synthesis, characteristics, use and applications of PLGA

1. PLGA Role in
Biopharmaceutics
Pharmacist
Ali Hussein
Dept. of
pharmaceutical
Chemistry

2. Polylactic glycolic acid
• Polyester poly(lactic-co-glycolide) (PLGA) is a copolymer of PLA and
polyglycolic acid (PGA).
• PLGA is the most well known and widely applied polymer in controlled
release systems. This synthetic polymer has found great success due to
its biocompatibility, biodegradability, and favorable release
kinetics.
• PLGA nanoparticles can be used safely for oral, nasal, pulmonary,
parenteral, transdermaland intra-ocular routes of administrationthe.

3. Synthesis of PLGA
• Melt Polycondensation:resulting in copolymers of low molecular
weight.

4. Synthesis of PLGA
• Ring opening polymerization: resulting in copolymers with high
molecular weight and therefore with better mechanical properties

5. Synthesis of PLGA
• Biodegradable polymeric nanoparticles are highly
preferred because they show promise in drug delivery
system.
• Such nanoparticles provide controlled/sustained release
property, subcellular size and biocompatibility with
tissue and cells.
• Lactide is more hydrophobic than glycolide, therefore
PLGA copolymers rich in lactide are less hydrophilic
and absorb less water, leading to a slower degradation
of the polymer chains

6. Synthesis of PLGA
• The PLGA nanoparticles can be prepared by different techniques.
• The most common technique is the emulsification solvent
evaporation technique because of its simplicity and high encapsulation
efficiency.
• The single emulsion method is only suitable for hydrophobic drugs and
leads to very poor encapsulation efficiency with regard to protein or
peptide drugs.
• The oil-in-oil (o/o) emulsification technique which is known as the
nonaqueous emulsion method is a new and efficient method for
encapsulation of hydrophilic drugs.

7. Synthesis of PLGA
• Monomer ratios of 70/30 and 50/50 (D,L-lactide/gly- colide)
have been used in the syntheses, these are the most commonly
used ratios in controlled drug delivery systems.
• If lactic acid is used in a higher ratio than glycolic acid, a more
hydrophobic copolymer is formed due to the higher
hydrophobicity of lactic acid. Such a change can be used to
reduce the rate of water penetration into a device.
• An increase in the ratio of glycolic acid in the copolymer
composition can be used to produce a more crystalline polymer
matrix

8. Lactide
Lactide has asymmetric carbons, which means that the
levorotatory (L-PLA), dextrorotatory (D-PLA) and ra-cemic
(D,L-PLA) polymeric forms may be obtained.
The levorotatory and dextrorotatory forms are semi-crystalline,
while the racemic form is amorphous due to the irregularities in
the polymer chain.
This is because the use of the racemic mixture yields a polymer
product that exhibits more amorphous features in its structure
to improve the homogeneous dispersion of drugs throughout
the PLGA polymer matrix when fabricating delivery devices

9. Figure Effect of Lactic Acid (LA) and Glycolic Acid (GA)
composition on degradation rate of poly(lactide-co-glycolic acid) in
an in vivo.

10. Fig. Type of biodegradable nanoparticles: According to the structural organization
biodegradable nanoparticles are classified as nanocapsule, and nanosphere.
The drug molecules are either entrapped inside or adsorbed on the surface.

11. MECHANISMS OF RELEASE
The mechanism of release is the rate limiting step or series of rate
limiting steps that control the rate of drug release from a device until
release is exhausted.
The major release mechanisms include:
1. Diffusion, solvent penetration/device swelling.
2. Degradation and erosion of the polymer matrix.
3. A combination of these mechanisms occurring on different time
scales that leads to a more complex release process.

12. MECHANISMS OF RELEASE

13. • The most desirable case is zero order release kinetics. In such a case the
rate of drug release is independent of its dissolved concentration in the
release medium and is delivered at a constant rate over time.This type of
release is unachievable by current polymeric release systems.
• Diffusion (2a) is the most common release mechanism and is
dependent on the concentration of the dissolved drug as described by
Fick’s second Law.
• Erodible delivery systems (2b) are also non-zero ordered and the
rate of release is dependent on the degradation kinetics of the polymer
used.
• Solvent penetration systems (2c) are also non-zero ordered and
their rate is dependent upon the permeability of the polymer used.

