An Overview of PLGA In-Situ Forming Implants

Pharmaceutical Development and Technology
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iphd20
An overview of PLGA in-situ forming implants

based on solvent exchange technique: effect of
formulation components and characterization
Tarek Metwally Ibrahim, Nagia Ahmed El-Megrab & Hanan Mohammed El-
Nahas
To cite this article: Tarek Metwally Ibrahim, Nagia Ahmed El-Megrab & Hanan Mohammed
El-Nahas (2021) An overview of PLGA in-situ forming implants based on solvent exchange
technique: effect of formulation components and characterization, Pharmaceutical Development
and Technology, 26:7, 709-728, DOI: 10.1080/10837450.2021.1944207
To link to this article: https://doi.org/10.1080/10837450.2021.1944207
Published online: 27 Jun 2021.
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PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
2021, VOL. 26, NO. 7, 709–728
https://doi.org/10.1080/10837450.2021.1944207
REVIEW ARTICLE
An overview of PLGA in-situ forming implants based on solvent exchange

technique: effect of formulation components and characterization
Tarek Metwally Ibrahim, Nagia Ahmed El-Megrab and Hanan Mohammed El-Nahas
Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
ABSTRACT ARTICLE HISTORY

As a result of the low oral bioavailability of several drugs, there is a renewed interest for parenteral Received 13 January 2021
administration to target their absorption directly into the blood bypassing the long gastrointestinal route Revised 13 June 2021
and hepatic metabolism. In order to address the potential side effects of frequent injections, sustained Accepted 14 June 2021
release systems are the most popular approaches for achieving controlled long-acting drug delivery.
KEYWORDS
Injectable in-situ forming implants (ISFIs) have gained greater popularity in comparison to other sustained In-situ forming implants;
systems. Their significant positive aspects are attributed to easier production, acceptable administration PLGA; biodegradable;
route, reduced dosing frequency and patient compliance achievement. ISFI systems, comprising bio- solvent exchange;
degradable polymers such as poly (lactide-co-glycolide) (PLGA) based on solvent exchange mechanisms, PEGylation
are emerged as liquid formulations that develop solid or semisolid depots after injection and deliver
drugs over extended periods. The drug release from ISFI systems is generally characterized by an initial
burst during the matrix solidification, followed by diffusion processes and finally polymeric degradation
and erosion. The choice of suitable solvent with satisfactory viscosity, miscibility and biocompatibility
along with considerable PLGA hydrophobicity and molecular weights is fundamental for optimizing the
drug release. This overview gives a particular emphasis on evaluations and the wide ranges of require-
ments needed to achieve reasonable physicochemical characteristics of ISFIs.
1. Introduction compliance especially in the case of daily medication regimens

and chronic conditions for a lifetime (Madhav et al. 2009). In add-
An increasing number of new active pharmaceutical ingredients
ition, non-adherence to oral medications, particularly in psychotic
suffer from low bioavailability after oral administration. Alternative
patients, is a deleterious problem that brings out several fluctua-
routes of administration such as pulmonary, nasal, buccal, trans-
tions in the plasma concentrations of drugs and retardation of
dermal, ocular and rectal routes have also shown drawbacks such
therapeutic outcomes (Kane et al. 2013). Therefore, parenteral sus-
as enzymatic degradation or low/variable absorption (Wen et al.
tained release systems are the most promising strategies for
2015). As a result, there is a renewed interest in parenteral admin-
achieving the long-term and controlled delivery of drugs.
istration, especially for achieving pain reduction patterns. The par- Parenteral formulations are sterile preparations tailored to be
enteral route is the most functional administration way for administered by injection, implantation or infusion into the body
delivery of drugs having low bioavailability and narrow thera- of humans or animals (Figure 1). Numerous pharmaceutical ameli-
peutic index (Gulati and Gupta 2011). For instance, intravenous, orations have been attained in the field of parenteral drug deliv-
subcutaneous, intramuscular, intraarterial and intradermal routes ery. This leads to the development of advanced systems that
can enhance the absorption and bioavailability of drugs. This can permit the achievement of drug targeting and sustained or con-
be achieved by targeting the absorption of drugs directly into the trolled release of parenteral drugs with the fulfillment of dosing
systemic circulation bypassing the long gastrointestinal route and frequency reduction and patient compliance (Nikam et al. 2013).
hepatic first-pass metabolism (Jivawala and Goyani 2017). Several systems have been developed in order to acquire a sus-
Nevertheless, many drugs are characterized not only by a high tained release of drugs such as microemulsions (Sabale and Vora
activity but also by a short half-life. The therapeutic value of 2012), vesicular systems (Verma et al. 2016), microspheres
drugs can be improved by controlling and/or prolonging their (Farhangi et al. 2017), polymeric micelles (Jhaveri and Torchilin
release from the pharmaceutical dosage form over time. In this 2014), nanoparticles (Qi et al. 2019) in addition to surgical solid
context, sustained-release forms are highly desirable to avoid con- implants (Metzger et al. 2007) and infusion devices (Forouzandeh
tinuous infusions or frequent injections (Santamaria et al. 2017). et al. 2019). The major drawbacks of these systems include the
These sustained-release preparations display several merits includ- migration of the drug from the site of injection, the time con-
ing promoted patient compliance and prevention of peaks and sumed for their formulation and scale-up problems (Homayun et
valleys in plasma concentrations, thus allowing the reduction of al. 2019).
total dose and minimizing the potential side effects (Parent et al. Microsphere systems are one of the most widely accepted
2013). On the other hand, conventional oral and transmucosal delivery systems that can be injected into the body by conven-
delivery systems can deliver drugs only within few hours. These tional needles. However, these formulations show a variety of lim-
systems are less effective for the enhancement of patient itations such as the necessity of a large volume of fluids, deep
CONTACT Tarek Metwally Ibrahim tarekmetwally333@gmail.com Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
ß 2021 Informa UK Limited, trading as Taylor & Francis Group
710 T. M. IBRAHIM ET AL.
Figure 1. Types of parenteral drug delivery.
of utilizing a non-biodegradable polymer such as NexplanonV and

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intramuscular injection as well as poor drug loading, difficult man-
IluvienV (Stewart et al. 2018). OzurdexV is rod-shaped biodegrad-
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ufacturing, syringe clogging and difficult removal from the body
able PLGA-based implants that depend on Allergan’s NovadurV
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(Patel et al. 2010). Surgical implants require surgical procedures to
insert and remove the drug-containing devices leading to tissue technology and are utilized for the treatment of diabetic macular
damage and increased risks of infection, inflammation and fibrosis edema via intravitreal dexamethasone administration (Jervis
at the site of implantation (Sinha and Khosla 1998; Rousselle et al. 2017). Drug-eluting stents are specific double-action systems gen-
2019). Vesicular systems are also versatile carriers that possess erally consisted of a stent as the device component and a drug-
several disadvantages such as low solubility, high costs and containing coating as the drug component. As an example,
CoroflexV ISAR NEO can provide a prolonged release of sirolimus,
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apparent leakage of drugs (Toh and Chiu 2013).
The U.S. pharmacopoeia gives more details about continuous embedded in the drug-eluting coating, used for prevention of
prolonged-release parenteral formulations, not only solid implant myointimal proliferation and reduction of restenosis with the
systems but also all preparations injected subcutaneously or into assistance of the mechanical support of the stent that can main-
a specific region of the body such as sinus, artery, eye or brain. In tain the open vasculature and arterial patency (Al-Jawadi et
particular, pellet implants, resorbable microspheres, drug suspen- al. 2018).
sions and in-situ gelling systems are considered injectable depots, It is noteworthy that, from the point of view of U.S. Food and
while polymeric implants and drug-eluting stents are regarded as Drug Administration (FDA), extended-release injection and implant
implantable ones (U.S. pharmacopoeia 2020). For illustration, pel- systems are considered complex formulations. They show several
let implants are sterile solid preparations that can control the critical issues such as achieving satisfactory in-vitro release models
drug release for several months where specific injection devices corresponding to the need for dedicated regulations and the
or surgical procedures are utilized for injection of the system development of suitable quality control standards (Burgess et al.
(McCullough 2014). TestopelTM is a subcutaneous testosterone- 2002). The establishment of an in-vitro/in-vivo correlation can
loaded pellet implant system prescribed for replacement testos- make in-vitro testing a more powerful tool. Therefore, the consid-
terone therapy by controlling the drug release over 3–6 months. eration of variables accounting for the physiological environment
Resorbable microspheres are sphere-shaped implants comprising is essential for reaching in-vivo relevance such as vascularity, body
of a polymeric bioresorbable biocompatible matrix in which the temperature, pH, osmolarity or any tissue responses (Larsen et al.
drug is dispersed. They are injected intramuscularly, subcutane- 2009). To get marketing authorization for a first-in-man product,
ously or deposited into a specific site of the body (Qi et al. 2019). full detailed information must be submitted to a national regula-
One of the most successful examples of this system is those tory agency. For instance, in U.S. FDA, the procedure of the New
based on the poly (lactide-co-glycolide) (PLGA) polymer such as Drug Application (NDA) including a full-described profile of the
SinuvaV, InductOsV and ZilrettaV. Extended-release suspensions
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proposed drug regarding its quality, safety and efficacy should be
are injectable liquid systems consisted of a suitable vehicle in followed (Al-Jawadi et al. 2018). Particularly, all information about
which the drug is suspended and then released over extended the physico-chemical properties of both drug and excipients in
periods such as Invega TrinzaV and AristadaV (Nkanga et al. 2020). addition to the in-vitro characterization and in-vivo performance
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In-situ gelling systems consist of a combination, of a drug being of the product should be described in detail. Besides, all critical
dissolved or suspended in a mixture of solvent and polymer such quality attributes of the product on basis of the intended use and
as PLGA, administered subcutaneously where the solvent diffusion administration route should be studied. Moreover, comparative in-
in the external aqueous body fluids results in precipitation of the vitro/in-vivo correlation studies should be also included in order
drug-entrapping PLGA matrix and sustaining the drug release to gather the results of formulations used in clinical studies to
(e.g. AtridoxV and EligardV) (Wang et al. 2012).
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those of final commercial formulations. Eventually, the marketing
On the other hand, polymeric implant systems are specific- authorization can be obtained when the benefit/risk balance
shaped masses that are composed of a biocompatible biodegrad- results are positive (Selmin et al. 2020). As examples of previously
able or non-biodegradable polymer. They are generally implanted approved products, anti-psychotic risperidone has been approved
in form of biodegradable PLGA-based microspheres (RisperdalV
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by using an injector device and must be finally removed in case
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 711
ConstaV) (FDA 2003) and in-situ gelling systems (PerserisV)

