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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5915_Библиотеки_им_академика_М_И_Перельмана
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9 Advances in Biodegradable Ocular Drug Delivery Systems
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Fig. 9.5 Random scission of polymer chains gradually occurs throughout the biodegradation process, and chain scission occurs more readily in center of the implant. Once chains reach a threshold
of reduced molecular weight, the shortened polymer chains become solubilized in the surrounding
medium and are liberated from the implant complex. This results in central hollowing of the
implant with gradual mass loss of the implant
9.3.2 Poly(e-Caprolactone)
Poly(e-caprolactone) (PCL) is a biodegradable, semicrystalline hydrophobic polymer with a low glass transition temperature (~60°C) and a melting point ranging
between 59 and 64°C (Silva-Cunha et al. 2009). Due to its crystallinity and hydrophobicity, biodegradation of PCL occurs very slowly (from months to 1 year), which
makes it suitable for a range of biomedical applications such as sutures, orthopedic
fixation devices, and a variety of extended-release drug delivery systems (Park et al.
2005; Silva-Cunha et al. 2009). PCL-based drug delivery systems degrade by a two-
phase process involving an initial phase of bulk hydrolysis followed by a second
phase characterized by loss of mass due to chain cleavage and drug diffusion from
the polymer matrix (Silva-Cunha et
tigated for the ocular delivery of triamcinolone acetonide (Beeley et al. 2005) and
dexamethasone (Silva-Cunha et al. 2009; Fialho et al. 2008) and have shown encouraging efficacy and tolerability results.
PCL also can be blended with other polymers to form copolymers with a range
of degradation characteristics. Examples of PCL copolymers investigated for
biomedical applications include poly(-e-caprolactone)-poly(ethylene glycol)
(PCL-PEG), poly(glycolide-co-lactide-co-caprolactone) (PGLC), and poly
(glycolide-e-caprolactone-trimethylene carbonate). PCL-PEG copolymers are
more hydrophilic than unmodified PCL and therefore have faster degradation
times (da Silva et al. 2009). PCL-PEG is being investigated for use in micro/
nanoparticle and hydrogel drug delivery systems (Wei et al. 2009). PGLC, a
copolymer of PCL and PLGA, has been studied as a drug delivery vehicle for
cyclosporine (Dong et al. 2006a) and tacrolimus (FK-506) (Shi et al. 2005) in
animal models of corneal allograft and uveitis (see Sect. 9.6).
al. 2009). PCL-based implants have been inves-
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9.3.3 Poly(Ortho Esters)
Poly(ortho esters) (POE) are a class of synthetic hydrophobic, bioerodible polymers
that have been under development since the 1970s. The orthoester link of POE is
less stable under acidic than basic conditions, and thus, the degradation rate of POE
can be controlled by incorporating acidic or basic excipients into the polymer matrix
(Park and Lakes 2007). Unlike polyesters, which degrade homogeneously throughout the polymer matrix, POEs are highly hydrophobic and water-impermeable, and
as a result, degrade via surface erosion (Fig. 9.4g–l). This property has generated
interest in the use of POEs for drug delivery, since they can conceivably be used to
deliver drugs at a constant rate (i.e., zero-order kinetics) without the burst effect
associated with bulk-eroding polymers.
To date, four POE families have been developed, designated as POE I, POE II,
POE III, and POE IV (Park et al. 2005; Heller et al. 2002). POE I, POE II, and POE
III have limited applicability in biomedicine due to extreme hydrophobicity and/or
difficulties in their synthesis. In contrast, POE IV, a modified version of POE II that
has a short segment based on lactic acid or glycolic acid incorporated into the polymer backbone, has the necessary attributes for use as a drug delivery vehicle and can
be fabricated to form wafers, strands, or microspheres (Heller et al. 2002; Park et al.
2005). POE has demonstrated good tolerability in animals following suprachoroidal
and intravitreal injection, suggesting its potential for use in drug delivery to the
posterior segment.
