Drug Discovery Today: Technologies
`
`Vol. 2, No. 1 2005
`
`Editors-in-Chief
`Kelvin Lam – Pfizer, Inc., USA
`Henk Timmerman – Vrije Universiteit, The Netherlands
`
`DRUG DISCOVERY
`
`TODAY
`TECHNOLOGIES
`
`Drug delivery/formulation and nanotechnology
`
`Subcutaneous drug delivery and the
`role of the lymphatics
`Danielle N. McLennan1, Christopher J.H. Porter2, Susan A. Charman1,*
`
`1Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Vic. 3052, Australia
`2Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Vic. 3052, Australia
`
`Subcutaneous injections are widely utilised as a deliv-
`
`ery route for compounds with limited oral bioavailabil-
`
`ity or as a means to modify or extend the release
`
`profile. In this review, factors affecting absorption from
`
`the subcutaneous space are discussed with particular
`
`emphasis on differential drug absorption into either the
`
`underlying blood or lymphatic capillaries. Formulation
`
`and targeted delivery approaches, which utilise the
`
`subcutaneous administration route, are reviewed with
`
`reference to associated technologies and future chal-
`
`lenges.
`
`Introduction
`Subcutaneous (SC) injections have been extensively utilised
`as a delivery route to circumvent low oral bioavailability, as
`an alternative administration route when oral dosing is not
`well tolerated and in some cases, to modify or extend the
`release characteristics in efforts to prolong systemic exposure.
`Despite the acceptance and frequency of utilisation of the SC
`route of drug administration, relatively little effort has been
`directed towards understanding the factors that govern the
`rate and extent of SC absorption and the relative roles of the
`lymphatics and vasculature in transporting xenobiotics to
`the systemic circulation.
`Characterisation of the SC absorption process is crucial to
`both the design of improved drug delivery systems and the
`interpretation and development of useful pharmacokinetic–
`pharmacodynamic relationships. This review provides an
`
`*Corresponding author: S.A. Charman (susan.charman@vcp.monash.edu.au)
`
`Section Editors:
`Daan J.A. Crommelin – Department of Pharmaceutical
`Sciences, Utrecht University, Utrecht, The Netherlands
`Gerrit Borchard – Enzon Pharmaceuticals, Piscataway, NJ,
`USA
`
`overview of the factors that govern SC absorption, describes
`research and technologies focused on utilising or modifying
`SC absorption and provides insight into future challenges for
`lymphatic delivery after SC administration.
`
`Absorption from subcutaneous injection sites
`Drug administration by SC injection results in delivery to the
`interstitial area underlying the dermis of the skin. The inter-
`stitium consists of a fibrous collagen network supporting a
`gel-phase comprising negatively charged glycosaminogly-
`cans (largely hyaluronan), salts and plasma-derived proteins
`[1,2]. The proteins present within the interstitial space are
`essentially the same as those in plasma although they are
`thought to be present at approximately 50% lower concen-
`tration [3].
`The physiology of the SC environment likely dictates the
`patterns of absorption of both typical ‘small’ drug molecules
`as well as macromolecular and particulate systems after SC
`administration. In general, small drug molecules (<1 kDa) are
`thought to be preferentially absorbed by the blood capillaries
`due to their largely unrestricted permeability across the vas-
`cular endothelium together with the high rate of filtration
`and reabsorption of fluid across the vascular capillaries (in the
`range of 20–40 L/day in comparison to approximately 2–4 L/
`day of fluid drained by the lymph). By contrast, the absorp-
`tion of small particulates (generally less than about 100 nm)
`
`1740-6749/$ ß 2005 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddtec.2005.05.006
`
`www.drugdiscoverytoday.com
`
`89
`
`CSL v. Shire, IPR2017-01512
`Shire Ex. 2007, Page 1
`
`

`

`Drug Discovery Today: Technologies | Drug delivery/formulation and nanotechnology
`
`Vol. 2, No. 1 2005
`
`[4,5] and macromolecules into the blood is restricted by their
`limited permeability across the vascular endothelia and in
`this case, the lymphatics provide an alternative absorption
`pathway from the interstitial space.
