PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY

2020, VOL. 25, NO. 1, 116–132

https://doi.org/10.1080/10837450.2019.1682607

REVIEW ARTICLE

Pharmaceutical implants: classification, limitations and therapeutic applications

Zahra Mohtashamia, Zahra Esmailia, Molood Alsadat Vakilinezhada, Ehsan Seyedjafarib and
Hamid Akbari Javara
a
Pharmaceutics Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; bDepartment of Biotechnology, Tehran
University, Tehran, Iran

ABSTRACT ARTICLE HISTORY

Controlled/sustained delivery systems have been developed rapidly which show the ability to overcome Received 29 May 2018
the obstacles of traditional delivery systems. Daily development of biomedical and biomaterial sciences Revised 16 October 2019
has brought more attention to the implantable delivery systems. As a result, these systems have found Accepted 16 October 2019
their position in the medical field since they were introduced. The advances in the polymeric science
KEYWORDS
along with the other fields, make the production of a wide variety of implantable systems, possible. The Pharmaceutical implants;
influence of these systems in medical field could not be denied Here’, the pharmaceutical applications chemotherapeutical
which have been mostly focused on, are discussed. Since these systems have proven to be beneficial, implants; contraceptive
researchers are trying to adjust their defects to the desired properties. Doing so, the path that implant- implants; ocular delivery;
able delivery systems have crossed so far should be studied, and that’s the aim of this review. In the pre- peptide delivery; pain
sent report, the advantages of these systems in chemotherapeutic, contraceptive, neuropsychology, pain management
management, peptide delivery, ocular delivery, cardiovascular, orthopedic, and dental fields have been
evaluated.

Introduction developed crystalline pellets of estrogen that were subcutane-

Tremendous conversions of traditional drug consumption to the
novel controlled drug delivery systems have changed the whole
concept of medical treatment. Many scientists have investigated
macro- or nanoscale drug delivery systems to increase the efficacy
of the drug and attract patients’ compliance mostly in the chronic
conditions requiring long- term or even lifetime therapy such as
chronic pain or mental diseases (Brudno and Mooney 2015; Pilon
ously placed in male chicken; after which they were used to treat
a young woman suffering from premature menopause. Regarding
the appealing results, this technique quickly spread to the other
types of drugs (Dash and Cudworth 1998; Kost and Langer 2012).
Folkman and Long proposed the possibility of using a sealed
segment of silicone rubber as a carrier for prolonged drug therapy
after they were able to anesthetize rabbits by passing gas into the
SilasticV arterio-venous shunt (Folkman et al. 1966; Hoffman 2008;
R

et al. 2016; Sanjay et al. 2018).
The ability of such systems to release the active agent during
the extended time or at the specific location considered as the
successful controlled,/sustained or targeted released delivery sys-
tems (Langer and Peppas 2003; Bhusal et al. 2016).
In some aspects, implants outweighed conventional delivery
systems; i.e. patients’ compliance would increase as the frequency
of drug administration decrease (Kempe and M€ader 2012; Brudno
and Mooney 2015), drugs’ side effects could be minimized by
reducing its required amount (Amsden 2015; Newman and Benoit
2016), drug concentration could be adjusted at a therapeutic level
(Kempe and M€ader 2012), undesired pharmacodynamics properties
of drug could be modified (Wang et al. 2016), the designed system
could circumvent metabolic or biological barriers and also sys-
temic circulation (Norouzi et al. 2016); and in general, the treat-
ment’s cost would drop a huge deal (Danckwerts and Fassihi 1991;
Bagherifard 2017). On the other hand, unprecedented rising inter-
est in biotechnological products demands the appropriate route of
administration since they have variable and partial absorption in
traditional routes of administration (Kempe and M€ader 2012).
The concept of implantable drug delivery systems was seemed
to overture in the medical field by Lafarge in 1861, designing the
implantable drug pellets. Using such concept, Parkes and Deansy
Meng and Hoang 2012). In 1969, a report was released by Dzuik
and Cook for ready penetration of steroidal hormone through sili-
con, and in the mid-1970s, Folkman and his former postdoc, Bob
Langer, published an influential paper revealing that protein could
be gradually released in its active form from non-degradable,
hydrophobic polymer matrices (Dash and Cudworth 1998). These
were the first steps of the long road of implantable drug delivery
systems. The exponential growth in implant usage not only as
delivery systems but also as biomedical devices in the cardiovascu-
lar disease like a heart valve or pacemaker or coronary stent, ocular
and orthopedic, and aesthetics like breast reconstructions, shows
their daily increasing values (Arsiwala et al. 2014; Ye et al. 2014).
The market revenue of implantable drug delivery devices was
estimated to rise from 11.6 billion USD in 2015 to 17.5 billion
USD in 2021 by Zion Market Research. According to the World
Health Organization report, the Global Medical Implants Market is
expected to grow at a CAGR of 7.07% during the forecast period
of 2017-2023.
Classifications of implantable delivery systems
There are many possible classifications for implantable systems. In
general, two major groups of “drug implants” and “implantable

CONTACT Hamid Akbari Javar akbarijo@tums.ac.ir Pharmaceutics Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

drug-loaded pumps” could be addressed. In the first group, i.e.
drug implants, various types of polymers, and polymeric mem-
branes are used to control the drug release from the delivery sys-
tem. The latter group, i.e. implantable drug-loaded pumps, utilize
a mechanical pump to control the drug release (Danckwerts and
Fassihi 1991). Following the technological advances in this area,
the third atypical group of implants has emerged. Different deliv-
ery systems such as sustained-release intraocular systems for the
treatment of glaucoma, hydroxyapatite cement systems used in
osteomyelitis, and transurethral injection systems for impotence
are a few examples.
Implants could also be classified based on the drug release
controlling mechanisms. These systems could be categorized as
diffusion-controlled, chemically controlled, swelling controlled,
osmotically controlled, magnetically controlled, etc. Every system
has its unique characteristics. Zero-order released could be
achieved in either reservoir or matrix type diffusion-controlled sys-
tems where the polymer layer and diffusional distance would con-
sider as rate-limiting factors respectively. In chemically controlled
systems, bioerosion of polymer is responsible for drug releasing
rate. The zero-order kinetic would achieve where the surface area
remains constant over time. In osmotically controlled systems,
osmotic pressure is a driving force of drug release through the
semipermeable membrane of the delivery system. So on.
In another classification, there are two categories of implant
devices; biodegradable and non-biodegradable implants.
The inert nature of non-biodegradable polymers and the sim-
plicity of their processing have fascinated researchers to discover
their function in biomedical applications. Over the past decades,
many non-biodegradable polymeric devices and implants have
been established and successfully used to help millions of
patients worldwide (Dash and Cudworth 1998). These systems
considered suitable for long- term treatment of chronic diseases
as they could release drugs longer than biodegradable ones. The
drug release rate could be controlled by the thickness of the per-
meable membrane and surface area of the drug-containing reser-
voir. Among all the benefits, the required minor surgery to
implant and remove these matrices considered risky for patient’s
compliance (Parent et al. 2013). The variety of non-biodegradable
polymers have been considered in drug delivery; e.g. polysacchar-
ide derivatives, acrylic polymer derivatives, dextran, polyethylene
oxide, polypropylene, silicone rubber (polydimethylsiloxane or
PDMS), Ethylene-vinyl acetate (EVA), Vinylidene Fluoride copoly-
mers, thermoplastic polyurethane (TPU) and lectins of plants or
microbial origins. The wide range of chemical and physical prop-
erties of these polymers could provide flexible characteristics for
the designed delivery system from short to long-term release pro-
file and also their ability to load hydrophobic or hydrophilic active
material among others.
Biodegradable polymeric systems offered a distinct advantage
over non-biodegradable ones; i.e. they do not need to be
removed after the treatment. However, the disadvantages shad-
owed the beneficial. They have complicated development tasks,
variable physical properties, more regulatory requirements, and
safety considerations (Tang and Singh 2009; Al-Jawadi et al.
2018). Besides, despite the lower unit price of the biodegradable
implants, the total cost of treatment would be higher than the
non-biodegradable implants because of their necessity for the
repeated implementation (Towler 2014). On the other hand, keep-
ing the constant rate of drug release is a beat challenging as too
many factors affecting the system’s degradation. Not only the sys-
tem’s characteristics but also alterations in body pH or
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 117
temperature could cause a transient increase or decrease in the
degradation rate of the system.
Despite all that, biodegradable implantable systems have been
investigated for the delivery of a wide range of therapeutic
agents. They are mostly considered in cancer chemotherapy and
chronic pain management (Kleiner et al. 2014). Among all bio-
degradable polymers, Polyester-based polymers, and Lactic- and
Glycolic- based aliphatic is the most widely investigated polymers
for drug delivery (Makadia and Siegel 2011). Other biodegradable
polymers considered in drug delivery are polyanhydrides, polya-
minoacids, polyphosphoesters, polyphosphazene, and chitosan.
Insitu forming implants
Implants design for drug delivery is not confined to the solid
form of biomaterials. Other types of formulation that form a
depot in the body could be considered as an implant as well,
named in-situ hydrogels/implants (Fakhari and Subramony 2015;
Liu et al. 2016). This kind of formulation mostly considered in tis-
sue engineering and regeneration, microfluidics, and cell
encapsulation.
The theory of in situ forming implants was first presented by
Dunn et al. in the ’90s in which liquid drug-polymerr formulation
solidifies in contact with body fluids once it is injected. The prin-
ciple is to dissolve a water-insoluble biodegradable polymer in an
organic solvent, miscible or partially miscible with water. When
the resulted solution or suspension injected into an aqueous
medium, the solvent diffuses to the surrounding environment
leading to phase separation and forming the drug depot at the
injection site. These systems have been generally categorized on
the basis of their formulation method resulting in three following
groups: (i) In situ solidifying organogels; hot melts that solidify on
cooling to physiological temperatures or lyotropic liquid crystals,
(ii) In situ cross-linking systems; wherein chemical crosslinking of
polymer chains is created by a change in temperature or ion con-
centration, and, (iii) In situ precipitating systems; in which the
polymer condensed under physiological conditions (Parent
et al. 2013).
There are various investigations in this area. The Atridox# and
DoxirobeTM are two in- situ forming implants designed for chronic
veterinary periodontitis therapy that locally release doxycycline
hyclate over a week after direct injection (Solanki et al. 2010).
There could be another classification based on product type or
their intended use considering the importance of long- term
delivery of certain drugs or delivering the drug to the specific
organ in the body. In this categorization, implantable delivery sys-
tems classified in Ophthalmology, Cardiovascular, Birth control/
contraception, Oncology, diabetes, chronic pain causing diseases,
etc. categories (Figure 1).
Herein, the authors tried to use this classification and discuss
the importance of implantable systems in application groups that
they are considered to be most helpful in.
Implants classification based on applications
Chemotherapeutical implants
Cancer is known as one of the significant challenges that jeopard-
izing world health since it afflicting almost 1.6 million and slaugh-
tering about 580 thousands US individuals in 2015; and also
predicted the diagnosis of 19.3 million new cases worldwide by
2025 (Norouzi et al. 2016; Tan et al. 2017). Different pathogenesis
has been attributed to cancer, e.g. genetic defect, heritage,
118 Z. MOHTASHAMI ET AL.
Figure 1. Implant classification based on their frequently use implantable sites.
alcohol consumption, bad nutrition, bio-infections, and pollutions
(Liu et al. 2016; Tan et al. 2017).
Treatment procedures vary from surgically removing the tumor
tissue to chemo-/radio-/immuno- therapies regarding cancer’s
type and its progression. The latter treatments are the most used
one, considering the limited applicability of the tumor resection
(Fonseca et al. 2015; Norouzi et al. 2016). However, orally adminis-
tration of most chemotherapeutical agents countering serious
problems since they are often poorly soluble in water (e.g. pacli-
taxel (Afrooz et al. 2017), Docetaxel (Xu et al. 2016), camptothecin
(Bastiancich et al. 2016), etoposide (Narvekar et al. 2014), 5-fluo-
rouracil (5-FU), and cisplatin (Yi et al. 2016)) or poorly absorbed
from gastrointestinal tract despite their proper water solubility
(e.g. Doxorubicin (Hu et al. 2016)).
Therefore, in order to achieve the therapeutic level, these
agents have to administrate in large amount exposing patients to
severe adverse effects. Local delivery of such drugs was proposed
as an excellent alternative aiming the longevity and enhancement
of patients’ lives quality (Yi et al. 2016; Nanaki et al. 2017).
Among the various local delivery systems, implants have
shown optimistic results in preclinical studies evaluating 5-FU,
Paclitaxel, Carboplatin, or Carmustine (BCNU) anticancer drugs
(Wolinsky et al. 2012; Bastiancich et al. 2016; Aguilar et al. 2018).
Implants are reflecting state of the art in drug delivery sys-
tems. The implants as structures, loaded by active agents, could
be planned designed in precise dimensions with the predictable
releasing pattern. One way to design such systems is 3 D-printing
(Norman et al. 2017; Zhang et al. 2017; Davoodi et al. 2018).
Using different 3 D-printing technology, various pharmaceutical
formulations, including implantable delivery systems, have been
developed (Jassim-Jaboori and Oyewumi 2015; Jamro z et al. 2018;
Jose and Gv 2018). Implantable device could be provided from
different polymers. Various chemotherapeutic agents would bene-
fit from such systems.
The implantable device could be prepared from different poly-
mers, and various chemotherapeutic agents would benefit from
such systems. Apparently, ZoladexV was the first chemotherapeu-
R
tic implant considered by FDA. These subcutaneously injectable
PLGA rods were designed to release goserelin over 14 weeks for
advanced prostate and breast cancer therapies (Dijkman
et al. 1990).
EligardV, an in situ forming implant used in advanced prostate
R
cancer, was formulated to release leuprolide for six months albeit
having. Its disadvantage was an enormous burst release; i.e.
almost 40% in the first 24 h (Ravivarapu et al. 2000; Solanki
et al. 2010).
A hydrogel implant, VantasTM, has also developed for subcuta-
neously subcutaneous delivering delivery of 50 mg of histrelin
acetate for in 12-months to relieve symptoms associated with
prostate cancer.
A flexible pretzel-shaped device has had been designed for
treating non-muscle invasive bladder cancer in which osmotic
pump made of silicone and nickel alloy wire could control the
drug delivery for several weeks.
Anticancer loaded implants for drug delivery in brain tumors
are considered as one of the most beneficial ones (Grossman
et al. 2015; Madhusudanan et al. 2017). Besides the problematic
accessibility, many other challenges encountered encounters drug

