Intra-articular depot formulation principles: Role in the ...

Intra-Articular Depot Formulation Principles: Role in theManagement of Postoperative Pain and Arthritic Disorders

CLAUS LARSEN,1 JESPER ØSTERGAARD,1 SUSAN W. LARSEN,1 HENRIK JENSEN,1 STINE JACOBSEN,2

CASPER LINDEGAARD,2 PIA H. ANDERSEN2

1Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen,Universitetsparken 2, DK-2100 Copenhagen, Denmark

2Department of Large Animal Science, Large Animal Surgery, Faculty of Life Sciences, University of Copenhagen,Dyrlaegevej 48, DK-1870 Copenhagen, Denmark

Received 20 July 2007; revised 9 November 2007; accepted 3 January 2008

Published online 27 February 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21346

Corresponde6466; Fax: þ45-

Journal of Pharm

� 2008 Wiley-Liss

4622 JOURN

ABSTRACT: The joint cavity constitutes a discrete anatomical compartment that allowsfor local drug action after intra-articular injection. Drug delivery systems providing localprolonged drug action are warranted in the management of postoperative pain and notleastarthriticdisorderssuchasosteoarthritis.Thepresentreviewsurveysvariousthemesrelated to the accomplishment of the correct timing of the events leading to optimal drugaction in the joint space over a desired time period. This includes a brief account on(patho)physiological conditionsandnovelpotentialdrugtargets (andtheir locationwithinthe synovial space). Particular emphasis is paid to (i) the potential feasibility of variousdepot formulationprinciples fortheintra-articularrouteofadministrationincludingtheirmanufacture, drug release characteristics and in vivo fate, and (ii) how release, masstransfer and equilibrium processes may affect the intra-articular residence time andconcentrationoftheactivespeciesattheultimatereceptorsite.�2008Wiley-Liss,Inc.andthe

American Pharmacists Association J Pharm Sci 97:4622–4654, 2008

Keywords: controlled release/delivery;
distribution; drug delivery system; formula-tion; intra-articular; osteoarthritis; parenteral depot formulation; postoperative pain;rheumatoid arthritis; targeted drug delivery
INTRODUCTION

Local drug action within the joint cavity is neededfor the treatment of arthritic disorders and therelief of pain and inflammation. After oral orparenteral (i.v., i.m., s.c.) administration, thetherapeutic agent is transported to the intra-articular site of action via the systemic circula-tion. In contrast, intra-articular (IA) injectionof suitable drug delivery systems (DDSs) mayenable the major part of the incorporated drug tobe released in the vicinity of the target area. Themost obvious advantage of this relatively simple

nce to: Claus Larsen (Telephone: þ45-3533-3533-6012.; E-mail: [email protected])

aceutical Sciences, Vol. 97, 4622–4654 (2008)

, Inc. and the American Pharmacists Association

AL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 11, NO

form of targeted drug delivery is that only aminimum amount of drug is required to exertthe desired pharmacological activity and thus,minimizing drug exposure to inappropriate sites.Further, direct joint instillation may constitutethe only realistic route of administration forchemical entities suffering from bioavailabilityproblems and extensive degradation in vivo.

Literature data indicate that dissolved small-molecule drugs are rapidly cleared from thesynovial space after IA injection. Maintenanceof therapeutic drug concentrations in the jointover extended periods of time can be achieved byrepeated IA administrations or more ideally, byimmobilization of the active agent in the form ofan injectable depot formulation from which thedrug is released in a controlled manner. Cur-rently, long-lasting (weeks) corticosteroid suspen-

VEMBER 2008

Figure 1. Schematic representation of the cross sec-tion of a synovial joint (top). Insert: An enlargement ofthe synovial lining. The arrows indicate ultrafiltrationof fluid from the fenestrated capillaries into the jointcavity and drainage of fluid from the cavity throughthe synovial interstitium into subsynovial space andlymphatics. Reprinted with permission from Micro-circulation.94

INTRA-ARTICULAR DEPOT FORMULATION PRINCIPLES 4623

sions constitute the only world wide availabledepot formulation type for the IA route ofadministration. Such depot injectables have beenused for more than three decades providingsymptomatic relief of pain in rheumatoid arthritis(RA) and osteoarthritis (OA).1–3 These two majorarthritic disorders strongly affect patient qualityof life and present significant costs to society interms of medical care and lost wages. The totalannual burden to arthritis has been estimated toequal 1–2.5% of the gross national product ofWestern nations.4 Identification of novel potentialdrug targets, not least in the area of OA,5–7 givesoptimism to the development of new disease-modifying therapies. These encouraging findingspose a strong incitement to the search forinnovative depot principles feasible for the IAroute of administration.8

The search for novel therapies providing localsustained drug action after IA administration ismultidisciplinary of nature since it has to befounded on adequate knowledge of chemical,pharmaceutical as well as biological disciplines.This may involve the identification of new targetsand subsequently, drug candidates effectivelyacting on such targets. Based on the knowledgeof (patho)physiological conditions, it furtherincludes the task of accomplishing (in a highlyreproducible manner) the correct timing of theevents leading to optimal drug action over adesired period of time.9 The primary aims of thisreview are (i) to discuss advantages/limitations ofvarious depot formulation principles in relation tothe IA route of administration and (ii) to give anaccount on factors influencing the fate of drugmolecules once released from the immobilizeddepot in the joint cavity. In the present review,attempts have also been made to present majorknowledge gained in various research areas thatis considered to constitute, at least in part, thebasis for rational design of novel prolonged releaseDDSs feasible for IA administration. Due tothe rather comprehensive literature related tosome of the latter research fields, the authors havefound it appropriate, in the treatise of certaintopics, to give references to recent reviews dealingwith these topics.

SYNOVIAL JOINTS

The bones of a synovial joint are separated by anarticular cavity containing the synovial fluid (SF)(Fig. 1). The adjoining surfaces of the bones are

DOI 10.1002/jps JOURNA

covered with a layer of articular cartilage and atwo-layer joint capsule encloses the cavity. Thejoint capsule consists of an outer fibrous capsuleand an inner synovial membrane (synovium).10

The various cell types populating the articularcartilage and the synovium as well as componentsof the synovial fluid are major targets for RA andOA related drug therapies. A brief account of thecomposition and function of these sites of drugaction is given below.

The Synovium

The synovial tissue has an extensive extracellularmatrix (ECM), the major components of whichare collagen and glycosaminoglycan (GAG). Thesuperficial synovial lining (synovial membrane)contains two cell types (type A/type B cells).Cellular adhesion molecules (CAMs), includingb1 integrins, probably play important roles in

L OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 11, NOVEMBER 2008

4624 LARSEN ET AL.

synovial lining organization through cell–cell andcell–ECM interactions.11 Immediately subjacentto the surface cells, a rich capillary network isfound. Lymphatic vessels are located in thesubsynovium. The synovium carries three majorfunctions (i) it constitutes a diffusional barrier tothe transport of solutes from the SF bulk solutionto the fenestrated microvessels and the lympha-tics (and visa versa), (ii) removal of foreignmaterial or debris from the SF by phagocyticaction of the type A cells of the synovial lining and,(iii) type B cell biosynthesis of hyaluronan andlubricin. The latter synovial fibroblasts aresuggested to play a major role in both initiatingand driving RA.12,13 In the arthritic synovium,macrophages (type A cells) are key players inchemokine production. These molecules exertchemotactic activity towards synovium-invadingleukocytes.14 Features of the synovium related tomass transfer processes are discussed in moredetail in a later section.

The Synovial Fluid

The synovial fluid (SF) fills the cavity of a synovialjoint. It is a viscous, non-Newtonian fluid exhibitingthixotropic properties. The normal human adultknee joint contains on the average 2 mL SF. Underpathological conditions the volume can increaseup to several hundred milliliters. The SF is con-sidered as a plasma dialysate and the concentra-tion of endogenous low molecular weight chemicalsubstances resembles that of plasma. In contrast,albumin and other proteins are present in the SFat a significantly lower concentration due to thesieving action of the synovial capillary walls andmatrix.15 Inflammation associated changes of theSF may include (i) a decrease of SF viscosity dueto enzyme-mediated cleavage of the hyaluronanchains, and (ii) an increase of the content ofplasma derived macromolecules caused by theenhanced leakiness of the synovial capillaries.16,17

Figure 2. Schematic representation of the sites ofaction of analgesics along the pain pathway from theperiphery to the central nervous system (CNS). Re-printed with permission from The Journal of Boneand Joint Surgery, Inc., Needham, MA, USA.26

The Articular Cartilage

Articular cartilage furnishes each moving, bonyportion of a joint with a smooth, frictionlesssurface. It is capable of reversible compression,distributing an applied load homogeneously, andminimizing contact stress to the underlying bone.These unique properties can be ascribed to thecomplex architecture of the avascular ECM of thecartilage which is composed of a highly organized

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 11, NOVEMBER 20

water-filled network of type II collagen fibers andaggrecan-type proteoglycans. Structure and func-tion of many ECM components have been thesubject of several reviews.18–20 The structure andbiochemistry of mature articular cartilage aremaintained throughout life by the residentchondrocytes.10,21 Alteration of the normal bal-ance between chondrocyte anabolic and catabolicactivities might be effected by various stimuliincluding mechanical stress.21 In addition tobiomedical approaches to modulate chondrocyteactivity, also the potential applicability of carti-lage tissue engineering has been the subject ofintense research.22–24

COMMON IA DRUG THERAPIES ANDPOTENTIAL NEW DRUG TARGETS

Postoperative Pain Management AfterArthroscopic Procedures

Modern postoperative pain control focuses onearly mobilization and rapid discharge of patientsfollowing surgery. Satisfactory postoperative painrelief adds to decrease patient morbidity and mayreduce the risk of development of chronic painafter surgery.25 Major sites of action of analgesicsare depicted in Figure 2.26 Drug entrance into thetarget area may be accomplished by (i) transportvia the systemic circulation or (ii) direct instilla-tion into the proximity of the site of action.Achievement of optimal localized, therapeuticactivity after drug administration into discreteanatomical compartments, such as the joints,appears particularly promising. In the following, abrief overview over present IA strategies aiming

08 DOI 10.1002/jps


at pain management after arthroscopic proce-dures of the knee is presented.

Although minimally invasive of nature, arthro-scopic procedures do produce pain and inflamma-tion. As a result patients may be prevented fromreturning to work for up to 2 weeks aftersurgery.26 Findings may suggest that aggressivepain management (including local IA drug thera-pies) in the early postoperative period can improveconvalescence after arthroscopy.27 Over the yearsthe efficacy of a significant number of drugs (anddrug combinations) to provide pain relief afterIA injection has been investigated. In recentreviews,26,28 attempts have been made to assessthe feasibility of such IA interventions. Analysesof compiled data indicate that efficacious IAmonotherapeutic approaches include (i) non-steroidal anti-inflammatory drugs (NSAIDs),29

(ii) local anesthetics30 (primarily bupivacaine),and (iii) morphine.31,32 A reasonable degree ofconsensus has, however, been reached that totalpostoperative pain relief is not achievable by useof a single analgesic agent or method. Therefore,multimodal analgesia (or balanced analgesia) ap-pears to constitute a rational approach to effectivepain management.33,34 Following arthroscopicprocedures promising pain alleviating effects ofdifferent IA multimodal analgesic regimens havebeen reported.35–38 Most of the combinations haveinvolved the use of 2–3 drug compounds selectedfrom the above mentioned groups comprisinglocal anesthetics, NSAIDs, and opiates. Further,interesting results have been reported by incor-porating anti-inflammatory steroids27,39–41 andthe a2-receptor agonist clonidine42,43 into suchmultimodal IA therapies. As regard future IAmultimodal therapies, particular attention hasto be paid to the optimization of the duration ofaction of the individual therapeutic agents.Tentatively, feasible depot formulations shouldenable simultaneous release of analgesics (localanesthetics or opiates over a 24 h period) and anti-inflammatory agents (NSAIDs or corticosteroidsover about 7 days). Potential pharmaceuticalavenues to reach this ambitious goal are discussedin a later section.

Figure 3. Pathogenesis of rheumatoid arthritis.Modified from Burrage et al.46

Arthritic Disorders

Among the more than 100 arthritic disorders, thetwo major diseases are RA and OA. Despite theinvolvement of different (and partly unknown)aetiologies and pathogeneses,44,45 the common


thread linking RA and OA is progressive irrever-sible destruction of the cartilage, ligaments andbone in the affected joints.46 In the US, OA aloneleads to more than 500000 total joint replace-ments annually.47 Prevalences are estimated toabout 1% (RA) and 7% (OA). These diseases giverise to long-term disability and impose substantialburden to both patients and society.48–50 No curesare available, and current pharmacological inter-ventions addressing the pain are only moderatelyeffective.21 In addition to palliation of pain,current therapies primarily aim at slowing downdisease progression (see below).

Rheumatoid Arthritis

Typically, RA manifests as a symmetric anderosive polyarthritis. It is suggested that anti-gen(s) (of unknown origin) present in the jointtrigger an acute inflammation which upon an un-balanced host immune response may develop intoa chronic inflammation through a complex cas-cade of events.51 Briefly, in this process immunecells and macrophages home to the joint wherethey release inflammatory cytokines includinginterleukin (IL)-1 and tumor necrosis factor-alpha(TNF-a)46 (Fig. 3). These cytokines stimulatesynoviocytes to secrete matrix metalloproteinases(MMPs), the proteinases largely responsible forthe irreversible destruction of cartilage in thejoint.


Figure 4. Pathogenesis of osteoarthritis. Modifiedfrom Burrage et al.46

4626 LARSEN ET AL.

Current drug treatment options fall intofour main categories52 (i) NSAIDs, (ii) disease-modifying anti-rheumatic drugs (DMARDs), (iii)corticosteroids (occasionally), and (iv) biologics(antibodies and recombinant proteins). Aspects ofthe use of NSAIDs including implications of theirCOX-1 to COX-2 selectivity ratio have recentlybeen reviewed.53 Early use of DMARDs with theaim of aggressively preventing or reducing jointdamage has found broad acceptance. DMARDcombinations, including in particular metho-trexate,54–56 has become the cornerstone of mostRA treatment regimens.57,58 Despite manage-ment with such orally administered agents, manypatients do not respond adequately. For patientswith persistent disease, so-called biologics mayconstitute new opportunities in the treatment ofRA.59–61 These rather costly biological agentsreduce various inflammatory and immunologicalresponses by selectively blocking the effects ofcytokines (TNF-a and IL-1). Six products, to beadministered by injection (i.v. or s.c.), are cur-rently approved for the treatment of RA in theUS.59

Osteoarthritis

In contrast to RA, OA is usually located to one ora few joints. The principal morphological char-acteristic of OA is a slowly developing breakdownof the articular cartilage. In addition, changesoccur in bone, muscle and synovium.4,62,63 It issuggested that the major events in OA pathogen-esis are located within the cartilage itself and thatthe chondrocytes are major contributors to thepathology of this disease.21,46 Upon mechanicalinsults chondrocytes may release matrix degrad-ing proteinases. In addition, these cells produceproinflammatory cytokines which again maystimulate neighboring chondrocytes to produceMMPs, thereby creating their own inflammatoryenvironment46 (Fig. 4). On disease progression,cartilage-breakdown products may give rise toepisodes of (usually mild to moderate) synovitisthat at the end will lead to further upregulation ofMMP production.46,62

Current medical therapies of OA reduce thesymptoms (mainly pain) but are only moderatelyeffective. Oral treatment options embrace acet-aminophen, opioid analgesics, and NSAIDs.53 IAdrug therapies to alleviate pain include long-acting glucocorticoids and the injection of varioushyaluronic acid (HA) preparations.64–67 The con-cept of viscosupplementation is based on the


hypothesis that IA injection of HA could helprestore the (lost) visco-elasticity of OA synovialfluid.64 In contrast to RA, there are no approveddisease-modifying osteoarthritis drugs (DMOADs).47

In recent years studies have been conducted toassess the disease-modifying capabilities of nutra-ceuticals (such as glucosamine and chondroitin),diacerhein and doxycycline.68,69 The efficacy ofthe above approaches, however, remains contro-versial.

Potential New Targets for Drug Regulationin OA and RA

In the area of arthritic disorders novel pharma-cotherapeutic options may emerge from theidentification of a vast number of potential targetsfor drug regulation. In depth treatise of thisexciting area is outside the scope of the presentreview. Since basic knowledge about targetenvironment and location is a prerequisite forthe formulation scientist, a brief account of somemajor targets is presented below (see also Tab. 1and the references given to recent reviews/original articles). The pro-inflammatory, cataboliccytokines, particularly TNF-a and IL-1, play acentral role in tissue destruction in OA and RA. InRA, inhibition of the activity of these cytokines (byuse of for example anti-TNF-a antibodies and IL-1receptor antagonists) have proven effective inretarding disease progression70 and such thera-pies might also be effective against OA.71–73

08 DOI 10.1002/jps

Table 1. Potential Targets for Drug Regulation inArthritic Disorders

Targets References

Pro-inflammatory cytokines(primarily TNF-a and IL-1)

21,51,70–72,87,280–283

Matrix degrading enzymesMatrix metalloproteinases

(MMPs)46

Aggrecanases (ADAMTSs) 46,284,285Cysteine-dependent cathepsins 77,78

Growth factors 21,82,84Cell adhesion molecules (CAMs) 11,85


Despite significant clinical success, there is still acohort of RA patients who do not respond tointerventions involving such biological thera-pies.70 This has encouraged the search foralternative anticytokine therapies including theuse of inhibitors of the enzymes responsible forgeneration of TNF-a (TACE: TNF-a convertingenzyme70,72) and IL-1 (ICE: IL-1 convertingenzyme7,74).

