Many coupled with the complexity and diversity of

Many drugs fail during
preclinical evaluations due to poor efficacy, limited bioavailability and other
challenges associated with effective drug delivery. These challenges, coupled
with the complexity and diversity of new pharmaceuticals are fuelling the evolution
of novel drug delivery systems that overcome bioavailability and delivery
obstacles. The objective of effective drug delivery is improving the
pharmacokinetics and pharmacodynamics of each therapeutic to enable drug
delivery to the right place. Polymer carriers loaded with therapeutics enable
controlled temporal and spatial release of a drug by controlling drug
diffusion, the rate of dissolution and degradation of the carrier.
Targeted Delivery Drug efficacy can be enhanced, and toxicity minimized by
localization at the target site. Targeting can be achieved by coating or
conjugating the carrier with affinity reagents such as nucleic acids, peptides,
antibodies, or others that bind specific cell receptor proteins, nucleic acids,
or polysaccharides.

Reservoir-Based Polymer Drug Delivery Systems:

Polymer selection greatly influences the performance of the
drug delivery system. Polymer selection will determine the mechanism for drug release
and the choice of polymer properties will influence release rate and impact
pharmacokinetics.in This system the drug is surrounded by polymers and
depending on the properties of these polymers and the physiochemical properties
of the drug such as solubility, particle size and molecular weight affect the
rate at which the drug is released. These reservoir-based systems are most
beneficial if the long-term administration of a medication is toxic (cancer
treatments). the reservoir based system can be classified as the following
categories:

Polymeric Microspheres & Nanoparticles:

microsphere and nanospheres are small size drug particle
that are coated with. Microspheres reduce the dosing frequency, they can
release a drug continuously over time, thereby providing a prolonged
therapeutic, microspheres allow for the targeted drug delivery of potent drugs
at reduced concentrations, thereby minimizing systemic exposure and adverse
side effects. Finally, polymeric microspheres facilitate manipulation of in
vivo behaviour, pharmacokinetic profile, tissue distribution, and cellular interaction
of the drug.2 Microspheres are typically comprised of biodegradable
polymers. These polymers degrade in vivo by hydrolysis of their ester backbone
into non-toxic products, which are excreted by the kidneys. PLGA microspheres
have been widely used to encapsulate drug molecules and have been used as
long-acting, sustained-release pharmaceutical formulations.

Polymeric nanospheres the use of
API-loaded polymeric nanoparticles for intravenous administration is a
promising approach for achieving the controlled release and site-specific
delivery of drugs. The nanoparticle delivery system can be designed to maintain
appropriate therapeutic concentration in the bloodstream (controlled release)
or to target a specific cell type (e.g., bone marrow, blood cells). Various
types of APIs, including small molecule drugs and biologic compounds, can be
incorporated into PLGA polymer nanoparticles by either microencapsulation or
surface conjugation. Nanoencapsulation can protect the API from early
degradation, facilitate cell entry, and increase solubility and
bioavailability. The surface properties of intravenously injected particles are
important factors determining in vivo organ distribution and fate. Furthermore,
surface modification can be an effective approach to targeting specific
tissues. Surface modification of nanoparticles with polyethylene glycol (PEG)
can be used to prolong the in vivo circulation lifetime of drug-loaded
nanoparticles. PEGylation of the nanoparticle can be accomplished by adding a
copolymer containing PEG chains during the nanoparticle fabrication process.
For example, the addition of an ethylene glycol monomer during lactide and
glycolide copolymerization can lead to a PEGylated PLGA polymer. PEGylation can
increase nanoparticle hydrophilicity and improve degradation rate and
crystallization.3 In addition to being biocompatible, PEG is resistant to
immunological recognition. PEG units on the NP surface prevent opsonin-NP
binding, thus preventing the nanoparticles from being recognized by monocytes
and macrophages and, therefore, increasing circulation time in the body.4 In
some circumstances nanoparticles have been shown to remain in circulation 40×
longer when coated with PEG compared to uncoated nanoparticles.5 Other
advantages of PEGylated nanoparticles include increased drug loading of
hydrophilic drugs, reduced initial burst and improved bioavailability.6
PEGylated nanoparticles have been used as carriers for vaccine and protein APIs
and are particularly useful in both sustained/controlled release and targeted
drug delivery systems. Currently, there are more than 35 U.S. FDA-approved
products utilizing PEG in their biomedical applications.4 Nanoparticles can
also facilitate the crossing of the blood brain barrier (BBB). Surfactants such
as Polysorbate 80 and Poloxamer 188 have been shown to facilitate the BBB
crossing of drug molecules encapsulated in polybutyl cyanoacrylate
nanoparticles or solid lipid nanoparticles.7 In some nanoparticle formulations,
the API is attached to the surface instead of being encapsulated inside the
particle. For example, a peptide for ocular delivery (POD) and a human
immunodeficiency virus trans-activator were conjugated to the surface of PLGA
nanoparticles, and the conjugate was found to improve ocular drug
bioavailability.8 The conjugation can be done by reacting the terminal
functional group (e.g., terminal COOH) on the PLGA molecule with a reactive
group (e.g., amino) on the peptide, API or protein. Finally, in some cases,
PLGA nanoparticles themselves can have therapeutic effects against
certain diseases.