delivery to brain tumors. In most cases, tumor tissue could not
fully resected, and chemotherapeutic drugs should be adminis-
trated. However, the blood-brain barrier robustly inhibited drug
penetration (Mangraviti et al. 2016; Park et al. 2017). In glioblast-
oma (GBM), after surgical removal of tangled tissue, radiation and
prescription of temozolomide or carmustine (BCNU) is the gold
standard. Various approaches have been proposed to maintain
drug concentration at a therapeutic level and prevent tumor
recurrence, which often reported after two years after the surgery
(Pourgholi et al. 2016).
GliadelV, the only FDA approved implant for a brain tumor,
R
was designed to overcome such obstacles, in which BCNU is
loaded in polymeric mixtures named BiodelV (Ravivarapu et al.
R
2000; Grossman et al. 2015). This implants inserted into the fissure
created by tumor removal, releasing the active agent in over
three weeks (Wadee et al. 2011; Tseng et al. 2016). Aside from its
drawbacks like the possibility of implant movement after insertion
and increasing intracranial pressure and risk of convulsion; it was
able to extend the patients’ lifetime up to 6 months in compari-
son to with placebo. It could and also reduced carmustine’s side
effects compared to its conventional routes of administration
(Bota et al. 2007; Ene et al. 2016).
Several implants’ formulations have also been preclinically
evaluated. As an example, the blend of PLGA and PCL (PLGA/PCL)
was loaded by 5-FU and formulated as a 3 D-printed implant
(Bastiancich et al. 2016). Evaluating it’s in vivo efficacy, the mean-
ingful reduction in tumor size of the induced pancreatic cancer in
the 6-week-old male BALB/C nude mouse was treated by implant
insertion underneath the cancerous region. The meaningful reduc-
tion in tumor size in comparison to the control group was wit-
nessed achieved. In the implant treated group, the plasma level
of 5-FU after one week was considerably smaller than the IV
injected group and the normal level of liver enzyme, glutamic
oxaloacetic transaminase, was almost normal founded by in 5-FU
implementation in comparison to its IV administration. The
implant success in local delivery of its active agent was confirmed
by replacing rhodamine B, instead of 5-FU, in which fluorescent
rays were detected only in implant inserted area, not the entire
body (Yi et al., 2016).
Methotrexate (MTX) was also formulated as an implant.
Despite its well-known effect against a different type of cancers
(Pourgholi et al. 2016; Park et al. 2017), its high distribution vol-
ume, narrow therapeutic window and swift elimination from the
body (Wadee et al. 2011; Pourgholi et al. 2016), limit its usage
(Vakilinezhad et al. 2018). MTX loaded Poly (e-caprolactone) (PCL)
implant decline the tumor volume, inflammation, and necrotic
tumoral tissue of Ehrlich tumor-induced mice meaningfully was
evaluated in Ehrlich tumor-induced mice. The meaningful decline
in tumor volume, inflammation, and necrotic tumoral tissue, in
contrast, comparison to the untreated group. The acquired results,
emphasis the local efficacy of designed implant (de Fatima Pereira
et al. 2014).
Doxorubicin (DOX) was also evaluated as in implant delivery
system to overcome its undesired properties, i.e. inhibiting its
accumulation in non-targeted tissues, reducing its adverse effects
and declining its quick degradation (Ren et al. 2016; Mosafer et al.
2017). Intratumoral injections of DOX solution and DOX hydrogel
were evaluated in B16F10 cancer cell bearing mice. The effect of
a single infusion of DOX solution only lasts for four days.
However, a single injection of DOX hydrogel and repeated injec-
tions of DOX solution effectively controlled the tumor size the
same as the repeated doses of DOX solution could do. They are
comparing to the control group. Evaluating its biodistribution,
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 119
starting from 90% on the first day and reaching 13% on the 15th
day, represented the prolong release of DOX from the hydrogel.
Taken together above information confirms that hydrogel loaded
DOX has the same effect as repeated DOX solution injections. The
acquired results are immensely talented not only in clinical but
also in an economic point of view (Kang et al. 2011).
Paclitaxel was formulated as chitosan-lipid based implant aim-
ing for treatment of ovarian cancer, the most deadly gyneco-
logical malignancy (van der Steen et al. 2017). The standard gold
treatment of ovarian cancer, i.e. a combination of surgical resec-
tion and platin based agents and paclitaxel, was not completely
effective due to resistance to chemotherapeutics or metastasis
and resistance to chemotherapeutics (Chen et al. 2016; Kasten
et al. 2017). One significant advantage of this implant was lack of
any burst release in studied release mediums. After 84 days, about
9.4% and 69% paclitaxel was released in PBS and IP medium,
respectively. Such a difference was attributed to the presence of
enzymes in the ascites fluid that accelerated implant degradation
and drug release. The designed implant could release its active
agent over a month, keeping its concentration in the therapeutic
window and below side effect appearing level (Soo et al. 2008).
Besides the implants as mentioned earlier, There are various
preclinically studied implants were designed for evaluation of
evaluating different chemotherapeutic agents (Talebian et al.
2018). Among the myriad efforts for conquering cancer, the
implant delivery systems are considered as a potentially successful
method worth working on.
Contraceptive implants
There is an unmet need for contraception not only in developing
but also in developed countries. In 2011, almost half of pregnan-
cies in women between the ages of 15 to 24 in the United States
were unintended (Finer and Zolna 2016; Sedgh et al. 2016). The
diverse methods for contraceptive administration were produced
to fulfill such need.
Injection of contraceptives was once one of the most used
methods to avert pregnancy. The use of such short- term method
seemed to be more common in Africa and Europe (Stanback et al.
2010). Apart from its merit in comparison to oral contraceptives,
the demand for frequently visiting health care centers to re-inject
the contraceptive, considered as its drawback. If one forgets to
reuse once, it could lead to unwanted pregnancy (Lakha et al
2005; Halpern et al. 2015).
Emerging the Long-acting reversible contraceptives, now
mostly used in Asia and Northern America (Amsden 2015), was
somehow more favorable than the conventional short-acting ones
(Blumenthal et al. 2011; Winner et al. 2012). Therefore, to achieve
the therapeutic level, these agents have to administrate in large
amount exposing patients to severe adverse effects. Local delivery
of such drugs was proposed as an excellent alternative aiming
the longevity and enhancement of patients’ lives quality (Nanaki
et al. 2017; Aguilar et al. 2018).
Among the various local delivery systems, implants have
shown optimistic results in preclinical studies evaluating 5-FU,
Paclitaxel, Carboplatin, or Carmustine (BCNU) anticancer drugs (Yi
et al. 2016; Norman et al. 2017; Zhang et al. 2017).
Implants are reflecting the state of art in drug delivery sys-
tems. The implants structures, loaded by active agents, could be
designed in precise dimensions with the predictable releasing pat-
tern. One way to design such systems is 3 D-printing (Davoodi
et al. 2018; Jamroz et al. 2018; Jose and Gv 2018). Using different
3 D-printing technology, various pharmaceutical formulations
120 Z. MOHTASHAMI ET AL.
including implantable delivery systems have been developed
(Dijkman et al. 1990; Ravivarapu et al. 2000; Jassim-Jaboori and
Oyewumi 2015)
The implantable device could be prepared from different poly-
mers, and various chemotherapeutic agents would benefit from
such systems. Apparently, ZoladexV was the first chemotherapeu-
R
tic implant considered by FDA. These subcutaneously injectable
PLGA rods were designed to release goserelin over 14 weeks for
advanced prostate and breast cancer therapies (Grossman
et al. 2015).
EligardV, an in situ forming implant used in advanced prostate
R
cancer, was formulated to release leuprolide for six months albeit
having a significant burst release; i.e. almost 40% in the first 24 h
(Madhusudanan et al. 2017; Tan et al. 2017).
A hydrogel implant, VantasTM, has also developed for subcuta-
neous delivery of 50 mg histrelin acetate in 12-months to relieve
symptoms associated with prostate cancer.
A flexible pretzel-shaped device had been designed for treat-
ing non-muscle invasive bladder cancer in which osmotic pump
made of silicone and nickel alloy wire could control the drug
delivery for several weeks.
Anticancer loaded implants for drug delivery in brain tumors
are considered as one of the most beneficial ones (Mangraviti
et al. 2016; Park et al. 2017). Besides the problematic accessibility,
many other challenges encounter drug delivery to brain tumors.
In most cases, tumor tissue could not fully resected, and chemo-
therapeutic drugs should be administrated. However, the blood-
brain barrier robustly inhibited drug penetration (Wadee et al.
2011; Pourgholi et al. 2016). In glioblastoma (GBM), after surgical
removal of tangled tissue, radiation and prescription of temozo-
loamide or carmustine (BCNU) is the gold standard. Various
approaches have been proposed to maintain drug concentration
at a therapeutic level and prevent tumor recurrence, which often
reported two years after the surgery (Tseng et al. 2016).
GliadelV, the only FDA approved implant for a brain tumor,
R
was designed to overcome such obstacles, in which BCNU is
loaded in polymeric mixtures named BiodelV (Bota et al. 2007;
R
Ene et al. 2016). This implants inserted into the fissure created by
tumor removal, releasing the active agent in over three weeks
(Bota et al. 2007; Vakilinezhad et al. 2018). Aside from its draw-
backs like the possibility of implant movement after insertion and
increasing intracranial pressure and risk of convulsion; it was able
to extend the patients’ lifetime up to 6 months in comparison
with placebo. It could also reduce carmustine’s side effects com-
pared to its conventional routes of administration (de Fatima
Pereira et al. 2014; Mosafer et al. 2017).
Several implants’ formulations have also been preclinically
evaluated. As an example, the blend of PLGA and PCL (PLGA/PCL)
was loaded by 5-FU and formulated as a 3 D-printed implant
(Nanaki et al. 2017). Evaluating its in vivo efficacy, the meaningful
reduction in tumor size of the induced pancreatic cancer in the 6-
week-old male BALB/C nude mouse in comparison with the con-
trol group was achieved. In the implant treated group, the plasma
level of 5-FU after one week was considerably smaller than the IV
injected group and the level of liver enzyme, glutamic oxaloacetic
transaminase, was almost normal in 5-FU implementation in com-
parison to its IV administration. The implant success in local deliv-
ery of its active agent was confirmed by replacing rhodamine B,
instead of 5-FU, in which fluorescent rays were detected only in
implant inserted area, not the entire body (Nanaki et al. 2017).
Methotrexate (MTX) was also formulated as an implant.
Despite its well-known effect against different type of cancers, its
high distribution volume, narrow therapeutic window, and swift
elimination from the body limit its usage (Vakilinezhad et al.
2018). MTX loaded Poly (e-caprolactone) (PCL) implant decline the
tumor volume, inflammation, and necrotic tumoral tissue of
Ehrlich tumor-induced mice meaningfully in comparison to the
untreated group. The acquired results, emphasis the local efficacy
of designed implant (de Fatima Pereira et al. 2014).
Doxorubicin (DOX) was also evaluated in implant delivery sys-
tem to overcome theundesired properties, i.e. inhibiting accumu-
lation in non-targeted tissues, reducing the adverse effects and
declining quick degradation (Ren et al. 2016; Mosafer et al. 2017).
Intratumoral injections of DOX solution and DOX hydrogel were
evaluated in B16F10 cancer cell bearing mice. The effect of a sin-
gle injection of DOX solution only lasts for four days. However, a
single injection of DOX hydrogel effectively controlled the tumor
size the same as the repeated doses of DOX solution could do.
evaluation of its biodistribution, starting from 90% on the first
day and reaching 13% on the 15th day, represented the prolong
release of DOX from the hydrogel. Taken together above informa-
tion confirms that hydrogel loaded DOX has the same effect as
repeated DOX solution injections. The acquired results are
immensely important not only in clinical but also in an economic
point of view (Kang et al. 2011).
Paclitaxel was formulated as chitosan-lipid based implant aim-
ing for treatment of ovarian cancer, the most deadly gyneco-
logical malignancy (van der Steen et al. 2017). The standard gold
treatment of ovarian cancer, i.e. a combination of surgical resec-
tion and platin based agents and paclitaxel, was not completely
effective due to resistance to chemotherapeutics or metastasis
(Chen et al. 2016; Kasten et al. 2017). One significant advantage
of this implant was lack of any burst release in studied release
mediums. After 84 days, about 9.4% and 69% paclitaxel was
released in PBS and IP medium, respectively. Such a difference
was attributed to the presence of enzymes in the ascites fluid
that accelerated implant degradation and drug release. The
designed implant could release its active agent over a month,
keeping its concentration in the therapeutic window and below
side effect appearing level (Soo et al. 2008).
Besides the implants as mentioned above, various preclinically
studied implants were designed for the evaluation of different
chemotherapeutic agents (Talebian et al. 2018). Among the myr-
iad efforts for conquering cancer, the implant delivery systems are
considered as a potentially successful method worth working on.
Contraceptive implants
There is an unmet need for contraception not only in developing
but also in developed countries. In 2011, almost half of pregnan-
cies in women between the ages of 15 to 24 in the United States
were unintended (Finer and Zolna 2016; Sedgh et al. 2016). The
diverse methods for contraceptive administration were produced
to fulfill such need.
Injection of contraceptives was once one of the most used
methods to avert pregnancy. The use of such short- term method
seemed to be more common in Africa and Europe (Stanback et al.
2010). Apart from its merit in comparison to oral contraceptives,
the demand for frequently visiting health care centers to re-inject
the contraceptive, considered as its drawback. If one forgets to
reuse once, it could lead to unwanted pregnancy (Lakha et al.
2005; Halpern et al. 2015).
Emerging the Long-acting reversible contraceptives, mostly
used in Asia and Northern America, was somehow more favorable
than the conventional short-acting ones (Blumenthal et al. 2011;
Winner et al. 2012). Therefore, there was a huge effort on the
 PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 121