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3.1. In-situ cross-linking systems
(FDA 2018a).
The in-situ cross-linking systems can be achieved where polymer
In the case of parenteral preparations, FDA states that the
cross-links are formed due to the temperature change (thermo-
qualitative (Q1) and quantitative (Q2) composition of the test and
responsive crosslinking), absorption of photons (photo-responsive
reference products should be similar and the product copies
crosslinking), ionic interaction between the anionic polymer and
should satisfy the Q1/Q2 sameness to be authorized with the
small cations (ion-responsive crosslinking) or presence of enzymes
Abbreviated New Drug Application (ANDA) (Hua et al. 2021). For (enzymatic-responsive crosslinking) (Hatefi and Amsden 2002;
example, the in-vitro and in-vivo performance of the polymeric Kondiah et al. 2016). Different examples of in-situ cross-linking
PLGA-based products can be significantly influenced by the altera- systems are represented in Figure 2. The cross-linked polymer net-
tions in the manufacturing process in addition to the changes in works are advantageous owing to their capability to regulate the
the chemical properties of PLGA polymer regarding its compos- diffusion of hydrophilic macromolecules and help release the pep-
ition, molecular weight and end-capping. This can result in major tides and proteins for extended periods (Musmade et al. 2019).
changes in the biopharmaceutical properties and bioavailability of
the proposed drug. Given the complexity of this context, FDA
requires a complete characterization of PLGA polymer to fulfill the 3.2. In-situ solidifying organogel systems
Q1/Q2 requirements by the comparison of polymer composition, The in-situ solidifying organogel systems are comprised of water
molecular weight distribution and polymer architecture (Zhou et insoluble amphiphilic lipids that are heated and dissolved in an
al. 2018). After the marketing authorization, the marketed product organic solvent such as ethanol. Then, they become swollen in
may introduce some changes or adverse outcomes that clearly water producing numerous kinds of lyotropic crystals. The charac-
may lead to alterations in the quality, safety and efficacy of the teristics of developed lyotropic crystals rely on multiple factors
drug. Therefore, several procedures including continuous clinical including the nature of the loaded drug, structural features of
study analyses in patients should be followed by the manufac- lipid, amount of water and temperature (Yaghmur et al. 2013).
turer to ensure the maintenance of positive long-term perform- Such amphiphilic lipids required for the development of in-situ
ance and safety of the product (FDA 2016, 2018b). organogels are mostly fatty acid esters combined with glycerol.
The aim of this review is to clearly focus on designing and For instance, glycerol monolinoleate, glycerol monopalmitostea-
evaluating the biodegradable in-situ forming implant (ISFI) sys- rate and glycerol monooleate are waxes at normal ambient tem-
tems that have gained great popularity owing to their significant perature (Borgheti-Cardoso et al. 2017). The heated components
positive aspects associated with ease of production, acceptable are found in a cubic liquid crystalline state when they come in
administration route, reduced dosing frequency and achievement contact with an aqueous medium (Figure 3). The liquid structure
of patient compliance and adherence. of lower viscosity is transformed to a highly viscous solid or semi-
solid gel-like nature after being cooled by injection into the body.
These systems possess desirable features such as ease of applica-
2. ISFI systems tion, site-specificity and prolonged drug release as reported by
Wu et al. 2014.
The ISFI systems are protruded as attractive parenteral formula-
tions in a liquid form that develop a solid depot after being
inserted into the body. ISFI systems can deliver drugs at a con- 3.3. In-situ phase separation systems
trolled rate over an extended period, hence reducing the dose The in-situ phase separation occurs with the help of various trig-
and frequency of administration (Gad 2016). The development of gering factors such as temperature change, pH change, light or
ISFI systems has been a topic of significant research interest over solvent exchange (Madan et al. 2009).
the past three decades (Dunn et al. 1990; Lambert and Peck 1995;
Eliaz and Szoka 2002; Astaneh et al. 2009; Ahmed et al. 2014; 3.3.1. Temperature-responsive systems
Bode et al. 2018; Kamali et al. 2020; Karp et al. 2021). They are Systems based on temperature-responsive polymers depend on
described as a variety of polymer-based systems that are initially the environmental temperature difference for achieving solution-
comprised of a liquid solution. This liquid solution can solidify gel transition. No external source of heat is required other than
after placement into the site of interest in the body (Patel et al. the body temperature for achieving effective gelation. These sys-
2010). The theory of ISFI systems was first displayed and expli- tems are classified as lower critical solution temperature (LCST)
cated by Dunn et al. 1990, 1994. Injectable ISFI systems have systems or upper critical solution temperature (UCST) systems
been evolved in recent years in order to obviate the surgical (Ahmed and Hussain 2010). The LCST systems, known as nega-
intervention associated with the administration and withdrawal of tively temperature-responsive systems, can contract by heating
conventional implants and thus improve patient compliance above the LCST. This increase in temperature can facilitate the
(Islam 2011). polymer chain association with rapid transformation into a hydro-
phobic structure, thus contributing to the phase separation. The
UCST systems, known as positively temperature-responsive sys-
tems can contract by cooling into the body for solution-gel turn-
3. Solidification mechanisms of ISFI systems
over. Where the polymeric solution is heated at 37–65 C
Musmade et al. 2019 has reported that ISFI systems can be classi- corresponding to the high glass transition temperature of the
fied according to their mechanisms of implant solidification upon polymer used. Upon injection into the body, it is transformed into
administration into the body. They can be classified into various the highly viscous depot, called thermoplastic paste, which is gen-
species such as in-situ cross-linking systems, in-situ solidifying erated by cooling at body temperature (Kanwar and Sinha 2019).
organogel systems and in-situ phase separation systems as eluci- These systems encounter several drawbacks such as painful
dated below. administration, scars formation at the injection site, extremely
Figure 2. Different examples of in-situ cross-linking systems.
Figure 3. Preparation of in-situ solidifying organogel systems.
slow release and possible instability of loaded drugs (Dhir et commonly related to polymers that carry ionizable functional
al. 2016). groups in their chemical structures (Ahmed and Hussain 2010).
Where the polymer solution exists as a free-flowing liquid at pH
3.3.2. pH-responsive systems below 5 and can be converted into gels by increasing the pH
The polymeric network conformation can be remarkably changed value. For example, Joshi et al. 1999 studied the implant systems
in response to the alterations in the pH of the medium. The inci- based on poly(methacrylic acid) that converted into water-
dence of solution-gel turnover caused by these alterations is insoluble polymeric complexes at a pH nearly 5.8. In addition,
Figure 4. Examples of commonly used temperature-responsive, pH-responsive and photo-responsive polymers.
weakly acidic or basic groups linked to the polymer’s structure or solidified depots after injection into the aqueous body fluids.
can impact the ionization state and swelling behavior of the sys- The drug is dissolved or dispersed in a concentrated solution of
tems along with the variation of environmental pH (Tang et al. water-insoluble biodegradable polymer and water-miscible bio-
2018). Although the pH-responsive systems have been reported compatible solvent. The solvent dissipates into the surrounding
to produce the controlled release of drugs, they necessitate com- area following injection, while water penetrates the polymeric
plex and high-cost processes on large scales (Zheng et al. 2015). matrix. The drug is entrapped within the matrix after solidification
of implants and then released by diffusion mechanism or after
3.3.3. Photo-responsive systems the implants start to biodegrade in the body (Figure 5) (Dunn et
Photo-responsive delivery systems are suitable especially for treat- al. 1994; Vhora et al. 2021). Several formulations have been
ing various ocular diseases owing to their merits including easy studied using various biodegradable polymers such as polylactide
application, safety, patient compliance achievement and site- (PLA) (Camargo et al. 2013), PLGA (Enayati et al. 2017) or polycap-
specific controlled release of drugs (Bisht et al. 2017). These rolactone (PCL) (Khodaverdi et al. 2020). Many biocompatible
systems comprise a photosensitive initiator and light source asso- solvents have been mixed with these polymers such as N-methyl-
ciated with the polymeric matrix. The photo-polymerization mech- 2-pyrrolidone (NMP) (Patki et al. 2021), dimethyl sulfoxide (DMSO)
anism is performed when the external stimulus (light) penetrates, (Wang et al. 2012) and benzyl benzoate (Wang et al. 2017).
by a non-invasive way, through the cornea causing solidification The solvent exchange technique has been developed into sev-
eral commercially available ISFI products. For example, AtridoxV is
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of the ISFI systems. Therefore, systems possessing rapid solution-
gel transition, high cross-linking density and enhanced mechanical the first ISFI system available in the market after FDA approval in
strength can be produced (Bisht et al. 2016). Light such as visible, 1998. This product contains doxycycline licensed for treating
ultraviolet or near-infrared light is inexpensive and can achieve chronic periodontal disease over 3 weeks by injecting the drug
into the periodontal pocket (Kempe and M€ader 2012). EligardV is
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instant delivery with a short response time, thus minimize the
burst release of drugs (Yan et al. 2012). a sustained release ISFI system administered subcutaneously to
Examples of commonly used temperature-responsive, pH- deliver leuprolide acetate for treating advanced prostate cancer
responsive and photo-responsive polymers are represented in with variable dosing regimens for 1, 3, 4 or 6 months
Figure 4. (Schwendeman et al. 2014). Lupron DepotTM is also an intramus-
cular prolonged-release ISFI product, with the same components
of EligardV, offering various doses for treatment of advanced pros-
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3.3.4. Phase separation systems by solvent exchange
Among the above-mentioned mechanisms, the in-situ polymer tate cancer over 3, 4 and 6 months. Lupron Depot-PedTM is
precipitation based on solvent removal or exchange is wide- another development of Lupron DepotTM available in market for
spread. The biodegradable polymer-based ISFI delivery systems treatment of central precocious puberty in children over 1 and 3
months (Thakur et al. 2014). SandostatinV LARV is loaded with
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are generally liquid formulations that are transformed into gel-like
Figure 5. Mechanism of ISFI formation by solvent exchange.
octreotide, a synthetic analogue of somatostatin, and commer- hurdles in controlling the initial burst drug release make these
cially available as a monthly intramuscular ISFI product. It is pre- delivery systems less widespread in the market (Islam 2011). The
scribed to treat acromegaly by controlling the growth hormone incidence of initial burst effect after a few minutes or hours of
levels and also to treat gastroenteropancreatic neuroendocrine injection as a result of the lag between injecting the liquid
tumors by controlling the gastrointestinal hormone secretions implant and forming the solid implant is still a challenging prob-
(Hadar et al. 2019). SublocadeV is a recently approved buprenor-
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lem. Consequently, the solidification of the drug-encapsulating
phine-loaded ISFI prescribed for the treatment of opioid use dis- matrix is delayed resulting in poor drug loading and local or sys-
order within 1 month period (Zhang and Fassihi 2020). The temic side effects (Patel et al. 2010). In addition, the high viscosity
aforementioned products comprise two syringes in which the of the polymeric solution may lead to problems during the
drug powder is filled in one syringe and the polymeric solution administration of ISFI systems (Haider et al. 2021).
(PLGA/NMP) is present in the other syringe. Before injection, both One of the recent strategies to overcome the complications of
syringes necessitate mixing several times to produce a homoge- ISFI systems is the inclusion of additives or the utilization of
neous combination. The duration of treatment using these prod- nano-carriers in combination with ISFI systems. This can provide
ucts depends on the variations in molecular weight of polymer new therapeutic approaches due to the synergistic advantages of
and ratio of polymer/solvent used (Thakur et al. 2014). the two technologies bypassing the limitations of using them sep-
arately (Pitorre et al. 2017). For illustration, nano-carrier systems
can demonstrate high loading and encapsulation efficiency of
4. Merits and complications of ISFI systems
drugs in nano-sized particles of adequate zeta potential. Besides,
The development of implantable drug delivery systems is prob- they can associate in achieving sustained release of drugs with a
ably the most widely investigated application of biodegradable low burst, prolonged systemic circulation, improved bioavailability
polymers. The ISFI systems possess several merits in comparison and reduced dosing frequency (Hosny et al. 2020). Merits of ISFI
to the conventional pre-formed implant systems. Due to their systems can be positively exploited regarding their high stability,
transient nature, implant placement is less invasive and less pain- biocompatibility, biodegradability in addition to their solution-gel
ful for patients thereby improving comfort and compliance (Patel phase transitions presented after injection resulting in depots for-
et al. 2010). Besides, the manufacturing process of fabrication is mation for a controlled and targeted delivery of drugs (Kumar et
proportionally mild and straightforward, allowing the ISFI systems al. 2013). Pineda-Hernandez et al. 2020 had formulated nanostruc-
to be appropriate to deliver fragile protein and peptide therapies. tured lipid carriers (NLC) loaded with estradiol showing desirable
Stable plasma levels of drugs can be attained resulting in satisfac- results of nano-size, zeta potential, entrapment and slow release.
tory therapeutic outcomes. The ISFI systems can also enhance The obtained NLC were incorporated inside a thermo-reversible
patient compliance by reducing the frequency of application and ISFI system that displayed satisfactory results towards viscosity,
easy administration with no requirement of surgery (Musmade et gelation temperature, injectability and more delayed sustained
al. 2019). release of estradiol when compared to that of drug solution and
However, the complications of the phase inversion process, drug-loaded NLC. The study of Elmotasem and Awad (2020) had
poor in-vitro/in-vivo correlations, possible solvent toxicity and presented an innovative non-invasive ocular drug delivery system
by blending fluconazole-hydroxypropyl-beta-cyclodextrin-loaded be prepared by enzymatic biochemical processes and chemical

niosomal vesicles and Eudragit nanoparticles as drug carriers with synthesis using chloroacetic acid and sodium hydroxide
ISFI systems. Thereby, the antimycotic action of fluconazole was (Avgoustakis 2008; Inkinen et al. 2011). As shown in Figure 6, lac-
promoted by enhancing its contact time, ocular permeation into tides and glycolides are cyclic dimers obtained from dehydration
the eye compartments sustained release and hence the patient of lactic acid and glycolic acid (Erbetta et al. 2012). PLGA polymer
compliance could be achieved. Dong et al. 2011 had studied the can be developed by the method of melt co-polymerization of
preparation of PLGA hybrid implants having improved sustained lactide and glycolide in the presence of stannous octoate, as a
risperidone release with low burst effect by changing the morph- catalyst, under a high vacuum. This is followed by polymerization
ology, phase inversion and injectability of systems after incorpor- of cyclic lactide and glycolide by ring-opening method with differ-
ation of solid lipid (glyceryl monostearate). ent initiators to obtain polylactic acid (PLA) and polyglycolic acid
(PGA) (Gentile et al. 2014). Initially, a low molecular weight
(2000–10 000 Da) oligomer is obtained that then forms the PLGA
5. Potential of smart polymers in ISFI preparation
polymer with a higher molecular weight on further heating. PLGA
Smart polymers represent a rapidly growing area with enormous polymer is purified by dissolution in chloroform and precipitation
technological and commercial potential in pharmaceutical and in ethanol, followed by drying in vacuum at room temperature
biomedical fields. These polymeric macromolecules can exhibit for 48 h (Zhang et al. 2019).
spectacular physico-chemical changes in response to small altera-
tions in the surrounding medium (external stimuli). These stimuli 5.1.2. Merits and complications of PLGA
may be temperature, pH, light, solvent, magnetic field, ions or Drug delivery systems comprising PLGA polymers are one of the
pressure (Cabane et al. 2012). most noteworthy drug carriers developed in respect of improving
These polymers are extensively used for the development of solubility, effectiveness, efficacy and safety of drugs. The remark-
injectable formulations and have acquired much concern over the able physico-chemical properties of PLGA can attain the sustained
last few years. The interest in using these smart polymers has release of drugs with the maintenance of their desirable thera-
been expanded due to the potential characteristics of these deliv- peutic ranges over extended periods (Martins et al. 2018).
ery systems including their biodegradability and improved patient Therefore, the tunable characteristics of PLGA are exploited to
compliance and comfort (Madan et al. 2009). For instance, they exhibit more exemplary drug-encapsulating candidates for appli-
can provide ease of application, localized drug delivery for the cation in diverse fields such as drug targeting (Olivier 2005), tissue
site-specific action, extended delivery periods, relatively low drug regeneration (Behrens et al. 2016), vaccine delivery (Gu et al.
dosage and concurrent reduction of possible undesirable side 2019), cosmeceuticals (Tsujimoto et al. 2007) and dentistry
effects (James et al. 2014). In addition, their glass transition tem- (Agossa et al. 2020). Commercially, different grades of PLGA are
perature above 37 C can provide rigid chain configuration and available corresponding to various molecular weights, inherent
reasonable mechanical strength at ambient temperature. These viscosities, ratios of lactic to glycolic acids and end-cappings
polymers are available in different grades and various molecular (Kapoor et al. 2015).
weights providing wide ranges of physico-chemical characteristics, However, different systems based on PLGA polymers may
release profiles and degradation properties (Gentile et al. 2014). encounter various challenges for encapsulation of proteins and
Different examples of biodegradable polymers used in the formu- peptides of pH-sensitive or rapid degradation properties. This is
lation of ISFI systems are shown in Table 1 (Kapoor et al. 2015; followed by their incomplete release and instability which are
Stewart et al. 2018). attributed to several causes (Allahyari and Mohit 2016). The
encapsulation process requires the removal of utilized organic sol-
vents, thus affecting the structure of the protein with the forma-
5.1. PLGA polymer
tion of aggregates and stability loss (Martins et al. 2018). Besides,
PLGA, as one of the phase-sensitive smart polymers, is approved PLGA undergoes auto-catalytic degradation resulting in the pro-
by FDA for several therapeutic applications because of its favor- duction of acidic by-products and the presence of a highly acidic
able biodegradability, biocompatibility, non-toxicity and sustained environment. This can negatively affect the stability of encapsu-
release properties (Reddy et al. 2015). During recent years, the lated proteins in addition to the incidence of local irritation of the
use of biodegradable PLGA polymer for controlling and targeting surrounding tissues (Agarwal and Rupenthal 2013). Therefore, sev-
drug delivery systems has ultimately increased. Table 2 shows eral strategies can be followed to face these troubles. The intro-
examples of previously reported drugs loaded in PLGA polymers duction of stabilizing additives into the PLGA-based formulations
of different grades for the preparation of ISFI systems. can inhibit the denaturing interactions between PLGA and protein
molecules (Hajavi et al. 2018). Tailoring the properties of PLGA
5.1.1. Synthesis of PLGA polymer by chemical modifications such as co-polymerization
Lactic acid is a methyl-substituted glycolic acid that can be pro- with polyethylene glycol (PEG), known as PEGylation, has also
duced in D and L forms by fermentation of corn and other agri- demonstrated ultimate success to generate more stable protein-
cultural sources. Glycolic acid is 2-hydroxyethanoic acid that can loaded preparations (Dutta et al. 2020). In addition, utilization of
Table 1. Examples of phase-sensitive biodegradable polymers for ISFI formulation.