`Passage through the interstitium to the vascular or lym-
`phatic capillaries can also present a barrier to efficient drug
`absorption after SC administration. Interstitial diffusion of
`macromolecular drugs is likely to be influenced by their
`physiochemical characteristics, including size, charge and
`hydrophilicity, and their interactions with endogenous com-
`ponents present within the interstitium. Electrostatic inter-
`actions with negatively
`charged glycosaminoglycans,
`interaction with interstitial proteins and the degree of inter-
`stitial hydration can all play a role in diffusion and absorption
`processes. Simple formulation characteristics, such as drug
`concentration, injection volume, ionic strength, viscosity
`and pH, together with the presence of formulation excipients
`can also influence the rate of diffusion from the SC injection
`site [6]. Other factors which can limit the extent of absorption
`of drugs from the interstitial space include susceptibility to
`enzymatic degradation at the injection site, cellular uptake by
`endocytic and phagocytic mechanisms [7] and simple pre-
`cipitation, aggregation or poor resolubilisation.
`
`Lymphatic structure and function in relation to drug
`absorption from the interstitium
`In addition to its role in the absorption and transport of
`dietary lipids and highly lipophilic compounds (such as lipid
`soluble vitamins and some drugs) from the intestine to the
`systemic circulation, the lymphatic system plays a key role in
`the maintenance of an effective immune system and the
`dissemination of metastases from several solid tumours.
`The lymphatic system also provides a unidirectional pathway
`from the peripheral tissues to the systemic circulation for
`materials, such as extravasated plasma proteins, excess fluid
`and cellular debris. This latter function is crucial to the
`maintenance of homeostasis and osmotic pressure but also
`underpins the role of the lymphatics in the absorption of
`therapeutic macromolecules and particulates from SC injec-
`tion sites.
`Lymph originates from the interstitial fluid and plasma
`exudate and initially drains into the smallest of the lymphatic
`vessels, the lymphatic capillaries, which are extensively dis-
`tributed throughout the body in close proximity to blood
`capillaries (Fig. 1). The lymphatic capillaries subsequently
`drain into larger collecting vessels that transport lymph via
`the lymph nodes to the thoracic duct, the largest of the
`lymphatic vessels. The thoracic lymph duct then ascends
`through the thoracic cavity and eventually empties into
`the systemic circulation at the junction of the left internal
`jugular and left subclavian veins [3]. The lymphatic capil-
`laries are blind-ended tubules that are densely distributed
`within the subcutaneous tissue and mucous membranes [8].
`
`90
`
`www.drugdiscoverytoday.com
`
`Figure 1. A diagrammatic representation of the subcutaneous
`injection site. Adapted, with permission from Elsevier, from Moffett
`et al. [47].
`
`The outer walls of the capillaries consist of a single layer of
`endothelial cells, which are highly attenuated and charac-
`terised by a discontinuous basement membrane [9]. Apposing
`endothelial cells are loosely adherent and overlap to form
`‘cleft-like’ intercellular junctions along the surface of the
`capillary (Fig. 2), which are estimated to be between 15 to
`20 nm and several microns wide [10]. These junctions pro-
`vide an uninterrupted channel from the interstitium into the
`capillary lumen [11] and open and close in response to
`changes in interstitial volume and pressure (for review, see
`[12]). It is this relatively ‘open’ structure of the lymphatic
`capillaries that facilitates the absorption of small particulates
`and macromolecules from the interstitial space into lymph.
`By contrast, the vascular capillary endothelium is charac-
`terised by the presence of tight junctions between apposing
`endothelial cells and an underlying basement membrane,
`which effectively restricts the free passage of macromolecules
`and particulates.