Table 1. The characteristics of the contraceptive implants. To reduce the risk of neuronal injury reported by implants
removal, NexplanonV designed with barium sulfate loaded rod to
R
Implant name Norplant/Jadelle Implanon Nexplanon
Rout of administration Subdermal Subdermal Subdermal locate the implant more feasibly (Friend 2016; Restrepo and
Strength 75 mg 68 mg 68 mg Spinner 2016).
Shape Cylindrical Rod Rod Intravaginal rings could also be considered as an implantable
Polymer DMS/ MVS EVA EVA
device. MAGNEZIXV, a silicone intravaginal ring, designed by
R

copolymer# copolymer copolymer

Active ingredient Levonorgestrel Etonogestrel Etonogestrel Pfizer to releases 2 mg estradiol in 90 days as a treatment for
Dimension 2.5  43 mm 2  40 mm 2  40 mm menopause- associated symptoms.
Duration of action 5 years 3 years 3 years NuvaRingV, an intravaginal ring made from polyethylene-vinyl
R

Company Population Organon Organon

council USA Inc. USA Inc.
Status in USA Discontinued Discontinued Prescription
Initial U.S. Approval 1996 2001 2001

EVA: Ethylene Vinyl Acetate.
#
Dimethylsiloxane/Methylvinylsiloxane.
development of longer-actingg contraceptive by using a higher
amount of active agent in each unit of administration and/or
imposing changes to the active agents’ structure and/or changing
the route of administration (Soo et al. 2008; Sedgh et al. 2016).
Considering these approaches, high doses of some formulation
never met the criteria for marketing as they could not be
removed when intended (Halpern et al. 2015) and Due to monet-
ary limitation and technical problems, among the hundreds of
synthesized compounds, only levonorgestrel butanoate (LNG-B),
made its way to clinical trial (Benagiano et al. 2012).
To produce the medium/long- acting reversible contraception,
the intrauterine devices, and contraceptive implants were
investigated.
Reportedly, more than one in a tenth women population in
the US are using contraceptive loaded implants (McNicholas et al.
2017). Table 1 shows the characteristics of the popular contracep-
tive implants. There are two main reasons for increasing contra-
ceptive implants popularity; first, they are easy to use so suppliers
are inclined to work on it, and second, they are successful in
pregnancy prevention and elimination of non-adherence risks
(Richards et al. 2017).
Nowadays scientists believe that implants are able to deliver
contraceptives for about 6 months or more by using special poly-
mers like poly(lactic-co-glycolic acid), PLGA; polycaprolactone,
PCL; poly anhydrides and even porous silicon (Sutherland et al.
2011; Halpern et al. 2015). Accordingly, many contraceptive
implants have been proposed. Only a few are mentioned here.
NorplantV, for instance, six silicon rods loaded by levonorges-
R
trel, that release in over 5 years, was marketed for almost 18 years
(from 1990 to 2008) (Croxatt 2002; Friend 2016).
JadelleV, 75 mg levonorgestrel-releasing two cylindrical
R
implants, is another contraceptive implant licensed for 5 years use
(Friend 2016). As reported by Roke et al., aside from the eighteen
percent, there was a high satisfaction through the first year of use
in the studied population (Roke et al. 2016). Although it reported
having almost the same bleeding pattern as NorplantV, bleeding
R
problem (prolongation or deregulation) was the prime reason for
premature implant removal (Croxatt 2002; Hickey and
d’Arcangues 2002).
ImplanonV, ethylene-vinyl acetate loaded by 68 mg etonoges-
R
trel, could prevent pregnancy for about 36 months after insertion
(Sutherland et al. 2011; Richards et al. 2017). Its advantage over
other contraceptive implants is that it contains progesterone per
se as an active agent (Friend 2016; Richards et al. 2017) so it can
be administered to women who are breastfeeding. It is beneficial
for postponing pregnancy since its effect and side-effect will dis-
appear after its removal (Bhatia et al. 2011; Balogun et al. 2016;
Duvan 2017).
acetate, could deliver 15 micrograms Ethinyl estradiol and 120
micrograms etonogestrel per day for 3 weeks.
Several multipurpose systems have also been under evaluation.
A polyurethane base intravaginal rings have been designed for
the delivery of the contraceptive and antiviral drug by a single
device. The thermoplastic polyurethane ring loaded by levonor-
gestrel and tenofovir and evaluating in phase I clinical trial (Clark
et al. 2014).
Another polyurethane intravaginal ring was designed for sus-
tained delivery of hydroxychloroquine, claiming that it could pre-
vent HIV transmission between (Chen et al. 2014).
A tenofovir alafenamide loaded PVA-coated silicone system
have been investigated subcutaneously in preclinical, by Oak
Crest Institute of Science, to prevent HIV and treat AIDS.
Vaginal rings could also be used in other situation like vaginal
dryness. A glycerin-based ring designed for such purpose.
Although the current designed system does not contain any
drugs or hormones, however, it could be loaded with some as
needed.
Inserting contraceptive-loaded implant enjoys the first place of
intention of their users for continuation of their treatment, how-
ever, there are some women who request for early withdrawal of
implant, most of them admitted that they were not satisfied with
other ways of administration as well and they had chosen implant
because their physician or health consultant proposed no alterna-
tives apart from implant (Lunde et al. 2017).
In general, implants are seemed to find their ways in women’s
health, to benefit and satisfying users as they desired.
Neuropsychological implants
In case of psychotic disorders, most patients required lifetime
treatments. However, sticking to the individual drug regimen is
the major problem. In schizophrenia, for instance, it was reported
that about 35% of patients withdraw drug consuming in less than
42 days. This number would increase to 74% within 24 months
(Rabin et al. 2008; Amann et al. 2010). Considering the conse-
quence of dropping the treatment in such patients, scientists are
seeking the solution which does not require daily drug adminis-
tration since the 1960s (Siegel 2005).
One solution is the depot injections; however, it only confined
to a certain group of drugs like those which could be esterified
by decanoate. Beside this limitation, there is no turning back
once it injected (Bhatia et al. 2011; Clark et al. 2014).
Implants are considered as another alternative not requiring
any derivatives form of the parent drug. Eluding the gastrointes-
tinal tracts side effects, reducing the pain accompanied depot
injections, and its possible removal in case of need are the
desired characteristics of this system encouraging patients adher-
ence to treatment (Konkle et al. 2003; Navitha et al. 2014; Park
et al. 2018).
In the case, as mentioned earlier, i.e. schizophrenia, the
implant of haloperidol was investigated in rodents. Circular pellets
implants were designed using variable compositions of PLGA
122 Z. MOHTASHAMI ET AL.
copolymers releasing haloperidol in five months. The implant was
designed in the reservoir form, and in case of need, it can be
removed easily (Siegel et al. 2002). Investigating the PLA implants
in rabbits has suggested the possibility of an annual delivery sys-
tem in such cases (Metzger et al. 2006).
Risperidone loaded non-biodegradable thermoplastic polyur-
ethane implants were designed by Endo & Braeburn
Pharmaceuticals as schizophrenia maintenance treatment for
6 months. Safety and efficacy of these implants are still under
investigation in phase IIb of the clinical trial. Besides, some risperi-
done loaded in situ microparticle formulations were studied to
provide safe and effective long-term therapy (Navitha et al. 2014;
Fellner 2017).
Studying the risperidone loaded implants manufactured with
the various compositions of PLGA copolymers showed that drug
could release from PLGA 75:25 in 120 days which was 3 times lon-
ger than PLGA 50:50. The absence of burst release in the in vivo
studies, suggests the success of the design delivery system at
some part (Rabin et al. 2008).
A neurological disorder like Alzheimer’s disease, often accom-
panied by psychotic problems. The fact that patients affected by
dementia would likely forget the drug consumption and probably
required other drugs like anti-hypertension medicines, considering
their age; their drug regimen could be complicated. The condition
might be deteriorated in the higher stage when patients face eat-
ing and swallowing problems (Guo et al. 2015; Vakilinezhad
et al. 2018).
Denture implants called Intelli Drug have been designed;
Using the advantages of implants for long- term therapy and
iontophoresis for drug transport through barriers. Using ionto-
phoresis, galantamine, could buccally transport from an implant
located in the mouth and be used in treating Alzheimer’s disease
(Moscicka et al. 2007).
Another type of implants, i.e. encapsulated cell bio delivery,
was also investigated for the treatment of Alzheimer’s disease.
NsG0202 implant, the implants loaded with genetically engi-
neered human cell line producing nerve growth factor, was
studied in a clinical trial for their applicability. Its safety and NGF
secretion in 12 months suggested its possible use not only in
Alzheimer’s disease but also in other neurosurgical situations
(Tuszynski et al. 2005; Wahlberg et al. 2012).
Epilepsy, as another disorder involving the central nervous sys-
tem, is afflicting 0.5-1% of the world population. Despite the suc-
cess of some medications in controlling the symptoms, side
effects, and trouble in reaching the brain hindered their effective-
ness. Valproate loaded PCL implants have been investigated as
local and long delivery systems when they surgically implanted in
the brain. Reducing the morbidity and increasing the life expect-
ancy, they seemed to work well enough for further investigations
(Rassner et al. 2015).
In another investigation, adenosine loaded microspheres were
embedded in silk scaffolds and investigated as adenosine aug-
mentation therapies for epilepsy treatment in the rat model.
Adenosine daily dose of about 1000 ng was effectively suppressed
seizures (Wilz et al. 2008; Bennewitz and Saltzman 2009).
Thyrotropin, the untraditional antiepileptic agent, were also
formulated as an implant. Releasing in almost 50 days, the kin-
dling procedure was reduced so as the seizures (Bennewitz and
Saltzman 2009).
Phenytoin loaded ethylene-vinyl acetate implants were also
investigated. Drug calculated to be released in 3.5 years; however,
in vivo studies in rat carried out for a year, and significant seizure
reduction was observed (Tamargo et al. 2002).
In general, implants are widely investigated for mitigating the
symptoms of neuropsychological disorders. The importance of
controlling such situation motivated the scientist to pursue
this way.
Opioid deterrence/pain killer’s loaded implants
Drug abuse and addiction have become global pitfall. Using illicit
substances, not only harmed addicted ones psychologically and
physically but also brought social problems to the people around
(White et al. 2009; Gordon et al. 2017).
Many scientists have been focused on treating these patients
manipulating the involved receptors; take naltrexone, for instance,
which is used as an opioid receptors’ antagonist. Although the
oral formulation is available; however, the lack of patients’ compli-
ance usually leads to treatment failure (Hulse et al. 2005; Iyer
et al. 2007; Kunøe et al. 2010). Different types of implantable for-
mulations were studied since 1997 to keep naltrexone in thera-
peutic level over a long period. Investigated naltrexone implant
seemed to be effective in treating the opioid addiction and also
in preventing overdosing; a common experience to the addicted
individuals; by providing 2 ng/ml of naltrexone in the blood circu-
lation for about six months (Stotts et al. 2009; Fareed et al. 2011;
Marienfeld et al. 2014).
Buprenorphine, a partial agonist of m receptors, is used sublin-
gually for treatment of heroin addiction. Its 15 min administration
and also its consult requirement with physicians or pharmacists
for each use, often lead to patients reluctant to continue their
treatment procedure. ProbuphineV, buprenorphine loaded
R
Ethylene-vinyl acetate subcutaneous implant designed by Titan
Pharmaceuticals, is able to keep constant drug level for six
months. Minor withdrawal symptoms and no serious safety issues
beside trivial response on implant insertion site in some patients,
make the designed implant as a golden alternative and valuable
substitution for sublingual formulation (Stotts et al. 2009;
Rosenthal et al. 2016; Barnwal et al. 2017).
Opioid advantages in patients suffering from chronic pain
could not be hindered by its disadvantages above. Anyhow, the
presented administration routes should be reconsidered as trans-
dermal absorption varies by body temperature; buccal formula-
tions albeit expensive have short-term effect; intravenous
administration demands patient hospitalization, and intraspinal
administration requires a particular operation. Implants formula-
tions are considered a potential alternative.
Hydromorphone loaded thermoplastic polyurethane implants
have been investigated subcutaneously to use in cancerous
patients or in chronic pain associated with HIV/AIDS- induced
neuropathy. Zero-order drug release kinetic for one to three
months without any abruption is expected. The great potency of
hydromorphone, in comparison with morphine, demands a tinier
implant than morphine pump (Lesser et al. 1996; Grossman and
Roberts 2011).
Lidocaine loaded silicone implant was designed to deliver dir-
ectly to the bladder of patients bearing interstitial cystitis. This
LiRIS program is currently in phase II of a clinical trial.
Following such investigations, pain pumps or Intrathecal drug
delivery systems have been proposed. Giving the medication dir-
ectly to the spinal cord through the catheter has its complica-
tions. So, it was maybe an option only when other methods failed
to relieve the patient’s chronic symptoms. The pump has a drug
reservoir holding the medicine and releases it in a programmable
manner. Reservoir pump could be refilled or even removed as
needed. Since the drug directly delivered to the cerebrospinal