Polymer Degradation time (months) Inherent viscosity (dl/gm) Density (gm/ml) Tensile strength (MPa)
PLGA (50:50) 1–2 0.55–0.75 1.34 40–55
PLGA (65:35) 3–4 0.55–0.75 1.20 40–55
PLGA (75:25) 4–5 0.55–0.75 1.20 40–55
PLGA (85:15) 5–6 0.55–0.75 1.27 40–55
PLA 18–24 0.90–1.20 1.24 55–80
PCL >24 1.6 2.2 1.15 10.5–16.1
PLGA: poly (lactide-co-glycolide); PLA: polylactide; PCL: polycapronolactone.
Astaneh et al. 2009

basic excipients with PLGA can facilitate the neutralization of
Enayati et al. 2017

Ahmed et al. 2014
Ahmed et al. 2016
Kamali et al. 2019

Wang et al. 2003
Wang et al. 2012
Wang et al. 2017

Dong et al. 2011
Bode et al. 2018
Amini-Fazl 2021
acidic environment exist after the PLGA auto-catalytic degrad-
References
Lin et al. 2012

Liu et al. 2010
ation, hence decelerating the instability of the protein (Hines and
Kaplan 2013).
5.1.3. Different co-polymers of PLGA

Modified co-polymerization techniques of PLGA polymer using
Release up
to (days)
other polymers have been extensively studied for producing a

17
28
30
16
60
28
30
7
16
90
35
28
28
miscellaneous variety of pharmaceutical and biomedical formula-
tions of better mechanical features and drug delivery (Huh et al.
NMP-benzyl benzoate mixture 2003). One of the most well-known polymers used in the co-poly-
merization of PLGA is the hydrophobic PCL polymer. Preparation
of PLGA-PCL copolymer can support the PCL to reduce the glass
benzyl benzoate-benzyl
NMP-triacetin mixture
transition temperature, enhance the flexibility and hinder the

Solvent
alcohol mixture
brittleness of PLGA polymer (Martins et al. 2018). In contrast,

benzyl benzoate
amphiphilc co-polymerization is more crucially required for the

successful performance of ISFI systems. This can be attained by
co-polymerizing the PLGA with a hydrophilic polymer such as PEG
DMSO
DMSO
NMP
NMP
NMP
NMP
NMP
NMP
NMP
in order to find a satisfactory balanced hydrophobic-hydrophilic

environment (Zhang, Tang, et al. 2014). The combination of PLGA
and PEG can represent synergistic advantages and better release
58 000, 65 000, 105 000, 113
000, 34 000 and 48 000
000, 34 000 and 48 000
20 000, 30 000 and 40 000
kinetics in comparison to using a single PLGA. The hydrophobic

Molecular weight (Da)
core of PLGA can enable the incorporation and encapsulation of

000 and 111 000
drug and the hydrophilic shell of PEG can restrain the adsorption
11 700 and 81 900
15 000 and 45 000
24 000–38 000
38 000–45 000
of opsonins and clearance of formulation through the phagocytic

60 000-70 000
30 000-60 000
38 000-54 000
7000–17 000
system, therefore prolonging its circulation time (Makadia and

Siegel 2011). The co-polymerization PLGA-PEG with PCL polymer
000
000
10 000
has recently evolved to produce spectacular classes of polymeric

17
12
12
50
systems for drug delivery and biomedical applications. This can

achieve in-vitro sufficient stability in addition to in-vivo prolonged
inherent viscosity
0.73 and 0.74
circulation time (Haggag, Ibrahim, et al. 2020).

Table 2. Examples of previously reported drugs loaded in PLGA polymers of different grades for ISFI preparation.
0.36, 0.49, 0.70,
0.18 and 0.54
The PLGA-PEG co-polymerization has been processed in the

0.32–0.44
0.45–0.60
(dl/g)
0.16–0.24
forms of diblock PLGA-PEG, triblock PLGA-PEG-PLGA or triblock

PEG-PLGA-PEG copolymer types. In diblock types, the PEG chains
0.13
0.45
0.5
can orient themselves around the external aqueous phase and act
–
–
–
–
–
–
as a barrier that performs steric repulsion and enhances the shelf

Lactide:glycolide ratio
stability (Makadia and Siegel 2011). Several studies have produced

50:50 (acid-capped)
50:50 (acid-capped)
50:50 (acid-capped)
50:50 (acid-capped)
potential results for desirable characteristics and applications of

of PLGA
50:50 and 75:25
PLGA-PEG diblock co-polymers in various drug delivery systems

such as microparticles (Mallarde et al. 2003), nanoparticles
(Haggag et al. 2016), micelles (Ashjari et al. 2012), hydrogels
50:50
50:50
50:50
70:30
75:25
50:50
50:50
75:25
(Maeda et al. 2019) and ISFI systems (Milacic and Schwendeman

2014). The presence of the PEG segment has gained popularity
owing to its biodegradability, biocompatibility, crystallinity, micro-
phase separation, safety and proven commercial potentials. In
addition, it can regulate the formulation hydrophobicity, control
Natural herb of anti-myocardial
the drug loading and release and consequently upgrade the over-
NMP: N-methyl-2-pyrrolidone; DMSO: dimethyl sulfoxide.
Treatment of prostate cancer
Treatment of prostate cancer
all bioavailability (Huh et al. 2003; Haggag, Elshikh, et al. 2020).

Cholesterol-lowering agent
Immuno-enhancing agent
Indication
Opiate antagonist agent
Furthermore, the triblock co-polymers can act as temperature-

Anti-psychotic agent
responsive co-polymers. They remain as free-flowing solutions at

ischemia activity
Anti-inflammatory
low temperatures (below the gelation temperature). They can be

Anti-psychotic
Anti-psychotic
Ani-asthmatic
transferred to highly viscous gels at body temperature after

Anti-emetic
Anti-cancer
administration (Maeda et al. 2019). This can readily minimize the

initial burst release of encapsulated drugs and provide no surgical
procedures for a temperature-induced solution to gel transition
(Jeong et al. 2000). These copolymers are emerged as attractive
candidates for hydrogel delivery systems (Osorno et al. 2020) and
Radix Ophiopogonis
injectable ISFI matrixes (Kamali et al. 2020) because of their ease

Leuprolide acetate
Leuprolide acetate
polysaccharide
Thymosin alpha1
Metoclopramide
of manufacture, formulation, filling and handling. There are many

Dexamethasone
important factors that can influence the properties and applica-

Paliperidone
Montelukast
Atorvastatin
Risperidone
Risperidone
Naltrexone
Paclitaxel
tions of amphiphilic co-polymers such as the nature, molecular

weight and length of hydrophobic PLGA segment, the molecular
Drug
weight of PEG segment, PLGA/PEG ratio and concentration of the

