tiberg, Markus Johnsson, Catalin Nistor,
`and Fredrik Joabsson
`
`17
`
`Implantable Drug Delivery Systems Based
`on the Principles of Osmosis ............................................................... ..
`John A. Culwell, Jose R. Gadea, Clarisa E. Peer,
`
`and Jeremy C. Wright
`
`18 Microtechnologies for Drug Delivery ................................................. ..
`Kristy M. Ainslie and Tejal A. Desai
`
`19 Drug-Eluting Stents ............................................................................. ..
`Jonathon Zhao and Lori Alquier
`
`20 Delivery of Peptides and Proteins via Long Acting
`Injections and Implants ....................................................................... ..
`Cynthia L. Stevenson, Christopher A. Rhodes,
`and Steven J. Prestrelski
`
`21
`
`Injectable PLGA Systems for Delivery of Vaccine Antigens ............ ..
`Vesna Milacic, Brittany Agius Bailey, Derek O’Hagan,
`and Steven P. Schwendeman
`
`22 Methods of Sterilization for Controlled Release Injectable
`and Implantable Preparations ............................................................ ..
`Alpaslan Yaman
`
`23
`
`In Vitro Drug Release Testing and In Vivo/In Vitro
`Correlation for Long Acting Implants and Injections ...................... ..
`Michail Kastellorizios and Diane J. Burgess
`
`24 Regulatory Issues and Challenges Associated
`with the Development of Performance Specifications
`for Modified Release Parenteral Products ......................................... ..
`
`Marilyn N. Martinez and Mansoor A. Khan
`
`221
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`239
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`263
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`295
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`315
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`335
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`359
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`383
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`409
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`429
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`459
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`475
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`505
`
`Index .............................................................................................................. ..
`
`537
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`©Wright,JeremyC.;Burgess,DianeJ.,Jan29,2012,LongActingInjectionsandImplantsSpringer,
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`©Wright,JeremyC.;Burgess,DianeJ.,Jan29,2012,LongActingInjectionsandImplantsSpringer,
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`Chapter 4
`Anatomy and Physiology of the Injection Site:
`Implications for Extended Release Parenteral
`Systems
`
`Arlene McDowell and Natalie J. Medlicott
`
`Abstract Understanding how the biological environment contributes to drug
`release following administration is increasingly becoming a focus for drug delivery
`research. Achieving therapeutic levels of a bioactive relies on appropriate drug
`release following parenteral administration that must be complimentary to subse—
`quent drug absorption, distribution, metabolism and elimination. The biological
`characteristics of the injection site can have an influence on the drug absorption
`process. In this chapter the intravenous, intramuscular and subcutaneous routes for
`parenteral administration of extended release products will be discussed.
`
`4.1
`
`Introduction
`
`There are many extended and controlled release injectable systems used to deliver
`drugs in human and veterinary medicine [1—5]. These systems are prepared from a
`variety of biocompatible materials and aim to release drug for an extended period
`following injection or implantation. Drug release is governed by the design of the
`dosage form, although the biological environment often influences drug release
`[6—9]. Understanding how the biological environment contributes to drug release
`following administration is increasingly becoming a focus for drug delivery research.
`Extended release parenteral delivery systems range from relatively simple aque-
`ous suspensions that prolong drug release due to slow dissolution at the injection
`site to more sophisticated in situ gelling implants and polymeric biodegradable
`microparticulate systems [4, 10, 11]. For example, long acting intramuscular aque—
`ous suspensions of penicillin have been available since the 1950s [12] and oily
`
`A. McDowell - N.J. Medlicott (8)
`School of Pharmacy, University of Otago, PO. Box 56, Dunedin 9054, New Zealand
`e-mail: natalie.medlicott@otago.ac.nz
`
`J.C. Wright and DJ. Burgess (edsi), Long Acting Injections and Implants,
`Advances in Delivery Science and Technology, DOI 10.1007/978-14614-0554-2_4,
`© Controlled Release Society, 2012
`
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`58
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`A. McDowell and NJ. Medlicott
`
`.
`inJeCtlonl.