`The paucity of data in the literature relating to lymphatic
`absorption of drugs following SC administration is linked, in
`part, to the technical difficulties associated with the establish-
`ment of animal models to study lymphatic absorption. The
`physical size of the collecting lymphatics dictates that rela-
`tively large animal models are required to allow access to
`these extremely small vessels, and as such, the costs and
`complexities of the surgical preparation are a significant
`barrier to their widespread applicability [13]. The site of
`cannulation also plays an important role in determining
`whether the data generated describe the absorption of mole-
`cules into the lymphatics directly draining the injection site
`or both absorption and subsequent transfer from the periph-
`
`CSL v. Shire, IPR2017-01512
`Shire Ex. 2007, Page 2
`
`

`

`Vol. 2, No. 1 2005
`
`Drug Discovery Today: Technologies | Drug delivery/formulation and nanotechnology
`
`Figure 2. Microscopic view of the lymphatic capillary illustrating a closed intercellular junction (a) and an open intercellular junction (b) allowing luminal
`access to molecules along the pathway indicated by the arrow. Adapted, with permission from The Rockefeller University Press, from Leak [48].
`
`eral lymphatics to the thoracic duct ultimately emptying into
`the systemic circulation. The generalised model shown in
`Fig. 3 illustrates that both lymphatic absorption and trans-
`port processes need to be considered to more accurately
`develop pharmacokinetic models to describe macromolecu-
`lar disposition following SC administration [14,15].
`
`Conventional formulations for SC administration
`A large number of studies have utilised the SC route for
`administration of drugs in aqueous or oily solutions, simple
`emulsions and suspension formulations (Table 1). Although
`isolated studies have examined the rate and extent of absorp-
`tion of drug molecules following SC injection and the influ-
`ence of formulation (as reviewed by [6]), relatively few studies
`have investigated the mechanism of drug absorption from SC
`injection sites, and in particular the role of the lymphatics in
`this process. This stems from the generally held assumption
`that absorption following SC injection is rapid and complete
`
`for most ‘small’ drug molecules. In comparison, the absorp-
`tion kinetics of therapeutic proteins have been extensively
`characterised because they represent a class of therapeutics
`that currently require parenteral administration and where
`SC administration can provide patient compliance advan-
`tages over intravenous or intramuscular administration
`routes. Following SC injection, the rate of absorption of
`protein drugs is typically prolonged as evidenced by a delay
`in the time to maximum concentration and a prolonged
`terminal half-life relative to that following IV administration.
`Both the rate and extent of absorption of protein therapeutics
`are variable depending on the injection site [16–18], but the
`basis for this variation has not been rigorously examined.
`Over recent years, several groups including ours have
`begun to examine the role of the lymphatics in the absorp-
`tion of protein therapeutics [14,15,19–22]. The combined
`results from these studies have demonstrated that an approxi-
`mately linear relationship exists between the molecular
`
`Figure 3. Generalised schematic representing SC absorption via the blood and lymphatic absorption pathways into the systemic circulation.
`
`www.drugdiscoverytoday.com
`
`91
`
`CSL v. Shire, IPR2017-01512
`Shire Ex. 2007, Page 3
`
`

`

`Drug Discovery Today: Technologies | Drug delivery/formulation and nanotechnology
`
`Vol. 2, No. 1 2005
`
`Table 1. Technologies associated with SC delivery
`
`Conventional SC formulations
`
`Modified release SC
`formulations
`
`Lymph-targeting SC
`delivery systems
`
`Examples of specific type
`of technology
`
`- Aqueous solutions
`- Oily solutions
`- Suspensions
`- Simple emulsions
`
`Names of specific
`technologies with
`associated companies
`and company websites
`
`No specific technologies available
`
`- Biodegradable in situ implants
`- Biodegradable microspheres
`- Osmotically controlled implants
`- Liposomes
`- Lipid nanoparticles
`
`1
`1
`DepotTM, DUROS
`,
`Alzamer
`1
`(ALZA Corporation,
`Stealth
`http://www.alza.com)
`1
`(Atrix Laboratories,
`Atrigel
`http://www.qltinc.com)
`1
`(Durect Corp,
`SABER
`http://www.durect.com)
`ProLease (Alkermes Inc,
`http://www.alkermes.com)
`1
`(SkyePharma Inc,
`DepoFoam
`http://www.skyepharma.com)
`SupraVailTM (Phares Drug Delivery
`AG, http://www.phares.biz)
`
`- Reduced dosing frequency,
`improved compliance
`- Improved efficacy/safety profile
`- Protection of labile compounds
`by encapsulation
`- Improved delivery of poorly
`soluble compounds
`- Ease of administration with in situ
`implants, micro- and nanospheres
`and nanoparticles
`- Removal of implantable devices
`allows immediate discontinuation
`of therapy
`
`- Nanoparticles, liposomes,
`microspheres
`- Dendrimers
`- Biodegradable polymers,
`conjugates, prodrugs
`- ISCOMs
`- Inorganic colloids (sulfur, iron)
`- Monoclonal antibodies
`
`No specific technologies available
`
`- Useful for targeting,
`imaging, diagnostics
`- Approaches allow lymphatic
`delivery of both small
`molecules and macromolecules
`- Flexibility and versatility in
`carrier characteristics
`- Localisation of drug in tissues
`(lymph, lymph nodes, tumour, etc.)
