Biodegradable polymers: emerging excipients for the

pharmaceutical and medical device industries.

Bhavesh Patel*, Subhashis Chakraborty

Technical Service-Pharma Polymer & Services, Evonik India Pvt Ltd, Research Centre India (RCI), Krislon house-first floor, Opp.
Marwah Centre, Sakivihar road, Sakinaka, Andheri (E), Mumbai 400 072, Maharashtra, India

Received: September 13, 2013; Accepted: October 12, 2013

Review Article

ABSTRACT

Worldwide many researchers are exploring the potential use of biodegradable polymerics as carriers for a wide
range of therapeutic applications. In the past two decades, considerable progress has been made in the
development of biodegradable polymeric materials, mainly in the biomedical and pharmaceutical industries
due to their versatility, biocompatibility and biodegradability properties. The present review focuses on the
use of biodegradable polymers in various therapeutic areas like orthopedic and contraceptive device, surgical
sutures, implants, depot parenteral injections, etc. Biodegradable polymers have also contributed significantly
to the development of drug-eluting stents (DES) used for the treatment of obstructive coronary artery disease,
such as angioplasty. Biodegradable synthetic polymers have potential applications in orthopedic device
fixation due to properties that impact bone healing, formation, regeneration or substitution in the human
body. The present review also emphasizes areas such as the chemistry of polymer synthesis, factors affecting
the biodegradation, methods for the production of biodegradable polymer based formulations, the application
of biodegradable polymers in dental implants, nasal drug deliveries, contraceptive devices, immunology, gene,
transdermal, ophthalmic and veterinary applications, as well as, the sterilization of biodegradable based
formulations and regulatory considerations for product filing.

KEY WORDS: Biodegradable polymers, degradation, orthopedic implants, sterilization, drug eluting stents, tissue
engineering

INTRODUCTION has not received much attention because of

their tendency to degrade under normal
The term “Biodegradable polymers” is quite environmental conditions. Interestingly, it was
fascinating in the pharmaceutical and medical later realized that this was an advantage for
device community. In fact, this class of designing a biodegradable implant which would
polymers has been known for more than a 100 avoid the necessity of a second surgical
years in the chemical industry but unfortunately procedure required to remove the remnants of
a previous implant, as was the case for metallic
implants. The first FDA approved
*
Corresponding author: Technical Service-Pharma Polymer & Services, biodegradable product, Dexon® was a suture
Evonik India Pvt Ltd, Research Centre India (RCI), Krislon house-first introduced in 1970 by Davis and Geck (1).
floor, Opp. Marwah Centre, Sakivihar road, Sakinaka, Andheri (E),
Mumbai 400 072, Maharashtra, India, Tel: +91 98337 46909; Fax: +91 22
6691 6996, E-Mail: [email protected]

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Since then, there has been a revolution in the pertaining to polymer chemistry, polymer
medical device industry which has introduced synthesis and optimal polymer selection for
several orthopaedic implants such as pins, pharmaceutical and medical applications. This
screws, cranio-maxilla-facial plates and so on. review also attempts to discuss factors
After about two decades, in the 1990s, the influencing the biodegradation process,
pharmaceutical industry entered in to this new together with recent developments in the area
era of biodegradable polymers introducing of novel drug delivery systems such gene and
depot injections. One of the most popular and cancer therapy, the application in dental and
commercially successful depot injection is orthopedic devices during surgery, drug eluting
Lupron®, manufactured by Takeda primarily stents, orthopedic devices, sutures for tissue
used for the treatment of prostate cancer (2,3). and scaffold engineering, veterinary and nasal
Although there has been significant scientific, drug delivery using biodegradable polymers.
as well as, commercial progress in this area, the
understanding of this technology remains CLASSIFICATION
limited to a few global companies. This is
primarily because of the complexities involved Broadly, biodegradable polymers can be
in the polymer chemistry, depot injection classified into natural or synthetic. Natural
formulation technology and high precision biodegradable polymers are proteins or
molding. There is tremendous scope for the polysaccharides e.g., alginate, chitosan, agarose
adoption of these technologies by a greater and collagen or starch based derivatives which
number of pharmaceutical and medical device undergo enzymatic degradation in the body.
companies. This will help in extending the Synthetic polymers contain hydrolysable
benefits of these novel technologies to larger linkages such as esters, amide, peptide, urea,
patient populations world-wide, offering better urethane or anhydride in the polymeric
patient compliance, especially in the case of backbone that easily hydrolyzes in the human
chronic disease management. body. Examples of such synthetic polymers
include (i) polyesters such as poly lactic acid
Through understanding polymer degradation in (PLA), poly glycolic acid (PGA), poly l-lactide
the presence of hydrolyzing agents available in co-glycolide (PLGA) co-polymer, poly ε-
the biological systems, various novel drug caprolactone (PCL) (ii) poly anhydrides (iii)
delivery systems for sustained and targeted poly ethylene glycol and their derivatives (iv)
release have been formulated as depot poly vinyl alcohol (v) poly peptide and poly
injections for weekly or monthly administration amide (vi) polyhydroxy alkonates (PHA)
as implants, microspheres, microcapsules, derivatives, etc., (5, 6). A broad classification of
nanoparticles, in situ gels etc., (4). Properties biodegradable polymers is shown in Table 1.
such as flexibility, durability and
biocompatibility have made these polymers the Polyester PLGA is a copolymer of poly lactic
preferred vehicles to administer safely in vivo for acid (PLA) and poly glycolic acid (PGA). It is
human use in the form of medical devices such currently considered the best biomaterial
dental and orthopedic implants, inserts, sutures, available for drug delivery with respect to
drug eluting stents, and contraceptive devices design and performance. Poly lactic acid
(4). Considering the sincere approach of contains an asymmetric carbon which is
environment protection, future outlook in the typically described as the D or L form and
area of biodegradable polymers seems to be sometimes as R and S form, in classical stereo
quite promising. chemical terms. The enantiomeric forms of the
polymer PLA are poly D-lactic acid (PDLA)
The objective of this review is to present a and poly L-lactic acid (PLLA).
consolidated view on the basic aspects

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Table 1 Classification of biodegradable polymers (5-7)

NATURAL
Sr. SYNTHETIC BIODEGRADABLE
BIODEGRADABLE
No POLYMER
POLYMER
Polyesters (Polyhydroxy alkanoates,
polycaprolactone, poly L-lactide, poly
lactic acid, poly p-dioxanones, poly Proteins based (collagen,
1
urethane, poly vinyl alcohol, nylon, Poly gelatin and albumin)
phosphor esters, Poly glycolic acid,
Poly lactic-co-glycolic acid)
Polysaccharides (starch,
Polyethers (Poly ethylene, polytetra
2 dextran, hyaluronic acid, and
methylene and poly propylene glycols)
chitosan)
3 Polyethylene (PE)
4 Polycarbonates (PC)
5 Polyphosphazenes
6 Polyamide and Polyimide
7 Polyacrylamide
8 Polytetra fluoro ethylene (PTFE)
9 Poly ortho esters (POE)
Figure 1 Synthesis and biodegradation cycle of PLGA
Poly anhydrides poly [bis(p-
based biodegradable polymer
10 carboxyphenoxy) propane-co-sebacic
acid]
and ε-caprolactone (see Figure 1).
PLGA is generally an acronym for poly D, L- When polymers are made of only one type of
lactic-co-glycolic acid where D- and L- lactic monomer, they are termed “homo-polymers”
acid forms are in equal ratio (7). Trade name e.g., poly glycolic acid (PGA), poly lactic acid
and major global manufacturers of (PLA) and poly-dioxanone. If polymers are
biodegradable polymer are shown in Table 2. generated using a combination of monomers,
they are termed as “co-polymers” e.g., poly (D,
Table 2 Trade name and some of global manufacturers
of biodegradable polymers (8, 9) L-lactide co-glycolide) (PLGA), poly-(l-lactide-
co-trimethylene carbonate), poly-(glycolide-co-
Sr. No COMPANY NAME TRADE NAME trimethylene carbonate), poly-(glycolide-co-
1 Galactic Galacid® trimethylene carbonate-co-caprolactone) and so
2 Chronopol Heplon®
3 Treofan Treofan®
on.
4 Mitsubishi Corporation Ecoloju®
5 Biomer Biomer® L
The basic monomer unit of PLA is lactic acid
6 Evonik Industries Resomer® and Lakeshore®
7 Dow Cargill NatureWorks ® and is primarily produced in large quantities
8 Toyota Eco Plastic® through bacterial fermentation of carbohydrates
Lacea®
9
10
Mitsui Chemicals
Purac Biochem L-PLA®
such as corn, sugar cane, whey, and so on, i.e.,
11 Shimadzu Corporation Lacty® rich carbon sources. The majority of the
12 Durect Corporation Lactel® fermentation processes are carried out using
13 BASF Ecoflex®, Ecovio®
14 DuPont Biomax®
Lactobacilli species which offer high yields of
15 Eastman Chemical company Eastar Bio Ultra copolyester lactic acid. After obtaining a monomer such as
16 Cereplast Bioplastic resin
lactic acid, PLA can be further synthesized
17 Procter and Gamble Nodax®
18 PolyScience Inc PLA-PGA and PCL co-polymer through a polycondensation reaction, or via
19 Metabolix Inc Poly hydroxyl alkanoates (PHA) ring-opening polymerization of cyclic diesters.
20 Wako speciality chemical PLA and PLGA
The monomer’s concentration, ratio and
sequence in the polymer and end group
Chemistry and synthesis
chemistry dictate their mechanical properties,
degradation kinetics, solubility, thermal and
PLGA polymers are polyester based
rheological properties, and water uptake.
biodegradable polymers, manufactured
Furthermore, the polymers can be tailored for
synthetically from monomers like lactic acid,
controlled degradation through the addition of
glycolic acid, dioxanone, tri-methyl carbonate
numerous functional groups including

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carboxylic acids, esters, amides, anhydrides, and surface erosion depends on the area exposed to
others. Synthetically, the polymers are prepared the hydrolytic environment and the rate of bulk
through ring-opening polymerization of the erosion depends on the crystalline nature and
monomers in the presence of a catalyst. Post porosity of the polymer matrix. The drug
synthesis, the polymers are purified using release pattern from the polymer matrix of
supercritical carbon dioxide (for crystalline microspheres and implants follow the following
polymers) or aqueous precipitation from three step process, that is an initial burst release
acetone (for amorphous polymers) in order to due to dissolution of surface drug, followed by
reduce the residual monomer content. The slow release due to degradation-dependent
overall low residual monomer content and network relaxation that creates sufficient free
minimal impurities imparts high quality and volume for drug dissolution, and finally an
stability to the final product (8). accelerated drug release. The accelerated drug
release is triggered by the acidic micro-
MECHANISM OF DEGRADATION environment within the particle generated by
the autocatalytic degradation of the polymers
The term degradation designates the process of into lactic and glycolic acids. Overall, the
polymer chain cleavage which leads to a loss in release profile is dependent on the nature of the
molecular weight. Degradation induces the drug, polymer degradation rate, water
subsequent erosion of the material which is permeability and drug-polymer matrix
defined as mass loss of material. For interaction. Once degraded, the solubilized
biodegradable polymer, mainly two different momomers/oligomers such as lactic acid and
processes of polymeric degradation can be glycolic acid are excreted by the kidney and
proposed (1) Bulk erosion and (2) Surface finally metabolized into carbon dioxide and
erosion. The difference between the two water through the tricarboxylic acid (Kreb’s)
degradation mechanisms is shown in Figure 2. cycle (10-12).

Biodegradable polymers contain a hydrolysable Various advanced analytical techniques are

backbone which is susceptible to hydrolysis or generally useful to understand and illustrate the
enzymatic degradation in the cell environment polymer degradation mechanisms. A simple but
by bulk erosion and surface erosion. The relatively effective technique to characterize the
former involves degradation all over the cross degradation of a polymeric matrix is by
section because of water penetration followed recording the loss of mass during the
by slow scissions of long polymer chains, while degradation process. In most cases the main
the latter is a surface phenomenon. The rate of
parameter used for monitoring degradation are
changes in molecular weight, crystallinity, pH
and thermal changes inside the core. Qualitative
evaluation of polymer degradation can be
performed using scanning electron microscopy
(SEM) and atomic force microscopy (AFM)
which offer insight into the external and
internal morphology of degradable polymer
systems. Other methods determine the
molecular weight reduction of the polymer by
means of gel permeation chromatography
(GPC) or by intrinsic viscosity. For the changes
that degradable polymers undergo during
Figure 2 Degradation mechanism of biodegradable degradation, thermal analysis such as
polymer

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differential scanning calorimetry (DSC) and The major global players using biodegradable
thermo gravimetric analysis (TGA) are polymers in the pharmaceutical industry are
somewhat beneficial. Some of the more mainly multinational companies such as
advanced techniques that are useful for the Abbott, Astra-Zeneca, Takeda, Novartis,
studying of polymer degradation are the Astellas and Sanofi Aventis. A review of the
determination of the molar fraction of the sales data of biodegradable formulations (such
monomer using nuclear magnetic resonance as depot injections or medical devices)
(1H NMR), changes in crystallinity using wide manufactured by the above key pharmaceutical
angle x-ray diffraction (XRD), determination of companies indicates revenues of approximately
monomer release using HPLC, end-group 4.2 billion Euros generated to the year 2010.
analysis using FT-IR and the study of polymer Out of the total revenue of 4.2 billion Euros,
structure and degradation using raman Janssen-Cilag has 72% of the market and the
scattering (12). rest is split between other customers. There is
an increasing trend in the growth of dosage
MARKET ANALYSIS FOR PLGA BASED forms and the the total volume of dosage forms
FORMULATION was 316 kilograms in 2007 increasing to 374
kilograms in 2009, i.e., at a rate of 9% increase
The worldwide manufacturing capacity of per annum. Fragmenting the volume of each
biodegradable polymers (natural and synthetic) individual dosage forms shows that Risperidone
has grown dramatically since the mid-1990s. In has the highest market share at 73% followed
1995, they were primarily produced on pilot by Leuprolide acetate with a 14% market share.
plant scale with total worldwide capacity The remaining dosage forms were formulations
accounting for not more that 25,000 to 30,000 of Goserelin, Buserelin and Octreotide (14).
tonnes. In 2005, the global capacity for
biodegradable polymer had increased to around EMERGING TRENDS IN FORMULATION
360,000 tones and continues to show an DEVELOPMENT USING BIODEGRADABLE
upward trend (9). POLYMERS

In March 2012 Global Industry Analyst, Inc There is a continuing increase in the number of
released a comprehensive global report on the drugs, drug therapies and diseases which
market for biodegradable polymers forecasting require different kinds of formulations using
that it is bound to reach 2.44 billion pounds by novel manufacturing technologies and modified
year 2017. The ever increasing demand in release kinetics. There is no single polymer that
packaging, the largest end-use market, growing can satisfy all these requirements. Therefore the
environmental concerns, soaring petroleum last 30 years has seen tremendous advances in
costs, launch of new types of biodegradable area of biodegradable polymer. The use of
polymers, concerns over depleting landfills, and biodegradable polymers in a formulation can
a shift towards renewable sources from aid in extending the release of the drug for a
traditional sources of fossil fuel are the key considerable period of time (weeks to months)
factors driving the demand for biodegradable and removes the need to remove device from
polymers. Markets could further grow through the patient at the end of the treatment period.
technological innovations, emerging In addition, they also offer advantages in terms
applications, increased regulations to prohibit of targeted delivery of the drug and stabilization
packaging waste and disposal at landfills and of the drug molecules in polymeric matrix (15-
improvements in infrastructure (13). 18). A list of some commercial formulations
manufactured using PLA/PLGA polymers are
shown in Table 3.