Figure 6. Synthesis of PLGA from lactic and glycolic acids.
polymeric solution (Osorno et al. 2020). Moreover, PEGylation of of viscosity, water affinity, capability for dissolving the polymer
PLGA can generate a benign environment for the encapsulation and safety (Kapoor et al. 2012). The organic solvent should pos-
of hydrophilic protein and peptide molecules. Further limitations sess good solubilization capacity for the used biodegradable poly-
of high burst and incomplete release of these molecules from mer. It should be biocompatible by dispersing or diffusing from
hydrophobic PLGA polymers can be alleviated by means of the the implant system causing no adverse biological reactions and
PEG segment (Dutta et al. 2020). Such hydrophilic residue can no tissue irritation at the site of injection. In addition, the capabil-
exert a protective role against the aggregation and inactivation of ity of organic solvents to facilitate the transformation of polymer
hydrophilic molecules by increasing the encapsulation efficiency solution into ISFI system and the deleterious effects of metabolic
and stability of the overall co-polymer (Haggag et al. 2018). products of solvents require to be taken into consideration (Patel
There are various natural polysaccharides that can be used in et al. 2015).
the amphiphilic co-polymerization of PLGA such as chitosan Furthermore, the solvent should have a suitable viscosity to
(Wang et al. 2010), dextran (Alibolandi et al. 2016), pullulan (Lee enhance the ease of injection of the ISFI formulations (named as
et al. 2015) and hyaluronic acid (Yadav et al. 2010). These promis- injectability or syringeability) (Patki et al. 2021). For example, sys-
ing alternatives are highly hydrophilic and render several charac- tems comprising water-immiscible solvents have high viscosities
teristic traits. For instance, the weak alkaline chitosan can assist in that complicate the injection of ISFI systems from syringe needles.
the neutralization of acidity that results from the degradation pro- Warming the ISFI-containing syringe maybe then required prior to
cess of PLGA (Niu et al. 2013). Besides its favorable bioadhesive injection. Therefore, the overall viscosity of the ISFI system should
properties, various bioactive groups of chitosan can be utilized in be within an acceptable range to be easily injectable (Kempe and
the conjugation of targeting ligands (Wang et al. 2010). Co-poly- M€ader 2012). In addition, injectability of ISFI systems can also be
merization of PLGA with dextran can also produce a particular co- facilitated by using solvents, named as good solvents, which have
polymer of branched structure and numerous functional moieties a high affinity to the polymer. This will actually enhance the dis-
that allow dramatic immuno-neutrality and protection against the solution profile and also reduce the overall viscosity of the poly-
reticuloendothelial system (Alibolandi et al. 2016). PLGA-pullulan meric solutions used in the ISFI formulation (Parent et al. 2013).
Also, good solvents can offer lower injected volumes that pro-
and PLGA-hyaluronic acid are other derivatives of PLGA amphi-
mote the possibility to attain higher loading of drugs in the poly-
philic co-polymers showing naturally non-immunogenic, non-toxic
meric formulations. This is beneficial in achieving both lower
and non-mutagenic features (Martins et al. 2018).
volume constraints of injections and lower solvent amounts to be
administered (Bode et al. 2018). In contrast, poor solvents having
6. Components of ISFI formulations low affinity to the polymer can support the polymer–polymer
6.1. Solvent interactions leading to increased viscosity with the formation of
aggregates. Hence, increased viscosity can delay the water entry
The solvent type is one of the formulation factors that exhibits a and drug diffusion, therefore diminishing the burst release and
marked impact on the initial burst release of drug and phase retarding the polymer degradation afterward (Camargo et
inversion rate of matrix. Thus, the aqueous solubility of solvents al. 2013).
affects the solvent exchange rate during the conversion of the Several solvents have formerly been used for the formulation
administered polymeric liquid into a gel (Ahmed et al. 2014). of ISFI systems. Commonly utilized solvents for dissolving the
The ideal solvent or solvent mixture used in the preparation of PLGA polymer can be differentiated into two major species: highly
ISFI systems necessitates possessing convenient features in terms water-miscible solvents and non-miscible ones. Common
examples of the former include NMP, DMSO, acetone, propylene more labile glycolide-lactide bonds into the polymeric backbone.
glycol, tetrahydrofuran, glycofurol, 2-pyrrolidone and benzyl Where, the increment of the content of glycolide can promote
alcohol. While, the latter includes benzyl benzoate, ethyl acetate, the rate of hydrolysis. Kamaly et al. (2016) reported that the dec-
triacetin and triethyl citrate (Wang et al. 2003). The highly water- rement of the number of lactic acid monomers and increment of
soluble organic solvents are known as strong solvents (Eliaz and glycolic acid monomers would promote the water uptake into the
Szoka 2002). These solvents enable the formation of homoge- ISFI system. This could be ascribed to the high exposure of ester
neous gel depots and help the system to be easily injected. This bonds to hydrolysis and the low content of methyl groups on the
is attributed to the development of a fast phase inverting system lactic acid moieties. Hence, an accelerated degradation rate could
formed within a few seconds or minutes. This can provide highly be exhibited.
hydrophilic environment and low viscous solution achieving an The molecular weight of PLGA polymer is another parameter
easy administration of injection (Che et al. 2014). On the other influencing the initial drug release and also the matrix erosion. It
hand, hydrophobic solvents are recognized as weak solvents is a fundamental property that can impact the physico-chemical
(Parent et al. 2013). Utilization of such solvents can result in the and mechanical characteristics of the system such as viscosity,
presence of a slow phase inverting system developed within glass transition temperature, solubility and diffusivity (Amini-Fazl
weeks or months. This system can minimize the affinity between 2021). It has been reported that smaller burst release of drugs
the polymeric solution and water resulting in the reduction of the would occur using high molecular weight PLGA in comparison
liquid-liquid phase separation rate and then the rate of gelation with medium or low molecular weight PLGA. Astaneh et al. (2009)
(Ahmed et al. 2014). pointed out that increasing the molecular weight of PLGA poly-
As biocompatibility and low toxicity are essential for approving mer in the ISFI system would significantly reduce the initial burst
the pharmaceutical preparations, selection and incorporation of release of leuprolide acetate in comparison to that of lower
the organic solvents in the ISFI systems are controversial because molecular weight PLGA polymer. Amini-Fazl (2021) reported that
of their possible toxicity and incompatibility (Parent et al. 2013). more interactions would present between functional groups of
For instance, NMP solvent is reported as safe owing to its paclitaxel and PLGA of higher molecular weight resulting in
pharmaceutical priority in the formulation of parenteral products. increasing the glass transition temperature of the ISFI system.
However, the free miscibility of NMP solvent in water is undesir- Then, a lower penetration rate and initial burst release of pacli-
able because of the rapid exchange that occurs between NMP taxel would be achieved when compared to those of low and
and water during the preparation of ISFI systems. Ibrahim et al. medium-molecular-weight PLGA-ISFI systems. Solorio et al. (2012)
2020 reported that unfavorable retarded solidification of NMP-ISFI had deduced that there was a direct relationship between increas-
systems and immediate extraction of NMP to the surrounding ing the molecular weight of polymer and viscosity of the ISFI sys-
medium were exhibited resulting in rapid diffusion of the dis- tem. Thus, the selection of the convenient grade of PLGA polymer
solved risperidone. Therefore, unsuitable large amounts of drug would be essential for the development of ISFI systems with suit-
and solvent may be initially released throughout short minutes or able viscosity.
hours leading to deleterious local or systemic irritations of Another parameter that can control the PLGA hydrophobicity
mucous membranes, skin and muscles after injection as reported is the type of chemical moieties present at the end of polymeric
by Thakur et al. 2014; Karp et al. 2021. As a result, water- chains either end-capped with free carboxylic acids or esters
immiscible solvents are useful but they may hinder the ISFI inject- (Lanao et al. 2013). Where, polymers of the ester end group are
ability resulting in the appearance of complicated biocompatibility relatively more hydrophobic than acid end group ones. Wang et
troubles. Therefore, utilization of a mixture of water-immiscible al. (2020) pointed out that utilization of ester-capped PLGA poly-
and water-miscible solvents is a preferable alternative to achieve mer can slow down the release rate and sustain the release
reasonable viscosity, appropriate phase inversion and low burst period of the drug, whereas the acid-terminated PLGA facilitated
release profile. Liu and Venkatraman (2012a) reported that a mix- much faster drug release. In addition, the end-capping of PLGA
ture of hydrophobic solvent (triacetin) and hydrophilic solvents chains has a marked impact on the type of solvent used in the
such as NMP and DMSO showed a reduction in the burst release preparation of ISFI systems. For example, ester-capped PLGA poly-
profile of metoclopramide monohydrochloride in comparison to mers are insoluble in hydrophilic solvents and need more hydro-
the pure hydrophilic solvents. In another study, Wang et al. (2017) phobic solvents to provide optimal solubility of the polymer and
pointed out that utilization of NMP and benzyl benzoate as mixed successful development of the ISFI systems (Jivawala and
solvents were suitable for sustaining the release of herbal polysac- Goyani 2017).
charides having short plasma half-life with low bioavailability. Furthermore, the end-capping can reduce the PLGA hydrolysis
rates since it can increase the lipophilicity of the polymer and
decrease the water uptake. The acid-capped PLGA can also
6.2. Polymer
increase the autocatalysis of the ester bond degradation. Thus,
The choice of PLGA grade may be considered as the key factor in esterified end groups could minimize the rates of PLGA hydrolysis
the process of modifying the drug release from PLGA-ISFI systems. (Kamaly et al. 2016). On the other hand, reduced burst release
Where, the polymer degradation, phase inversion dynamics and may be obtained with the acid-capped polymers compared to
polymeric matrix erosion are strongly influenced by proper selec- ester-capped polymers. This can be seen in the case of active
tion of PLGA type and grade (Ahmed et al. 2014; Woodard and drugs that possess functional groups interacting with polymer
Grunlan 2018). The composition of PLGA is a critical point for con- acidic ends. For instance, Chhabra et al. (2007) reported that a
trolling drug delivery through ISFI systems. The proportion and great reduction in burst release was obtained by using acid--
distribution of both lactide and glycolide inside the PLGA chains capped polymers. This might be attributed to the chemical link-
are fundamental parameters to modulate the system’s hydropho- ages formed between the amino acid residues of studied
bicity and crystallinity and to influence the solvent-water lysozyme with the carboxylic acid end groups of the polymer.
exchange rate and degradation (Jerbic 2018). Glycolide has a Moreover, the simplest strategy to diminish the burst release
slightly higher hydrophilic nature than lactide. This can represent of drugs from ISFI systems is the increment of polymer
concentration. This can result in decreasing the water affinity of PLGA-ISFI systems. Therefore, the drug was reported to be chem-
the solution, formation of thicker solidified polymer and generally ically stable when dispersed in the polymeric suspensions rather
minimizing the diffusivities in the ISFI systems. This also can slow than being dissolved in the PLGA solutions. Meanwhile, PLGA-
down the solvent-water exchange and produce a less porous based ISFI systems are not compatible for drugs being degraded
polymeric texture (Bode et al. 2018). In addition, increasing the by water and also unsuitable for drugs highly susceptible to the
PLGA concentration can tend to increase the viscosity of ISFI sys- acidic environment exhibited following degradation of polymeric
tems. Thus, the release of the drug into the external medium can texture. Hence, following modified strategies by introducing sta-
be decelerated producing a slow burst release pattern with more bilizers, basic excipients or PEGylation had manifested fundamen-
injectability obstruction and great power needed for injection tal success in preparing stable PLGA-ISFI systems of satisfactory
from syringe needles (Sheshala et al. 2019). release as previously reported by Hines and Kaplan (2013), Hajavi
et al. (2018) and Dutta et al. (2020).
6.3. Drug
The drug solubility, loading and stability are also substantial fac- 6.4. Additives
tors that require to be taken into consideration during the devel-
The incorporation of additives into the polymeric solution is con-
opment of ISFI systems (Patel et al. 2015). Concerning the drug
sidered one of the alternative methods to control the release of
solubilization capacity of solvent or polymer solution used, the
drugs from ISFI systems. These additives can be divided into three
drug may either present in a dissolved or dispersed state in the
prepared formulation forming a homogeneous or heterogeneous species as hydrophilic, hydrophobic and amphiphilic (Parent et al.
solution (Lin et al. 2012). Therefore, the different nature and solu- 2013). Using hydrophilic additives can help to enhance the liquid-
bility of the drug in the system may bring out different release liquid demixing and produce a high burst release of drugs.
profiles. Wang et al. 2012 and Ibrahim et al. 2020 studied the Examples of these additives are mannitol (Wang and Friess 2018)
effect of risperidone solubility in different organic solvents such and polyvinylpyrrolidone (Yarnsuphawong et al. 2015). Such
as NMP and DMSO to formulate the PLGA-ISFI systems. However, additives can increase the phase separation permitting a great dif-
a high risperidone release rate was observed in the homogenous fusion capacity. Jain et al. (2000) studied the fast leaching of
ISFI systems containing NMP solvent, a slower release rate and these additives during the initial burst release causing alterations
high retention of drug in implants with reduced initial burst in the water penetration and overall morphology of the system.
release were represented by the heterogeneous systems contain- On the other hand, the addition of hydrophobic additives can
ing DMSO solvent. lower the burst release of drugs causing alterations in the morph-
Moreover, injectable formulations with high drug loadings ology of the system. Examples of these additives are stearic acid,
have the advantage that the formulation volume can be reduced glycerol monostearate, methyl heptanoate, ethyl heptanoate and
considering a fixed-dose to be administered (Bittner et al. 2018). ethyl nonanoate (Bakhshi et al. 2006; Dong et al. 2011; Kamali et
This is interesting from an economic point of view and the al. 2019). These additives can retain more amounts of solvent,
patients’ point of view because the time of pain exposure can be produce less porous sponge-like matrices and result in decreased
reduced. Patki et al. 2021 reported that increased remdesivir load- initial burst and extended-release of drugs.
ing could be achieved by reduction of PLGA concentration, there- Furthermore, small morphological changes with reduced burst
after decreasing the total work required for injection and the pain release of drugs can be achieved by using amphiphilic additives
resulted during the injection. such as PluronicV (poly(ethylene)oxide–poly(propylene)oxide–po-
R
Drug stability is also regarded as one of the important criteria ly(ethylene)oxide) (PEO-PPO-PEO) (Parent et al. 2013). Selection of
to be targeted in ISFI preparation. The drug should be compatible PluronicV concentration and chain length can help to achieve a
R
with the polymer and solvent used (Patel et al. 2015). The chem- hydrophilic-lipophilic balance. This balance is exhibited between
ical interactions may be exhibited between the drug and ISFI exci- the higher water absorption carried out by the hydrophilic PEO
pients. The drug can either promote polymer degradation or may ends and the diffusion barrier performed by the lipophilic PPO
be degraded while being in contact with the ISFI components chains (Augusthyet al. 2017). In addition, PluronicV can induce a
R
(Parent et al. 2013). On one side, the drug may contain water or
considerable separation during the phase inversion corresponding
help to form hydrogen bonds with the polymer chains resulting
to the specific location of its chains in the system. Where, the
in boosting the exposition of ester bonds to water and then the
lipophilic PPO chains are embedded into the polymeric matrix
polymer degradation. Tang and Singh (2008) pointed out that
resulting in the reduction of drug adsorption and enhancement
higher hydrophilicity of aspirin could enhance its release from
of system biocompatibility. The hydrophilic PEO ends are diffused
PLGA-ISFI systems and thereafter accelerate the rate of PLGA deg-
into the external medium, hence producing a diffusion barrier
radation. In addition, the higher aspirin acidity facilitated its local-
ization as an ionized form in the aqueous zones of ISFI systems (Figure 7) (Gyulai et al. 2011).
with raising the acidity of the whole system that caused rapid
bulk erosion of the PLGA core. On another side, the polymer and/ 7. Mechanism of drug release from polymeric PLGA-
or solvent may support the degradation or inactivation of the ISFI systems
drug. Dong et al. (2006) reported that the PLGA degradation
using hydrophilic NMP solvent in leuprolide acetate-loaded ISFI The drug release from ISFI systems is generally characterized by
preparations was faster than that with hydrophobic triacetin solv- an initial burst during the solidification of the matrix, followed by
ent. Regarding the dissolved or dispersed state of leuprolide acet- a second period mainly controlled by diffusion processes. Finally,
ate in NMP and triacetin respectively, the dissolved drug could subsequent drug release is driven by polymeric carrier degrad-
completely release its bound water and participate in the PLGA ation and erosion (Ahmed et al. 2016). Mechanism of matrix
degradation. However, leuprolide acetate in a dispersed state solidification and successive stages of release of drugs from ISFI
could reduce the water content forming more stable drug-loaded systems are explained below.
Figure 7. Physical gelation mechanism of PluronicV in water.

R
7.1. Matrix solidification phase

The precipitation of polymer can be carried out as a result of con-
tact of PLGA-ISFI systems with the aqueous body fluids. This
occurs because of the phase inversion step triggered in the poly-
meric solutions (Gad 2016). Nevertheless, the immediate forma-
tion of the ultimate solid depot is not achieved but relies on the
kinetics of the phase inversion. Where, an exchange between the
solvent used and non-solvent (i.e. water or body fluids) can exist.
The occurrence of both non-solvent influx and solvent outflow is
the key factor of the ISFI phase inversion dynamics (Thakur et al.
2014). The phase inversion dynamics can be tailored by control-
ling the composition of ISFI systems towards the polymer and/or
solvent. Such changes in ISFI components can directly exert
impacts on the initial burst drug release within the first hours of
release and also on the next diffusion and erosion release stages.
This may be attributed to the significant consequences performed
on the morphology of the polymeric matrix and its degradation.
Morphological studies conducted by Liu and Venkatraman
(2012b) pointed out that highly hydrophobic PLA polymer could
undergo faster phase inversion and precipitation followed by the
formation of a highly porous structure and higher burst release of
metoclopramide. In comparison, utilization of lower hydrophobic
PLGA polymer could present a smoother and continuous matrix Figure 8. Release profile stages of fast and slow inverting systems (1) initial
of slower phase inversion and drug release. burst release (2) diffusion-controlled release (3) erosion-controlled release; (A)
After an initial period of time upon injection, the drug and solv- constant release pattern (B) continuous diffusion-controlled release pattern.
ent release by diffusion is represented as the appropriate transport
mechanism during the matrix solidification. The initial amount of formed matrix. The drug release can be influenced by various key
drug released can be ascribed to the physico-chemical properties of factors such as its diffusivity within the polymeric matrix, solubility
a studied drug such as partition coefficient, solubility, diffusivity, and loading in addition to the porosity and tortuosity of diffusion
molecular weight and dissociation constant (Versypt et al. 2013). In pathway and matrix dimensions. Parent et al. 2013 reported that
addition, the miscibility of utilized solvent in water displays a defini- a small amount of drug released throughout the diffusion phase
tive function in controlling the drug release owing to its potential can result in a nearly constant release pattern between the initial
on the environment of drug diffusion. Ibrahim et al. 2020 reported burst and erosion stages (Figure 8(A)). However, a continuous dif-
that the high solubility of risperidone in water-immiscible solvent fusion-controlled drug release (Figure 8(B)) over time can be
(triacetin) resulted in a lag period between injecting the ISFI system achieved by a controlled modification in the ISFI composition and
into a buffer and its solidification. Therefore, more amounts of drug then the phase inversion dynamics. Fredenberg et al. (2011)
were diffused into the external environment in contrast to that pointed out that the drug can present higher diffusivity especially
exerted by the water-miscible DMSO solvent having lower solubil- through the polymer of lower molecular weight and more flexible
ization capacity of risperidone.
polymeric chains. Mittal et al. (2007) stated that the estradiol dif-
fusion through low molecular weight PLGA followed zero-order
7.2. Drug diffusion phase
owing to the increased diffusion coefficient caused by degrad-
The diffusion mechanism relies on the physico-chemical proper- ation. In comparison, constant diffusion coefficient following the
ties of both drug and polymer and also the morphology of the Higuchi model was exhibited by using PLGA of higher molecular
weight. In another study, Ibrahim et al. (2014) reported that the benchtop rheology method can represent widely acceptable, sim-
meloxicam diffusion was reduced by increasing the PLGA concen- ple, quick and inexpensive measurements to help study the solu-
tration and viscosity. Besides, although increments of NMP levels tion-gel transitions. This method is utilized as a complement to
demonstrated positive impacts on the burst release of meloxicam, the viscosity measurements as a function of temperature (Pineda-
non-significant effects on the diffusion and cumulative release of Hernandez et al. 2020). In this test, the formulation vial is trans-
the drug were monitored. ferred to a thermostatically controlled water bath at 4 C. The
temperature is then increased gradually till reaching the region of
7.3. Implant erosion phase the solution-gel transition temperature. By inverting the vial at an