`
`- Generally biocompatible
`- Ease of manufacture
`- Suitable for local and
`systemic exposure
`- Some scope for delayed release
`with suspensions, oily solutions
`- Lymphatic absorption
`dictated primarily by
`molecular size
`
`Pros
`
`Cons
`
`- Rapid release from aqueous solutions
`- Deactivation/instability at
`the injections site
`- Variable absorption from
`suspension depots
`- Challenge of mimicking pulsatile
`physiological release
`- Hypersensitivity
`
`- Limited drug payload
`- Hypersensitivity
`- Manufacturing considerations for
`micro- and nanosphere preparations
`- Specialised insertion for implants
`and devices
`- Potential long-term biocompatibility
`issues of implantable devices
`
`- Limited drug payload
`- Polydispersity in size
`characteristics
`- Regional differences in SC
`blood flow and lymphatic drainage
`- Biological fate of carrier
`- Potential immunogenicity
`and toxicity
`
`References
`
`[6,14,15,19–25,49]
`
`[27–38]
`
`[34,35,39–46]
`
`weight (as a surrogate for molecular size) of an injected
`protein and the proportion of the dose absorbed into the
`peripheral lymphatics draining the SC injection site in sheep
`(Fig. 4). This correlation reinforces the importance of the
`lymphatics in the absorption of proteins of increasing mole-
`cular size. Importantly, for large proteins in the molecular
`weight range of approximately 30–40 kDa, almost complete
`absorption via the peripheral lymphatics was observed in
`sheep. Furthermore, molecular size did not limit the extent
`of lymphatic absorption up to at least 84 kDa (Fig. 4)
`
`although it is probable that there is a maximum size range
`above which reduced absorption from the injection site
`might occur.
`The importance of apparent molecular size in dictating the
`rate of absorption following SC injection is illustrated by the
`effect of self-association on the rate of absorption of insulin.
`Using radiolabelled tracer techniques, a strong correlation
`has been demonstrated between the average insulin dissocia-
`tion state and the rate of disappearance of radiolabelled
`insulin from the SC injection site [23]. This relationship
`
`92
`
`www.drugdiscoverytoday.com
`
`CSL v. Shire, IPR2017-01512
`Shire Ex. 2007, Page 4
`
`

`

`Vol. 2, No. 1 2005
`
`Drug Discovery Today: Technologies | Drug delivery/formulation and nanotechnology
`
`Suspensions represent the simplest method for creating a
`SC depot and rely on slow dissolution of active drug at the
`injection site. This approach has been utilised extensively for
`intermediate- and long-acting insulin preparations (e.g. NPH,
`Lente and Ultralente insulin) and has recently been applied to
`a long acting formulation for medroxyprogesterone acetate
`(Depo-Subq Provera 104TM). Depot liquid and microsphere
`formulations, containing biodegradable polymers such as
`poly(lactide-coglycolic acid) (PLGA), poly(lactic acid) (PLA)
`or collagen, have also been utilised to provide extended
`release up to approximately one month [27]. Liquid depot
`formulations typically form gels or solids upon injection thus
`providing an in situ depot for extended release [28–30]. Micro-
`spheres prepared with biodegradable polymers [31–33] have
`been extensively explored for the controlled release of several
`agents including proteins, peptides, antigens and low mole-
`cular weight drugs and one depot formulation for human
`growth hormone is now commercially available (Nutropin
`1
`). Other prolonged release delivery systems that can
`Depot
`be administered either by SC or IV injection, such as lipo-
`somes [34–36] and nanoparticles [37], often rely on an
`extended circulation time for the delivery system rather than
`delayed release of active at the injection site.