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Table 3 PLA/PLGA based commercial formulation (19- microsphere morphology analysed (22).
21) Although this is a simple procedure it may not
be suitable for proteins and peptides which may
PRODUCT DOSAGE DURATION
NAME FORM
MANUFACTURER ACTIVE
MONTHS be denatured in the presence of organic
Decapeptyl® Microparticle Ferring
Triptorelin
acetate
1 solvents. It is also important to note that the
Decapeptyl SR ®
Microparticle Ipsen-Beaufour
Triptorelin
acetate
1, 3, 6 (PLGA) encapsulation efficiency achieved by this
Zoladex® Implant AstraZeneca Goserelin acetate 1, 3 (PLGA) process is quite low and therefore may not be a
Lupron Depot® Microparticle Takeda –Abbott
Leuprolide
acetate
1, 3, 4 (PLGA) practical approach for manufacturing (23-24).
Sandostatin Octreotide
Microparticle Novartis 1 (PLGA)
LAR® acetate
Nutropin ®
Microparticle Genentech
Somatropin
1,2 (PLGA)
Multiple (double) emulsification (w/o/w or
Depot (hrGH)
®
Profact Depot Implant Sanofi-Aventis Buserelin acetate 2, 3 (PLGA)
o/o/w) technique
Suprecur® MP Microparticle Sanofi-Aventis Buserelin acetate 1

Eligard® Implant Sanofi-Aventis

Leuprolide
acetate
1, 3 (PLGA) The microencapsulation process in which
Luprogel® Liquid MediGene AG
Leuprolide
acetate
1
emulsification (single or multiple) is followed
Trelstar® Depot Microparticle Watson
Triptorelin
1 (PLGA)
by the removal of the solvent has been widely
pamoate

® Triptorelin
used for the preparation of PLGA based
Trelstar LA Microparticle Watson-Debio 1, 3 (PLGA)

Arestin® Microparticle OraPharma

pamoate
Minocycline HCl 0.5
microspheres and microcapsules.
Atridox® Implants CollaGenex Doxycycline 0.25 (PLA)
Risperdal®
Consta
Microparticle Johnson & Johnson Risperidone 0.5 (PLGA) w/o/w multiple emulsification
SMARTShot
Microparticle Stockguard Vitamin B12 4, 8
B12
®
Vivitrol Microparticle Alkermes Naltrexone 1 (PLGA)
In general, this method is used for the
Revalor -XS®
Implant Intervet
Trenbolone/estra
diol
6 hydrophilic drug moieties which are easily
Ozurdex® Implant Allergan Dexamethasone 1 soluble in aqueous media. First, an aqueous
Gliadel® Implants MGI Pharma Carmustine 20
phase containing dissolved drug (~ 0.5 to 1 ml)
is emulsified into an oil phase (containing a
PLGA polymer) (~ 5 to 10 ml) using a high
VARIOUS APPROACHES TO DEVELOP speed homogenizer. Suitable emulsifiers or
BIODEGRADABLE POLYMER BASED
FORMULATIONS
surfactants such as Poloxamer 407 or 188
(~2% w/v) or Span 20 (1% to 20% v/v) can be
Single emulsion (w/o or o/w) technique incorporated during the initial emulsification
process. Then the initial emulsion is added to a
Lakshmana et al., proposed a simple greater volume of different concentrations of
emulsification process followed by solvent poly vinyl alcohol (0.1 to 1% w/w) (~ 200 to
evaporation for the preparation of sustained 300 ml) continuously stirring using a
release microspheres containing Aceclofenac. mechanical stirrer to form a w/o/w multiple
Using this method, microspheres were prepared emulsions. Homogenization is continued for a
by dissolving the polymer and the drug into a few hours at room temperature until the
common solvent such as dichloromethane solvent has completely evaporated. The
followed by adding this oil phase into the microparticles that are generated are collected
higher volume of aqueous phase containing through suitable size filtration and are further
emulsifying agent, PVA (0.1 to 1% w/v) under washed with purified water and dried overnight
continuous stirring for a specified period of at room temperature (25-27). Giovagnoli et al.,
time and revolutions per minute in a propeller used a similar method to prepare microspheres
stirrer. This mixture was then immediately of Capreomycin molecules using PLGA (50:50
transferred to a magnetic stirrer for complete ratio, Mw: 10 kDa) for pulmonary delivery (28),
solvent evaporation. The microspheres were as did Herman and Bodmeier who prepared
collected through filtration, washed with de- microspheres of Somatostatin using PLA (Mw
ionized water and dried in vacuum desiccators = 6,000 Da) using this method.
and then further characterized and the

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The above studies showed that using various using emulsification based solvent evaporation
salts such as NaCl or CaCl2 in the internal or are shown in Table 4.
external aqueous phases affected directly the
drug release pattern because of the formation Phase separation (co-acervation) method
of micro pore like structures in the microsphere
(29). Crotts and Park prepared microspheres of Phase separation, also known as a co-acervation
bovine serum albumin (BSA) using PLGA technique, is a process focused on the
(75:25 ratio, Mw: 82,000 D) and studied the preparation of microspheres through non-ionic
effect of the inner aqueous phase volume on liquid-liquid phase separation techniques. Phase
the morphology and porosity of microspheres, separation methods consist of decreasing the
under the assumption that the volume of the solubility of the encapsulating polymer by
inner phase is directly related to the rate of adding a third immiscible component to the
solvent removal. It was found that at 5.6% polymer solution. Similar to a solvent
inner aqueous volume fraction, dense and evaporation technique, this method is also used
nonporous microspheres were formed while at for both hydrophilic and hydrophobic drugs.
22.7% more porous microspheres were Water-soluble drugs such as peptides and
generated (30). Pandey et. al., prepared proteins are dissolved in water and dispersed in
nanoparticles encapsulating the anti- the polymer solution to make a w/o emulsion.
tuberculosis drugs Isoniazid and Rifampicin Hydrophobic drugs, such as steroids, are either
incorporating PLGA (50:50 ratio). They solubilized or dispersed in the polymer
observed effective encpsulation of both drugs solution.
(~ 60%) and a prolonged blood circulation and
anti-tubercular (TB) effect up to 9-11 days
suggests that drug therapy based on PLGA
nanoparticles can be capable of reducing dosing
frequency (31).

o/o/w multiple emulsification

In general, the method of o/o/w multiple

emulsification is suitable and, has been widely
used, for lipophilic drugs. PLA or PLGA is
dissolved in an oil phase (O2) such as
dichloromethane (~ 5 ml) together with an
emulsifier e.g,. Labrafil as a lipid vehicle. The
primary o/o emulsion is prepared by adding
olive oil (O1) (~ 0.2 to 1 ml) into a second oil
phase such as dichloromethane and then the
mixture is sonicated using a probe type
sonicator for ~30 seconds. Finally, the primary
emulsion is re-emulsified into distilled
deionized water containing PVA (0.1 to 1%
w/v; ~ 100 ml) using a vigorous
homogenization process for 3 minutes. After
complete solvent evaporation the microspheres
are collected by centrifugation and washed with
distilled de-ionized water (32). A schematic
diagram of multiple emulsification process is Figure 3 Schematic illustration of multiple emulsifications
shown in Figure 3. A list of drugs manufactured followed by solvent evaporation method

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Table 4 List of drugs encapsulated using emulsification based solvent evaporation techniques

PREPARATION
No NAME OF DRUG POLYMER USED REF
METHOD
1 Capreomycin Sulfate PLGA 50:50 (Mw =10 kd) w/o/w multiple emulsion (28)
2 Bovine serum albumin PLGA 75:25 (Mw = 82,000D) w/o/w multiple emulsion (30)
3 Isoniazid + Rifampicin PLGA 50:50 (Mw = 25,000D) w/o/w multiple emulsion (31)
4 Labragfil® M 1944 PLA Mw = 2kDa o/o/w multiple emulsion (32)
5 Triptoreline PLGA 50:50 w/o/w multiple emulsion (33)
6 Bovine Superoxide Dismutase PEG 6000 s/o/w multiple emulsion (34)
7 Ganciclovir PLGA 65:35 Mw = 70,000D o/w emulsion (36)
8 Somatostatin PLA Mw = 6,000 D w/o/w emulsion (37)
9 Insulin PLGA 50:50 o/o emulsion (38)

10 Bovine serum albumin PLGA 50:50 Mw = 13,600D w/o/w multiple emulsion (39)

11 Diclofenac Sodium PLGA 50:50 Mw = 34,000D o/w emulsion (40)

12 5- Fluoro uracil PLA Mw = 3,400 D o/o emulsion (41)
13 ABT 627 (NCE) PLGA 50:50 Mw = 34,000D o/w emulsion (42)
14 Risperidone PLGA 75:25 o/w emulsion (43)
15 Dexamethasone PLGA 50:50 Mw = 60,000D o/w emulsion (44)
16 Leuprolide Acetate PLA and PLGA o/o/w multiple emulsion (45)
17 Doxorubicin PLGA 50:50 Mw = 13,000D o/w emulsion (46)
18 Campothecin PLGA 50:50 iv: 0.32-0.44 dl/g o/w emulsion (47)
19 Octreotide Acetate PLGA 50:50 Mw = 53,600D w/o/w multiple emulsion (48)
20 Insulin PLA Mw = 17,000D and PLGA 50:50 Mw = 14,100D w/o/w multiple emulsion (49)
21 Isoniazid+ Rifampicin PLGA 50:50 Mw = 2,500D Double emulsification (50)

Organic non-solvents such as liquid paraffin, the polymer has sufficient time to precipiate
silicone, coconut or sunflower oil is then added and coat evenly onto the drug particle surface
to the solvent system (containing both the drug during the co-acervation (57).
and polymer) under continuous stirring to
extract the polymer solvent from the mixture. Jayan et. al., developed gelatin microspheres
As a result, the polymer is subjected to phase containing salbutamol sulphate using a co-
separation forming very soft coacervate acervation phase separation method utilizing
droplets (size controlled by stirring) which temperature change. Gelatin was selected as a
entrap the drug. This system is then added to a water-soluble naturally occurring biodegradable
large quantity of another organic non-solvent polypeptide which is easily hydrolyzed by
such as formaldehyde or glutaraldehyde to proteolytic enzymes present in the body. The
harden the micro-droplets and form the final microspheres obtained were uniform and
microspheres which are collected by washing, spherical in shape with mean particle size
sieving, filtrating/ centrifuging, and finally around 12.58 µm providing sustained drug
drying (51-56). Thus, the co-acervation process release over a period of 8 1/2 hours (58).
includes the following three steps: (1) phase Surendiran et. al., developed microspheres from
separation of the coating polymer solution by a gelatin-carbopol polymeric mixture using
adding a third component (2) removal of the ibuprofen as the model drug using a similar
polymer solvents and adsorption of the method where microspheres with a high
coacervate around the drug particles and (3) amount of carbopol showed more sustained
solidification of microparticles and collection of drug release when compared to microspheres
the microspheres by washing, filtrating/ that contained a high amount of gelatin (59).
centrifuging and freeze drying. In a phase These studies provide a basis for selecting
separation method, the rate of adding the first suitable excipients for the design of sustained
non-solvent must be controlled to ensure that release biodegradable microspheres.
the polymer solvent is extracted slowly so that

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Supercritical CO2 anti-solvent precipitation semi- continuous compressed CO2 anti-solvent

method precipitation wherein the drug was released in
the active form and the antibacterial activity
Submicrometer-sized and nano-sized particles was maintained up to 45 days (66).
can be designed using various supercritical fluid
(SCF) methods. A supercritical fluid can either Kluge et. al., prepared PLGA micro- and
be a liquid or gas and is used above its nanocomposites (50:50 ratio) using supercritical
thermodynamic critical point of temperature fluid extraction of emulsions (SFEE) for the
and pressure. Most commonly used SCFs are delivery of lysozyme. Particle sizes of around
carbon dioxide (CO2) and water (60). In this 100 nm and encapsulation efficiency of 48.5%
process, the hydrophilic drug is dissolved in a was observed (67). Similarly, Lee et. al.,
common solvent and injected in supercritical prepared PLA based microparticles using
CO2 with an ultrasonic field for enhanced supercritical anti-solvent using an enhanced
molecular mixing. Supercritical CO2 rapidly mass transfer (SAS-EM) process wherein drug
extracts methanol leading to the instantaneous encapsulation efficiency achieved was 83.5%
precipitation of drug nanoparticles which are and the drug release was controlled for more
encapsulated in PLGA polymeric microspheres than 30 days. As compared to conventional
using a non-aqueous anhydrous solid-oil-oil-oil SAS processes, SAS-EM process has major
(s/o/o/o) technique. In this technique, PLGA advantage of effective residual organic solvents
is dissolved in dichloromethane (DCM) solvent removal (68).
into which drug nanoparticles are added
continuously whilst stirring. In the next step, a Spray/freeze drying
small amount of silicone oil is added to the
mixture resulting in the precipitation of PLGA When freeze drying a solution of PLA or
in the form of the drug encapsulated in PLGA it is first dissolved in organic solvents
microspheres. Finally, the suspension is added which are further emulsified into an aqueous
to a large quantity of precooled hexane to PVA solution using a homogenization process.
extract the DCM and silicone oil. This emulsion is then immediately added drop
by drop to liquid nitrogen. The water and
Thote et. al., developed PLGA (50:50 ratio, organic solvent is removed from the frozen
inherent viscosity: 0.39 dl/g) nanoparticles (150 sample under vacuum at 0EC, leaving behind
- 200 nm) containing dexamethasone as the the dry hollow PLA or PLGA particles.
model drug using a supercritical CO2 method. Similarly, when spray drying an organic solution
Interestingly, in vitro dissolution of the that contains the polymer and a suitable
microencapsulated nanoparticles showed surfactant such as dimethyl carbonate it is
sustained release over a period of 700 hours atomized using a coaxial spray nozzle under
without an initial burst release (61-64). Jordan
pressure. Then the sprayed particles are
et. al., developed PLGA (50:50 ratio, inherent
collected in liquid nitrogen and dried under
viscosity: 0.16-0.24 dl/g) based sustained
release microspheres of human growth vacuum at room temperature. In order to
hormone using the SCF method for encapsulate the drug, these hollow PLA
subcutaneous injections. The sustained release particles are dispersed into an aqueous solution
effect was observed for 14 days with minimal of the drug by placing the solution in an
burst release. The formulation was well ultrasonic bath for several seconds. Micro
tolerated by both rats and monkeys without any capsules are finally formed after stirring with
evidence of subcutaneous inflammation or the plasticizing solution (DCM/CO2 in excess).
chronic inflammatory response (65). Salmaso et. Later the solution is washed through
al., prepared PLA (Mw: 102 kDa) nanoparticles centrifugation/dispersion with water and then
(200-400 nm) of Nisin as the model drug using dried under vacuum (69). Christopher et. al.,