`Implantation site
`depm
`
`
`
`Implant
`
`or
`depot
`
`
`release
`
`free
`
`drug in
`
`tissue
`
`
`
`
`
`:
`:
`E
`
`E
`
`E
`E
`:
`:
`l
`
`metabolites
`
`degraded drug
`
`I
`:
`l
`
`l
`
`E
`:
`E
`;
`l
`
`bound drug
`(tissue or
`protein)
`
`‘
`
`to systemic
`circulation
`
`
`
`absorption
`
`lg
`
`
`.
`Blood or lymphatic
`
`
`l\dug in
` protein
`
`distribution
`
`plasma /
`
`bound drug
`
`metabolism
`and
`elimination
`
`Fig. 4.1 Schematic showing pharmacokinetics for a drug administered as an extended release
`intramuscular or subcutaneous system
`
`formulations of neuroleptic drugs since the 1970s [13]. More recently, sustained
`release microparticulate polymeric formulations of leuprolide have been developed
`for prostate cancer [1, 14, 15]. For all implanted extended release delivery systems,
`balancing the in vivo drug release from the delivery system with drug absorption,
`distribution, metabolism and elimination processes is key to achieving target drug
`levels in the body (Fig. 4.1). Hence, careful consideration of drug pharmacokinetics
`and knowledge of target plasma and tissue drug concentrations can guide the devel-
`opment of extended and controlled release parenteral drug delivery systems. One
`useful way to categorize parenteral delivery systems has been suggested by
`Washington et al. for intramuscular injections [16]. According to this, injectable
`delivery systems can be divided into those in which the pharrnacokinetics are
`predominately controlled by the implant (or device) and those controlled by the
`process of absorption into blood or lymphatic capillaries at the implant site (i.e.
`perfusion limited pharmacokinetics), as shown in Fig. 4.2. If drug release from the
`device is slow and drug absorption from the tissue is fast, then a situation results
`where the appearance of drug in the blood is closely controlled by the release char-
`acteristics of the extended release device (Type I). At the other extreme, an aqueous
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`4 Anatomy and Physiology of the Injection Site...
`
`59
`
`ka
`drug in
`1"
`Device
`or depot —') tissue _’ Type 1: kr < ka : device-limited PK
`
`kl”
`
`drug in
`
`ka
`
`—> tissue —) Type 2: kr > ka:perfUS10n-llmlted PK
`
`'
`
`_
`
`_
`
`Fig. 4.2 Pharmacokinetic (PK) classification of intramuscular implantable delivery systems.
`Modified from Washington et al. [16]
`
`Imflar
`
`Epidemis
`Dennis
`
`Muscle
`
`Subcutaneous tissue
`
`Fig. 4.3 Potential sites for injection of extended release parenteral dosage forms
`
`solution of a water—soluble drug provides its dose immediately following injection
`and in this case, the absorption processes (k3) may limit the appearance of drug in
`the blood (Type H). Many extended release parenteral delivery systems fall between
`these two extremes so it is important to consider the biological processes at injec—
`tion sites that contribute to drug absorption. A further example of extended release
`systems are those designed to deliver drugs locally at the implantation site. For
`these local delivery systems, a balance between drug release and drug absorption
`that maintains a constant local drug concentration may be the goal. The previous
`chapter has shown that while implantable extended release systems must be bio—
`compatible, they cannot be considered biologically inert because the patient will
`react to the presence of the implant.
`The aims of this Chapter are to review the anatomy and physiology of injection
`sites (intravenous, intramuscular and subcutaneous — Fig. 4.3) and to summarize the
`biological variables that affect drug release and absorption at these sites.
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`A. McDowell and NJ. Medlicott
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`4.2
`
`Intravenous Route
`
`The intravenous route of administration for injectable products provides direct
`access into the blood stream and so therapeutic agents delivered by this route are
`available immediately in the systemic circulation. The plasma concentration is
`determined by the initial dose injected, the drug distribution and rates of metabo-
`lism and elimination according to Eqs. (4.1) and (4.2) for first-order elimination
`kinetics.
`
`
`Dose
`C0 = V ,
`
`C, = C0 x e‘“,
`
`(4.1)
`
`(4.2)
`
`where: C0=initial plasma concentration, V= volume of distribution, Ctzplasma
`concentration at time t and k: first—order elimination rate constant.
`
`Controlled drug release can be achieved using the intravenous route when par-
`ticulate systems such as liposomes or polymeric nanoparticles are used [2, 17, 18].