`Implantable systems including biodegradable matrices,
`which are injected via a large bore needle or removable
`devices that are surgically implanted, can provide a long
`duration of exposure ranging from weeks up to a year [27].
`Biodegradable implants using PLGA have been the subject of
`considerable research, with one of the best-known implan-
`table formulations being a commercially available prepara-
`1
`1
`). Viadur
`is a commercial
`tion of goserelin acetate (Zoladex
`example of an osmotically driven implantable device for
`chronic administration of leuprolide acetate which provides
`reliable and consistent drug release over prolonged time
`periods [38].
`
`SC delivery approaches to target the lymphatics
`Specific access to the lymphatics after SC administration has
`potential utility in the treatment of lymph and lymph node-
`resident diseases such as infection and tumour metastases,
`and also in improved lymphatic visualisation with attendant
`benefits in disease detection, diagnosis and treatment. A large
`number of formulation approaches and delivery systems have
`been investigated as potential strategies to target therapeutics
`to the lymphatics following SC administration (Table 1). In
`general, these approaches utilise the differential anatomy
`(and more specifically permeability) of lymphatic versus
`blood capillaries to promote selective lymphatic access.
`As previously described, molecules of increasing molecular
`size preferentially drain from SC injection sites into the
`lymphatics. Macromolecular prodrugs have therefore been
`used to promote selective delivery to the regional lymphatics
`after SC administration and in general, larger cationic com-
`
`www.drugdiscoverytoday.com
`
`93
`
`Figure 4. Relationship between the proportion of the dose
`absorbed into peripheral lymph (mean  SEM, n = 3–5) and the
`molecular weight for selected proteins and low molecular weight
`compounds after SC administration in sheep. Data for
`fluorodeoxyuridine (*), inulin (~), cytochrome c (&) and
`interferon-a (5) from Supersaxo et al. [20], human growth hormone
`(^) [21], soluble insulin (*) [22], r-metHu-Leptin (~) [14], an
`analogue of Leptin (&) [49], epoietin alfa (!) [15], darbepoetin alfa
`(^) [49] and a high molecular weight protein ( ) [49].
`
`has formed the basis for research on insulin analogues with
`reduced tendencies to self-associate with the aim of providing
`a more rapid onset of action (e.g. Lispro [24] and Aspart
`insulin [25]). The conventional view has been that dissocia-
`tion of insulin hexamers and dimers to monomeric protein is
`required before absorption by the blood capillaries and that
`absorption via the lymph does not occur to any significant
`extent [26]. However, recent studies conducted using a can-
`nulated sheep model indicated first, that insulin was partially
`absorbed via the lymphatics following SC injection, and
`second, that the extent of lymphatic absorption exceeded
`what would be expected for a molecule the size of monomeric
`insulin [22]. These results raised the possibility that asso-
`ciated forms of insulin (and indeed other proteins) could
`potentially be absorbed directly via the lymphatic capillaries
`before dissociation.
`
`Modified release formulations for SC administration
`An increasing body of work has explored the utility of mod-
`ified or sustained release formulations to extend the timescale
`of drug absorption from SC injection sites thus providing
`prolonged exposure and a reduction in the maximum plasma
`concentration (Table 1). SC depots and implantable delivery
`systems control the rate of drug release whereas the mechan-
`ism of absorption of released drug via either the blood or the
`lymph is expected to be dictated by the characteristics (e.g.
`size) of the delivered agent as highlighted in the previous
`section.