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 Review Article

prepared spray dried nanoparticles of The scaffold was prepared using a PLGA
ovalbumin using a PLGA (50:50 ratio) polymer (50/50) casted into a screw-cap.
containing an antigen carrier device for vaccine Sodium chloride particles with diameters of
delivery. Electron microscopy confirmed that 200–450 µm as porogens were inserted into the
the cross-penetration of the microencapsulated nanofibrous matrixes (72). After 7 days the cells
antigen occurred quite easily wherein lysosomes were observed to show good morphology
were retained within the endosome for up to 3 indicating their viability for tissue repair.
days (70).
IMPLANT PREPARATION TECHNIQUES
The laser ablation method Solvent casting and compression molding

The laser ablation method involves the Biodegradable implants, particularly PLGA- or
production of microparticles by cutting a PLA- based implants can be prepared using
stream of drug-polymer-solvent solution using solvents. A PLA or PLGA based polymer and
a pulsating laser, powerful enough to vaporize drug mixture is dissolved in an appropriate
at intervals, thus producing continuous beads solvent (e.g., dichloromethane,
of micron-size particles. In this process, the trichloromethane or acetone) in the desired
PLGA polymer is dissolved in an organic proportion, and the solvent is cast over a teflon
solvent such as DCM and the solution is mold at room temperature or slightly higher
continuously pumped through a glass capillary temperature and finally vacuum dried to
with an opening of 10-100 µm. A modulated remove the residual solvent. The resultant
laser constantly fires at the ejected stream to cut structure is a composite material of the drug
it into discrete droplets which are then collected together with the polymer. The solvent cast
material is then compressed into the desired
in a large quantity of a PVA solution. This is
form at around 80EC and 25,000 psi obtaining
then left overnight to harden the microparticles
a final density of 1 g/cc. Such an implant can
by extraction of DCM. The extracted particles
be subcutaneously delivered into the body. A
are then collected by ultracentrifuge and dried drawback of the above method is the presence
or lyophilized to obtain the final product (71). of an organic solvent in the formula. Therefore
There are only a few studies demonstrating this stability of the incorporated drug becomes an
approach, probably because of the lack of issue, particularly for therapeutic proteins. It is
access to the necessary equipment. necessary to test the stability of a drug in the
presence of an organic solvent (73-75).
Micro and nano fibrous scaffolds
Extrusion
In tissue engineering, an ideal scaffold should
stimulate the growth of a natural extracellular Solvent casting techniques are not ideal for
matrix (ECM) in order to support cell industrial scale-up for several reasons. First, the
attachment and guide three-dimensional (3D) process requires large amounts of organic
tissue formation. PLGAs work as superior solvents increaseing the risk of denaturation of
biodegradable candidates satisfying the needs of the drug and/or protein during the
various tissue repairs. Pores should also be large encapsulation. Such inactive entities can cause
enough to facilitate the growth of tissue cells unpredictable side effects, e.g., immunogenicity
(72). or other toxicity. Second, this process requires a
very long time for complete solvent removal
Jifu et al., prepared PLGA based macroporous from the final product. It is a batch process
and nanofibrous scaffolds together with salt which may result in increased occurrences of
particles using a phase separation technique. batch-to-batch variation in the composition of

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the implants. Unlike solvent casting, extrusion denaturation can take place. Therefore, the
is a continuous process of pressing the extrusion process poses a limitation for drugs
polymer-drug mixture through a die to create that cannot be used because of their melting
implants of fixed cross-sectional profile without point, polymorph stability and chemical
any use of solvent (73). interactions with PLGA (76-79).

Felt-Baeyens et. al., prepared triamcinolone Atrix Laboratories, USA developed an

acetonide loaded biodegradable scleral implants injectable in situ implant where a PLGA
using a modified compression molding method polymer together with the drug was dissolved
for ocular drug delivery. In vivo studies indicated into a biocompatible solvent (N-methyl
that stearic acid acted as an excellent plasticizer pyrollidone (NMP) and Dimethyl sulfoxide
together with the polymer resulting in stable (DMSO). This manufacturing technology is
implants that had good ocular biocompatibility also known as the “Atrigel Delivery System”.
in rabbit eyes showing no inflammatory Once injected, the polymer precipitates out or
reaction and provided drug release for up to 5 coagulates immediately in the body fluid due to
weeks (74). Witt et. al., developed biodegradable its water insolubility. The key factor in the
implants for parenteral and controlled drug above system is the precipitation threshold (i.e.,
delivery systems using ABA triblock the limit above which the polymer may
copolymers, consisting of poly (lactide-co- precipitate out from the aqueous media) and
glycolide) A-blocks and poly (oxyethylene) B- the polymer solubility in different solvents
blocks, and PLG, poly (lactide-co-glycolide) which can be calculated using the Flory
polymer by compressing them using a ram Huggins solubility equation. When the
extruder. An electron paramagnetic resonance formulation was subcutaneously administered
study showed that the implants remains intact into rats, the formulation with a polymer
and swells during erosion due to presence of content below the precipitation threshold had
PEO blocks as well as the pH inside the ABA twice the initial release compared to the
triblock copolymers remains in the neutral formulation where the polymer content was
range which indicates that ABA triblock above the precipitation threshold (80).
copolymers are promising biomaterials for the
parenteral delivery of pH-sensitive drugs (75). Rothen-Weinhold et. al., studied the influence
of extrusion and injection molding on in vitro
The extrusion process is the most convenient degradation and release profile. PLA (Mw: 6000
route for manufacturing implants. Screw D) implants were prepared using a
extruders are basically inside a stationary Somatostatin analogue such as Vapreotide as a
cylindrical barrel with either a single or twin model drug. In the extrusion method, implants
helical rotating screws. The extruder is mainly were prepared by extruding a mixture of PLA
divided into three subdivisions: feeding zone, and Vapreotide using a laboratory scale ram
transition zone, and mixing zone. The process extruder. In this method, a powder mixture of
constitutes an extruder and polymer-drug the drug and the polymer was put into a barrel
mixture with required micron size feed material. which had a 10 mm inside diameter at 80°C as
During the process, the polymer-drug mixture the extrusion temperature. The die diameter
is heated to a semi-liquid state achieved by the was 4.6 mm die and the rods were cut into 2.75
combination of heating elements and shear cm long implants (81). Although both methods
stress from the extrusion screw. The screw proved to be feasible for manufacturing the
pushes the mixture through the die. The implants, the most important difference
resulting extrudate is then cooled and solidified observed between these two methods was the
before cutting into desired lengths for implants in vitro release rate of Vapreotide which was
or other applications. Exposure of drug to high higher in the extruded implants. The possible
temperature can be disadvantageous as reason may be the significant porosity observed

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in extrusion molded implants (81). drug release rate from PLGA microspheres
follows a triphasic profile: (1) an initial burst
Kunou et al., developed controlled release release of surface and pore associated drug, (2)
implants of Ganciclovir using PLGA (75:25 a lag phase until sufficient polymer erosion has
Mw: 20,000 D) based on lyophilisation taken place and (3) a secondary burst with
compression molding. The drug, together with approximately zero order release kinetics (85,
a PLGA polymer was first dissolved in acetic 86). In addition, the PLGA polymer is insoluble
acid and lyophilized to obtain a homogeneous in water, but it is unstable in hydrolytic media
cake. The cake was then further compressed on and is degraded through hydrolytic attacks on
a hot plate in the temperature range of 80 to its ester bonds. Due to this hydrolytic attack,
100°C. In vivo drug release studies in rabbits random chain degradation occurs, resulting in
showed that the fragments of implants the generation of smaller monomers such as
disappeared from the subconjunctival space lactic acids and glycolic acids.
after 5 months (82).
Various factors can influence the
Orloff et. al., prepared biodegradable implants biodegradation of a PLGA based formulation
for repairing vascular thrombosis which and simultaneously affect the release profile of
showed good results in a broad variety of microspheres, e.g., (1) polymeric properties
vascular disorders (83). Baro et. al., developed such as molecular weight, the lactide:glycolide
PLA (Mw:30 kDa) based bone implants ratio and the end group and viscosity of the
containing gentamicin sulfate as a model drug polymer, (2) the solubility of the drug, (3) the
using a compression molding technique using a type of solvent, (4) the rate of agitation, (5)
hydraulic press and further coated with PLA solvent evaporation, (6) the temperature (7) the
(Mw: 200 kDa). Mixtures of hydroxyapatite and drug loading (8) sterilization (9) residual
tricalcium phosphate powder were used in the solvents (10) porosity and (11) the pH of the
manufacturing of PLA based ceramic implants, biodegradation media (86).
because it has similar chemical composition to
bone minerals acting as a good carriers for The effect of polymer composition
treating bone infection. In vitro gentamicin
release was delayed due to an additional PLA Higher glycolic acid content in the polymeric
coating but when tested in the femur of rabbits, composition can increase the intensity of the
it showed faster release which was probably due loss of molecular weight and simultaneous
to a greater degree of PLA degradation, degradation of the polymer. For example, the
changes in the concentration of phosphate PLGA 50:50 (PLA/PGA) has a faster
blend along with PLA polymer and in vivo degradation rate than the PLGA 65:35 due to
invading of the implant by the bone tissue (84). the higher hydrophilicity of the glycolic acid in
the PLGA 50:50. Subsequently PLGA 65:35
FACTORS INFLUENCING THE DEGRADATION has a faster degradation rate than the PLGA
OF PLGA BASED FORMULATIONS 75:25 and PLGA 75:25 than PLGA 90:10. The
reason for the lower degradation rate of lactic
In general, the polymer degradation/ hydrolysis acid compared to glycolic acid is the presence
rate is accelerated by greater hydrophilicity in of an additional methyl group in the structure
the backbone or end groups, amorphous of lactic acid, which acts as hydrophobic
nature, lower molecular weight, and smaller size moieties and minimizes the attack by the water
of the finished device. In order to understand molecules. The amount of glycolic acid is a
the release rate of a drug entrapped in the critical parameter in controlling the
biodegradable polymeric matrix the erosion rate hydrophilicity of the polymer and, thus the
of the polymer must be understood. In general, degradation and drug-release rate (87). Janoria
et. al., studied the effect of different lactic acid

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 Review Article

and glycolic acid on drug release. They used prepared by a double emulsification solvent
PLGA 50:50 and PLGA 65:35 to prepare evaporation method. They used two different
microspheres of Ganciclovir (GCV) as a model PLGA 50:50 polymer grades (Mw = 1,00,000
drug using an o/o emulsification followed by daltons and i.v. = 0.8 dl/g and Mw = 14,000,
solvent evaporation. The Tg of the PLGA i.v. = 0.2 dl/g). The formulation with the
65:35 was higher than the PLGA 50:50 due to higher mol/wt polymer took 0.6 days to release
the higher lactide content. Although the lactide 50% of the drug together with a burst release
content in the polymer composition did not compared to the other which took about 6.3
affect the Ganciclovir release, the higher lactide days to release 50% of the drug without any
content of the polymer provided better burst release. This experiment demonstrates the
entrapment properties due to its lipophilic influence of Mw and i.v. on the rate of drug
nature (88). release (91).

The effect of crystallinity (or Tg) of polymer Physicochemical properties of incorporated

drugs
The degree of crystallinity and melting point of
a polymer is directly related to its molecular In general, polymer-drug matrix degradation
weight. The glass transition temperature (Tg) of and the drug release rate vary as a function of a
PLGA copolymers are reported to be above the drug’s physicochemical properties. The
physiological temperature of 37°C, hence are solubility of encapsulated drug(s) may
glassy in nature and thus exhibiting a fairly rigid significantly influence the degradation rate of
chain structure. The Tg of the PLGA decreases the polymeric matrix. For example, the
with decreasing lactide in the copolymer presence of a high amount of hydrophilic water
composition and molecular weight (88). soluble groups (-OH or -COOH group)
Copolymer compositions also affect important increases the uptake of water molecules from
properties such as the Tg and the crystallinity the surrounding environment into the
which have an indirect effect on the polymeric matrix. This process may result in
degradation rate. At the moment, there are the leaching of a water soluble drug from the
conflicting opinions on the effect of polymer matrix and create a highly porous
crystallinity on the degradation rate. In addition, membrane-like structure very quickly. In
crystallinity of lactic acid (PLA) increases the contrast, a hydrophobic drug can retard the
degradation rate as a result of an increase in the water diffusion into the polymeric matrix and
hydrophilicity of polymer (89). simultaneously slow down the polymeric
degradation. In addition, highly acidic or basic
The effect of molecular weight drug(s) may also influence the polymeric
degradation kinetics. Studies indicate that such
PLGA polymers are usually characterized in drug moieties auto catalyze the ester backbone
terms of intrinsic viscosity which is directly hydrolysis resulting in an enhanced polymeric
related to their molecular weight (Mw) and degradation rate (91, 92). The presence of
degradation rate. In general, a polymer with a specific functional groups such as amines in the
higher molecular weight contains long drug molecule can induce polymeric chain
polymeric chains resulting in lower degradation degradation through nucleophilic reaction
rates. As the Mw of the polymer decreases, the wherein nitrogen atom works similar to oxygen
degradation rate increases due to reduced Tg. atom in water (93).
Polymers with higher molecular weight polymer
exhibiting high Tg value are glassy in nature The effect of size and shape of the matrix
and have slow degradation kinetics (87, 90).
Graves et. al., studied the effect of Mw on a The ratio of surface area to volume has been
PLGA polymer on Pendamidine microspheres found to be a significant factor for degradation

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 Review Article

of large devices in general. Greater surface area compared to neutral pH. Thermal and
to volume ratio leads to a greater degradation morphological analysis showed that in an acidic
of the matrix (94). Witt et. al., studied the environment the oligomeric units of the
erosion of parenteral delivery systems such as polymer accumulate within the microspheres
rods, tablets, films and microspheres generated due to their low solubility in acidic pH
using PLGA (50:50 lactide to glycolide ratio) compared to the neutral pH (pKa of lactic acid:
polymers. Upon evaluation of the onset time 3.8). These are crystallized inside the matrix and
for bulk erosion (tonset) and the apparent rate of impart a brittleness to polymer due to which
mass loss (kapp) parameters for each device, it they become more susceptible to fracturing and
was found that in the case of PLGA, the tonset rapid release (97).
was 16.2 days for microspheres, 19.2 days for
films and 30.1 days for cylindrical implants and The effect of monomer content and purity on
tablets. The kapp was 0.04 days-1 for degradation
microspheres, 0.09 days-1 for films, 0.11 days-1
for implants and 0.10 days-1 for tablets. The Synthesis of PLGA based biodegradable
results indicate that the rate of erosion polymer involves a continuous chain co-
decreased in the following order: rods and polymerization process between the lactic acid
tablets > film > microspheres and was and the glycolic acid molecules. There may be a
dependent on the size of device (95). chance of free traces of monomer remaining in
the final product even after purification with
The effect of pH and salts concentration different solvents. This free monomer content
in the final product may get converted
The in vitro biodegradation/hydrolysis of PLGA reversibly into the polymer during the storage
showed that both alkaline and strongly acidic of the product which may affect the drug
media accelerates the polymer degradation release. During the manufacturing of any
process. The degradation was also found to be PLGA based formulation the monomer
affected by the salt concentration in buffered content of the PLGA product must be
solutions, suggesting that the cleavage reaction considered. PLGA polymers with monomer
of the polymer ester bonds is accelerated content as low as 0.5% are considered highly
through the conversion of the acidic purified (98). Several purification steps are
degradation product into neutral salts. Studies carried out in the final stage of the polymer
by Li et. al., showed that at alkaline pH (10.08) manufacturing e.g., ultrafiltration,
microparticles exhibit rapid weight loss but crystallization, distillation or passing of
slower molecular weight decrease and the supercritical CO2, etc., to remove free residual
degradation pattern was close to surface monomers from the amorphous polymer blend
degradation. However, in acidic pH (1.2) it and to provide a better purity of the final
showed faster reduction in molecular weight product. Unbound monomers contain higher
while slower weight loss and homogeneous free acid contents and acts as an impurity and
degradation (96). Recently, Zolnik and Burgess source for faster degradation of the product.
have studied the effect of acidic (pH 2.4) and
neutral (pH 7.4) condition on the degradation PHARMACEUTICAL APPLICATION OF PLGA
of a PLGA polymer and drug release kinetics. BASED MEDICAL DEVICES
In vitro dissolution studies indicated that the
initial burst and lag phases were similar for both Biodegradable polymers have become an
pH values, but the secondary drug release important group of materials with an increasing
kinetics was substantially higher in acidic pH as diversity in biomedical devices. Major