fluid, it bypasses the oral path will be effective enough to allevi-
ate the pain (Coffey et al. 1993; Winkelmuller 1996; Campos and
Pope 2018; Carvajal et al. 2018; Kim et al. 2018).
SynchroMedV, V is a programmable peristaltic roller system
R R
pump made of silicone and titanium approved by FDA for deliv-
ery of morphine and ziconotide as pain management or baclofen
for muscle spasticity. This system generated millions of dollars
each year since it was marketed in 1998, but in 2015 it had been
recalled claiming the patient safety concerns. Another program-
mable pump, Prometra pump, has also approved by FDA for mor-
phine delivery in pain management. By using a driving force of
pressurized gas chamber, low energy requires for the system.
Hence the battery needs to be surgically replaced in a 10-year or
so. MedStream pump is another programmable pump for baclo-
fen delivery in muscle spasticity treatment with the FDA approval
using the compressed gas for drug delivery. Using the negative
pressure reservoir, another programmable implantable system,
Medallion, is designed and currently evaluated in the clinical trial.
Drug delivery by the intrathecal delivery routes seemed to be
effective in controlling drug addiction and relieving chronic pain.
Since it could directly deliver the drug to the spinal fluid and its
receptors, the intrathecal drug delivery reduces the administration
of the oral or transdermal opioids. However, each delivery pump
has its advantages and disadvantages considering its mechanism
of action. There are many advances to be achieved in this field,
and there are many investigations still going on to prove their
safety and efficacy.
Peptide-loaded implants
There is no demand for explaining the critical effect that peptide
and protein have brought to the medical field. These natural com-
pounds considered to be the key treatment in most diseases;
however, their sensitivity blocked the way.
Protein’s formulations encounters tremendous challenges as
they are vulnerable to environmental stress, high temperature,
changing pH, exposing to surface-active agents and organic sol-
vents (Jain et al. 2015; Khan et al. 2015); not to mention their
degradation in gastrointestinal condition, restricted absorption
(Agarwal and Rupenthal, 2013), short eliminating time in body
(Wildemann et al. 2004; Kempen et al. 2008) and immune-stimu-
lating characteristics (Horiuchi and Winter 2015).
Despite the various efforts conducted in protein formulating in
oral form, so far injections considered as a well-suited rout of
administration. The high frequency of injections resulted from the
short half-life of these compounds, not only reduce patient’s com-
pliance but also may cause side effects like lipodystrophy
(Agarwal and Rupenthal 2013).
In order to reduce the injection frequency and prolong the
release of the active substance, many formulations of pellet,
microsphere, or insertion have been conducted (Stankovic et al.
2013). Despite the delicate structures of proteins which restrict
most formulations, implants are considered as a potential option
for their delivery (Agarwal and Rupenthal 2013).
Owing to all the restrictions of designing an implant formula-
tion, some crucial factors should be summed up for proteins.
Preserving protein’s stability, their conformation, and specific sites
of action, are one of the major concerns (Appel et al. 2006;
Stankovic et al. 2015).
Due to the presence of different functional groups on their
surfaces, proteins could be susceptible to participate in reactions
with polymeric substances. As an example, bovine serum albumin,
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 123
BSA, would thioesterically bond to PLGA, forming an insoluble
agglomeration (Ghalanbor et al. 2012, 2013).
On the other hand, the hydrophilic characteristics of polymer
and protein should be matched to some extents. For instance,
hydrophobic polymers like poly (e-caprolactone) (PCL) are not a
suitable option for hydrophilic proteins. In such cases, hydrophilic
moieties like PEG could be added to result in the better loading
of proteins and also swellability of polymers, providing prolong
and stable diffusion of active agents through the time (Stankovic
et al. 2015).
Stankovic et al. claimed that hot-melt extrusion could be a
suitable choice for preparation of protein loaded implants
(Stankovic et al. 2013). No solvent requirement, appropriate mix-
ing process, and a high production rate are benefits of this sys-
tem (Stankovic et al. 2013). However, the rising temperature is of
concern (Ghalanbor et al. 2013; Rajagopal et al. 2013).
Despite all these difficulties and considerations, many efforts
have been put into formulating the protein-loaded implants.
Diabetes is one of the diseases that could be controlled by
protein administration. Implantable delivery systems have been
investigated for the monitoring and treatment of these patients.
Some subcutaneously implantable sensors have been commer-
cialized for continuous glucose monitoring. Dexcom’s G4
PlatinumTM, Medtronic’s EnliteV, and GlySens ICGMTM are some
R
examples.
There are some implants for diabetes treatment, as well. In the
early 1970s, the implantable pumps were introduced to the clin-
ical field. They were used liquefied Freon to continually delivering
the drugs. In the evolution process, pumps were advanced to be
controlled electronically.
A non-biodegradable implantable system, ITCA 650, was
designed to treat type II diabetes. ITCA 650 is a DUROSV implant
R
technology, an osmotic pump of cylindrical titanium alloy releas-
ing exenatide, a glucagon-like peptide-1 receptor agonist, through
a semipermeable membrane at a steady level for 12 months.
Exenatide has also been loaded in Delpor’s titanium implant-
able device. Beside Diabetes, Delpor’s system has been investi-
gated for drug delivery in bipolar disorder, growth hormone
deficiencies, and hepatitis C.
NanoPortalTM is another titanium implant designed for exena-
tide delivery in type II diabetes.
Minimized Medtronic Insulin delivery pump, Medtronic
Synchromed, is a programmable peristaltic titanium pump which
was designed for delivering insulin itself.
In an advanced way, biocapsules were designed. They have
contained the pancreatic islet cells, producing and delivering insu-
lin. A subcutaneous implant, VC-01TM, was developed using
ViaCyte’s EncaptraV drug delivery system to deliver human embry-
R
onic stem cells (pancreatic PEC-01TM cells) for treatment of type I
diabetes (Borges 2016).
Implants were also evaluated for immunization. Pellets of
ethylene-vinyl acetate loaded by bovine serum albumin as anti-
gen was evaluated for effective immunization. Continuous admin-
istration of antigen estimated to enhance the immune response.
There are various effects for designing the other peptides and
proteins loaded implants. Stability of somatostatin analog has
been studied in polylactic acid implants (Rothen-Weinhold et al.
1999). PLGA in situ forming implants were evaluated to prolong
plasma half-life of thymosin alpha 1, an immune-enhancing agent
in chemotherapy (Liu et al. 2010). Leuprolide loaded titanium
alloy implants were designed for the treatment of prostate cancer
(Wright et al. 2001). The effect of the dental implant of titanium
covered by chitosan-gold nanoparticle and loaded with insulin-
124 Z. MOHTASHAMI ET AL.
like growth factor was evaluated on the osteogenic disorder in rat
(Bhattarai et al. 2015).
This list is expanding daily as implantable systems have shown
promises in keeping the peptide’s stability and bypassing the bar-
rier on its way to the target.
Ocular implants
Present of various anatomical and physiological barriers in the
eye makes ocular drug delivery a bit challenging. Topical eye
products are most effective in ocular anterior segment diseases,
e.g. keratitis or anterior uveitis; however, drugs often could not
reach their therapeutic concentration in posterior segments
(Vemulakonda et al. 2008; Wang et al. 2013).
Posterior segment diseases directly impact the patient’s vision.
It was estimated that about 285 million people become visually
impaired or blind, with an increasing rate of at least seven million
per year. That’s why treating such diseases become a health con-
cern (Yasin et al. 2014).
Currently, in such cases, i.e. diabetic retinopathy, neovascular
age-related or macular degeneration, intravitreal injection is an
available treatment. However, such a method is limited due to
the risk of severe adverse reactions in recurrent injections, includ-
ing retinal detachment, endophthalmitis, vitreous hemorrhage,
cataract formation, and rise of intraocular pressure with cortico-
steroid use.
Sustained delivery systems could devoid these adverse effects.
Delivery systems like implants and inserts have been studied to
reduce frequent intraocular injections, increasing the drug con-
centration in targeted ocular tissues, and improving patient com-
pliance (Villanueva et al. 2016).
Multiple drugs- loaded PLGA implants were designed for intra-
ocular management of proliferative vitreoretinopathy. These
implants consisted of 5-fluorouridine, triamcinolone, and human
recombinant tissue plasminogen activator (Zhou et al. 1998).
Ganciclovir loaded PLGA implants, reported by Noriyuki Kunou
et al. (1995) were seemed to be efficient in the long- term deliv-
ery of Ganciclovir for treatment of cytomegalovirus retinitis.
SurodexTM, a rod-shaped biodegradable matrix implant, fabri-
cated from PLGA and hydroxypropyl methylcellulose (HPMC) and
provides a constant release rate of dexamethasone (60 lg over
7–10 days) from capsular bag to both anterior and posterior
chambers. The implant is inserted in the anterior chamber follow-
ing cataract surgery to control postoperative inflammation
(Chennamaneni et al. 2013).
OzurdexV is a biodegradable intravitreal implant consisting of
R
0.7 mg dexamethasone within a solid, rod-shaped PLGA copoly-
mer matrix which was approved for the treatment of macular
edema associated with retinal vein occlusion edema, secondary to
diabetic retinopathy uveitis. The drug pellet inserted into the vit-
reous by a single-use applicator. The patient’s comfort during six
months of its usage, make this implant an excellent potential for
the treatment of increasing chronic and age-related ocular dis-
eases (Lee et al. 2010; Villanueva et al. 2017).
Poly (methylidene malonate) scleral discs were manufactured
as a replacement for repeated intravitreal injection of KenacortV,
R
triamcinolone acetonide. These well-tolerated implants were able
to release significant concentrations of triamcinolone acetonide in
the vitreous and the sclera throughout five weeks (Felt-Baeyens
et al. 2006).
The VerisomeV is a biodegradable sustained-release intravitreal
R
drug delivery platform, releasing the therapeutic level of triamci-
nolone acetonide up to 1 year (Wang et al. 2013).
A Novadur-based implant evaluated for the delivery of brimo-
nidine tartrate in patient suffering from retinitis pigmentosa, glau-
comatous optic neuropathy, age-related macular degeneration,
and rhegmatogenous macula-off retinal detachment
(Chennamaneni et al. 2013).
DurasertTM is a biodegradable implant, inserted in the sub-con-
junctival space to release latanoprost for ocular hypertension and
glaucoma.
Ocusert, pilocarpine loaded alginic acid reservoir surrounded by
ethylene-vinyl acetate release controlling membrane, was designed
for controlling intraocular pressure (Mohammed Zaki et al. 2012).
LacrisertV was introduced as a rod-shaped biodegradable oph-
R
thalmic insert consists of hydroxypropyl cellulose (HPC) that
administered into the inferior cul-de-sac daily to treat the dry-eye
syndrome. Hydroxypropyl cellulose release slowly from formula-
tion and act as a moisturizer, thickening the precorneal tear film
and prolonging tear breakup time. This formulation can be self-
administered up to twice daily using a specially designed applica-
tor. The patients find it favorable over traditional artificial tears
(Lee et al. 2010).
Vitrasert, the first FDA-approved non-biodegradable scleral
implant, consists of an inner permeable layer of polyvinyl alcohol
and the outer impermeable coating of ethylene-vinyl acetate. It
found to be effective for 5 to 8 months treatment of CMV retinitis
in AIDS patients.
The first intravitreal implant/insert for the treatment of chronic
noninfectious uveitis, Retisert, consists of PVA and silicon lamin-
ate. The system could release 0.3-0.4 mcg fluocinolone acetonide
per day for approximately three years (Wang et al. 2013).
IluvienTM is a non-biodegradable implant, effective in chronic
diabetic macular edema by releasing fluocinolone acetonide
through a poly(vinyl alcohol) membrane for 36-month once
injected into the vitreous (Mansoor et al. 2009).
In advance, on Demand Therapeutics (ODT) has developed a
light-responsive implant for vitreous delivery. In stimuli-responsive
systems, drug release would be controlled by external stimuli
such as changes in temperature, light, pH, electric current, mag-
netic field, or ultrasound (Wang et al. 2018).
The translucent nature of the cornea and lens makes the light-
activated systems applicable for drug delivery to the eyes. By
applying specific wavelength of EMR on the surface of the
implant for a short time, the impermeable outer membrane
scratched and the containing drug released. This light-activated
type of implant offers a platform for controlled delivery of some
types of medications in the treatment of posterior segment dis-
eases especially when different drug concentrations are required
at various time intervals depending on the disease state
€ undag
(Ust€ -Okur et al. 2015; Sepahvandi et al. 2016). Table 2
shows the characteristics of ocular implants.
Cardiovascular implants
There are various cardiovascular medical devices like artificial
heart valves, pacemakers or coronary stents, designed for implant-
ing in the patient’s body.
Bare-metal coronary stents are considered preferred therapeutic
method over the traditional ones; i.e. balloon angioplasty and athe-
rectomy; as they could reduce the restenosis (Serruys et al. 2006).
Although reducing the restenosis risk, patients were still vul-
nerable to neointimal tissue growth, narrowing, or blocking the
implanted artery. In order to eliminate this problem, drug-eluting
stents were designed to deliver antiproliferative drugs directly to
the arterial wall (Hwang et al. 2001).