luprolide acetate is a PLGA
polymeric microspheres that’s approved by the FDA used for the treatment of
prostate cancer and endometriosis, luprolide is subcutaneously administered
over long intervals at 1month, 3month, or 6month intervals

The first Food and Drug
Administration (FDA)–approved controlled-release system was Lupron Depot,
injectable microspheres composed of lactic acid–glycolic acid copolymer and
leuprolide acetate. This system was introduced in 1989 to treat prostate
cancer, and the drug release lasted for 30 days.3 Other microsphere or
nanosphere drug delivery systems subsequently approved by the FDA include
AmBisome (liposomal amphotericin B for fungal infection treatment),16 Adagen
(PEG-adenosine deaminase for severe combined immunodeficiency disease),17
Doxil/Caelyx (Stealth PEG-stabilized liposomal doxorubicin for refractory
ovarian and breast cancer),18 DepoCyt (liposomal cytosine arabinoside for
meningitis),19 ONTAK (denileukin diftitox for cutaneous T-cell lymphoma),20
Mylotarg (gemtuzumab ozogamicin for CD33+ relapsed acute myeloid leukemia),21
PEG-Intron (PEG-interferon ?-2b for hepatitis C),22 and Neulasta (pegfilgrastim
for reduction of febrile neutropenia associated with chemotherapy).23

Hydrogels:

Hydrogel consist of crosslinked
networks of hydrophilic polymer chains that form colloidal gels. They are made
from either natural (chitosan and alginate) or synthetic polymeric (poly vinyl
alcohol (PVA), poly ethylene glycol (PEG), poly ethyleneimine (PEI), poly vinyl
pyrrolidone, and poly-N-isopropylacrylamide) networks. The highly porous nature
of hydrogels makes the drug release rate significantly depend on the diffusion coefficient
of the drug molecules through the gel network. Through controlling the degree
of cross-linking The porosity of hydrogels can be adjusted, which will affect
the release rate of the entrapped drug particles.5,24,25 Crosslinking
between polymer chains can be triggered chemically or physically. Physical
cross-linking can be triggered by the change of pH, temperature, and ionic
strength and a variety of physicochemical interactions, chemical cross-linking
involves adding additional cross-linking entities to covalently bond to
hydrogels, leading to the chemical modification of the system. Since Hydrogels
are highly absorbent (up to 99.9% water) they can encapsulate water-soluble,
small molecule APIs that are difficult to encapsulate using traditional biodegradable
polymeric particles comprised of PLGA and PCL. As a result, these gels are
particularly suitable for the sustained release of water-soluble drugs or
proteins. Other advantages of hydrogel particles include their high drug
loading and activity, biocompatibility, and biodegradability. Also, the
manufacturing of hydrogels does not require organic solvents. Hydrogel systems
have various applications including oral, transdermal, nasal, rectal, and
ocular drug delivery. Embolization therapy is another application of hydrogel
microspheres. It is typically used to prevent the growth of cancer cells by
blocking the blood supply to the feeding artery.