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applications of PLGA polymers in some novel is mainly useful to inhibit neointimal growth
areas are shown in Table 5. (due to the proliferation of smooth muscle
cells), arterial restenosis and neointimal
Table 5 Novel areas of PLGA application hyperplasia. Generally combinations of
immuno-suppressive and anti-proliferative
BIOMEDICAL APPLICATION AREA OF APPLICATION drugs (Sirolimus, Paclitaxel and Everolimus) are
Biodegradable surgical suture Wound closure
Screws, plates & pins for hard tissue
used for medical applications in coronary
Biodegradable medical device fixation and tissue regeneration,
contraceptive device, dental implants
stents. Because metal is a foreign substance, it
Solid rods, injectable microparticles (as
can induce inflammation, scarring, and
Long active parenteral drug
suspensions), in situ forming systems,
depot controlled release injection,
thrombosis (clotting). DES coated with
delivery system oncological application, gene therapy and
proteomics, xenobiotics, immunology and
polymers of biocompatible nature largely
veterinary application prevent some of these effects. However,
Nasal and ocular delivery Nasal and ocular drug application
Third generation fully Very innovative therapeutic approach for
neointimal hyperplasia occurring within the
biodegradable stents recovery after heart attack or stroke stent leading to in-stent restenosis is a main
obstacle in the long-term success of
percutaneous coronary intervention (PCI).
Drug eluting stents Many large randomized clinical trials using DES
have shown a remarkable reduction in
In order to minimize the formation of fibrosis, angiographic restenosis and target vessel
thrombosis or clots, a metallic stent can be revascularization when compared with bare
inserted within the peripheral or coronary artery metal stents. DES has revolutionized the field
by a cardiologist or radiologist performing of interventional cardiology by proving its
angioplasty surgery. These bare metallic stents safety and efficacy to prevent restenosis of
(BMS) made of cobalt or stainless steel are the coronary arteries using local drug delivery in
1st generation stents. They comprise of an many clinical trials (100-116).
elaborate mesh-like design to allow expansion,
flexibility and, in some cases, the ability to Recently, 3rd generation stents have been
enlarge constricted blood vessels. Cobalt developed and clinically approved. Here the
chrome alloy is stronger and more radio- metallic components have been completely
opaque than the usual 316L stainless steel replaced with a biodegradable polymer
(L605 CoCr alloy has less nickel than 316L framework. The benefit of 3rd generation stents
stainless steel and so may be less allergenic). In is that they prevent problems such as
order to avoid graft rejection, thrombosis and at the same reduces the
immunosuppressants are administered orally necessity of taking lifelong medication of anti-
usually minimizing adverse effects (99). platelets. The development of these types of
stents has been a breakthrough innovation in
2nd generation stents are drug-eluting stents the treatment of obstructive coronary artery
(DES) which were approved by the FDA after disease since the introduction of balloon
being clinically proven to be better than BMS. angioplasty. Ma et. al., prepared Paclitaxel/
DES contain a coating, typically of a Sirolimus loaded DES using a PLGA (65:35
biodegradable polymer such as PLGA on the lactide:glycolide ratio) polymer for the
metallic stents which holds and releases (elutes) treatment of coronary artery disease. The stent
the drug into the arterial wall by contact provided controlled release of Paclitaxel and
transfer. The stents are typically spray or dip Sirolimus for 21 days both in vitro and in vivo
coated. One to three, or more, layers can be with minimal burst release. This study showed
coated e.g. a base layer for adhesion, a main that the combination of two drugs in a DES
layer for holding the drug, and sometimes a top will not affect the individual drug release kinetic
coat to slow down the release of the drug and and, therefore, can be developed for the
to extend its effect. DES contains a drug which treatment of coronary arterial diseases (117).

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Similarly, Raval et. al., successfully developed a presence or absence of polyethylene glycol
Dexamethasone loaded DES using poly L- (PEG) in the formulation, molecular weight
lactide-co-caprolactone as the biodegradable and amount of PEG, presence of osmotically
polymer for intravascular drug administration active agents, etc., (128). Similarly, Nonomura
for the treatment of tissue hyperplasia. The in et. al., developed a LH-RH antagonist loaded
vitro dissolution profile showed that the release intrauterine device (IUD) to release the drug
of Dexamethasone can be modulated up to 3 for a prolonged period of time using a PLGA
weeks by optimizing the concentration of the block co-polymer (75:25 lacide: glycolide ratio).
polymeric blend. SEM data also showed a Once inserted into the uterus, the drug
smooth surface of DES without any gradually released from the IUD during a
irregularities which suggests that the coating period of several months (129).
process parameters were optimum and efficient
for a multiple layer coating (118). Dental implants

Contraceptive devices Though useful, the potential of biodegradable

polymers have unfortunately not been explored
Biodegradable polymers have recently been in the field of medicated dental implants.
applied for the controlled release delivery of Dental or orthodontic braces are devices used
hormones and fertility regulating agents. in orthodontics that align and straighten teeth,
Biodegradable or erodible delivery systems are help to position them with regard to a person's
represented by contraceptive devices where the bite and also improves dental health. Braces can
matrix dissolves to release the drug and other be either cosmetic or structural. A
components into the systemic circulation. An biodegradable polymer could be good
implantable contraceptive is likely to be a replacement for metallic dental braces because
promising new option for fertility control, as subsequent operative procedures are not
well as, for the long term treatment of sexually required and it aligns the teeth in a particular
transmitted diseases such as AIDS. These period of time. In the past, dental implants
biodegradable systems have primarily two made of tinidazole were formulated using poly
advantages: (1) no need for surgical removal of (e-caprolactone) which showed good clinical
the system after the completion of the drug efficacy to control acute periodontitis (130-
delivery period and, (2) the device reservoirs 138).
show zero order release kinetics which is
necessary for efficient therapeutic treatment. Nasal delivery
Contraceptive systems that provide sustained
release of low doses of synthetic hormones are Intranasal (IN) administration has attracted
of special interest because they have important considerable interest because it provides a non-
clinical advantages over conventional oral invasive method for bypassing the blood brain
contraceptive pills (119-127). barrier (BBB) delivering drugs directly to the
brain. The nasal cavity is a promising site for
Alaee et. al., developed PLA (Mw = 680,000, the delivery of vaccines because (1) its reduced
i.v. = 3.3 to 4.3 dl/g) based reservoir type of enzymatic activity compared to other possible
implantable contraceptive device for the administration routes (e.g. oral route), (2) its
controlled delivery of levonorgestrol (300 days) moderately permeable epithelium, and (3) the
using a simple dip casting method. Dissolution high availability of immune-reactive sites (139-
studies showed that the drug was released from 141).
the reservoir for at least 9 months. Moreover, it
was found that various formulation and Vila et. al., developed PLA-PEG based
manufacturing processes affected the release of nanoparticles to enhance the absorption of
the drug from implants such as implant weight, protein molecules across the nasal mucosa

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using, for example, tetanus toxoid (TT) as a polymer should be absorbed completely into
model drug. They showed that the efficacy in in the body after fulfilling its function, (c) the
vivo studies of the vaccine developed using nano mechanical properties of the scaffold materials
particles showed approximately 70-80% must not collapse during handling, nor during a
bioavailability compared to intravenous patient’s routine activities and (d) the material
administration (142). Yildiz et. al., developed must be easily sterilizable to prevent unwanted
heparin loaded microspheres using poly lactic infections (146-158).
acid. A SEM study showed a uniform particle
size of heparin loaded microparticles with Suture materials are classified into two broad
smooth surface at around 1-5 micron. In vitro categories, biodegradable and non-
and in vivo analysis showed a sustained release biodegradable. Biodegradable sutures lose their
profile for heparin of up to 8 hours and good entire tensile strength within 2-3 months, while
absorption confirmed by a 143.63 % AUC level non-biodegradable materials retain their
(143). Recently, Seju et. al. developed a PLGA strength longer than 2-3 months. Biodegradable
(50:50 as lactide to glycolide content) loaded or bioresorbable sutures are made from either
Olanzepine nanoparticulate system for direct
collagen derived from sheep intestinal sub
nose-to-brain delivery. In vivo studies indicated
mucosa or synthetic polymers such as PGA.
an increased drug uptake at ~10 times which
was more efficient for the treatment of central Surgical suture is a term used for medical
nervous system disorders (144). Li et. al., devices which are used to close body tissue
developed microspheres using α-Cobrotoxin as after an injury or surgery. Suture threads comes
a model drug and a mixture of biodegradable in very specific sizes and can be classified as
polymers comprised of PLGA (50:50, i.v. = 0.8 mainly absorbable (made from biodegradable
dl/g) and poly [1,3-bis(p-carboxy-phenoxy) polymers such as PGA, PLA or poly
propane-co–p-(carboxyethylformamido) dioxonones) or non-absorbable (made from
benzoic anhydride CPP:CEFB] using a w/o/o polypropylene, polyesters or nylon) depending
emulsion solvent evaporation method for on weather or not, the body will naturally
intranasal delivery. The microspheres showed degrade and absorb the suture material over
high entrapment efficiency (80%) with a 25 µm period of time. Absorbable surgical sutures are
mean particle size and effective sustained sometimes also coated with an antimicrobial
release profile (145). Tail flick assay indicated substance to reduce the chance of infection of
that compared to free α-cobrotoxin and PLGA
the wound.
microspheres, PLGA/P(CPP:CEFB)
microspheres showed an apparent increase in
the strength and duration of antinociceptive Park et. al., developed biodegradable polymeric
effect at the same dose of α-cobrotoxin (80 micro needles using PLA and PLGA based
Ag/kg body weight) (145). synthetic polymers for transdermal drug
delivery. They concluded that the new
Tissue engineering arthroscopic fixation device utilized knotless
suture-based anchors eliminating the need for
Tissue engineering uses a combination of knot tying during arthroscopic surgery (159).
engineering and biologic materials to improve Casalini et. al., successfully developed a transient
biological functions, as well as, for successful 1-dimensional model to show the release rate
tissue and bone replacement. The requirements from a bioresorbable drug eluting suture
of a scaffold material for tissue engineering are together with its pharmacologic behavior and
important to support cell growth and
biodegradation rate (160). The model primarily
proliferation as follows: (a) the material must
highlights the degradation kinetics of a drug
not induce any unresolved inflammatory
reaction or any foreign body reaction, (b) the loaded resorbable suture in the tissue, as well

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as, the behavior of a drug in the tissue. A model show any signs of tissue reaction at the end of
can provide predictive data without expensive 18 months (167). Enislidis et. al., investigated
and time consuming experimental activity based zygomatic fracture fixation using a
on the principal laws of conservation, mass biodegradable osteosynthesis system
transfer and hydrolysis (160). Morizumi et. al., (BioSorbFX®) to evaluate its stability, as well as,
developed a novel drug eluting suture coated complications observed during the first
with Tacrolimus for the treatment of postoperative year. They found that fixation of
fractures of the zygoma using the BioSorbFX®
neointimal hyperplasia. In vivo results from a
system was simple and safe without showing
porcine model confirmed that the DE-sutures
any post-operative complication (168). Tasca et.
can successfully inhibit neointimal hyperplasia al., successfully performed thyroid cartilage
at the anastomotic suture site without any fracture surgery on a 29-year old man (injured
inflammatory response indicating usefulness of while playing rugby) using Inion biodegradable
this novel suture in both coronary artery bypass plates that had been made with lactic and
graft surgery and peripheral vascular bypass glycolic acid based polymers and specifically
surgery (161). designed with the consideration of the thyroid
cartilage structure and recommended in the
Orthopedic devices treatment of laryngeal fractures (169). Kyriakou
et. al., performed clinical studies on 20 patients
During orthopedic surgery, bone fragments or between the ages of 18 to 40 years (both male
filaments are usually fixed with metallic plates and female) with facial skeleton maxilla
and screws. When the fracture has healed these fractures treated with resorbable plates. They
metallic plates are usually removed from the found that none of the patient reported any
body through a second surgery requiring infection or secondary mobility indicating
general anesthesia to minimize pain. In order to excellent biocompatibility for resorbable plates
avoid the second surgery, resorbable polymers (170).
can be used as alternative materials in a range of
devices in trauma and fracture surgery satisfying Ocular drug delivery
various operational and technical requirements
(162, 163). This is because they can overcome Currently, the most common way of
various issues such as stress protection, administering therapeutic agents to the eye is
potential for corrosion, wear and debris using topical applications placed into the
formation, as well as, the necessity of implant conjunctival cul-de-sac. Eye drops or ointments
removal (164). are, however, not very effective as they are
rapidly cleared from the eye by continuous
These devices also maintain adequate eyelid movements and drainage through
mechanical properties in vivo for the time lachrymal fluids. In order to increase the
required for a bone fracture to heal and contact time between ophthalmic formulations
decompose gradually wherein the stresses are and the eye corneal, more invasive procedures
transferred gradually to the healing bone or must be used such subconjunctival injections,
tissues so that no stress shielding occurs (165, retro-ocular injections containing biodegradable
166). Rangdal et al., performed clinical studies polymers to minimize clinical complication and
to see how PLGA based biodegradable plates side effects (171). Choonara et. al., developed a
and screws affect the tissues of patients novel doughnut-shaped mini tablet (DSMT)
suffering of bimalleolar fractures. They found containing different PLGA (50:50, i.v. = 0.16 -
that only one patient had tissue reaction at 14 8.2 dl/g) grades loaded with two anti-retroviral
weeks post-surgery which settled down by drugs such as foscarnet and ganciclovir for
debridement without the need of implant intraocular drug delivery. They used a special
removal while the rest of the patients did not set of punches fitted with a central-rod in a