`
`CSL v. Shire, IPR2017-01512
`Shire Ex. 2007, Page 5
`
`

`

`Drug Discovery Today: Technologies | Drug delivery/formulation and nanotechnology
`
`Vol. 2, No. 1 2005
`
`plexes appear to be retained in regional lymph nodes whereas
`smaller anionic materials appear to flow more readily
`through the nodes and into larger
`lymphatic vessels
`(reviewed in [39]). Radiolabelled synthetic macromolecules
`(such as 99Tcm-dextran) and monoclonal antibodies have also
`been extensively used to image the regional lymphatics (see,
`e.g. [40–42]).
`Realisation that increased molecular size results in a larger
`proportion of an SC dose accessing the lymphatics has led to
`the investigation of the lymph-directing or lymphotropic
`properties of a large range of colloidal and micro- and
`nano-particulate systems, immune stimulating complexes
`(ISCOMs), dendrimers and liposomes (for
`reviews, see
`[5,7,39,40,43]). For this approach to work effectively, parti-
`cles must be sufficiently large to preclude absorption across
`the vasculature, but sufficiently small that relatively facile
`absorption from the injection site is possible. Clearly this
`depends on the interfacial properties of the delivery system,
`but in general, an optimal particle size range of approxi-
`mately 50 nm has been suggested [4,40]. Technological diffi-
`culties associated with the manufacture of very small particles
`has limited close examination of particles in the 1–10 nm size
`range; however, recent studies using polymeric dendrimers
`suggest that lymphatic transport of materials of this size is
`possible [44].
`A relatively recent advance in the field of nanoparticle and
`liposome engineering has been the development of pegylated
`nanoparticulate systems, where adsorption or grafting of
`polyethylene oxide chains to the surface of a microparticulate
`reduces recognition by prospective opsonins, reduces uptake
`by the cells of the reticuloendothelial system and promotes
`retention in the circulation after intravenous administration
`[35]. Far fewer studies have examined the effect of pegylation
`on particle uptake into the lymph; however, enhanced drai-
`nage from the SC injection site and the ability to tailor
`retention (or not) in the regional lymph nodes has been
`described [5,7,34].
`An interesting combination of molecular and colloidal
`approaches has been described by Supersaxo et al. [45],
`who utilised the physical size of phospholipid-bile salt
`micelles to promote lymphatic uptake, and in parallel synthe-
`sised a lipophilic prodrug of the anticancer compound 5-
`FUdR to facilitate improved micellar solubilisation. This
`combination of approaches led to the uptake of approxi-
`mately 60% of an SC-injected dose into the lymphatics
`and can provide an additional generic mechanism for
`improved access of small molecules to the lymphatics.
`
`Conclusions
`Subcutaneous delivery is a commonly utilised administration
`route, particularly for molecules where low bioavailability
`precludes oral administration and where prolonged release
`might be desirable. Although the factors that govern the rate
`
`94
`
`www.drugdiscoverytoday.com
`
`and extent of SC absorption are incompletely defined, the
`recent trends observed for protein drugs and particulates in
`animal models suggest that size is a crucial determinant of the
`relative roles of the blood and lymphatic absorptive path-
`ways. While increasing the molecular size appears to enhance
`access to the lymph, it should be acknowledged that increas-
`ing the size is likely to eventually retard movement through
`the interstitial space and thus restrict lymphatic drainage.
`This concept is well illustrated by the lack of facile lymphatic
`access for larger colloidal materials (>100 nm).
`Realisation that the lymphatics can play a significant or
`indeed primary role in the absorption of molecules of increas-
`ing molecular size has considerable therapeutic and toxico-
`logical ramifications. Indeed, the relatively small volume of
`fluid in the lymphatic system and apparent lack of distribu-
`tion of materials out of the lymphatics on transport to the
`systemic circulation dictates that for drugs where lymphatic
`transport is significant, concentrations in the central lymph
`are typically one to two orders of magnitude higher than the
`corresponding plasma concentrations. This obviously pro-
`vides exciting opportunities for the improved targeting of the
`lymphatics for the treatment of lymph resident diseases but
`also introduces complexity into the design of pharmacoki-
`netic and toxicokinetic studies, where variation in the extent
`of lymphatic transport can lead to significant differences in
`lymphatic and systemic exposure. A further, potentially com-
`plicating factor is that variations in subcutaneous blood flow
`and lymphatic drainage rates throughout the body can lead
`to regional differences in absorption rates and corresponding
`differences in the relative contributions of the vascular and
`lymphatic absorption pathways. To further understand these
`processes and to provide a means for assessing lymphatic
`targeting of therapeutic agents, there is a clear need to
`examine issues of interspecies scaling and the predictability
`of absorption patterns in humans given that variations in
`lymphatic architecture can lead to differences in lymphatic
`transport across animal models and humans.