It appears that increased levels of ECMdegrading enzymes, prostaglandins, nitric oxideand other markers in arthritic fluids and tissuesare related to elevated levels of TNF-a and IL-1.71

Whereas the formation of reactive oxygen andnitrogen species at the site of inflammation givesrise to oxidative injuries in RA,75 a relationshipbetween cartilage lesion severity and cartilage orblood redox state in OA has apparently not beenestablished.76 Major enzyme families involved inthe degradation of proteins of the cartilage ECMencompass the MMPs, the ADAMTSs metallopro-teinases, and cysteine-dependent proteases suchas the cathepsins. Collagen degradation is mediatedalmost exclusively by MMPs. Members of theADAMTSs family participate in the cleavage ofcartilage proteoglycans. Traditionally, the cathe-psins were believed to exert nonspecific bulkproteolysis within the acidic environment of thelysosome. However, there is growing evidence forspecific extracellular functions of these enzymes.77,78

A decrease in pH from 7.1 to 5.5 at the cartilagesurface of OA patients has been observed. This lowpH may favor the action of cathepsins over variousmetalloproteases as regards ECM degradation.79

The ECM degrading enzymes are expressed bydifferent cells within the joint space. Theirrelative contribution to disease progression maydepend on disease stage and type of disease. Tothis end, it appears that the protease activity in


RA synovial fluid, in general, exceeds that of OAsynovial fluid.80,81

In addition to hormones and cytokines, growthfactors (GFs) are endogenous molecules involvedin the regulation of cellular functions.82 Themetabolism of mature articular cartilage isregulated by a number of GFs that originate fromcellular production within the cartilage, as well asfrom the SF and surrounding tissues.83 Thesesignaling molecules have (among other functions)the capacity to stimulate chondrocyte anabolicactivity.21 GFs, such as insulin-like growth factor(IGF-1), the bone morphogenetic proteins (BMPs),and the transforming growth factor b (TGF-b),may therefore exert potentially reparative effectsin cartilage.21,47 In general, many GFs act overshort distances and have short biological half-lives. Thus, development of DDS that are capableof maintaining sufficiently high levels of variousGFs at defect sites for prolonged periods maysurmount this problem.84

The ability of cells to adhere to other cellsand extracellular matrices through CAMs plays acritical regulatory role in a variety of biologicalprocesses, including tissue remodeling and thedevelopment of inflammation. These molecules (orreceptors) are classified into four families.11 Theintegrin family comprises heterodimeric adhesionreceptors involved in the regulation of a number ofcellular processes, including cell growth, differ-entiation, apoptosis, as well as the regulation ofcell adhesion, migration and activation.85 Integ-rins are expressed in chondrocytes. Signalingthrough integrin adhesion molecules has beenassociated with cartilage damage, and with theproduction of proteinases and cartilage compo-nents by chondrocytes.46 Also synovial fibroblastsand macrophages express integrins which prob-ably are involved in synovial lining organizationthrough cell–ECM interactions.11 CAMs havegained acceptance as viable drug targets andanti-CAM biotherapeutics have reached the mar-ket in the treatment of autoimmune diseases likechronic plaque psoriasis, multiple sclerosis andCrohn’s disease.11,85 These antibodies haveyielded effective therapies, however, in manycases patients develop antibodies against thetherapeutic antibodies themselves. This has givenfurther incitement to the search for small-molecule drugs targeting CAMs such as collagenbinding integrins. Interestingly, also heparin-likemolecules may inhibit the action of leukocyteintegrins.86 As discussed in the following section,drug targeting might be accomplished by exploit-


4628 LARSEN ET AL.

ing small-molecule ligands with affinity for CAMsas so-called functionalized transport groups inprodrug and DDS design. Examples of chemicalstructures of novel potential small-molecule drugcandidates in the area of arthritic disorders havebeen reported.7,74,78,87 Some of the above men-tioned potential targets for drug intervention inOA and RA are also of major interest in the area ofcancer research where several reviews have dealtwith the role of proteases (including MMPs)88–90

and integrins91,92 in tumor invasion and meta-stasis. Small-molecule prodrug approaches incancer drug targeting has recently been reviewedby de Groot.93

DRUG TRANSPORT AND DISTRIBUTIONPROCESSES IN A SYNOVIAL ENVIRONMENT

In the joint cavity, the solute drug molecule, oncereleased from the immobilized depot, may takepart in a number of reactions and distribution(equilibrium) processes before it is eventuallycleared from the synovial space. These processes,the relative importance of which is determined bythe physicochemical properties of the drug sub-stance and the barrier properties of the synoviumare sketched in Figure 5. Concomitant to bindingto components of the SF, (i) transport anddistribution into the synovium and articularcartilage, and (ii) subsequent uptake by synovio-cytes and chondrocytes, may occur. The presentsection will discuss the barrier properties of thesynovium and the cartilage as well as mechanismsrelated to transport into these joint tissues.Special attention is paid to the articular cartilagecontaining the perhaps least accessible drugtargets, that is, the chondrocytes and pharmaco-logically active agents released by these cells.

Transsynovial Transport

Due to its architecture, the synovium (Fig. 1)constitutes the main barrier for drug transport

Figure 5. Schematic representation of drug trans-port and distribution processes of the joint.


out of the joint cavity. The healthy synovial liningis thin (60 mm94) and discontinuous withoutintercellular junctions. Together with the ECM,the synoviocytes function as a permeable, inho-mogeneous matrix.94 The healthy joint is pene-trated by capillaries close to the surface of thesynovium (modal depth 35 mm in man).94 Inchronic RA, thickening of the synovium occurs.This leads to an increase in the transport pathfrom the microvessels to the synovium—SFinterface.94 The synovial capillaries have fenes-trations facing the joint cavity thus adding toefficient solute exchange.94,95 Due to the fenestra-tion of the capillaries, plasma protein and bounddrug as well as the unbound (free) drug may enterinto the synovium.96 This tissue can be consideredas two barriers placed in series, that is, theinterstitial matrix and the synovial capillaryendothelium.97–99 The ECM constitutes the majordiffusional barrier for entry of small moleculesinto the synovial cavity whereas passage of theendothelium is the critical barrier for proteins.Flanking the synovium is the subsynoviumconsisting of loose connective tissue and fat cells.At the border between the synovium and sub-synovium are the terminal lymphatics drainingfluid and macromolecules from the joint cavity(Fig. 1).

Transsynovial transport and solute concentra-tions in the SF have been assessed in the evalu-ation of the efficiency of drug treatment regimensin relation to RA and OA where the SF concen-tration has been taken as a surrogate measure ofdrug concentrations in synovium and cartilage.96

Upon oral drug administration, observed jointCmax and tmax values are usually lower and occurat later time points, respectively, than the corres-ponding parameters in plasma.96,100,101 For manyNSAIDs, plasma/SF drug concentration ratioshave been found to reflect plasma/synovial proteinconcentration ratios. Further, free NSAID con-centrations have been found to be similar in thetwo compartments after attainment of steadystate conditions.96,100,101 Often the SF concen-trations are more sustained than plasma concen-trations after oral or i.v. administration.96,100,101

Due to continuous drug entrance from the bloodcompartment, IA elimination half-lives (t1/2)estimated from pharmacokinetic profiles obtainedfollowing oral administration may tend to under-estimate the ‘‘true’’ rate of drug disappearancefrom the SF after IA administration.96 By appro-priate corrections, however, reasonable estimatesof rates of disappearance from joints relevant to IA

08 DOI 10.1002/jps


administration can be extracted from oral phar-macokinetic data. Table 2 contains a compilationof SF disappearance half-lives for some lowmolecular weight solutes and drugs as well as afew macromolecules. Additional data can be foundin the works of Day et al.96 (drugs) and Simkin andNilson102 (radio isotopes and albumin). As appar-ent, relatively fast disappearance from the jointis observed for small solutes with t1/2 values inthe range of about 0.1 to 6 h. In this connectiondisappearance kinetics from the joint cavity hasoften been described by simple first-order kinetics.However, several studies, for example,103–109 havefound biphasic clearance patterns after IA injec-tion, indicating the presence of a distributionphase associated with drug distribution from theSF to other joint tissues. An initial distributionphase is probably always present upon IAinstillation but may or may not be observeddepending on the study design.

For small molecules diffusion through the ECMis the major barrier because such solutes readilytraverse the fenestrated endothelium of thecapillaries. The concentration gradient requiredfor effective clearance of small molecules fromthe joint is maintained by the synovial bloodflow.110,111 Simkin and Pizzorno112 found synovialpermeability to correlate with diffusion coeffi-cients in water for benzyl alcohol, tritiated water,urate, urea, glucose and sucrose. Among thesesolutes benzyl alcohol disappeared significantlyfaster from the joint, which was suggested toreflect the lipophilicity of the molecule, allowingdiffusion to occur not only in the aqueous pores ofthe ECM between the synoviocytes but also acrosscell membranes. Collectively, these studies indi-cate that most small molecules cross the synoviumin both directions by diffusion. In a follow upstudy, Simkin and Pizzorno97 evaluated thesynovial permeability of plasma protein as wellas the above set of molecules in knee joints ofRA patients and normal individuals. The resultsobtained led to the proposal of the two barriermodel of the synovium. Owen et al. determinedthe disappearance half-lives of 125I-albumin,acetaminophen, salicylate and diclofenac uponIA administration to RA patients.103 The terminalhalf-lives of the drugs (listed in Tab. 2) were foundto increase with the fraction of drug bound toproteins (albumin) in the SF. Lymphatic clearanceof albumin was suggested to contribute to the drugefflux due to clearance of albumin bound drugamounting to 1%, 13%, and 48% of the totalclearance for acetaminophen, salicylate and diclo-


fenac, respectively. An implication of the con-ducted analysis was a limiting half-life of highlyalbumin bound drugs equal to the terminal half-life of the albumin molecule itself (13.1 h).103

Simkin et al.113 also investigated the effect ofprotein binding on articular kinetics. Based on anexamination of data from oral dose studiesinvolving highly bound NSAIDs (>99%), theauthors found that synovial transport was muchtoo fast to be accounted for by synovial clearanceof albumin bound drug solely (Tab. 2). It wassuggested that fast association/dissociation kine-tics relative to drug transit time through thesynovial capillaries would make most of the bounddrug available for diffusion across the endothe-lium. Thus, synovial disappearance rates may notjust depend on drug affinity for proteins but alsoon binding avidity.98,113 Further studies arewarranted to elucidate this aspect of IA drugdisappearance kinetics. It is difficult to unravelthe exact importance of drug characteristics (e.g.,size, lipophilicity, charge, and protein binding) tosynovial disappearance rates. Lipophilicity hasbeen proposed to play a role.100,106,112 However, ahighly lipophilic drug may experience slow effluxfrom the joint as compared to small polarmolecules. This is the case for the lipophilic gas133Xe which was found to be extensively parti-tioned into fat tissue of the joint.106 Apparently,little information is available on the effect ofcharge on disappearance rates through thesynovium. In the early study of Simkin andPizzorno,112 it was found that synovial perme-ability of magnesium and calcium was lower thanfor the other small molecules investigated (e.g.,urea and benzyl alcohol).

Plasma proteins enter the SF (to differentextents) by crossing the endothelium and diffus-ing through the interstitial matrix. This process issize selective, that is, albumin escapes thecapillaries more readily as compared to fibrinogenand macroglobulins.98,114–116 This size depen-dency is partly reflected in the SF/serum proteinconcentration ratios although other factors affectthe concentration ratio as well.116 Inflammationincreases the endothelial permeability for pro-teins and consequently the SF protein concentra-tions as this is not fully counteracted by changesin lymphatic flow.97,99 The permeability increasefor proteins associated with inflammation is notalways followed by a similar increase in synovialpermeability of small solutes due to the dualbarrier construction (the ECM being the criticalbarrier to the transport of small molecules rather


Table 2. Synovial Disappearance Half-Lives (t1/2) and Molecular Weights (MW) of Various Solutes�

Compound t1/2 (h) MW (g/mol) Comments References

131I-cartilage proteoglycan 12.5 2.5� 106 Rabbit knee 1223H-hyaluronan 10.2 0.09� 106 Rabbit knee 1243H-hyaluronan 13.2 >6� 106 Rabbit knee 12414C-hyaluronan 20.6 2.0� 106 Rabbit knee 286Hyaluronan 21.8–26.3 �3� 106 Rabbit knee 123131I-albumin 3.9 6.7� 104 Rabbit knee 122Albumin 1.23 6.7� 104 Rabbit knee 123125I-ulinastatin 1.3a; 5.6b 6.7� 104 Rabbit knee; affinity

for synovial tissue105

Sodium pertechnetate 0.82/1.78 186 Normal/arthritic rabbit knee 122Acridine orange 0.23 370 Rabbit knee 111Patent blue V 0.40 582 Rabbit knee 111Evans blue 0.92 963 Rabbit knee 111131I-albumin 5.9/12.2 6.7� 104 Canine wrist/knee 119131I� 0.55/0.78 131 Canine wrist/knee 119133Xe 0.11–0.18a; 0.57–1.3b 133 Canine knee 106Ceftiofur 5.1 524 Horse antebrachiocarpal joint 108Procaine 0.80 236 Horse hock joint; hydrolysis

occurs simultaneously287

131I-cross-linked hyaluronan 1.5; 39; 720 Triexponential kinetics,the latter t1/2 reflectingthe cross-linked HA

288

125I-albumin 13.1 6.7� 104 RA 103D2O 0.26 20 Normal and RA 150THO 0.19–0.26 20 Human knee, various conditions 11724Na 0.23/0.20/0.11 24 Normal/minor/more severe RA activity 14924Na 0.39 24 Normal and RA 150131I� 0.64/0.53 131 RA/OA 117133Xe 0.06a; 0.63b 133 RA 107133Xe 0.07–0.26a;0.58–4.0b 133 Human knee, various conditions 106Lidocaine 0.35 234 Arthroscopy patients 289Methotrexate 0.59a; 2.90b 454 RA 104Ceftazidime 0.6 547 Septic arthritis patient 290Diclofenac 5.2 296 RA 103Salicylic acid 2.4 138 RA 103Paracetamol 1.1 151 RA 103Diclofenac 1.5 296 RA/OA, oral dosing 291Etodolac 4.1 287 RA/OA, oral dosing 291Ibuprofen 1.9 206 RA/OA, oral dosing 291(R)- and (S)-ibuprofen 2.6 (R) and 2.3 (S) 206 RA, OA or gouty arthritis, oral dosing 292Indomethacin 3.3 358 RA/OA knee, oral dosing 291Tenoxicam 2.6 337 RA/OA knee, oral dosing 291Aclofenac 2.9 RA, oral dosing 113Flurbiprofen 3.4 244 RA, oral dosing 113Indomethacin 2.8 358 RA, oral dosing 113Ketoprofen 1.9 254 RA, oral dosing 113Naproxen (550 mg) 1.6 230 RA, oral dosing 113Naproxen (500 mg) 1.6 230 RA, oral dosing 113Naproxen (1000 mg) 3.1 230 RA, oral dosing 113Tenoxicam 2.8 337 RA, oral dosing 113Tiaprofenic acid 1.5 260 RA, oral dosing 113Tolmetin 2.2 257 RA, oral dosing 11314C-cortisone 1.3, 1.5 360 Two RA patients 15114C-hydrocortisone 1.0, 1.46, 1.8 362 Three RA patients 15114C-hydrocortisone 0.37a; 2.5–4.2b 362 RA 109

�Values relate to intra-articular administration in human knee joint unless otherwise noted.aSynovial distribution phase.bSynovial elimination phase.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 11, NOVEMBER 2008 DOI 10.1002/jps


than the endothelium of the microvessels).97,117 Incontrast, escape of proteins from the joint occursthrough the lymphatic system, a process which isnot size selective for molecules with the size ofplasma proteins.102,114,116,118–120 In relation to thedesign of DDS it is of interest to know the sizelimitations to the lymphatic clearance from thejoint cavity. Rodnan and MacLachlan found thatthe human synovium was equally permeable toalbumin (67 kDa; res¼ 3.6 nm) and g-globulin(150 kDa; res¼ 5.6 nm).120 The res values areEinstein-Stokes diffusion radii.99 Studies in micerevealed diminished protein clearance rates of67–150 kDa proteins as compared to those oflower molecular weight proteins (14–47 kDa).121

To this end it has been found that hyaluronanand cartilaginous proteoglycans are not readilycleared by lymphatic drainage (Tab. 2).122–124 Thefate of particulate and vesicular DDS upon IAadministration is discussed in a following section.

Drug Transport into Cartilage

As revealed above, drugs are likely to distributefrom the SF into various joint tissues after IAadministration. Calculations on glucose trans-port, to feed the chondrocytes of the articularcartilage, have revealed that diffusion of thisnutrient in the relatively viscous SF, per se, mightbe too slow for reaching the center of larger joints.Instead joint motion is suggested to generateadditional solute transport by convection.94,125

Upon attainment of a uniform glucose concentra-tion in the SF, diffusion into cartilage is suffi-ciently fast to supply the chondrocytes with thisnutrient. Similar considerations may be of rele-vance for drug distribution in the joint cavity. Atthe SF-cartilage interface two major parametersgovern the efficiency of solute transport into thecartilage ECM, that is, the size and the charge ofthe solute. Quantitative descriptions relatingrates of diffusion and the latter intrinsic diffusant(drug) properties are lacking. Physicochemicalaspects of the effect of molecular size and chargeon drug accumulation within the cartilage arebriefly presented below.

For solutes, the effective (apparent) diffusioncoefficient for transport in cartilage, D, can berelated to the diffusion coefficient in aqueoussolution D via a so-called turtuosity factor l(expresses the actual solute diffusion lengthper unit thickness of cartilage) and a solute-membrane friction coefficient FSM (a size exclu-


sion effect):126

D

D¼ 1

l2

1

1 þ DFSM

� �(1)

For macromolecules like dextran 10 and 40(about 10 and 40 kDa, respectively) D is very smallcompared to D due to a significantly enhancedfriction between the solute molecules and thepore walls (DFSM� 1). In this case (Eq. 2) mayapply:126

D ¼ 1

l2

1

FSM

� �(2)

Interestingly, studies may indicate that evenvery large molecules such as hemoglobulin(68 kDa) and dextran 40, may diffuse into carti-lage albeit at very low rates.126 This might beascribed to a rather inhomogeneous structure ofthe cartilage.127–130 In case of large molecules,transport efficiency into cartilage might to someextent be influenced by convection due to dynamiccompression.131–134

Cartilage proteoglycans are composed of a coreprotein to which at least one GAG chain is co-valently attached. The latter negatively chargedpolysaccharides are mainly chondroitin and ker-atin sulfate.18 Since overall electroneutrality hasto be maintained in cartilage the fixed negativecharges of the proteoglycans have to be balancedby more mobile cations. Consequently an osmoticpressure gradient as well as a potential differenceare created. The phenomenon corresponds to aDonnan exclusion effect. Therefore attempts havebeen made to model drug salt distribution in carti-lage within classical ion exchange theory.126,135–137

Within the cartilage, the total concentration ofcations for an electrolyte salt can be expressed as:

ZcationCcation ¼ ZanionCanion þ Cimmobile anion (3)

where C is the molar concentration in cartilage.Due to the fixed negative charge of the collagenousfiber network, cationic drug molecules have ahigher tendency to distribute into cartilagecompared to anions.135 Based on these earlyobservations efforts have been devoted to exploitthe ion exchange properties of the ECM toenhance drug accumulation in the cartilagetissue. Various positively charged organic mole-cules have been observed to distribute intocartilage.138–147 This includes (i) radiodiagnosticagents for joint imaging containing a N-quatern-ary functional group,142,143 (ii) N-quaternary


4632 LARSEN ET AL.

analogues of anti-inflammatory oxicams,140,144

and (iii) a derivative of the potential DMOADdoxycycline.147

Modeling Joint Escape Kinetics

The elimination of low molecular weight drugs inthe solute state from the synovial cavity has beendescribed by first-order kinetics (Tab. 2). This isconsistent with the view that the interstitialmatrix is the limiting (diffusional) barrier.97,99

Accordingly, Ficks first law may be a suitablestarting point for describing the rate of drugdisappearance from the synovial cavity:112

dN

dt¼ �DA

xðCs � CpÞ (4)

where N is the number of drug molecules in thesynovial cavity, Cs and Cp are the drug concen-trations in the SF and plasma, respectively, D isthe diffusion coefficient, A the available area fordiffusion and x is the length of the diffusion path.Introducing Vs as the SF volume and assumingthat the systemic circulation acts essentially as asink (Cp 0) (Eq. 4) may be rewritten

dCs

dt¼ �kCs (5)

where k (¼DA/xVs) is the synovial escape (clear-ance) rate constant due to simple diffusion.Difference in chemical potential is the drivingforce of diffusion and in simple systems, such as adialysis cell, this can be approximated by theconcentration gradient. Pursuing the analogybetween the joint and a dialysis apparatus witha porous membrane impermeable to proteins andmacromolecules, it is apparent that Cs in (Eqs. 4and 5) should be the free drug concentrationrather than the total analytical concentrationnormally measured. A number of experimentalfindings complicate this simplified view: theinteraction of drug substances with the macro-molecules of the SF and articular cartilage as wellas the transport of protein bound drug out of thejoint cavity.103,113 As regard binding to tissuecomponents and macromolecules in the SF, directproportionality between the free and total drugconcentration may be found in case (i) the drugconcentration is much smaller than the concen-tration of binding sites148 and (ii) the attainmentof the distribution equilibria are fast. It may bedifficult to evaluate whether these prerequisitesare fulfilled. However, it may be the case forNSAIDs since the therapeutic drug concentra-tions are much smaller than that of their primary


transport protein (albumin). The clearancekinetics of the SF proteins by the lymphaticshas been found to obey first-order kinetics119,122

and, consequently, this can also be expected forprotein bound drugs.103 Altogether, drug effluxfrom the joint cavity should follow first-orderkinetics when the following (idealized) conditionsprevail: the drug binding phenomena are con-centration independent and the various contri-buting transport processes can be characterizedas first-order processes. However, the rate con-stant k in (Eq. 5) should be replaced by a compositerate constant k0, which describes the observedtime dependence of the total synovial drugconcentration upon IA instillation. Support tothe adequacy of (Eq. 5) to describe synovialkinetics may be found in the series of studiesfollowing first-order kinetics for several half-livesfor various solutes119,122,149–151 This equation,however, does not take into account the distribu-tion phase observed in some studies (e.g.103,104)upon IA administration of drug solutions.