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 Review Article

tableting press to manufacture the DSMT multi-block copolymers and investigated them
device providing a first-order release of both for use as anti-cancer drug carriers. The
anti-retrovirals. The novel geometric design and thermo-sensitive nanoparticles responded well
veracity of the DSMT device was retained even to local hypothermic temperatures and the
after 24 weeks of use (172). release of doxorubicin was also dependent on
the temperature at the tumor site (175). Bhuske
Transdermal drug delivery et al., developed PLGA based nanoparticles
containing Curcumin which is a poorly soluble
Biodegradable polymer based transdermal anti-cancer drug. They demonstrated an
patches usually do not require removal post- improvement in the aqueous solubility and
implantation and as a result these systems have anticancer activity of the drug (176). PLGA
become quite common (173). Colloidal polymers have also been used for tumor
nanoparticles developed from poly (alkyl imaging, for example Diou et al., reported the
cyanoacrylate) (PACA) based biodegradable use of PEGylated PLGA nanocapsules
polymers have opened up new and exciting containing per-fluorooctyle bromide by 19F
avenues in the field of transdermal drug MRI (177). There are numerous other reports
delivery due to their biocompatibility and small of using PLGA based applications for targeting
size which permits increased transport across increased drug delivery at target site and cancer
the epithelium and intracellular penetration. treatment (178-181).
Miyazaki et. al., developed poly n-
butylcyanoacrylate (PNBCA) polymer based Recently, Jin et. al., developed doxorubicin–poly
biodegradable nanocapsules loaded with (d,l lactic- co-glycolic acid)–poly(ethylene
indomethacin to evaluate the possibility of glycol) (DOX–PLGA–PEG) micelles decorated
delivering the drug systemically after its topical with the bivalent fragment HAb18 F(ab’)2 for
application. Nanocapsules prepared by an treatment of hepatocellular carcinoma (HCC).
interfacial polymerization process showed 188 They found that the developed micelles had an
nm as average particle size with 76.6% drug acceptable morphology and high drug loading
loading. Conventional gel formulations efficiency. Cellular uptake and accumulation in
containing indomethacin made from Pluronic the tumor was observed to be dependent on the
F-127 was used as a reference formulation for dual effects of passive and active targeting. The
in vivo comparison which showed a higher drug drug-loaded micelles showed cytotoxicity on
plasma concentration for the nanocapsule tumor cells in vitro and in vivo considered
formulation than the conventional gel responsible for the improvement in the
formulation containing Pluronic F-127. Due to therapeutic response (178). Similarly, Li et. al.,
the ultra-fine particle size and their oily prepared polymer-coated magnetic
vesicular nature, alkylcyanoacrylate nanoparticles as carriers for doxorubicin using a
nanocapsules can easily cross the stratum double emulsification method (179). Current
corneum layer of the skin and act as a micro- research also shows the usefulness of
reservoir to provide sustained drug release multiblocks such as dicarboxylated poly
(174). (ethylene glycol) (PEG; Mw 2000) with poly (l-
lactic acid) (PLLA)/PEG/PLLA triblock
Cancer treatment copolymers for targeting cancer cells.
Various biodegradable polymer-based novel Gene therapy and proteomic applications
formulations such as depot injections
containing microparticles or nanoparticles can Luten et. al., demonstrated the use of PLGA
be useful in chemotherapy treatment. Recently, and other biodegradable polymers in plasmid
Kun et al., prepared nanoparticles using poly gene delivery by developing DNA loaded micro
(ethylene glycol)/ poly (L-lactic acid) alternating and nanoparticles (182). Recently, Ahn et. al.,

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 Review Article

developed a PLA and PEG based non-viral (pDNA) delivery. It is known that DNA has
gene carrier by synthesizing a multi-block co- negatively charged macromolecules which
polymer (183). Benfer and Kissel prepared hinders its entry into the tumor cells through
PLGA based nanoparticles using poly [vinyl-3- the negatively charged lipid bilayer. Therefore,
(dialkylamino) alkylcarbamate-co-vinylacetate- the calcium phosphate was used to neutralize
co-vinylalcohol]-graft-poly (D,L-lactide-co- the DNA before entry and to achieve increased
glycolide) or DEAPA-PVA-g-PLGA loaded efficiency with improved release kinetics. Based
with siRNA to improve the cellular uptake and on promising in vitro transfection efficiency
thus increase therapeutic activity (184). Lewis et. formulations, calcium phosphate embedded
al., demonstrated that oligonucleotides can be PLGA nanoparticles can be considered a
entrapped into a PLGA matrix to improve suitable vector for pDNA based gene delivery
nuclease stability in serum, and thus achieve an (191). Much work has been carried out in
acceptable release profile of antisense recent years to improve the delivery of DNA
oligopeptides such as very potent anti-HIV (192-196), gene (197), growth hormone (198),
phosphorothioates (185). peptide (199) and bovine serum albumin (200)
using PLGA devices or formulations.
Much attention has been focused on proteins
(186-188), oligopeptide (189) and RNA (190) Immunological applications
delivery using PLGA devices. It has been
shown that specific genes such as synthetic A considerable amount of research has been
short interfering RNA (siRNA) is a promising carried out in the field of immunology using
route for specific and efficient therapy of PLGA devices. Slutter et. al., worked on particle
disease-related genes. However, in vivo engineering for nasal vaccine delivery and
application of siRNA requires an effective demonstrated good absorption of N-
delivery system. Commonly used siRNA trimethylated chitosan along with PLGA via
carriers are based on polycations which form nasal mucosa (201). Sivakumar et. al., developed
electrostatic complexes with siRNA and such an alternative adjuvant for Hepatitis B vaccine
poly- or lipoplexes are of restricted use in vivo (HBsAg) that provides a long-lasting immune
due to severe problems associated with toxicity, response after a single administration. The
serum instability and non-specific immune- suitability of poly (D, L)-lactide-co-glycolic acid
responses. In order to minimize some (PLGA), poly lactic acid (PLA) and chitosan
complications associated with non- polymers as adjuvants for HBsAg (202) were
biodegradable polymers, Cun et. al., developed studied. Salvador et. al., studied combinations of
nanoparticles (NPs) loaded with siRNA using different immune stimulating adjuvants using
biodegradable PLGA polymers without PLGA microspheres to improve the immune
including polycations. The NPs were found to response of a model vaccine. In this study,
be spherical in shape with an average particle PLGA microspheres containing BSA was co-
size of 300 nm, poly dispersibility index < 0.2, encapsulated with different adjuvants such as
encapsulation efficiency of 57% and zeta monophosphoryl lipid A (MPLA), polyinosinic-
potential value of ~ 40mV. The integrity of polycytidylic acid, α-galactosyl ceramide and
siRNA was preserved during the preparation alginate. It was observed that a mixture of
indicating that siRNA-NPs based on PLGA MPLA and α-galactosyl ceramide within the
polymers without any cationic excipient can microspheres provided a higher cellular
work as a potential and promising carrier for response to increase vaccines immunogenicity
the delivery of siRNA (190). Recently, Tang et. as compared to other adjuvants (203). Other
al., developed calcium phosphate embedded studies in this area include imaging (204), auto
PLGA nanoparticles for plasmid DNA booster vaccines (205) and immunogenic

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 Review Article

properties of antigens delivered through PLGA packaging of a product by placing the device or
microparticles (206). formulation in an airtight moisture-proof
container containing a desiccant.
Veterinary applications
For example, sutures are wrapped around a
In the recent years there has been an increasing specially dried paper holder that acts as a
interest in biodegradable polymers for desiccant. The final devices should not be
veterinary use because they could provide sterilized by autoclaving or dry heat because
significant benefits such as a reduction in stress this may degrade the device since even dry heat
resulting from reduced animal handling, no can contain a lot of moisture (210). Gamma
need to physically remove the delivery system radiation, particularly at doses above 2 Mrad,
and reduced cost in terms of the time spent by can result in significant degradation of the
animal owner or caretaker. Presently, only a few polymer chain, resulting in a reduced molecular
biodegradable formulations are commercially weight and altered mechanical properties and
available for veterinary use. The possible reason degradation times. Poly (glycolide), poly
behind it is the cost of the biodegradable (lactide) and poly (dioxanone) are especially
device, followed by regulatory considerations sensitive to gamma radiation and are usually
and challenges in formulation stability (207). sterilized by exposure to EtO (210). However,
Walduck et. al., developed biodegradable residual EtO is very toxic and takes a long time
implants using a cholesterol and lecithin for degassing which adds to the final cost.
polymeric mixture for recombinant antigen Typically, a device is sterilized using gamma
delivery to sheep. They also investigaged the radiation (211-213), ethylene oxide (EtO) gas
release profiles of antigen in vitro as well as in (214, 215), or other less-known techniques such
vivo and found that sheep produced significant as synchroton or electron beam irradiation
levels of antibodies when immunized with (216).
implants showing promising tissue
compatibility (208). Khan et. al., developed The effect of gamma radiation in either vacuum
biodegradable implantable matrix systems or in air at a dose of 25 kGy on the stability of
(pellets) from a cholesterol and lecithin mixture PLGA 50:50 (Mw = 34000 D and i.v. = 0.39
containing bovine serum albumin (BSA) as a dl/g) based microsphere was studied.
model antigen for parenteral delivery in mice. Microspheres irradiated under vacuum were
For in vivo studies, pellets were subcutaneously found to be stable over a period of 6 months
injected into the mice which provided sustained and microsphere irradiated in presence of air
drug release until 40 days with significant shows showed that release rate were increased
antibodies generation (209). by 10% but did not change further during the
storage time. Electronic paramagnetic
resonance analysis confirmed the free radicals
Packaging and sterilization
generated from both the polymeric matrix and
the active ingredient during gamma radiation.
As discussed previously, these polymers are In addition, they also confirmed the radio-
very sensitive to moisture which cause stabilizing effect of the drug (clonazepam) by
degradation during manufacturing, as well as, polymer/clonazepam spin transfer reactions.
during product storage. Therefore to minimize Furthermore, due to the same radio stabilizing
the effects of moisture uptake, biodegradable effect, microspheres showed a 54% decrease in
polymers are typically stored under refrigerated overall radiation yield as compared to placebo
conditions. The solution for hydrolysis microspheres because the radiation was
instability is simple in theory, eliminate absorbed by the clonazepam during the
moisture and prevent degradation. Therefore, sterilization process. It can be concluded that
precautions should be taken during the final the type of API , as well as, the sterilization

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 146
 Review Article

conditions must be considered carefully on case roughness, porosity, surface area of device,
to case basis (217). Mohr et. al., studied the coating layer or thickness as well as the effect of
effect of gamma radiation on the stability of sterilization on properties of formulation and
PLGA micropsheres. Interestingly, on exposing shelf life of product with specific
microspheres to 5.1 to 26.6 kGy gamma recommendation storage guidelines should be
radiations it was found that the drug loaded clearly mentioned (224, 225).
microspheres were converted to conjugation
products with PLGA. The average molecular CONCLUSION
weight decreased with an increasing irradiation
dose (218). Another study showed that gamma Biodegradable polymers are used extensively in
irradiation exposure has no apparent effect on pharmaceutical formulations, from drug
the integrity and formulation properties such us delivery to implants and stents. To this effect,
morphology, size and peptide loading. Upon PLGA devices can be said to have become
subcutaneous administration of irradiated and widely utilized in the pharmaceutical industry
non-irradiated PLGA microspheres into mice because of their many useful properties and
induced a similar immune response (219). compatibility with in vivo conditions. As evident,
these polymers have found usage within various
Regulatory consideration
categories of drugs such as anti-cancer,
For example, the maximum daily intake or IIG antibiotics, contraceptive devices, orthopedic
limit of lactic acid is known (220). If the devices and biotechnology products such as
quantity of the polymer is higher than the IIG antibodies and vaccines. Their flexibility is also
limit, toxicity data from the manufacturers of defined through their various routes of
the polymer can be submitted as a supportive administration such as parental, subcutaneous,
documents to the regulatory agencies for nasal or ocular and, therefore, has the potential
product approval. To obtain FDA approval for to be used widely in pharmaceutical
formulations based on microspheres it is formulations.
necessary to submit various clinical data, e.g.,
preclinical and toxicity data of biodegradable An in-depth knowledge and thorough
polymers, monomer content in the final understanding of the factors influencing
formulation, the molecular structure of the polymeric degradation and release rate are very
polymer, residual solvent levels in the final important to achieve a successful product. At
formulation, composite formulations including any stage, drug delivery using PLGA based co-
number of laminates, etc. In addition, it is also polymers is an attractive area with countless
mandatory to state possible clinical adverse opportunities for further research and
information in detail on the product label (221, developmental work. However, the
222). Tegnander et. al., reported swelling at the achievement in these areas depends on the deep
site of administration and sinus formulation efforts and extensive research of scientists from
when a patient with a fracture was treated with diverse disciplines such as microbiology,
PGA or PLA based pins (223). In vivo and in
pharmacy and polymer science to ensure much
vitro testing of polymeric materials should be
better health service to mankind as well as
designed to investigate polymer-skin interface
reactions, effects on the subsurface tissue and nature.
systemic effects. In vivo procedures usually
REFERENCES
involve a subcutaneous and/or intramuscular
implant test and a surface patch test for acute
1 ASTM FDA workshop on absorbable medical
and chronic toxicity study. Preclinical and device. Presented by Byron Hayes. Nov 28, 2012.
toxicological studies must be performed in FDA White Oak campus, Maryland, USA. Available
accordance with guidelines set by FDA to o n l i n e a t :
http://www.fda.gov/downloads/MedicalDevices/N
eliminate formulations that are too toxic for ewsEvents/WorkshopsConferences/UCM331546.p
human use. Similarly, for dossier submission, df

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 147
 Review Article

in-vivo delivery of drugs and vaccines. J

2 Huh KM, Cho YW, Park K. PLGA-PEG block Nanobiotechnol, 9:55-67, 2011.
copolymers for drug formulations. Drug Dev
Delivery, 3: 5-12, 2003. 16 Ghosh D, Pramanik P. Review article: low molecular
weight biodegradable polymer based nanoparticles as
3 Middleton JC, Tipton AR. Synthetic biodegradable potential delivery systems for therapeutics: the way
polymers as medical devices, Med. Plastics Biomater. forward? Int J Pharm Sci Drug Res, 2: 31-34, 2010.
M a g . 1 9 9 8 , 3, 30; A v a i l a b l e o n l i n e :
http://www.devicelink.com/mpb/archive/98/03/0 17 Aarayne M, Sultana N. Review: Porous nanoparticles
02.html in drug delivery system. Pak J Pharm Sci, 19: 155-
158, 2006.
4 Kolybaba M, Tabil L, Panigrahi S, Crerar WJ, Powell
T, Wang B. Biodegradable polymers: past, present,
and ASAE Annual Intersectional Meeting, North 18 Hughes GA. Review: Nanostructure-mediated drug
Dakota, USA, 2001. delivery. Nanomedicine: NBM, 1: 22-30, 2005.

5 Vroman I, Tighzert L. Biodegradable polymers. 19 Dong, W., Multiparticulate drug delivery system for
Materials, 2: 307-344, 2009. lipophilic drugs and macromolecule drugs, Chapter 1
in Dissertation Freie Universität Berlin, 2005,
6 Park JH, Mingli Y, Park K. Biodegradable polymers http://www.diss.fu-berlin.de/diss/receive/FUDISS
for microencapsulation of drugs. Molecules, 10: 146- _thesis_000000001718;jsessionid=B520D0FB61553
61, 2005. BA696869F51FD515426

7 Premraj R, Mukesh D. Biodegradation of polymers. 20 Mishra N, Goyal AK, Khatri K, Vaidya B, Pliwal R,
Indian J Biotechnol, 4:189-193, 2005. Rai S, Mehta A, Tiwari S, Vyas S, Vyas SP.
Biodegradable polymer based particulate carrier(s)
8 Gupta AP, Kumar V. New emerging trends in for the delivery of proteins and peptides. Anti-
synthetic biodegradable polymers – Polylactide: A Inflammatory & Anti-Allergy Agents in Medicinal
critique. Eur Polym J, 43:4053-4074, 2007. Chemistry, 7: 240-251, 2008.