`The prolonged effect of these dosage forms is primarily attributed to the time taken
`for the bioactive to be released from the circulating particles. Properties of nanopar-
`ticles such as: method of preparation, method of drug association (e.g., encapsulated
`or surface-adsorbed) and the type of polymer used can be manipulated to alter the
`drug release profile and the in vivo fate of the drug. For example, nanoparticles that
`have the drug dispersed uniformly throughout a matrix generally release drug in a
`first-order process controlled by diffusion and polymer degradation [19].
`Nanoparticulate systems administered by the intravenous route can also be used to
`facilitate drug targeting to specific tissues and cell types. Active targeting can be
`achieved through surface modifications, such as conjugation of ligands, e.g., biotin
`to poly(D,L—1actide-co-glycolide) nanoparticles to deliver paclitaxel to tumors [20].
`Restrictions are placed on the size of particulates that can be injected into the
`circulatory system so that controlled release systems designed for intravenous use
`are typically within colloidal range with diameters less than 500 nm [21]. With
`increasing research into particulate delivery systems, understanding of the tissue
`distribution of colloidal particles following administration into the blood has
`advanced. Moghimi et al. [22], in a review of long-circulating and target-specific
`nanoparticles, reported that passive tissue distribution patterns of intravenously
`administered particles depended on size and defonnability of the particles as well as
`their surface chemistry. Slack et a1.
`[23] showed polystyrene-divinylbenzene
`microparticles with diameters 7.4 and 11.6 um were deposited mainly in the lungs,
`while particles with diameter 3.4 pm deposited in the liver and spleen following
`intravenous administration. Smaller nanoparticles (less than 150 nm) appear to be
`distributed more widely than larger colloids with particles seen in the liver, spleen,
`bone marrow, bone, heart, kidney and stomach [21, 24, 25]. At tumor sites and sites
`of tissue inflammation, the spaces between endothelial cells lining blood capillaries
`are enlarged so that correctly sized nanoparticles can escape the vasculature into
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`4 Anatomy and Physiology of the Injection Site...
`
`61
`
`underlying tissue in these sites [25—27]. This mechanism is exploited in the target-
`ing of cytotoxic drugs to tumors [28, 29] or anti-inflammatory drugs to sites of
`tissue inflammation [27]. Tumors at different sites of the body, however, appear to
`have different levels of microvasculature porosity, which may affect the accumula-
`tion of particulate delivery systems [25]. Pore sizes ranging from 200 nm to 1.2 pm
`were reported with experimental subcutaneous tumors, but lower pore size (less
`than 500 nm) was reported in brain tumors. The microvascular pore size also varied
`depending on the tumor cell line [25]. At even smaller sizes, particles may be elimi-
`nated from the body by filtration through the kidney. Choi et al. suggested that
`particles less than 5 nm diameter were freely filtered in the kidneys, while those
`with diameter greater than 5 nm were retained in the body [30]. This suggests that
`there is also a lower particle size limit (5 nm) as well as the higher one (500 nm) for
`particulate systems administered via the intravenous route.
`
`4.3
`
`Intramuscular Route
`
`The intramuscular site is reached by injection through the hypodemris into the
`underlying skeletal muscle. The structure of musculature is such that vasculature
`extends into the muscle and each muscle fiber is surrounded by a number of capil-
`laries lying parallel to each fiber with transverse vessels between muscle fibers [31].
`Thus, muscle tissue is typically highly perfused with blood for the delivery of
`oxygen and nutrients to muscle cells and for the removal of waste material and so
`can be utilized for the systemic delivery of therapeutics. Extracellular fluid in skel-
`etal muscle is reported to have a pH of 7.1 at rest but decreases with exercise to 6.8
`due to lactate accumulation [32].1 This slightly acidic pH may influence release and
`absorption properties of weakly acidic or basic drugs. Lymphatic vessels are also
`present within the connective tissue that surrounds the muscle fibers and bundles;
`however, the lymph system is more extensive in the subcutaneous site compared to
`the intramuscular site [33]. Drug characteristics that promote absorption into the
`lymphatic system are discussed later.