14. Schematic of processes that contribute to PLGA device release mechanism:
a) Initial drug loaded device
b) Water penetration and drug diffusion
c) Bulk degradation and erosion
d) Autocatalytic PLGA degradation and accelerated drug diffusion
e) Total degradation and exhaustion of drug release

15. MECHANISMS OF RELEASE
• A biphasic curve for drug release as a result of PLGA
biodegradation has been shown to display following pattern:
• Initial burst of drug release is related to drug type, drug
concentration and polymer hydrophobicity.
• Drug on the surface, in contact with the medium, is released as a
function of solubility as well as penetration of water into
polymer matrix. Random scission of PLGA decreases molecular
weight of polymer significantly, but no appreciable weight loss
and no soluble monomer product are formed in this phase.

16. MECHANISMS OF RELEASE
• In the second phase, drug is released progressively through
the thicker drug depleted layer. The water inside the matrix
hydrolyzes the polymer into soluble oligomeric and monomeric
products.
• This creates a passage for drug to be released by diffusion and
erosion until complete polymer solubilization. Drug type also
plays an important role here in attracting the aqueous phase
into the matrix.

17. PROPERTIES THAT EFFECT THE RELEASE
MECHANISM

18. MATHEMATICAL MODELING OF
PLGA RELEASE SYSTEMS
• The classic Higuchi equation;
QtQ∞=1L2Cw*A∫0tP(t)dt
Where Qt is the cumulative mass of drug release per unit release
area at time t.
C* w is the solubility of the drug in the release medium.
P is the time dependent permeability.
A is the drug loading, L is the half thickness of the matrix.
Qinf is the drug loading per unit release area

19. MATHEMATICAL MODELING OF PLGA
RELEASE SYSTEMS
• A release model based on Fick’s second law for a spherical
geometry depends on a changing polymer molecular weight:
Mt=4πr2[2(C0−Cs)CsDt+4CsDt9r(Cs2C0−Cs−3)]
• Where Mt is the cumulative mass released at time t.
• r is the radius of the micro particle.
• C0 is the initial drug concentration within the polymer matrix.
• Cs is the solubility of the drug in the medium.
• D is the diffusion coefficient

20. Degredation

21. Degredation Equation
ln(X) = intercept − kdt
X is the number of bond cleavages per initial number-average
molecule.
 kd is the copolymer degradation rate constant.
t is time.
 X is calculated by the measurements of the initial number
average molecular weight and the number average molecular
weight at degradation time t via size exclusion chromatography.

22. Factors Affecting Degradation
• Effect of Composition:PLGA 50:50 (PLA/PGA) exhibited a faster degradation
than PLGA 65:35 due to preferential degradation of glycolic acid proportion
assigned by higher hydrophilicity.
• Effect of Crystallinity: the crystallinity of lactic acid (PLLA) increases the
degradation rate because the degradation of semi-crystalline polymer is
accelerated due to an increase in hydrophilicity.
• Effect of Weight Average Molecular Weight (Mw): Polymers having higher
molecular weight have longer polymer chains, which require more time to degrade
than small polymer chains.
• Effect of Drug Type: one must seriously consider the effect of the chemical
properties of the drug to explain the drug-release mechanisms of a particular
system using biodegradable polymers.

23. Factors Affecting Degradation
• Effect of Size and Shape of the Matrix: The ratio of surface area to
volume has shown to be a significant factor for degradation of large devices.
Higher surface area ratio leads to higher degradation of the matrix.
• Effect of pH: The in vitro biodegradation/hydrolysis of PLGA showed that
both alkaline and strongly acidic media accelerate polymer degradation.
• Effect of Enzymes: It has been proposed that PLGA degrades primarily
through hydrolytic degradation but it has also been suggested that enzymatic
degradation may play a role in the process.
• Effect of Drug Load: Matrices having higher drug content possess a larger
initial burst release than those having lower content because of their smaller
polymer to drug ratio.