Table 2. The characteristics of the ocular implants.
Implant Rout of
name administration Active ingredient Indication
Vitrasert Scleral Ganciclovir CMV retinitis in AIDs patients
Retisert Intravitreal Flucinolone Chronic noninfectious uveitis
Ozurdex Intravitreal Dexamethasone Macular edema following
BRVO or CRVO,
noninfectious posterior
uveitis
Iluvien Intravitreal Fluocinolone Chronic DME
I-vation Intravitreal Triamcinolone DME
Surodex Anterior chamber Dexametazone Postoperative
Inflammation
NT-503 Intravitreal Ciliary neurotrophic AMD#, Retinitis pigmentosa
factor

diabetic macular edema.
#
age related macular edema.
The first approved of such stents was loaded with sirolimus;
called sirolimus-eluting Cypher stent. Soon after, Taxus stent,
paclitaxel- loaded stents got the FDA approved too.
As a foreign object, physiological reactions to the stent are
predictable. Thrombosis formation could be suppressed by anti-
clotting drugs, often given orally (Finn et al. 2007). However, the
major concern is the healing of the arterial endothelial layer,
which prevented by anti-proliferative drugs loaded in the stent,
prolonging patients risk of thrombosis. So beside its benefits,
there are some considerations too (Bavry et al. 2006; Daemen and
Serruys 2007; Yamamoto et al. 2011).
Many resorbable stents have also been studied using poly lac-
tic acid, polycarbonate, or magnesium absorbable stent (Ormiston
and Serruys 2009; Nikam et al. 2014).
Orthopedic implants
An orthopedic implant is a medical device manufactured to
replace a missing joint or bone or to support damaged ones.
They mainly fabricated from stainless steel or metal alloys (titan-
ium, magnesium) for conserving their strength and the plastic
coat that acts as artificial cartilage. The poor osteoconductivity of
metallic implants and the surrounding fibrous tissue membrane is
counted as a serious threat for the implant’s long activity.
However, coating CaP on the implant has been demonstrated to
recruit a bioactive fixation after surgery and prolong their activity.
PMMA, a non-biodegradable polymer, is frequently used in
Orthopedics as bone cement since 1958 to anchor joint replace-
ments. Although adverse or allergic reaction rarely occurred, how-
ever, due to its non-degradable characteristics, it could not
exhibit optimal release kinetic as a drug carrier, reportedly as an
antibiotic carrier (Kluin et al. 2013).
A few biodegradable delivery devices, consisting of collagen
fleeces, calcium sulfate, and calcium phosphate are commercially
available which release the drug within a day.
Stable or long-lasting metal implants such as macroporous
stainless steel or macroporous titanium were also evaluated. The
results have shown their mechanical support and ability to control
prolonged drug delivery at target tissues. It was demonstrated
that a hollow titanium implant perforated with microholes could
be delivered dexamethasone up to 7 weeks after its implementa-
tion (Andani et al. 2014; Gimeno et al. 2015).
Studied have shown the possibility of new bone formation in
the gap between the implant and host bone, using the alendro-
nate loaded porous tantalum implant coated with microporous
CaP (Zou et al. 2003) or zoledronate loaded titanium implant
coated with Hyaluronic acid (Kettenberger et al. 2015) or
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 125
Duration of action Company
5–8 months Bausch & Lomb FDA approved (19960
Up to 3 yrs Bausch & Lomb FDA approved (2005)
Up to 6 month Allergan FDA approved (2009)
3 yrs Alimera Science FDA approved (2014)
2 yrs SurModics Phase 2b clinical trials
7–10 days Allergan Phase 3 clinical trials
Up to 12 months Neurotech Phase 2 clinical trials
designing growth factor containing implant (Lo et al. 2012;
Brudno and Mooney 2015).
In recent years, biodegradable magnesium alloys have received
too much attention as smart implants in orthopedic applications.
Although magnesium implants could stimulate the formation of
new bone, however, it could highly be degraded (Chen
et al. 2014).
The MAGNETIC screw is the first commercially available mag-
nesium-based orthopedic product which has obtained Europe CE
mark for medical applications.
To stimulate osteoblast proliferation and differentiation,
exogenous growth factor was loaded in CaP- coated implants.
These implants have shown to induce osseointegration, renovat-
ing mobility, reducing pain, and improving the quality of life in
millions of people each year (Bose and Tarafder 2012).
Despite all the achievements in this field, the susceptibility of
the implant to surface colonization make it a major concern.
Many efforts have conducted to solve this problem. Some has
been focused on the passive coating of the implant to alter its
physiochemical surface properties, producing anti-adhesive surfa-
ces for bacteria. Crystalline anatase-TiO2, hydrophilic polymetha-
crylic acid, polyethylene oxide, and protein resistant polyethylene
glycol are among the coating materials.
Some researchers have designed implants by micro- or nano-
structure surfaces that could mimic natural surfaces; less suscep-
tible to bacterial adhesion (Zhang 2008; Gimeno et al. 2015).
As an example, a titanium alloy implant has been coated with
doxycycline loaded biodegradable Polymer-Lipid Encapsulated
MatriX (PLEX). The coated layer could be used as a prophylactic
strategy against implant-associated osteomyelitis.
Another antibiotic releasing system, Gentamicin-loaded bone
cement beads, shows a reduction in acute and chronic infections
even in the most severe fractures (Eke et al. 2015).
Implantable devices have a huge market in the orthopedic
field. In most cases, they are not loaded with any active substan-
ces, but in new strategies, drug loading is somehow a preferable
option.
Dental implants
Periodontitis is a highly dominant, chronic inflammatory disease
affecting 47% of the US adults and 64% of people older than
65 years. Periodontitis is characterized by a broadminded loss of
alveolar bone and periodontal ligament, and formation of peri-
odontal pockets, leading to tooth loss if remains untreated (Silva-
Boghossian et al. 2009, 2013).
126 Z. MOHTASHAMI ET AL.
Poor drug penetration into the periodontal pockets and rapid
elimination of the drug by gingival crevicular fluid from the site
of action are the main challenging factors in the treatment of
periodontitis. Biodegradable in-situ forming implants seemed to
be desirable systems for drug delivery to these areas. However, its
adherence to human tissue is the matter of concern as the signifi-
cant flow of gingival crevicular fluid could often result in the
uncontrolled ejection of implant fragments from the periodontal
pockets (Tomme et al. 2008).
However, an in-situ forming implant formulation based on
poly (lactic-co-glycolic acid) and hydroxypropyl methylcellulose
has been proposed which slowly released minocycline once
injected into patients’ periodontal pockets. The designed in-situ
forming implant formulation exhibit a promising potential in peri-
odontitis treatment (Silva-Boghossian et al. 2009, 2013).
Local administration of fluoride antibacterial and antibiotics is
another dental application of implants. Dental cement could be
blended with stannous fluoride to achieve fluoride sustain release.
Hydroxyethyl methacrylate and methyl methacrylate copolymer
hydrogel could be used for manufacturing buccally attached
hydrogels with the ability to release fluoride at a specific rate
(Mohammed Zaki et al. 2012).
The release pattern of implants
Considering polymer and drug properties, implants characteristics
and implementation environment, different mechanisms are
involved in drug release.
In biodegradable polymeric implants, polymer weight and con-
centration, the swelling ability, presence of excipients acting as
surfactant or pore formers, and implant dimension determine the
release rate and mechanism (Soo et al. 2008; Kreye et al. 2011;
Aqil et al. 2012). Polymeric erosion by hydrolysis or bioactive com-
ponents, water absorption, drug diffusion, and desorption of
weakly bonded active agents are among the release mechanism
for such systems (Herrmann et al. 2007; Tobias et al. 2010;
Hamlekhan et al. 2015).
In non-biodegradable implants like an osmotic pump, factors
such as orifice diameter and its position, the viscosity of formula-
tion and osmolality of the osmotic part in formulation take a part
in determining the release rate and mechanism. Any variations in
the aforementioned items can insert fluctuation in drug delivery
systems; for example, large orifice could lead to burst diffusion of
the active substrate (Tobias et al. 2010; Hill et al. 2012; Thakur
et al. 2014).
There were some attempts to predict the kinetics of drug
release from implants quantitatively. One of which, predict the
influence of dimensions in lipid-based implants. Different release
period could be acquired by different formulation based factors
like various lipids by achieving the mathematical theory for drug
release pattern. In such lipid-based implants, diffusion reported to
be the dominant mechanism regardless of the drug’s hydrophil-
icity properties (Allababidi and Shah 1998; Kreye et al. 2011).
Implants preparation factors also affect the release mechanism.
As it was reported, increasing the imposed pressure on the
implant component while producing, would decrease the released
fraction of active agent significantly through time (Herrmann
et al. 2007).
On the other hand the use of hydrophilic excipients like PEG
in the hydrophobic matrix, could increase the drug release rate
by increasing the connection of pores network, involving another
release mechanism beside diffusion (Herrmann et al. 2007).
Drug loading amount would also affect the release. It was
shown that the advent of hollow space or porosity after drug
release would increase permeability; therefore, increasing the
release rate is predicted (Guse et al. 2006).
The desired release pattern for implants would be the drug
delivery in a zero-order or time-independent manner (Krenzlin
et al. 2012; Thakur et al. 2014). However, some type of implants,
like those produced by phase inversion, mostly presented a burst
release followed by a slow-release stage. Such in situ systems
often have a final rapid release stage causing by polymer degrad-
ation (Thakur et al. 2014).
In advance, smart systems, programmed implantable pump or
self-regulated systems, were designed to achieve precise kinetics
of release.
Implants drawbacks
Despite the unrivaled benefits that implants could bring to the
pharmaceutical field, its mounting in the body comes with some
complications. Invasive implementation and removal may be
accompanied by scar formation and uncomfortable feeling at the
insertion site or surgery-related complications which leads to
reduce patients’ compliance. Regional damage like tissue inflam-
mation or infection, possible implant dislocation, and danger of
drug delivery failure are also among their disadvantages (Gulati
et al. 2012; Trajkovski et al. 2012; Hellegaard and Hansen 2014;
Weiser and Saltzman 2014).
The importance of these pitfalls would increase when the brain
is engaged because its tissue inflammation along with the pres-
ence of mechanical stress and limitation in signals transmission
could lead to unconsciousness, instability, and death (Kozai et al.,
2015). On the other hand, a high concentration of drug at the
brain’s tumor tissue could cause bleeding, headache, and even
convulsion (Bastiancich et al. 2016).
Implant’s infection is another serious challenge. It can arise
from the bacteria presented on its own surface or on the spot of
surgery and skin, causing immediate infection. Besides, there is a
competition between human cells and infecting microorganisms
in attaching to the implants. The phagocyte activation and cyto-
kines liberation would increase the possibility of bacterial success
in the attachment battle with human cells. Late implant’s infec-
tion could also cause by the persistence of small bacterial accu-
mulation on the peri-surgery tissues, e.g. provisional infection on
urinary tract (Singh and Chye 1998; Hickok and Shapiro 2012;
Seng et al. 2015).
In any case of implant’s infection, installation of new implant
instead of the infected one, i.e. arthroplasty, would become more
susceptible to infection than the first implant (Hickok and
Shapiro 2012).
To make the implant resistant to bacterial infection, many fac-
tors should be considered. Material composition, surface quality,
hydrophilicity, implant’s forms and dimensions are among the
critical factors (Hickok and Shapiro 2012; Shemesh et al. 2015).
As a foreign object, implants are susceptible to provoke the
body’s inflammatory reactions. Improving implant flexibility, form-
ability, and surface properties would lead to its acceptance in the
body. Loading implants with anti-inflammatory agents, despite
their disadvantages, could alleviate the inflammation reaction
(Kozai et al. 2015; Li et al. 2015).
Many attempts have been conducted to reduce the problems
facing implants’ usage. However, they should be encountered
individually.