9.3.4 Polyanhydrides
PAHs are hydrophobic polymers with hydrolytically labile anhydride linkages. PAH
is characterized by a fast rate of degradation, which occurs via surface erosion, but
the polymer composition of PAHs can be varied to produce drug delivery systems
capable of providing sustained release for days to weeks (Park et al. 2005; Kuno and
Fujii 2010). Degradation of PAHs depends on the rate of water uptake, determined
by hydrophilicity and crystallinity of the polymer. PAHs are thought to provide
more controllable, near-zero order drug release as compared with polymers that
degrade by bulk erosion, because drug release depends mainly on the surface degradation of polymers rather than drug diffusion (Fig. 9.4). PAH polymers generally
show minimal inflammatory effects in vivo and degrade into nontoxic monomeric
acids (Park et al. 2005). The most commonly used PAH for drug delivery is a copo-
lymer of bis(p-carboxyphenoxy) propane and sebacic acid. Its degradation byproducts are carboxyphenoxypropane, which is eliminated via the kidney, and sebacic
acid, an endogenous fatty acid, which is metabolized by the liver and expired as CO2
(Kuno and Fujii 2010).
PAHs will react with drugs containing free amino groups, which limit their use
as a drug-delivery matrix, and the thermal and mechanical properties of PAHs are
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not as useful as those of PCL, since the former contain many more –CH2 groups in
the main chain (Park and Lakes 2007). Another drawback is that most PAHs must
be stored frozen under anhydrous conditions because of the hydrolytic instability of
the anhydride bond (Park et al. 2005).
A PAH copolymer of bis(p-carboxyphenoxy) propane and sebacic acid (80:20
ratio) has been approved by the US FDA as a carmustine delivery system
(Gliadel®) for the treatment of brain cancer. PAH has also been investigated as
a drug delivery vehicle in glaucoma filtration surgery (see Sect. 9.6); however,
the application of PAH for posterior segment drug delivery has yet to be
reported.
9.4 Biodegradable Polymers in Nonocular Biomedical
Applications
Biodegradable polymers have a long history of successful use in a variety of medical applications for general surgery, orthopedics, reconstructive surgery, dentistry,
and vascular repair (Table 9.4, Fig. 9.6). Sutures and fixation devices composed
from biodegradable polymers have been developed to eliminate the need for extra
postsurgical removal procedures that would otherwise be required with nonabsorbable materials, thereby providing not only cost and resource savings, but also better
healing and greater convenience and safety for patients (Törmälä et al. 1998).
Biodegradable polymers, particularly those composed from PLA and PGA, are
ideal for such uses because they have a range of physical and chemical properties
that can be custom engineered to suit specific biomedical applications. For example,
the molecular structure, copolymer ratio, crystallinity, and viscosity of biodegradable polymeric materials can be manipulated to optimize mechanical strength and
degradation characteristics.
The first use of biodegradable polymers in medicine was reported in 1966 by
Kulkarni and associates, who utilized PLA to develop biodegradable sutures and
rods for the repair of mandibular fractures (Kulkarni et al. 1966). In 1971, the
first commercial synthetic biodegradable multifilament suture Dexon® (Covidien
AG, Switzerland), consisting of 100% PGA, was introduced. This was followed
soon after by the commercial introduction of Vicryl® multifilament sutures
(Johnson & Johnson Corp., New Brunswick, NJ) composed of PLGA (90:10
PGA:PLA) (Wassermann and Versfelt 1974). Other biodegradable multifilament
sutures that were later developed for commercial use include Polysorb® (U.S.
Surgical, North Haven, CT) and Panacryl® (Johnson & Johnson), both of which
are composed of PLGA. In addition to multifilament sutures, monofilament
sutures have been developed using biodegradable polymers; for example, PDS
®
sutures, composed from poly-p-dioxane (PDS) (Doddi et al. 1977), and
II
Maxon® sutures composed from PGA and TMC (trimethylene carbonate)
(Rosensaft and Webb 1981).