24. ADVANTAGES
• Less toxic compared to non-biodegradable polymers
• Much higher doses of the drug can be delivered locally
• Controlled drug release from the formulation
• Stabilization of drug
• Localized delivery of drug
• Decrease in dosing frequency
• Reduce side effects
• Improved patient compliance
• Polymer retain its characteristics till the depletion of drug

25. CONSIDERATIONS IN THE EVALUATION
OF MODIFIEDRELEASE PRODUCTS
The development of a modified-release formulation has to be
based on a well-defined clinical need and on an integration of
physiological, pharmacodynamic (PD), and pharmacokinetic (PK)
considerations.
The two important requirements in the development of extended-
release products are
(1) demonstration of safety and efficacy and
(2) demonstration of controlled drug release.

26. Pharmacodynamic and Safety Considerations
• The most critical issue is to consider whether the modified-
release dosage form truly offers an advantage over the same
drug in an immediate-release (conventional) form. This
advantage may be related to better efficacy, reduced toxicity, or
better patient compliance.
• Ideally, the extended-release dosage form should provide a
more prolonged pharmacodynamic effect compared to the same
drug given in the immediate-release form. However, an
extended-release dosage form of a drug may have a different
pharmacodynamic activity profile compared to the same drug
given in an acute, intermittent, rapid-release dosage form.

27. Alpha-1 antitrypsin
• Alpha 1- antitrypsin (α1AT) is a 54 kDa glycoprotein which belongs to the
superfamily of serpin. The protein inhibits serine protease and a broad group of
other proteases.
• It protects the lungs from cellular inflammatory enzymes, especially elastase,
therefore it is known as the human neutrophil elastase inhibitor.
• In the absence of α1AT, the neutrophil elastase released by lung macrophages, is not
inhibited, thus leading to elastin breakdown and the loss of lung elasticity. This
causes degradation of the lung tissue resulting in pulmonary complications, such as
emphysema or chronic obstructive pulmonary disease COPD in adults.
• The commercially available plasma derived product of α1AT is administered
intravenously. Such an intravenous augmentation therapy has disadvantages, such
as high costs, viral contaminations and immune reactions because of prolonged
retention of the drug in circulation.

28. Encapsulation of Alpha-1 antitrypsin in
PLGA nanoparticles
• The pulmonary route is an alternative, potent and noninvasive route
for systemic and local delivery of macromolecules. The aerosolized
α1AT not only affects locally the lung, its main site of action, but also
avoid remaining and circulation for a long time in peripheral blood.
• prepare a wide range of particle size as a carrier of protein-loaded
nanoparticles to deposit in different parts of the respiratory system
especially in the deep lung.
• The lactic acid to glycolic acid ratio affects the release profile of α1AT.
Hence, PLGA with a 50:50 ratios exhibited the ability to release %60
of the drug within 8, but the polymer with a ratio of 75:25 had a
continuous and longer release profile.

30. Particle sizes and Distribution
• Preparation method affects particle size and distribution.
• Particles produced by nonaqueous emulsion technique have smaller
size and wider size distribution.
• Nanoparticles obtained by double w/o/w technique have slightly
bigger size and narrower distribution.

34. a schematic representation of nanoparticle passage
and decomposition in lung.

35. Refrences
• Synthesis and Characterization of Poly(D,L-Lactide-co-Glycolide) Copolymer,
Cynthia D’Avila Carvalho Erbetta1, Ricardo José Alves2, Jarbas Magalhães
Resende3, Roberto Fernando de Souza Freitas1, Ricardo Geraldo de Sousa1
• Science and Principles of Biodegradable and Bioresorbable Medical Polymers by
Xiang Zhang 2017.
• Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery
Carrier Hirenkumar K. Makadia 1 and Steven J. Siegel 2;2011.
• Poly (lactic-co-glycolic acid) controlled release systems: experimental and
modeling insights Daniel J. Hines and David L. Kaplan, 2013.
• Encapsulation of Alpha-1 antitrypsin in PLGA nanoparticles: In Vitro
characterization as an effective aerosol formulation in pulmonary diseases,
Nazanin Pirooznia, 2012.