The transport equation outlined above may becombined with knowledge on the drug releasemechanism of a specific drug delivery system, toestimate the IA drug concentration versus timeprofile. Two limiting cases can be envisioned. Fordelivery systems providing a constant rate of drugrelease (krel; mole drug released per time and unitSF volume) an approximately constant synovialdrug concentration may be achieved for a period oftime:

dCs

dt¼ krel � k0Cs (6)

In contrast, for a DDS where release is governedby drug partitioning between the vehicle and theSF phase, the overall joint escape can be expectedto apply to first-order kinetics. Delivery systemsapproximating the former case (zero order drugrelease) may be suspensions of poorly solublesteroids. Indications, that this is the case, are thealmost constant plasma steroid concentrationsfound for prolonged time periods following aninitial phase of rapid drug appearance in thesystemic circulation.

ON FUTURE IA DRUG DELIVERY STRATEGIES

In this section a rationale for localized drugdelivery (based on pharmacokinetic considera-tions) is presented. Several parenteral depot

08 DOI 10.1002/jps


formulation technologies have been investigatedfor the IA route of administration. A more com-prehensive treatise of aspects of the applicabilityof major depot formulation principles is given.This includes prolonged release properties, in vivofate and issues related to their manufacture.These considerations are also expected to be ofrelevance for other mentioned depot DDS typesof potential utility for novel IA depots in the areaof postoperative pain control and OA. Further, therole of in vitro models for quality control and theassessment of the controlled release capabilities ofpotential IA depot formulations is discussed. Theintriguing concept of gene transfer to arthriticjoints has been the subject of several reviews152–156

and is not considered further in the presentcontext.

Rationale for Localized Drug Delivery

For drugs that have to be transported to a discretesite of action (e.g., a knee joint) by the systemiccirculation, the fraction of the administered dosethat enters the target site is dependent on theextent of drug distribution to other tissues ofthe body.148 After completion of the drug distribu-tion phase, the amount of drug in the body at(steady state) equilibrium (CVD) is given by

CVD ¼ CVp þ CXn

i¼1

ViKi (7)

where C is the plasma concentration, VD is theapparent volume of distribution and, Vp refersto the plasma volume. Vi and Ki represent thevolume and the tissue-to-plasma ratio of drugconcentrations for the specific tissue (i), respec-tively, and n refers to the total number of tissuecompartments. Thus, the fraction of a given drugdose that reaches the particular joint ( fjoint) mightroughly be estimated from

fjoint ¼VjointKjoint

VD(8)

For major weight-bearing joints K values closeto unity are to be expected for most small-moleculedrugs. Although the magnitude of Vjoint mightvary to some extent with type and severity ofdisease, the key parameter influencing the size offjoint is VD that may vary widely (7–40000 L/70 kgbody weight) depending on the physicochemicalproperties of the individual drug compound.148 Tothis end it can be mentioned that after oral dosing,


a steady state VD of about 90 L has been reportedfor the selective COX-2 inhibitor rofecoxib.157 Thisdrug has now been withdrawn from the marketdue to severe side effects after oral administra-tion. In addition to drug mixtures for multimodalanalgesia, local administration might thereforealso be considered for anti-arthritic drug candi-dates that are prohibited from oral administrationdue to severe systemic side effects or bioavail-ability problems. Direct IA instillation of depotformulations appears most realistic for futureanti-osteoarthritic drugs based on the fact that inOA only few joints are affected. The clinical courseof RA is characterized by a variable diseaseactivity of spontaneous remissions and exacerba-tions (flare-ups) of the chronic inflammatory jointprocess. In the case of episodes of discrete jointflare-ups158 and to treat resistant knee mono-arthritis159–161 local anti-inflammatory therapymight also be indicated.

Potential IA Depot Drug Delivery Systems

Aqueous glucocorticoid suspensions remain theonly world wide, commercially available depottype for IA injection. In addition, the performanceof a variety of depot principles have beeninvestigated in vivo (Tab. 3). Most of these studieshave been carried out in animals with the rabbitbeing the most frequently used animal model. Theadequacy of employed injection methodologies tominimize trauma, tissue damage and extra-articular leakage162–164 has not been optimallyaddressed in any of these experimental studies.Another common feature is the apparent lack ofinformation about the robustness of the obtainedin vivo data to minor changes in depot character-istics such as size (particles/droplets) and charge.In several studies it was reported that the IAadministered formulation in question was welltolerated. Although the lack of significant localtoxicity has to be documented through morecomprehensive studies, feasible biocompatibilitymight, in general, be anticipated since pharma-ceutical excipients of several of these formulationsalready constitute the building blocks of marketeddepots intended for other parenteral routes ofadministration.165

As apparent from Table 3, far the majority of theinvestigated therapeutic systems have involvedliposome or microsphere-based DDS. Numerousreports indicate that advanced drug deliveryliposomes might be of potential utility to overcome


Ta

ble

3.

Over

vie

wof

Exp

erim

enta

lD

rug

Del

iver

yS

yst

ems

Ad

min

iste

red

Intr

a-A

rtic

ula

rly

Dru

g/M

odel

Com

pou

nd

An

imal

Mod

el/H

um

an

Com

men

tsR

efer

ence

s

Lip

osom

esC

orti

sol

21-p

alm

itate

Rabbit

(in

du

ced

art

hri

tis)

Dru

gin

corp

orate

din

lip

idbil

ayer

.177

Part

icle

size

not

defi

ned

.S

ust

ain

edan

ti-i

nfl

am

mato

ryef

fect

of3

days

171,1

73

Cor

tiso

l21-p

alm

itate

RA

pati

ents

Dru

gin

corp

orate

din

lip

idbil

ayer

.P

art

icle

size

not

defi

ned

.S

ust

ain

edan

ti-i

nfl

am

mato

ryef

fect

of14

days

174

Tri

am

cin

olon

eace

ton

ide

21-p

alm

itate

Rabbit

(in

du

ced

art

hri

tis)

Dru

gin

corp

orate

din

lip

idbil

ayer

.P

art

icle

size

not

defi

ned

.P

rolo

nged

rete

nti

onin

the

join

tca

vit

y(3

8%

rem

ain

ing

aft

er8

h)

com

pare

dto

free

tria

mci

nol

one

ace

ton

ide

inso

luti

on

172

Dex

am

eth

aso

ne

21-p

alm

itate

Rabbit

(hea

lth

y)

Dru

gin

corp

orate

din

lip

idbil

ayer

.P

art

icle

size

ran

ge:

0.1

–30m

m.

Op

tim

al

end

ocyto

sis

inp

art

icle

size

ran

ge:

0.7

5–5m

m175

Dex

am

eth

aso

ne

21-p

alm

itate

Rabbit

(hea

lth

yan

din

du

ced

art

hri

tis)

Dru

gin

corp

orate

din

lip

idbil

ayer

.P

art

icle

size

ran

ge:

160–750

nm

.T

he

am

oun

tof

dru

gre

main

ing

inth

ejo

int

incr

ease

sw

ith

part

icle

size

.P

rolo

nged

rete

nti

onin

the

join

t(3

6%

rem

ain

ing

aft

er6

h)

com

pare

dto

mic

rocr

yst

all

ine

tria

mci

nol

one

ace

ton

ide.

Up

tak

eof

lip

osom

al

dru

gin

the

syn

oviu

m1–2

days

aft

erin

ject

ion

.R

eten

tion

enh

an

ced

inh

ealt

hy

join

tsco

mp

are

dto

infl

am

edjo

ints

176

Met

hot

rexate

Rabbit

(hea

lth

yan

din

du

ced

art

hri

tis)

Dru

gen

trap

ped

inth

eaqu

eou

sp

hase

.M

ean

part

icle

size

:1.0

7m

m.

Rap

idle

ak

age

ofso

me

dru

gfr

omli

pos

omes

.P

rolo

nged

rete

nti

onin

the

join

t(4

6%

rem

ain

ing

aft

er24

h)

com

pare

dto

an

aqu

eou

sso

luti

onof

the

free

dru

g.

Low

up

tak

eof

lip

osom

e(d

ose

dep

end

ent)

by

syn

oviu

m

180

Met

hot

rexate

Rat

(in

du

ced

art

hri

tis)

Met

hot

rexate

an

alo

gu

e(a

ph

osp

hol

ipid

covale

ntl

ybou

nd

tom

eth

otre

xate

via

am

ide

bon

d)

inco

rpor

ate

din

toli

pid

bil

ayer

.M

ean

part

icle

size

:100

nm

(sm

all

)an

d1.2

mm

(larg

e).

Su

stain

edan

ti-i

nfl

am

mato

ryef

fect

for

21

days

(larg

eli

pos

omes

).P

rolo

nged

rete

nti

onin

the

join

t(6

%an

d29%

rem

ain

ing

aft

er24

hfo

rsm

all

an

dla

rge

lip

osom

es,

resp

ecti

vel

y)

com

pare

dto

the

free

dru

g

293

Tra

nsf

orm

ing

gro

wth

fact

or-b

1(T

GF

-b1)

Rabbit

(fu

ll-t

hic

kn

ess

art

icu

lar

cart

ilage

def

ects

)In

dic

ati

ons

ofan

acc

eler

ate

dea

rly-s

tage

rep

air

ofth

eart

icu

lar

cart

ilage

def

ects

294

Lact

ofer

rin

Mou

se(i

nd

uce

dart

hri

tis)

Dru

gm

ost

lik

ely

entr

ap

ped

inth

eaqu

eou

sp

hase

.P

osit

ivel

yan

dn

egati

vel

ych

arg

edli

pos

omes

.P

art

icle

size

not

defi

ned

.F

ast

dru

gre

lease

from

lip

osom

es.

Pro

lon

ged

rete

nti

onti

me

inth

ejo

int

ofth

ep

osit

ive

charg

edli

pos

ome

(15%

rem

ain

ing

aft

er24

h)

com

pare

dto

an

aqu

eou

sso

luti

onof

the

free

dru

g

295

Lid

ocain

eR

abbit

(hea

lth

y)

No

chara

cter

izati

onof

lip

osom

es.

Fast

dru

gtr

an

sfer

toth

eblo

odfo

rfr

eed

rug

as

wel

las

lip

osom

een

trap

ped

lid

ocain

e179


4634 LARSEN ET AL.

Ta

ble

3.

(Con

tin

ued

)

Dru

g/M

odel

Com

pou

nd

An

imal

Mod

el/H

um

an

Com

men

tsR

efer

ence

s

Dic

lofe

nac

Rabbit

(in

du

ced

art

hri

tis)

Dru

gen

trap

ped

inth

eaqu

eou

sp

hase

.L

ipos

omes

an

dn

ioso

mes

inco

rpor

ate

din

hyd

rop

hil

icp

olym

ergel

s(l

ipog

elos

omes

an

dn

iogel

osom

es).

Part

icle

size

:200–250

nm

.F

ast

dru

gre

lease

from

lip

osom

es(9

3%

aft

er48

h).

Slo

wer

rele

ase

from

lip

ogel

osom

es(5

0%

aft

er48

h).

Lon

ges

tre

ten

tion

inth

ejo

int

wit

hli

pog

elos

ome

(50–70%

rem

ain

ing

aft

er24

h)

178

Clo

dro

nate

Sh

eep

(in

du

ced

art

hri

tis)

Dru

gm

ost

lik

ely

entr

ap

ped

inth

eaqu

eou

sp

hase

.N

och

ara

cter

izati

onof

lip

osom

es.

Up

tak

eof

lip

osom

esin

the

syn

oviu

m.

No

ther

ap

euti

cef

fect

296

Clo

dro

nate

Mou

se(h

ealt

hy

an

din

du

ced

art

hri

tis)

Dru

gm

ost

lik

ely

entr

ap

ped

inth

eaqu

eou

sp

hase

.M

ean

part

icle

size

:1m

m.

Dep

leti

onof

ph

agoc

yti

cli

nin

gce

lls

wit

hin

3d

ays

297,2

98

Clo

dro

nate

Rabbit

(in

du

ced

art

hri

tis)

Dru

gm

ost

lik

ely

entr

ap

ped

inth

eaqu

eou

sp

hase

.P

art

icle

size

:200–300

nm

.195

Up

tak

eof

lip

osom

esin

syn

oviu

mte

mp

orary

an

ti-i

nfl

am

mato

ryan

dan

tier

osiv

eef

fect

299

Clo

dro

nate

RA

pati

ents

Dru

gm

ost

lik

ely

entr

ap

ped

inth

eaqu

eou

sp

hase

.P

art

icle

size

:120–160

nm

.D

eple

tion

ofsy

nov

ial

lin

ing

macr

oph

ages

.D

ecre

ase

exp

ress

ion

ofad

hes

ion

mol

ecu

les

inth

esy

nov

ial

lin

ing

(red

uce

din

flam

mati

on)

300

51C

r(r

ad

ion

ucl

ide)

Rabbit

(in

du

ced

art

hri

tis)

Aco

mp

lex

of51C

ran

da

lip

oph

ilic

chel

ato

rw

as

inco

rpor

ate

din

toth

eli

pid

ph

ase

.M

ean

part

icle

size

:100

nm

.M

ore

than

41%

rem

ain

ing

inth

ejo

int

aft

er21

days.

Acc

um

ula

tion

ofra

dio

act

ivit

yin

the

syn

oviu

m

301

Ben

zop

orp

hyri

nd

eriv

ate

-mon

oaci

dri

ng

Rabbit

(in

du

ced

art

hri

tis)

No

chara

cter

izati

onof

the

lip

osom

es.

Hig

hass

ocia

tion

ofth

ed

rug

toth

esy

nov

ium

.P

ossi

bil

ity

ofu

sin

gp

hot

odyn

am

icth

erap

yin

man

agem

ent

ofau

toim

mu

ne

dis

ord

ers

302

Dru

g/M

odel

Com

pou

nd

An

imal

Mod

el/H

um

an

Com

men

tsR

efer

ence

s

Mic

rosp

her

esN

one

Rabbit

(hea

lth

y)

Pol

yla

ctic

aci

d,

pol

ybu

tylc

yan

oacr

yla

te,

gel

ati

nan

dalb

um

inm

icro

sph

eres

.P

art

icle

size

:1–10m

m.

Alb

um

inm

icro

sph

eres

bes

tto

lera

ted

by

the

syn

ovia

lti

ssu

e.U

pta

ke

ofm

icro

sph

eres

into

the

syn

oviu

m.

Maxim

um

up

tak

efo

rp

art

icle

size

<5m

m

303

Ros

eB

engal

Rabbit

(in

du

ced

art

hri

tis)

Alb

um

inm

icro

sph

eres

.M

ean

part

icle

size

:3.5

mm

.R

ap

idin

itia

lre

lease

.P

rolo

nged

rete

nti

onin

the

join

t(9

–25%

rem

ain

ing

aft

er7

days)

com

pare

dto

the

free

mod

elco

mp

oun

d.

Up

tak

eof

mic

rosp

her

esin

toth

esy

nov

ium

304

(Con

tin

ued

)

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 11, NOVEMBER 200


8

Ta

ble

3.

(Con

tin

ued

)

Dru

g/M

odel

Com

pou

nd

An

imal

Mod

el/H

um

an

Com

men

tsR

efer

ence

s

Pre

dn

isol

one

ortr

iam

cin

olon

eR

abbit

(hea

lth

y)

Hea

td

enatu

rate

dalb

um

inm

icro

sph

eres

.M

ean

part

icle

size

:23m

m.

Dec

rease

dp

lasm

aabso

rpti

onra

tefr

omm

icro

sph

eres

com

pare

dto

that

ofsu

spen

sion

s.N

ou

pta

ke

into

the

syn

oviu

m.

Pot

enti

al

ad

sorp

tion

ofm

icro

sph

eres

tosy

nov

ium

305

Dic

lofe

nac

Rabbit

(in

du

ced

art

hri

tis)

Alb

um

inan

dp

oly(l

act

ide-

co-g

lyco

lid

e)m

icro

sph

eres

.P

art

icle

size

:5–15m

m.

Sig

nifi

can

tin

itia

lbu

rst

rele

ase

(in

vit

ro).

No

sust

ain

edre

lease

effe

ctin

viv

o

306,3

07

Cel

ecox

ibR

at

(in

du

ced

art

hri

tis)

Ch

itos

an

mic

rosp

her

es.

Part

icle

size

:8–16m

m.

Sig

nifi

can

tin

itia

lbu

rst

rele

ase

(in

vit

ro).

Lim

ited

sust

ain

edre

lease

effe

ctin

viv

o

308,3

09

Nap

roxen

Rabbit

(in

du

ced

art

hri

tis)

Alb

um

inan

dp

oly(l

act

ide-

co-g

lyco

lid

e)m

icro

sph

eres

.P

art

icle

size

:5–10m

m.

Som

ein

itia

lbu

rst

rele

ase

(in

vit

ro).

PL

GA

mic

rosp

her

esm

ore

pro

mis

ing

than

alb

um

inm

icro

sph

eres

310

Dex

am

eth

aso

ne

Rabbit

(hea

lth

y)

Pol

y(D

,L-l

act

ide)

mic

rosp

her

es.

Part

icle

size

:40–110m

m.

Incr

ease

dm

olec

ula

rw

eigh

tof

pol

ym

erre

sult

edin

slow

erin

vit

rore

lease

from

mic

rosp

her

es.

No

dru

gd

etec

ted

inse

rum

wit

hin

24

h.

Dru

gd

etec

ted

insy

nov

ial

cavit

y(n

otin

the

SF

)u

pto

7d

ays

311

Cou

mari

n(fl

uor

esce

nt

dye)

Rabbit

(hea

lth

y)

D,L

-lact

icaci

dol

igom

erm

icro

sph

eres

.P

art

icle

size

s:20–100m

m;

100–200m

m.

Mic

rosp

her

elo

cali

zed

inp

opli

teal

fat

tiss

ue

(in

dep

end

ent

onp

art

icle

size

an

dm

olec

ula

rw

eigh

tof

olig

omer

)

312

Pacl

itaxel

Rabbit

(in

du

ced

art

hri

tis)

Pol

y(l

act

ide-

co-g

lyco

lid

e),

pol

y(L

-lact

ide)

,p

oly(c

ap

rola

cton

e)m

icro

sph

eres

.P

art

icle

size

s:1–20m

m;

35–100m

m.

Sh

ort

bu

rst

rele

ase

(5–7%

)fo

llow

edby

sust

ain

edre

lease

for

30

days

(in

vit

ro).