`The most common muscles into which injections are made in humans are the
`gluteus maximus, vastus lateralis and deltoid. Blood flow in these muscles is reported
`to be fastest in the deltoid, and slowest in the gluteus maxirnus giving rise to potential
`differences in drug absorption rates at different sites of administration [34].
`Differences in muscle perfusion can be expected to have the greatest effect on drug
`absorption when uptake into injection site capillaries is the rate-limiting step in drug
`absorption. For example, more rapid absorption of diazepam from injections into the
`deltoid muscle compared with the vastus lateralis has been reported [35]. Additionally,
`when muscle perfusion is the rate—limiting step for drug absorption, activities that
`increase local blood flow such as exercise, and local muscle massage may be expected
`to increase the rate of drug absorption following intramuscular injection [36].
`Increased absorption has been reported for both intramuscular administration of
`
`1pH can also be lowered by the foreign body reaction to implants (see Chap. 3).
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`62
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`A. McDowell and NJ. Medlicott
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`b01o01
`
`.0 01
`
`
`
`Relativespreadingofradioactivity
`
`0
`
`4
`
`8
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`12
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`16
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`20
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`24
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`28
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`Time (h)
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`Fig. 4.4 Graph of the spread following intramuscular injection of hydrophilic radioactive markers
`into thigh muscle of rabbit. Spreading is represented as relative to aprotinin encapsulated in an
`emulsion with 60% w/w aqueous phase. (Open circle) 30% w/w aqueous phase emulsion contain-
`ing aprotinin; open inverted triangle 60% w/w aqueous phase emulsion containing aprotinin;
`(Filled cirrle)30% w/w aqueous phase emulsion containing radioactive pertechnetate; (filled
`inverted triangle) 60% w/w aqueous phase emulsion containing radioactive pertechnetate; (filled
`diamond) solution of aprotinin in PBS administered intramuscularly. Figure with permission from
`Bjerregaard et a1. [39]
`
`penicillin and diazepam with exercise [37]. However, when drug release from the
`depot is slow, then the effects of increased muscle perfusion may not be great. Soni
`et al. showed no significant effects of injection site, massage or muscle activity on
`plasma levels from a depot injection of fluphenazine decanoate [38]. Muscle activity
`may also have an effect on the surface area available for drug release for low to inter-
`mediate viscosity systems as exercise could affect the spreadability of the extended
`release depot within the muscle tissue. For example, absorption of the protein apro—
`tinin [39] was found to be greater from formulations with a lower viscosity that
`spread more extensively within the muscle compared to the formulations with higher
`viscosity, 30% and 60% w/w emulsions, respectively (Fig. 4.4).
`The amount of fat associated with the muscle can also modulate absorption from
`intramuscular injections and has been given as an explanation for the slower rate of
`drug absorption following injection into the gluteus maximus in females compared
`to males [40]. Cockshott et a]. have shown that injections intended for intramuscular
`administration into the gluteal muscle may not reach the muscle and may indeed
`be made most of the time into the fat surrounding the muscle [41]. Their study of
`63 men and 60 women indicated that at any given weight, the skin to muscle dis-
`tance in the gluteal region was approximately 2.5 cm greater in women than in men.
`If a standard 3.5 cm length needle was used, then under 5% of women would receive
`
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`4 Anatomy and Physiology of the Injection Site...
`
`63
`
`the intramuscular injection at the desired depth of at least 0.5 cm into the muscle
`[41]. Hence, the reported slower absorption following intramuscular injection into
`the gluteus maximus site may be due to injection into fat overlying the muscle rather
`than muscle itself.
`
`4.4 Subcutaneous Route
`
`The subcutaneous tissue or hypoderrnis is situated directly below the dermis layer
`of the skin and exterior to the muscle layer [16]. The characteristic feature of this
`site is the storage of dietary adipose within loose connective tissue in the interstitial
`space [16]. The interstitial space comprises a collagen network embedded in a gel
`of glycosaminoglycans, salts and proteins [42] and has a pH of 7.3 [43]. The acces-
`sibility of the subcutaneous site and relative ease of injection with short, fine needles
`contribute to its popularity for self—administration of medications such as insulin.
`Implants, particulates or in situ gelling systems can sit comfortably within the
`connective tissue of the subcutaneous site and release drug that is then absorbed
`into surrounding blood or lymph capillaries.