9 David K Platt. Book chapter. Biodegradable 21 D’Souza SS, Deluca PP. Methods to assess in-vitro
polymers market report. 2006. Smithers Rapra drug release from injectable polymeric particulate
Limited, UK. systems. Pharm Res, 23: 460-474, 2006.

10 Edlund U, Aalbertsson AC. Degradable polymer 22 Lakshmana PS, Shirwaikar AA, Shirwaikar A, Kumar
microspheres for controlled drug delivery. Adv A. Formulation and evaluation of sustained release
Polym Sci, 157:67-112, 2002. microspheres of rosin containing aceclofenac. Ars
Pharm, 50:51-62, 2009.
11 Winzenberg G, Schmidt C, Fuchs S, Kissel T.
Biodegradable polymers and their potential use in 23 Odonell PB. Mcginity JW. Preparation of
parenteral veterinary drug delivery systems. Adv microspheres by the solvent evaporation technique.
Drug Deliver Rev, 56: 1453-1466, 2004. Adv Drug Del Rev, 28: 25-42, 1997.

12 Engineer C, Parikh J, Raval A. Review on hydrolytic 24 Li M, Rouaud O, Poncelet D. Review

degradation behavior of biodegradable polymers Microencapsulation by solvent evaporation: state of
from controlled drug delivery system. Trends the art for process engineering approaches. Int J
Biomater Artif Organs, 25:79-85, 2011. Pharm, 363: 26-39, 2008.

13 San Jose, CA. 2012. Biodegradable polymers: A 25 Sopimmath KS, Aminabhavi TM, Kulkarni AR,
g l o b a l b u s i n e s s r e p o r t . Av a i l a b l e a t : Rudzinski WE. Review: biodegradable polymeric
http://www.prweb.com/releases/biodegradablepoly nanoparticles as drug delivery devices. J Control
mers/biopolymers/prweb9311798.htm (Last Release, 70:1-20, 2001.
accessed 20 December 2012)
26 Jain RA. The manufacturing techniques of various
14 PLGA drug product market and development over drug loaded biodegradable poly (lactide-co-glycolide)
the past three years. Source: IMS Health Midas, 2010 (PLGA) devices. Biomaterials, 21: 2475-2490, 2000.
Available online at: www.imshealth.com (Last
accessed 15 March 2013) 27 Jena KK, Nayak B. Biodegradable polymers (PLA
and PLGA) based nanoparticles for protein and
15 Mahapatro A, Singh DK. Biodegradable plasmid delivery. Thesis submitted to National
nanoparticles are excellent vehicle for site directed Institute of Technology, Rourkela, 2011. Available

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 148
 Review Article

at: http://ethesis.nitrkl.ac.in/2209/ (Last accessed solvent evaporation method. Colloids Surf B:

12 April 2013) Biointerfaces, 74: 340-349, 2009.

28 Giovagnoli S, Blasi P, Schoubben A, Rossi C, Ricci 39 Ravi S, Peh KK, Darwis Y, Murthi K, Singh TRR,
M.. Preparation of large porous biodegradable Mallikarjun C. Development and characterization of
microspheres by using a simple double-emulsion polymeric microsphere for controlled release protein
method for capreomycin sulfate pulmonary delivery. loaded drug delivery system. Indian J Pharm Sci, 70:
Int J Pharm, 333: 103-111, 2007. 303-309, 2008.

29 Herrmann J, Bodmeier R. The effect of particle 40 Cetin M, Atila A, Kadioglu Y. Formulation and in
microstructure on the somvastatin release from poly vitro characterization of Eudragit® L100 and
lactide microsphere prepared by w/o/w solvent Eudragit® L100-PLGA nanoparticles containing
evaporation method. J Control Release, 36: 63-71, diclofenac sodium. AAPS PharmSciTech, 11: 1250-
1995. 1256, 2010.

30 Crotts G, Park TG. Preparation of porous and 41 Monitera T, Ogura Y, Honda Y, Wada R, Hyon SH,
nonporous biodegradable polymeric hollow Ikada Y. Microspheres of biodegradable polymers as
microspheres. J Control Release, 35: 91-105, 1995. a drug-delivery system in the vitreous. Invest
Ophthal Visual Sci, 32:1785-1790, 1991.
31 Pandey R, Zahoor A, Sharma S, Khuller GK.
Nanoparticle encapsulated antitubercular drugs as a 42 Mao S, Shi Y, Li L, Xu J, Schaper A, Kissel T.
potential oral drug delivery system against murine Effects of process and formulation parameters on
tuberculosis. Tuberculosis, 83: 373-378, 2003. characteristics and internal morphology of poly (d,l-
lactide-co-glycolide) microspheres formed by the
32 Yoo HS. Preparation of biodegradable polymeric solvent evaporation method. Eur J Pharm
hollow microspheres using o/o/w emulsion Biopharm, 68: 214-223, 2008.
stabilized by Labrafil ® . Colloids Surf B:
Biointerfaces, 52: 47-51, 2006. 43 Hu Z, Liu Y, Yuan W, Wu F, Su J, Jin T. Effect of
bases with different solubility on the release
33 Alireza M, Hashemein SK, Moghadam S, Atyabi F, behavior of risperidone loaded PLGA microspheres.
Dinarvand R. Preparation and in-vitro evaluation of Colloids Surf B: Biointerfaces, 86: 206-211, 2011.
controlled release PLGA microparticles containing
triptoreline. Iranian J Pharm Res, 9: 369-378, 2010. 44 Galeska I, Kim TK, Patil SD, Bhardwaj U,
Chattopadhyay D, Burgess D. Controlled release of
34 Morita T, Sakamura Y, Horikiri Y, Yoshino H. dexamethasone from PLGA microspheres
Protein encapsulation into biodegradable embedded within polyacid-containing PVA
microspheres by a novel s/o/w emulsion method hydrogels. AAPS Journal, 7: E231-E240, 2005.
using poly (ethylene glycol) as a protein
micronization adjuvant. J Control Release, 69: 435- 45 Luan X, Bodmeier R. Influence of the poly (lactide-
444, 2000. co-glycolide) type on the leuprolide release from in
situ forming microparticle systems. J Control
35 Rosca ID, Watari F, Uo M. Microparticle formation Release, 110:266-272, 2006.
and its mechanism in single and double emulsion
solvent evaporation. J Control Release, 99: 271-280, 46 Zolnik BS, Burgess DJ. Evaluation of in vivo–in
2004. vitro release of dexamethasone from PLGA
microspheres. J Control Release, 127:137-145, 2008.
36 Duvvuri S, Janoria KG, Mitra AK. Development of
a novel formulation containing poly (d,l-lactide-co- 47 Ertl B, Platzer P, Wirth M, GabOr F. Poly (D, L-
glycolide) microspheres dispersed in lactic-co-glycolic acid) microspheres for sustained
PLGA–PEG–PLGA gel for sustained delivery of delivery and stabilization of camptothecin. J Control
ganciclovir. J Control Release, 108: 282-293, 2005. Release, 61: 305-317, 1991.

37 Herrmann J, Bodmeir R. The effect of particle 48 Wang J, Wang BM, Schwendeman SP. Mechanistic
microstructure on the somvastatin release from poly evaluation of the glucose-induced reduction in initial
lactide microsphere prepared by w/o/w solvent burst release of octreotide acetate from poly (d,l-
evaporation method. J Control Release, 36: 63-71, lactide-co-glycolide) microspheres. Biomaterials, 25:
1995. 1919-1927, 2004.

38 Hamishehkar H, Emami J, Najafabadi AR, Gilani K, 49 Ibrahim MA, Ismail A, Fetouh MI, Gopfreich A.
Minaiyan M, Mahdavi H, Nokhodchi A. The effect Stability of insulin during the erosion of poly (lactic
of formulation variables on the characteristics of acid) and poly (lactic-co-glycolic acid) microspheres.
insulin-loaded poly (lactic-co-glycolic acid) J Control Release, 106: 241-252, 2005.
microspheres prepared by a single phase oil in oil

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 149
 Review Article

50 Dutt M, Khuller GK. Liposomes and PLG

microparticles as sustained release antitubercular 62 Wang Y, Pfeffer R, Dave R. Polymer encapsulation
drug carriers—an in vitro–in vivo study. Int J of fine particles by a supercritical antisolvent
Antimicrob Agents, 18 : 145-252, 2001. process. AIchE J, 51: 440-455, 2005.

51 Mi FL, Lin YM, Wu YB, Shyu SS, Tsai YH. 63 Mohanraj VJ, Chen Y. Nanoparticles- a review.
Chitin/PLGA blend microspheres as a Tropical J Pharm Res, 5: 561-573, 2006.
biodegradable drug-delivery system: phase-
separation, degradation and release behavior. 64 Thote AJ, Gupta RB. Formation of nanoparticles of
Biomaterials, 23: 3257-3267, 2002. a hydrophilic drug using supercritical carbon dioxide
and microencapsulation for sustained release.
52 Jain RA. The manufacturing techniques of various Nanomedicine: NBM, 1: 85-90, 2005.
drug loaded biodegradable poly (lactide-co-glycolide)
(PLGA) devices. Biomaterials, 21: 2475-2490, 2000. 65 Jordan F, Naylor A, Kelly CA, Howdle SM, Lewis A,
Illum L. Sustained release hGH microsphere
53 Basu SK, Kavitha K, Rupeshkumar M. Evaluation formulation produced by a novel supercritical fluid
of ketorolac tromethamine microspheres by technology: In vivo studies. J Control Release, 141:
chitosan/gelatin B complex coacervation. Scientia 153-160, 2010.
Pharm, 78: 79-82, 2010.
66 Salmaso S, Elvassore N, Bertucco A, Lante A,
54 Gangadhar CB, Sunder SR, Varma VK, Raju S, Caliceti P. Nisin-loaded poly-l-lactide nano-particles
Kiran S. Formulation and evaluation of produced by CO2 anti-solvent precipitation for
Indomethacin microspheres using natural and sustained antimicrobial activity. Int J Pharm, 287:
synthetic polymers as controlled release dosage 163-173, 2004.
forms. Int J Drug Discovery, 2:8-16, 2010.
67 Kluge J, Fusaro F, Casas N, Mazzotti M, Muhrer D.
55 Arunachalam A, Rathinaraj BM, Choudhary PK, Production of PLGA micro- and nanocomposites
Reddy AK, Fareedullah M. Preparation and by supercritical fluid extraction of emulsions: I.
evaluation of ofloxacin microsphere using natural Encapsulation of lysozyme. J Supercritical Fluids, 50:
gelatin polymer. Int J App Biology Pharm Technol, 327-335, 2009.
1:61-67, 2010.
68 Lee LY, Wang CH, Smith KA. Supercritical
56 Sunitha S, Amareshwar P, Santosh KM, Chakravarti antisolvent production of biodegradable micro- and
P. Study on effect of solvents & nonsolvents on nanoparticles for controlled delivery of paclitaxel. J
microspheres of ciprofloxacin: coacervation phase Control Release, 125: 96-106, 2008.
separation. J Adv Sci Res, 1: 24-33, 2010.
69 Weisi Y, Yates MZ. Encapsulation and sustained
57 Nihant N, Grandfils C, Jerome R, Teyssie P. release from biodegradable microcapsules made by
Microencapsulation by coacervation of poly (lactide- emulsification/freeze drying and spray/freeze
co- glycolide) IV. Effect of processing parameters drying. J Colloid Interf Sci, 336: 155-161, 2009.
on coacervation. J Control Release, 35: 117-125,
1995. 70 Schliehe C, Thiry M, Tromsdorf UI, Henthchel J,
Weller H, Groettrup M.. Microencapsulation of
58 Jayan SC, Sandeep AV, Rifash M, Mareema C, inorganic nanocrystals into PLGA microsphere
Shamseera S. Design and in-vitro evaluation of vaccines enables their intracellular localization in
gelatin microspheres of salbutamol sulphate. Hygeia, dendritic cells by electron and fluorescence
1: 17-20, 2009. microscopy. J Control Release, 151: 278-285, 2011.

59 Surendiran NS, Yuvaraj TV. Preparation and 71 Baojun X. Preparation of uniform biodegradable
valuation of Ibuprofen microspheres by using co- microparticles using laser ablation. Int J Pharm, 325:
acervation phase separation technique. Int J 194-196, 2006.
ChemTech Res, 2: 1214-1219, 2010.
72 Jifu M, Shun D, Anna S, Cai Q, Deng X, Yang X.
60 Mishra B, Patel BB, Tiwari S. Colloidal nanocarriers: Macroporous and nanofibrous poly (lactide-co-
a review on formulation technology, types and glycolide) (50/50) scaffolds via phase separation
applications toward targeted drug delivery. combined with particle-leaching. Mat Sci Eng C, 32:
Nanomedicine: NBM, 6: 9-24, 2010. 1407-1414, 2012.

61 Porta DG, Castalado F, Scognamiglio M, 73 Shuwisitkul D. Biodegradable implants with

Parascandolla P, Reverchon E. Bacteria different drug release profiles. Dissertation
microencapsulation in PLGA microdevices by submitted to the department of biology, chemistry
supercritical emulsion extraction. J Supercritical and pharmacy of Freie University, Berlin; May 2011.
Fluids, 63: 1-7, 2012. A v a i l a b l e o n l i n e a t

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 150
 Review Article

http://www.diss.fu-berlin.de/diss/receive/FUDISS 85 Saez V, Hernandez JR, Peniche C. Microsphere as

_thesis_000000023117 delivery system for the controlled release of peptide
and proteins. Biotecnologia Aplicada, 24: 108-116,
74 Felt-Baeyens O, Eperson S, Mora P, Limal D, 2007.
Sagodira S, Breton P, Simmonazi B, Nobs LB,
Crosier G, Gurny R. Biodegradable scleral implants 86 Zolnik BS, Leary PE, Burgess DJ. Elevated
as new triamcinolone acetonide delivery systems. Int temperature accelerated release testing of PLGA
J Pharm, 322: 6-12, 2006. microspheres. J Control Release, 112: 293-300, 2006.