Infl

am

mato

ryre

spon

seu

sin

gsm

all

part

icle

size

sw

her

eas

larg

erp

art

icle

size

sw

ere

fou

nd

tobe

bio

com

pati

ble

313

Non

eR

at

(hea

lth

y)

Pol

y(D

,L-l

act

ide-

co-g

lyco

lid

e)m

icro

-an

dn

an

osp

her

esw

ith

mea

np

art

icle

size

sof

265

nm

an

d26.5

mm

,re

spec

tivel

y.

Dis

per

sion

ofm

icro

sph

eres

inth

ejo

int

cavit

y(p

oten

tial

ad

hes

ion

toth

esu

rface

ofth

esy

nov

ium

).U

pta

ke

ofn

an

osp

her

esin

the

syn

oviu

m.

314

Bet

am

eth

aso

ne

sod

ium

ph

osp

hate

Rabbit

(in

du

ced

art

hri

tis)

Pol

y(D

,L-l

act

ide-

co-g

lyco

lid

e)n

an

osp

her

es.

Part

icle

size

:300–490

nm

.D

ecre

ase

ofin

itia

lbu

rst

rele

ase

by

incr

easi

ng

ofth

em

olec

ula

rw

eigh

tof

the

pol

ym

er.

Su

stain

edan

ti-i

nfl

am

mato

ryef

fect

for

21

days

315


4636 LARSEN ET AL.

Ta

ble

3.

(Con

tin

ued

)

Dru

g/M

odel

Com

pou

nd

An

imal

Mod

el/H

um

an

Com

men

tsR

efer

ence

s

Met

hot

rexate

Rabbit

(hea

lth

y)

Pol

y(L

-lact

ide)

mic

rosp

her

es.

Part

icle

size

:60–190m

m.

Rap

idbu

rst

rele

ase

(in

vit

ro).

Ind

icati

onof

asl

igh

tly

pro

lon

ged

dru

gre

lease

com

pare

dto

the

free

dru

gin

aso

luti

on.

Rec

over

yof

small

dru

gam

oun

tsin

the

syn

ovia

lti

ssu

esaft

er24

h.

Pot

enti

al

dep

osit

ion

ofm

icro

sph

eres

inth

ead

ipos

ela

yer

316,3

17

Insu

lin

Mou

se(h

ealt

hy)

Pol

y(D

,L-l

act

ide-

co-g

lyco

lid

e)m

icro

sph

eres

.R

ap

idbu

rst

rele

ase

(in

vit

ro).

Insu

lin

act

ivit

y(s

tim

ula

tion

ofE

CM

syn

thes

is)

aft

erre

lease

from

mic

rosp

her

es

318

Hol

ium

-166

Rabbit

(hea

lth

y)

Pol

y(L

-lact

ide)

mic

rosp

her

es.

Part

icle

size

:2–13m

m.

Ret

enti

onin

the

join

tsp

ace

(98%

aft

er120

h).

No

up

tak

eby

the

lym

ph

nod

es319

Hol

ium

-166

Pati

ents

wit

hR

AC

hit

osan

mic

rosp

her

es.

Part

icle

size

not

defi

ned

.M

ost

ofth

ein

ject

edd

ose

rem

ain

slo

cate

din

the

join

tca

vit

y320,3

21

DD

SD

rug/M

odel

Com

pou

nd

An

imal

Mod

elC

omm

ents

Ref

eren

ces

Mis

cell

an

eou

sD

DS

Su

per

para

magn

etic

iron

oxid

en

an

opart

icle

sF

luor

esce

nt

dye

(Cy3.5

)S

hee

p(h

ealt

hy)

Su

per

para

magn

etic

iron

oxid

en

an

opart

icle

sco

ate

dw

ith

pol

yvin

yl

alc

ohol

.E

nfo

rced

up

tak

ein

toth

esy

nov

ium

by

an

extr

aco

rpor

all

yap

pli

edm

agn

et

322

Zyn

-Lin

ker

sTM

Re-

186

orY

-90

Rabbit

(hea

lth

y)

Syn

thet

icli

pid

–li

ke

mol

ecu

les

des

ign

edfo

rlo

cal

del

iver

y,

for

exam

ple

,of

rad

ion

ucl

ides

for

rad

iosy

nov

ecto

my.

Rap

idbin

din

gof

Zyn

-Lin

ker

sto

the

syn

oviu

m.

Loc

ali

zati

onan

dre

ten

tion

inth

ek

nee

regio

n(>

90%

aft

er4–6

days)

323

Com

ple

xG

ad

olin

ium

tetr

aaza

cycl

odod

ecan

ete

traace

tic

aci

d

Dog

(hea

lth

y)

Gd

-com

ple

xas

con

trast

agen

tsin

MR

imagin

gof

the

join

ts.

Mea

nIA

half

-lif

eof

the

com

ple

xcl

ose

to2

h

324

Ela

stin

-lik

ep

olyp

epti

des

(EL

P)

Non

eR

at

(hea

lth

y)

Th

erm

ogel

lin

gbio

pol

ym

ers

(EL

P)

that

aggre

gate

up

onIA

inje

ctio

n.

Pro

lon

ged

rete

nti

onin

the

join

tca

vit

y(n

onaggre

gati

ng

EL

P,

t 1/2¼

3.4

h;

aggre

gati

ng

EL

P,

t 1/2¼

3.7

days)

201

Calc

ium

alg

inate

Tra

nsf

orm

ing

gro

wth

fact

or-b

Rabbit

(ost

eoch

ond

ral

def

ects

)Im

pla

nta

tion

ofalg

inate

bea

ds

into

oste

och

ond

ral

def

ects

.S

low

invit

rore

lease

ofT

GF

-bfr

omalg

inate

(30%

to40%

rete

nti

onaft

er5

days)

.Im

pro

ved

rep

air

ofth

eart

icu

lar

cart

ilage

def

ects

325

(Con

tin

ued

)

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 11, NOVEMBER 2008


Ta

ble

3.

(Con

tin

ued

)

DD

SD

rug/M

odel

Com

pou

nd

An

imal

Mod

elC

omm

ents

Ref

eren

ces

Gel

ati

nh

yd

rogel

mic

rosp

her

esB

asi

cfi

bro

bla

stgro

wth

fact

or(b

FG

F)

Rabbit

(hea

lth

yan

din

du

ced

art

hri

tis)

Mea

np

art

icle

size

:70m

m.

Ret

enti

onin

the

join

tca

vit

y(3

%re

main

ing

aft

er7

days)

.L

ocali

zati

onof

bF

GF

inso

ftti

ssu

e(i

ncl

ud

ing

syn

oviu

m)

bu

tn

otin

art

icu

lar

cart

ilage.

Ind

icate

ind

uce

dan

abol

icef

fect

son

cart

ilage

an

dsu

pp

ress

ion

ofth

ep

rogre

ssio

nof

OA

326

Gel

ati

n/c

hon

dro

itin

6-s

ulf

ate

mic

rosp

her

esA

lbu

min

an

dca

tala

se(m

odel

pro

tein

s)M

ouse

(hea

lth

y)

No

ph

agoc

yto

sis

ofth

em

icro

sph

eres

.M

icro

sph

eres

wer

efo

un

dto

be

non

infl

am

mato

ryin

viv

o196

Late

xp

art

icle

sN

one

Rat

(hea

lth

y)

Pol

yst

yre

ne

late

xaver

age

part

icle

size

:240

nm

.P

hagoc

yto

sis

ofsy

nov

ial

cell

sat

the

syn

oviu

m-c

art

ilage

jun

ctio

nw

as

stu

die

d.

Pot

enti

al

invol

vem

ent

ofbot

hty

pe

A(m

acr

oph

age-

lik

e)an

dty

pe

B(fi

bro

bla

st-l

ike)

syn

ovia

lce

lls,

chon

dro

cyte

san

dte

nd

once

lls

inth

ep

hagoc

yto

sis

327

4638 LARSEN ET AL.


various barriers to drug delivery includingbiocompatibility, fast elimination and targetaccess.166,167 A safety concern to be consideredis, however, that one of the most frequentlyencountered clinical problems after infusion ofPEGylated liposomes into certain subjects is theinitiation of non-IgE-mediated hypersensitivityreactions. These pseudoallergic reactions arebelieved to arise via complement activation.168,169

In liposome-based product development alsocritical technology-oriented challenges mightemerge. These might relate to the large-scale(aseptic) manufacturing process as well as to theachievement of acceptable long-term physicalstability of the formulation.170 Water-solubledrugs are mainly entrapped in the aqueous space,whereas more lipophilic compounds can be inter-calated into the phospholipid bilayer. In the lattercase only modest drug loads can be accomplished.Liposomal preparations containing lipophilic cor-ticosteroid derivatives (Tab. 3) afforded sustainedanti-inflammatory activity after IA injection inthe rabbit and in man.171–176 The steroids weremost likely incorporated into the phosholipidbilayer. Shaw177 observed a diminished retentionof cortisol derivatives in dipalmitoyl phosphati-dylcholine liposomes as a function of decreasinglipophilicity of the investigated compounds afterapplying such liposomes to aqueous buffer. Incomparison to the steroid preparations, the morepolar drugs methotrexate, lidocaine and diclofe-nac experienced a much less pronounced prolon-gation of the IA residence time from liposomeformulations.178–180 Despite the limited number ofstudies performed (involving different experimen-tal conditions) it appears that the inherentsustained release capability of conventional lipo-some preparations is questionable. For drugsdissolved in the aqueous core, drug release isexpected to proceed through diffusion across theintact bilayer whereas burst release may resultfrom destruction of the phospholipid membranes.Analogously, drug liberation from degraded lipidmembranes, in case of the steroid liposomeformulations, will most likely lead to precipitationof the poorly soluble steroid derivative. Sinceadequate reference formulations containing therespective steroid derivative were not included inthe above mentioned studies it cannot be excludedthat the observed sustained anti-inflammatoryeffects were afforded by slow dissolution of theprecipitated drugs in the joint cavity. In thiscontext it should be mentioned that the Depo-Foam1 technology, that may show some resem-

08 DOI 10.1002/jps


blance to multivesicular liposomes, may be usefulfor sustained drug delivery.181

Sustained release properties of biodegradablemicrosphere preparations (with the active agentdissolved or dispersed in a polymer-based matrix)are well-established. A number of microsphere-based products (duration of therapeutic activityranging from about 2 weeks to 3 months) areapproved for parenteral administration in areassuch as cancer and schizophrenia.182 Owing totheir excellent biocompatibility, the biodegrad-able polyesters poly(lactide-co-glycolide) (PLGA)are the most frequently used materials for themicroencapsulation of drugs. Despite the fact thatPLGA-based products have been launched, thedevelopment of therapeutic PLGA microspheresmight, however, be far from straightforward asdiscussed in more detail elsewhere.183,184 Othersynthetic polymers frequently used in the designof microparticles include polyanhydrides,185,186

poly(ortho esters)187 and poly-e-caprolactone.188

Polymeric matrices comprising polymers of nat-ural origin, such as albumin189 and chitosan,190

have also been investigated. The in vivo studiesperformed (Tab. 3) do not provide a clear-cutpicture of the capability of the microsphereapproach to substantially prolong the IA resi-dence time of drugs. In general, modification ofdrug release can be accomplished by the employ-ment of copolymers consisting of synthetic poly-mers endowed with different susceptibilities toundergo hydrolytic degradation or throughchange of drug lipophilicity by prodrug forma-tion.191 Basically, after an initial burst, drugliberation from such depots may involve (i) drugdiffusion out of the matrix, (ii) erosion of thematrix or (iii) a combination of these two releasemechanisms. Diffusion controlled release is tobe expected for small-molecule water-solubledrugs imbedded in hydrophilic polymer networkssuch as chitosan microspheres.192 As to themore hydrophobic synthetic polymers, poly-e-caprolactone188 and poly(ortho ester)187 micro-spheres degrade mainly by bulk hydrolysis andsurface erosion, respectively. In contrast PLGA(and probably also polyanhydride-based) micro-spheres may undergo both surface and bulk ero-sion. The underlying mechanism for bulk erosion(and the accompanying significant decrease in corepH) is not fully elucidated.183,193,194 Like lipo-somes, microspheres might be taken up by syno-vial macrophages after instillation into the jointspace. Size-dependent phagocytotic uptake havebeen observed (Tab. 3) but parameters like surface


charge might also influence the efficiency of endo-cytosis where apparently a net negative surfacecharge prohibits extensive phagocytosis.195,196

Seemingly, glucocorticoids represent the onlydrug class that has been injected intra-articularlyin the form of depot suspensions. As mentioned ina previous section such formulations are reason-ably well tolerated although ‘‘steroid flare’’ reac-tions occasionally occur.197 In vitro phagocytosisof steroid crystals by leukocytes has beenreported,198 however, information about uptakeof solid steroid particles by synovial cells in vivo isapparently lacking. Drug appearance in the SFafter IA injection of aqueous suspensions ismainly governed by the dissolution rate of thepoorly soluble agent. According to the Noyes-Whitney equation, the dissolution rate is directlyproportional to the drug solubility and the totalsurface area of the solid particles. The parenteralsuspension may be an advantageous dosage formfrom the perspective that high drug load can beachieved and only a minimum of pharmaceuticalexcipients is needed. However, in spite of thesimplicity of this formulation type, parenteralsuspensions pose certain challenges to the man-ufacturing process and physical stability.199,200

Interestingly, aqueous solutions of certainelastin-like polypeptides (biopolymers with mole-cular weights in the order of 50 kDa) are observedto exhibit a phase transition above a giventransition temperature characterized by the for-mation of micron or submicron size aggregates(potential drug vehicles). In situ aggregate for-mation after IA injection of aqueous solutions ofsuch biopolymers in rats resulted in a significantlyprolonged IA residence time as compared to that ofthe dissolved biopolymer.201 Also patented depotDDS principles based on in situ gel formationmight be of potential interest for the IA route ofadministration.202,203 In fact, the in situ formingparenteral DDS approach may, in general, con-stitute a means to circumvent various criticalissues, such as physical stability and sterilization,related to the development of microparticulatesystems.204–206

On Novel IA Approaches for PostoperativePain Control

It is to be expected that future IA depots acting ina multimodal fashion should comprise at least oneanalgesic agent and one anti-inflammatory drug.In addition to the IA depot principles dealt withabove, it can be mentioned that in the area of


4640 LARSEN ET AL.

local anesthetics several approaches to achievesustained drug action after various parenteralroutes of administration have been investigated.The therapeutic agents, mainly bupivacaine andlidocaine, have been incorporated into micro-spheres,207–216 liposomal formulations,217–223

lipid solutions (iophendylate),224–226 vegetableoil,227 liquid synthetic polymers,228 lipid–protein–sugar particles,229 injectable gels,230 dry emul-sions to be reconstituted prior to use,231 andlipospheres.232 Interestingly, inclusion of smallamounts of dexamethasone (about 0.04%) inbupivacaine microspheres has been demonstratedto prolong bupivacaine analgetic activity signifi-cantly in animal studies.211,212 Similar effectshave been observed in man as regards intercostalblockade207 and after subcutaneous infiltration ofbupivacaine microspheres.208 The mechanismsbehind the blockade-prolonging effect of gluco-corticoids are far from fully elucidated.208

Assuming that optimal pain relief after minorjoint surgery requires analgetic and anti-inflam-matory action locally at the site of trauma overabout 1 and 7 days, respectively, the first step inthe search for achievement of this therapeuticgoal might be to investigate the possibility ofusing combinations of already marketed drugproducts. Although sufficiently prolonged anti-inflammatory activity can be accomplished byusing suspensions of glucocorticoid ester deriva-tives such as methylprednisolone acetate (Depo-Medrol1), their onset of action might be relativelyslow. Also suspensions of poorly soluble esterprodrugs of the more potent steroid betametha-sone (e.g., Diprospan1)233 are used for IA injec-tion. In addition to the 17,21-dipropionylesterderivative, the latter product also containsbetamethasone in the form of the water-soluble21-phosphate ester. The rationale for incorpora-tion of the water-soluble prodrug is apparently toensure fast onset of drug action. After entranceinto the systemic circulation, 21-phosphate estersof various glucocorticoids are cleaved relativelyfast to give the parent drug.234,235 After i.v.injection of dexamethasone phosphate ester thein vivo conversion rate exceeded that observedafter prodrug incubation in full blood by a factor ofabout 25, suggesting that the major sites forphosphate ester bond cleavage are the highlyperfused organs, that is, the liver and kidney.236

In this connection, determination of betametha-sone pharmacokinetics after combined IA injec-tion of the acetate and phosphate 21-esters of thecorticosteroid led to the suggestion that the


phosphate ester did seem to be an unnecessarypart of the combination due to rapid clearancefrom the joint cavity.237 Aqueous solutions ofmorphine and bupivacaine are marketed, andboth drugs (and in combinations) have demon-strated positive analgesic effects after IA injec-tion. However, as discussed in more detailelsewhere26 their effectiveness in the immediatepostoperative period are relatively short-lived (atbest 8–12 h in case of morphine).