`Extended release injections containing contraceptive hormones have been in use
`since the late 1960s, initially with intramuscular Depo Provera®, a long acting
`aqueous suspension of medroxyprogesterone acetate administered once every three
`months [44] and more recently a lower dose subcutaneous form, depo—subQ Provera
`[45]. The duration of effective contraceptive action was further extended with the
`introduction of levonorgestrel containing polydimethylsiloxane implants. The first
`of these were the Norplant® implants of the 19805, which gave slow release over
`5 years following subcutaneous administration. Six rod shaped implants were
`needed for treatment with Norplant, and re-design of this product allowed the
`number of implants to be reduced to two [46]. More recently a single rod implant
`for subcutaneous administration has been developed incorporating etonogestrel in
`ethylene vinyl acetate (ImplanonTM) to provide contraceptive effects over a period
`of three years [47].
`Blood perfusion in the subcutaneous tissue is recognized to be lower than in the
`intramuscular site, which translates into comparatively slower absorption, lower
`maximum plasma concentrations and longer times to maximum plasma concentra—
`tion as illustrated for the antibiotic cefotaxime in sheep (Fig. 4.5). A further delay
`in the appearance of drug within the systemic circulation results if drug is absorbed
`into subcutaneous lymphatic capillaries because time is required for the drug to
`transverse the lymphatic system and enter the blood circulation. The lymphatic
`system has unidirectional flow and maintains interstitial pressure through the col-
`lection of fluid and proteins from the interstitial fluid through a series of draining
`lymph nodes and is eventually returned to systemic circulation [49]. Lymph capil-
`laries are more permeable than blood capillaries because they are lined with a single
`layer of endothelial cells that have an incomplete basal layer and lack coherent tight
`junctions between adjacent endothelial cells [42]. The composition of protein in the
`lymph is similar to that in blood plasma and lymph flow rate is 100—500 times
`
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`(ug/mL)
`PlasmaConcentration
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`0
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`l
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`2
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`3
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`4
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`5
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`Time (hours)
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`Fig. 4.5 Comparative plasma concentrations following injection of an aqueous solution cefo—
`taxime (50 mg/kg) via the (filled circle) intramuscular and (open circle) subcutaneous routes in
`sheep. Data with permission from Guerrini et a1. [48]
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`slower than the flow in blood vessels [49]. The importance of the lymphatic system
`for absorption of drugs is increasingly recognized for large molecular weight pro-
`tein drugs that do not partition well into blood capillaries [50]. Small drug mole-
`cules (<1 kDa) are predominantly absorbed into blood capillaries as their small size
`means they can partition relatively easily across the capillary endothelium and their
`diffusion through the interstitial fluid is not restricted [51, 52]. For larger peptide
`and protein compounds, absorption into blood vessels is limited primarily by their
`poor permeability across the capillary endothelial cell wall due to their large size.
`Consequently, these remain in the extracellular fluid until taken up by the lymphatic
`system. Porter and Charman have shown that the fraction of a dose absorbed into the
`lymphatic system is directly proportional to molecular weight [50]. Compounds
`with a molecular weight greater than 30 kD have been shown to be predominantly
`absorbed from into the lymphatic capillaries [52]. Colloidal particles may also be
`absorbed into the lymphatic system, with an optimal size for uptake reported to be
`10—100 nm [49] and larger particles taking longer to be absorbed [53]. Whilst
`absorption into the lymphatic vessels appears not to be selective, the rate of
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`AstraZeneca Exhibit 2157 p. 12
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`4 Anatomy and Physiology of the Injection Site...
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`65
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`diffusion of the solute through the extracellular matrix of the interstitial fluid is
`determined by size, charge and hydrophilicity of the drug and so will influence
`lymphatic uptake [49, 50].
`The spread of formulations within the subcutaneous tissue is another potentially
`important variable affecting in vivo drug release as it will have an effect on the
`available surface area across which drug can escape from the delivery system. The
`influence of depot spreadability on drug absorption can be demonstrated by the
`effects of co—administration of formulations with the enzyme hyaluronidase. This
`enzyme degrades hyaluronic acid within the subcutaneous interstitial matrix and
`basement membrane, reducing the resistance to flow of injected material through
`the subcutaneous tissue [54]. Bookbinder et al. [55] described the effects on sub—
`cutaneous injection spread on co—administration of a recombinant form of
`hyaluronidase with trypan blue dye. The area of spread of the trypan blue dye was
`dose dependant over 0.05—5.0 units hyaluronidase per injection and because the
`enzyme acts only on the hyaluronic acid and not the collagen network, a significant
`structural matrix still existed. This enzyme also allowed the spread of small particu—
`lates (less than 200 nm) within the subcutaneous tissue [55].