Conclusion and perspective
Considering the rate of unwanted pregnancies, growing incidence
of cancer, chronic pain, and systematic diseases and their compli-
cations along with the ability of implantable drug delivery sys-
tems to address therapeutic control for such situations, the
expanding market for implantable systems is forecasting. Such
systems offer a potential solution to most of the limitations of
conventional methods and signify useful devices particularly suit-
able for long term drug delivery. Although these systems are con-
sidered effective in some aspects, however, the system failure
forcing the product recall is one of the global market concerns.
Scientists hope for self-regulated on-demanded systems but what
will happen in the future, only time would show.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work supported by national institute for medical research
development ministry of health and medical education, I.R.Iran
Grant No: 962506.
ORCID
Ehsan Seyedjafari http://orcid.org/0000-0003-3773-2830
References
Afrooz H, Ahmadi F, Fallahzadeh F, Mousavi-Fard SH, Alipour S.
2017. Design and characterization of paclitaxel-verapamil co-
encapsulated PLGA nanoparticles: potential system for over-
coming P-glycoprotein mediated MDR. J Drug Deliv Sci Tech.
41:174–181.
Agarwal P, Rupenthal I. 2013. Injectable implants for the sustained
release of protein and peptide drugs. Drug Discov Today. 18(7-
8):337–349.
Aguilar LE, Thomas RG, Moon MJ, Jeong YY, Park CH, Kim CS.
2018. Implantable chemothermal brachytherapy seeds: a syner-
gistic approach to brachytherapy using polymeric dual drug
delivery and hyperthermia for malignant solid tumor ablation.
Eur J Pharm Biopharm. 129:191–203.
Al-Jawadi S, Capasso P, Sharma M. 2018. The road to market
implantable drug delivery systems: a review on US FDA’s regu-
latory framework and quality control requirements. Pharm Dev
Technol. 23(10):953–963.
Allababidi S, Shah JC. 1998. Kinetics and mechanism of release
from glyceryl monostearate-based implants: evaluation of
release in a gel simulating in vivo implantation. J Pharm Sci.
87(6):738–744.
Amann LC, Gandal MJ, Lin R, Liang Y, Siegel SJ. 2010. In vitro-
in vivo correlations of scalable PLGA-risperidone implants for
the treatment of schizophrenia. Pharm Res. 27(8):1730–1737.
Amsden B. 2015. Novel biodegradable polymers for local growth
factor delivery. Eur J Pharm Biopharm. 97(Pt B):318–328.
Andani MT, Shayesteh Moghaddam N, Haberland C, Dean D,
Miller MJ, Elahinia M. 2014. Metals for bone implants. Part 1.
Powder metallurgy and implant rendering. Acta Biomater.
10(10):4058–4070.
Appel B, Maschke A, Weiser B, Sarhan H, Englert C, Angele P,
Blunk T, Go € pferich A. 2006. Lipidic implants for controlled
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 127
release of bioactive insulin: effects on cartilage engineered
in vitro. Int J Pharm. 314(2):170–178.
Aqil F, Jeyabalan J, Kausar H, Bansal SS, Sharma RJ, Singh IP,
Vadhanam MV, Gupta RC. 2012. Multi-layer polymeric implants
for sustained release of chemopreventives. Cancer Lett. 326(1):
33–40.
Arsiwala A, Desai P, Patravale V. 2014. Recent advances in micro/
nanoscale biomedical implants. J Control Release. 189:25–45.
Bagherifard S. 2017. Mediating bone regeneration by means of
drug eluting implants: from passive to smart strategies. Mater
Sci Eng C Mater Biol Appl. 71:1241–1252.
Balogun OR, Adeniran AS, Adewole AA. 2016. Haematological and
biochemical effects of etonogestrel subdermal implant
(Implanon) in Ilorin Nigeria. Int J Health Sci (Qassim). 10(4):
499–506.
Barnwal P, Das S, Mondal S, Ramasamy A, Maiti T, Saha A. 2017.
ProbuphineV (buprenorphine implant): a promising candidate
R
in opioid dependence. Ther Adv Psychopharmacol. 7(3):
119–134.
Bastiancich C, Danhier P, Preat V, Danhier F. 2016. Anticancer
drug-loaded hydrogels as drug delivery systems for the local
treatment of glioblastoma. J Control Release. 243:29–42.
Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL.
2006. Late thrombosis of drug-eluting stents: a meta-analysis of
randomized clinical trials. Am J Med. 119(12):1056–1061.
Benagiano G, D’Arcangues C, Harris Requejo J, Schafer A, Say L,
Merialdi M. 2012. The special programme of research in human
reproduction: forty years of activities to achieve reproductive
health for all. Gynecol Obstet Invest. 74(3):190–217.
Bennewitz MF, Saltzman WM. 2009. Nanotechnology for delivery
of drugs to the brain for epilepsy. Neurotherapeutics. 6(2):
323–336.
Bhatia P, Nangia S, Aggarwal S, Tewari C. 2011. Implanon: subder-
mal single rod contraceptive implant. J Obstet Gynecol India.
61(4):422–425.
Bhattarai G, Lee Y-H, Lee M-H, Park I-S, Yi H-K. 2015. Insulin-like
growth factor binding protein-3 affects osteogenic efficacy on
dental implants in rat mandible. Mater Sci Eng C Mater Biol
Appl. 55:490–496.
Bhusal P, Harrison J, Sharma M, Jones DS, Hill AG, Svirskis D. 2016.
Controlled release drug delivery systems to improve post-
operative pharmacotherapy. Drug Deliv Transl Res. 6(5):
441–451.
Blumenthal PD, Voedisch A, Gemzell-Danielsson K. 2011.
Strategies to prevent unintended pregnancy: increasing use of
long-acting reversible contraception. Hum Reprod Update.
17(1):121–137.
Borges AMR. 2016. Development of subcutaneous prolonged
release of protein drugs by implants. Coimbra, Portugal:
Universidade de Coimbra.
Bose S, Tarafder S. 2012. Calcium phosphate ceramic systems in
growth factor and drug delivery for bone tissue engineering: a
review. Acta Biomater. 8(4):1401–1421.
Bota DA, Desjardins A, Quinn JA, Affronti ML, Friedman HS. 2007.
Interstitial chemotherapy with biodegradable BCNU (GliadelV)
R
wafers in the treatment of malignant gliomas. Ther Clin Risk
Manag. 3(5):707–715.
Brudno Y, Mooney D. 2015. On-demand drug delivery from local
depots. J Control Release. 219:8–17.
Campos LW, Pope JE. 2018. Intrathecal drug delivery: trialing. In:
Diwan S, Deer T, editor. Advanced procedures for pain manage-
ment. Switzerland: Springer Nature. p. 385–392.
128 Z. MOHTASHAMI ET AL.
Carvajal G, Dupoiron D, Seegers V, Lebrec N, Bore F, Dubois P-Y,
Leblanc D, Delorme T, Jubier-Hamon S. 2018. Intrathecal drug
delivery systems for refractory pancreatic cancer pain: observa-
tional follow-up study over an 11-year period in a comprehen-
sive cancer center. Anesth Analg. 126(6):2038–2046.
Chen X, Wu Q-S, Meng F-C, Tang Z-H, Chen X, Lin L-G, Chen P,
Qiang W-A, Wang Y-T, Zhang Q-W, et al. 2016.
Chikusetsusaponin IVa methyl ester induces G1 cell cycle arrest,
triggers apoptosis and inhibits migration and invasion in ovar-
ian cancer cells. Phytomedicine. 23(13):1555–1565.
Chen Y, Traore YL, Li A, Fowke KR, Ho EA. 2014. Development of
polyether urethane intravaginal rings for the sustained delivery
of hydroxychloroquine. Drug Des Devel Ther. 8:1801–1815.
Chen Y, Xu Z, Smith C, Sankar J. 2014. Recent advances on the
development of magnesium alloys for biodegradable implants.
Acta Biomater. 10(11):4561–4573.
Chennamaneni SR, Mamalis C, Archer B, Oakey Z, Ambati BK.
2013. Development of a novel bioerodible dexamethasone
implant for uveitis and postoperative cataract inflammation. J
Control Release. 167(1):53–59.
Clark JT, Clark MR, Shelke NB, Johnson TJ, Smith EM, Andreasen
AK, Nebeker JS, Fabian J, Friend DR, Kiser PF, et al. 2014.
Engineering a segmented dual-reservoir polyurethane intravagi-
nal ring for simultaneous prevention of HIV transmission and
unwanted pregnancy. PLoS One. 9(3):e88509.
Coffey RJ, Cahill D, Steers W, Park TS, Ordia J, Meythaler J,
Herman R, Shetter AG, Levy R, Gill B, et al. 1993. Intrathecal
baclofen for intractable spasticity of spinal origin: results of a
long-term multicenter study. J Neurosurg. 78(2):226–232.
Croxatt HB. 2002. Progestin implants for female contraception.
Contraception. 65(1):15–19.
Daemen J, Serruys PW. 2007. Drug-eluting stent update 2007: part
II: unsettled issues. Circulation. 116(8):961–968.
Danckwerts M, Fassihi A. 1991. Implantable controlled release
drug delivery systems: a review. Drug Dev Indust Pharm.
17(11):1465–1502.
Dash AK, Cudworth GC, 2nd. 1998. Therapeutic applications of
implantable drug delivery systems. J Pharmacol Toxicol
Methods. 40(1):1–12.
Davoodi P, Lee LY, Xu Q, Sunil V, Sun Y, Soh S, Wang CH. 2018.
Drug delivery systems for programmed and on-demand release.
Adv Drug Deliv Rev. 132:104–138.
de Fatima Pereira A, Mara da Costa V, Cristina Magalh~aes Santos
M, Maciel de A Ribeiro RI, Gabriela Silva A, Carmo Horta Pinto
F, Vieira Teixeira Vidigal P, Rodrigues Da Silva G. 2014.
Evaluation of the effects of methotrexate released from poly-
meric implants in solid Ehrlich tumor. Biomed Pharmacother.
68(3):365–368.
Dijkman GA, Fernandez del Moral P, Plasman JWMH, Kums JJM,
Delaere KPJ, Debruyne FMJ, Hutchinson FJ, Furr BJA. 1990. A
new extra long acting depot preparation of the LHRH analogue
Zoladex. First endocrinological and pharmacokinetic data in
patients with advanced prostate cancer. J Steroid Biochem Mol
Biol. 37(6):933–936.
Duvan CI. 2017. Effects of the etonogestrel contraceptive implant
(ImplanonV) on bone metabolism during lactation: a prospect-
R
ive study. J Fam Plann Reprod Health Care. 43(2):113–117.
Eke PI, Dye BA, Wei L, Slade GD, Thornton-Evans GO, Borgnakke
WS, Taylor GW, Page RC, Beck JD, Genco RJ, et al. 2015. Update
on prevalence of periodontitis in adults in the United States:
NHANES 2009 to 2012. J Periodontol. 86(5):611–622.
Ene CI, Nerva JD, Morton RP, Barkley AS, Barber JK, Ko AL,
Silbergeld DL. 2016. Safety and efficacy of carmustine (BCNU)
wafers for metastatic brain tumors. Surg Neurol Int. 7(12):
295–S299.
Fakhari A, Subramony J. 2015. Engineered in-situ depot-forming
hydrogels for intratumoral drug delivery. J Control Release.
220(Pt A):465–475.
Fareed A, Stout S, Casarella J, Vayalapalli S, Cox J, Drexler K. 2011.
Illicit opioid intoxication: diagnosis and treatment. Subst Abuse.
5:17–25.
Fellner C. 2017. New schizophrenia treatments address unmet
clinical needs. P T. 42(2):130–134.
Felt-Baeyens O, Eperon S, Mora P, Limal D, Sagodira S, Breton P,
Simonazzi B, Bossy-Nobs L, Guex-Crosier Y, Gurny R, et al. 2006.
Biodegradable scleral implants as new triamcinolone acetonide
delivery systems. Int J Pharm. 322(1-2):6–12.
Finer LB, Zolna MR. 2016. Declines in unintended pregnancy in
the United States, 2008-2011. N Engl J Med. 374(9):843–852.
Finn AV, Nakazawa G, Joner M, Kolodgie FD, Mont EK, Gold HK,
Virmani R. 2007. Vascular responses to drug eluting stents:
importance of delayed healing. ATVB. 27(7):1500–1510.
Folkman J, Long DM, Rosenbaum R. 1966. Silicone rubber: a new
diffusion property useful for general anesthesia. Science.
154(3745):148–149.
Fonseca AC, Serra AC, Coelho JFJ. 2015. Bioabsorbable polymers
in cancer therapy: latest developments. EPMA J. 6:22.
Friend DR. 2016. Development of controlled release systems over
the past 50 years in the area of contraception. J Control
Release. 240:235–241.
Ghalanbor Z, Ko €rber M, Bodmeier R. 2012. Protein release from
poly(lactide-co-glycolide) implants prepared by hot-melt extru-
sion: thioester formation as a reason for incomplete release. Int
J Pharm. 438(1-2):302–306.
€ rber M, Bodmeier R. 2013. Interdependency of
Ghalanbor Z, Ko
protein-release completeness and polymer degradation in
PLGA-based implants. Eur J Pharm Biopharm. 85(3):624–630.

Gimeno M, Pinczowski P, Perez M, Giorello A, Martınez MA,
Santamarıa J, Arruebo M, Lujan L. 2015. A controlled antibiotic
release system to prevent orthopedic-implant associated infec-
tions: an in vitro study. Eur J Pharm Biopharm. 96:264–271.
Gordon MS, Vocci FJ, Fitzgerald TT, O’Grady KE, O’Brien CP. 2017.
Extended-release naltrexone for pre-release prisoners: a
randomized trial of medical mobile treatment. Contemp Clin
Trials. 53:130–136.
Grossman R, Burger P, Soudry E, Tyler B, Chaichana KL, Weingart
J, Olivi A, Gallia GL, Sidransky D, Quin ~ones-Hinojosa A, et al.
2015. MGMT inactivation and clinical response in newly diag-
nosed GBM patients treated with Gliadel. J Clin Neurosci.
22(12):1938–1942.
Grossman SA, Roberts N. 2011. Analgesic applications for a sub-
cutaneous implant that continuously releases hydromorphone.
Eur J Pain Suppl. 5(S2):439–442.
Gulati K, Aw MS, Findlay D, Losic D. 2012. Local drug delivery to
the bone by drug-releasing implants: perspectives of nano-
engineered titania nanotube arrays. Ther Deliv. 3(7):857–873.
Guo W, Quan P, Fang L, Cun D, Yang M. 2015. Sustained release
donepezil loaded PLGA microspheres for injection: preparation,
in vitro and in vivo study. Asian J Pharm Sci. 10(5):405–414.
Guse C, Koennings S, Kreye F, Siepmann F, Goepferich A,
Siepmann J. 2006. Drug release from lipid-based implants: elu-
cidation of the underlying mass transport mechanisms. Int J
Pharm. 314(2):137–144.
Halpern V, Stalter RM, Owen DH, Dorflinger LJ, Lendvay A,
Rademacher KH. 2015. Towards the development of a longer-