In summary, it appears conceivable to suggestthat optimal IA multimodal analgesia is presentlynot achievable by combinations of existing pro-ducts due to the lack of sufficiently long-actingtherapies for abolishment of the acute painfollowing surgical injuries. Although speculative,prolongation of the effects of morphine andbupivacaine might potentially be achieved byadministering these agents in the form of poorlysoluble salts. It is well known that pamoic acidforms poorly soluble salts with many drugscontaining an amine functional group.238,239 Alsoother aromatic ortho-hydroxycarboxylic acidshave been observed to render relatively poorlysoluble amine salts240,241 including the NSAIDdiflunisal, that forms salts with morphine, bupi-vacaine as well as lidocaine. Use of the commonion effect for prolonging the release of bupivacainefrom mixed salt suspensions in vitro have recentlybeen reported.242 Compared with the use ofcombinations of drug products, an IA depot typecapable of controlled parallel release of ananalgesic and an anti-inflammatory agent may,a priori, exhibit therapeutic advantages. To thisend lipid solutions might be of potential interest.Oil depot injectables (mainly ester prodrugs ofantipsychotics and steroid hormones dissolvedin vegetable oils) for intramuscular and subcuta-neous administration have been in the market-place for decades.243–245 The fact that drug releaserates from such oil vehicles, at least in part, areinfluenced by the oil–water distribution coeffi-cient of the drug246,247 opens for the possibility ofdesign of depots with feasible delivery character-istics since manipulation of distribution coeffi-cients might be accomplished through prodrugformation (e.g., morphine ester prodrugs248) oroptimization of oil vehicle composition.249

On Novel IA Approaches in Arthritic Disorders

Whereas inhibition or modification of the activityof components of the SF might be of relevance in

08 DOI 10.1002/jps


the treatment of arthritic disorders, the synoviumand the articular cartilage are considered addi-tional major target tissues for drug action asregard RA and OA, respectively. In a recentreview,250 approaches for targeting the inflamedsynovium via the systemic circulation have beendealt with in a highly competent manner. Inaddition to liposome approaches to providesynovial macrophage depletion following endocy-tosis,251 some of the strategies to confer regionalor cell-specific homing of therapeutic agents mightalso give inspiration to the development of novelIA depot formulations providing sustained as wellas targeted drug action. Based on results obtainedby using integrin antagonists,252–255 the prospectsfor the use of novel small-molecule antagonists ofcell-specific CAM molecules as pro-moieties injoint-targeted prodrug design appears especiallyattractive. Also synovial-specific transductionpeptides may be used as transport vectors tofacilitate drug access to activated synovial fibro-blasts.256 In case the ultimate target is locatedin the SF or within the articular cartilage,nonspecific phagocytotic uptake of the injecteddepot DDS by cells of the synovial lining isunwanted. Due to the architecture of the carti-lage, electrically neutral solute molecules withmolecular weights above approximately 10 kDahave been shown to get modest access to the innerspace of the ECM. It is therefore less likely thateven nanosize DDS should accumulate to anysignificant extent within the cartilage microen-vironment. These considerations may suggestthat prolonged delivery to cartilage sites of drugaction can only be accomplished when the drug isreleased from the immobilized depot directly intothe SF or perhaps preferably, at the interfacebetween the SF and the cartilage. In addition tosize, also the charge of the active agents isexpected to influence transport into the ECM ofthe cartilage. The high negative charge density ofthis matrix may limit the entrance of anionic drugcompounds. Transient masking of such negativecharges by prodrug design might abolish or atleast minimize this barrier to effective drugdistribution into the cartilage. Since nonspecificphagocytosis, at least theoretically, can be avoidedby careful control of particle size (distribution)and overall surface charge, it appears conceivableto suggest that a number of microparticulate-based depot types possesses the potential ofenabling slow drug release into the SF after IAinstillation. More detailed information about thein vivo fate of such depot types including the


kinetics of drug release from the depot has,however, to be established through future studies.Interestingly, modulation of drug release mightalso be accomplished by using depot buildingblocks that are susceptible to degradationmediated by enzymes, the SF level of which isexpected to vary with the state of inflammation.To this end it has been shown that model proteinrelease rates from gelatin-chondroitin 6-sulfatemicrospheres varied with the concentration ofmatrix metalloproteases in the SF.196 Althoughspeculative, chitosan-based drug delivery systemsmight provide some degree of drug release at theSF-cartilage interface. Despite the fact that theamine groups of this polysaccharide are onlypartly ionized at physiological pH (pKa 6.3190)some affinity to the anionic ECM of the cartilagecan not be excluded. Further, this polysaccharideis of significant interest in the design of in situforming depot systems, since the physical proper-ties of polymeric chitosans change with theenvironmental pH. Under acidic conditions itforms a viscous solution, whereas the compoundtransforms into a gel at pH 7.4.257

In Vitro Release Models for Quality Control andFormulation Development Purposes

From a regulatory point of view the drug productspecifications is a key document through whichreproducible product quality, or in other wordsbatch to batch consistency of product perfor-mance, has to be documented. This documentationmay, dependent on the formulation type in ques-tion, embrace different product characteristics.On the other hand control of drug release ratefrom the formulation has to be demonstrated forall parenteral depots. In this field, therefore,development of suitable in vitro release models(for quality control as well as formulationdevelopment purposes) constitutes a significantchallenge, Currently, no regulatory approvedstandard methods exist for testing drug releasefrom controlled release parenteral products. Asregard such quality control methods, acceleratedin vitro release testing might be of particularutility for parenteral depots characterized by aduration of action exceeding a few weeks.258–260

Basically, employed in vitro release methodsmight be divided into three broad categories (i)sample and separate methods, (ii) continuous flowmethods, and (iii) dialysis techniques.261,262 TwoUSP (United States Pharmacopeia) apparatus,


4642 LARSEN ET AL.

the reciprocal cylinder (apparatus 3) and the flowthrough cell (apparatus 4) have been recom-mended for controlled release parenterals.258–260

In addition to the use in quality control andformulation development, the in vivo relevance ofemployed in vitro methods should also be con-sidered.260 Dialysis membrane-based models arein general considered feasible only for the studyof drug release from depots intended for admin-istration sites for which drug release undernonsink conditions is prevailing.262,263 The dia-lysis technique has been used to study drug rele-ase from a variety of formulations, for example, oilsolutions,247 aqueous suspensions,241,242 micro-spheres,264,265 liposomes,266–268 nanoparticles,269

emulsions,270,271 and in situ forming DDS.272

Different experimental setups have been used,with the relatively simple dialysis bag techniquebeing the most widely used model.268–272 Thisincludes the Float A Lyzer1 tube system thatrecently has gained considerable inter-est.261,264,265 A bulk reverse dialysis bag techni-que270,271 has been applied in order to circumventproblems related to the maintenance of sinkconditions during the release studies. Othermodel modifications include the side-by-sidediffusion cell,270 a fractional dialysis method,267

the reciprocating dialysis tubes273 and the rotat-ing dialysis cell.241,242,246,247,249,274–279 Sincemodel related factors vary from model to model,rate constants obtained by using different meth-ods are not directly comparable.

In case of IA injection, the depot is administeredinto a small compartment (the joint cavity) inwhich the drug is released under nonsink condi-tions. Due to the noncontinuous nature of thesynovial lining, small-molecule drugs are mainlytransported out of this compartment and into theblood driven by a diffusional process.

In particular the rotating dialysis cell model,consisting of a small donor compartment (max.10 mL) and a large acceptor compartment (max.1000 mL) might appear attractive for investiga-tion of some key parameters influencing IA drugresidence times after local instillation of variousdepot DDS.241,242,247,276 In the area of in vitro–in vivo correlations, however, the latter method isexpected to be applicable primarily for simpledrug formulations. To this end the disappearanceof drugs (molecular weight range 137–2068 Da),applied to the donor cell of this model in the formof aqueous solutions, was found to obey strict first-order kinetics with half-lives in the range of 0.2–8 h.276 Interestingly, quite similar IA elimination


half-lives have been reported in the literature(Tab. 2). The applicability of the rotating dialysiscell model to simulate the drug transfer rates outof the joint cavity is presently under investigationin our lab.

CONCLUDING REMARKS

Compared to oral administration, the advantageof intra-articular drug instillation is that only aminimum amount of drug is required to exert localactivity within the joint space. This relativelysimple form of localized drug delivery minimizesdrug exposure to inappropriate sites. Since drugsdissolved in the synovial fluid are rapidly elimi-nated from the joint (t1/2 of about 0.1–6 h),maintenance of therapeutic concentrations overextended periods of time necessitates the admin-istration of the drug in the form an injectabledepot formulation. There is still an unmet need forIA therapies providing optimal pain relief afterminor joint surgery. Such alleviation of post-operative pain, based on the concept of multi-modal analgesia, may involve concomitant releaseof analgesics and anti-inflammatory agents fromthe IA delivery system over about 1 and 7 days,respectively. In the area of osteoarthritis, approv-ed disease-modifying therapies are lacking. Noveltreatment options may arise from the identifica-tion of a vast number of potential targets for drugaction. Since OA usually affects a single or only afew joint(s), long-lasting IA technologies compris-ing future anti-arthritic agents hold promise.Several formulation principles are used in mar-keted (non-IA) parenteral depots despite the factthat, for example, their manufacture and physicalstability are far from straightforward. The per-formance of these depot types (and many others)after IA injection has been investigated primarilyin animal models. Promising results are achievedbut need to be substantiated by future studies. Tothis end, it has to be realized that localized drugdelivery not necessarily is synonymous withtargeted drug delivery, especially when the drugtarget is located in the articular cartilage whichmay constitute a significant barrier to highmolecular weight drugs. However, already avail-able results suggest that intra-articular depotformulations, containing drug mixtures for multi-modal analgesia or future arthritic disease-modifying agents, are likely to emerge within areasonable time horizon.

08 DOI 10.1002/jps


ACKNOWLEDGMENTS

The present contribution has been supportedby the Danish Medicinal Research Council, theDanish Rheumatism Association, and the DrugResearch Academy, Copenhagen Denmark.

REFERENCES

1. Caldwell JR. 1996. Intra-articular corticosteroids.Guide to selection and indications for use. Drugs52:507–514.

2. Hunter JA, Blyth TH. 1999. A risk-benefit assess-ment of intra-articular corticosteroids in rheu-matic disorders. Drug Saf 21:353–365.

3. Bellamy N, Campbell J, Robinson V, Gee T,Bourne R, Wells G. 2006. Intraarticular corticos-teroid for treatment of osteoarthritis of the knee.Cochrane Database Syst Rev 2:CD005328.

4. Buckwalter JA, Martin JA. 2006. Osteoarthritis.Adv Drug Deliv Rev 58:150–167.

5. Baker CL, Ferguson CM. 2005. Future treatmentof osteoarthritis. Orthopedics 28:S227–S234.

6. Evans CH. 2005. Novel biological approaches tothe intra-articular treatment of osteoarthritis.BioDrugs 19:355–362.

7. Wieland HA, Michaelis M, Kirschbaum BJ, Rudol-phi KA. 2005. Osteoarthritis. An untreatable dis-ease. Nat Rev Drug Discov 4:331–344.

8. Abramson S. 2006. Drug delivery in degenerativejoint disease: Where we are and where to go? AdvDrug Deliv Rev 58:125–127.

9. Tomlinson E. 1987. Theory and practice of site-specific drug delivery. Adv Drug Deliv Rev 1:87–198.

10. Gardner E. 1972. The structure and function ofjoints. 8 edition. Philadelphia: Lea and Febiger.pp. 32–50.

11. Agarwal SK, Brenner MB. 2006. Role of adhesionmolecules in synovial inflammation. Curr OpinRheumatol 18:268–276.

12. Pap T, M-Ladner U, Gay RE, Gay S. 2007. Fibro-blast biology. Role of synovial fibroblasts in thepathogenesis of rheumatoid arthritis. ArthritisRes 2:361–367.

13. Stanczyk J, Ospelt C, Gay RE, Gay S. 2006. Syno-vial cell activation. Curr Opin Rheumatol 18:262–267.

14. Szekanecz Z, Szucs G, Szanto S, Koch AE. 2006.Chemokines in rheumatic diseases. Curr DrugTargets 7:91–102.

15. Evans CH, Gouze E, Gouze JN, Robbins PD, Ghi-vizzani SC. 2006. Gene therapeutic approaches-transfer in vivo. Adv Drug Deliv Rev 58:243–258.

16. Jessar RA. 1972. The study of synovial fluid. 8edition. Philadelphia: Lea and Febiger. pp. 67–81.


17. Tercic D, Bozic B. 2001. The basis of the synovialfluid analysis. Clin Chem Lab Med 39:1221–1226.

18. Carney SL, Muir H. 1988. The structure and func-tion of cartilage proteoglycans. Physiol Rev 68:858–910.

19. Aigner T, Stove J. 2003. Collagens—Major com-ponent of the physiological cartilage matrix, majortarget of cartilage degeneration, major tool in carti-lage repair. Adv Drug Deliv Rev 55:1569–1593.

20. Hardingham TE, Fosang AJ. 1992. Proteoglycans—Many forms and many functions. FASEB J 6:861–870.

21. Goldring MB. 2006. Update on the biology of thechondrocyte and new approaches to treating car-tilage diseases. Best Pract Res Clin Rheumatol20:1003–1025.

22. Vinatier C, Guicheux J, Daculsi G, Layrolle P,Weiss P. 2006. Cartilage and bone tissue engineer-ing using hydrogels. Biomed Mater Eng 16:S107–S113.

23. Nesic D, Whiteside R, Brittberg M, Wendt D,Martin I, Mainil-Varlet P. 2006. Cartilage tissueengineering for degenerative joint disease. AdvDrug Deliv Rev 58:300–322.

24. Lee S-H, Shin H. 2007. Matrices and scaffolds fordelivery of bioactive molecules in bone and carti-lage tissue engineering. Adv Drug Deliv Rev 59:339–359.

25. Brown AK, Christo PJ, Wu CL. 2004. Strategiesfor postoperative pain management. Best PractRes Clin Anaesthesiol 18:703–714.

26. Reuben SS, Sklar J. 2000. Current conceptsreview. Pain management in patients whoundergo outpatient arthroscopic surgery of theknee. J Bone Joint Surg 82-A:1754–1766.

27. Rasmussen S, Larsen AS, Thomsen ST, Kehlet H.1998. Intra-articular glucocorticoid, bupivacaineand morphine reduces pain, inflammatoryresponse and convalescence after arthroscopicmeniscectomy. Pain 78:131–134.

28. Gupta A. 2003. Update on intra-articular analge-sia. Techniq Reg Anesth Pain Man 7:155–160.

29. Rømsing J, Møiniche S, Østergaard D, Dahl JB.2000. Local infiltration with NSAIDs for post-operative analgesia: Evidence for a peripheralanalgesic action. Acta Anaesthesiol Scand 44:672–683.

30. Møiniche S, Mikkelsen S, Wetterslev J, Dahl JB.1999. A systematic review of intra-articular localanesthesia for postoperative pain relief afterarthroscopic knee surgery. Reg Anesth Pain Med24:430–437.

31. Kalso E, Smith L, McQuay HJ, Moore RA. 2002.No pain, no gain: Clinical exellence and scientificrigour—Lessons learned from IA morphine. Pain98:269–275.

32. Gupta A, Bodin L, Holmstrom B, Berggren L.2001. A systematic review of the peripheral


4644 LARSEN ET AL.

analgesic effects of intraarticular morphine.Anesth Analg 93:761–770.

33. Kehlet H, Dahl JB. 1993. The value of multimodalor balanced analgesia in postoperative pain treat-ment. Anesth Analg 77:1048–1056.

34. Kehlet H, Werner M, Perkins F. 1999. Balancedanalgesia—What is it and what are its advantagesin postoperative pain? Drugs 58:793–797.

35. Elhakim M, Nafie M, Eid A, Hassin M. 1999.Combination of intra-articular tenoxican, lido-caine and pethidine for outpatient knee arthro-scopy. Acta Anaesthesiol Scand 43:803–808.

36. Talu GK, Ozyalcm S, Koltka K, Erturk E, AkmerO, Asik M, Pembeci K. 2002. Comparison of effi-cacy of intraarticular application of tenoxicam,bupivacaine and tenoxicam: Bupivacaine combi-nation in arthroscopic knee surgery. Knee SurgSports Traumatol Arthrosc 10:355–360.

37. Uysalei A, Kecik Y, Kirdemir P, Sayin M, BinnetM. 1995. Comparison of intraarticular bupiva-caine with the addition of morphine or fentanylfor analgesia after arthroscopic surgery. Arthro-scopy 11:660–663.

38. Reuben SS, Connelly NR. 1995. Postoperativeanalgesia for outpatient arthroscopic knee surgerywith intraarticular bupivacaine and ketorolac.Anesth Analg 80:1154–1157.

39. Rasmussen S, Lorentzen JS, Larsen AS, ThomsenST, Kehlet H. 2002. Combined intra-articular glu-cocorticoid, bupivacaine and morphine reducespain and convalescence after diagnostic kneearthroscopy. Acta Orthop Scand 73:175–178.

40. Rasmussen S, Kehlet H. 2000. Intraarticular glu-cocorticoid, morphine and bupivacaine reducespain and convalescence after arthroscopic anklesurgery: A randomized study of 36 patients. ActaOrthop Scand 71:301–304.

41. Kizilkaya M, Yildirim OS, Dogan N, Kursad H,Okur A. 2004. Analgesic effects of intraarticularsufentanil and sufentanil plus methylpredniso-lone after arthroscopic knee surgery. AnesthAnalg 98: 1062–1065.

42. Buerkle H, Huge V, Wolfgart M, Steinbeck J,Mertes N, Van Aken H, Prien T. 2000. Intra-articular clonidine analgesia after knee arthro-scopy. Eur J Anaesthesiol 17:295–299.

43. Reuben SS, Connelly NR. 1999. Postoperativeanalgesia for outpatient arthroscopic knee surgerywith intraarticular clonidine. Anesth Analg 88:729–733.

44. Sandell LJ, Aigner T. 2001. Articular cartilageand changes in arthritis. An introduction: Cellbiology of osteoaerthritis. Arthritis Res 3:107–113.

45. McIlwraith CW. 2005. Use of synovial fluid andserum biomarkers in equine bone and joint dis-ease: A review. Equine Vet J 27:473–482.


46. Burrage PS, Mix KS, Brincherhoff CE. 2006.Matrix metalloproteinases: Role in arthritis. FrontBiosci 11:529–543.

47. Abramson SB, Attur M, Yazici Y. 2006. Prospectsfor disease modification in osteoarthritis. Nat ClinPract Rheumatol 2:304–312.

48. Cooper NJ. 2000. Economic burden of rheumatoidarthrtis: A systematic review. Rheumatology (Oxford)39:28–33.

49. Elders MJ. 2000. The increasing impact of arthri-tis on public health. J Rheumatol 27:6–8.

50. Reginster JY, Khaltaev NG. 2002. Introductionand WHO perspective on the global burdenof musculoskeletal conditions. Rheumatology(Oxford) 41:1–2.

51. Choy EH, Panayi GS. 2001. Cytokine pathwaysand joint inflammation in rheumatoid arthritis.N Engl J Med 344:907–916.

52. Cannella AC, O’Dell JR. 2006. Early rheumatoidarthritis—Pitfalls in diagnosis and review ofrecent clinical trials. Drugs 66:1319–1337.

53. Steinmeyer J, Konttinen YT. 2006. Oral treatmentoptions for degenerative joint disease-presenceand future. Adv Drug Deliv Rev 58:168–211.

54. Haagsma CJ, Russel FG, Vree TB, Van Riel PL,Van de Putte LB. 1996. Combination of methotrex-ate and sulphasalazine in patients with rheuma-toid arthritis: Pharmacokinetic analysis andrelationship to clinical response. Br J Clin Phar-macol 42: 195–200.

55. Proudman SM, Conaghan PG, Richardson C, Grif-fiths B, Green MJ, McGonagle D, Wakefield RJ,Reece RJ, Miles S, Adebajo A, Gough A, HelliwellP, Martin M, Huston G, Pease C, Veale DJ, IsaacsJ, van der Heijde DM, Emery P. 2000. Treatmentof poor-prognosis early rheumatoid arthritis. Arandomized study of treatment with methotrex-ate, cyclosporin A, and intraarticular corticoster-oids compared with sulfasalazine alone. ArthritisRheum 43:1809–1819.

56. Wilke WS, Mackenzie AH. 1986. Methotrexatetherapy in rheumatoid arthritis current status.Drugs 32:103–113.

57. Mullan RH, Bresnihan B. 2003. Disease-modifyinganti-rheumatic drug therapy and structuraldamage in early rheumatoid arthritis. Clin ExpRheumatol 21:S158–S164.

58. Smith RJ. 2005. Therapies for rheumatoid arthri-tis: Hope springs eternal. Drug Discov Today 10:1598–1606.

59. Gartlehner G, Hansen RA, Jonas BL, Thieda P,Lohr KN. 2006. The comparative efficacy andsafety of biologics for the treatment of rheumatoidarthritis: A systematic review and metaanalysis.J Rheumatol 33:2398–2408.

60. Fleurence R, Spackman E. 2006. Cost-effective-ness of biologic agents for the treatment of auto-

08 DOI 10.1
002/jps


immune disorders: Structured review of the litera-ture. J Rheumatol 33:2124–2131.

61. Christodoulou C, Choy EH. 2006. Joint inflamma-tion and cytokine inhibition in rheumatoid arthri-tis. Clin Exp Med 6:13–19.

62. Aigner T, Sachse A, Gebhard PM, Roach HI. 2006.Osteoarthritis: Pathobiology-targets and ways fortherapeutic intervention. Adv Drug Deliv Rev 58:128–149.

63. Pelletier JP, Martel-Pelletier J, Abramson SB.2001. Osteoarthritis, an inflammatory disease—Potential implication for the selection of new ther-apeutic targets. Arthritis Rheum 44:1237–1247.