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Application Polymer(s)
Sutures
Dexon
®
PGA
Vicryl
®
PGA/PLLA
Polysrb PGA/PLLA
Panacryl PGA/PLLA
PDS II PDO
Maxon PGA/PLTMC/PGA
Monocryl PGA/PCL/PGA
Biosyn PGA/PDO/PLTMC/PGA
Caprosyn PGA/PCL/PLTMC/PLLA
Orthopedic fixation devices (screws, pins, staples, anchors)
Lactosorb
®
screws PLGA
BiosorbPDX screws/anchors PLGA
Biologically Quiet staples PLGA
SD sorb meniscal staples/anchors PLGA
SmartPinPDX pins PLGA
Biofix pins PGA
OrthoSorb pins PDO
Bionx screws, pins, and meniscus arrows PLA
Biofix meniscus arrows PLGA
Cervical spinal fixation plates PLA
Nonocular drug delivery implants
Nutropin
®
Depot (human growth hormone) PLGA
Sandostatin LAR
®
(octreotide) PLGA
Trelstar
®
Depot (triptorelin pamoate) PLGA
Zoladex
®
(goserelin acetate) PLGA
Tissue scaffolds
InnoPol PLGA
Other Various
Drug-eluting and nondrug eluting stents
Excel stent (sirolimus) PLA
Cura™ stent (sirolimus) PLA
Biomatrix™ stent (Biolimus A9) PLA
Nobori™ stent (Biolimus A9) PLA
Synchronnium™ stent (sirolimus/heparin) ND
Coronnium™ stent (genistein/sirolimus) PLA/PLGA
Mahoroba™ stent (tacrolimus eluting) PLGA
Bile duct stents PLGA
Igaki-Tamai™ stent PLLA
ND not disclosed; PAH polyanhydride; PCL poly(e-caprolactone); PDO polydioxane;
PFF polypropylene fumarate; PGA poly(glycolic acid); PGLC poly(glycolide-co-
lactide-co-caprolactone); PLLA poly(l-lactic acid); PLA poly(lactic acid); PLGA
poly(lactic-co-glycolic acid); PMM polymethylidene malonate; POE poly(ortho
ester); PLTMC poly(l-lactide-co-1,3-trimethylene carbonate); PVP poly(N-vinyl
pyrrolidone)
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Table 9.4 Examples of nonocular biomedical applications for biodegradable polymers
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Fig. 9.6 Timeline of
important milestones in
the development of
biodegradable drug delivery
systems for ophthalmic
diseases
Bioabsorbable sutures have been used in a wide range of applications for the
closure of soft-tissue wounds and repair of tendons, ligaments, and dislocated
joints. Early research on biodegradable suture materials indicated good tissue
compatibility and raised the possibility of using biodegradable polymer implants
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for other clinical applications. Solid, macroscopic, bioabsorbable implants have
been used clinically for fixation in orthopedics and reconstructive surgery for
more than 25 years. The first clinical studies on applications of this nature were
initiated in 1984 by Rokkanen and colleagues, who studied the use of self-reinforced PGA/PLLA rods for the fixation of displaced malleolar fractures (Rokkanen
et al. 1985; Törmälä et al. 1998). Since that time, several biodegradable implant
devices have become available commercially for orthopedic use (see reviews by
Athanasiou et al. 1996, 1998; Törmälä et al. 1998; Park and Lakes 2007; Chu
2008; Navarro et al. 2008). These comprise pins, screws, rods, and plates for bone
fixation; interference screws for anterior cruciate ligament reconstruction; softtissue anchors; and suture anchors for labrum or ligament reattachment in the
shoulder. Examples of commercially marketed products include Biologically
Quiet (Instrument Makar, Okemos, MI) and SD sorb (Surgical Dynamics,
Norwalk, CT) suture anchors; orthopedic fixation devices such as Lactosorb
(Biomet, Warsaw, IN) and BiosorbPDX (Bionx Implants, Bluebell, PA) screws
for craniomaxillofacial fixation; Biologically Quiet staples (Instrument Makar)
for anterior cruciate ligament reconstruction; SD sorb meniscal staples (Surgical
Dynamics) for meniscus repair; SmartPinPDX (Bionx) and OrthoSorb (DePuy)
pins for fracture fixation. PLGA copolymers are the most common biomaterials
used for the manufacture of such devices, although PLA, PGA, PCL, PDS, and
polycarbonate have also been employed (Navarro et
al. 2008). Polymers such as
PLA degrade relatively slowly and therefore retain their strength for a longer time
as compared with PGA, which is more brittle and undergoes more rapid degradation (Athanasiou et al. 1998).