acting injectable contraceptive: past research and current
trends. Contraception. 92(1):3–9.
Hamlekhan A, Sinha-Ray S, Takoudis C, Mathew MT, Sukotjo C,
Yarin AL, Shokuhfar T. 2015. Fabrication of drug eluting
implants: study of drug release mechanism from titanium diox-
ide nanotubes. J Phys D Appl Phys. 48(27):275401.
Hellegaard L, Hansen TB. 2014. Long term follow up in patients
with radiologically loose trapeziometacarpal total joint implants.
Rheumatology (Sunnyvale). S4(011):2161–1149.
Herrmann S, Winter G, Mohl S, Siepmann F, Siepmann J. 2007.
Mechanisms controlling protein release from lipidic implants:
effects of PEG addition. J Control Release. 118(2):161–168.
Hickey M, d’Arcangues C. 2002. Vaginal bleeding disturbances and
implantable contraceptives. Contraception. 65(1):75–84.
Hickok N, Shapiro I. 2012. Immobilized antibiotics to prevent
orthopaedic implant infections. Adv Drug Deliv Rev. 64(12):
1165–1176.
Hill A, Geißler S, Weigandt M, M€ader K. 2012. Controlled delivery
of nanosuspensions from osmotic pumps: zero order and non-
zero order kinetics. J Control Release. 158(3):403–412.
Hoffman AS. 2008. The origins and evolution of “controlled” drug
delivery systems. J Control Release. 132(3):153–163.
Horiuchi S, Winter G. 2015. CMC determination of nonionic surfac-
tants in protein formulations using ultrasonic resonance tech-
nology. Eur J Pharm Biopharm. 92:8–14.
Hu M, Shen Y, Zhang L, Qiu L. 2016. Polymersomes via self-assem-
bly of amphiphilic b-cyclodextrin-centered triarm star polymers
for enhanced oral bioavailability of water-soluble chemothera-
peutics. Biomacromolecules. 17(3):1026–1039.
Hulse GK, Tait RJ, Comer SD, Sullivan MA, Jacobs IG, Arnold-Reed
D. 2005. Reducing hospital presentations for opioid overdose in
patients treated with sustained release naltrexone implants.
Drug Alcohol Depend. 79(3):351–357.
Hwang C-W, Wu D, Edelman ER. 2001. Physiological transport
forces govern drug distribution for stent-based delivery.
Circulation. 104(5):600–605.
Iyer SS, Barr WH, Karnes HT. 2007. Characterization of a potential
medium for ‘biorelevant’ in vitro release testing of a naltrexone
implant, employing a validated stability-indicating HPLC
method. J Pharm Biomed Anal. 43(3):845–853.
Jain NK, Sahni N, Kumru OS, Joshi SB, Volkin DB, Russell
Middaugh C. 2015. Formulation and stabilization of recombin-
ant protein based virus-like particle vaccines. Adv Drug Deliv
Rev. 93:42–55.
z W, Szafraniec J, Kurek M, Jachowicz R. 2018. 3D printing in
Jamro
pharmaceutical and medical applications – Recent achieve-
ments and challenges. Pharm Res. 35(9):176.
Jassim-Jaboori AH, Oyewumi MO. 2015. 3D printing technology in
pharmaceutical drug delivery: prospects and challenges. J
Biomol Res Ther. 4(4):e141.
Jose PA, Gv PC. 2018. 3D printing of pharmaceuticals – A poten-
tial technology in developing personalized medicine. Asian J
Pharm Res Dev. 6(3):46–54.
Kang YM, Kim GH, Kim JI, Kim DY, Lee BN, Yoon SM, Kim JH, Kim
MS. 2011. In vivo efficacy of an intratumorally injected in situ-
forming doxorubicin/poly(ethylene glycol)-b-polycaprolactone
diblock copolymer. Biomaterials. 32(20):4556–4564.
Kasten BB, Arend RC, Katre AA, Kim H, Fan J, Ferrone S, Zinn KR,
Buchsbaum DJ. 2017. B7-H3-targeted 212Pb radioimmunother-
apy of ovarian cancer in preclinical models. Nucl Med Biol. 47:
23–30.
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 129
Kempe S, M€ader K. 2012. In situ forming implants – An attractive
formulation principle for parenteral depot formulations. J
Control Release. 161(2):668–679.
Kempen DHR, Lu L, Classic KL, Hefferan TE, Creemers LB, Maran A,
Dhert WJA, Yaszemski MJ. 2008. Non-invasive screening
method for simultaneous evaluation of in vivo growth factor
release profiles from multiple ectopic bone tissue engineering
implants. J Control Release. 130(1):15–21.
Kettenberger U, Latypova A, Terrier A, Pioletti DP. 2015. Time
course of bone screw fixation following a local delivery of
Zoledronate in a rat femoral model-a micro-finite element ana-
lysis. J Mecha Behav Biomed Mater. 45:22–31.
Khan T, Mahler H, Kishore R. 2015. Key interactions of surfactants
in therapeutic protein formulations: a review. Eur J Pharm
Biopharm. 97(Pt A):60–67.
Kim PS, Li S, Deer TR, Wallace MS, Staats P. 2018., Intrathecal drug
delivery systems. In: Manchikanti L, Kaye AD, Falco FJE, Hirsch
JA, editors. Essentials of interventional techniques in managing
chronic pain, Switzerland: Springer Nature. p. 671–681.
Kleiner LW, Wright JC, Wang Y. 2014. Evolution of implantable
and insertable drug delivery systems. J Control Release. 181:
1–10.
Kluin OS, van der Mei HC, Busscher HJ, Neut D. 2013.
Biodegradable vs non-biodegradable antibiotic delivery devices
in the treatment of osteomyelitis. Expert Opin Drug Deliv.
10(3):341–351.
Konkle ATM, Sreter KB, Baker SL, Bielajew C. 2003. Chronic paroxe-
tine infusion influences macronutrient selection in male
Sprague–Dawley rats. Pharmacol Biochem Behav. 74(4):
883–890.
Kost J, Langer R. 2012. Responsive polymeric delivery systems.
Adv Drug Deliv Rev. 64:327–341.
Kozai TDY, Jaquins-Gerstl AS, Vazquez AL, Michael AC, Cui XT.
2015. Brain tissue responses to neural implants impact signal
sensitivity and intervention strategies. ACS Chem Neurosci. 6(1):
48–67.
Krenzlin S, Vincent C, Munzke L, Gnansia D, Siepmann J,
Siepmann F. 2012. Predictability of drug release from cochlear
implants. J Control Release. 159(1):60–68.
Kreye F, Siepmann F, Siepmann J. 2011. Drug release mechanisms
of compressed lipid implants. Int J Pharm. 404(1-2):27–35.
Kreye F, Siepmann F, Willart JF, Descamps M, Siepmann J. 2011.
Drug release mechanisms of cast lipid implants. Eur J Pharm
Biopharm. 78(3):394–400.
Kunøe N, Lobmaier P, Vederhus JK, Hjerkinn B, Hegstad S, Gossop
M, Kristensen Ø, Waal H. 2010. Retention in naltrexone implant
treatment for opioid dependence. Drug Alcohol Depend. 111(1-
2):166–169.
Kunou N, Ogura Y, Hashizoe M, Honda Y, Hyon S-H, Ikada Y. 1995.
Controlled intraocular delivery of ganciclovir with use of bio-
degradable scleral implant in rabbits. J Control Release. 37(1-2):
143–150.
Lakha F, Henderson C, Glasier A. 2005. The acceptability of self-
administration of subcutaneous Depo-Provera. Contraception.
72(1):14–18.
Langer R, Peppas NA. 2003. Advances in biomaterials, drug deliv-
ery, and bionanotechnology. AIChE J. 49(12):2990–3006.
Lee SS, Hughes P, Ross AD, Robinson MR. 2010. Biodegradable
implants for sustained drug release in the eye. Pharm Res.
27(10):2043–2053.
Lesser GJ, Grossman SA, Leong KW, Lo H, Eller S. 1996. In vitro
and in vivo studies of subcutaneous hydromorphone implants
designed for the treatment of cancer pain. Pain. 65(2):265–272.
130 Z. MOHTASHAMI ET AL.
Li J, Chu MKL, Gordijo CR, Abbasi AZ, Chen K, Adissu HA, Lo €hn M,
Giacca A, Plettenburg O, Wu XY, et al. 2015. Microfabricated
microporous membranes reduce the host immune response
and prolong the functional lifetime of a closed-loop insulin
delivery implant in a type 1 diabetic rat model. Biomaterials.
47:51–61.
Liu L, Gao Q, Lu X, Zhou H. 2016. In situ forming hydrogels based
on chitosan for drug delivery and tissue regeneration. Asian J
Pharm Sci. 11(6):673–683.
Liu Q, Zhang H, Zhou G, Xie S, Zou H, Yu Y, Li G, Sun D, Zhang G,
Lu Y, et al. 2010. In vitro and in vivo study of thymosin alpha1
biodegradable in situ forming poly(lactide-co-glycolide)
implants. Int J Pharm. 397(1-2):122–129.
Lo KW-H, Ulery BD, Ashe KM, Laurencin CT. 2012. Studies of bone
morphogenetic protein-based surgical repair. Adv Drug Deliv
Rev. 64(12):1277–1291.
Lunde B, Littman L, Stimmel S, Rana R, Jacobs A, Horowitz CR.
2017. “Just wear dark underpants mainly”: learning from
adolescents’ and young adults’ experiences with early discon-
tinuation of the contraceptive implant. J Pediatr Adolesc
Gynecol. 30(3):395–399.
Madhusudanan P, Reade S, Shankarappa S. 2017. Neuroglia as tar-
gets for drug delivery systems: a review. Nanomedicine. 13(2):
667–679.
Makadia HK, Siegel SJ. 2011. Poly lactic-co-glycolic acid (PLGA) as
biodegradable controlled drug delivery carrier. Polymers. 3(3):
1377–1397.
Mangraviti A, Gullotti D, Tyler B, Brem H. 2016.
Nanobiotechnology-based delivery strategies: new frontiers in
brain tumor targeted therapies. J Control Release. 240:443–453.
Mansoor S, Kuppermann B, Kenney M. 2009. Intraocular sustained-
release delivery systems for triamcinolone acetonide. Pharm
Res. 26(4):770–784.
Marienfeld C, Iheanacho T, Issa M, Rosenheck RA. 2014. Long-act-
ing injectable depot naltrexone use in the Veterans’ Health
Administration: a national study. Addict Behav. 39(2):434–438.
McNicholas C, Swor E, Wan L, Peipert JF. 2017. Prolonged use of
the etonogestrel implant and levonorgestrel intrauterine device
– Two years beyond FDA-approved duration. Am J Obstet
Gynecol. 216(6):586.e1–586.e6.
Meng E, Hoang T. 2012. Micro-and nano-fabricated implantable
drug-delivery systems. Ther Deliv. 3(12):1457–1467.
Metzger KL, Shoemaker JM, Kahn JB, Maxwell CR, Liang Y,
Tokarczyk J, Kanes SJ, Hans M, Lowman AM, Dan N, et al. 2006.
Pharmacokinetic and behavioral characterization of a long-term
antipsychotic delivery system in rodents and rabbits.
Psychopharmacology. 190(2):201–211.
Mohammad Zaki AJ, Patil SK, Baviskar DT, Jain DK. 2012.
Implantable drug delivery system: a review. Int J PharmTech
Res. 4(1):280–292.
Mosafer J, Abnous K, Tafaghodi M, Mokhtarzadeh A, Ramezani M.
2017. In vitro and in vivo evaluation of anti-nucleolin-targeted
magnetic PLGA nanoparticles loaded with doxorubicin as a
theranostic agent for enhanced targeted cancer imaging and
therapy. Eur J Pharm Biopharm. 113:60–74.
Moscicka AE, Czarnecka K, Ciach T. 2007. IntelliDrug implant for
medicine delivery in alzheimer’s disease treatment. Macromol
Symp. 253(1):134–138.
Nanaki S, Siafaka PI, Zachariadou D, Nerantzaki M, Giliopoulos DJ,
Triantafyllidis KS, Kostoglou M, Nikolakaki E, Bikiaris DN. 2017.
PLGA/SBA-15 mesoporous silica composite microparticles
loaded with paclitaxel for local chemotherapy. Eur J Pharm Sci.
99:32–44.
Narvekar M, Xue HY, Eoh JY, Wong HL. 2014. Nanocarrier for
poorly water-soluble anticancer drugs-barriers of translation
and solutions. AAPS PharmSciTech. 15(4):822–833.
Navitha A, Jogala S, Krishnamohan C, Aukunuru J. 2014.
Development of novel risperidone implants using blends of
polycaprolactones and in vitro in vivo correlation studies. J Adv
Pharm Technol Res. 5(2):84–89.
Newman M, Benoit D. 2016. Local and targeted drug delivery for
bone regeneration. Curr Opin Biotechnol. 40:125–132.
Nikam N, Steinberg TB, Steinberg DH. 2014. Advances in stent
technologies and their effect on clinical efficacy and safety.
Med Devices (Auckland). 7:165–178.
Norman J, Madurawe RD, Moore CMV, Khan MA, Khairuzzaman A.
2017. A new chapter in pharmaceutical manufacturing: 3D-
printed drug products. Adv Drug Deliv Rev. 108:39–50.
Norouzi M, Nazari B, Miller D. 2016. Injectable hydrogel-based
drug delivery systems for local cancer therapy. Drug Discov
Today. 21(11):1835–1849.
Ormiston JA, Serruys PWS. 2009. Bioabsorbable coronary stents.
Circ Cardiovasc Interv. 2(3):255–260.
Parent M, Nouvel C, Koerber M, Sapin A, Maincent P, Boudier A.
2013. PLGA in situ implants formed by phase inversion: critical
physicochemical parameters to modulate drug release. J
Control Release. 172(1):292–304.
Park C-W, Lee H-J, Oh D-W, Kang J-H, Han C-S, Kim D-W. 2018.
Preparation and in vitro/in vivo evaluation of PLGA micro-
spheres containing norquetiapine for long-acting injection.
DDDT. Volume 12:711–719.
Park J, Aryal M, Vykhodtseva N, Zhang Y-Z, McDannold N. 2017.
Evaluation of permeability, doxorubicin delivery, and drug
retention in a rat brain tumor model after ultrasound-induced
blood-tumor barrier disruption. J Control Release. 250:77–85.
Pilon RN, Narang S, Desai SP. 2016. A report on the consequences
of the first implanted device for long-term analgesia in refrac-
tory cancer pain. J Clin Anesth. 32:289–293.
Pourgholi F, Hajivalili M, Farhad J-N, Kafil HS, Yousefi M. 2016.
Nanoparticles: novel vehicles in treatment of Glioblastoma.
Biomed Pharmacother. 77:98–107.
Rabin C, Liang Y, Ehrlichman RS, Budhian A, Metzger KL,
Majewski-Tiedeken C, Winey KI, Siegel SJ. 2008. In vitro and
in vivo demonstration of risperidone implants in mice.
Schizophr Res. 98(1-3):66–78.
Rajagopal K, Wood J, Tran B, Patapoff TW, Nivaggioli T. 2013.
Trehalose limits BSA aggregation in spray-dried formulations at
high temperatures: implications in preparing polymer implants
for long-term protein delivery. J Pharm Sci. 102(8):2655–2666.
Rassner MP, Hebel JM, Altenm€ uller D-M, Volz S, Herrmann LS,
Feuerstein TJ, Freiman TM. 2015. Reduction of epileptiform
activity through local valproate-implants in a rat neocortical
epilepsy model. Seizure. 30:6–13.
Ravivarapu H, Moyer K, Dunn R. 2000. Sustained activity and
release of leuprolide acetate from an in situ forming polymeric
implant. AAPS PharmSciTech. 1(1):1–8.
Ren S, Dai Y, Li C, Qiu Z, Wang X, Tian F, Zhou S, Liu Q, Xing H,
Lu Y, et al. 2016. Pharmacokinetics and pharmacodynamics
evaluation of a thermosensitive chitosan based hydrogel con-
taining liposomal doxorubicin. Eur J Pharm Sci. 92:137–145.
Restrepo CE, Spinner RJ. 2016. Major nerve injury after contracep-
tive implant removal: case illustration. J Neurosurg. 124(1):
188–189.
Richards M, Teal SB, Sheeder J. 2017. Risk of luteal phase preg-
nancy with any-cycle-day initiation of subdermal contraceptive
implants. Contraception. 95(4):364–370.