64. Watterson JR, Esdaile JM. 2000. Viscosupplemen-tation: Therapeutic mechanisms and clinicalpotential in osteoarthritis of the knee. J Am AcadOrthop Surg 8:277–284.

65. Uthman I, Raynauld JP, Haraoui B. 2003. Intra-articular therapy in osteoarthritis. PostgradMed J 79:449–453.

66. Gerwin N, Hops C, Lucke A. 2006. Intraarticulardrug delivery in osteoarthritis. Adv Drug DelivRev 58:226–242.

67. Gossec L, Dougados M. 2006. Do intra-articulartherapies work and who will benefit most? BestPract Res Clin Rheumatol 20:131–144.

68. Curtis CL, Harwood JL, Dent CM, Caterson B.2004. Biological basis for the benefit of nutraceu-tical supplementation in arthritis. Drug DiscovToday 9:165–172.

69. Hogenmiller MS, Lozada CJ. 2006. An update onosteoarthritis therapeutics. Curr Opin Rheumatol18:256–260.

70. Tremoulet AH, Albani S. 2006. Novel therapies forrheumatoid arthritis. Expert Opin Investig Drugs15:1427–1441.

71. Goldring MB. 2001. Anticytokine therapy forosteoarthritis. Expert Opin Biol Ther 1:817–829.

72. Abramson SB, Yazici Y. 2006. Biologics in devel-opment for rheumatoid arthritis: Relevance toosteoarthritis. Adv Drug Deliv Rev 58:212–225.

73. Chevalier X, Giraudeau B, Conrozier T, MarliereJ, Kiefer P, Goupille P. 2005. Safety study ofintraarticular injection of interleukin 1 receptorantagonist in patients with painful knee osteoar-thritis: A multicenter study. J Rheumatol 32:1317–1323.

74. Cornelis S, Kersse K, Festjens N, Lamkanfi M,Vandenabeele P. 2007. Inflammatory caspases:Targets for novel therapies. Curr Pharm Des 13:365–383.

75. Valko M, Leibfritz D, Moncol J, Cronin MTD,Mazur M, Telser J. 2007. Free radicals and anti-oxidants in normal physiological functions andhuman disease. Int J Biochem Cell Biol 39:44–84.

76. Henrotin Y, Kurz B, Aigner T. 2005. Oxygen andreactive oxygen species in cartilage degradation:Friends or foes? Osteoarthr Cartil 13:643–654.


77. Vasiljeva O, Reinheckel T, Peters C, Turk D, TurkK, Turk B. 2007. Emerging roles of cysteine cathe-psins in disease and their potential as drug tar-gets. Curr Pharm Des 13:385–401.

78. Yasuda Y, Kaleta J, Bromme D. 2005. The role ofcathepsins in osteoporosis and arthritis: Rationalefor the design of new therapeutics. Adv Drug DelivRev 57:973–993.

79. Konttinen YT, Mandelin J, Li TF, Salo J, Lassus J,Liljestrom M, Hukkanen M, Takagi M, Virtanen I,Santavirta S. 2002. Acidic cysteine endoproteinasecathepsin K in the degeneration of the superficialarticular hyaline cartilage in osteoarthritis.Arthritis Rheum 46:953–960.

80. Nakano S, Ikata T, Kinoshita I, Kanematsu J,Yasuoka S. 1999. Characteristics of the proteaseactivity in synovial fluid from patients with rheu-matoid arthritis and osteoarthritis. Clin ExpRheumatol 17:161–170.

81. Mantle D, Falkous G, Walker D. 1999. Quantifica-tion of protease activities in synovial fluid fromrheumatoid and osteoarthritis cases: Comparisonwith antioxidant and free radical damage mar-kers. Clin Chim Acta 284:45–58.

82. Holland TA, Mikos AG. 2003. Advances in drugdelivery for articular cartilage. J Control Release86:1–14.

83. Schmidt MB, Chen EH, Lynch SE. 2006. A reviewof the effects of insulin-like growth factor andplatelet derived growth factor on in vivo cartilagehealing and repair. Osteoarthr Cartil 14:403–412.

84. Issack PS, DiCesare PE. 2003. Recent advancestoward the clinical application of bone morphoge-netic proteins in bone and cartilage repair. Am JOrthop 32:429–436.

85. Vanderslice P, Woodside DG. 2006. Integrinantagonists as therapeutics for inflammatory dis-eases. Expert Opin Investig Drugs 15:1235–1255.

86. Ludwig RJ, Alban S, Boehncke WH. 2006. Struc-tural requirements of heparin and related mole-cules to exert a multitude of anti-inflammatoryactivities. Mini Rev Med Chem 6:1009–1023.

87. Paul AT, Gohil VM, Bhutani KK. 2006. Modulat-ing TNF-alpha signaling with natural products.Drug Discov Today 11:725–732.

88. Reuning U, Magdolen V, Wilhelm O, Fischer K,Lutz V, Graeff H, Schmitt M. 1998. Multifunc-tional potential of the plasminogen activation sys-tem in tumor invasion and metastasis (review). IntJ Oncol 13:893–906.

89. Curran S, Murray GI. 2000. Matrix metalloprotei-nases: Molecular aspects of their roles in tumourinvasion and metastasis. Eur J Cancer 36:1621–1630.

90. Overall CM, Lopez-Otin C. 2002. Strategies forMMP inhibition in cancer: Innovation for thepost-trial era. Nature Rev Cancer 2:657–672.


4646 LARSEN ET AL.

91. Thorpe PE. 2004. Vascular targeting agents ascancer therapeutics. Clin Cancer Res 10:415–427.

92. Mizejewski GJ. 1999. Role of integrins in cancer:Survey of expression patterns. Proc Soc Exp BiolMed 222:124–138.

93. de Groot V. 2007. Targeting: Cancer—Small mole-cules. In: Stella VJ, Borchardt RT, Hageman MJ,Oliyai R, Maag H, Tilley JW, editors. Prodrugs:Challenges and rewards. New York: Springer.pp. 447–506.

94. Levick JR. 1995. Microvascular architecture andexchange in synovial joints. Microcirculation 2:217–233.

95. Levick JR, Smaje LH. 1987. An analysis of thepermeability of a fenestra. Microvasc Res 33:233–256.

96. Day RO, McLachlan AJ, Graham GG, WilliamsKM. 1999. Pharmacokinetics of nonsteroidal anti-inflammatory drugs in synovial fluid. Clin Phar-macokinet 36:191–210.

97. Simkin PA, Pizzorno JE. 1979. Synovial perme-ability in rheumatoid arthitis. Arthritis Rheum22:689–696.

98. Simkin PA. 2005. Synovial physiology. In: Koop-man WJ, Moreland LW, editors. Arthiritis andallied conditions: A textbook of rheumatology.15 edition. Philadelphia: Lippincott Williamsand Wilkins. pp. 175–187.

99. Levick JR. 1981. Permeability of rheumatoid andnormal human synovium to specific plasma pro-teins. Arthritis Rheum 24:1550–1560.

100. Wallis WJ, Simkin PA. 1983. Antirheumatic drugconcentrations in human synovial fluid and syno-vial tissue. Observations on extravascular phar-macokinetics. Clin Pharmacokinet 8:496–522.

101. Netter P, Bannwarth B, Royer-Morrot M-J. 1989.Recent findings on the pharmacokinetics of non-steroidal anti-inflammatory drug in the synovialfluid. Clin Pharmacokinet 17:145–162.

102. Simkin PA, Nilson KL. 1981. Trans-synovialexchange of large and small molecules. ClinRheum Dis 7:99–129.

103. Owen SG, Francis HW, Roberts MS. 1994. Disap-pearance kinetics of solutes from synovial fluidafter intra-articular injection. Br J Clin Pharma-col 38:349–355.

104. Wigginton SM, Chu BC, Weisman MH, HowellSB. 1980. Methotrexate pharmacokinetics afterintraarticular injection in patients with rheuma-toid arthritis. Arthritis Rheum 23:119–122.

105. Ohzawa N, Takahashi Y, Ogihara T, Nakai Y,Ishiguro J. 1997. Metabolic fate of ulinastatin(2); pharmacokinetics in rabbits following intra-articular administration. Biol Pharm Bull 20:732–738.

106. Phelps P, Steele AD, McCarthy DJ. 1972. Signifi-cance of xenon-133 clearance rate from canine andhuman joints. Arthritis Rheum 15:360–370.


107. St Onge RA, Dick WC, Bell G, Boyle JA. 1968.Radioactive xenong (133Xe) disappearance ratesfrom the synovial cavity of the human knee jointin normal and arthritic subjects. Ann Rheum Dis27:163–166.

108. Mills ML, Rush BR, St Jean G, Gaughan EM,Mosier D, Gibson E, Freeman L. 2000. Deter-mination of synovial fluid and serum concentra-tions, and morphologic effects of intraarticularceftiofur sodium in horses. Vet Surg 29:398–406.

109. Winter JA, Sandberg AA, Saroff J, SlaunwhiteWR. 1967. Disposition and metabolism of intra-articularly injected 4-C14-cortisol in rheumatoidarthritis. Arthritis Rheum 10:352–356.

110. Harris R, Millard JB. 1956. Clearance of radio-active sodium from the knee joint. Clin Sci 15:9–15.

111. Poli A, Scott D, Bertin K, Miserocchi G, MasonRM, Levick JR. 2001. Influence of actin cyto-skeleton on intra-articular and interstitial fluidpressures in synovial joints. Microvasc Res 62:293–305.

112. Simkin PA, Pizzorno JE. 1974. Transsynovialexchange of small molecules in normal humansubjects. J Appl Physiol 36:581–587.

113. Simkin PA, Wu MP, Foster DM. 1993. Articularpharmacokinetics of protein-bound antirheumaticagents. Clin Pharmacokinet 25:342–350.

114. Brown DL, Cooper AG, Bluestone R. 1969.Exchange of IgM and albumin between plasmaand synovial fluid in rheumatoid arthritis. AnnRheum Dis 29:644–651.

115. Wallis WJ, Simkin PA, Nelp WB. 1987. Proteintraffic in human synovial effusions. ArthritisRheum 30:57–63.

116. Weinberger A, Simkin PA. 1989. Plasma proteinsin synovial fluids of normal human joints. SeminArthritis Rheum 19:66–76.

117. Simkin PA, Bassett JE, Koh E-M. 1995. Synovialperfusion in the human knee: A methodologicanalysis. Semin Arthritis Rheum 25:56–66.

118. Bauer W, Short CL, Bennett GA. 1933. The man-ner of removal of proteins from normal joints.J Exp Med 57:419–433.

119. Simkin PA, Benedict RS. 1990. Iodide and albu-min kinetics in normal canine wrists and knees.Arthritis Rheum 33:73–79.

120. Rodnan GP, MacLachlan MJ. 1960. The absorp-tion of serum albumin and gamma globulin fromthe joint of man and rabbit. Arthritis Rheum3:152–157.

121. van Lent PL, van den BL, Grutters GJ, van denBerg WB. 1989. Fate of antigen after intravenousand intraarticular injection into mice. Role ofmolecular weight and charge. J Rheumatol 16:1295–1303.

122. Page-Thomas DP, Bard D, King B, Dingle JT.1987. Clearance of proteoglycan from joint cav-ities. Ann Rheum Dis 46:934–937.

08 DOI 10.1002/jps


123. Coleman PJ, Scott D, Ray J, Mason RM, LevickJR. 1997. Hyaluronan secretion into the synovialcavity of rabbit knees and comparison with albu-min turnover. J Physiol 503:645–656.

124. Brown TJ, Laurent UBG, Fraser JFE. 1991. Turn-over of hyaluronan in synovial joints: Eliminationof labelled hyaluronan from the knee joint of therabbit. Exp Physiol 76:125–134.

125. Maroudas A, Bullough P, Swanson SAV, FreemanMAR. 1968. The permeability of articular carti-lage. J Bone Joint Surg Br 50B:166–177.

126. Maroudas A. 1970. Distribution and diffusion ofsolutes in articular cartilage. Biophys J 10:365–379.

127. Gonsalves M, Barker AL, Macpherson JV, UnwinPR, O’Hare D, Winlove CP. 2000. Scanning elec-trochemical microscopy as a local probe of oxygenpermeability in cartilage. Biophys J 78:1578–1588.

128. Gonsalves M, Macpherson JV, O’Hare D, WinloveCP, Unwin PR. 2000. High resolution imaging ofthe distribution and permeability of methyl violo-gen dication in bovine articular cartilage usingscanning electrochemical microscopy. BiochimBiophys Acta 1524:66–74.

129. Leddy HA, Guilak F. 2003. Site-specific moleculardiffusion in articular cartilage measured usingfluorescence recovery after photobleaching. AnnBiomed Eng 31:753–760.

130. Stolz M, Raiteri R, Daniels AU, VanLandinghamMR, Baschong W, Aebi U. 2004. Dynamic elasticmodulus of porcine articular cartilage determinedat two different levels of tissue organization byindentation-type atomic force microscopy. BiophysJ 86:3269–3283.

131. Evans RC, Quinn TM. 2006. Dynamic compressionaugments interstitial transport of a glucose-likesolute in articular cartilage. Biophys J 91:1541–1547.

132. Evans RC, Quinn TM. 2006. Solute convection indynamically compressed cartilage. J Biomech 39:1048–1055.

133. Quinn TM, Morel V, Meister JJ. 2001. Staticcompression of articular cartilage can reducesolute diffusivity and partitioning: Implicationsfor the chondrocyte biological response. J Biomech34:1463–1469.

134. Quinn TM, Kocian P, Meister JJ. 2000. Staticcompression is associated with decreased diffusiv-ity of dextrans in cartilage explants. Arch BiochemBiophys 384:327–334.

135. Maroudas A. 1968. Physicochemical properties ofcartilage in light of ion exchange theory. Biophys J8:575–595.

136. Nimer E, Schneiderman R, Maroudas A. 2003.Diffusion and partition of solutes in cartilageunder static load. Biophys Chem 106:125–146.


137. Maroudas A. 1980. Physical chemistry of articularcartilage and the intervertebral disc. In: SokoloffL, editor. The joints and synovial fluid. New York:Academic Press. pp. 239–291.

138. Olsen GD, Chan EM, Riker WK. 1975. Binding ofD-tubocurarine di[methyl-C-14] ether iodide andother amines to cartilage, chondroitin sulfate andhuman plasma-proteins. J Pharmacol Exp Ther195:242–250.

139. Maurizis JC, Ollier M, Nicolas C, Madelmont JC,Garrigue H, Veyre A. 1992. In vitro binding ofoxime acetylcholinesterase reactivators to proteo-glycans synthesized by cultured chondrocytes andfibroblasts. Biochem Pharmacol 44:1927–1933.

140. Bannwarth B, Netter P, Lapicque F, Mainard D,Fener P, Gillet P, Gaucher A. 1991. Tenoxicamconcentrations in synovium and joint cartilage inhumans. Agents Actions 32:295–298.

141. Giraud I, Rapp M, Maurizis JC, Madelmont JC.2002. Synthesis and in vitro evaluation of qua-ternary ammonium derivatives of chlorambuciland melphalan, anticancer drugs designed forthe chemotherapy of chondrosarcoma. J MedChem 45:2116–2119.

142. Giraud I, Rapp M, Maurizis JC, Madelmont JC.2000. Application to a cartilage targeting strategy:Synthesis and in vivo biodistribution of C-14-labeled quaternary ammonium-glucosamine con-jugates. Bioconjug Chem 11:212–218.

143. Maurizis JC, Rapp M, Nicolas C, Ollier M, VernyM, Madelmont JC. 2000. Disposition in rats of N-pyridinium-propyl-cyclam, N-triethylammonium-propyl-cyclam, and N-[Triethylammonium]-3-propyl-[15]ane-N5, potential cartilage imagingagents. Drug Metab Dispos 28:418–422.

144. Nicolas C, Verny M, Giraud I, Ollier M, Rapp M,Maurizis JC, Madelmont JC. 1999. New quater-nary ammonium oxicam derivatives targetedtoward cartilage: Synthesis, pharmacokinetic stu-dies, and antiinflammatory potency. J Med Chem42:5235–5240.

145. Rapp M, Giraud I, Maurizis JC, Madelmont JC.2003. Synthesis and pharmacokinetic profile of aquaternary ammonium derivative of chlorambucil,a potential anticancer drug for the chemotherapyof chondrosarcoma. Bioorg Med Chem 11:5007–5012.

146. Rapp M, Giraud I, Maurizis JC, Galmier MJ,Madelmont JC. 2003. Synthesis and in vivobiodisposition of [C-14]-quaternary ammonium-melphalan conjugate, a potential cartilage-targetedalkylating drug. Bioconjug Chem 14:500–506.

147. Vidal A, Sabatini M, Rolland-Valognes G, RenardP, Madelmont JC, Mounetou E. 2007. Synthesisand in vitro evaluation of targeted tetracyclinederivatives: Effects on inhibition of matrix metal-loproteinases. Bioorg Med Chem 15:2368–2374.


4648 LARSEN ET AL.

148. Rowland M, Tozer TN. 1989. Clinical pharmaco-kinetics. Concepts and applications. 2nd edition.Philadelphia-London: Lea and Febiger.

149. Harris R, Millard JB, Banerjee SK. 1958. Radio-sodium clearance from the knee joint in rheuma-toid arthritis. Ann Rheum Dis 17:189–195.

150. Scholer JF, Lee PR, Polley HF. 1959. The absorp-tion of heavy water and radioactive sodium fromthe knee joint of normal persons and patients withrheumatoid arthritis. Arthritis Rheum 2:426–432.

151. Peterson RE, Black RL, Bunim JJ. 1959. Disposi-tion of intra-articularly injected cortisone andhydrocortisone. Arthritis Rheum 2:433–439.

152. Moritz F, Distler O, Ospelt C, Gay RE, Gay S.2006. Technology insight: Gene transfer and thedesign of novel treatments for rheumatoid arthri-tis. Nat Clin Pract Rheumatol 2:153–162.

153. Evans CH, Ghivizzani SC, Robbins PD. 2006.Gene therapy for arthritis—What next? ArthritisRheum 54:1714–1729.

154. Keller M. 2005. Lipidic carriers of RNA/DNA oli-gonucleotides and polynucleotides: What a differ-ence a formulation makes. J Control Release103:537–540.

155. Evans CH, Gouze JN, Gouze E, Robbins PD, Ghi-vizzani SC. 2004. Osteoarthritis gene therapy.Gene Ther 11:379–389.

156. Gelse K, Schneider H. 2006. Ex vivo gene therapyapproaches to cartilage repair. Adv Drug DelivRev 58:259–284.

157. Matheson AJ, Figgitt DP. 2001. Rofecoxib—Areview of its use in the management of osteoar-thritis, acute pain and rheumatoid arthritis.Drugs 61:833–865.

158. van de Loo F, de Hooge A, Smeets RL, Bakker AC,Bennink AC, Arntz OJ, Joosten LAB, van Beunin-gen HM, van der Kraan PK, Varley AW, vanden Berg WB. 2004. An inflammation-inducibleadenoviral expression system for local treatmentof the arthritic joint. Gene Ther 11:581–590.

159. Schatteman L, Gyselbrecht L, De Clercq L,Mielants H. 2006. Treatment of refractory inflam-matory monoarthritis in ankylosing spondylitis byintraarticular injection of infliximab. J Rheumatol33:82–85.