Biodegradable polymers also have been used to manufacture various types of
nonocular drug delivery systems. Examples of such drug delivery implants, all of
®
which utilize PLGA, include Zoladex
LA (goserelin acetate, AstraZeneca UK
Ltd., UK) for the treatment of prostate cancer, Nutropin® Depot (human growth
hormone; Genentech, Inc., South San Francisco, CA) for growth deficiencies,
Trelstar
®
Depot (triptorelin pamoate) for prostate cancer, and Sandostatin LAR®
(octreotide; Novartis AG, Switzerland) for acromegaly (Avgoustakis 2008). The
diseases that these drug delivery systems are designed to treat are all chronic in
nature and require long-term treatment; thus, sustained drug release using biodegradable polymers can reduce the number of treatments needed as compared with
conventional shorter acting treatments, thereby minimizing inconvenience to
patients and potentially improving treatment compliance. For example, Zoladex
(goserelin acetate), which is a pituitary down regulator used to lower testosterone
levels in patients with prostate cancer, is normally administered by subcutaneous
abdominal injection every 4 weeks; however, with Zoladex LR, a longer-acting
PLGA-based subcutaneous implant, treatment is only required at 12-week intervals. Nutropin Depot is a subcutaneously injected suspension consisting of recombinant human growth hormone (somatotropin) in PLGA-based microsomes. This
long-acting, biodegradable formulation, used for the treatment of growth hormone
deficiency in children, is administered 1–2 times monthly and offers the potential
for improved convenience and compliance by decreasing the number of injections
®
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and frequency of administration as compared with conventional once-daily injections of growth hormone (Silverman et al. 2002). However, Nutropin Depot may
not be as effective as once-daily treatment in promoting growth rates (Nutropin
Depot Prescribing Information 2005).
Stents are devices that are widely used in vascular surgery to maintain blood
vessel patency following angioplasty. Bare metal stents, used as a structural scaffold, represent the first generation of devices developed for this purpose; however,
restenosis was a frequently associated complication. Second-generation drugeluting metallic stents were subsequently developed for the delivery of therapeutic agents to promote vascular repair as well as to provide structural support;
however, these devices were also associated with restenosis, and controversy
emerged regarding their value relative to traditional bare-metal stents (Sakhuja
and Mauri
2010; Bates 2008). Biodegradable polymer-based stents have been
developed as a means of overcoming the limitations of both drug-coated and
uncoated nonbiodegradable stents (Rogacka et al. 2008). Such devices can
potentially maintain vessel patency as effectively as nonpolymeric stents, while
limiting restenosis and other complications and eliminating the possible need for
device removal/replacement. Drug-coated biodegradable stents can also be used
for drug delivery as an alternative to metallic drug-eluting stents. A variety of
biodegradable stents incorporating PLGA and/or PLA have been developed;
these include both nondrug eluting types [e.g., bile duct (Xu et al. 2009) and
Igaki-Tamai™ (Rogacka et al. 2008) stents] and drug-eluting types to deliver
drugs such as sirolimus (Excel, Cura™, and Synchronnium™ stents), Biolimus
A9 (Biomatrix™ and Nobori™ stents), genistein (Coronnium™ stent), and
tacrolimus (Mahoroba™ stent) (Rogacka et al. 2008).
In addition to the aforementioned commercial applications, biodegradable polymers have been tested as vascular grafts, vascular couplers for vessel anastomosis,
nerve growth conduits, ligament/tendon prostheses, intramedullary plugs for total
hip replacement, and anastomosis rings for intestinal surgery, and to augment
defective bone (Chu 2008). Biodegradable polymers have also shown promise for
tissue engineering because they can be fashioned into porous scaffolding systems
and carriers of cells, extracellular matrix components, and bioactive agents to facilitate bone grafts and enhance the healing potential of musculoskeletal tissue
(Hutmacher et al. 2007). First-generation tissue scaffolds composed of PCL, which
have been through extensive clinical testing, have been approved by the US FDA
and are available commercially. Tissue scaffolds composed of natural polymers in
combination with hydroxyapatite (e.g., collagen-hydroxyapatite composites, chitosan–hydroxyapatite) and synthetic polymers (PLA, PLA-polyethylenglycol,
PCL) are also being investigated (Hutmacher et al. 2007; Guelcher 2008). To overcome limitations in the use of synthetic polymeric tissue scaffolds in high-load
bearing areas, a composite scaffolding matrix system based on PLLA/PDLLA
(copolymer ratio 70:30) is under investigation as a carrier for proteins and growth
factors (Hutmacher et al. 2007).