angle of 90 , the solution-phase is defined as a flowing liquid
Polymer degradation is the process of hydrolytic cleavage of poly- while the gel-phase is defined as a non-flowing gel. The tempera-
meric chains that are cut into oligomers and then into monomers. ture at which the gel does not flow upon tilting is recorded as
The prerequisite for polymeric erosion is the degradation of poly- the solution-gel transition temperature (Barakat et al. 2017).
meric implant mass. This can be induced by releasing the water- Another method that can be followed to measure such tempera-
soluble degradation products from the PLGA matrix after the ture is called the stirring magnet bar method (Zhang, Shi, et al.
hydrolysis process (Vhora et al. 2021). Lactic and glycolic acids are 2014). At fixed stirring speed, the formulation vial is placed on a
examples of monomeric end products that are easily eliminated
thermo-stated magnetic stirrer and the temperature is then
by the Krebs cycle (Elsawy et al. 2017). Moreover, the water can
increased slowly. The solution-gel transition temperature is con-
penetrate the polymer rapidly than the polymer bonds are
sidered at which the motion of the magnet bar stops.
degraded. Therefore, the polymer is hydrolyzed over the whole
Various factors can be taken into consideration to affect the
matrix homogeneously forming the degradation products, and
temperature of the gelation process such as composition, concen-
then the bulk erosion occurs. These degradation products contain
tration and molecular weight of polymers (Wang et al. 2018),
carboxylic chain ends that can autocatalyze the ester bond
solubilization capacity and concentration of used solvents
hydrolysis and then accelerate the degradation of the whole poly-
(Phaechamud et al. 2012) and other included excipients. These
meric matrix (Kamaly et al. 2016). Amini-Fazl (2021) studied the
relationship between the pH, amount of released monomers and factors can be tuned to coordinate the application requirements
amount of paclitaxel released during the degradation stage of of ISFI formulations showing good feasibility and controlled
PLGA-ISFI systems. The pH of the system was reduced as a result release of drugs.
of acidic products released during the degradation, consequently
increasing the drug release. 8.3. Texture profile analysis
The measurement of mechanical properties such as hardness,
8. Physico-chemical characterization of ISFI systems compressibility, adhesiveness, cohesiveness and elasticity is a key
8.1. Viscosity determination mechanical parameter to be considered during ISFI preparation
(Patlolla et al. 2019). In this test, a texture profile analyzer
Viscosity measurement is one of the important parameters equipped with a cylindrical probe of specific weight in a compres-
required for the evaluation of ISFI systems. This parameter should sion mode can be used. The analytical probe is compressed down
be considered pre and post-thermo-conversion of the ISFI systems into the studied ISFI formulation to a definite depth with a con-
designed to be subcutaneously injected (Musmade et al. 2019). stant speed. Two compression cycles are applied to the formula-
The Injectability of ISFI systems before thermo-conversion is com- tion and the resulted mechanical parameters can be calculated
monly controlled by their rheology. Where, the highly viscous sys- from the area under the curve (AUC) derived from the obtained
tems can produce various challenges during their manufacturing.
force-time curves. The texture profile analysis helps to determine
After conversion into gels at the body temperature, the viscosity
the maximum forces (injectability) required to expulse the pre-
of ISFI systems should be taken into consideration when being
pared polymeric ISFI formulations from syringe needles as an indi-
localized in the body tissues providing an extended drug diffusion
cation of their administration in-vivo (Sheshala et al. 2019).
with no difficulties or pain at the site of injection (Vineetha and
The mechanical parameters of this test can be defined as pre-
Koland 2017). Gad (2016) pointed out that low viscous ISFI sys-
viously described by Patlolla et al. (2019) and Agossa et al. (2020).
tems containing DMSO solvent showed faster spreading, while
Briefly, hardness can be determined as the maximum compression
systems containing highly viscous triacetin solvent resulted in
force needed to produce sample deformation in the first compres-
lower spreading throughout the aqueous media, less time for
PLGA precipitation and inability to form a depot. This was sion cycle. Lower hardness values express the easy administration
ascribed to the lag time between the solution injection in the and good spreadability of ISFI formulations. Compressibility can
external medium and its solidification process. be measured as the work done for achieving sample deformation
throughout the first cycle of compression. Its low value indicates
the easy removal of the formulation from the container before
8.2. Solution-gel transition temperature administration. In addition, adhesiveness is the AUC of the first
The ISFI systems can exhibit promising potentials for several clin- peak. It expresses the work required to detach the probe from
ical applications when they show satisfactory solution-gel transi- the tested formulation as a relative of its adhesive tendency to
tion at the in-situ application site. It is significant for the the tissue surface. Cohesiveness can be also measured to observe
successful preparation of ISFI possessing more adhesion and the strength of the internal structure of ISFI samples in addition
retention of drugs (Yadav et al. 2020). In previous studies, the to their resistance to rupture. This value is calculated as the ratio
solution-gel transition was examined by rheology methods that of the AUC of the second compression cycle to the first one. The
suffer from several limitations such as time-consuming and risks return rate of the deformed sample to its beginning state can be
of dehydration of gels (Chenite et al. 2001; El-hefian and Yahaya described as elasticity which is required to have a low value. Okur
2010). Alternatively, the vial inversion method also called as et al. (2020) reported that ISFI formulations of higher hardness,
adhesiveness and cohesiveness can produce a slow and con- or chromatographically to calculate the mean values of drug uni-
trolled release of drugs. formity according to the following equation (Prabhu et al. 2005):
Actualdrugamount
Druguniformitypercent ¼ 100
8.4. Gel strength Theoreticaldrugamount
The gel strength parameter, as an indication of ISFI viscosity
under physiological conditions, can be followed to describe the 8.7. In-vitro drug release studies
stiffness of gel networks. The ideal gel strength can promote the
easy administration of solution without leakage from the injection The in-vitro release testing methods intended for studying the
site, therefore governing the drug release rate after injection extended-release of drugs from injectable ISFI systems include
(Kanwar and Sinha 2019). This test can be performed by using gel various procedures such as sample and separate method, continu-
strength apparatus. The formulation is transferred into a grad- ous flow cell method and dialysis method as discussed below.
uated cylinder and placed into a heated water bath at 37 C till
being converted into a gel. A piston of specific weight is then 8.7.1. Sample and separate method
placed onto the gel surface and the time in seconds required for The sample and separate method is one of the most extensively
moving the piston down by 5 cm is recorded as gel strength used methods for testing the extended-release of drugs from
(Chaudhary and Verma 2014). Values within the range of 25–50 s nanoparticulates and ISFI systems. The drug release can be
are considered sufficient and good for the formulation to be read- studied by using a water bath shaker thermostatically controlled
ily administered. Values lower than 25 s indicate the insufficient at 37 ± 0.5 C and suitable speed. The tested formulations are
integrity of the ISFI structure that may flow rapidly away from the injected into capped bottles comprising the receptor medium fol-
site of injection. While, formulations of strength greater than 50 s lowing the maintenance of suitable sink conditions. Samples are
possess higher hardness causing patient discomfort during admin- withdrawn at different time intervals and subsequently analyzed
istration (Hosny and Rizg 2018). The gel strength parameter can spectrophotometrically or chromatographically to determine the
be alternatively measured by using a rheometer. The formulation mean values of the cumulative release of the drug (Ahmed et al.
is heated at 37 C using a water bath and then a probe is pushed 2016). Direct and accurate evaluation of in-vitro release of drugs
slowly through the formed gel. The alteration of loads applied on can be provided by this method. Yang et al. (2021) pointed out
the probe can be recorded as gel strength as a function of the the appropriate capability of such a method for discriminating the
depth of immersed probe below the gel surface (Dhir et al. 2016). eprinomectin-ISFI systems and predicting their in-vivo performan-
In another study, Walewijk et al. (2008) had utilized the texture ces in animals. Despite these advantages, it possesses some limi-
profile analyzer to record the strength of in-situ gels by measuring tations such as inappropriate agitation and difficult comparison
the force required to penetrate the probe of the instrument into between formulations resulted from using bottles of variable
the gel. dimensions (D’Souza and DeLuca 2006; Shen and Burgess 2013).
For optimal administration of ISFI systems in-vivo with satisfac-
tory gel strength and residence time at the injection site, it is per- 8.7.2. Continuous-flow cell method
tinent to concern with the concentration, type, grade and The continuous flow cell method can be followed to study the
molecular weight of the polymer and regulates its proportion to release of drugs using USP apparatus 4 as reported by Neubert et
solvents and additives utilized (Pineda-Hernandez et al. 2020). al. (2008) and Browne and Kieselmann (2010). The parenteral ISFI
systems can be placed into flow-through cells together with glass
beads in order to restrain the system aggregation and enhance
8.5. Optical and scanning electron microscopy
the laminar flow of release media throughout cells. The release
The impact of phase inversion dynamics and solution-gel turn- media is distributed through the flow-through cells then the
overs on the internal and external morphology of ISFI systems release profile is observed from the open (effluent) or closed
can be examined. Wang et al. 2012 studied the effect of phase (exterior media reservoir) systems (Shen and Burgess 2012). The
inversion of ISFI systems at different morphologies on the release USP apparatus 4 necessitates a sampling pump for the release
profile of risperidone and paliperidone. The dense external layer medium since the rate of dissolution depends directly on the rate
of ISFI systems formed by NMP solvent had delayed the solvent- of flow of such medium when pumped into the flow-through the
water exchange during ISFI solidification, therefore accelerating cell (Uddin et al. 2011). The apparatus can mimic the in-vivo sub-
the diffusion of the loaded drugs. While, utilization of DMSO solv- cutaneous environment because the constant circulation can
ent had created a thick front layer and hard dense matrix that resemble the dynamic in-vivo environment. This method is com-
slowed down the penetration of water and diffusion of drugs. monly used for many parenteral formulations administered at
Another study by Sheshala et al. (2019) and Ibrahim et al. (2021) minimal doses (Shen and Burgess 2012; Zhang and Fassihi 2020).
reported that the PLGA-ISFI systems were degraded over time However, the pump precision that influences the results is neces-
confirming the biodegradation of the PLGA polymer. Therefore, sary and the fractioned primary data may lead to experimental
no surgery would be needed to remove the pre-injected ISFI sys- errors or erroneous data when computed to cumulative release
tems owing to their natural loss inside the body. profiles (Uddin et al. 2011).
8.7.3. Dialysis method

8.6. Drug uniformity
The dialysis method is considered one of the attractive methods
The drug uniformity of ISFI formulation can be calculated by dir- for studying the drug release from ISFI systems (G€ uven et al.
ect recovery of the loaded drug from the polymeric solution. The 2019). In order to develop a convenient dialysis method for
formulation is mixed with a known volume of a specific solvent achieving the extended release of drugs from the ISFI systems,
using a vortex and then centrifuged at room temperature. The several parameters should be pursued such as volumes of donor
supernatant is filtered and then analyzed spectrophotometrically and acceptor, agitation conditions and molecular weight cutoff of
dialysis membrane. In addition, the outer release media should be References