160. Conti F, Priori R, Chimenti MS, Coari G, Anno-vazzi A, Valesini G, Signore A. 2005. Successfultreatment with intraarticular infliximab for resi-stant knee monarthritis in a patient with spondy-larthropathy—A role for scintigraphy withTc-99m-infliximab. Arthritis Rheum 52:1224–1226.

161. Veale DJ, Reece RJ, Parsons W, Radjenovic A,O’Connor PJ, Orgles CS, Berry E, Ridgway JP,Mason U, Boylston AW, Gibbon W, Emery P. 1999.Intra-articular primatised anti-C D4: Efficacy inresistant rheumatoid knees. A study of combined


arthroscopy, magnetic resonance imaging, andhistology. Ann Rheum Dis 58:342–349.

162. Holland T, Jones R, Basford A, Child T, Smith A.2000. An intra-articular method for assessing topi-cal application to a synovial joint. Lab Anim 34:298–300.

163. Wind WM, Smolinski RJ. 2004. Reliability of com-mon knee injection sites with low-volume injec-tions. J Arthroplasty 19:858–861.

164. Ingpen ML. 1995. Joint injections: Intra-articularand periarticular techniques. Modern Med 38:20–27.

165. Shi Y, Li LC. 2005. Current advances in sustained-release systems for parenteral drug delivery.Expert Opin Drug Deliv 2:1039–1058.

166. Torchilin VP. 2005. Recent advances with lipo-somes as pharmaceutical carriers. Nat Rev DrugDiscov 4:145–160.

167. Metselaar JM, Storm G. 2005. Liposomes in thetreatment of inflammatory disorders. Expert OpinDrug Deliv 2:465–476.

168. Moghimi SM, Hamad I, Bunger R, Andresen TL,Jorgensen K, Hunter AC, Baranji L, Rosivall L,Szebeni J. 2006. Activation of the human comple-ment system by cholesterol-rich and pegylatedliposomes—Modulation of cholesterol-rich lipo-some-mediated complement activation by elevatedserum LDL and HDL levels. J Liposome Res 16:167–174.

169. Moghimi SM, Hamad I, Andresen TL, JorgensenK, Szebeni J. 2006. Methylation of the phosphateoxygen moiety of phospholipid-methoxy(polyethy-lene glycol) conjugate prevents PEGylatedliposome-mediated complement activation andanaphylatoxin production. FASEB J 20:2591–2593.

170. Sharma A, Sharma US. 1997. Liposomes in drugdelivery: Progress and limitations. Int J Pharm154:123–140.

171. Phillips NC, Thomas DP, Knight CG, Dingle JT.1979. Liposome-incorporated corticosteroids. II.Therapeutic activity in experimental arthritis.Ann Rheum Dis 38:553–557.

172. Lopez-Garcia F, Vazquez-Auton JM, Gil F, LatooreR, Moreno F, Villalain J, Gomez-Fernandez JC.1993. Intra-articular therapy of experimentalarthritis with a derivative of triamcinolone acet-onide incorporated in liposomes. J Pharm Phar-macol 45:576–578.

173. Dingle JT, Gordon JL, Hazleman BL, Knight CG,Page Thomas DP, Phillips NC, Shaw IH, FildesFJ, Oliver JE, Jones G, Turner EH, Lowe JS. 1978.Novel treatment for joint inflammation. Nature271:372–373.

174. de Silva M, Hazleman BL, Thomas DP, Wraight P.1979. Liposomes in arthritis: A new approach.Lancet 1:1320–1322.

08 DOI 10.1002/jps


175. Bonanomi MH, Velvart M, Weder HG. 1987. Fateof different kinds of liposomes containing dexa-methasone palmitate after intra-articular injec-tion into rabbit joints. J Microencapsul 4:189–200.

176. Bonanomi MH, Velvart M, Stimpel M, Roos KM,Fehr K, Weder HG. 1987. Studies of pharmacoki-netics and therapeutic effects of glucocorticoidsentrapped in liposomes after intraarticular appli-cation in healthy rabbits and in rabbits with anti-gen-induced arthritis. Rheumatol Int 7:203–212.

177. Shaw IH, Knight CG, Dingle JT. 1976. Liposomalretention of a modified anti-inflammatory steroid.Biochem J 158:473–476.

178. Turker S, Erdogan S, Ozer AY, Ergun EL, TuncelM, Bilgili H, Deveci S. 2005. Scintigraphic imagingof radiolabelled drug delivery systems in rabbitswith arthritis. Int J Pharm 296:34–43.

179. Hou SM, Yu HY. 1997. Comparison of systemicabsorption of aqueous and liposomal lidocainefollowing intra-articular injection in rabbits.J Formos Med Assoc 96:141–143.

180. Foong WC, Green KL. 1988. Retention and dis-tribution of liposome-entrapped [3H]methotrexateinjected into normal or arthritic rabbit joints.J Pharm Pharmacol 40:464–468.

181. Mantripragada S. 2002. A lipid based depot (Depo-Foam((R)) technology) for sustained release drugdelivery. Prog Lipid Res 41:392–406.

182. Sinha VR, Trehan A. 2005. Biodegradable micro-spheres for parenteral delivery. CRC Crit RevTher Drug Carrier Syst 22:535–602.

183. Jiang WL, Gupta RK, Deshpande MC, Schwen-deman SP. 2005. Biodegradable poly(lactic-co-glycolic acid) microparticles for injectable deliveryof vaccine antigens. Adv Drug Deliv Rev 57:391–410.

184. Freitas S, Merkle HP, Gander B. 2005. Microen-capsulation by solvent extraction/evaporation:Reviewing the state of the art of microspherepreparation process technology. J Control Release102:313–332.

185. Jain JP, Modi S, Domb AJ, Kumar N. 2005. Roleof polyanhydrides as localized drug carriers.J Control Release 103:541–563.

186. Kumar N, Langer RS, Domb AJ. 2002. Polyanhy-drides: An overview. Adv Drug Deliv Rev 54:889–910.

187. Heller J, Barr J, Ng SY, Abdellauoi KS, Gurny R.2002. Poly(ortho esters): Synthesis, characteriza-tion, properties and uses. Adv Drug Deliv Rev54:1015–1039.

188. Sinha VR, Bansal K, Kaushik R, Kumria R, Tre-han A. 2004. Poly-epsilon-caprolactone micro-spheres and nanospheres: An overview. Int JPharm 278:1–23.

189. Patil GV. 2003. Biopolymer albumin for diagnosisand in drug delivery. Drug Dev Res 58:219–247.


190. Kumar MNVR, Muzzarelli RAA, Muzzarelli C,Sashiwa H, Domb AJ. 2004. Chitosan chemistryand pharmaceutical perspectives. Chem Rev 104:6017–6084.

191. Sung KC, Han RY, Hu OYP, Hsu LR. 1998. Con-trolled release of nalbuphine prodrugs from biode-gradable polymeric matrices: Influence of prodrughydrophilicity and polymer composition. Int JPharm 172:17–25.

192. Liu C, Desai KGH, Tang X, Chen X. 2006. Drugrelease kinetics of spray-dried chitosan micro-spheres. Drying Technol 24:769–776.

193. von Burkersroda F, Schedl L, Gopferich A. 2002.Why degradable polymers undergo surface erosionor bulk erosion. Biomaterials 23:4221–4231.

194. Schliecker G, Schmidt C, Fuchs S, Wombacher R,Kissel T. 2003. Hydrolytic degradation of poly(lactide-co-glycolide) films: Effect of oligomers ondegradation rate and crystallinity. Int J Pharm266:39–49.

195. Monkkonen J, Liukkonen J, Taskinen M, HeathTD, Urtti A. 1995. Studies on liposome formula-tions for intraarticular delivery of clodronate.J Control Release 35:145–154.

196. Brown KE, Leong K, Huang CH, Dalal R, GreenGD, Haimes HB, Jimenez PA, Bathon J. 1998.Gelatin/chondroitin 6-sulfate microspheres forthe delivery of therapeutic proteins to the joint.Arthritis Rheum 41:2185–2195.

197. Berger RG, Yount WJ. 1990. Immediate ‘‘steroidflare’’ from intraarticular triamcinolone hexaceto-nide injection: Case report and review of theliterature. Arthritis Rheum 33:1284–1286.

198. Kahn CB, Hollander JL, Schumacher HR. 1970.Corticosteroid crystals in synovial fluid. JAMA211:807–809.

199. Akers MJ, Fites AL, Robinson RL. 1987. Formula-tion design and development of parenteral suspen-sions. J Parenter Sci Technol 41:88–96.

200. Hiestand EN. 1964. Theory of coarse suspensionformulation. J Pharm Sci 53:1–18.

201. Betre H, Liu W, Zalutsky MR, Chilkoti A, KrausVB, Setton LA. 2006. A thermally responsivebiopolymer for intra-articular drug delivery.J Control Release 115:175–182.

202. Zentner GM, Rathi R, Shih C, Mcrea JC, Seo MH,Oh H, Rhee BG, Mestecky J, Moldoveanu Z,Morgan M, Weitman S. 2001. Biodegradableblock copolymers for delivery of proteins andwater-insoluble drugs. J Control Release 72:203–215.

203. Sartor O. 2003. Eligard: Leuprolide acetate in anovel sustained-release delivery system. Urology61:25–31.

204. Hatefi A, Amsden B. 2002. Biodegradable inject-able in situ forming drug delivery systems.J Control Release 80:9–28.


4650 LARSEN ET AL.

205. Matschke C, Isele U, van Hoogevest P, Fahr A.2002. Sustained-release injectables formed in situand their potential use for veterinary products.J Control Release 85:1–15.

206. Packhaeuser CB, Schnieders J, Oster CG, KisselT. 2004. In situ forming parenteral drug deliverysystems: An overview. Eur J Pharm Biopharm58:445–455.

207. Kopacz DJ, Lacouture PG, Wu D, Nandy P,Swanton R, Landau C. 2003. The dose responseand effects of dexamethasone on bupivacainemicrocapsules for intercostal blockade (T9 toT11) in healthy volunteers. Anesth Analg 96:576–582.

208. Holte K, Werner MU, Lacouture PG, Kehlet H.2002. Dexamethasone prolongs local analgesiaafter subcutaneous infiltration of bupivacainemicrocapsules in human volunteers. Anesthesiol-ogy 96:1331–1335.

209. Heller J, Barr J, Ng S, Shen H-R, Gurny R,Schwach-Abdelaoui K, Rothen-Weinhold A, vande Weert M. 2002. Development of poly(orthoesters) and their application for bovine serumalbumin and bupivacaine delivery. J ControlRelease 78:133–141.

210. Garry MG, Jackson DL, Geier HE, Southam M,Hargreaves KM. 1999. Evaluation of the efficacy ofa bioerodible bupivacaine polymer system on anti-nociception and infammatory mediator release.Pain 82:49–55.

211. Drager C, Benziger D, Gao F, Berde CB. 1998.Prolonged intercostal nerve blockade in sheepusing controlled-release of bupivacaine and dexa-methasone from polymer microspheres. Anesthe-siology 89:969–979.

212. Castillo J, Curley J, Hotz J, Uezono M, Tigner J,Chasin M, Wilder R, Langer R, Berde C. 1996.Glucocorticoids prolong rat sciatic nerve blockadein vivo from bupivacaine microspheres. Anesthe-siology 85:1157–1166.

213. Curley J, Castillo J, Hotz J, Uezono M, HernandezS, Lim JO, Tigner J, Chasin M, Langer R, Berde C.1996. Prolonged regional nerve blockade—Inject-able biodegradable bupivacaine/polyester micro-spheres. Anesthesiology 84:1401–1410.

214. Le Corre P, Estebe JP, Chevanne F, Malledant Y,Le Verge R. 1995. Spinal controlled delivery ofbupivacaine from DL-lactic acid oligomer micro-spheres. J Pharm Sci 84:75–78.

215. Le Corre P, Le Guevello P, Chevanne F, LeVerge R. 1994. Preparation and characterizationof bupivacaine-loaded polylactide and polylactide-co-glycolide microspheres. Int J Pharm 107:41–49.

216. Masters DB, Berde CB, Dutta S, Turek T, LangerR. 1993. Sustained local anesthetic release frombioerodible polymer matrices: A potential methodfor prolonged regional anesthesia. Pharm Res10:1527–1532.


217. Yu HY, Sun P, Hou WY. 1998. Prolonged localanesthetic effect of bupivacaine liposomes in rats.Int J Pharm 176:133–136.

218. Grant GJ, Lax J, Susser L, Zakowski M, Weiss-man TE, Turndorf H. 1997. Wound infiltrationwith liposomal bupivacaine prolongs analgesiain rats. Acta Anaesthesiol Scand 41:204–207.

219. Mowat JJ, Mok MJ, McLeod BA, Madden TD.1996. Liposomal bupivacaine—Extended dura-tion nerve blockade using large unilamellar vesi-cles that exhibit a proton gradient. Anesthesiology85:635–643.

220. Grant GJ, Vermeulen K, Langerman L, ZarkowskiM, Turndorf H. 1994. Prolonged analgesia withliposomal bupivacaine in a mouse model. RegAnesth 19:264–269.

221. Mashimo T, Uchida I, Pak M, Shibata A, Nishi-mura S, Inagaki Y, Yoshiya I. 1992. Prolongationof canine epidural anesthesia by liposome encap-sulation of lidocaine. Anesth Analg 74:827–834.

222. Grant GJ, Barenholz Y, Piskoun B, Bansinath M,Turndorf H, Bolotin EM. 2001. DRV liposomalbupivacaine: Preparation, characterization, andin vivo evaluation in mice. Pharm Res 18:336–343.

223. Grant GJ, Barenholz Y, Bolotin EM, Bansinath M,Turndoft H, Piskoun B, Davidson EM. 2004.A novel liposomal bupivacaine formulation to pro-duce ultralong-acting analgesia. Anesthesiology101:133–137.

224. Langerman L, Grant GJ, Zakowski M, Golomb E,Ramanathan S, Turndorf H. 1992. Prolongation ofepidural anesthesia using a lipid drug carrier withprocaine, lidocaine, and tetracaine. Anesth Analg75:900–905.

225. Langerman L, Grant GJ, Zakowski M, Rama-nathan S, Turndorf H. 1992. Prolongation ofspinal anesthesia—Differential action of a lipiddrug carrier on tetracaine, lidocaine, and pro-caine. Anesthesiology 77:475–481.

226. Langerman L, Golomb E, Benita S. 1991. Spinalanesthesia: Significant prolongation of the phar-macologic effect of tetracaine with lipid solution ofthe agent. Anesthesiology 74:105–107.

227. Soderberg L, Dyhre H, Roth B, Bjorkman S. 2006.Ultralong peripheral nerve block by lidocaine:Prilocaine 1:1 mixture in a lipid depot formula-tion—Comparison of in vitro, in vivo, and effectkinetics. Anesthesiology 104:110–121.

228. Shikanov A, Domb AJ, Weiniger CF. 2007. Longacting local anesthetic-polymer formulation toprolong the effect of analgesia. J Control Release117:97–103.

229. Kohane DS, Lipp M, Kinney RC, Lotan N, LangerR. 2000. Sciatic nerve blockade with lipid-protein-sugar particles containing bupivacaine. PharmRes 17:1243–1249.

230. Paavola A, Yliruusi J, Kajimoto Y, Kalso E, Wahl-strom T, Rosenberg P. 1995. Controlled release of

08 DOI 10.1002/jps


lidocaine from injectable gels and efficacy inrat sciatic nerve block. Pharm Res 12:1997–2002.

231. Dollo G, Le Corre P, Chevanne F, Le Verge R.2004. Bupivacaine containing dry emulsion canprolong epidural anesthetic effects in rabbits. EurJ Pharm Sci 22:63–70.

232. Masters DB, Domb AJ. 1998. Liposphere localanesthetic timed-release for perineural site appli-cation. Pharm Res 15:1038–1045.

233. Hetland ML, Stengaard-Pedersen K, Junker P,Lottenburger T, Ellingsen T, Andersen LS,Hansen I, Skjodt H, Pedersen JK, LauridsenUB, Svendsen A, Tarp U, Podenphant J, HansenG, Lindegaard H, de Carvalho A, Østergaard M,Horslev-Petersen K. 2006. Combination treatmentwith methotrexate, cyclosporine, and intraarticu-lar betamethasone compared with methotrexateand intraarticular betamethasone in early activerheumatoid arthritis—An investigator-initiated,multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Arthritis Rheum54:1401–1409.

234. Melby JC, St. Cyr M. 1961. Comparative studieson absorption and metabolic disposal of water-soluble corticosteroid esters. Metab Clin Exp 10:75–82.

235. Mollmann H, Rohdewald P, Schmidt EW, SalomonV, Derendorf H. 1985. Pharmacokinetics of triam-cinolone acetonide and its phosphate ester. Eur JClin Pharmacol 29:85–89.

236. Hare LE, Yeh KC, Ditzler CA, Mcmahon FG,Duggan DE. 1975. Bioavailability of dexametha-sone. 2. Dexamethasone phosphate. Clin Pharma-col Ther 18:330–337.

237. Derendorf H, Mollmann H, Gruner A, Haack D,Gyselby G. 1986. Pharmacokinetics and pharma-codynamics of glucocorticoid suspensions afterintra-articular administration. Clin PharmacolTher 39:313–317.

238. Randell TT, Ostman PLG, Flanagan DR, PerngCY, Hrdy J. 1994. Prolonged analgesia after epi-dural injection of a poorly soluble salt of fentanyl.Anesth Analg 79:905–910.

239. Gido C, Langguth P, Mutschler E. 1994. Pre-dictions of in-vivo plasma-concentrations fromin-vitro release kinetics—Application to doxepinparenteral (Im) suspensions in lipophilic vehiclesin dogs. Pharm Res 11:800–808.

240. Nakano NI, Kawahara N, Amiya T, Gotoh Y,Furukawa K. 1978. 3-Hydroxy-2-naphthoates oflidocaine, mepivacaine, and bupivacaine and theirdissolution characteristics. Chem Pharm Bull 26:936–941.

241. Østergaard J, Larsen SW, Parshad H, Larsen C.2005. Bupivacaine salts of diflunisal and otheraromatic hydroxycarboxylic acids: Aqueous solu-bility and release characteristics from solutions


and suspensions using a rotating dialysis cellmodel. Eur J Pharm Sci 26:280–287.

242. Larsen SW, Østergaard J, Poulsen SV, Schulz B,Larsen C. 2007. Diflunisal salts of bupivacaine,lidocaine and morphine Use of the common ioneffect for prolonging the release of bupivacainefrom mixed salt suspensions in an in vitro dialysismodel. Eur J Pharm Sci 31:172–179.

243. Zuidema J, Kadir F, Titulaer HAC, Oussoren C.1994. Release and absorption rates of intramuscu-larly and subcutaneously injected pharmaceuti-cals (Ii). Int J Pharm 105:189–207.

244. Chien YM. 1981. Long-acting parenteral drugformulations. J Parenter Sci Technol 35:106–139.

245. Benson HAE, Prankerd RJ. 1998. Optimisation ofdrug delivery 6. Modified-release parenterals.Aust J Hosp Pharm 28:99–104.

246. Larsen DB, Parshad H, Fredholt K, Larsen C.2002. Characteristics of drug substances in oilysolutions. Drug release rate, partitioning and solu-bility. Int J Pharm 232:107–117.

247. Larsen SW, Østergaard J, Friberg-Johansen H,Jessen MN, Larsen C. 2006. In vitro assessment ofdrug release rates from oil depot formulationsintended for intra-articular administration. EurJ Pharm Sci 29:348–354.