`It is apparent that molecules, analogues or prodrugs of
`increasing molecular size, will increasingly access the lym-
`phatics after interstitial injection and that even ‘small’ mole-
`cules can be directed to the lymph by formulation in
`appropriate colloidal carriers. While the benefit of this
`approach is evident in several diagnostic and imaging pro-
`ducts, application of these lymph-targeting approaches to a
`commercial therapeutic agent has not yet been forthcoming.
`To this end, a recent discussion article has reiterated the
`challenges associated with colloidal drug delivery and in
`particular, the contradictory requirements for appropriate
`encapsulation (e.g. to facilitate efficient lymphatic targeting)
`and facile drug release [46]. Nonetheless, examples of success-
`ful second-generation colloidal drug delivery systems such as
`1
`are evident and may eventually be applied to enhance
`Doxil
`local lymphatic uptake into the regional lymphatics.
`
`CSL v. Shire, IPR2017-01512
`Shire Ex. 2007, Page 6
`
`

`

`Vol. 2, No. 1 2005
`
`Drug Discovery Today: Technologies | Drug delivery/formulation and nanotechnology
`
`Related articles
`
`Supersaxo, A. et al. (1990) Effect of molecular weight on the lymphatic
`absorption of water-soluble compounds following subcutaneous
`administration. Pharm. Res. 7, 167–169
`Zuidema, J. et al. (1994) Release and absorption rates of
`intramuscularly and subcutaneously injected pharmaceuticals (II). Int. J.
`Pharm. 105, 189–207
`Hawley, A.E. et al. (1995) Targeting of colloids to lymph nodes:
`influence of lymphatic physiology and colloidal characteristics. Adv.
`Drug Deliv. Rev. 17, 129–148
`Porter, C.J.H and Charman, S.A. (2000) Lymphatic transport of
`proteins after subcutaneous administration. J. Pharm. Sci. 89, 297–310
`Oussoren, C. and Storm, G. (2001) Liposomes to target the lymphatics
`by subcutaneous administration. Adv. Drug Deliv. Rev. 50, 143–156
`
`A more complete understanding of the molecular and
`formulation-related determinants of absorption from SC
`injection sites and the physiological factors which dictate
`SC absorption profiles has the capacity to improve the design
`of SC delivery systems, inform the development of pharma-
`cokinetic–pharmacodynamic models and potentially provide
`for enhanced access to the local lymphatic system.
`
`Outstanding issues
`
` The influence of regional variations in lymphatic and vascular
`architecture on SC absorption processes.
` Interspecies variations in lymphatic versus vascular absorption from
`SC absorption sites and the ability to extrapolate animal data to
`humans.
` Further evaluation of formulation technologies (e.g. implants, nano-
`and micro-particulates, colloidal and liquid crystalline systems)
`designed to provide sustained or pulsatile release from SC injection
`sites and/or targeting to the lymphatics.
` Further assessment of the therapeutic benefit of lymphatic targeting
`for the treatment of lymph resident diseases.
`
`References
`1 Zweifach, B.W. and Silberberg, A. (1979) The interstitial-lymphatic flow
`system. In International Review of Physiology, Cardiovascular Physiology III,
`(Vol. 18) (Guyton, A.C. and Young, D.B., eds) pp. 215–260, University
`Park Press
`2 Schmid-Schonbein, G.W. (1990) Microlymphatics and lymph flow.