at a range of 6–10 times larger than the inside volume of the dia-
lysis sac in order to achieve a driving force for drug crossing via Agarwal P, Rupenthal ID. 2013. Injectable implants for the sus-
tained release of protein and peptide drugs. Drug Discov
the dialysis membrane (D’Souza and DeLuca 2006). However,
Today. 18(7–8):337–349.
alteration in the drug release profiles, aggregation caused by
Agossa K, Delepierre A, Lizambard M, Delcourt-Debruyne E,
insufficient agitation within the dialysis sacs and changes of sink
Siepmann J, Siepmann F, Neut C. 2020. In-situ forming implants
conditions emerge as the prevalent limitations of this method
for dual controlled release of chlorhexidine and ibuprofen for
(Shen and Burgess 2012). periodontitis treatment: microbiological and mechanical key
properties. J Drug Deliv Sci Technol. 60:101956.
Ahmed TA, Alharby YA, El-Helw AM, Hosny KM, El-Say KM. 2016.
9. Conclusions Depot injectable atorvastatin biodegradable in situ gel: devel-
opment, optimization, in vitro, and in vivo evaluation. Drug Des
Biodegradable ISFI systems have gained great popularity in com-
Devel Ther. 10:405–415.
parison to other sustained-release systems such as microemul-
Ahmed TA, Hussain Z. 2010. Preparation of parenteral in situ gel
sions, vesicular systems, microspheres, micelles, nanoparticles and
formulation based on smart PLGA polymer: concepts to
surgical solid implants. This is owing to their noteworthy merits
decrease initial drug burst and extend drug release. In: Rohman
including easy production, acceptable administration route, G, editor. Biodegradable polymers: recent developments and
reduced dosing frequency and achievement of patient compli- new perspectives. Croatia: IAPC Publishing. Chapter 9; p.
ance. ISFI systems can be classified according to their solidifica- 315–336.
tion mechanism into in-situ cross-linking systems, in-situ Ahmed TA, Ibrahim HM, Samy AM, Kaseem A, Nutan MTH,
solidifying organogel systems and in-situ phase separation sys- Hussain MD. 2014. Biodegradable injectable in situ implants
tems under triggering factors of temperature change, pH change, and microparticles for sustained release of montelukast: in vitro
light or solvent exchange. PLGA, as FDA approved phase-sensitive release, pharmacokinetics, and stability. AAPS PharmSciTech.
smart polymer, has emerged as a widespread biodegradable, bio- 15(3):772–780.
compatible and non-toxic polymer with numerous applications in Alibolandi M, Alabdollah F, Sadeghi F, Mohammadi M, Abnous K,
drug delivery, surgical devices, drug targeting, tissue regeneration, Ramezani M, Hadizadeh F. 2016. Dextran-b-poly(lactide-co-gly-
vaccine delivery, cosmeceuticals and dentistry. Commercially, dif- colide) polymersome for oral delivery of insulin: in vitro and in
ferent grades of PLGA are available corresponding to various vivo evaluation. J Control Release. 227:58–70.
molecular weights, inherent viscosities, ratios of lactide/glycolide Al-Jawadi S, Capasso P, Sharma M. 2018. The road to market
and end-cappings. Modified co-polymerization techniques of implantable drug delivery systems: a review on US FDA’s regu-
PLGA using other polymers such as PCL, PEG and natural polysac- latory framework and quality control requirements. Pharm Dev
charides have exhibited more exemplary drug-encapsulating can- Technol. 23(10):953–963.
didates of better mechanical features and drug delivery. Selection Allahyari M, Mohit E. 2016. Peptide/protein vaccine delivery sys-
of grade and molecular weight of PLGA and choosing an ideal tem based on PLGA particles. Hum Vaccin Immunother. 12(3):
solvent of suitable water affinity, viscosity and safety are the key 806–828.
Amini-Fazl MS. 2021. Biodegradation study of PLGA as an inject-
factors for driving the drug release in a controlled manner from
able in situ depot-forming implant for controlled release of
PLGA-ISFI systems. In addition, the loaded drug can either pro-
paclitaxel. Polym Bull. 1–14.
mote the PLGA degradation or may be degraded or inactivated
Ashjari M, Khoee S, Mahdavian AR, Rahmatolahzadeh R. 2012.
while being in contact with the ISFI components. This review pro- Self-assembled nanomicelles using PLGA-PEG amphiphilic block
vides a particular brief about designing and evaluating the ISFI copolymer for insulin delivery: a physicochemical investigation
systems and outlines the mechanism of matrix solidification and and determination of CMC values. J Mater Sci Mater Med. 23(4):
successive stages of drug release from ISFI systems. For future 943–953.
perspectives, more innovative strategies should be developed for Astaneh R, Erfan M, Moghimi H, Mobedi H. 2009. Changes in
incorporating multiple drugs into PLGA-ISFI systems to be avail- morphology of in situ forming PLGA implant prepared by dif-
able in the market for achieving multi-target drug approaches. ferent polymer molecular weight and its effect on release
behavior. J Pharm Sci. 98(1):135–145.
Augusthy AR, Chandran S, Vipin KV. 2017. Design and evaluation
of an in situ forming implant system of an anti-inflammatory
Acknowledgments
drug. Indo Am J Pharm Res. 4(4):983–994.
The authors thank Mohamed S. Attia at the Faculty of Pharmacy, Avgoustakis K. 2008. Polylactic-co-glycolic acid (PLGA). In: Wnek
Zagazig University for his assistance in creating the study figures GE, Bowlin GL, editors. Encyclopedia of biomaterials and bio-
by using www.biorender.com. medical engineering. 2nd ed. New York (NY): Informa
HealthCare; p. 2259–2269.
Bakhshi R, Vasheghani-Farahani E, Mobedi H, Jamshidi A,
Khakpour M. 2006. The effect of additives on naltrexone hydro-
Disclosure statement
chloride release and solvent removal rate from an injectable in
No potential conflict of interest was reported by the author(s). situ forming PLGA implant. Polym Adv Technol. 17(5):354–359.
Barakat SS, Nasr M, Ahmed RF, Badawy SS, Mansour S. 2017.
Intranasally administered in situ gelling nanocomposite system
ORCID
of dimenhydrinate: preparation, characterization and pharmaco-
Hanan Mohammed El-Nahas http://orcid.org/0000-0002- dynamic applicability in chemotherapy induced emesis model.
9148-3276 Sci Rep. 7(1):9910.
Behrens AM, Kim J, Hotaling N, Seppala JE, Kofinas P, Tutak W. forming drug delivery systems. J Control Release. 115(2):
2016. Rapid fabrication of poly(DL-lactide) nanofiber scaffolds 158–167.
with tunable degradation for tissue engineering applications by Dunn RL, English JP, Cowsar DR, Vanderbilt DP, inventors;
air-brushing. Biomed Mater. 1(3):1–17. Southern Research Institute, assignee. 1990. Jul 03.
Bisht R, Jaiswal JK, Chen Y, Jin J, Rupenthal ID. 2016. Light-respon- Biodegradable in situ forming implants and methods of pro-
sive in situ forming injectable implants for effective drug deliv- ducing the same. United States patent US 4,938,763.
ery to the posterior segment of the eye. Expert Opin Drug Dunn RL, English JP, Cowsar DR, Vanderbilt DP, inventors; Atrix
Deliv. 13(7):953–962. Laboratories Inc, assignee. 1994. Jan 11. Biodegradable in situ
Bisht R, Jaiswal JK, Oliver VF, Eurtivong C, Reynisson J, Rupenthal forming implants and methods of producing the same. United
ID. 2017. Preparation and evaluation of PLGA nanoparticle- States patent US 5,278,201.
loaded biodegradable light-responsive injectable implants as a Dutta K, Das R, Ling J, Monibas RM, Carballo-Jane E, Kekec A,
promising platform for intravitreal drug delivery. J Drug Deliv Feng DD, Lin S, Mu J, Saklatvala R, et al. 2020. In situ forming
Sci Technol. 40:142–156. injectable thermoresponsive hydrogels for controlled delivery
Bittner B, Richter W, Schmidt J. 2018. Subcutaneous administration of biomacromolecules. ACS Omega. 5(28):17531–17542.
of biotherapeutics: an overview of current challenges and El-Hefian EA, Yahaya AH. 2010. Rheological study of chitosan and
opportunities. BioDrugs. 32(5):425–440. its blends: an overview. Maejo Int J Sci Technol. 4(02):210–220.
Bode C, Kranz H, Siepmann F, Siepmann J. 2018. In-situ forming Eliaz R, Szoka F. 2002. Robust and prolonged gene expression
PLGA implants for intraocular dexamethasone delivery. Int J from injectable polymeric implants. Gene Ther. 9(18):
Pharm. 548(1):337–348. 1230–1237.
Borgheti-Cardoso LN, Kooijmans SAA, Fens MHAM, Van der Meel Elmotasem H, Awad GE. 2020. A stepwise optimization strategy to
R, Vicentini FTMC, Fantini MCA, Bentley MVLB, Schiffelers RM. formulate in situ gelling formulations comprising fluconazole-
2017. In situ gelling liquid crystalline system as local siRNA hydroxypropyl-beta-cyclodextrin complex loaded niosomal
delivery system. Mol Pharm. 14(5):1681–1690. vesicles and Eudragit nanoparticles for enhanced antifungal
Browne DC, Kieselmann K. 2010. Low-level drug release-rate test- activity and prolonged ocular delivery. Asian J Pharm Sci. 15(5):
ing of ocular implants using USP Apparatus 4 dissolution and 617–636.
HPLC end analysis. Dissolution Technol. 17(1):12–14. Elsawy MA, Kim KH, Park JW, Deep A. 2017. Hydrolytic degrad-
Burgess DJ, Hussain AS, Ingallinera TS, Chen ML. 2002. Assuring
ation of polylactic acid (PLA) and its composites. Renew Sustain
quality and performance of sustained and controlled release
Energy Rev. 79:1346–1352.
parenterals: AAPS workshop report, co-sponsored by FDA and
Enayati M, Mobedi H, Hojjati-Emami S, Mirzadeh H, Jafari-
USP. Pharm Res. 19(11):1761–1768.
Nodoushan M. 2017. In situ forming PLGA implant for 90 days
Cabane E, Zhang X, Langowska K, Palivan CG, Meier W. 2012.
controlled release of leuprolide acetate for treatment of pros-
Stimuli-responsive polymers and their applications in nanome-
tate cancer. Polym Adv Technol. 28(7):867–875.
dicine. Biointerphases. 7(1-4):9.
Erbetta CDC, Alves RJ, Resende JM, Freitas RFDS, Sousa RGD.
Camargo JA, Sapin A, Nouvel C, Daloz D, Leonard M, Bonneaux F,
2012. Synthesis and characterization of poly(d,l-lactide co-glyco-
Six JL, Maincent P. 2013. Injectable PLA-based in situ forming
lide) copolymer. J Biomater Nanobiotechnol. 3(2):208–225.
implants for controlled release of Ivermectin a BCS Class II
Farhangi M, Dadashzadeh S, Bolourchian N. 2017. Biodegradable
drug: solvent selection based on physico-chemical characteriza-
gelatin microspheres as controlled release intraarticular delivery
tion. Drug Dev Ind Pharm. 39(1):146–155.
system: the effect of formulation variables. Indian J Pharm Sci.
Chaudhary B, Verma S. 2014. Preparation and evaluation of novel
in situ gels containing acyclovir for the treatment of oral her- 79(1):105–112.
[FDA] Food and Drug Administration . 2003. United States: Food
pes simplex virus infections. Sci World J. 2014:1–7.
Che X, Wang L, Li Q, Liu H. 2014. Injectable long-term control- and Drug Administration. [accessed 2021 May 28]. https://www.
released in-situ gels of hydrochloric thiothixene for the accessdata.fda.gov/drugsatfda_docs/nda/2003/21346_Risperda
treatment of schizophrenia: preparation, in-vitro and in-vivo lTOC.cfm
evaluation. Int J Pharm. 469(1):23–30. [FDA] Food and Drug Administration . 2016. United States: Food
Chenite A, Buschmann M, Wang D, Chaput C, Kandani N. 2001. and Drug Administration. [accessed 2021 May 28]. https://www.
Rheological characterisation of thermogelling chitosan/glycerol- fda.gov/drugs/guidance-compliance-regulatory-information/
phosphate solutions. Carbohydr Polym. 46(1):39–47. postmarket-requirements-and-commitments
Chhabra S, Sachdeva V, Singh S. 2007. Influence of end groups on [FDA] Food and Drug Administration . 2018a. United States: Food
in vitro release and biological activity of lysozyme from a and Drug Administration. [accessed 2021 May 28]. https://www.
phase-sensitive smart polymer based in situ gel forming con- accessdata.fda.gov/drugsatfda_docs/nda/2018/
trolled release drug delivery system. Int J Pharm. 342(1–2): 210655Orig1s000TOC.cfm
72–77. [FDA] Food and Drug Administration . 2018b. United States: Food
D’Souza SS, DeLuca PP. 2006. Methods to assess in vitro drug and Drug Administration. [accessed 2021 May 28]. https://www.
release from injectable polymeric particulate systems. Pharm fda.gov/drugs/guidance-compliance-regulatory-information/
Res. 23(3):460–474. surveillance
Dhir S, Saffi KA, Kamalpuria N, Mishra D. 2016. An overview of in Forouzandeh F, Zhu X, Ahamed NN, Walton JP, Frisina RD,
situ gelling system. Int J Pharm Life Sci. 7(8):5135–5156. Borkholder DA. 2019. Modular microreservoir for active implant-
Dong S, Wang S, Zheng C, Liang W, Huang Y. 2011. An in situ- able drug delivery. BioRxiv. 1–18.
forming, solid lipid/PLGA hybrid implant for long-acting anti- Fredenberg S, Wahlgren M, Reslow M, Axelsson A. 2011. The
psychotics. Soft Matter. 7(12):5873–5878. mechanisms of drug release in poly(lactic-co-glycolic acid)-
Dong WY, Ko €rber M, Lo
pez Esguerra V, Bodmeier R. 2006. Stability based drug delivery systems – a review. Int J Pharm. 415(1–2):
of poly(D,L-lactide-co-glycolide) and leuprolide acetate in in-situ 34–52.
Gad HA. 2016. Simvastatin in-situ forming implants: preparation nanotransfersomes to enhance the anti-proliferative activity.
and characterization. Int J Pharm Pharm Sci. 7(4):44–57. Pharmaceutics. 12(3):263.
Gentile P, Chiono V, Carmagnola I, Hatton PV. 2014. An overview Hua Y, Wang Z, Wang D, Lin X, Liu B, Zhang H, Gao J, Zheng A.
of poly(lactic-co-glycolic) acid (PLGA)-based biomaterials for 2021. Key factor study for generic long-acting PLGA micro-
spheres based on a reverse engineering of VivitrolV. Molecules.
R
bone tissue engineering. Int J Mol Sci. 15(3):3640–3659.
Gu P, Wusiman A, Zhang Y, Liu Z, Bo R, Hu Y, Liu J, Wang D. 26(5):1247.
2019. Rational design of PLGA nanoparticle vaccine delivery Huh KM, Cho YW, Park K. 2003. PLGA-PEG block copolymers for
systems to improve immune responses. Mol Pharm. 16(12): drug formulations. Drug Deliv Technol. 3(5):44–49.
5000–5012. Ibrahim HM, Ahmed TA, Hussain MD, Rahman Z, Samy AM,
Gulati N, Gupta H. 2011. Parenteral drug delivery: a review. Recent Kaseem AA, Nutan MT. 2014. Development of meloxicam in
Pat Drug Deliv Formul. 5(2):133–145. situ implant formulation by quality by design principle. Drug
€ven UM, Berkman MS, Şenel B, Yazan Y. 2019. Development
Gu Dev Ind Pharm. 40(1):66–73.
and in vitro/in vivo evaluation of thermo-sensitive in situ gel- Ibrahim TM, Eissa RG, El-Megrab NA, El-Nahas HM. 2021.
ling systems for ocular allergy. Braz J Pharm Sci. 55:e17511. Morphological characterization of optimized risperidone-loaded
Gyulai G, Penzes CB, Mohai M, Lohner T, Petrik P, Kurunczi S, Kiss in-situ gel forming implants with pharmacokinetic and behav-
E. 2011. Interfacial properties of hydrophilized poly(lactic-co-gly- ioral assessments in rats. J Drug Deliv Sci Technol. 61:102195.
colic acid) layers with various thicknesses. J Colloid Interface Ibrahim TM, El-Megrab NA, El-Nahas HM. 2020. Optimization of
Sci. 362(2):600–606. injectable PLGA in-situ forming implants of anti-psychotic ris-
Hadar J, Skidmore S, Garner J, Park H, Park K, Wang Y, Qin B, peridone via Box-Behnken Design. J Drug Deliv Sci Technol. 58:
Jiang X. 2019. Characterization of branched poly(lactide-co-gly- 101803.
colide) polymers used in injectable, long-acting formulations. J Inkinen S, Hakkarainen M, Albertsson AC, So €dergård A. 2011. From
Control Release. 304:75–89. lactic acid to poly(lactic acid) (PLA): characterization and ana-
Haggag Y, Abdel-Wahab Y, Ojo O, Osman M, El-Gizawy S, El- lysis of PLA and its precursors. Biomacromolecules. 12(3):
Tanani M, Faheem A, McCarron P. 2016. Preparation and in vivo 523–532.
evaluation of insulin-loaded biodegradable nanoparticles pre- Islam S. 2011. Lipophilic and hydrophilic drug loaded PLA/PLGA in
pared from diblock copolymers of PLGA and PEG. Int J Pharm.
situ implants: Studies on thermal behavior of drug & polymer
499(1–2):236–246.
and observation of parameters influencing drug burst release
Haggag Y, Elshikh M, El-Tanani M, Bannat IM, McCarron P,
with corresponding effects on loading efficiency & morphology
Tambuwala MM. 2020. Nanoencapsulation of sophorolipids in
of implants. Int J Pharm Pharm Sci. 3(3):181–188.
PEGylated poly(lactide-co-glycolide) as a novel approach to tar-
Jain RA, Rhodes CT, Railkar AM, Malick AW, Shah NH. 2000.
get colon carcinoma in the murine model. Drug Deliv Transl
Controlled release of drugs from injectable in situ formed bio-
Res. 10(5):1353–1366.
degradable PLGA microspheres: effect of various formulation
Haggag YA, Faheem AM, Tambuwala MM, Osman MA, El-Gizawy
variables. Eur J Pharm Biopharm. 50(2):257–262.
SA, O’Hagan B, Irwin N, McCarron PA. 2018. Effect of poly(ethyl-
James HP, John R, Alex A, Anoop KR. 2014. Smart polymers for
ene glycol) content and formulation parameters on particulate
the controlled delivery of drugs – a concise overview. Acta
properties and intraperitoneal delivery of insulin from PLGA
Pharm Sin B. 4(2):120–127.
nanoparticles prepared using the double-emulsion evaporation
Jeong B, Bae YH, Kim SW. 2000. In situ gelation of PEG-PLGA-PEG
procedure. Pharm Dev Technol. 23(4):370–381.
Haggag YA, Ibrahim RR, Hafiz AA. 2020. Design, formulation and triblock copolymer aqueous solutions and degradation thereof.
in vivo evaluation of novel honokiol-loaded PEGylated PLGA J Biomed Mater Res. 50(2):171–177.
nanocapsules for treatment of breast cancer. Int J Jerbic IS. 2018. Biodegradable synthetic polymers and their appli-
Nanomedicine. 15:1625–1642. cation in advanced drug delivery systems (DDS). Nano Tech
Haider M, Elsayed I, Ahmed IS, Fares AR. 2021. In situ-forming Appl. 1(1):1–9.
microparticles for controlled release of rivastigmine: in vitro Jervis LP. 2017. A summary of recent advances in ocular inserts
optimization and in vivo evaluation. Pharmaceuticals. 14(1):66. and implants. J Bioequivalence Bioavailab. 9(1):320–323.
Hajavi J, Ebrahimian M, Sankian M, Khakzad MR, Hashemi M. 2018. Jhaveri AM, Torchilin VP. 2014. Multifunctional polymeric micelles
Optimization of PLGA formulation containing protein or pep- for delivery of drugs and siRNA. Front Pharmacol. 5:77.
tide-based antigen: recent advances. J Biomed Mater Res A. Jivawala R, Goyani M. 2017. A novel approach to deliver thera-
106(9):2540–2551. peutic agents using in situ forming implant based on solvent
Hatefi A, Amsden B. 2002. Biodegradable injectable in situ form- induced phase separation technique for long term controlled
ing drug delivery systems. J Control Release. 80(1–3):9–28. release. Int J Adv Res Rev. 2(12):50–62.
Hines DJ, Kaplan DL. 2013. Poly(lactic-co-glycolic) acid-controlled- Joshi R, Robinson DH, Himmelstein KJ. 1999. In vitro properties of