75 Witt C, Mader K, Kissel T. The degradation, 87 Makadia HK, Siegel SJ. Poly lactic-co-glycolic acid
swelling and erosion properties of biodegradable (PLGA) as biodegradable controlled drug delivery
implants prepared by extrusion or compression carrier. Polymers, 3: 1377-1397, 2011.
moulding of poly (lactide-co-glycolide) and ABA
triblock copolymers. Biomaterials, 21: 931-938, 88 Janoria KG, Mitra AK. Effect of lactide/glycolide
2000. ratio on the in vitro release of ganciclovir and its
lipophilic prodrug (GCV-monobutyrate) from
76 Mohl S. The Development of a Sustained and PLGA microspheres. Int J Pharm, 338: 133-141,
Controlled Release Device for pharmaceutical 2007.
Proteins based on Lipid Implants. Dissertation
submitted to Ludwig-Maximilians-University, 89 Alexis F. Factors affecting the degradation and drug-
Munich; November 2004. release mechanism of poly (lactic acid) and
poly(lactic acid)-co-(glycolic acid). Polym Int, 54: 36-
77 Gopferich A. Bioerodible implants with 46, 2005.
programmable drug release. J Control Release, 44:
271-278, 1997. 90 Wu XS, Wang N. Synthesis, characterization,
biodegradation, and drug delivery application of
78 Iyer SS, Barr WH, Karnes HT. A ‘biorelevant’ biodegradable lactic/ glycolic acid polymers. Part II:
approach to accelerated in vitro drug release testing Biodegradation. J Biomater Sci Polymer Edition, 12:
of a biodegradable, naltrexone implant. Int J Pharm, 21-34, 2001.
340: 119-125, 2007.
91 Graves RA, Pamujula S, Moiseyev R, Freeman T,
79 Ma G, Song C, Sun H, Yang J, Leng X. A Bostanian LA, Mandal TK. Effect of different ratios
biodegradable levonorgestrel-releasing implant made of high and low molecular weight PLGA blend on
of PCL/F68 compound as tested in rats and dogs. the characteristics of pentamidine microcapsules. Int
Contraception, 74:141-147, 2006. J Pharm, 270: 251-282, 2004.

80 Shively MF, Coonts BA, Renner WD, Southard JL, 92 Ali SAM, Dohetry PJ, Williams DF. Mechanism of
Bennett AT. Physico-chemical characterization of a polymer degradation in implantable devices. J
polymeric injectable implant delivery system. J Biomedical Med Res, 27: 1409-1418, 1993.
Control Release, 33: 237-243, 1995.
93 Freiberg S, Jhu XX. Polymer microspheres for
81 Rothen-weinhold A, Besseghir K, Vuaridel E, Sublet controlled drug release. Int J Pharm, 282: 1-18, 2004.
E, Oudry N, Kubel F, Gurny R. Injection-molding
versus extrusion as manufacturing technique for the 94 Witt C, Kissel T. Morphological characterization of
preparation of biodegradable implants. Eur J Pharm microspheres, fillms and implants prepared from
Biopharm, 48: 113-121, 1999. poly (lactide-co-glycolide) and ABA triblock
copolymers: is the erosion controlled by
82 Kunou N, Ogura Y, Hashizoe M, Honda Y, Hyon degradation, swelling or diffusion? Eur J Pharm
SH, Ikada Y. Controlled intraocular delivery of Biopharm, 51: 171-181, 2001.
ganciclovir with use of biodegradable scaleral
implants in rabbits. J Control Release, 37: 143-150, 95 Biodegradable polymers: chemistry, degradation and
1995. applications. Available online at:
http://www.bioen.utah.edu/faculty/pat/Courses/bi
83 Orloff LA, Domb AJ, Teomim D, Fishbein I, omaterials2006/Degradable%20Materials.ppt (Last
Golomb G. Biodegradable implant strategies for accessed on 14 January 2013)
inhibition of restenosis. Adv Drug Deliver Rev, 24:
3-9, 1997. 96 Li J, Jiang G, Ding F. The Effect of pH on the
polymer degradation and drug release from PLGA-
84 Baro M, Sanchez E, Delgado A, Perera A, Evora C.. mPEG microparticles. J App Polym Sci, 109: 475-
In vitro–in vivo characterization of gentamicin bone 482, 2008.
implants. J Control Release, 83: 353-364, 2002.

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 151
 Review Article

97 Zolnik BS, Burgess DJ. Effect of acidic pH on

PLGA microsphere degradation and release. J 110 Tokar JL, Benerjee S, Barth BA. Drug-
Control Release, 122: 338-344, 2007. eluting/biodegradable stents. Gastrointestinal
Endoscopy, 74: 954-958, 2011.
98 Gopferich A. Mechanism of polymer degradation
and erosion. Biomaterials, 17: 103-114, 1996. 111 Huang Y, Venkatraman SS, Boey F, Lahti EM,
Umashankar PR, Mohanty M, Arumugam S,
99 Drug Eluting stent- Wikipedia. Available online at: Khanolkar M, Vaishnav S. In vitro and in vivo
http://en.wikipedia.org/wiki/Drug-eluting_stent performance of a dual drug-eluting stent (DDES).
Biomaterials, 31: 4382-4391, 2010.
100 Muni NI, Califf RM, Foy JR, Boam AB, Zuckerman
BD, Kuntz RE, Mass B. Coronary drug-eluting stent 112 Zhang F, Qian J, Dong L, Ge J. Coronary aneurysm
development: Issues in trial design. Amer Heart J, formation following biodegradable polymer drug-
149: 415-433, 2005. eluting stent implantation. Int J Cardiology, 160: e8-
e9, 2012.
101 Iakovou I. Do the new data on second-generation
drug eluting stents provide reassurance on safety, 113 Han Y, Jing Q, Xu B, Yang L, Liu H, Shang X, Jiang
efficacy, even for off-label use? Hospital Chronicles, T, Li Z, Zhang H, Li H, Qiu J, Liu Y, Li Y, Chen X,
1: 141-144, 2010. Gao R. Safety and efficacy of biodegradable
polymer-coated sirolimus-eluting stents in “real-
102 Alfonso F, Fernandez C. Second-generation drug- world” practice. JACC: Cardiovascular Intervention,
eluting stents: moving the field forward. J Am Coll 4: 303-309, 2009.
Cardiol, 58: 1-4, 2011.
114 Boam AB. Drug-eluting stents current approach to
103 Sheiban I, Villata G, Bollati M, Sillano D, Lotrionte review. Available online at:
M, Zoccai GB. Next-generation drug-eluting stents ttp://www.fda.gov/ohrms/dockets/dockets/03n02
in coronary artery disease: focus on everolimus- 03/03n-0203-ts00010-Boam.ppt (Last accessed 08
eluting stent (Xience V®). Vascular Health and Risk January 2013)
Management, 4: 31-38, 2008.
115 Byrne RA, Kastrati A, Massberg S, Weiczorek A,
104 Kukreja N, Onuma Y, Daemen J, Serruys PW. The Laugwitz KL, Hadamitzky M, Schulz S, Pache J,
future of drug-eluting stents. Pharmacol Res, 57: Fusaro M, Mehilli J. Biodegradable polymer versus
171-180, 2008. permanent polymer drug-eluting stents and
everolimus- versus sirolimus-eluting stents in
105 Raval A, Parmar A, Raval A, Bahadur P. Preparation patients with coronary artery disease. J Amer College
and optimization of media using Pluronic® micelles Cardiol, 58: 1325-1331, 2011.
for solubilization of sirolimus and release from the
drug eluting stents. Colloids Surf B: Biointerfaces, 116 Htay T, Liu MW. Drug-eluting stent: a review and
93: 180-187, 2012. update. Vascular Health and Risk Management, 1:
263-276, 2005.
106 Pan CH, Tang JJ, Weng YJ, Wang J, Huang N.
Preparation, characterization and anticoagulation of 117 Ma X, Oyamada S, Gao F, Wu T, Robich MP, Wu
curcumin-eluting controlled biodegradable coating H, Wang X, Buchholz B, McCcarthy S, Gu Z,
stents. J Control Release, 116: 42-29, 2006. Bianchi CF, Selke FW, Laham R.
Paclitaxel/sirolimus combination coated drug-
107 Pan CJ, Wang J, Huang N. Preparation, eluting stent: In vitro and in vivo drug release studies. J
characterization and in vitro anticoagulation of Pharm Biomed Analysis, 54: 807-811, 2011.
emodin-eluting controlled biodegradable stent
coatings. Colloids Surf B: Biointerfaces, 77: 155-160, 118 Raval A, Parikh J, Engineer C. Dexamethasone
2010. eluting biodegradable polymeric matrix coated stent
for intravascular drug delivery. Chem Eng, 88: 1479-
108 Pan CJ, Tang JJ, Weng YJ, Wang J, Huang N. 1484, 2010.
Preparation and in vitro release profiles of drug-
eluting controlled biodegradable polymer coating 119 Conville CM, Major I, Friend DR, Clark MR,
stents. Colloids Surf B: Biointerfaces, 73: 199-206, Woolfson AD, Malcolm RK. Development of
2009. polylactide and polyethylene vinyl acetate blends for
the manufacture of vaginal rings. J Biomed Mat Res
109 Bege N, Steinmuller SO, Kalinowski M, Reul R, B: App Biomat, 100: 891-895, 2012.
Klaus S, Petersen H, Curdy C, Janek J, Kissel T.
Drug eluting stents based on Poly (ethylene 120 Benagiano G, Gabelnick HL. Biodegradable systems
carbonate): Optimization of the stent coating for the sustained release of fertility-regulating agents.
process. Eur J Pharm Biopharm, 80: 562-570, 2012. J Steroid Biochem, 11: 449-455, 1979.

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 152
 Review Article

121 Rohan LC, Sassi AB. Vaginal drug delivery systems

for HIV prevention. AAPS J, 11: 78-87, 2009. 135 Baht V, Prasad K, Balaji S, Bhat A. Role of tissue
engineering in dentistry. J Indian Academy Dental
122 Stroock & Lavan LLP. Non-hormonal vaginal Specialist, 2: 37-42, 2011.
contraceptive, U.S. Patent 2,400,71 (2006)
136 Hacking SA and Khademhosseini A. Applications of
123 Goldsmith A. Long- acting contraception. Papers microscale technologies for regenerative dentistry. J
presented at the symposium on long-acting Dental Res, 88: 409-421, 2009.
contraception. Alexandria, Egypt dated on
November 3-4, 1983 137 Yuan Z, Nie H, Wang S, Lee CH, Li A, Fu SY,
Zhou H, Chen L, Mao JJ. Biomaterial selection for
124 Darney PD. Hormonal implants: contraception for a tooth regeneration. Tissue Eng Part B 2011;17:373-
new century. Am J Obstet Gynecol, 170: 1536-1543, 88.
1994.
138 Moioli EK, Clark PA, Xin X, Lal S, Mao JJ. Matrices
125 Hill Lifecare Ltd. A novel intrauterine device with and scaffolds for drug delivery in dental, oral and
controlled copper release, WO Patent 2,012,063,262 craniofacial tissue engineering. Adv Drug Deliver
(2012) Rev, 59: 308-324, 2007.

126 Srivastav UK. Controlled-release hormone delivery 139 Illum L. Nasal drug delivery- recent developments
systems for long -term fertility control: the missing and future prospects. J Control Release, 161: 254-
dimension. Current R and D Highlights, 16: 14-18, 263, 2012.
1993.
140 Alpar HO, Somavarapu S, Atuah KN, Bramwell
127 Whaley KJ, Hanes J, Shattock R, Cone RA, Friend VW. Biodegradable mucoadhesive particulates for
DR. Novel approaches to vaginal delivery and safety nasal and pulmonary antigen and DNA delivery.
of microbicides: biopharmaceuticals, nanoparticles, Adv Drug Deliver Rev, 57: 411-430, 2005.
and vaccines. Antiviral Res, 88: S55-S-66, 2010.
141 Csaba N, Garcia-Fuentes M, Alonso MJ.
128 Alaee M, Moghadam SH, Sayyar P, Atyabi F, Nanoparticles for nasal vaccination. Adv Drug
Dinarvand R. Preparation of a reservoir type Deliver Rev, 61: 140-157, 2009.
levonorgestrel delivery system using high molecular
weight poly L-lactide. Iranian J Pharm Res, 8: 87-93, 142 Vila A, Sanchez A, Evora C, Sorino I, McCallion O,
2009. Alonso MJ. PLA-PEG particles as nasal protein
carriers: the influence of the particle size. Int J
129 Takeda Chemical Industries Ltd. Pharmaceutical Pharm, 292: 43-52, 2005.
product for application to uterus mucosa. U.S.
Patent 6,08,3916 (2000) 143 Yildiz A, Okyar A, Baktir G, Araman A, Ozsoy Y.
Nasal administration of heparin-loaded
130 Nagaraju R, Udupa N, Mathew J, Varma BRR. microspheres based on poly (lactic acid). II Farmaco,
Clinival efficacy of biodegradable dental implants of 60: 919-924, 2005.
tinidazole in periodontitls. Indian J Physiol
Pharmacol, 43: 125-128, 1999. 144 Seju U, Kumar A, Sawant KK. Development and
evaluation of olanzapine-loaded PLGA
131 Nakao K, Tsuji T. Dental regenerative therapy: Stem nanoparticles for nose-to-brain delivery: In vitro and
cell transplantation and bioengineered tooth in vivo studies. Acta Biomaterialia, 7:4169-4176,
replacement. Japanese Dental Sci Rev, 44:70-75, 2011.
2008.
145 Li Y, Jiang HL, Zhu KJ, Liu ZH, Hao YL.
132 Link DP, Dolder JV, Jourgens WJFM, Wolke J, Preparation, characterization and nasal delivery of a-
Jansen JA. Mechanical evaluation of implanted cobrotoxin-loaded poly (lactide-co-glycolide)/
calcium phosphate cement incorporated with PLGA polyanhydride microspheres. J Control Release, 108:
microparticles. Biomaterials, 27: 4941-4947, 2006. 10-20, 2005.

133 Mendonca G, Mendonca DBS, Aragao FJL, Cooper 146 Armentano I, Dottori M, Fortunati E, Mattiolli S,
LF. Advancing dental implant surface technology – Kenny JM. Biodegradable polymer matrix
from micron to nanotopography. Biomaterials, 29: nanocomposites for tissue engineering: A review.
3822-3835, 2008. Polym Deg Stability, 95: 2126-2146, 2010.

134 Rosa V, Bona AD, Cavalcanti BN, Eduardo J. 147 Tomihata K, Suzuki M, Oka T, Ikada Y. A new
Tissue engineering: from research to dental clinics. resorbable monofilament suture. Polym Deg
Dental materials, 28: 341-348, 2012. Stability, 59: 13-18, 1998.