`Physiol. Rev. 70, 987–1028
`3 Yoffey, J.M. and Courtice, F.C. (1970) Lymphatics, Lymph and the
`Lymphomyeloid Complex. Academic Press
`4 Strand, S.E. and Bergqvist, L. (1989) Radiolabeled colloids and
`macromolecules in the lymphatic system. Crit. Rev. Ther. Drug Carrier Syst.
`6, 211–238
`5 Oussoren, C. and Storm, G. (2001) Liposomes to target the lymphatics by
`subcutaneous administration. Adv. Drug Deliv. Rev. 50, 143–156
`6 Zuidema, J. et al. (1994) Release and absorption rates of intramuscularly
`and subcutaneously injected pharmaceuticals (II). Int. J. Pharm. 105,
`189–207
`7 Hawley, A.E. et al. (1995) Targeting of colloids to lymph nodes: influence
`of lymphatic physiology and colloidal characteristics. Adv. Drug Deliv. Rev.
`17, 129–148
`
`8 Weiss, L. (1983) Lymphatic vessels and lymph nodes. In Histology: Cell and
`Tissue Biology (Weiss, L., ed.), pp. 527–543, Macmillan Press
`9 Schmid-Schonbein, G.W. (1990) Mechanisms causing initial lymphatics
`to expand and compress to promote lymph flow. Arch. Histol. Cytol. 53
`(Suppl.), 107–114
`10 O’Driscoll, C.M. (1992) Anatomy and physiology of the lymphatics. In
`Lymphatic Transport of Drugs (Charman, W.N. and Stella, V.J., eds), pp. 1–
`35, CRC Press
`11 Leak, L.V. (1976) The structure of lymphatic capillaries in lymph
`formation. Fed. Proc. 35, 1863–1871
`12 Swartz, M. (2001) The physiology of the lymphatic system. Adv. Drug Deliv.
`Rev. 50, 3–20
`13 Porter, C.J.H. et al. (2001) Lymphatic transport of proteins after s.c.
`injection: implications of animal model selection. Adv. Drug Deliv. Rev. 50,
`157–171
`14 McLennan, D.N. et al. (2003) Pharmacokinetic model to describe the
`lymphatic absorption of r-metHu-leptin after subcutaneous injection to
`sheep. Pharm. Res. 20, 1156–1162
`15 McLennan, D.N. et al. (2005) Lymphatic absorption is the primary
`contributor to the systemic availability of Epoietin alfa following
`subcutaneous administration to sheep. J. Pharmacol. Exp. Ther. 313, 345–351
`16 Beshyah, S.A. et al. (1991) The effect of subcutaneous injection site on
`absorption of human growth hormone: abdomen versus thigh. Clin.
`Endocrinol. 35, 409–412
`17 Macdougall, I.C. et al. (1991) Subcutaneous erythropoietin therapy:
`comparison of three different sites of injection. Contrib. Nephrol. 88, 152–156
`18 ter Braak, E.W. et al. (1996) Injection site effects on the pharmacokinetics
`and glucodynamics of insulin lispro and regular insulin. Diabetes Care 19,
`1437–1440
`19 Supersaxo, A. et al. (1988) Recombinant human interferon alpha-2a:
`delivery to lymphoid tissue by selected modes of application. Pharm. Res.
`5, 472–476
`20 Supersaxo, A. et al. (1990) Effect of molecular weight on the lymphatic
`absorption of water-soluble compounds following subcutaneous
`administration. Pharm. Res. 7, 167–169
`21 Charman, S.A. et al. (2000) Systemic availability and lymphatic transport
`of human growth hormone administered by subcutaneous injection. J.
`Pharm. Sci. 89, 168–177
`22 Charman, S.A. et al. (2001) Lymphatic absorption is a significant
`contributor to the subcutaneous bioavailability of insulin in a sheep
`model. Pharm. Res. 18, 1620–1626
`23 Kang, S. et al. (1991) Subcutaneous insulin absorption explained by
`insulin’s physicochemical properties. Evidence from absorption studies of
`soluble human insulin and insulin analogues in humans. Diabetes Care 14,
`