release systems: experimental and modeling insights . Crit Rev an in situ forming gel for the parenteral delivery of macromol-
Ther Drug Carrier Syst. 30(3):257–276. ecular drugs. Pharm Dev Technol. 4(4):515–522.
Homayun B, Lin X, Choi H. 2019. Challenges and recent progress Kamali H, Khodaverdi E, Hadizadeh F, Mohajeri SA, Nazari A,
in oral drug delivery systems for biopharmaceuticals. Jafarian AH. 2019. Comparison of in-situ forming composite
Pharmaceutics. 11(3):129. using PLGA-PEG-PLGA with in-situ forming implant using PLGA:
Hosny KM, Rizg WY. 2018. Quality by design approach to optimize in-vitro, ex-vivo, and in-vivo evaluation of naltrexone release. J
the formulation variables influencing the characteristics of bio- Drug Deliv Sci Technol. 50:188–200.
degradable intramuscular in-situ gel loaded with alendronate Kamali H, Khodaverdi E, Kaffash E, Saffari AS, Shiadeh SN,
sodium for osteoporosis. PLoS One. 13(6):e0197540. Nokhodchi A, Hadizadeh F. 2020. Optimization and in vitro
Hosny KM, Rizg WY, Khallaf RA. 2020. Preparation and optimiza- evaluation of injectable sustained-release of levothyroxine using
tion of in situ gel loaded with rosuvastatin-ellagic acid PLGA-PEG-PLGA. J Pharm Innov. 1–11.
Kamaly N, Yameen B, Wu J, Farokhzad OC. 2016. Degradable con- Liu H, Venkatraman SS. 2012b. Effect of polymer type on the
trolled-release polymers and polymeric nanoparticles: mecha- dynamics of phase inversion and drug release in injectable in
nisms of controlling drug release. Chem Rev. 116(4):2602–2663. situ gelling systems. J Biomater Sci Polym Ed. 23(1-4):251–266.
Kane JM, Kishimoto T, Correll CU. 2013. Non-adherence to medica- Madan M, Bajaj A, Lewis S, Udupa N, Baig JA. 2009. In situ form-
tion in patients with psychotic disorders: epidemiology, contri- ing polymeric drug delivery systems. Indian J Pharm Sci. 71(3):
buting factors and management strategies. World Psychiatry. 242–251.
12(3):216–226. Madhav NV, Shakya AK, Shakya P, Singh K. 2009. Orotransmucosal
Kanwar N, Sinha VR. 2019. In situ forming depot as sustained- drug delivery systems: a review. J Control Release. 140(1):2–11.
release drug delivery systems. Crit Rev Ther Drug Carrier Syst. Maeda T, Kitagawa M, Hotta A, Koizumi S. 2019. Thermo-respon-
36(2):93–136. sive nanocomposite hydrogels based on PEG-b-PLGA diblock
Kapoor DN, Bhatia A, Kaur R, Sharma R, Kaur G, Dhawan S. 2015. copolymer and laponite. Polymers. 11(2):250.
PLGA: a unique polymer for drug delivery. Ther Deliv. 6(1): Makadia HK, Siegel SJ. 2011. Poly lactic-co-glycolic acid (PLGA) as
41–58. biodegradable controlled drug delivery carrier. Polymers. 3(3):
Kapoor DN, Katare OP, Dhawan S. 2012. In situ forming implant 1377–1397.
for controlled delivery of an anti-HIV fusion inhibitor. Int J Mallarde D, Boutignon F, Moine F, Barre E, David S, Touchet H,
Pharm. 426(1–2):132–143. Ferruti P, Deghenghi R. 2003. PLGA-PEG microspheres of tever-
Karp F, Turino LN, Helbling IM, Islan GA, Luna JA, Estenoz DA. elix: influence of polymer type on microsphere characteristics
2021. In situ formed implants, based on PLGA and Eudragit and on Teverelix in vitro release. Int J Pharm. 261(1–2):69–80.
blends, for novel florfenicol controlled release formulations. J Martins C, Sousa F, Ara ujo F, Sarmento B. 2018. Functionalizing
Pharm Sci. 110(3):1270–1278. PLGA and PLGA derivatives for drug delivery and tissue regen-
Kempe S, M€ader K. 2012. In situ forming implants – an attractive eration applications. Adv Healthc Mater. 7(1):1–24.
formulation principle for parenteral depot formulations. J McCullough A. 2014. A review of testosterone pellets in the treat-
Control Release. 161(2):668–679. ment of hypogonadism. Curr Sex Health Rep. 6(4):265–269.
Khodaverdi E, Delroba K, Mohammadpour F, Khameneh B, Tabassi Metzger KL, Shoemaker JM, Kahn JB, Maxwell CR, Liang Y,
SAS, Tafaghodi M, Kamali H, Hadizadeh F. 2020. In-vitro release Tokarczyk J, Kanes SJ, Hans M, Lowman AM, Dan N, et al. 2007.
Pharmacokinetic and behavioral characterization of a long-term
evaluation of growth hormone from an injectable in-situ form-
antipsychotic delivery system in rodents and rabbits.
ing gel using PCL-PEG-PCL thermosensitive triblock. Curr Drug
Psychopharmacology . 190(2):201–211.
Deliv. 17(2):174–183.
Milacic V, Schwendeman SP. 2014. Lysozyme release and polymer
Kondiah P, Choonara Y, Kondiah P, Marimuthu T, Kumar P, Du
erosion behavior of injectable implants prepared from PLGA-
Toit LC, Pillay V. 2016. A review of injectable polymeric hydro-
PEG block copolymers and PLGA/PLGA-PEG blends. Pharm Res.
gel systems for application in bone tissue engineering.
31(2):436–448.
Molecules. 21(11):1580.
Mittal G, Sahana DK, Bhardwaj V, Kumar MNVR. 2007. Estradiol
Kumar D, Jain N, Gulati N, Nagaich U. 2013. Nanoparticles laden
loaded PLGA nanoparticles for oral administration: effect of
in situ gelling system for ocular drug targeting. J Adv Pharm
polymer molecular weight and copolymer composition on
Technol Res. 4(1):9–17.
release behavior in vitro and in vivo. J Control Release. 119(1):
Lambert WJ, Peck KD. 1995. Development of an in situ forming
77–85.
biodegradable poly-lactide-coglycolide system for the con-
Musmade N, Jadhav A, Moin P, Patil S, Gupta A. 2019. An over-
trolled release of proteins. J Control Release. 33(1):189–195. view of in situ gel forming implants: Current approach towards
Lanao RPF, Jonker AM, Wolke JGC, Jansen JA, Hest JCM,
alternative drug delivery system. JBCC. 5(1):14–21.
Leeuwenburgh SCG. 2013. Physicochemical properties and Neubert A, Sternberg K, Nagel S, Harder C, Schmitz KP, Kroemer
applications of poly(lactic-co-glycolic acid) for use in bone HK, Weitschies W. 2008. Development of a vessel-simulating
regeneration. Tissue Eng Part B Rev. 19(4):380–390. flow-through cell method for the in vitro evaluation of release
Larsen C, Larsen SW, Jensen H, Yaghmur A, Østergaard J. 2009. and distribution from drug-eluting stents. J Control Release.
Role of in vitro release models in formulation development and 130(1):2–8.
quality control of parenteral depots. Expert Opin Drug Deliv. Nikam KR, Pawar MG, Jadhav SP, Bairagi VB. 2013. Novel trends in
6(12):1283–1295. parenteral drug delivery system: Review. Int J Pharm Technol.
Lee SJ, Shim Y, Oh J, Jeong Y, Park I, Lee HC. 2015. Folic-acid-con- 5(2):2549–2577.
jugated pullulan/poly(dl-lactide-co-glycolide) graft copolymer Niu X, Wang L, Chen P, Li X, Zhou G, Feng Q, Fan Y. 2013.
nanoparticles for folate-receptor-mediated drug delivery. Emulsion self-assembly synthesis of chitosan/poly(lactic-co-
Nanoscale Res Lett. 10(1):43. glycolic acid) stimuli-responsive amphiphiles. Macromol Chem
Liu Q, Zhang H, Zhou G, Xie S, Zou H, Yu Y, Li G, Sun D, Zhang G, Phys. 214(6):700–706.
Lu Y, et al. 2010. In vitro and in vivo study of thymosin alpha1 Nkanga CI, Fisch A, Rad-Malekshahi M, Romic MD, Kittel B, Ullrich
biodegradable in situ forming poly(lactide-coglycolide) T, Wang J, Krause RWM, Adler S, Lammers T, et al. 2020.
implants. Int J Pharm. 397(1–2):122–129. Clinically established biodegradable long acting injectables: an
Lin X, Yang S, Gou J, Zhao M, Zhang Y, Qi N, He H, Cai C, Tang X, industry perspective. Adv Drug Deliv Rev. 167:19–46.
Guo P. 2012. A novel risperidone-loaded SAIB–P LGA mixture Okur NU, Yozgatli V, Senyigit Z. 2020. Formulation and detailed
matrix depot with a reduced burst release: effects of solvents characterization of voriconazole loaded in situ gels for ocular
and P LGA on drug release behaviors in vitro/in vivo. J Mater application. J Fac Pharm Ankara. 44(1):33–49.
Sci Mater Med. 23(2):443–455. Olivier J. 2005. Drug transport to brain with targeted nanopar-
Liu H, Venkatraman SS. 2012a. Cosolvent effects on the drug ticles. NeuroRx. 2(1):108–119.
release and depot swelling in injectable in situ depot-forming Osorno LL, Maldonado DE, Whitener RJ, Brandley AN, Yiantsos A,
systems. J Pharm Sci. 101(5):1783–1793. Medina JD, Byrne ME. 2020. Amphiphilic PLGA-PEG-PLGA
triblock copolymer nanogels varying in gelation temperature Shen J, Burgess DJ. 2013. In vitro dissolution testing strategies for
and modulus for the extended and controlled release of hyalur- nanoparticulate drug delivery systems: recent developments
onic acid. J Appl Polym Sci. 137(25):48678. and challenges. Drug Deliv Transl Res. 3(5):409–415.
Parent M, Nouvel C, Koerber M, Sapin A, Maincent P, Boudier A. Sheshala R, Hong GC, Yee WP, Meka VS, Thakur RRS. 2019. In situ
2013. PLGA in situ implants formed by phase inversion: critical forming phase-inversion implants for sustained ocular delivery
physicochemical parameters to modulate drug release. J of triamcinolone acetonide. Drug Deliv Transl Res. 9(2):534–542.
Control Release. 172(1):292–304. Sinha VR, Khosla L. 1998. Bioabsorbable polymers for implantable
Patel A, Ansari T, Vimal P, Goyani M, Deshmukh A, Akbari B. 2015. therapeutic systems. Drug Dev Ind Pharm. 24(12):1129–1138.
A review on PLGA based solvent induced in-situ forming Solorio L, Olear AM, Hamilton JI, Patel RB, Beiswenger AC, Wallace
implant. Inventi Rapid. 2015(4):1–14. JE, Zhou H, Exner AA. 2012. Noninvasive characterization of the
Patel RB, Solorio L, Wu H, Krupka T, Exner AA. 2010. Effect of effect of varying PLGA molecular weight blends on in situ form-
injection site on in situ implant formation and drug release in ing implant behavior using ultrasound imaging. Theranostics.
vivo. J Control Release. 147(3):350–358. 2(11):1064–1077.
Patki M, Palekar S, Reznik S, Patel K. 2021. Self-injectable extended Stewart SA, Domınguez-Robles J, Donnelly RF, Larran ~eta E. 2018.
release formulation of remdesivir (SelfExRem): a potential for- Implantable polymeric drug delivery devices: classification,
mulation alternative for COVID-19 treatment. Int J Pharm. 597: manufacture, materials, and clinical applications. Polymers.
120329. 10(12):1379.
Patlolla VGR, Holbrook WP, Gizurarson S, Kristmundsdottir T. 2019. Tang H, Zhao W, Yu J, Li Y, Zhao C. 2018. Recent development of
Doxycycline and monocaprin in situ hydrogel: Effect on stabil- pH-responsive polymers for cancer nanomedicine. Molecules.
ity, mucoadhesion and texture analysis and in vitro release. 24(1):4.
Gels. 5(4):47. Tang Y, Singh J. 2008. Controlled delivery of aspirin: effect of
Phaechamud T, Mahadlek J, Charoenteeraboon J, Choopun S. aspirin on polymer degradation and in vitro release from PLGA
2012. Characterization and antimicrobial activity of N-methyl-2- based phase sensitive systems. Int J Pharm. 357(1–2):119–125.
pyrrolidone-loaded ethylene oxide-propylene oxide block Thakur RR, McMillan HL, Jones DS. 2014. Solvent induced phase
copolymer thermosensitive gel. Indian J Pharm Sci. 74(6): inversion-based in situ forming controlled release drug delivery
498–504. implants. J Control Release. 176:8–23.
Pineda-Hernandez MT, Perez-Urizar JT, Ganem-Rondero A. 2020. Toh MR, Chiu GNC. 2013. Liposomes as sterile preparations and
Thermo-reversible in situ forming implant with nanostructured limitations of sterilisation techniques in liposomal manufactur-
lipid carriers (NLC) as a delivery system for the administration ing. Asian J Pharm Sci. 8(2):88–95.
of estradiol valerate. Drug Deliv Transl Res. 10(5):1393–1402. Tsujimoto H, Hara K, Tsukada Y, Huang C, Kawashima Y, Arakaki
Pitorre M, Gonde H, Haury C, Messous M, Poilane J, Boudaud D, M, Okayasu H, Mimura H, Miwa N. 2007. Evaluation of the per-
Kanber E, Ndombina GAR, Benoit J, Bastiat G. 2017. Recent meability of hair growing ingredient encapsulated PLGA nano-
advances in nanocarrier-loaded gels: which drug delivery tech- spheres to hair follicles and their hair growing effects. Bioorg
nologies against which diseases? J Control Release. 266: Med Chem Lett. 17(17):4771–4777.
140–155. Uddin R, Saffoon N, Sutradhar KB. 2011. Dissolution and dissol-
Prabhu S, Tran LP, Betageri GV. 2005. Effect of co-solvents on the ution apparatus: a review. Int J Curr Biomed Pharm Res. 1(4):
controlled release of calcitonin polypeptide from in situ bio- 201–207.
degradable polymer implants. Drug Deliv. 12(6):393–398. U.S. Pharmacopoeia. 2020. Pharmaceutical dosage forms <1151>.
Qi F, Wu J, Li H, Ma G. 2019. Recent research and development of In: U.S. pharmacopoeia. 43th ed.
PLGA/PLA microspheres/nanoparticles: a review in scientific and Verma P, Prajapati SK, Yadav R, Senyschyn D, Shea PR, Trevaskis
industrial aspects. Front Chem Sci Eng. 13(1):14–27. NL. 2016. Single intravenous dose of novel flurbiprofen-loaded
Reddy P, Acharya SR, Acharya NS. 2015. Optimization of size con- proniosome formulations provides prolonged systemic expos-
trolled poly (lactide-co-glycolic acid) nanoparticles using quality ure and anti-inflammatory effect. Mol Pharm. 13(11):3688–3699.
by design concept. Asian J Pharm. 9(3):152–161. Versypt ANF, Pack DW, Braatz RD. 2013. Mathematical modeling
Rousselle SD, Ramot Y, Nyska A, Jackson ND. 2019. Pathology of of drug delivery from autocatalytically degradable PLGA micro-
bioabsorbable implants in preclinical studies. Toxicol Pathol. spheres – a review. J Control Release. 165(1):29–37.
47(3):358–378. Vhora I, Khatri N, Misra A. 2021. Applications of polymers in par-
Sabale V, Vora S. 2012. Formulation and evaluation of microemul- enteral drug delivery. In: Misra A, Shahiwala A, editors.
sion-based hydrogel for topical delivery. Int J Pharm Investig. Applications of polymers in drug delivery. 2nd ed. Netherlands:
2(3):140–149. Elsevier Inc; p. 221–261.
Santamaria CM, Woodruff A, Yang R, Kohane DS. 2017. Drug deliv- Vineetha K, Koland M. 2017. Investigation of a biodegradable
ery systems for prolonged duration local anesthesia. Mater injectable in situ gelling implantable system of rivastigmine tar-
Today . 20(1):22–31. trate. Asian J Pharm. 11(4):S731–S738.
Schwendeman SP, Shah RB, Bailey BA, Schwendeman AS. 2014. Walewijk A, Cooper-White J, Dunstan D. 2008. Adhesion measure-
Injectable controlled release depots for large molecules. J ments between alginate gel surfaces via texture analysis. Food
Control Release. 190:240–253. Hydrocoll. 22(1):91–96.
Selmin F, Musazzi UM, Magri G, Rocco P, Cilurzo F, Minghetti P. Wang B, Friess W. 2018. Lipid-coated mannitol core microparticles
2020. Regulatory aspects and quality controls of polymer-based for sustained release of protein. Eur J Pharm Biopharm. 128:
parenteral long-acting drug products: the challenge of approv- 91–97.
ing copies. Drug Discov Today. 25(2):321–329. Wang B, Wang J, Shao J, Kouwer PHJ, Bronkhorst EM, Jansen JA,
Shen J, Burgess DJ. 2012. Accelerated in-vitro release testing Walboomers XF, Yang F. 2020. A tunable and injectable local
methods for extended-release parenteral dosage forms. J drug delivery system for personalized periodontal application. J
Pharm Pharmacol. 64(7):986–996. Control Release. 324:134–145.
Wang L, Kleiner L, Venkatraman S. 2003. Structure formation in structural characterization and release properties. J Drug Deliv
injectable poly(lactide-co-glycolide) depots. J Control Release. Sci Technol. 23(4):325–332.
90(3):345–354. Yan B, Boyer J, Habault D, Branda NR, Zhao Y. 2012. Near infrared
Wang L, Lin X, Hong Y, Shen L, Feng Y. 2017. Hydrophobic mixed light triggered release of biomacromolecules from hydrogels
solvent induced PLGA-based in situ forming systems for loaded with upconversion nanoparticles. J Am Chem Soc.
smooth long-lasting delivery of radix ophiopogonis polysac- 134(40):16558–16561.
charide in rats. RSC Adv. 7(9):5349–5361. Yang S, Hu M, Liu W, Hou N, Yin K, Shen C, Shang Q. 2021.
Wang L, Wang A, Zhao X, Liu X, Wang D, Sun F, Li Y. 2012.
Fabrication of PLGA in situ forming implants and study on their
Design of a long-term antipsychotic in situ forming implant
correlation of in vitro release profiles with in vivo performances.
and its release control method and mechanism. Int J Pharm.
J Biomater Sci Polym Ed. 9:1–15.
427(2):284–292.
Yarnsuphawong P, Thipkunok W, Silaon W, Sritananuwat P,
Wang M, Feng Q, Niu X, Tan R, She Z. 2010. A spheres-in-sphere
structure for improving protein-loading poly (lactide-co-glyco- Puapermpoonsiri U. 2015. The study of factors and components
lide) microspheres. Polym Degrad Stab. 95(1):6–13. in situ forming gel formulation comprising of PLGA. Isan J
Wang Q, Sun C, Xu B, Tu J, Shen Y. 2018. Synthesis, physicochemi- Pharm Sci. 11(5):135–143.
cal properties and ocular pharmacokinetics of thermosensitive Zhang K, Shi X, Lin X, Yao C, Shen L, Feng Y. 2014. Poloxamer-
in situ hydrogels for ganciclovir in cytomegalovirus retinitis based in situ hydrogels for controlled delivery of hydrophilic
treatment. Drug Deliv. 25(1):59–69. macromolecules after intramuscular injection in rats. Drug
Wen H, Jung H, Li X. 2015. Drug delivery approaches in address- Deliv. 22(3):375–382.
ing clinical pharmacology-related issues: opportunities and Zhang K, Tang X, Zhang J, Lu W, Lin X, Zhang Y, Tian B, Yang H,
challenges. AAPS J. 17(6):1327–1340. He H. 2014. PEG-PLGA copolymers: their structure and struc-
Woodard LN, Grunlan MA. 2018. Hydrolytic degradation and ero- ture-influenced drug delivery applications. J Control Release.
sion of polyester biomaterials. ACS Macro Lett. 7(8):976–982. 183:77–86.
Wu W, Chen H, Shan F, Zhou J, Sun X, Zhang L, Gong T. 2014. A Zhang Q, Fassihi R. 2020. Release rate determination from in situ
novel doxorubicin-loaded in situ forming gel based high con-
gel forming PLGA implant: a novel ‘shape-controlled basket in
centration of phospholipid for intratumoral drug delivery. Mol
tube’ method. J Pharm Pharmacol. 72(8):1038–1048.
Pharm. 11(10):3378–3385.
Zhang Y, Garcıa-Gabilondo M, Rosell A, Roig A. 2019. MRI/
Yadav AK, Agarwal A, Rai G, Mishra P, Jain S, Mishra AK, Agrawal
Photoluminescence dual-modal imaging magnetic PLGA nano-
H, Agrawal GP. 2010. Development and characterization of hya-
luronic acid decorated PLGA nanoparticles for delivery of 5-flu- capsules for thernaostics. Pharmaceutics. 12(1):16.
orouracil. Drug Deliv. 17(8):561–572. Zheng H, Tai C, Su J, Zou X, Gao F. 2015. Ultra-small mesoporous
Yadav R, Kanwar IL, Haider T, Pandey V, Gour V, Soni V. 2020. In silica nanoparticles as efficient carriers for pH responsive
situ gel drug delivery system for periodontitis: an insight releases of anti-cancer drugs. Dalton Trans. 44(46):20186–20192.
review. Future J Pharm Sci. 6(1):1–13. Zhou J, Hirota K, Ackermann R, Walker J, Wang Y, Choi S,
Yaghmur A, Rappolt M, Larsen S. 2013. In situ forming drug deliv- Schwendeman A, Schwendeman SP. 2018. Reverse engineering
the 1-month lupron depotV. AAPS J. 20(6):105.
R
ery systems based on lyotropic liquid crystalline phases:

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An overview of PLGA in-situ forming implants

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An overview of PLGA in-situ forming implants based on solvent exchange

ABSTRACT ARTICLE HISTORY

1. Introduction compliance especially in the case of daily medication regimens

Figure 1. Types of parenteral drug delivery.

of utilizing a non-biodegradable polymer such as NexplanonV and

ConstaV) (FDA 2003) and in-situ gelling systems (PerserisV)

Figure 2. Different examples of in-situ cross-linking systems.

Figure 3. Preparation of in-situ solidifying organogel systems.

Figure 4. Examples of commonly used temperature-responsive, pH-responsive and photo-responsive polymers.

Figure 5. Mechanism of ISFI formation by solvent exchange.

by blending fluconazole-hydroxypropyl-beta-cyclodextrin-loaded be prepared by enzymatic biochemical processes and chemical

Table 1. Examples of phase-sensitive biodegradable polymers for ISFI formulation.

Astaneh et al. 2009

Enayati et al. 2017

Kamali et al. 2019

Wang et al. 2012

Wang et al. 2017

Bode et al. 2018

Lin et al. 2012

5.1.3. Different co-polymers of PLGA

other polymers have been extensively studied for producing a

transition temperature, enhance the flexibility and hinder the

brittleness of PLGA polymer (Martins et al. 2018). In contrast,

amphiphilc co-polymerization is more crucially required for the

in order to find a satisfactory balanced hydrophobic-hydrophilic

20 000, 30 000 and 40 000

kinetics in comparison to using a single PLGA. The hydrophobic

core of PLGA can enable the incorporation and encapsulation of

of opsonins and clearance of formulation through the phagocytic

system, therefore prolonging its circulation time (Makadia and

has recently evolved to produce spectacular classes of polymeric

systems for drug delivery and biomedical applications. This can

0.73 and 0.74

circulation time (Haggag, Ibrahim, et al. 2020).

0.36, 0.49, 0.70,

0.18 and 0.54

The PLGA-PEG co-polymerization has been processed in the

forms of diblock PLGA-PEG, triblock PLGA-PEG-PLGA or triblock

as a barrier that performs steric repulsion and enhances the shelf

stability (Makadia and Siegel 2011). Several studies have produced

potential results for desirable characteristics and applications of

50:50 and 75:25

PLGA-PEG diblock co-polymers in various drug delivery systems

(Maeda et al. 2019) and ISFI systems (Milacic and Schwendeman

Treatment of prostate cancer

all bioavailability (Huh et al. 2003; Haggag, Elshikh, et al. 2020).

Opiate antagonist agent

Furthermore, the triblock co-polymers can act as temperature-

responsive co-polymers. They remain as free-flowing solutions at