Results from human studies on the safety of biodegradable polymeric devices
have generally been favorable; reports of severe adverse reactions are rare, and
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most of the reported problems are associated with implants made of PGA or
PGA copolymers. The majority of clinical studies in which complications were
reported involved mild reactions suggestive of a nonspecific foreign-body
reaction to crystallites as the cause. Most of these complications resolve with
time or after minimal intervention (Athanasiou et al. 1998). The host response to
polymeric implants is multifactorial and affected by the physical and chemical
properties of the polymer and by the physical properties of the implant (volume,
shape, and surface characteristics). The response is tissue dependent, organ
dependent, and species dependent (Shive and Anderson
PLGA in bone or soft tissue of animals causes no inflammatory response, or only
a mild response that diminishes with time, and is not associated with toxicity or
allergy.
1997). Implantation of
9.5 Clinically Evaluated Biodegradable Ocular
Drug Delivery Systems
Several biodegradable polymer-based ocular drug delivery systems have been
approved for the treatment of human ocular disorders, and several others are now
being evaluated in clinical trials. These include Ozurdex, Surodex, Verisome,
Lacrisert, a brimonidine-PLGA/PLA drug delivery system, and punctal plugs for
the delivery of bimatoprost and latanoprost (Table 9.5).
9.5.1 Ozurdex™
Dexamethasone is one of the most potent of the corticosteroids but has a short halflife following intravitreal injection (Kwak and D’Amico 1992). Ozurdex™, a sustained-release implantable dexamethasone posterior-segment drug delivery system
(formerly Posurdex, Allergan Inc, Irvine, CA) has been developed to deliver therapeutic concentrations of dexamethasone in the eye for up to 6 months from a single
implant. Ozurdex is a biodegradable implant consisting of 0.7 mg dexamethasone
within a solid, rod-shaped PLGA copolymer (Novadur™, Allergan, Inc.) matrix
(Figs. 9.7 and 9.8). The implant is designed to release dexamethasone biphasically,
with peak doses for 2 months initially, followed by lower therapeutic doses for up
to 6 months. A novel single-use applicator is used to insert the drug pellet
(6.5 × 0.45 mm) into the vitreous through a 22-gauge pars plana injection (Fig. 9.7).
The procedure is performed in-office rather than in a surgical setting and does not
require sutures for wound closure.
A 6-month, randomized, phase 2 trial evaluated the efficacy and safety of Ozurdex
(0.7 or 0.35 mg) inserted via pars plana incision in patients with persistent macular
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9 Advances in Biodegradable Ocular Drug Delivery Systems
Brand name Manufacturer Materials Active agent
Duration of drug
release Characteristics Eye diseases
Biodegradable implants
Surodex
®
(Lee and Chee
2005; Lee et al. 2008;
Chang et
al. 1999;
Tan et al. 1999, 2001;
Seah et al. 2005;
Mansoor et al. 2009)
Allergan, Inc. PLGA, HPMC Dexamethasone
(60 mg)
7–10 Days Biodegradable pellet Investigational:
Postoperative
inflammation
Ozurdex
TM
(Haller et al.
2009; Kuppermann
et
al. 2007)
Allergan, Inc. PLGA Dexamethasone
(0.7 mg)
6 Months Biodegradable,
rod-shaped
intravitreal implant
FDA approved for the
treatment of
macular edema
following branch
RVO or central
RVO
a
Investigational:
DME, uveitis
(Clinicaltrials.gov
ID# NCT00168337;
NCT00168389;
NCT00333814)
Lacrisert
®
(Lacrisert
Prescribing Information
2007)
Aton Pharma HPC
b
HPC (5 mg) 1 Day Biodegradable,
translucent,
rod-shaped,
water-soluble
insert
FDA approved for the
treatment of
moderate to severe
dry eye syndrome,
including keratitis
sicca
a
(continued)
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Table 9.5 Biodegradable drug delivery implants for the treatment of chronic ocular diseases: approved systems and devices under clinical development
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associated with
retinal vein
Duration of drug
release Characteristics Eye diseases
Up to 1 year Biodegradable Investigational: CME
occlusion and
postoperative
cataract surgery
Brand name Manufacturer Materials Active agent
Table 9.5 (continued)
acetonide
(6.9–13.8 mg)
Proprietary Triamcinolone
Bioscience,
Inc.
ICON
(Hu et al. 2008;
Lim et al. 2009)
IBI 20089/Verisome™
See individual product labels for complete information
CME cystoid macular edema; DME diabetic macular edema; FDA Food and Drug Administration; HPC hydroxypropyl cellulose; HPMC hydroxypropyl
a
methylcellulose; PLGA poly(lactic-co-glycolic acid); RVO retinal vein occlusion
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