Hydrogels provide a suitable
vehicle for localized administration of APIs such as proteins and small molecules
by maintaining a high local concentration of a drug. Hydrogels can also bypass
the need for systemic drug administration and provide a reservoir of the drug
to be released slowly over time. Poly ethylene glycol (PEG) have been studied
extensively for drug delivery because of its favourable characteristics:
non-toxic, biocompatible and are non-biodegradable that made PEG hydrogels an
ideal drug delivery vehicle.1 also the mechanical properties of PEG
hydrogels are well-defined and can be tuned for application, including the drug
delivery site and drug diffusion kinetics, by modifying PEG molecular weight
and crosslink density.2 PEG can be end-functionalized with a variety of
other groups, including methoxy, hydroxy, maleimide, thiol, and azide The diversity
of functional groups allows unique crosslinkers with different crosslinking
chemistry, such as Michael-type additions, thiolene and Diels-Alder click
reactions, enzymatic reactions, and carbonyl additions.3 Drug delivery
from a hydrogel involves the diffusion of an encapsulated pharmaceutical agent
through the bulk of the gel into the immediate microenvironment surrounding the
delivery site. Depending on the porosity, hydrophilicity, and other
physicochemical properties of the hydrogel and the drug, the loaded drug can
elute slowly over time in a pharmacokinetically controlled manner that prolongs
circulation time.5

Implants:

Implants are less commonly used, they consist of a core drug
molecule surrounded by a permeable polymer membrane, the permeability and the
thickness of the polymer membrane determine the extent at which the drug is
released. Implants have been utilized in ophthalmology. The driving force of
the drug release is constant diffusion through the polymer coating, and
zero-order release kinetics can be achieved. Depending on the polymer used, the
implant systems can be classified into nonbiodegradable (silicone, polyvinyl
alcohol (PVA) and ethylene vinyl acetate (EVA) and biodegradable (PLA, PGA and
polylactic-co-glycolic PLGA copolymer).

 

Polymer based-drug conjugated:

Polymer based conjugate improve the aqueous solubility of drug
molecules and hence increasing the bioavailability. This is of significant
relevance as it has been estimated that 40–60% of drugs in development exhibit
poor bioavailability due to low aqueous solubility. In addition, polymer-drug
conjugates reduce the flocculation with periodic dosing and administration
decreasing the undesired side effects and the possible organ toxicity due to
high concentration of the drug. Polymer conjugation also increases the
circulation time in plasma This is particularly useful for drugs which exhibit
a short blood plasma half-life due to rapid metabolism or clearance or for
drugs which exhibit off target toxicities (i.e. anticancer agents). As previously mentioned, another
major advantage that can be realized through drug-polymer conjugation is the
inclusion of targeting moieties, which function to carry the drug to the site
of pharmacological action. Poly ethylene glycol (PEG) and N-(2-hydroxypropyl)
methacrylamide (HPMA) are the most investigated polymers into drug conjugated Larson and Ghandehari 2013.

Poly ethylene glycol (PEG) gained importance due to its ability to
protect proteins, when proteins are conjugated with (PEG) it prevents protein
degradation by enzymes and reduces uptake by reticuloendothelial system Pasut 2008. Protein PEGylation has led
to the development of numerous therapeutics, including PEG-asparaginase
(Oncaspar), PEG-adensoine deaminase (Adagen), PEG-interferon ?-2a (Pegasys),
PEG-interferon ?-2b (PEG-Intron), PEG-granulocyte colony-stimulating factor
(Neulasta), and PEG-growth hormone receptor antagonist (Somavert). The biocompatibility
of PEG has led to this development in PEG drug conjugates, but since PEG non-biodegradable
this might lead for conjugate accumulation and toxic side effects another disadvantage
of PEG-drug conjugates is the low drug loading that is achieved due to
conjugation at only the end chains of PEG. To overcome these limitations, branched and
multiarm PEGs have been investigated which can be excreted more easily
following biodegradation Larson and
Ghandehari 2013.

N-(2-hydroxypropyl) methacrylamide
(HPMA) copolymers showed great hydrolytic stability upon the Substitution ?-carbon
and the presence of an amide linkage in the side. In addition, side chains
which include drugs, targeting moieties, imaging agents, or reactive groups can
be combined with relative synthetic ease. The development of oligopeptide
sequences drug linkers greatly pushed for further of HPMA as drug. They were
designed to ensure hydrolytic stability during systemic transport because of
their ability to be enzymatically cleaved by lysosomal enzymes following
cellular internalization Larson and Ghandehari
2013. PK1 polymer-drug conjugate for cancer therapy consists of
the anticancer anthracycline antibiotic doxorubicin (8.7% of weight) attached
to a HPMA copolymer backbone via the lysosomally degradable sequence GFLG. PK1
demonstrated higher tumor accumulation of doxorubicin by 17–70 fold than free
doxorubicin in melanoma tumor bearing mice. These promising results led to the
further clinical development of PK1. Also, PK1 was generally well tolerated
with and no anthracycline related cardiotoxicity until doses greater than 1680
mg/m2 Seymour LW 2009.