248. Jorgensen A, Christrup LL, Fullerton A, Chris-tensen CB, Bundgaard H. 1994. Prolonged releasefrom the injection site of morphine from morphineesters in an oil vehicle given by intramuscularinjection to pigs. Pharmacol Toxicol 75:319–320.

249. Larsen DB, Fredholt K, Larsen C. 2001. Additionof hydrogen bond donating excipients to oil solu-tion: Effect on in vitro drug release rate andviscosity. Eur J Pharm Sci 13:403–410.

250. Garrood T, Pitzalis C. 2006. Targeting theinflamed synovium: The quest for specificity.Arthritis Rheum 54:1055–1060.

251. Richards PJ, Williams AS, Goodfellow RM, Wil-liams BD. 1999. Liposomal clodronate eliminatessynovial macrophages, reduces inflammation andameliorates joint destruction in antigen-inducedarthritis. Rheumatology (Oxford) 38:818–825.

252. Badger AM, Blake S, Kapadia R, Sarkar S, LevinJ, Swift BA, Hoffman SJ, Stroup GB, Miller WH,Gowen M, Lark MW. 2001. Disease-modifyingactivity of SB 273005,an orally active, nonpeptidealpha(v)beta(3) (vitronectin receptor) antagonist,in rat adjuvant-induced arthritis. Arthritis Rheum44:128–137.

253. Gerlag DM, Borges E, Tak PP, Ellerby HM, Bre-desen DE, Pasqualini R, Ruoslahti E, FiresteinGS. 2001. Suppression of murine collagen-inducedarthritis by targeted apoptosis of synovial neovas-culature. Arthritis Res 3:357–361.

254. Koning GA, Schiffelers RM, Wauben MHM,Kok RJ, Mastrobattista E, Molema G, ten HagenTLM, Storm G. 2006. Targeting of angiogenic


4652 LARSEN ET AL.

endothelial cells at sites of inflammation by dexa-methasone phosphate-containing RGD peptideliposomes inhibits experimental arthritis. Arthri-tis Rheum 54:1198–1208.

255. Pasqualini R, Koivunen E, Kain R, Lahdenranta J,Sakamoto M, Stryhn A, Ashmun RA, Shapiro LH,Arap W, Ruoslahti E. 2000. Aminopeptidase N isa receptor for tumor-homing peptides and a targetfor inhibiting angiogenesis. Cancer Res 60:722–727.

256. Mi ZB, Lu XL, Mai JC, Bobby GN, Wang GQ,Lechman ER, Watkins SC, Rabinowich H, RobbinsPD. 2003. Identification of a synovial fibroblast-specific protein transduction domain for deliveryof apoptotic agents to hyperplastic synovium. MolTher 8:295–305.

257. Suzuki YS, Momose Y, Higashi N, Shigematsu A,Park KB, Kim YM, Kim JR, Ryu JR. 1998. Biodis-tribution and kinetics of holmium-166-chitosancomplex (DW-166HC) in rats and mice. J NuclMed 39:2161–2166.

258. Burgess DJ, Hussain AS, Ingallinera TS, ChenML. 2002. Assuring quality and performance ofsustained and controlled release parenterals:Workshop report. AAPS Pharmsci 4:E7.

259. Burgess DJ, Crommelin DJ, Hussain AS, ChenML. 2004. Assuring quality and performance ofsustained and controlled release parenterals:EUFEPS workshop report. AAPS Pharmsci 6:E11.

260. Burgess DJ, Crommelin DJ, Hussain AS, ChenML. 2004. Assuring quality and performance ofsustained and controlled released parenterals.Eur J Pharm Sci 21:679–690.

261. D’Souza SS, Deluca PP. 2006. Methods to assess invitro drug release from injectable polymeric par-ticulate systems. Pharm Res 23:460–474.

262. Washington C. 1990. Drug release from microdis-perse systems—A critical-review. Int J Pharm58:1–12.

263. Washington C. 1989. Evaluation of non-sink dia-lysis methods for the measurement of drug releasefrom colloids—Effects of drug partition. Int JPharm 56:71–74.

264. D’Souza SS, Deluca PP. 2005. Development of adialysis in vitro release method for biodegradablmicrospheres. AAPS Pharmscitech 6:E323–E328.

265. D’Souza SS, Faraj JA, Deluca PP. 2005. A model-dependent approach to correlate acceleratedwith real-time release from biodegradable micro-spheres. AAPS Pharmscitech 6:E553–E564.

266. Gabriels M, Plaizier-Vercammen J. 2003. Physicaland chemical evaluation of liposomes, containingartesunate. J Pharm Biomed Anal 31:655–667.

267. Henriksen I, Sande SA, Smistad G, Agren T,Karlsen J. 1995. In-vitro evaluation of drug-release kinetics from liposomes by fractional dia-lysis. Int J Pharm 119:231–238.


268. Saarinen-Savolainen P, Jarvinen T, Taipale H,Urtti A. 1997. Method for evaluating drug releasefrom liposomes in sink conditions. Int J Pharm159:27–33.

269. Leo E, Cameroni R, Forni F. 1999. Dynamic dia-lysis for the drug release evaluation from doxor-ubicin-gelatin nanoparticle conjugates. Int JPharm 180:23–30.

270. Chidambaram N, Burgess DJ. 1999. A novel invitro release method for submicron sized dispersedsystems. AAPS Pharmsci 1:E11.

271. Levy MY, Benita S. 1990. Drug release from sub-micronized o/w emulsion—A new in vitro kineticevaluation model. Int J Pharm 66:29–37.

272. Kranz H, Bodmeier R. 2007. A novel in situ form-ing drug delivery system for controlled parenteraldrug delivery. Int J Pharm 332:107–114.

273. Itoh S, Teraoka N, Matsuda T, Okamoto K, TakagiT, Oo C, Danny KH. 2006. Reciprocating dialysistube method: Periodic tapping improved in vitrorelease/dissolution testing of suppositories. Eur JPharm Biopharm 64:393–398.

274. Lootvoet G, Beyssac E, Shiu GK, Aiache JM,Ritschel WA. 1992. Study on the release of indo-methacin from suppositories—In vitro-in vivo cor-relation. Int J Pharm 85:113–120.

275. Oribe T, Yamada M, Takeuchi K, Tsunemi S,Imasaka K, Shirakura O, Ishimaru S, TakayamaK, Nagai T. 1995. Formulation and in-vivo in-vitrocorrelation of the dissolution property of lemildi-pine solid dispersions-incorporated suppositories.Int J Pharm 124:27–35.

276. Pedersen BT, Østergaard J, Larsen SW, Larsen C.2005. Characterization of the rotating dialysiscell as an in vitro model potentially useful forsimulation of the pharmacokinetic fate of intra-articularly administered drugs. Eur J Pharm Sci25:73–79.

277. Fredholt K, Larsen DH, Larsen C. 2000. Modifica-tion of in vitro drug release rate from oily parent-eral depots using a formulation approach. Eur JPharm Sci 11:231–237.

278. Larsen DH, Fredholt K, Larsen C. 2000. Assess-ment of rate of drug release from oil vehicle usinga rotating dialysis cell. Eur J Pharm Sci 11:223–229.

279. Schultz K, Mollgaard B, Frokjaer S, Larsen C.1997. Rotating dialysis cell as in vitro releasemethod for oily parenteral depot solutions. Int JPharm 157:163–169.

280. Simmons DL. 2006. What makes a good anti-inflammatory drug target? Drug Discov Today11:210–219.

281. Malemud CJ. 2004. Cytokines as therapeutic tar-gets for osteoarthritis. Biodrugs 18:23–35.

282. Connell L, McInnes IB. 2006. New cytokine tar-getsin inflammatory rheumatic diseases. BestPract Res Clin Rheumatol 20:865–878.

08 DOI 10.1002/jps


283. Fernandes JC, Martel-Pelletier J, Pelletier JP.2002. The role of cytokines in osteoarthritis patho-physiology. Biorheology 39:237–246.

284. Glasson SS, Askew R, Sheppard B, Carito B, Blan-chet T, Ma HL, Flannery CR, Peluso D, Kanki K,Yang ZY, Majumdar MK, Morris EA. 2005. Dele-tion of active ADAMTS5 prevents cartilage degra-dation in a murine model of osteoarthritis. Nature434:644–648.

285. Stanton H, Rogerson FM, East CJ, Golub SB,Lawlor KE, Meeker CT, Little CB, Last K, FarmerPJ, Campbell IK, Fourie AM, Fosang AJ. 2005.ADAMTS5 is the major aggrecanase in mousecartilage in vivo and in vitro. Nature 434:648–652.

286. Komatsu S, Iwata H, Nabeshima T. 1999. Studieson the kinetics, metabolism and re-utilisationafter intra-articular administration of hyaluronanto rabbits. Arzneimittelforschung 49:427–433.

287. Wintzer HJ, Fitzek A, Frey HH. 1981. Pharmaco-kinetics of procaine injected into the hock joint ofthe horse. Equine Vet J 13:68–69.

288. Lindqvist U, Tolmachev V, Kairemo K, Astrom G,Jonsson E, Lundqvist H. 2002. Elimination ofstabilised hyaluronan from the knee joint inhealthy men. Clin Pharmacokinet 41:603–613.

289. Biswas NR, Mandal NG, PGL LK. 1995. Pharma-cokinetic profile of intra-articular lignocaine dur-ing knee joint arthroscopy. Indian J Pharmacol27:193–194.

290. Kay EA, Klimiuk PS, Ronson G, Bailie GR. 1988.Failure of intraarticular ceftazidime in a patientwith Pseudomonas aeruginosa septic arthritis.Drug Intell Clin Pharm 22:315–316.

291. Elmquist WF, Chan KKH, Sawchuk RJ. 1994.Transsynovial drug distribution: Synovial meantransit time of diclofenac and other nonsteroidalantiinflammatory drugs. Pharm Res 11:1689–1697.

292. Day RO, Williams KM, Graham GG, Lee EJ,Knihinicki RD, Champion GD. 1988. Stereoselec-tive disposition of ibuprofen enantiomers in syno-vial fluid. Clin Pharmacol Ther 43:480–487.

293. Williams AS, Camilleri JP, Goodfellow RM, Wil-liams BD. 1996. A single intra-articular injectionof liposomally conjugated methotrexate sup-presses joint inflammation in rat antigen-inducedarthritis. Br J Rheumatol 35:719–724.

294. Abe T, Yamada H, Nakajima H, Kikuchi T,Takaishi H, Tadakuma T, Fujikawa K, ToyamaY. 2003. Repair of full-thickness cartilage defectsusing liposomal transforming growth factor-beta1.J Orthop Sci 8:92–101.

295. Trif M, Guillen C, Vaughan DM, Telfer JM,Brewer JM, Roseanu A, Brock JH. 2001. Lipo-somes as possible carriers for lactoferrin in thelocal treatment of inflammatory diseases. Exp BiolMed (Maywood) 226:559–564.

296. Highton J, Guevremont D, Thomson J, Carlisle B,Tucker I. 1999. A trial of clodronate-liposomes as


anti-macrophage treatment in a sheep model ofarthritis. Clin Exp Rheumatol 17:43–48.

297. van Lent PL, van den BL, van den Hoek AE, van deEM, Dijkstra CD, Van RN, Van de Putte LB, vanden Berg WB. 1993. Reversible depletion of syno-vial lining cells after intra-articular treatmentwith liposome-encapsulated dichloromethylenediphosphonate. Rheumatol Int 13:21–30.

298. van Lent PL, Holthuysen AE, Van RN, Van dePutte LB, van den Berg WB. 1998. Local removalof phagocytic synovial lining cells by clodronate-liposomes decreases cartilage destruction duringcollagen type II arthritis. Ann Rheum Dis 57:408–413.

299. Ceponis A, Waris E, Monkkonen J, Laasonen L,Hyttinen M, Solovieva SA, Hanemaaijer R, BitschA, Konttinen YT. 2001. Effects of low-dose, non-cytotoxic, intraarticular liposomal clodronate ondevelopment of erosions and proteoglycan loss inestablished antigen-induced arthritis in rabbits.Arthritis Rheum 44:1908–1916.

300. Barrera P, Blom A, van Lent PL, van BL, BeijnenJH, Van RN, de Waal Malefijt MC, Van de PutteLB, Storm G, van den Berg WB. 2000. Synovialmacrophage depletion with clodronate-containingliposomes in rheumatoid arthritis. ArthritisRheum 43:1951–1959.

301. Bard DR, Knight CG, Page Thomas DP. 1983.The retention and distribution in the rabbit kneeof a radionuclide complexed with a lipophilicchelator in liposomes. Clin Exp Rheumatol 1:113–117.

302. Chowdhary RK, Ratkay LG, Canaan AJ, Water-field JD, Richter AM, Levy JG. 1998. Uptake ofverteporfin by articular tissues following systemicand intra-articular administration. BiopharmDrug Dispos 19:395–400.

303. Ratcliffe JH, Hunneyball IM, Smith A, Wilson CG,Davis SS. 1984. Preparation and evaluation ofbiodegradable polymeric systems for the intra-articular delivery of drugs. J Pharm Pharmacol36:431–436.

304. Ratcliffe JH, Hunneyball IM, Wilson CG, Smith A,Davis SS. 1987. Albumin microspheres for intra-articular drug delivery: Investigation of theirretention in normal and arthritic knee joints ofrabbits. J Pharm Pharmacol 39:290–295.

305. Burgess DJ, Davis SS. 1988. Potential use of albu-min microspheres as a drug delivery system. 2.In vivo deposition and release of steroids. Int JPharm 46:69–76.

306. Tuncay M, Calis S, Kas HS, Ercan MT, Peksoy I,Hincal AA. 2000. In vitro and in vivo evaluation ofdiclofenac sodium loaded albumin microspheres.J Microencapsul 17:145–155.

307. Tuncay M, Calis S, Kas HS, Ercan MT, Peksoy I,Hincal AA. 2000. Diclofenac sodium incorporatedPLGA (50:50) microspheres: Formulation consid-


4654 LARSEN ET AL.

erations and in vitro/in vivo evaluation. Int JPharm 195:179–188.

308. Thakkar H, Sharma RK, Mishra AK, Chuttani K,Murthy RS. 2004. Efficacy of chitosan micro-spheres for controlled intra-articular delivery ofcelecoxib in inflamed joints. J Pharm Pharmacol56:1091–1099.

309. Thakkar H, Sharma RK, Mishra AK, Chuttani K,Murthy RS. 2004. Celecoxib incorporated chitosanmicrospheres: In vitro and in vivo evaluation.J Drug Target 12:549–557.

310. Bozdag S, Calis S, Kas HS, Ercan MT, PeksoyI, Hincal AA. 2001. In vitro evaluation andintra-articular administration of biodegradablemicrospheres containing naproxen sodium. JMicroencapsul 18:443–456.

311. Ramesh DV, Tabata Y, Ikada Y. 1999. Bio-absorbable microspheres for local drug releasein the articulus. J Bioact Compat Polym 14:137–149.

312. Nishide M, Kamei S, Takakura Y, Tamai S,Tabata Y, Ikada Y. 1999. Fate of biodegradableDL-lactic acid oligomer microspheres in the articu-lus. J Bioact Compat Polym 14:385–398.

313. Liggins RT, Cruz T, Min W, Liang L, Hunter WL,Burt HM. 2004. Intra-articular treatment ofarthritis with microsphere formulations of pacli-taxel: Biocompatibility and efficacy determina-tions in rabbits. Inflamm Res 53:363–372.

314. Horisawa E, Kubota K, Tuboi I, Sato K, YamamotoH, Takeuchi H, Kawashima Y. 2002. Size-depen-dency of DL-lactide/glycolide copolymer particulatesfor intra-articular delivery system on phagocytosisin rat synovium. Pharm Res 19:132–139.

315. Horisawa E, Hirota T, Kawazoe S, Yamada J,Yamamoto H, Takeuchi H, Kawashima Y. 2002.Prolonged anti-inflammatory action of DL-lactide/glycolide copolymer nanospheres containing beta-methasone sodium phosphate for an intra-articu-lar delivery system in antigen-induced arthriticrabbit. Pharm Res 19:403–410.

316. Liang LS, Jackson J, Min W, Risovic V, WasanKM, Burt HM. 2004. Methotrexate loaded poly-(L-lactic acid) microspheres for intra-articulardelivery of methotrexate to the joint. J PharmSci 93:943–956.

317. Liang LS, Wong W, Burt HM. 2005. Pharmaco-kinetic study of methotrexate following intra-articular injection of methotrexate loaded poly-(L-lactic acid) microspheres in rabbits. J PharmSci 94:1204–1215.


318. Cai L, Okumu FW, Cleland JL, Beresini M, HogueD, Lin Z, Filvaroff EH. 2002. A slow release for-mulation of insulin as a treatment for osteoarthri-tis. Osteoarthr Cartil 10:692–706.

319. Mumper RJ, Mills BJ, Ryo UY, Jay M. 1992.Polymeric microspheres for radionuclide synovect-omy containing neutron-activated holmium-166.J Nucl Med 33:398–402.

320. Song J, Suh CH, Park YB, Lee SH, Yoo NC, LeeJD, Kim KH, Lee SK. 2001. A phase I/IIa study onintra-articular injection of holmium-166-chitosancomplex for the treatment of knee synovitis ofrheumatoid arthritis. Eur J Nucl Med 28:489–497.

321. Lee SH, Suh JS, Kim HS, Lee JD, Song J, Lee SK.2003. MR evaluation of radiation synovectomy ofthe knee by means of intra-articular injection ofholmium-166-chitosan complex in patients withrheumatoid arthritis: Results at 4-month follow-up. Korean J Radiol 4:170–178.

322. Schulze K, Koch A, Schopf B, Petri A, Steitz B,Chastellain M, Hofmann M, Hofmann H, VonRechenberg B. 2005. Intraarticular applicationof superparamagnetic nanoparticles and theiruptake by synovial membrane—An experimentalstudy in sheep. J Magnetism Magn Mater 293:419–432.

323. Ohlsson-Wilhelm BM, McDevitt MR, Gray BD,Lorinc R, McIlvain HB, Sheth K, Weeks SA, Muir-head KA. 1994. Zyn-Linker delivery of antirheu-matic agents. Immunol Res 13:82–95.

324. Rahmouni A, Mathieu D, Chambon C, Dao TH,Hernigou P, Vasile N. 1995. Intraarticular toler-ability and kinetics of gadolinium tetra-azacyclo-dodecane tetraacetic acid. Acad Radiol 2:413–417.

325. Mierisch CM, Cohen SB, Jordan LC, RobertsonPG, Balian G, Diduch DR. 2002. Transforminggrowth factor-beta in calcium alginate beads forthe treatment of articular cartilage defects in therabbit. Arthroscopy 18:892–900.

326. Inoue A, Takahashi KA, Arai Y, Tonomura H,Sakao K, Saito M, Fujioka M, Fujiwara H, TabataY, Kubo T. 2006. The therapeutic effects of basicfibroblast growth factor contained in gelatin hydrogelmicrospheres on experimental osteoarthritis inthe rabbit knee. Arthritis Rheum 54:264–270.

327. Senda H, Sakuma E, Wada I, Wang HJ,Maruyama H, Matsui N. 1999. Ultrastructuralstudy of cells at the synovium-cartilage junction:Response of synovial cells of the rat knee joint tointra-articularly injected latex particles. Kaibo-gaku Zasshi 74:525–535.

08 DOI 10.1002/jps

Intra-articular depot formulation principles: Role in the ...

Documents

Transcript of Intra-articular depot formulation principles: Role in the ...