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`4.5 Effects of the Tissue Response on Extended
`Release Parenteral Systems
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`For many extended release parenteral systems, extensive in vitro characterization is
`carried out and understanding of the effects of formulation and processing variables on
`the release characteristics are determined. In vitro release methods to study the release
`of drugs from extended release parenteral delivery systems make only small attempts
`to simulate the in vivo environment and methods used may be categorized as: sample
`and separate, continuous flow and dialysis—based methods as recently reviewed by
`Larsen et al. [51]. These methods mimic the poorly stirred, limited fluid conditions that
`are expected in intramuscular and subcutaneous sites and little is done to account for
`the effect of the tissue inflammatory reaction on release characteristics.
`For intravenous nanoparticulate systems, protein adsorption to the particulate
`surface and uptake by the reticuloendothelial system reduce the circulation time
`within the blood. Much recent work has shown that these effects can be reduced by
`surface pegylation so that residence time of nanoparticulate systems in the circula-
`tion are now significantly extended [56]. This strategy has had wide application in
`the formulation of particulate-targeted delivery systems. Ideally, the drug remains
`within the particulate system while it is circulating in the blood, but is released
`following deposition in the target tissue (e.g. tumor). In vitro evaluation of particle
`size and retention of the drug within the nanoparticle are important studies to char-
`acterize these delivery systems prior to in vivo use. However, it is the rate of in vivo
`particle opsonization, uptake by reticuloendothelial system cells and interactions
`with microvasculature that will ultimately determine the in vivo fate and effective-
`ness of intravenously injected nanoparticles.
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`AstraZeneca Exhibit 2157 p. 13
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`NewYork,ISBN:9781461405542
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`toxic concentration
`
`
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`Plasmaconcentration
`
`
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`therapeutic range
`
`. minimum effective
`concentration
`
`Time
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`Fig. 4.6 Plasma versus time profile for an ideal controlled release delivery system
`
`Intramuscular and subcutaneous extended release systems are expected to stay at
`the administration site and release drug slowly over time to achieve constant plasma
`drug concentrations as shown in Fig. 4.6. For some systems, the biological environ-
`ment has a large influence on the in vivo release profile and understanding how drug
`release occurs in vivo may allow optimization of in vivo release profiles to achieve
`target plasma drug concentrations. The biological environment can trigger physical
`change in the injected materials such as the solution to semi—solid transformation
`occurring for in situ gelling systems ([57—60]; see also Chap. 9). For others the
`opposite occurs and a solid material may be implanted, which hydrates to form a
`semi-solid depot at the injection site [61, 62]. In situ gelling implant materials tran—
`sition from liquid to solid in response to environmental changes such as temperature
`changes, e.g., poloxamer gels [63, 64], or loss of organic solvent into surrounding
`tissue, e.g., polylactide—co-glycolide organic solutions [65—67]. The tissue reaction
`at the implantation site can additionally influence the in vivo performance and may
`be involved in drug release. Kempe et al. described the in vivo solidification process
`for PLGA implants from n-methyl-2—pyrrolidone solutions as a two—stage process
`involving firstly surface solidification to form a shell over about 30 min, followed
`by a slower process of complete solidification over 24 h [67]. In the first stage of
`solidification they reported about 75% of the polymer precipitated. As well as alter-
`ing the physical form of the implanted material, the biological environment may
`affect drug release and implant degradation and erosion rates. An early example was
`reported by Olanoff et al. for a tetracycline containing methacrylate tri-laminate
`film system [68, 69]. These films released tetracycline with a zero-order profile in
`both in vitro studies [69] and following subcutaneous implantation in rats [68]. The
`tissue response 1—2 weeks after implantation was described as mild inflammatory
`with tissue oedema, loose granulation tissue and the beginning of fibrous capsule
`formation. The fibrous capsule developed further ove