Roke C, Roberts H, Whitehead A. 2016. New Zealand women’s
experience during their first year of JadelleV contraceptive
R
implant. J Prim Health Care. 8(1):13–19.
Rosenthal RN, Lofwall MR, Kim S, Chen M, Beebe KL, Vocci FJ.
2016. Effect of buprenorphine implants on illicit opioid use
among abstinent adults with opioid dependence treated with
sublingual buprenorphine. A randomized clinical trial. JAMA.
316(3):282–290.
Rothen-Weinhold A, Besseghir K, Vuaridel E, Sublet E, Oudry N,
Gurny R. 1999. Stability studies of a somatostatin analogue in
biodegradable implants. Int J Pharm. 178(2):213–221.
Sanjay ST, Zhou W, Dou M, Tavakoli H, Ma L, Xu F, Li X. 2018.
Recent advances of controlled drug delivery using microfluidic
platforms. Adv Drug Deliv Rev. 128:3–28.
Sedgh G, Ashford LS, Hussain R. 2016. Unmet need for contracep-
tion in developing countries: examining women’s reasons for
not using a method. New York: Guttmacher Institute.
Seng P, Bayle S, Alliez A, Romain F, Casanova D, Stein A. 2015.
The microbial epidemiology of breast implant infections in a
regional referral centre for plastic and reconstructive surgery in
the South of France. Int J Infect Dis. 35:62–66.
Sepahvandi A, Eskandari M, Moztarzadeh F. 2016. Drug delivery
systems to the posterior segment of the eye: implants and
nanoparticles. BioNanoSci. 6(4):276–283.
Serruys PW, Kutryk MJB, Ong ATL. 2006. Coronary-artery stents. N
Engl J Med. 354(5):483–495.
Shemesh S, Kosashvili Y, Groshar D, Bernstine H, Sidon E, Cohen
N, Luria T, Velkes S. 2015. The value of 18-FDG PET/CT in the
diagnosis and management of implant-related infections of the
tibia: a case series. Injury. 46(7):1377–1382.
Siegel SJ, Winey KI, Gur RE, Lenox RH, Bilker WB, Ikeda D, Gandhi
N, Zhang WX. 2002. Surgically implantable long-term anti-
psychotic delivery systems for the treatment of schizophrenia.
Neuropsychopharmacology. 26(6):817–823.
Siegel SJ. 2005. Extended release drug delivery strategies in
psychiatry: theory to practice. Psychiatry. 2(6):22–31.
Silva-Boghossian CM, Luiz RR, Colombo APV. 2009. Periodontal
status, sociodemographic, and behavioral indicators in subjects
attending a public dental school in Brazil: analysis of clinical
attachment loss. J Periodontol. 80(12):1945–1954.
Silva-Boghossian CM, Neves AB, Resende FAR, Colombo APV.
2013. Suppuration-associated bacteria in patients with chronic
and aggressive periodontitis. J Periodontol. 84(9):e9–e16.
Singh K, Chye GC. 1998. Adverse effects associated with contra-
ceptive implants: incidence, prevention and management. Adv
Contracept. 14(1):1–13.
Solanki HK, Thakkar JH, Jani GK. 2010. Recent advances in
implantable drug delivery. Int J Pharm Sci Rev Res. 4(3):
168–177.
Soo PL, Cho J, Grant J, Ho E, Piquette-Miller M, Allen C. 2008.
Drug release mechanism of paclitaxel from a chitosan-lipid
implant system: effect of swelling, degradation and morph-
ology. Eur J Pharm Biopharm. 69(1):149–157.
Stanback J, Spieler J, Shah I, Finger WR. 2010. Community-based
health workers can safely and effectively administer injectable
contraceptives: conclusions from a technical consultation.
Contraception. 81(3):181–184.
Stankovic M, de Waard H, Steendam R, Hiemstra C, Zuidema J,
Frijlink HW, Hinrichs WLJ. 2013. Low temperature extruded
implants based on novel hydrophilic multiblock copolymer for
long-term protein delivery. Eur J Pharm Sci. 49(4):578–587.
Stankovic M, Hiemstra C, de Waard H, Zuidema J, Steendam R,
Frijlink HW, Hinrichs WLJ. 2015. Protein release from water-
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 131
swellable poly(d,l-lactide-PEG)-b-poly(e-caprolactone) implants.
Int J Pharm. 480(1-2):73–83.
Stotts AL, Dodrill CL, Kosten TR. 2009. Opioid dependence treat-
ment: options in pharmacotherapy. Expert Opin Pharmacother.
10(11):1727–1740.
Sutherland EG, Otterness C, Janowitz B. 2011. What happens to
contraceptive use after injectables are introduced? an analysis
of 13 countries. Int Perspect Sex Reprod Health. 37(04):
202–208.
Talebian S, Foroughi J, Wade SJ, Vine KL, Dolatshahi-Pirouz A,
Mehrali M, Conde J, Wallace GG. 2018. Biopolymers for antitu-
mor implantable drug delivery systems: recent advances and
future outlook. Adv Mater. 30(31):1706665.
Tamargo RJ, Rossell LA, Kossoff EH, Tyler BM, Ewend MG,
Aryanpur JJ. 2002. The intracerebral administration of pheny-
toin using controlled-release polymers reduces experimental
seizures in rats. Epilepsy Res. 48(3):145–155.
Tan KX, Danquah MK, Sidhu A, Ongkudon CM, Lau SY. 2017.
Towards targeted cancer therapy: aptamer or oncolytic virus?
Eur J Pharm Sci. 96:8–19.
Tang Y, Singh J. 2009. Biodegradable and biocompatible thermo-
sensitive polymer based injectable implant for controlled
release of protein. Int J Pharm. 365(1-2):34–43.
Thakur R, McMillan H, Jones D. 2014. Solvent induced phase inver-
sion-based in situ forming controlled release drug delivery
implants. J Control Release. 176:8–23.
Tobias IS, Lee H, Engelmayr GC, Jr, Macaya D, Bettinger CJ, Cima
MJ. 2010. Zero-order controlled release of ciprofloxacin-HCl
from a reservoir-based, bioresorbable and elastomeric device. J
Control Release. 146(3):356–362.
Tomme SRV, Storm G, Hennink WE. 2008. In situ gelling hydrogels
for pharmaceutical and biomedical applications. Int J Pharm.
355(1-2):1–18.
Towler HM. 2014. New technologies and drugs in the manage-
ment of diabetic retinopathy. Pract Diab. 31(7):275–280a.
Trajkovski B, Petersen A, Strube P, Mehta M, Duda GN. 2012. Intra-
operatively customized implant coating strategies for local and
controlled drug delivery to bone. Adv Drug Deliv Rev. 64(12):
1142–1151.
Tseng Y, Kau Y, Liu S. 2016. Advanced interstitial chemotherapy
for treating malignant glioma. Expert Opin Drug Deliv. 13(11):
1533–1544.
Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, Patel P,
Blesch A, Vahlsing HL, Ho G, et al. 2005. A phase 1 clinical trial
of nerve growth factor gene therapy for Alzheimer disease. Nat
Med. 11(5):551–555.
€ undag
Ust€ -Okur N, Go€kçe EH, Bozbıyık D_I, Eg €
rilmez S, Ertan G, Ozer
€ 2015. Novel nanostructured lipid carrier-based inserts for
O.
controlled ocular drug delivery: evaluation of corneal bioavail-
ability and treatment efficacy in bacterial keratitis. Expert Opin
Drug Deliv. 12(11):1791–1807.
Vakilinezhad MA, Alipour S, Montaseri H. 2018. Fabrication and
in vitro evaluation of magnetic PLGA nanoparticles as a poten-
tial methotrexate delivery system for breast cancer. J Drug
Deliv Sci Tech. 44:467–474.
Vakilinezhad MA, Amini A, Akbari Javar H, Baha’addini Beigi
Zarandi BF, Montaseri H, Dinarvand R. 2018. Nicotinamide
loaded functionalized solid lipid nanoparticles improves cogni-
tion in Alzheimer’s disease animal model reducing Tau hyper-
phosphorylation. Daru. 26(2):165–177.
van der Steen SC, Raave R, Langerak S, van Houdt L, van
Duijnhoven SM, van Lith SA, Massuger LF, Daamen WF,
Leenders WP, van Kuppevelt TH. 2017. Targeting the
132 Z. MOHTASHAMI ET AL.
extracellular matrix of ovarian cancer using functionalized, drug
loaded lyophilisomes. Eur J Pharm Biopharm. 113:229–239.
Vemulakonda G, Hariprasad SM, Mieler WF, Prince RA, Shah GK,
Van Gelder RN. 2008. Aqueous and vitreous concentrations fol-
lowing topical administration of 1% voriconazole in humans.
Arch Ophthalmol. 126(1):18–22.
Villanueva JR, Bravo-Osuna I, Herrero-Vanrell R, Molina Martınez IT,
Guzman Navarro M. 2016. Optimising the controlled release of
dexamethasone from a new generation of PLGA-based micro-
spheres intended for intravitreal administration. Eur J Pharm
Sci. 92:287–297.
Villanueva JR, Villanueva LR, Navarro MG. 2017. Pharmaceutical
technology can turn a traditional drug, dexamethasone into a
first-line ocular medicine. A global perspective and future
trends. Int J Pharm. 516(1-2):342–351.
Wadee A, Pillay V, Choonara YE, Du Toit LC, Penny C, Ndesendo
VM, Kumar P, Murphy CS. 2011. Recent advances in the design
of drug-loaded polymeric implants for the treatment of solid
tumors. Expert Opin Drug Deliv. 8(10):1323–1340.
Wahlberg LU, Lind G, Almqvist PM, Kusk P, Tornøe J, Juliusson B,
So€derman M, Sellden E, Seiger Å, Eriksdotter-Jo
€nhagen M, et al.
2012. Targeted delivery of nerve growth factor via encapsulated
cell biodelivery in Alzheimer disease: a technology platform for
restorative neurosurgery. J Neurosurg. 117(2):340–347.
Wang C, Seo S-J, Kim J-S, Lee S-H, Jeon J-K, Kim J-W, Kim K-H,
Kim J-K, Park J. 2018. Intravitreal implantable magnetic micro-
pump for on-demand VEGFR-targeted drug delivery. J Control
Release. 283:105–112.
Wang J, Jiang A, Joshi M, Christoforidis J. 2013. Drug delivery
implants in the treatment of vitreous inflammation. Mediators
Inflamm. 2013(780634):1.
Wang Q, Huang J-Y, Li H-Q, Zhao AZ-J, Wang Y, Zhang K-Q, Sun
H-T, Lai Y-K. 2016. Recent advances on smart TiO2 nanotube
platforms for sustainable drug delivery applications. Int J
Nanomed. 12:151–165.
Weiser J, Saltzman W. 2014. Controlled release for local delivery of
drugs: barriers and models. J Control Release. 190:664–673.
White J, Bell J, Saunders JB, Williamson P, Makowska M,
Farquharson A, Beebe KL. 2009. Open-label dose-finding trial of
buprenorphine implants (Probuphine) for treatment of heroin
dependence. Drug Alcohol Depend. 103(1-2):37–43.
Wildemann B, Kandziora F, Krummrey G, Palasdies N, Haas NP,
Raschke M, Schmidmaier G. 2004. Local and controlled release
of growth factors (combination of IGF-I and TGF-beta I, and
BMP-2 alone) from a polylactide coating of titanium implants
does not lead to ectopic bone formation in sheep muscle. J
Control Release. 95(2):249–256.
Wilz A, Pritchard EM, Li T, Lan J-Q, Kaplan DL, Boison D. 2008. Silk
polymer-based adenosine release: therapeutic potential for epi-
lepsy. Biomaterials. 29(26):3609–3616.
Winkelmuller M, Winkelmuller W. 1996. Long-term effects of con-
tinuous intrathecal opioid treatment in chronic pain of nonma-
lignant etiology. J Neurosurg. 85:458–467.
Winner B, Peipert JF, Zhao Q, Buckel C, Madden T, Allsworth JE,
Secura GM. 2012. Effectiveness of long-acting reversible contra-
ception. N Engl J Med. 366(21):1998–2007.
Wolinsky JB, Colson YL, Grinstaff MW. 2012. Local drug delivery
strategies for cancer treatment: gels, nanoparticles, polymeric
films, rods, and wafers. J Control Release. 159(1):14–26.
Wright JC, Tao Leonard S, Stevenson CL, Beck JC, Chen G, Jao RM,
Johnson PA, Leonard J, Skowronski RJ. 2001. An in vivo/in vitro
comparison with a leuprolide osmotic implant for the treat-
ment of prostate cancer. J Control Release. 75(1-2):1–10.
Xu H-L, Mao K-L, Lu C-T, Fan Z-L, Yang J-J, Xu J, Chen P-P, ZhuGe
D-L, Shen B-X, Jin B-H, et al. 2016. An injectable acellular matrix
scaffold with absorbable permeable nanoparticles improves the
therapeutic effects of docetaxel on glioblastoma. Biomaterials.
107:44–60.
Yamamoto M, Takano M, Murakami D, Inami T, Kobayashi N,
Inami S, Okamatsu K, Ohba T, Ibuki C, Hata N, et al. 2011. The
possibility of delayed arterial healing 5 years after implantation
of sirolimus-eluting stents: serial observations by coronary
angioscopy. Am Heart J. 161(6):1200–1206.
Yasin MN, Svirskis D, Seyfoddin A, Rupenthal ID. 2014. Implants
for drug delivery to the posterior segment of the eye: a focus
on stimuli-responsive and tunable release systems. J Control
Release. 196:208–221.
Ye X, Shokrollahi K, Rozen WM, Conyers R, Wright P, Kenner L,
Turner SD, Whitaker IS. 2014. Anaplastic large cell lymphoma
(ALCL) and breast implants: breaking down the evidence. Mutat
Res Rev Mutat Res. 762:123–132.
Yi H-G, Choi Y-J, Kang KS, Hong JM, Pati RG, Park MN, Shim IK,
Lee CM, Kim SC, Cho D-W. 2016. A 3D-printed local drug deliv-
ery patch for pancreatic cancer growth suppression. J Control
Release. 238:231–241.
Zhang F. 2008. Silk-functionalized titanium surfaces for enhancing
osteoblast functions and reducing bacterial adhesion.
Biomaterials. 36:4751–4759.
Zhang J, Feng X, Patil H, Tiwari RV, Repka MA. 2017. Coupling 3D
printing with hot-melt extrusion to produce controlled-release
tablets. Int J Pharm. 519(1-2):186–197.
Zhou T, Lewis H, Foster RE, Schwendeman SP. 1998. Development
of a multiple-drug delivery implant for intraocular management
of proliferative vitreoretinopathy. J Control Release. 55(2-3):
281–295.
Zou X, Xue Q, Li H, B€ unger M, Lind M, B€ unger C. 2003. Effect of
alendronate on bone ingrowth into porous tantalum and car-
bon fiber interbody devices. An experimental study on spinal
fusion in pigs. Acta Orthop Scand. 74(5):596–603.
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