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 153
 Review Article

160 Casalini T, Masi M, Perale G. Drug eluting sutures:

148 Rezwan K, Chen QZ, Blaker JJ, Boccaccini AR. A model for in vivo estimations. Int J Pharm, 429:
Biodegradable and bioactive porous 148-157, 2012.
polymer/inorganic composite scaffolds for bone
tissue engineering. Biomaterials, 27: 3413-3431, 161 Morizumi S. Inhibition of neointimal hyperplasia
2006. with a novel tacrolimus-eluting suture. J Am College
Cardiology, 58: 441-444, 2011.
149 Robbe R, George A, Paletta J. Knotless suture-based
anchors. Operative Techniques in Sports Medicine, 162 Gogolewski S. Bioresorbable polymers in trauma
12: 221-224, 2004. and bone surgery. Int J Care Injured, 31: 28-32,
2000.
150 Martina M, Hutmacher DW. Biodegradable
polymers applied in tissue engineering research: a 163 Vieira AC, Guedes RM, Marques AT. Development
review. Polym Int, 56: 145-157, 2007. of ligament tissue biodegradable devices: A review. J
Biomechanics, 42: 2421-2430, 2009.
151 Lombardi AV, Berend KR, Adams JB. Advancing
suture technology: A stitch in time. Seminars in 164 Elmi A, Kajbafzadeh AM, Sadeghi Z, Tanhaeivash
Arthoplasty, 22: 179-181, 2011. R, Mirzadeh H. Biodegradable mini plate and screw:
A secure method for internal fixation of symphysis
152 Kroeze RJ, Helder MN, Govaert LE, Smit TH. pubis in animal model of pubic diastasis. Paediatric
Biodegradable polymers in bone tissue engineering. Urology, 75: 676-683, 2010.
Materials, 2: 833-856, 2009.
165 Middleton JC, Tipton AJ. Synthetic biodegradable
153 Nair LS, Laurencin CT. Polymers as biomaterials for polymers as orthopedic devices. Biomaterials, 21:
tissue engineering and controlled drug delivery. Adv 2335-2346, 2000.
Biochem Engin/Biotechnol, 102: 47-90, 2006.
166 Rokkanen PU, Bostman O, Hirvensalo E, Makela A,
154 Makela P, Pohjonen T, Tormala P, Waris T, Partio EK, Patiala H, Vainionppa S, Vihtonen K,
Ashammakhi N. Strength retention properties of Tormala P. Bioabsorbable fixation in orthopaedic
self-reinforced poly l-lactide (SR-PLLA) sutures surgery and traumatology. Biomaterials, 21: 2607-
compared with polyglyconate (MaxonR) and 2613, 2000.
polydioxanone (PDS) sutures. An in vitro study.
Biomaterials, 23: 2587-2592, 2002. 167 Rangdal S, Singh D, Joshi N, Soni A, Sament R.
Functional outcome of ankle fracture patients
155 Gunatillake PA and Adhikari R. Biodegradab;le treated with biodegradable implants. Food and ankle
synthetic polymes for tissue engineering. Eur Cells surgery, 18: 153-156, 2012.
Mat, 5: 1-16, 2003.
168 Enislidis G, Yerit K, Wittwer G, Kohnke R, Schragl
156 Yarlagadda P, Chandrasekharan M, Shyam JYM. S, Ewers R. Self-reinforced biodegradable plates and
Recent advances and current developments in tissue screws for fixation of zygomatic fractures. J Cranio-
scaffolding. Bio-Medical Mat Eng, 15: 159-177, Maxillofac Surg, 33: 95-102, 2005.
2005.
169 Tasca RA, Sherman IW, Wood GD. Thyroid
157 Dash TK and Konkimalla B. Poly-є-caprolactone cartilage fracture: Treatment with biodegradable
based formulations for drug delivery and tissue plates. British J Oral Maxillofac Surg, 46: 159-160,
engineering: A review. J Control Release, 158: 15-33, 2008.
2012.
170 Kyriakou S, Parara E, Papadogeorgakis N,
158 Mano JF, Sousa RA, Boesel LF, Neves NM, Reis Christopoulos P, Perisanides C, Dimtas S,
RL. Bio inert, biodegradable and injectable Alexendridis K. Use of resorbable plates for
polymeric matrix composites for hard tissue traumology of facial skeleton- 3 years review. Int J
replacement: state of the art and recent Oral Maxillofac Surg, 34: S1-S181, 2005.
developments. Composites Sci Technol, 64: 789-
817, 2004. 171 Merkli A, Tabatabay C, Gurny R, Heller J.
Biodegradable polymers for the controlled release of
159 Park JH, Allen MG, Prausnitz MR. Biodegradable ocular drugs. Prog Polym Sci, 23: 563-580, 1998.
polymer microneedles: fabrication, mechanics and
transdermal drug delivery. J Control Release, 104: 172 Choonara YE, Pillay V, Carmichael T, Danckwerts
51-66, 2005. MP. An in vitro study of the design and
development of a novel doughnut-shaped mini
tablet for intraocular implantation. Int J Pharm, 310:
15-24, 2006.

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 154
 Review Article

185 Lewis KJ, Irwin WJ, Akhtar S. Biodegradable poly

173 Sharma K, Singh V, Arora A. Natural biodegradable (L-lactic acid) matrices for the sustained delivery of
polymers as matrices in transdermal drug delivery. antisense oligonucleotides. J Control Release, 37:
Int J Drug Dev Res, 3: 85-103, 2011. 173-183, 1995.

174 Miyazaki S, Takahashi A, Kubo W. Poly n- 186 Choi SH, Park TG. G-CSF loaded biodegradable
butylcyanoacrylate (PNBCA) nanocapsules as a PLGA nanoparticles prepared by a single oil-in-
carrier for NSAIDs: in vitro release and in vivo skin water emulsion method. Int J Pharm, 311: 223-228,
penetration. J Pharm Pharmaceut Sci, 6: 240-245, 2006.
2003.
187 Chen DW, Hsu YH, Liao JY., Sustainable release of
175 Kun N, Lee KH, Lee DH, Bae YH. Biodegradable vancomycin, gentamicin and lidocaine from novel
thermo-sensitive nanoparticles from poly (L-lactic electrospun sandwich-structured PLGA/collagen
acid)/ poly (ethylene glycol) alternating multi-block nanofibrous membranes. Int J Pharm, 430, 335-341,
copolymer for potential anti-cancer drug carrier. Eur 2012.
J Pharm Sci, 27: 115-122, 2006.
188 Tran VT, Karam JP, Garric X. Protein-loaded
176 Buske J, Konig C, Bassarab S, et al., Influence of PLGA–PEG-PLGA microspheres: A tool for cell
PEG in PEG-PLGA microspheres on particle therapy. Eur J Pharm Sci, 45: 128-137, 2012.
properties and protein release. Eur J Pharm
BioPharm, 81: 57-63, 2012. 189 Wang M, Feng O, Guo X, et al. A dual microsphere
based on PLGA and chitosan for delivering the
177 Diou O, Tsapis N, Giraudeau C. Long-circulating oligopeptide derived from BMP-2. Polym Deg
perfluorooctyl bromide nanocapsules for tumor Stability, 96: 107-113, 2011.
imaging by 19FMRI. Biomaterials, 33: 5593-5602,
2012. 190 Cun D, Foged C, Yang M. Preparation and
characterization of poly (DL-lactide-co-glycolide)
178 Jin C, Yang W, Bai L, Wang X. Preparation and nanoparticles for siRNA delivery. Int J Pharm, 390:
characterization of targeted DOX-PLGA–PEG 70-75, 2010.
micelles decorated with bivalent fragment HAb18
for treatment of hepatocellular carcinoma. J Control 191 Tang J, Chen JY, Liu J, et al., Calcium phosphate
Release, 152: 14-15, 2011. embedded PLGA nanoparticles: A promising gene
delivery vector with high gene loading and
179 Li F, Sun J, Zhu H, Wen X. Preparation and transfection efficiency. Int J Pharm, 431: 210-211,
characterization novel polymer-coated magnetic 2012.
nanoparticles as carriers for doxorubicin. Colloids
Surf B: Biointerfaces, 88: 58-62, 2011. 192 Panyam J, Labhasetwar V. Biodegradable
nanoparticles for drug and gene delivery to cells and
180 Parveen S and Sahoo SK. Long circulating tissue. Adv Drug Deliver Rev, 55: 329-347, 2003.
chitosan/PEG blended PLGA nanoparticle for
tumor drug delivery. Eur J Pharmacol, 670: 372-383, 193 Oster CG, Wittmar M, Bakowsky U, Kissel T. DNA
2011. nano-carriers from biodegradable cationic branched
polyesters are formed by a modified solvent
181 Feng SS. Nanoparticles of biodegradable polymers displacement method. J Control Release, 111: 371-
for new-concept chemotherapy. Expert Rev Medical 381, 2006.
Devices, 1: 115-125, 2004.
194 Zeng P, Xu Y, Zeng C., Chitosan- modified poly
182 Luten J, Van Nostrum CF, Smedt SCD, Hennink (D,L-lactide-co-glycolide) nanospheres for plasmid
WE. Biodegradable polymers as non-viral carriers DNA delivery and HBV gene-silencing. Int J Pharm,
for plasmid DNA delivery. J Control Release, 126: 415: 259-266, 2011.
97-110, 2008.
195 Yan Q, Major TC, Bartlett RH, Meyerhoff ME.,
183 Ahn CH, Chae AY, Bae YH, Kim SW., Synthesis of Intravascular glucose/lactate sensors prepared with
biodegradable multi-block copolymers of poly (L- nitric oxide releasing poly (lactide-co-glycolide)-
lysine) and poly (ethylene glycol) as a non-viral gene based coatings for enhanced biocompatibility.
carrier. J Control Release, 97: 567-574, 2004. Biosens Bioelectron, 26: 4276-4282, 2011.

184 Benfer M, Kissel T. Cellular uptake mechanism and 196 Fay F, Quinn DJ, Gilmore BF, et al., Gene delivery
knockdown activity of siRNA-loaded biodegradable using dimethyldidodecyl ammonium bromide-coated
DEAPA-PVA-g-PLGA nanoparticles. Eur J Pharm PLGA nanoparticles. Biomaterials, 31: 4214-4222,
Biopharm, 80: 247-256, 2012. 2010.

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 155
 Review Article

197 Mayo AS, Ambati BK, Kompella UB. Gene delivery veterinary vaccines: design, manufacture and
nanoparticles fabricated by supercritical fluid antibody responses in sheep. J Control Release, 51:
extraction of emulsions. Int J Pharm, 387: 278-285, 269-280, 1998.
2010.
209 Khan MJI, Tucker IG, Opdebeeck JP. Cholesterol
198 Nastaran NV and Reza A. An approach to the and lecithin implants for sustained release of antigen:
design of a particulate system for oral protein release and erosion in-vitro, and antibody response
delivery II. Preparation and stability study of rhGH- in mice. Int J Pharm, 76: 161-170, 1991.
loaded microspheres in simulated gastrointestinal
fluids. Iranian J Pharm Res, 10: 183-192, 2011. 210 Middleton JC and Tipton AJ. Synthetic
199 Astayeh R, Moghimi HR, Erfan M, Mobedi H. biodegradable polymers as orthopedic devices.
Formulation of an injectable implant for peptide Biomaterials, 21: 2335-2346, 2000.
delivery and mechanistic study of the effect of
polymer molecular weight on its release behaviour. 211 Faisant N, Siepmann J, Richard J, Benoit JP.
Daaru, 14: 65-70, 2006. Mathematical modeling of drug release from
bioerodible microparticles: effect of gamma-
200 Pareta R and Edirisinghe MJ. A novel method for irradiation. Eur J Pharm Biopharm, 56: 271-279,
the preparation of biodegradable microspheres for 2003.
protein drug delivery. J R Soc Interface, 3: 573-582,
2006. 212 Mohanan D, Gander B, Kundig TM, Johansen P.
Encapsulation of antigen in poly (D,L-lactide-co-
201 Slutter B, Bal S, Keijzer C, et al., Nasal vaccination glycolide) microspheres protects from harmful
with N-trimethyl chitosan and PLGA based effects of c-irradiation as assessed in mice. Eur J
nanoparticles: Nanoparticle characteristics determine Pharm Biopharm, 80: 274-281, 2012.
quality and strength of the antibody response in
mice against the encapsulated antigen. Vaccine, 28: 213 Lee JS, Chae GS, Khang G. The effect of gamma
6282-6291, 2010. irradiation on PLGA and release behavior of BCNU
from PLGA wafer. Macromol Res, 11: 352-356,
202 Sivakumar SM, Sukumaran N, Nirmala L. 2003.
Immunopotentiation of hepatitis B vaccine using
biodegradable polymers as an adjuvant. J Microbiol 214 Friess W and Schlapp M. Sterilization of gentamicin
Immunol Infec, 43: 265-270, 2010. containing collagen/PLGA microparticle
composites. Eur J Pharm Biopharm, 63: 176-187,
203 Salvador A, Igartua M, Hernandez AM, Pedraz JL. 2006.
Combination of immune stimulating adjuvants with
poly (lactide-co-glycolide) microspheres enhances 215 Choi Y, Kim SY, Moon MH, Kim SH, Lee KS,
the immune response of vaccines. Vaccine, 30: 589- Byun Y. Poly (ethylene glycol)} poly (l-lactide)
596, 2012. diblock copolymer prevents aggregation of poly (l-
lactide) microspheres during ethylene oxide gas
204 Srinivas M, Cruz LJ, Bonetto F., Customizable, sterilization. Biomaterials, 22: 995-1004, 2001.
multi-functional fluorocarbon nanoparticles for
quantitative in vivo imaging using 19F MRI and 216 Wollersheim O, Zumaque H, Hormes J, Kadereit D,
optical imaging. Biomaterials, 31: 7070-7077, 2010. Langen J, Haubling L, Hoessel P, Hoffmann G.
Quantitative studies of the radiation chemical
205 Tshikhudo N, Pretorius A, Putterill J, Kleef MV. behaviour of PMMA and poly ( lactides). Nucl
Preparation and in vitro characterisation of Ehrlichia Instrum Methods Phys Res Sec B, 97: 273-278,
ruminantium plasmid DNA and proteins 1995.
encapsulated into and DNA adsorbed onto
biodegradable microparticles. Ticks and Tick-borne 217 Montanari L, Cilurzo F, Valvo L, Faucitano A,
Diseases, 1: 186-193, 2010. Buttafava A, Groppo A, Genta I, Conti B. Gamma
irradiation effects on stability of poly (lactide-co-
206 Yang Y, Kuang Y, Liu Y. Immunogenicity of glycolide) microspheres containing clonazepam. J
multiple-epitope antigen gene of HCV carried by Control Release, 75: 317-330, 2001.
novel biodegradable polymers. Comp Immunol
Microbiol Infec Disease, 34: 65-72, 2011. 218 Mohr D, Wolff M, Kissel T. Gamma irradiation for
terminal sterilization of 17b-estradiol loaded poly-
207 Winzenburg G, Schmidt C, Fuchs S, Kissel T. (d,l-lactide-co-glycolide) microparticles. J Control
Biodegradable polymers and their potential use in Release, 61:203-217, 1999.
parenteral veterinary drug delivery systems. Adv
Drug Deliver Rev, 56: 1453-1466, 2004. 219 Igartua M, Hernandez RM, Rosas JE, Patarroyo ME,
Pedraz JL. c-Irradiation effects on biopharmaceutical
208 Walduck AK, Opdebeeck JP, Benson HE, Prankerd properties of PLGA microspheres loaded with
R. Biodegradable implants for the delivery of

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 156
 Review Article

SPf66 synthetic vaccine. Eur J Pharm Biopharm, 69:

519-526, 2008.

220 Inactive ingredient search for approved drug

products. Available online at:
http://www.accessdata.fda.gov/scripts/cder/iig/ind
ex.cfm (Last accessed on 14 January 2013).

221 Sinha VR, Trehan A. Biodegradable microspheres

for protein delivery. J Control Release, 90: 261-280,
2003.

222 Sadrieh N. Regulatory considerations for

nanomaterial-containing therapeutics. 2009, PQRI
Workshop, December 2009

223 Tegnander A, Engebresten L, Bergh K. Activation

of the complement system and adverse effects of
biodegradable pins of polylactic acid (Biofix) in
osteochondritis dissecans. Acta Orthop Scand, 65:
472-475, 1994.

224 Guidance document for testing biodegradable

polymer implant device. Available at:
http://www.fda.gov/medicaldevices/deviceregulatio
nandguidance/guidancedocuments/ucm080265.htm

225 Sahoo SK, Prusty AK. Toxicological and regulatory

consideration of pharmaceutically important
nanoparticles. J Curr Pharm Res, 3: 8-12, 2010.

This Journal is © IPEC-Americas Inc December 2013 J. Excipients and Food Chem. 4 (4) 2013 - 157